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Volume 31

OCToBER/DECEMBER

Number 4

Official Journal of the Brazilan Society of Coloproctology FOUNDER Klaus Rebel - RJ EDITOR Eduardo de Paula Vieira - RJ Coeditors João de Aguiar Pupo Neto Francisco Sergio Pinheiro Regadas Helio Moreira Junior Olival de Oliveira Junior Editorial board Angelita Habr-Gama - SP Antonio Booz Senna Silva Ferreira - PE Boris Barone  - SP Cláudio Saddy Rodrigues Coy - SP Elísio Meirelles De Miranda - MG Fang Chia Bin - SP Fernando Zaroni Swaybricker - RJ Flávio Antonio Quilici - SP Flávio Ferreira Diniz - RS Francisco Lopes Paulo - RJ Francisco Sergio Pinheiro Regadas - CE Galdino José Sitonio Formiga - SP Geraldo Magela Gomes da Cruz - MG Hélio Moreira - GO Henrique Sarubbi Fillmann - RS João Francsico Xavier Mussnichi - RS João Gomes  Netinho - SP Joaquim José Ferreira - RJ José Alfredo dos Reis Junior - SP José Alfrredo Reis Neto - SP

José Hypolito da Silva -  SP José Reinan Ramos - RJ José Ribamar Baldez - MA Julio César M. dos Santos Junior - SP Karen Delacoste Pires Mallmann - RS Klaus Rebel - RJ Lusmar Veras Rodrigues - CE Maria Cristina Sartor - PR Mauro de Souza Leite Pinho - SC Paulo Gonçalves de Oliveira - DF Paulo Roberto Arruda Alves - SP Raul Cutait - SP Renato Araújo Bonardi - PR Robert William de Azevedo Bringel - SP Roberto Misici - CE Rogerio Saad Hossne - SP Rubens Valarini - PR Sergio Carlos Nahas - SP Sidney Nadal - SP Sinara Monica de Oliveira Leite - MG Foreign correspondents

Ezio Ganio ‑ Ivreia ‑ Itália Fidel Ruiz Healy ‑ México D.F. ‑ México Mario Trompetto ‑ Ivreia ‑ Itália Michael R.B. Keighley ‑ Birmingham - Inglaterra Brazilian Society of Coloproctology Av. Marechal Câmara, 160 ‑ Conj. 916 / 917 Edifício Orly CEP 20020‑080 ‑ Rio de Janeiro ‑ RJ Fax (21) 2220‑5803 * Telefone: (21) 2240‑8927 Homepage: http://www.sbcp.org.br * E-mail: sbcp@sbcp.org.br

Pedro Morgado Nieves ‑ Caracas ‑ Venezuela Saúl Sokol ‑ Dallas ‑ EUA Steven D. Wexner ‑ Fort Lauderdale ‑ EUA

Study Center Pitanga Santos Av. Marechal Câmara, 160 ‑ sala 1202 Edifício Orly CEP 20020‑080 ‑ Rio de Janeiro ‑ RJ Fax: (21) 2220-5803

Impressão e Acabamento: Prensa


Brazilian Society of Coloproctology – Board 2011/2012 PRESIDENT Luciana Maria Pyramo Costa (MG) Elected president Carlos Walter Sobrado Junior (SP) Vice-president Paulo Gonçalves de Oliveira (DF) General secretary Ronaldo Coelho Salles (RJ) First secretary Alice Capobiango (MG) Second secretary Afonso Henrique da Silva e Souza Junior (SP) First treasurer Diógenes Guilherme Castro Alvarenga (RJ) Second treasurer David de Lanna (MG)

Consulting council

Committee of the expert title

Arminda Caetano de Almeida Leite (GO) João de Aguiar Pupo Neto (RJ) Renato Valmassoni Pinho (PR) Karen Delacoste Pires Mallmann (RS) Sergio Carlos Nahas (SP) Francisco Lopes Paulo (RJ) Francisco Sergio Pinheiro Regadas (CE)

André da Luz Moreira (RJ) Afonso Henrique B. Moniz de Aragão (RJ) Antonio Lacerda Filho (MG) Carlos Augusto Real Martinez (SP) Rogerio Saad Hossne (SP) Mauro de Souza Leite Pinho (SC) Sthela Maria Murad Regadas (CE) Odorino Hideyoshi Kagohara (SP) Mario Jorge Jucá (AL) Roberto Misici (CE) Antonio Sergio Brenner (PR) Henrique Sarubbi Fillmann (RS) Magda Maria Profeta da Luz (MG) - RELATORA Ilson Geraldo da Silva (MG) Claudia Rosali Esmeraldo Justo (PE)

Scientific committee Sinara Monica de Oliveira Leite (MG) José luiz Barbieux (RS) Fabio Guilherme Caserta M. Campos (SP)

Teaching and medical residency committee Journal committee Eduardo de Paula Vieira (RJ) Hélio Moreira Junior (GO) Olival de Oliveira Junior (PR)

Class defense committee Luiz Alberto Mendonça de Freitas (DF) Marcelo Rodrigues Borba (SP) Sidney Roberto Nadal (SP)

Galdino José Sitonio Formiga (SP) Fernando Cordeiro (SP) Silvio Augusto Ciquini(SP) Fabio Lopes de Queiroz (MG) César de Paiva Barros (RJ) João Batista de Sousa (DF) Paulo Gustavo kotze (PR) Manoel Alvaro de Freitas Lins Neto (AL) Francisco Luis Altenburg (SC) Juvenal da Rocha Torres Neto (SE) Lusmar Veras Rodrigues (CE) Erico Ernesto Pretzel Fillmann (RS) Fernando Zaroni Sewaybricker (RJ) Marlise Mello Cerato (RS) Rubens Valarini (PR)

SBCP delegates at SBCP Titular Sergio Carlos Nahas (SP) Afonso Henrique da Silva e Souza Junior (SP) Alternates Paulo Fernando de Carvalho (RJ) Flavia Rachel Starling Schwanz (ES)


VOLUME

Number

31

4

Contents

Original Article Prognostic impact of the lymph node metastatic ratio on 5-year survival of patients with rectal cancer not submitted to preoperative chemoradiation Alfredo luiz jacomo, carlos augusto real martinez, marcia milena pivatto serra, flávia emi akamatsu, josé aires pereira, mauro figueiredo carvalho de andrade, nelson fontana margarido�������311

October / December 2011

Evaluation of quality parameters of rectal cancer surgery at the Coloproctology Unit of Hospital de Braga Mafalda Araújo Pimenta de Castro, Sandra Fátima Fernandes Martins����������������������������������������������������������������������������������362

CASE REPORT

Biological therapy in the treatment of moderate-to-severe ulcerative colitis patients: can colectomy be prevented? Fábio Vieira Teixeira, Rogério Saad Hossne, Paulo Gustavo Kotze, Rafael Denadai, Sender Jankiel Miszputen������������������������������325

Chagasic megacolon and large bowel neoplasms: case series and literature review Maxwel Capsy Boga Ribeiro, Raquel Franco Leal, Cláudio Saddy Rodrigues Coy, Priscilla de Sene Portel Oliveira, Débora Helena Gonçalves Rossi, João José Fagundes, Maria de Lourdes Setsuko Ayrizono�������������������������������������������������������������������372

Body mass index as a predictor of complications and conversion in patients undergoing laparoscopic colectomy Breno Xaia Martins da Costa, Fábio Lopes de Queiroz, Paulo César de Carvalho Lamounier, Antônio Lacerda Filho, Rodrigo de Almeida Paiva, Paulo Rocha França, Rodrigo Soares Napoleão do Rego, Fernanda Elias Ferreira Rabelo��������������������������������������330

Non-Hodgkin lymphoma as a cause of acute intestinal obstruction/perforation in patients with adenocarcinoma of the sigmoidcolon: a case report Marcelo Pandolfi Basso, Adriana Borgonovi Christiano, Letícia Vieira Guerrer, Francisco De Assis Gonçalves Filho, João Gomes Netinho����������������������������������������������������������������������������������378

Evaluation of response to neoadjuvant treatment, by nuclear magnetic resonance, as a predictor of oncologic results and survival of patients with rectal cancer Rodrigo Soares Napoleão do Rêgo, Fábio Lopes de Queiroz, Breno Xaia Martins da Costa, Fernanda Elias Ferreira Rabelo, Paulo Cesar de Carvalho Lamounier, Luciana Costa Silva, Valdivino Alves Filho, Maria Zuleime Carmona��������������������������������������334

Treatment of rectal leiomyoma by endoscopic resection Rafael Denadai Pigozzi Silva, Rogério Saad-Hossne, Rafael Aliceda Ferraz, Marcus de Medeiros Matsushita, Roberto Falzoni, Fábio Vieira Teixeira�����������������������������������������������������������������382

Questionnaire assessment based on signs, symptoms and history in the prevention of colorectal cancer Walysson Alves Tocantins de Sousa, Leonardo Carvalho Moura Fé, Lory Noronha de Castro Monte������������������������������������������339 Treatment of patients with colorectal cancer at a public hospital in Porto Alegre Gabriel Volpato, Denize Schmitt, Cleber Antônio Nogueira Santos Júnior, Luciano Pinto de Carvalho, Ruy Takashi Koshimizu, Afonso Calil Mury Mallmann���������������������������������������������������346 Prototype system to manage data on coloproctology surgery Huei Diana Lee, Wilson Jung, Adrieli Cristina da Silva, Luiz Henrique Dutra da Costa, Bianca Espindola, Cláudio Saddy Rodrigues Coy, João José Fagundes, Feng Chung Wu���������������351

Laparoscopic left lateral segmentectomy for metachronic metastases of small intestine adenocarcinoma: a case report Sergio Renato Pais-Costa, Sergio Luiz Melo Araujo, Olímpia Alves Teixeira Lima, Marcio Almeida Paes, Sandro José Martins�������387 Fungal Colitis by Paracoccidioides brasiliensis: a case report Carlos José Galeazzi, Cássia Fernanda Estofolete, Antônio Carlos Soares de Moraes Filho, Anderson Lubito Simoni, Francisco de Assis Gonçalves Filho, João Gomes Netinho���������������������������393 Complication related to colostomy orifice: intestinal evisceration Valdemir José Alegre Salles, Eduardo Saba, Endrigo Rodrigues Pissinin, Eduardo Rubens Francisco Arguello, Hugo Nunes Machado Filho��������������������������������������������������������������������������397 Superior mesenteric artery compression syndrome - case report Paulo Rocha França Neto, Rodrigo de Almeida Paiva, Antônio Lacerda Filho, Fábio Lopes de Queiroz, Teon Noronha�����������401


Special Sessions

Services accredited���������������������������������������� 420

Intestinal spirochetosis Luis Roberto Manzione Nadal, Sidney Roberto Nadal������������405

Index��������������������������������������������������������������������������� 423

Crohn’s Disease: Current state of biological therapy Júlio César Monteiro Santos Júnior, TSBP�������������������������������407


Indexed: Literatura Latino-Americano e do Caribe em Ciências da Saúde (LILACS), Scientific Electronic Library Online (SciELO), SCOPUS, Directory of Open Access Journals (DOAJ)

Information for Authors 1. OBJECTIVE The JOURNAL OF COLOPROCTOLOGY is published under the coordination of the Editorial Board, and the authors are responsible for the concepts presented in the studies. The purpose of the JOURNAL is to present studies about Human Medicine and Surgery, conducted by national or international experts, provided that they follow the *Study Guideline*. 2. OVERVIEW The JOURNAL OF COLOPROCTOLOGY is published quarterly, in one annual indexed issue in December. It is sent exclusively to subscribers, collaborators, libraries, hospitals, medical communities, study centers and national and international journals with which it exchanges materials. The JOURNAL OF COLOPROCTOLOGY follows the concepts of a guideline published in 1997 by the Committee on Publication Ethics (COPE) and suggests and recommends that the authors read the instructions provided in such guideline before they submit their studies for approval. 3. REGULATION OF STUDIES 3.1. General Instructions The studies should not have been published in any other journal and should be exclusively submitted to the JOURNAL OF COLOPROCTOLOGY. Review articles will be inserted at the Editorial Board’s discretion. In exceptional cases of republishing national or international studies, these should contain the formal authorization of the author and the periodical that owns the copyright. *Study Protocols* Preliminary Elements-a) *Title* - article title, in Portuguese, and the full names of the authors. b) *Scientific affiliation and corresponding author’s address.*Text: Whenever possible, the text should be in accordance with the conventional scheme of a scientific article-a) *Introduction* - It should explain clearly the purpose of the study, relating it with others from the same field and providing a brief presentation of the current situation of the investigated problem. Long literature reviews should be replaced for references to more recent studies, in which such reviews have already been presented. b) *Patients and Methods* - The Methods description should present only the necessary to allow the reader’s perfect understanding and repetition; the techniques already described in other studies will be referred to only by quoting, unless they have been considerably modified. c) *Results* - They should be clearly presented, and, as required, bring tables and proper illustrative material. d) *Discussion* - It should be limited to presenting the obtained data and results, correlating the new contributions with prior knowledge. Avoid hypotheses or generalizations that are not based on the study results. e) *Conclusion* - They should be based on the manuscript. The regulations below are based on the concept proposed by the International Committee of Medical Journal Editors and published in the article: “Uniform requirements for manuscripts submitted to biomedical journals”, which was updated in October 2004 and can be accessed at http://www.icmje.org/. For randomized clinical trials, the CONSORT guidelines (Begg C, Cho N, Eastwood S et al. Improving the quality of reporting of randomized clinical trials: the CONSORT statement. JAMA 1996;276:637-9) are recommended as reference. A checklist is presented in the JAMA website: htt://jama.ama-assn.org. ARTICLE JUDGEMENT PROCESS The manuscripts submitted to the JOURNAL that meet the “Instructions to Study Authors” and these editorial guidelines are sent to 4 members of the Editorial Board, who will consider the scientific merit of the contribution. The manuscripts are previously sent to committee members and randomly selected by the Editors. Anonymity is ensured during the whole judgement process. The decision of approving the manuscript is made by the Editors, after an evaluation by 4 members of the Editorial Board; also, the manuscript publication should be recommended by at least 3/4 of the members. Copies of the opinions can be sent to authors and committee members; the latter may use an exchange system with each other.

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Books in which the editors (organizers) are authors Norman IJ, Redfern SJ, editors. Mental health care for elderly people. New York: Churchill Livingstone; 1996. Theses Kaplan SJ. Post-hospital home health care: the elderly’s access and utilization [dissertation]. St Louis (MO): Washington Univ.; 1995 Studies presented in congresses Bengtsson S, Solheim BG. Enforcement of data protection, privacy and security in medical informatics. In: Lun KC Degoulet P, Piemme TE, Rienhoff O, editors. MEDINFO 92. Proceedings of the 7th World Congress on Medical Informatics; 1992 Sep 6-10; Geneva, Switzerland. Amsterdam: North-Holland; 1992. p. 1561-5. Article from a periodical in electronic format Morse SS. Factors in the emergence of infectious diseases. Emerg Infect Dis [serial on the Internet] 1995 Jan-Marc [cited 1996 Jun 5]; 1(1): [about 24 screens]. Available from: URL: http://www.cdc.gov/ncidod/EID/eid.htm Other types of reference should follow the document of the International Committee of Medical Journal Editors (Vancouver Group), available at www. icmje.or, October 2004. 4. SUBMISSION OF ORIGINAL TEXTS The articles should be sent by e-mail (sbcp@sbcp.org.br). In this case, it is essential to have the permission for material reproduction with the approval of the Ethics Committee of the Institution where the study was conducted, when involving (diagnostic or therapeutic) interventions in human beings, and a letter signed by all authors stating the pioneer characteristic of the study, to be sent by fax to RBCP (fax number: 55 21 2220 5803). 5. THE JOURNAL OF COLOPROCTOLOGY Reserves all rights, including translation rights, in all countries that are signatories to the Pan-American Convention and the International Copyright Convention regarding the following: 6. The total or partial reproduction of the studies in other periodicals – with mandatory quotation of the source – will be at the JOURNAL’s discretion. 7. For commercial purposes, the translation and total or partial reproduction of the studies published in this JOURNAL is prohibited. 8. The JOURNAL OF COLOPROCTOLOGY does not accept a paid article in its editorial space, and it does not pay any amount, in kind or other currencies, to the authors of studies published in its pages. 9. The JOURNAL reserves the right to refuse original texts that are not considered to be adequate (presentation, items covered, etc.) and propose modifications, according to the evaluation of Consultants and the Editorial Board. 10. The JOURNAL, if required, will automatically adapt all studies approved for publication to these guidelines.


VOLUME

Number

31

4 October / December 2011 ORIGINALS ARTICLES

Prognostic impact of the lymph node metastatic ratio on 5-year survival of patients with rectal cancer not submitted to preoperative chemoradiation ALFREDO LUIZ JACOMO1, CARLOS AUGUSTO REAL MARTINEZ2, MARCIA MILENA PIVATTO SERRA3, FLÁVIA EMI AKAMATSU4, JOSÉ AIRES PEREIRA5, MAURO FIGUEIREDO CARVALHO DE ANDRADE6, NELSON FONTANA MARGARIDO7 Associate Professor of Human Structural Topography, Surgery Department of the Medical School of Universidade de São Paulo (USP) – São Paulo (SP), Brazil. 2Full Professor, Surgery Department of FMUSP – São Paulo (SP), Brazil; Adjunct Professor, Postgraduate Program in Health Sciences, Universidade São Francisco (USF) – Bragança Paulista (SP), Brazil. 3 Assistant Professor, Doctor of Statistics, Medical Sciences at USF – Bragança Paulista (SP), Brazil. 4Professor and Doctor of Human Structural Topography, Surgery Department of the Medical School of USP – São Paulo (SP), Brazil. 5Assistant Professor, Master in Pathology, Medical Sciences at USF – Bragança Paulista (SP), Brazil. 6Professor and Doctor of Human Structural Topography, Surgery Department of the Medical School of USP – São Paulo (SP), Brazil. 7Full Professor of Human Structural Topography, Medical School of USP – São Paulo (SP), Brazil. 1

JACOMO AL, MARTINEZ CAR, SERRA MMP, AKAMATSU FE, PEREIRA JA, ANDRADE MFCD, MARGARIDO NF. Prognostic impact of the lymph node metastatic ratio on 5-year survival of patients with rectal cancer not submitted to preoperative chemoradiation. J Coloproctol, 2011;31(4):311-324. Abstract: Lymph node metastases are a major prognostic factor in colorectal cancer. Inadequate lymph node resection is related to shorter survival. The lymph nodes ratio (LNR) has been used as a prognostic factor in patients with colon cancer. Few studies have evaluated the impact of LNR on the 5-year survival of patients with rectal cancer. Objective: To evaluate the impact of LNR on the survival of patients with rectal cancer not submitted to preoperative chemoradiotherapy. Methods: Ninety patients with rectal cancer excluding colon tumors, synchronous tumors, hereditary colorectal cancer and those undergoing preoperative chemoradiation. The patients were divided into three groups according to the LNR: LNR-0, no lymph nodes; LNR-1, 1 to 20% of compromised lymph nodes; and LNR-2, more than 21% of compromised lymph nodes. The cutoff identification for the selected sample was obtained from the curve of receiver operating characteristics (ROC). Survival was assessed by Kaplan-Meier test, the difference among groups by Cox-Mantel test and the correlation among variables by Pearson’s test, adopting a significance level of 5% (p≤ 0.05). Results: The 5-year survival was related to the Dukes classification, TNM, number of metastatic lymph nodes and

Study carried out at the LIM-02, Human Structural Topography, Surgery Department of the Medical School of Universidade de São Paulo (USP) – São Paulo (SP), Brazil. Postgraduate Program in Health Sciences, Universidade São Francisco (USF) – Bragança Paulista (SP), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted on:04/08/2011 Approved on: 06/09/2011

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Journal of Coloproctology October/December, 2011

Prognostic impact of the lymph node metastatic ratio on 5-year survival of patients with rectal cancer not submitted to preoperative chemoradiation Alfredo Luiz Jacomo et al.

Vol. 31 Nº 4

LNR. A difference was observed in 5-year survival between the different classes of LNR. Patients classified as LNR-0 had a survival rate of 85%, while classes LNR-1 and LNR-2, 73 and 19%, respectively (p=0.0001). Conclusions: The results showed that the LNR has an impact on 5-year survival of patients with rectal cancer not submitted to neoadjuvant therapy. Keywords: rectum; colorectal neoplasms; lymph nodes; lymph node excision; survival analysis.

INTRODUCTION

of studies showing that 80% of the patients without metastases in regional LNs survive five years, while only 50% of those with compromised LNs survive for the same period12. The lowest OS of these patients required complementary therapies associated with the surgical treatment to improve these rates, regardless of the number of compromised LNs4. Then, patients with only one compromised LN are submitted to the same complementary treatment protocol as those with more extensive lymph node involvement4. The precise evaluation of the presence of lymp node metastases is possible only when a proper number of LNs is examined5. Studies have shown that the DFS and OS in patients with CRC are directly related to the number of examined LNs12. Modern international guidelines recommend that the minimum number of 12 LNs should be analyzed to enable proper staging12-15. However, the number of examined LNs in the surgical specimen is influenced by different variables. The number of identified LNs is directly related to the surgeon’s experience and practice, the histological technique used in the lymph node recovery (fresh dissection immediately after resection, fat clearing techniques for fast recovery) and the pathologist’s experience and patience to identify them16. The neoplasm location – colon or rectum – can also influence the number of recovered LNs17. In colon cancer (CC), the number of dissected LNs is usually higher when compared to CRC18. Despite such peculiarities, the international guidelines recommend that the same number of LNs should be studied for a proper CRC staging19. The difficult recovery of the minimum number of LNs in CRS is even more critical when considering that many patients with CRC are submitted to neoadjuvant chemoradiation (NCR) protocols, in which the number of LNs is reduced by around 30%, further increasing the pathologist’s uncertainties regarding the correct disease staging20,21. A recent study quantifying the number of LNs recovered after the CRC resec-

Colorectal cancer (CRC) is the third most prevalent neoplasm in the world and the second cause of death related to cancer in western countries1. Epidemiological studies have shown a 2.4-fold increase in the incidence of CRC in the oriental countries2. In the last two decades, despite the increase in the number of proximal colon tumors, rectal tumors are still more prevalent3. Many clinical, histopathological, molecular and genetic variables have been related to overall survival (OS) and disease-free survival (DFS) in patients with CRC4. Despite the importance of all variables, the parietal invasion, the lymph node involvement and the presence of metastases remain as the variables of more power to predict the OS, DFS and guide the adjuvant therapy indication5-7. In 1932, Dukes8 developed the first classification system for colorectal (CR) staging. In this system, the different stages of the disease were classified according to the extent of rectal wall involvement and the presence (or not) of lymph node metastases. Later, several alterations were proposed to improve the OS prediction capability of the original classification9,10. Today, the TNM system recommended by the AJCC (American Joint Committee on Cancer) and the UICC (International Union Against Cancer), which stages neoplasms based on the tumor-lymph node (LN)-metastasis triad, is the most frequently used worldwide9-11. In the TNM system, the patients are divided into groups and subgroups, according to the extent of tumor invasion in the colon wall, presence and number of metastases in the LNs and the involvement of distant organs11. Lymph node involvement is determined by using the number of metastatic LNs and subdivided into: N0 for no LN involvement; N1 for metastases in up to three LNs; and N2 for when four or more LNs are taken by neoplasm11. The importance of lymph node involvement in the OS and DFS in CRC can be better evaluated by results 312


Journal of Coloproctology October/December, 2011

Prognostic impact of the lymph node metastatic ratio on 5-year survival of patients with rectal cancer not submitted to preoperative chemoradiation Alfredo Luiz Jacomo et al.

tion, comparing patients submitted or not to the NCR, showed that the patients submitted to NCR had the mean value of recovered LNs of 6.29 per examined specimen, while those not submitted to NCR presented 13.5, i.e., half the minimum number recommended for a precise staging18. The importance of a proper lymph node resection is evident with the results of studies showing that the recovery of less than 12 LNs in the surgical specimen is directly related to lower OS and DFS in patients with CRC22,23. In order to find a variable that could improve the accuracy of staging systems, especially in patients submitted to improper lymph node resection, the incorporation of lymph node ratio (LNR) into staging systems as an additional variable has been proposed24. LNR is defined as the relation between the total number of examined LNs and the number of compromised LNs. Initially, the prognostic value of LNR was evaluated in patients with stomach25,26, bladder27, breast28 and pancreas29 cancer, presenting correlation with DFS and OS. In patients with gastric cancer submitted to improper lymphadenectomy, LNR presented greater prognostic power when compared to the number of comproimsed LNs, when using the current staging systems25. The routine incorporation of LNR into the staging systems was able to reduce the effects of stage migration4,30. Berger et al.31 were the first to analyze whether the LNR also related to OS and DFS in patients with CC. They observed that, after the curative resection, the LNR was an important prognostic variable, recommending its use in future studies to analyze adjuvant treatments31. Later, a series of studies confirmed the importance of LNR as a prognostic factor in patients with CC4,5,32-41. However, few studies have evaluated the importance of LNR as a variable related to OS in patient with CRC42-44. The evaluation in patients with CRC is more difficult to be performed, because the patients submitted or not to LNR protocols are usually evaluated as a single group, which influences the number of recovered LNs in the surgical specimen. It would be interesting to first study the impact of LNR, subdividing the patients into two groups: one of patients submitted and one of patients not submitted to the NCR, to confirm whether the LNR has predictive power in OS in both groups. After that, the impact of LNR on a group of patients with CRC

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submitted to NCR could be evaluated. However, according to our knowledge, no study has evaluated the impact of LNR on OS in patients with CRC not submitted to NCR. If the LNR had any impact on OS, it could become a useless strategy to minimize the surgeon and the pathologist’s concern about substaging. For this reason, the purpose of this study was to evaluate the impact of LNR on OS of patients with CRC not submitted to NCR. CASE REPORT AND METHOD The study was conducted according to all phases established by the Research Ethics Committee of the Universidade São Francisco and requirements of the Research Ethics Council of the Comissão Nacional de Ética em Pesquisa (CONEP), Ministry of Health (Resolution CNS196/96). This is a retrospective study, a review in the database of the Coloproctology and Pathology Group of the Hospital Universitário São Francisco, Bragança Paulista. From total 348 patients with CRC monitored from 2001 to 2010, 90 were eligible for the study, with confirmed histological diagnosis of rectal adenocarcinoma, in any stage according to the TNM classification, and who had been submitted to complete resection of primary tumor. The study excluded synchronic tumors, patients with suspicion of belonging to families with hereditary CRC (familial adenomatous polyposis and non-polypoid CRC) or CRC associated with intestinal inflammatory disease and patients submitted to NCR. The study considered as rectal tumors neoplasms located below the sacral promontory, according to data collected from the surgical description. All patients were operated through laparotomy and none of them received drainage of lateral chain pelvic LNs. The mean follow-up period was 40.87 months (2-68  months). Thirty-two patients in stages III e IV received adjuvant chemotherapy, performed in six cycles, with 5-fluorouracil and leucovorin (5FU 450 mg/m2 + 20 mg/m2 leucovorin) repeated in intervals of four to five weeks. Twenty-six patients concluded the proposed adjuvant scheme. In the database review, the following variables were analyzed: age (over or under 65 years old), gender (male or female), ethnic group (white, black and yellow), histological degree of neoplasm (well, moderate313


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Table 1. Anatomo-clinical characteristics of the studied sample.

ly and poorly differentiated), type of neoplasm (mucus producer and non-producer), angiolymphatic invasion (present or absent), Dukes classifications (A, B and C) and TNM (I to IV), number of resected LNs (mean and median values), number of metastatic LNs (mean and median values), LNR (LNR-0, LNR-1 and LNR-2), follow-up period after the surgery (in months), death date and five-year survival. The OS, in months, was defined using the death date or the period between the surgery date and the last doctor’s appointment. The histological blades of each patient were hematoxylin-eosin (HE) stained, then analyzed by the Pathology Department and reviewed by an pathologist with experience in digestive tract neoplasms to confirm the histopathological diagnosis and review the considered variables. In the previous anatomopathological study, LN dissection was performed with fixed specimen. No fat clearing method was used to enhance LN recovery. Wall invasion was evaluated according to the involvement extent of mucosa, submucosa, muscularis propria, serous membrane, adipose tissue or adjacent organs. The review of neoplastic involvement of resected LNs was analyzed exclusively through the HE technique, not using the immunohistochemical method to study micrometastases. The LNR calculation was performed using the ratio between the total number of compromised and examined LNs, categorizing the patients into three groups according to the LNR: LNR-0 for no LNs compromised by neoplasm; LNR-1: (0.01–0.20) for neoplastic involvement between 1% and 20% in the studied LNs; LNR-2: (0.21–1.0) when more than 21% of the analyzed LNs were compromised by neoplasm. The ideal cut-off for the classification of groups, considering the best specificity and sensitivity values to the selected sample, was obtained from the receiver operating characteristics (ROC) curve, in order to find the ideal LNR for the case classification. Descriptive statistics was used to describe the clinical characteristics of the selected case and the histopathological data of neoplasm. The correlations between variables used the Pearson’s test. The OS curves in a 5-year follow-up were determined using the Kaplan-Meyer method, with the Cox-Mantel test used in comparisons. The results obtained were analyzed using SPSS for Windows version 13.0, adopting the significance level of 5% (p<0.05) in all tests.

Variables Gender Male Female Age <65 years ≥65 years Ethnic group White Black Yellow Histological degree (differentiation) Well differentiated Moderately differentiated Poorly differentiated Histological type Usual Mucinous Tumor size <5 cm ≥5 cm Invasion of colon wall (T) T1 T2 T3 T4 Number of committed LNs (N) N0 N1 N2 Dukes classification A B C TNM Staging (Stage) I II III IV Angiolymphatic invasion Present Absent Number of resected lymph nodes Total Mean Median Metastatic lymph node ratio (LNR) LNR-0 LNR-1 LNR-2 314

n (%) 49 (54.4) 41 (45.56) 59 (62.2) 34 (37.8) 78 (86.68) 8 (8.88) 4 (4.44) 23 (25.55) 63 (70.0) 4 (4.44) 80 (88.89) 10 (11.11) 45 (49.9) 44 (49.8) 4 (4.48) 31 (34.4) 50 (55.5) 5 (5.55) 61 (67.77) 17 (18.88) 22 (24.44) 15 (16.67) 45 (50.0) 30 (33.33) 17 (18.89) 41 (45.56) 29 (32.22) 3 (3.33) 32 (35.55) 56 (62.22) 1,226 13.6 12 61 (67.70) 15 (16.67) 14 (15.56)


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Metastatic Lymph Node Ratio (LNR)

Dukes Classification A B p<0.0001 C

1.0 0.6

1.0

0.4

0 1 p<0.0001 2

0.8

Censored patients

Survival

Survival

0.8

0.2 0.0

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0.6

Censored patients

0.4 0.2

0

20 40 Months

60

0.0

Figure 1. Five-year survival according to Dukes classification. A=Stage A; B=Stage B and C=Stage C. Kaplan-Meier Curve. Cox-Mantel Test. (p=0.0001).

0

20 40 Months

60

Figure 3. Five-year survival according to LNR-0=no committed LNs. LNR-1 = <20% committed LNs; LNR-2=≥21% committed LNs. Kaplan-Meier Curve. Cox-Mantel Test (p=0.0001).

TNM (AJCC/UICC) Classification 1.0 0.8 Survival

LNR (p=0.46), but a significant correlation was observed between the number compromised LNs and the LNR (p=0.00001; 95%CI 0.50–0.75). The evaluation of OS did not find any significant difference when analyzing age (p=0.08), gender (p=0.06), histological type (p=0.85), tumor size (p=0.053), extent of invasion in the rectal wall (p=0.06) and histological degree (p=0.07). Fifteen patients (16.67%) were classified as stage A in Dukes classification, 45 (50%) as B and 30 (33.3%) as C. Figure 1 shows the OS according to Dukes classification. Worsened OS is observed in more advanced stages in Dukes classification (p=0,0001). Seventeen patients (18.8%) were classified as stage I in the TNM classification, 41 (45.56%) as II, 29 (32.22%) as III and 3 (3.33%) as stage IV. Figure 2 shows the OS according to the TNM classification. The analysis showed that the patients in more advanced stages presented lower OS (p=0.0001). Sixty-one patients (67.77%) did not present any compromised LN (N0), while 15 (16.67%) had less than three compromised LNs (N1) and 14 (15.56%) more than three LNs with metastasis (N2). Eighty per cent of the patients classified as N0 survived five years, while 73% of the N1 patients no patient classified as N2 survived for a similar period. The OS was reduced when considering the number of compromised LNs (p=0.0003). Sixty-one patients (67.70%) were classified as LNR-0 for not presenting any compromised lymph

I II p<0.0001 III III

0.6

Censored patients

0.4 0.2 0.0 0

20 40 Months

60

Figure 2. Five-year survival according to TNM (AJCC/UICC) classification. I=Stage I; II=Stage II; III=Stage III and IV=Stage IV. Kaplan-Meier Curve. Cox-Mantel Test (p=0.0001).

RESULTS In total, 1,226 LNs were resected, mean of 13.6 (2–40) and median of 12. In the whole analysis, 140 compromised LNs, mean of 1.55 (minimum 1 and maximum 28), were found. The mean follow-up period was 40.87 months (2–68). Table 1 shows the selected patients’ clinical and histopathological characteristics. A correlation was observed between the number of resected LNs and the number of compromised LNs (p=0.04; 95%CI 0.00–0.40). No correlation was observed between the number of resected LNs and the 315


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node, 15 (16.67%) as LNR-1 for having 20% or less and 14 (15.56%) as LNR-2 for having more than 21% compromised LNs. Patients classified as LNR-0 presented OS greater than 85%, while those classified as LNR-1 presented 73% OS and, finally, the patients with this index above 73% (LNR-2), it was less than 19%. Figure 3 shows the OS when considering the LNR. The results confirm that the greater the LNR, the worse the prognosis (p<0.0001).

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tive system confirmed these results and demonstrated that the number of LNs in the rectum is changed depending on the site taken into account48. After removal of the entire rectum and mesorectum into a ‘monobloc’ before the specimens were fixed, the authors counted the number of dissected LNs in each of the nine proportional axial cuts made in the upper, middle and lower thirds. They dissected total 412 LNs, with mean 34.3±2.1 LNs per cadaver, and confirmed that the mean number they found significantly varied with the cut height. They found on average 22.2 LNs in cranial cuts (upper rectum), 9.8 LNs in the intermediate cuts (middle rectum) and only 2.3 in caudal cuts (lower rectum). Later, other authors, when dissecting 30 cadavers, counted the number of LNs in the mesorectum, comparing the lymph node recovery through manual dissection to the adipose tissue clearing technique. The authors also divided the mesorectum into three segments (upper, middle and lower). The mean recovered LNs per cadaver was 6.2±1.3 (5–9); with 5.89±1.24 recovered in the group of manual dissection and 6.60±1.29 in the group of fat clearing, a difference that was not statistically significant. However, they point out the fact that, in the lower third of the mesorectum, the clearing technique enabled the recovery of a greater number of LNs of small sizes49. These findings are essential when the number of recovered LNs is studied in patients with CRC located below the peritoneal reflection. As this region has a lower number of LNs – exactly where the CRC is more frequent – the pathologist finds it more difficult to recover a sufficient number of LNs that enables to establish the lymph node involvement with certainty and, consequently, the patient staging. In addition, it should be emphasized that the best recommendations for the CRC treatment propose the use of NCR exactly in the patients with tumors located in the middle and lower rectum, where the number of LNs is lower. The use of NCR reduces not only the size, but especially the quantity of recovered LNs for histological analysis. Marks et al.50, when studying specimens from 176 patients with CRC submitted to NCR, found more than 12 LNs only in 28% of the analyzed specimens and less than 6 LNs in 32%50. In our group, Habr-Gama et al.51 demonstrated that the number of resected LNs in CRC surgery plays an essential role in ensuring the proper staging and indicating the curative

DISCUSSION The number of resected and examined LNs is essential for the proper staging of patients with CRC. A considerable number of LNs in the surgical specimen ensures neoplasm staging certainty and suggests the surgical resection execution according to the recommended oncologic standards, demonstrating that the extracted specimen had been submitted to a detailed histopathological analysis5,45,46. Despite all precaution of surgeons and pathologists, other variables can interfere in the number of studied LNs. Proximal colon tumors have shown to recover a significantly greater number of LNs when compared to distal colon tumors47. These numbers are even more evident when comparing the number of resected LNs in CC and CRC12,15,19,22,23,48. These differences are attributed to the possibility of resecting a greater number of lymph node chains in the proximal colon than in the distal colon and rectum47. This possibility is confirmed by the results of a study that analyzed 388 patients of CRC, showing that the mean value of recovered LNs in the right colon was higher than in the left colon (18.9 versus 12.6)47. Another study, which evaluated 2,340 patients with CRC and compared the number of recovered LNs between patients with CC and CRC, showed that the mean value of recovered LNs among 1,314 patients with CRC was nine LNs, while among 1,026 patients with CC was 10 LNs, significant differences33. Our group also found similar results in a previous study, which analyzed only patients with CC and CRC located above the peritoneal reflection, with mean value of recovered LNs of 22.7(12–99). However, in this study, for which only patients with CRC were selected, the mean value was 13.6 (2–40) and median was 12 LN4. Recently, a study that dissected 12 cadavers of patients that died of diseases not related to the diges316


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resection. However, they point out that these findings are not completely applicable when using NCR, at NCR, besides reducing the number of recovered LNs, creates a group of patients without LN in the surgical specimen, changing the post-chemoradiation staging. From total 281 patients submitted to NCR, 32 (11%) did not present LNs in the surgical specimen51. They suggest that the absence of LN may reflect a better response to NCR therapy, instead of worsened surgical radicality51. With these findings, they proposed that the surgical treatment could be avoided in patients with complete clinical, endoscopic and radiological response to NCR, with the indication of a rigorous postoperative follow-up only, and the surgical therapy could be indicated to cases of unsatisfactory response or recurrence, identified through clinical, endoscopic and imaging exams during the follow-up52,53. However, there are no sufficient evidences, based on wellconducted multi-center studies, that justify the indication of non-surgical treatments to patients that present complete response after NCR54,55. All these evidences suggest that lymph node staging in patients with CRC submitted to NCR, based on the number of identified LNs only, is controversial and should be interpreted as a precaution54. The surgical and histological technique also influences the number of recovered LNs in the surgical specimen. A study analyzing 15 patients submitted to NCR, rectal resection with total excision of mesorectum and lateral chain LN dissection, showed the recovery of 331 LNs. The study reported mean resected LNs per patient of 22.1, comprised of 258 perirectal, 73 pararectal and 27 lateral LNs. In this study, 20% of the patients showing no compromised LNs in the lateral chain at the conventional histological exam, when studied through immunohistochemistry to analyze cytokeratins (AE1/AE3), presented hidden micrometastases, and one of them had presented complete response to the tumor56. Surgeon training is also considered an important variable for a proper lymphadenectomy. A study evaluating total 371 patients showed that the number of resected LNs significantly increases when the patients are operated by surgeons specialized in CRC treatment57. This study showed that the number of LNs removed by the trained surgeons was, on average, of 19.9±10.6, while the number of LNs removed by non

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trained surgeons was 14.8±10.6, significant differences57. These differences increased even more in obese patients (BMI≥30), who presented a lower number of resected LNs (17.3±10.0 versus 19.9±11.5). All these arguments suggest that, when combining the proper surgeon training, histological technique, utilization of NCR and aspects related to the patient, such as obesity and the fact of being a male, the number of identified LNs in the CRC specimens can be lower, further aggravating the correct prognostic classification18,20. Perhaps, the most important objective of a proper lymphadenectomy in patients with CRC is to select, with superior accuracy, those who will benefit from a complementary adjuvant treatment43. When comparing the OS of patients with CRC in relation to the number of extirpated LNs, it is observed that the improper resection significantly worsens the disease prognosis16,58. The ideal number of LN to be resected in the CRC is still a reason for controversies4,12,36. Most authors consider the range of 10 and 17 LNs as ideal12,36,59,60. In the USA, the National Quality Forum and other organizations have recently defined that, in patients with CRC, the minimum number of 12 LNs should be resected, in this parameter, which is one of the most important in the quality analysis of a unit specialized in the disease treatment61. Then, resections with less than 12 LNs can be considered improper, not enabling the correct staging. Many pathologists prefer to classify patients with less than 12 LNs identified in the surgical specimen as NX or add a note to the anatomopathological study report emphasizing the risk of predicting the lymph node status based on the number of dissected LNs4,37. Resections with insufficient number of LNs contribute to the phenomenon of stage migration described by Feinstein et al. in 198530, known as Will Rogers phenomenon. In fact, it is a frequent phenomenon in oncology, which occurs when the prediction of favorable survival is threatened by unfavorable progress4,30. The phenomenon is even more frequent in cases of CRC, in which, after NCR, the number of recovered LNs is usually still low. In order to improve the lymph node staging and reduce the possibility of stage migration, the incorporation or new strategies has been studied. Investigations have evaluated the importance of LNR as a variable related to OS in patients with CRC4,5,24,31-41. Berger et al.31 evaluated the OS and DFS in patients 317


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with CC classified as stages II and III and submitted to adjuvant chemotherapy. They selected patients who presented the mean number of 13 LNs analyzed. From total 3,411 patients, 648 (19%) did not have lymph node metastases, 1,857 (54%) had up to three compromised LNs and 906 (27%) had more than three metastatic LNs. When they classified the same patients into groups according to the LNR (LNR<0.05; 0.05–0.19; 0.2–0.39 and 0.4–1.0), they observed that the LNR was related to the OS and DFS in patients with 10 to 15 or more than 15 resected LNs, but not in those with less than 10 LNs in the surgical specimen31. Unlike this study, De Ridder et al.40, when comparing the TNM classification to a system that included the LNR, in a group of patients that presented mean 10 LNs, observed that the capability to establish with higher precision the prognostic stages using the LNR was 31 versus 25% only with the TNM classification. They concluded that the LNR is a variable that can improve staging in improper lymph node resection. A multi-center study published by Wang et al.33 that evaluated 24,477 patients with CC in stage III according to the TNM classification, observed that it was possible to recover more than 15 LNs in the surgical specimen in 7,469 (30.5%) of them. They categorized the patients into four groups according to the LNR (no involvement, 1/14, 1/4 and 1/2, respectively). They observed that the OS for patients in stages IIIA, IIIB and IIIC was 71.3, 51.7 and 34.0%, respectively. No significant differences were found in OS, according to the LNR, in the patients classified as stage IIIA. In the patients classified as stage IIIB, the OS according to the four classification classes (LNR-1 to LNR-4) was 63.5, 54.7, 44.4 and 34.2%, respectively, confirming that the higher the LNR, the worse the OS. In patients classified as stage IIIC, the OS according to LNR-2, LNR-3 and LNR-4 was 49.6, 41.7, and 25.2%, respectively, confirming that the LNR was also a variable related to OS and DFS. Curiously, Derwinger et al.62 observed that the LNR could also be considered a prognosis factor in 136 patients with CRC classified as stage IV according to the TNM system. They categorized the patients into three groups: LNR=0–0.15, LNR=0.16–0.65 and LNR=0.66–1. Through a univariate analysis, they reported that the LNR showed to be a more important prognostic factor to predict the OS and indication of

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adjuvant chemotherapy than the number of compromised LNs. Rosenberg et al.35 studied the importance of LNR in 3,026 patients, 1,763 (58.2%) with CC and 1,263 (41.8%) with CRC. The rate of potentially curative surgeries was 77.4% and the mean proportions of resected and metastatic LNs to each patient were 18.3 and 2.6, respectively. After the statistic study, they established that the best cohort level for the LNR classification was 0.17, 0.41 and 0.69. They observed that the OS of patients without compromised LNs was 87%, while in patients with compromised LNs, it was 60.3, 34.4 and 17.6%, increasing around 5% when the LNR classification was adopted. When considering all patients as a single group, they observed that the LNR presented a greater prognostic power than the number of compromised LNs. When they categorized the patients into two groups – with CC and with CRC –, they observed that the LNR remained as an independent prognostic variable to both groups35. A series of studies performed later evaluated the importance of LNR in CRC4,38,39,43,63-65. In all of them, the LNR was considered an independent variable for OS and DFS of patients with CRC, especially in patients of stages II and III in the TNM classification. In Brazil, to our knowledge, only two studies have evaluated the importance of LNR in patients with CRC36,37. In the first, the authors analyzed 106 patients, most were males (53.8%). The median value of dissected LNs per patient was 11.5 (3–45) and only 58.5% of the patients had more than 10 dissected LNs. The mean follow-up period was 25.05±15.21 months (2–64 months), and 32.1% of patients died of the disease. The univariate analysis showed that the OS of patients included in the study was related to LNR, disease staging and tumor recurrence. However, in the multivariate analysis, they observed that the only independent factor related to OS was TNM. Perhaps, these findings are related to the fact that more than half the selected patients in the study (58.1%) belonged to stage IV according to the TNM classification – patients known to have the worst prognosis – and that the number of LNs considered for the multivariate analysis was 10 and, even so, in a small number of patients36. The authors justify that the possible explanations for the fact that the LNR does not predict OS were: sample heterogeneity in relation to the initial tumor staging, number of dissected LN, short follow-up 318


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period, small sample and non evaluation of presence of serious comorbidities and postoperative complications36. In the second study published in Brazil, the authors studied 113 patients with CC and upper CRC37. They excluded patients with middle and lower CRC, as they had been submitted to NCR, and patients with less than 12 LNs in the surgical specimen. They categorized the patients according to the LNR into three groups: LNR-0, with patients without lymph node involvement; LNR-1: involvement of max. 20% of examined LN; and LNR-2: with neoplastic involvement in 21% or more of examined LNs. They found a significant difference in OS when analyzing that in the patients belonging to LNR-0, the OS was above 80%, while in patients classified as LNR-1 and LNR-2 the OS was under 60% and 40%, respectively. With the multivariate analysis, they reported that the LNR can be considered an independent prognostic variable. The results of all these studies were confirmed by a recently-published systematic literature review that selected total 16 studies with good level of evidence. The authors included 33,984 patients with CC or CRC classified as stage III. The results showed that the capability to predict OS as provided by the LNR was greater than that found only through the number of committed LNs66. They found the relative risk for OS of 2.36 (95%CI 2.14–2.61) and for DFS of 3.71 (95%CI 2.56–5.38). However, most studies that have evaluated the LNR as a possible variable related to OS studied patients with CC31-34,38-41 or with CC and CRC as a single group4,5,24,35-38,62,63. Few studies have evaluated whether the LNR could be related to OS in patients exclusively with CRC, and even so, these studies do not clearly state whether the patients were categorized according to the criterion of having been submitted to NCR or not, which could influence the LNR calculation42,44,64-66. Peng et al.42 studied, for the first time in the literature, the relation between LNR and OS in 318 patients with CRC previously submitted to curative-intention resection. With mean follow-up of 41 months and mean number of 12 resected LNs, they observed that OS and DFS were 58.82 and 59.8%, respectively. The multivariate analysis showed that, when considered as a continuous variable, LNR was the most important prognostic factor in OS. When they categorized the patients into three groups (LNR<0.4, between 0.14–0.40

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and between 0.5–1), they observed that the OS was 72.19, 61.92 and 38.47%, respectively, statistically significant differences. They concluded that the LNR can also be considered an important prognostic factor in patients with CRC who presented positive LNs43. In the same year, Peschaud et al.44 also evaluated the prognostic power of LNR in patients with CRC. They analyzed OS, DFS and LNR in 307 patients with CRC and examined the mean number of 22 LNs. From the 307 patients, 178 (57.9%) did not show lymph node involvement, 67 (21.8%) had up to three committed LNs and 62 had more than three metastatic LNs. When they categorized the patients into four groups, according to: LNR=0 (no involvement), LNR=0.01 to 0.07, LNR>0.07 to 0.2 and LNR>0.2, they observed that the LNR was a variable related to OS, not the number of committed LNs. When they individually analyzed the patients with less than 12 examined 12 LNs, even so, the LNR was related to OS and DFS. They concluded that the LNR is the variable with the greatest prognostic power of both OS and DFS in patients with CRC, even in those whose surgical specimen presents less than 12 studied LNs. Recently, Kang et al.67, in an attempt to evaluate the importance of LNR in patients with CRC and positive LNs, even after they had been submitted to NCR (positive ypNs), studied total 75 patients, categorizing them into two groups, based on median LNR (0.143). They observed that the abdominoperineal resection of the rectum, the involvement of circumferential margins and LNR>0.143 were variables related to reduced OS. They concluded that the LNR is an independent prognostic variable in patients with CRC submitted to NCR, allowing also a better categorization than ypN staging. They propose that the LNR should be considered an additional prognostic factor in patients with CRC after NCR. Another study with a similar objective, when evaluating 281 patients with CRC submitted to NCR associated with total resection of the mesorectum, categorized the patients according to LNR into: small (0–0.09), moderate (0.09–0.36) and high (≥0.36)68. They observed that the patients with CRC previously submitted to NCR frequently present less than 12 dissected LNs, despite the intense surgical rigor and careful pathological analysis. They concluded that, in patients with CRC with less than 12 studied LNs, 319


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cal reports showing no involvement of proximal, distal and circumferential margins in all selected specimens, and the mean number of 13.6 resected LNs, with median of 12 LNs combined with similar OS to other studied centers, allows to conclude that the patients were submitted to surgical resection following the best oncologic principles. In this study, when analyzing the clinical variables, age, gender and ethnic group in relation to OS, no significant differences were observed. When the histological type of the tumor is considered, previous studies demonstrated that mucus-secreting tumors or with signet-ring cells present lower OS, although accounting for 15% of the CRC cases73,74. They also demonstrated that the mean survival of these patients is 45.4 months, compared to 78.5 months in patients with tumors of tubular pattern73. In this study, no relation was found between the histological type of the tumor and OS. This finding is probably related to the small number (8.98%) of mucus-secreting tumors in the studied cases. Perhaps this small number is due to the fact that only patients with CRC were selected, and in these patients, the proportion of this histological type is smaller when compared to CC patients, and due to the fact that the study excluded patients with suspicion of belonging to families with HNPCC, which present higher incidence of mucus-secreting tumors75. Although tumors with worse histological degree are also associated to worse OS, this study did not observe any relation between worse histological degree and smaller OS. Perhaps the small number of little differentiated tumors found in the study (4.4%), just as it happened when considering the histological type, influenced the result. Regarding the tumor size, the study observed that tumor of more than five centimeters presented marginal significance in relation to OS (p=0.053), while the extent of colon wall invasion had no relation with worsened prognosis. Regarding the tumor size, the results obtained agree with those found in the literature. Larger tumors usually present small chances of curative resection (R0), greater possibility of invasion of adjacent structures (prostate, bladder, vagina, presacral fascia), locoregional recurrence and distant metastases, factors that influence the OS. When considering the extent of rectal wall penetration as a variable

the LNR is a better prognostic factor for OS than the number of recovered or metastatic LNs. A study conducted by the Japanese Society of Colorectal Cancer (JSCRC) to define the impact of LNR on patients with lower CRC in stage III, analyzed 501 patients submitted to curative resection with total excision of the mesorectum, coming from 12 institutions, and categorized them into four groups according to the LNR69. From total 501 patients, 381 were submitted to dissection of LNs from the lateral pelvic wall. The mean number of resected LNs in patients submitted or not to lateral dissection was 45 and 17, respectively. The study excluded 45 patients who had less than 12 LNs in the surgical specimen. Among the several clinical and pathological parameters analyzed, they observed that the number of committed LNs and LNR were variables related to the disease prognosis. When they added LNR to the seventh edition of TNM classification as a covariable, they observed that the new staging system and LNR were independent prognostic variables in patients with CRC in stage III. The Japanese Society proposes to add the LNR concept to the staging system of AJCC to improve the accuracy of LN status in patients with lower CRC. This idea is defended by others who believe that the LNR can become a better method to select patients with CRC eligible to adjuvant therapy43,70,71. Recently, investigators observed that the LNR is a variable that predicts the development of pulmonary metastases in patients with CRC72. To our knowledge, in Brazil, the relation between LNR and OS in patients with CRC submitted or not to NCR protocols has not been evaluated. In this study, the authors decided to study the impact of LNR and other variables on OS exclusively in patients with CRC. The study selected only patients that had been submitted to surgical resection, regardless of the number of recovered LNs in the surgical specimen, and that had not received NCR. The study excluded patients submitted to NCR to prevent the LNR-based categorization from having interferences related to the reduction of total and committed LNs due to NCR. The main purpose was to observe whether the systematic surgery alone for CRC, with total excision of the mesorectum, and performed by a trained medical team for the disease treatment, could confirm the relation between LNR and OS. The review of histopathologi320


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their biotype, gender, tumors in different locations of the rectum, of distinct histological types and degrees, operated by surgeons with different levels of experience and, mainly, patients submitted to distinct protocols of adjuvant or neoadjuvant treatment. Another factor of crucial importance is the absence of standardization at the cohort levels used to categorize the patients into groups according to the LNR in different studies. Only with the results of systematic reviews of multi-center, prospective studies, with an expressive number of cases, better standardization of inclusion criteria and that use standardized cohort levels it will be possible to definitively confirm the prognostic impact of LNR and propose its inclusion as a useful variable to improve the staging systems currently available. Until then, due to the easy-to-use calculation of no additional cost, the routine use of LNR is recommended as a valid instrument to help the correct categorization of patients with CRC, reducing staging errors.

related to OS, no relation with OS was found. Perhaps the high concentration of tumors TII and TIII, 89.94% of the studied cases, may have influenced the result. The Dukes classification, the TNM system, the number of committed LNs and the LNR were variables related to OS. The study observed that the patients classified as LNR-0 presented SG above 85%, while the patients classified as LNR-1 presented 73%, and those classified as LNR-3 presented OS below 19%. The results of this study showed that the greater the LNR, the worse the OS of patients with CRC, even in those not submitted to NRC. The study confirmed that the LNR has greater predictive power of OS than the number of committed LNs identified in the surgical specimen and that it is similar to Dukes staging and LNR systems. It should be noted that the LNR could predict the OS even in patients with less than 12 recovered LNs (results not shown) and who would be properly categorized according to the best current directions for CRC staging. Although the study evaluated only patients with CRC not submitted to NRC, the results obtained confirmed the impact of LNR on OS of patients with CRC. However, some considering should be pointed out. Most authors that have evaluated the prognostic impact of LNR on OS have analyzed a small number of cases, patients with differences regarding

CONCLUSION In the circumstances of this study, the results obtained allow to confirm the impact of LNR on the fiveyear survival of patients with CRC not submitted to preoperative chemoradiation treatment.

Resumo: Metástases linfonodais representam um dos principais fatores prognósticos no câncer colorretal. A ressecção linfonodal inadequada relaciona-se à menor sobrevida. A proporção entre linfonodos metastáticos (PLM) vem sendo utilizada como fator prognóstico em doentes com câncer de cólon. Poucos estudos avaliaram o impacto da PLM na sobrevida de doentes com câncer retal. Objetivo: Avaliar o impacto da PLM na sobrevida de doentes com câncer de reto não submetidos à quimioradioterapia préoperatória. Métodos: Foram incluídos 90 doentes com adenocarcinoma retal excluindo-se tumores de cólon, tumores sincrônicos, câncer colorretal hereditário e aqueles submetidos a tratamento radioquimioterápico pré-operatório. Os doentes foram divididos em três grupos segundo a PLM: PLM-0, sem linfonodos comprometidos; PLM-1, 1 a 20% dos linfonodos comprometidos; e PLM-2, mais de 21% dos linfonodos comprometidos. A identificação do ponto de corte da amostra selecionada foi obtida a partir da curva de características de operação do receptor (curva ROC). A sobrevida foi avaliada pelo teste de Kaplan-Meier, a diferença entre os grupos pelo teste de Cox-Mantel e a correlação entre as variáveis pelo teste de Pearson, adotando-se um nível de significância de 5% (p≤0,05). Resultados: A sobrevida em cinco anos relacionou-se à classificação de Dukes, TNM, número de linfonodos metastáticos e PLM. Houve diferença na sobrevida ao compararem-se as diferentes classes de PLM. Doentes classificados como PLM-0 apresentaram sobrevida de 85%, enquanto os pertencentes às classes PLM-1 e PLM-2, de 73 e 19%, respectivamente (p=0,0001). Conclusão: Os resultados encontrados mostraram que a PLM tem impacto na sobrevida de doentes com câncer de reto não submetidos à neoadjuvância. Palavras-chave: reto; neoplasias colorretais; linfonodos; excisão de linfonodo; análise de sobrevida.

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Original Article

Biological therapy in the treatment of moderate-to-severe ulcerative colitis patients: can colectomy be prevented? Fábio Vieira Teixeira1, Rogério Saad Hossne2, Paulo Gustavo Kotze3, Rafael Denadai4, Sender Jankiel Miszputen5 MD, PhD, Visiting Assistant Professor at the Division of Coloproctology, Department of Surgery, Botucatu Medical School, Universidade do Estado de São Paulo (UNESP) – Botucatu (SP); Gastroenterological surgeon and consultant of UNIGASTRO – Associação Beneficente Hospital Universitário and Clínica Gastrosaúde – Marília (SP), Brazil. 2Titular da Sociedade Brasileira de Coloproctologia (TSBCP); MD, PhD, Associate Professor at the Division of Coloproctology, Department of Surgery, Botucatu Medical School, UNESP – Botucatu (SP), Brazil. 3 Resident of General Surgery at Hospital Mari Gatti – Campinas (SP), Brazil. 4Surgery resident at Hospital Dr. Mario Gatti (HMMG) – Campinas (SP), Brazil. 5MD, PhD, Associate Professor at the Department of Gastroenterology, Universidade Federal de São Paulo (UNIFESP) – São Paulo (SP), Brazil. 1

Teixeira FV, Hossne RS, Kotze PG, Denadai R, Miszputen SJ. Biological therapy in the treatment of moderate-to-severe ulcerative colitis patients: can colectomy be prevented? J Coloproctol, 2011;31(4):325-329. Abstract: ulcerative colitis treatment intends to induce remission, and its maintenance. Biological drugs, such as infliximab, have been indicated in moderate and severe cases of the disease, which are unresponsive to conventional medication. Randomized controlled trials proved the efficacy of biological treatment with high rates of sustained disease remission and mucosal healing. Recently, the concept of mucosal healing has been inversely associated with surgical treatment. Patients treated with infliximab have lower colectomy rates than those receiving conventional therapies. We suppose that earlier use of biological drugs in disease’s course would lead to better clinical control and mucosal healing, with a consequent reduction in colectomy rates. To support this hypothesis, a literature review from January, 1996 to April, 2011 was performed. Keywords: biological therapy; colectomy; colitis, ulcerative; treatment outcome.

Introduction

The pro-inflammatory cytokine TNF-α plays an important role in the inflammatory process of IBD, mainly in Crohn’s disease. However, its role in the pathogenesis of non-specific ulcerative colitis (UC) is still an issue of debate1-4. The clinical control of UC patients is based on salicylate therapy, such as sulphasalazine and mesalazine. In refractory cases, most authors recommend im-

The treatment of inflammatory bowel disease (IBD) has dramatically changed since the introduction of biological medications, especially the monoclonal antibodies against tumor necrosis factor (anti-TNFα). The main anti-TNF drugs used in clinical practice are: infliximab, adalimumab, and more recently certolizumab pegol1-13.

Study carried out at Universidade do Estado de São Paulo (UNESP) – Botucatu (SP) and at the Coloproctology Service of Clínica GAstrosaude – Marília (SP), Brazil. Funding source: none. Conflict of interest: nothing to declare. Submitted on: 26/10/2011 Approved on: 28/11/2011

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munomodulators. Steroid treatment is only indicated for a few weeks in the remission induction, but it is not suggested for remission maintenance. The main objective of medical treatment is to induce and maintain disease remission, avoiding flare-ups and the need for steroids. Remission maintenance of the disease is inversely associated with indication of a surgical procedure, such as total colon removal and ileal pouch anal anastomosis (IPAA)5-10. Even so, despite clinical treatment, around 9% of patients with distal colitis and 35% of those with diffuse colitis (pancolitis) undergo surgery and have their colons removed during the course of the disease5-10. Several pilot studies have been performed using anti-TNF, especially infliximab, with the aim of treating patients with UC unresponsive to conventional medication1-4. The most important study in this topic was published in 20055. Two recent randomized, controlled and double-blinded trials with UC patients denominate ACT 1 and ACT 2 (Active Colitis Trial 1 and 2) demonstrated the efficacy of infliximab for induction and maintenance of remission in patients with moderate to severe UC not responding to conventional treatment5. More than 60% of the patients included in this study who received infliximab achieved disease remission and intestinal mucosa healing5. Jarnerot et al.6, reported that infliximab can be used as a rescue therapy in patients with moderate to severe persistent UC, which is associated with significant reduction colectomy rates. We wondered whether earlier use of biological therapy during disease course, as well as being used in treating Crohn’s disease – top-down approach – could lead to better clinical control and mucosa healing, with a consequent reduction in colectomy rates12-13. To support this hypothesis, a wide literature review was carried out to find better evidence over a period from January, 1996 to April, 2011.

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scopic improvement compared to the Placebo Group, but without statistical significance. Amongst the initial 60 patients planned for inclusion, only 11 were randomized: 3 received placebo and the others, different infliximab doses. All three placebo patients had colectomies at the end of the study and among the eight receiving infliximab, only four underwent surgery2. Jarnerot et al.6, in a multicenter Scandinavian study, evaluated the efficacy of infliximab as a rescue therapy in patients with UC resistant to conventional drugs and indicated for colectomy. Forty-five patients were included (24 treated with infliximab and 21 with placebo). Twenty-nine per cent (7/24) of infliximab patients were submitted to surgery, while 67% of the Placebo Group (14/21) had their colons removed due to lack of response. This was the first report in literature with strong evidence supporting the use of infliximab as a rescue therapy before colectomy indication5. In a multicenter retrospective study performed in Italy, Kohn et al.10 reported infliximab use in 83 patients with an acute moderate or severe episode of UC indicated for colectomy, due to resistance to intravenous corticosteroids. As a rescue therapy before colectomy, all patients received between one and three doses of infliximab (5 mg/kg) every two or four weeks, without any pre-established protocol. Those who did not respond to treatment were submitted to colectomy. Eighty-two per cent avoided colectomy at two months. Sixty-one patients (73%) reached clinical remission at one month. Seventy patients (84%), who attained the primary endpoint (no colectomy or death), were followed-up for a median period of 23.4 months. Over this period, 97% patients discontinued glucocorticoids. There was a total of 12 (29%) colectomies among the 83 patients included in the study10. Rutgeerts et al.5 performed a randomized, controlled, double-blinded, clinical study – ACT-1 and ACT-2. They reported about the efficacy of infliximab in patients with moderate and severe UC resistant to conventional therapy with corticosteroids and immunomodulators5. In a recently published post-hoc analysis of ACT-1 and ACT-2, Sandborn et al.9 observed 41% reduction risk of colectomy in the Infliximab Group during the treatment period of 54 weeks. The objective of this post-hoc analysis was to establish whether infliximab could reduce the number of colectomies over a one-year period. Treatment with

INFLIXIMAB AND UC Since the beginning of this decade, anti-TNFs, especially infliximab, have been used in the treatment of moderate to severe UC resistant to conventional treatment. Sands et al.2 published one of the first studies regarding using infliximab in patients with UC. Those who received infliximab presented clinical and endo326


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this biologic led to a 7% reduction in absolute risk of colectomy. This was statistically significant in patients treated with 10 mg/kg infliximab (18/242, 8%, p=0.0007), but it was not statistically significant in patients treated with 5 mg/kg (28/242, 12%, p=0.166), when compared to placebo (36/242, 17%)5,9.

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in patients with extensive colitis16. Furthermore, in an univariate analysis, it was found a positive relationship between mucosal healing and fever at baseline in patients with Crohn’s disease and also by the significant predictive role of other symptoms, such as pain on subsequent mucosal healing16. Indeed, this fact supports the hypothesis and it allows us to speculate that, maybe, patients with extensive disease or severe symptoms may have been treated earlier and more aggressively. The authors suggested that we must adopt a strategy for the earliest possible treatment in both children and adults. Such strategy can reduce hospitalization and surgery costs and may prevent complications and disability at a young age16. The natural history of inflammatory intestinal diseases can be changed if we adopt an effective treatment, which heals intestinal mucosa12,16. Recently, a Swedish/Danish group published the long-term efficacy of infliximab as a rescue therapy in severe UC patient7. the ones who participated in the first study published in 2005 were followed-up for a median of 55 months (range 36 to 79 months)6-7. In the original study, patients with severe UC were randomized to receive a single infusion of infliximab or placebo, and colectomy rates were measured after 90 days6. Patients of the same cohort were followed-up for three years. Additional anti-TNF therapy was allowed for clinical relapse. Clinical remission was defined as total Mayo score ≤1 and endoscopic remission as Mayo endoscopic subscore=05,7. Eleven of 15 patients that did not undergo surgery at follow-up were in clinical remission and 12 of 15 patients not operated were in endoscopic remission. Fifty percent (7/14) of the patients who had their colon removed were not in endoscopic remission in the moment of operation. On the other hand, none (0/8) of the patients in endoscopic remission was operated. After three years, the authors reported a significant reduction in colectomy rates observed in the first study6. Fifty percent (12/24) of the patients treated with infliximab were operated compared to 76% (16/21) treated with placebo (p=0.012)7. The anti-TNF drugs used in Crohn’s disease and UC therapy intend to the macroscopic healing of the intestinal mucosa (absence of erosion and ulcers)12,14,15,17. Also, infliximab is associated with an improvement of inflamed tissue ultra-structure17. Fra-

INFLIXIMAB, MUCOSAL HEALING, AND COLECTOMY Currently, the main purpose of treating Crohn’s disease is to promote intestinal mucosal healing12. There is no question regarding intestinal healing as the main predictive factor related to long-term clinical remission12,14,15. In analogy to Crohn’s disease, the early use of biological drugs since disease diagnosis – top-down therapy – could also lead to improved intestinal healing rates for UC patients with the consequent long-term control of symptoms12,13. A Norwegian, population-based, cohort study of UC patients reported that mucosal healing after one year of treatment was associated with low risk of future colectomy16. A population-based cohort of 843 incident cases of IBD in Norway was collected from 1990 to 1994 and subjected to a scheduled prospective follow-up, with a one-year visit and a five-year visit. Data from a total of 513 incident UC patients were available from the inflammatory bowel disease in Southeastern Norway (IBSEN) study. After exclusion of patients undergoing colectomy during the first year after diagnosis (n=15), and some patients who did not meet follow-up criteria, 448 patients with UC were eligible for the one-year follow-up. Of the patients with mucosal healing at the one-year follow-up, three were recorded as having undergone surgery at five years, compared with 13 in the group without mucosal healing at one year (p=0.02). Moreover, multiple logistic regression analyses were performed with mucosal healing or endoscopic inflammatory activity as the dependent variable and different subsets of variables. Only educational level and disease extension (proctitis, proctosigmoiditis, left sided, extensive colitis) were recognized as significant mucosal healing predictors (p=0.004 and p=0.02, respectively). The authors concluded that, indeed, there is a relationship between disease’s extension and mucosal healing as a result of more aggressive treatment 327


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tila and Craciun17 reported intracellular improvement in the mucosa of UC patients treated with infliximab. Four weeks after receiving two infusions of infliximab (5 mg/kg) – weeks 0 and 2 –, patients were submitted to colonoscopy and inflamed colon mucosa biopsy. An important intracellular improvement was seen after infliximab treatment. The authors reported improvement in the morphology and function of the epithelial organelles, rich mucus secretion, and recovery of the chorionic components. At the end of treatment, the new ultra-structural assessment clearly showed signs of epithelial barrier recovery, with appearance of the goblet cells, microvillus border, Golgi complex, and mitochondria, resulting in a general aspect of tissue healing. The metabolic activity and the energetic function were re-engaged due to numerous vesicles synthesized in the cytoplasm and electron-dense normal mitochondria17. Therefore, it is evident that treatment with biological drugs promotes an improvement in clinical symptoms, and macroscopic (endoscopy) and microscopic mucosa healing, including the cellular level17. Such findings may indicate a change in the disease’s natural history. At present, unfortunately, there is no scientific evidence that support the theory that top-down approach in UC patients would be better than conventional treatment. However, in patients with moderate to severe UC, it has shown higher rates of mucosal healing when comparing infliximab to conventional therapy5. Therefore, it is pertinent to speculate whether patients treated early with infliximab and who received a regular maintenance dose every two

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months, would have healed colon, and in the longterm, reduced number of complications and lower probability of colectomies. Conclusions Anti-TNF biological drugs are a landmark in the treatment of inflammatory bowel disease, especially infliximab and adalimumab5-11,13-22. The anti-TNFs promote healing of the inflamed intestinal mucosa with reduction in the local inflammatory process, erosions, and ulcerations5,16. Also, the use of infliximab in UC can lead to the ultra-structural improvement in inflamed cells17. Such macroscopic and ultra-structural changes observed in intestinal mucosa after treatment with anti-TNFs were defined in literature as mucosal healing. Healing of the mucosa is directly associated with the reduction in number of colectomies in UC patients who received anti-TNF therapy7-10,16,20-22. Finally, just as we see a modification in the natural history of Crohn’s disease, patients who receive early biological – top down therapy –have sustained disease remission, fewer relapses, fewer hospitalizations, and consequent reduction in intestinal surgery, we believe that the UC patients could also have the same favorable clinical evolution if treated early with biological therapy12,16. Acknowledgment The authors thank Juliana Interdonato and Colin Knaggs for medical writing and for polishing the English language.

Resumo: O tratamento da colite ulcerativa tem como objetivo induzir a remissão, além da manutenção da remissão da doença. Agentes biológicos como o infliximabe têm sido indicados em casos moderados e graves da doença, os quais não respondem à medicação convencional. Ensaios clínicos randomizados comprovaram a eficácia do tratamento biológico com altas taxas de remissão da doença e cicatrização sustentada da mucosa. Recentemente, o conceito de cicatrização da mucosa tem sido inversamente associado com o tratamento cirúrgico. Pacientes tratados com infliximabe têm taxas mais baixas de colectomia se comparados com aqueles que receberam terapias convencionais. Supõe-se que quanto mais cedo for introduzida a terapia biológica no curso da doença, melhor seriam o controle clínico e a cicatrização da mucosa, com consequente redução nas taxas de colectomia. Para apoiar esta hipótese, foi realizada uma revisão da literatura entre janeiro de 1996 e abril de 2011. Palavras-chave: terapia biológica; colectomia; colite ulcerativa; resultado do tratamento. 

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REFERENCES

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remission in patients with early-stage Crohn’s disease. Gastroenterology. 2010;138:463-8. 13. Teixeira FV, Saad-Hossne R, Carpi MR, Teixeira ACA, Teixeira Jr P. Infliximab: First line therapy in ulcerative colitis. Preliminary report. J Coloproctol. 2008;28:289-93. 14. Lichtenstein GR, Rutgeerts P. Importance of mucosal healing in ulcerative colitis. Inflamm Bowel Dis. 2010; 16:338-46. 15. Rubin DT, Huo D, Hetzel JT, Bunnag AP, Sedrak M, Hart JA, et al. Increased degree of histological inflammation predicts colectomy and hospitalization in patients with ulcerative colitis. Gastroenterology. 2007;132(Suppl 2):A19. 16. Frøslie KF, Jahnsen J, Moum BA, Vatn MH; IBSEN Group. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology. 2007;133:412-22. 17. Fratila OC, Craciun C. Ultrastructural evidence of mucosal healing after infliximab in patients with ulcerative colitis. J Gastrointestin Liver Dis. 2010;19:147-53. 18. Schirbel A, Reichert A, Roll S, Baumgart DC, Büning C, Wittig B, et al. Impact of pain on health-related quality of life in patients with inflammatory bowel disease. World J Gastroenterol. 2010;16:3168-77. 19. Meyer AL, Teixeira MG, de Almeida MG, Kiss DR, Nahas SC, Cecconello I. Quality of life in the late followup of ulcerative colitis patients submitted to restorative proctocolectomy with sphincter preservation over ten years ago. Clinics (Sao Paulo). 2009;64:877-83. 20. Caviglia R, Ribolsi M, Rizzi M, Emerenziani S, Annunziata ML, Cicala M. Maintenance of remission with infliximab in inflammatory bowel disease: efficacy and safety long-term follow-up. World J Gastroenterol. 2007; 13:5238-44. 21. Russo EA, Harris AW, Campbell S, Lindsay J, Hart A, Arebi N, et al. Experience of maintenance infliximab therapy for refractory ulcerative colitis from six centres in England. Aliment Pharmacol Ther. 2009;29:308-14. 22. Travis SP, Higgins PD, Orchard T, Van Der Woude CJ, Panaccione R, Bitton A, et al. Review article: defining remission in ulcerative colitis. Aliment Pharmacol Ther. 2011;34:113-24.

1. Evans RC, Clarke L, Heath P, Stephens S, Morris AI, Rhodes JM. Treatment of ulcerative colitis with an engineered human anti-TNFalpha antibody CDP571. Aliment Pharmacol Ther. 1997;11:1031-5. 2. Sands BE, Tremaine WJ, Sandborn WJ, Rutgeerts PJ, Hanauer SB, Mayer L, et al. Infliximab in the treatment of severe, steroid-refractory ulcerative colitis: a pilot study. Inflamm Bowel Dis. 2001;7:83-8. 3. Probert CS, Hearing SD, Schreiber S, Kühbacher T, Ghosh S, Arnott ID, et al. Infliximab in moderately severe glucocorticoid resistant ulcerative colitis: a randomised controlled trial. Gut. 2003;52:998-1002. 4. Ochsenkühn T, Sackmann M, Göke B. Infliximab for acute, not steroid-refractory ulcerative colitis: a randomized pilot study. Eur J Gastroenterol Hepatol. 2004;16:1167-71. 5. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;8; 353:2462-76. 6. Jarnerot G, Hertervig E, Friis-Liby I, Blomquist L, Karlen P, Granno C, et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebocontrolled study. Gastroenterology. 2005;128:1805-11. 7. Gustavsson A, Järnerot G, Hertervig E, Friis-Liby I, Blomquist L, Karlén P, et al. Clinical trial: colectomy after rescue therapy in ulcerative colitis - 3-year follow-up of the Swedish-Danish controlled infliximab study. Aliment Pharmacol Ther. 2010;32:984-9. 8. Aratari A, Papi C, Clemente V, Moretti A, Luchetti R, Koch M, et al. Colectomy rate in acute severe ulcerative colitis in the infliximab era. Dig Liver Dis. 2008;40:821-6. 9. Sandborn WJ, Rutgeerts P, Feagan BG, Reinisch W, Olson A, Johanns J, et al. Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab. Gastroenterology. 2009;137:1250-60. 10. Kohn A, Daperno M, Armuzzi A, Cappello M, Biancone L, Orlando A, et al. Infliximab in severe ulcerative colitis: shortterm results of different infusion regimens and long-term follow-up. Aliment Pharmacol Ther. 2007;26:747-56. 11. Gies N, Kroeker KI, Wong K, Fedorak RN. Treatment of ulcerative colitis with adalimumab or infliximab: long-term follow-up of a single-centre cohort. Aliment Pharmacol Ther. 2010;32:522-8. 12. Baert F, Moortgat L, Van Assche G, Caenepeel P, Vergauwe P, De Vos M, et al. Mucosal healing predicts sustained clinical

Correspondence to: Fábio Vieira Teixeira Avenida Maria Cecília Alves, 268 – Parque das Esmeraldas CEP: 17516-660 – Marília (SP), Brazil E-mail: fabioteixeira@unimedmarilia.com.br

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Original Article

Body mass index as a predictor of complications and conversion in patients undergoing laparoscopic colectomy Breno Xaia Martins da Costa1, Fábio Lopes de Queiroz2, Paulo César de Carvalho Lamounier2, Antônio Lacerda Filho2, Rodrigo de Almeida Paiva2, Paulo Rocha França2, Rodrigo Soares Napoleão do Rego1, Fernanda Elias Ferreira Rabelo1 ¹Resident, Coloproctology at the Hospital Felício Rocho – Belo Horizonte (MG), Brazil. ²Coloproctologist at the Hospital Felício Rocho – Belo Horizonte (MG), Brasil.

Costa BXM, Queiroz FL, Lamounier PCC, Lacerda Filho A , Paiva RA, França PR, Rego RSN, Rabelo FEF. Body mass index as a predictor of complications and conversion in patients undergoing laparoscopic colectomy. J Coloproctol, 2011;31(4): 330-333. Abstract: Objective: Evaluate the predictive value of body mass index (BMI) for hospital length-of-stay, surgical conversion, and postoperative complications in laparoscopic colorectal surgeries. Methods: Retrospective analysis of 152 patients undergoing laparoscopic colorectal surgery. Patients were divided into two groups: group I (BMI≤30) and group II (BMI>30). The average hospital length-of-stay and the complication and conversion rates of the groups were compared. Results: Group II had a longer average hospital length-of-stay (9.852 versus 7.112 days) and higher conversion rate (33.3 versus 14.4%). BMI>30 is a risk factor for conversion, with odds ratio (OR) of 2.972 (95% confidence interval - CI 1.157–7.633). No significant difference was observed between the groups regarding complications. Conclusions: Obesity (BMI>30) significantly increases the conversion rate of laparoscopic colorectal surgery and increases the average hospital length-of-stay of patients. Keywords: body mass index; laparotomy; laparoscopy; colorectal surgery; postoperative complications.

INTRODUCTION

from the oncologic perspective, as well as the laparoscopy advantages, such as reduced pain, morbidity, ileum, hospital length-of-stay and postoperative infection rates8,9, laparoscopic colectomy has become the method of choice for colon surgeries in large centers. Today, laparoscopic colectomy is widely used in specialized centers, with 40% of elective colectomy procedures performed in the USA between 2005 and 20069. The increasingly common use of this technique has enabled a detailed and individualized evaluation of the risk factor for the conversion to the laparotomy technique and postoperative complications10. The availability of proper material and the surgeon’s experience are examples of deeply studied factors. Other conditions, such as the influence of excessive weight, are still points to be discussed.

Laparoscopic colon resection, described for the first time in 19911 for diverticular disease treatment, is today an alternative technique for the treatment of most benign or malign diseases that affect this segment of intestine. Despite the initial difficulties, the experience acquired has allowed to extend indications to obese, elderly, intestinal inflammatory disease2 patients and patients submitted to prior laparotomy. Once the equivalence of oncologic radicality of laparoscopy in relation to conventional surgeries, the procedure was extended to the treatment of malign tumors of colon and rectum, promoting the technique and its consolidation as a safe alternative for the treatment of colorectal diseases3-7. With the procedure safety, also

Study carried out at the Coloproctology Clinic at the Hospital Felício Rocho – Belo Horizonte (MG), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 08/05/2011 Approved on: 09/06/2011

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PATIENTS AND METHODS

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in Group II, 16 were males (59.3%) and 11 females (40.7%) (Table 1). When considering the age group distribution, Fisher’s exact test showed no significant difference between the groups (test result: 0.551). The test also showed homogeneous groups in terms of frequency of malign and benign diseases in each group (test result: 0.291) (Table 1). Statistically significant differences were observed in relation to hospital length-of-stay and rate of conversion to conventional surgery between the groups. In terms of in-hospital complications, no statistically significant differences were observed. Group I had mean hospital length-of-stay lower than Group II (7.112 versus 9.852 days), with p=0.048 (Table 2). Group I presented the conversion rate of 14.4 versus 33.3% from Group II (p=0.020). The OR of this association was 2.972 ( 95% confidence interval - CI 1.157–7.633). Therefore, the patients in Group II have a conversion chance 2.972 higher than the patients in Group I (Table 3).

This was a retrospective and observational study, based on the analysis of specific protocols of patients submitted to laparoscopic colorectal surgery at the Hospital Felício Rocho (MG), from October 2007 to June 2011. In this period, 152 laparoscopic colorectal surgeries were performed and the corresponding protocols were analyzed. The patients were sorted into two groups. Group I had patients with BMI of 30 or less, totaling 125 (82.2%). Group II had patients with BMI over 30, totaling 27 (17.8%) (Table 1). The rates of conversion to conventional surgery, inhospital complications and the mean hospital length-ofstay were compared between the two groups. In-hospital complications considered in the analysis were as follows: hypovolemia, atelectasis, pneumonia, pulmonary thromboembolism, deep venous thrombosis, urinary infection, urinary retention, surgical site infection, intestinal fistula, pelvic abscess, intestinal ischemia, evisceration, acute myocardial infarction and subcutaneous emphysema. Fisher’s exact test was used to evaluate the homogeneity of the groups in relation to age and presence or absence of malignity, in each of both associations. Odds ratio (OR) was used as an association measurement to compare the conversion and complication rates during the hospital length-of-stay between the two groups. The t test was used to evaluate the mean hospital length-of-stay. The study was evaluated and approved by the Research Ethics Committee of the Hospital Felício Rocho – protocol nº 364/11.

Table 2. Mean hospital length-of-stay.   Up to 30 >30 General

n

Mean

125 27 152

7,11 9,85 7,60

Standard deviation 5,408 10,148 6,546

Table 3. Conversion rate versus grouped index. Up to 30 Over 30 Converted 14.4% 33.3% Did not convert 85.6% 66.7% 100.0% 100.0% Responders 125 27

RESULTS From the 125 patients in Group I, 57 were males (45.6%) and 68 females (54.4%). From the 27 patients

body mass Total 17.8% 82.2% 100.0% 152

Table 1. Table showing the comparisons between the groups. BMI Up to 30 >30 Total

Number 125 (82.2%) 27 (17.8%) 152 (100.0%)

Male

Female

57 68 (45.6%) (54.4%) 16 11 (59.3%) (40.7%) 73 79 (48.0%) (52.0%)

<60 years 61–80 years >80 years of age of age of age 73 47 5 (58.4%) (37.6%) (4.0%) 13 13 1 (48.1%) (48.1%) (3.7%) 86 60 6 (56.6%) (39.4%) (3.9%) 331

Benign

Malign

27 (21.8%) 3 (11.5%) 30 (20.0%)

97 (78.2%) 23 (88.5%) 120 (80.0%)


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Table 4. Complication rate versus grouped body mass index. Up to 30 >30 Total Without 11.2% 11.1% 11.2% complications With 88.8% 88.9% 88.8% complications 100.0% 100.0% 100.0% Responders 25 27 152

Group I had 11.2% of in-hospital complications and Group II, 11.1% (OR: 1.009, 95%CI 0.260– 3.787). Therefore, as data were collected, there are no evidences of difference in the chances of in-hospital complications between the two groups (Table 4). DISCUSSION Obesity increases hospital length-of-stay of patients submitted to laparoscopic colorectal surgery. According to Kurmann et al., BMI over 27 increases the risk of surgical site infection, a fact that considerably enhances hospital length-of-stay (15 versus 8 days)12. In a retrospective study that evaluated laparoscopic colectomy exams from 2002 to 2007, Kim C. Lu et al. concluded that obesity is a predictive factor for conversion and that, when compared to fully laparoscopic surgery, the converted surgery leads to longer hospital length-of-stay13. Chew et al., when analyzing 418 patients, concluded that, the greater the BMI, the longer that mean hospital length-of-stay14. The results of our study confirm the literature mentioned and show that the BMI over 30, in the studied group, increased the mean hospital length-of-stay (9.85 versus 7.11 days). On the other hand, a study conducted by Delaney et al. did not show any difference in hospital length-of-stay when comparing obese and non-obese patients15. The surgical conversion rate is greater in obese patients. According to a study developed by Chew et  al., higher BMI increases the conversion rate (OR: 1.15)14. The conversion risk due to obesity was confirmed by other authors, such as Kim C. Lu et al.13 (OR: 1.9). The results of this study also indicate obe-

sity as a predictive factor for conversion, showing that patients with BMI over 30 have a conversion chance 2.972 higher than the patients with BMI under 30. The comparative analysis of post-laparoscopic colectomy between obese and non-obese patients shows divergent results in the literature. It occurs probably due to the absence of standardization of which complications are considered and computed. Just as Tuech et al.16, our study did not show any significant difference in complication rates when comparing obese and non-obese patients. This study was a retrospective analysis, in which 152 patients submitted to laparoscopic colorectal surgery has their results analyzed. The study results agree with most available reports in the literature, showing longer hospital length-ofstay (9.85 versus 7.11 days) and greater conversion rate (OR: 2.972) in patients with BMI over 30. Regarding postoperative complications, the studied population did not show any statistically significant difference when comparing the groups with BMI over or under 30.

Resumo: Objetivo: Avaliar o valor preditor do índice de massa corporal (IMC) para o tempo de internação hospitalar, conversão cirúrgica e complicações pós-operatórias nas cirurgias laparoscópicas colorretais. Métodos: Realizada análise retrospectiva de 152 pacientes submetidos à cirurgia laparoscópica colorretal. Os pacientes foram divididos em dois grupos: grupo I (IMC≤30) e grupo II (IMC>30). Os grupos tiveram as médias de permanência hospitalar, as taxas de complicações e de conversão comparadas. Resultados: O grupo II apresentou maior tempo médio de permanência hospitalar (9,852 versus 7,112 dias) e maior taxa de conversão (33,3 versus 14,4%), sendo o IMC>30 um fator de risco para conversão, com odds ratio (OR) de 2,972 (Intervalo de confiança - IC 95% 1,1577,633). Não houve diferença significativa entre os grupos com relação às complicações. Conclusões: A obesidade (IMC>30), aumenta significativamente a taxa de conversão da cirurgia colorretal laparoscópica, assim como aumenta a média de tempo de permanência hospitalar dos pacientes. Palavras-chave: índice de massa corporal; laparotomia; laparoscopia; cirurgia colorretal; complicações pós-operatórias.

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REFERENCES

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10. Weizman D, Cyriac J, Urbach DR. What is a meant when a laparoscopic surgical procedure is described as “safe”? Surg Endosc 2007;21:1369-72. 11. King PM, Blazeby JM, Ewings P, Franks PJ, Longmam RJ, Kendrick AH. Randomized clinical trial comparing laparoscopic and open surgery for colorectal cancer within an enhanced recovery programme. Br J Surg 2006;93:300-8. 12. Kurmann A, Vorburger SA, Candinas D, Beldi G. Operation time and body index are significant risk factors for surgical site infection in laparoscopic sigmoide resection: a multicenter study. Surg Endosc 2011;25:3531-4. 13. Lu KC, Cone MM, Diggs BS, Rea JD, Herzig DO. Laparoscopic converted to open colectomy: predictors and outcomes from the Nationwide Inpatient Sample. Am J Surg 2011;201:630-4. 14. Chew MH, Ng KH, Fook-Chong MC, Eu KW. Redefining conversion in laparoscopic colectomy and its influence on outcomes: analysis of 418 cases from a single institution. World J Surg 2011;35:178-85. 15. Delaney CP, Pokala N, Senagore AJ, Casillas S, Kiran RP, Brady KM, et al. Is laparoscopic colectomy applicable to pacientes with body mass index > 30? A case-matched comparative study with open colectomy. Dis Colon Rectum 2005;48:975-81. 16. Tuech JJ, Regenet N, Hennekinne S, Pessaux P, Bergamaschi R, Arnaud JP. Laparoscopic colectomy for sigmoid diverticulitis in obese and nonobese patients: a prospective comparative study. Surg Endosc 2001;15:1427-30.

1. Jacobs M, Verdeja JC, Goldstein HS. Minimally invasive colon resection (laparoscopic resection). Surg Laparosc Endosc 1991;1:144-50. 2. Msika S, Iannelli A, Deroide G, Jouet P, Soulet JP, Kianmanesh R, et al. Can laparoscopy reduce hospital stay in the treatment of Crohn`s diseases? Dis Colon Rectum 2001;44:1661-6. 3. Lacy AM, García-Valdecasas JC, Delgado S, Castells A, Taurá P, Piqué JM, et al. Laparoscopy-assisted colectomy versus open colectomy for treatment of non-metastatic colon cancer: a randomised trial. Lancet 2002;359:2224-9. 4. Lacy A. Colon cancer: laparoscopic resection. Ann Oncol 2005;16:88-92. 5. Fleshman J, Sargent DJ, Gree E, Anvari M, Stryker SJ, Beart RW Jr, et al. Laparoscopic colectomy for cancer is not inferior to open surgery based on 5-year data from the COST study group trial. Ann Surg 2007;246:655-64. 6. Guilou PJ, Quirke P, Thorpe H, Walker J, Jayne DJ, Smith AM, et al. Short-term endpoints of conventional versus laparoscopic-assisted surgery in patients with colorectal cancer (MRC CLASICC trial): multicentre, randomised controlled trial. Lancet 2005;365:1718-26. 7. Veldkamp R, Kuhry E, Hop WC, Jeekel J, Kazemier G, Bonjer HJ, et al. The Colon Cancer or Open Resection Study Group (COLOR). Laparoscopic surgery versus open surgery for colon cancer: short-term outcomes of a randomised trial. Lancet Oncol 2005;6:477-84. 8. Dowson H, Cowie A, Ballard K, Gage H, Rockall T. Systematic review of quality of life following laparoscopic and open colorectal surgery. Colorectal Dis 2008;10:757-68. 9. Kennedy GD, Heise C, Rajamanickam V, Harms B, Foley EF. Laparoscopy decreases postoperative complication rates after abdominal colectomy: results from the national surgical quality improvement program. Ann Surg 2009;249:596-601.

Correspondence to: Breno Xaia Martins da Costa Avenida do Contorno, 9530, Barro Preto CEP 30110-934 – Belo Horizonte (MG), Brazil E-mail: brenoxmc@yahoo.com.br

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Original Article

Evaluation of response to neoadjuvant treatment, by nuclear magnetic resonance, as a predictor of oncologic results and survival of patients with rectal cancer Rodrigo Soares Napoleão do Rêgo1, Fábio Lopes de Queiroz2, Breno Xaia Martins da Costa1, Fernanda Elias Ferreira Rabelo1, Paulo Cesar de Carvalho Lamounier3, Luciana Costa Silva5, Valdivino Alves Filho4, Maria Zuleime Carmona4 Resident, Service of Coloproctology of the Hospital Felício Rocho – Belo Horizonte (MG), Brazil. 2Coordinator of Residency, Service of Coloproctology of the Hospital Felício Rocho – Belo Horizonte (MG), Brazil. 3Coordinator, Service of Coloproctology of the Hospital Felício Rocho – Belo Horizonte (MG), Brazil. 4Preceptor, Service of Coloproctology of the Hospital Felício Rocho - Belo Horizonte (MG), Brazil. 5Professor, Department of Propedeutics of the Medical School of the Universidade Federal de Minas Gerais – Belo Horizonte (MG), Brazil. 1

Rêgo RSN, Queiroz FL, Costa BXM, Rabelo FEF, Lamounier PCC, Silva LC, Alves Filho V, Carmona MZ. Evaluation of response to neoadjuvant treatment, by nuclear magnetic resonance, as a predictor of oncologic results and survival of patients with rectal cancer. J Coloproctol, 2011;31(4):334-338. ABSTRACT: Introduction: Neoadjuvant chemoradiation promotes tumor size reduction and staging before the surgery, reducing the risk of involving the circumferential resection margin and local recurrence. For patients who have been submitted to the neoadjuvant therapy, the usefulness of a second nuclear magnetic resonance (MRI) after chemoradiation has not been clearly explained. Objective: Assess the degree of tumor regression and downstaging after chemoradiation using MRI, compared with the pathology, and its correlation with surgical outcomes and patient prognosis. Methods: This study investigated 13 patients. Their mean age was 52.3 years and 69.23% were male. Results: The agreement in T and N staging was 30.76%, between the second MRI and pathology, overestimated in 55.55% of the remaining. T staging agreement was 53.84% and N staging agreement, 61.53%. The circumferential resection margin was free of cancer in 100%. The survival rate was 92%, with 75% disease-free in a mean follow-up of 1-2 years. Conclusion: A second MRI after chemoradiation can evaluate the degree of tumor regression, but with low compliance in relation to pathology, with tendency to overstaging. More studies are required to confirm these initial observations. Keywords: magnetic resonance imaging; rectal cancer; neoadjuvant therapy.

INTRODUCTION

tion margin (CRM) an important prognostic indicator of local recurrence, distant metastases and worsened survival1,2. Neoadjuvant chemoradiation (NACR) promotes tumor size reduction and staging before the surgery, reducing the risk of involving the CRM and local recurrence3. This procedure is indicated for tumors T3, T4 and/or with lymph node involvement4. Magnetic Resonance Imaging (MRI) can assess staging, involvement of radial circumference margin and the

Rectal cancer corresponds to 30 to 50% of all colorectal tumors. Its prognosis is influenced by several factors, such as lateral extension of tumor, lymph node involvement and presence of distant metastases. The rate of local recurrence, after isolated surgical treatment, ranges from 3 to 32%, with the presence of tumor less than 1 mm from the circumferential resec-

Study carried out at the Service of Coloproctology of the Hospital Felício Rocho – Belo Horizonte (MG), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 08/05/2011 Approved on: 09/06/2011

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extramural venous invasion with high accuracy, identifying factors of difficult prognosis1,5. For patients with rectal cancer submitted to neoadjuvant therapy, the usefulness of a second MRI after chemoradiation to assess the response to the treatment, and performed just before the surgical procedure, has not been clearly explained. The potential benefits that have been reported are: accurate identification of tumor regression for an adequate CRM, after a standard surgery with total mesorectal excision, and warn for possible points requiring more careful dissection or wider resection. In addition, some studies relate the response to the NACR to the prognosis. Few studies have assessed the predictive value of MRI after NACR as a predictor of oncologic results and survival of patients with rectal cancer. This study has the purpose of assessing the degree of tumor regression and downstaging obtained after chemoradiation through MRI, comparing it to the anatomopathological (AP) study and its correlation with the patients’ surgical results and prognosis.

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T and N staging used in the study followed the UICC (Union for International Cancer Control) classification. The degree of tumor regression was assessed following the modified Dworak classification, which is Degree 0: no regression, similar aspect to the original tumor; Degree 1: dominating tumor mass with small areas of fibrosis/mucin; Degree 2: predominance of fibrotic or mucin alterations and visible intermediate sign; Degree 3: dense fibrosis, with no obvious residual tumor; and Degree 4: no evidence of tumor (complete response). This study was approved by the Research Ethics Committee of the Hospital Felício Rocho, under CAAE (Certificado de Apresentação para Apreciação Ética) protocol 0008.0.240.000-11. RESULTS This study analyzed 13 patients. Table 1 shows the patients’ characteristics. Nine patients (69.23%) were male. Their mean age was 52.3 years old. All patients were submitted to the surgery of low anastomosis of colon with total mesorectal excision performed by the same surgeon. One patient presented hepatic metastases at the diagnosis, which was later resected. All patients presented free circumferential resection margins. The AP study showed compliance in relation to T staging of 53.84% (7/13) estimated in the post-neoadjuvant therapy MRI, with tendency to overstaging of 83.33% (5/6) in the others. Regarding the lymph node status, the AP study agreed with the post-NACR MRI in 61.53% (8/13). When assessing associated T and N staging, the compliance was 30.76% (4/13); also with tendency to overstaging of 55.55% (5/9) in the other patients (Table 2). In the follow-up period of the 13 patients, one patient died due to postoperative complications (staged patient, T3N0 at the first examination, with tumor regression estimated as Degree 2 by MRI, remained T3N0 after the NACR and the AP study indicated T2N0), one patient had local recurrence and distant metastases one year and eight months after the surgery (a T3N2 patient, with tumor regression estimated as Degree 3, but with T3N0 staging after the NACR and the AP study indicating T3N0) and died six months after the recurrence; two resected he-

METHODS This is a prospective observational study that included patients treated between August 2008 and December 2010. These patients were submitted to preoperative staging by thorax, abdomen and carcinoembryonic antigen (CEA) tomography, as well as a clinical evaluation. Locoregional staging was performed through pelvic MRI. The patients classified to MRI as T3/T4 and/or with affected lymph nodes were submitted to chemoradiation (radiotherapy of 4500 to 5040 cGy for 5 weeks, associated with chemoradiation with the combination of 5-fluorouracil 350 mg/m2/day and folinic acid 20 mg/m2/day for 5 days in weeks 1 and 5). The surgery was performed eight weeks after the neoadjuvant therapy, using the technique of total mesorectal excision. One week before the surgery, one more pelvic MRI was performed to assess the degree of tumor regression. Later, the preoperative MRI results were compared to the AP study of the surgical specimen. Then, the predictive value of MRI was evaluated in relation to the response to the neoadjuvant therapy, as well as the relation between the response to neoadjuvant therapy and the prognosis of these patients. 335


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patic metastases (one patient with metastases at the diagnosis, T3N2, with tumor regression estimated as Degree 3, T3N0 at the second MRI and the AP study indicating TxN1; and another T3N2 patient, of tumor regression classified as Degree 1, who remained T3N2 at the post-NACR MRI and the AP study showing T2N2). The nine other patients (69.23%) have had the disease under control so far, without recurrence and/or metastases. Regarding the two patients that presented local and/or distant recurrence, 1 (50%) showed tumor regression at the second MRI. And only one out of the nine patients showing tumor regression with reduction at staging presented recurrence (Table 3).

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which is an important prognostic factor of local recurrence and survival1,5. This study shows initial observations indicating that the post-neoadjuvant therapy MRI could not estimate the reduction at the post-neoadjuvant therapy staging, showing compliance in relation to the AP Table 2. Compliance index of the anatomopathological analysis in relation to the condition indicated in postneoadjuvant therapy MRI. POST-NACR Confirmation % STAGING MRI (n) – AP T 13 7 53.84 N 13 8 61.53 TN 13 4 30.76

DISCUSSION

AP: anatomopathological study; MRI: magnetic resonance imaging; NACR: neoadjuvant chemoradiation.

MRI with emphasis on the rectum can classify rectal tumors according to prognostic factors and assess T and N staging with 85-90% accuracy3,6. For this reason, it enables a better surgical planning, showing the points of high vulnerability during mesorectal dissection to the surgeon and leading to a lower rate of involvement of circumferential resection margins,

Table 3. Evaluation of recurrence in relation to tumor regression. Recurrence Yes No Yes 1 8 Tumor Regression No 1 1

Table 1. Clinical characteristics of patients. PREPOSTDWORAK   Patient NACR MRI NACR MRI r 1 AFS T2N2 T2N0 2 2 AGF T4bN2 T4bN1 3 3 BNT T3aN0 T2N0 2 4 DT T3bN0 T0N0 4 5 DPC T3dN1 T3dN0 1 6 KAS T2N0 T2N0 1

Free Free Free Free Free Free

Time to surgery 1-2 YEARS 1-2 YEARS 1-2 YEARS 1-2 YEARS >2 YEARS >2 YEARS

AP CRM T2N0 T4N0 T2N0 T0N1 T3N2 T1N1

7

MLD

T3N0

T3N0

2

T2N0 Free

1-2 YEARS

8 9 10

OAS ORM PFM

T3N2 T3bN0 T3aN0

T3N2 T0N0 T1N0

1 2 3

T2N2 Free T2N0 Free T1N0 Free

1-2 YEARS <1 YEAR 1-2 YEARS

11

SH

T3bN2

T3N0

3

T0N1 Free

<1 YEAR

12

TJLJ

T3aN0

T3aN0

2

T0N0 Free

1-2 YEARS

13

VF

T3cN2

T3cN0

3

T3N0 Free

>2 YEARS

Clinical status No recurrence No recurrence No recurrence No recurrence No recurrence No recurrence Death – surgical complications Resected hepatic Mtx No recurrence No recurrence Resected hepatic metastases No recurrence Recurrence + Lung and bone metastases – death

AP: anatomopathological study; CRM: circumferential resection margin; Mtx: metastases; MRI: magnetic resonance imaging; NACR: neoadjuvant chemoradiation.

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study of 30.76%. The other patients presented tendency to overstaging. According to Barbaro et al., MRI sensitivity and specificity are approximately 80%, with tendency to overtsaging6. When MRI shows staging higher than the AP results, it does not affect the oncologic surgical quality, as the surgeon tends to consider a wider resection margin, for a free CRM. If, after the resection, the actual staging is lower than the value estimated in MRI, the non-involvement of margins is kept. This overstaging tendency occurs especially due to the difficult differentiation of initial T2 to T3, and the radiologist tends to classify as overstaging. In addition, post-neoadjuvant therapy fibrosis makes this differentiation between tumor and cicraticial tissue more difficult, which favors overstaging. When trying to avoid an undertreated patient, in an oncologic perspective, overstaging occurs in case of any doubt, leading to a more aggressive treatment, with higher morbidity, but oncologically adequate. In neoadjuvant NACR, precise staging to assess the response to treatment is very important, as it can guide through surgical approach optimization, such as sphincter preservation in low tumors, less aggressive resection of initially advanced tumors or intraoperative radiation therapy, according to the tumor response6,7. NACR results in reduced number and size of both benign and malign mesorectal lymph nodes. Dow Mu-Koh et al.3 report that NACR is useful in the assessment of lymph node response to neoadjuvant treatment, with 88% accuracy, but it is uncertain in terms of how much this response can be translated into survival3,8. The compliance found in lymph node status after NACR was 61.53%. In the evaluation of mesorectal lymph nodes, the utilization of morphological criteria (outline irregularity and sign heterogeneity) offers improved accuracy than the size to distinguish malign from non-malign lymphatic ganglia. Three patients (23.07%) presented complete pathological response, without evidence of tumor tissue in the specimen, only fibrosis and inflammatory alterations. Only 1 (33,33%) of them presented postNACR MRI suggesting complete remission. In another case, MRI indicated complete remission, but the AP study showed neoplastic tissue. In the evaluation of complete pathological response, MRI presented the positive predictive value of 50.0% and the negative predictive value of 83.3%.

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Pre-NACR MRI influenced the proper surgical planning, especially in larger tumors, resulting in 100% free CRM, which improves the prognosis, since a compromised CRM leads to local recurrence rate of 83.0%6. Regarding the prognosis, two deaths occurred. One patient died of postoperative complications and one patient after the disease recurrence. Survival in this mean follow-up period of 1 to 2 years was 91.7% and 75.0% are free from the disease. These are initial observations and require longer follow-up periods for a better survival evaluation. The patients with worse response, who presented local recurrence or distant metastases, were those with tumors in advanced stage. At pre-NACR MRI, all patients were staged as T3N2, configuring a worsened prognosis, regardless of the response to NACR when evaluated through MRI or the AP study. The first, with tumor recurrence and distant metastases diagnosed after 20 months, was T3N2, with tumor regression classified as Degree 3, but with T3N0 staging after NACR and the AP study indicated T3N0, and died six months after the salvage surgery due to recurrence. The second, with hepatic metastasis diagnosed when the clinical condition appeared, was T3N2, with regression classified as Degree 3, post-NACR MRI indicating T3N0 and the AP study indicating TxN1, is now well, after metastasis resection, receiving clinical and oncologic follow-up care for seven months. The third, was T3N2, with regression Degree 1, post-NACR MRI still indicating T3N2 and the AP study showing T2N2, was submitted to hepatic metastasis resection and is receiving follow-up care. These patients, even after the lesion size reduction, with tumor regression after NACR, still showed advanced staging at the second MRI (all were T3 and one was N2). The AP study of two patients showed lymph node involvement despite the tumor regression and one showed no tumor regression at the degree of wall invasion, only tumor size reduction (leading to patient’s death). The AP study confirmed T staging with poor response indicated at MRI in all these three patients. It is important to point out that 7 (77.78%) out of total 9 patients that now have no locoregional or distant metastases presented good response as indicated at MRI, characterized by tumor regression of 337


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CONCLUSION

Degrees 2, 3 and 4. Even a patient who was T4N2, presenting good response at NACR and whose MRI indicated Degree 3 regression, with the AP study showing T4N0, has the disease now under control, in 2-year follow-up. Although the second MRI tends to overstage the lesion, these patients who were good responders, according to the radiologic criteria, and later confirmed by the AP study, or the patients who presented better pathological response, are those without disease recurrence.

Our results indicate that the second MRI after the neoadjuvant therapy can show tumor regressions, if any, but it is of little use in the determination of downstaging, when compared to the AP study, tending to overstaging. Patients with tumors in advanced phases, lymph node involvement and poor response as evaluated through MRI, tend to show worsened prognosis. Further studies are required to confirm these first observations.

RESUMO: Introdução: A radioquimioterapia neoadjuvante promove redução do tamanho e do estadiamento dos tumores do reto antes da cirurgia, reduzindo o risco de acometimento de margem de ressecção circunferencial e da recorrência local. Para pacientes que se submeteram a neoadjuvância, a realização de uma segunda ressonância magnética (RNM) após a radioquimioterapia, para avaliação do resultado do tratamento, pode trazer dados relevantes para a programação cirúrgica e previsão do prognóstico, porém sua utilização ainda é controversa. Objetivo: Avaliar a capacidade da RNM prever o grau de regressão tumoral e o downstaging obtidos e a correlação entre o grau de regressão tumoral com o prognóstico dos pacientes. Métodos: Foram incluídos 13 pacientes até o momento; desses 69,23% eram do sexo masculino e a idade média foi de 52,3 anos. Resultados: O anatomopatológico (AP) mostrou conformidade em relação ao estadiamento T e N estimado pela RNM pós-neoadjuvância de 30,76%; nos demais pacientes, houve tendência ao superestadiamento em 55,55%. No estadiamento T houve concordância de 53,84% e quanto ao status linfonodal, concordância 61,53%. A margem de ressecção circunferencial foi livre de neoplasia em 100%. A sobrevida foi de 92%, com 75% de sobrevida livre de doença num seguimento médio de 1-2 anos. Conclusão: Uma segunda ressonância após neoadjuvância pode avaliar se houve regressão tumoral, porém com baixa conformidade em relação ao anatomopatológico, com tendência ao superestadiamento. Mais estudos são necessários para corroborar essas impressões iniciais. Palavras-chave: imagem por ressonância magnética; câncer de reto; terapia neoadjuvante.

REFERENCES

radiotherapy and chemotherapy. Int J Radiat Oncol Biol Phys 2006;65:445-51. 6. Barbaro B, Vitale R, Leccisotti L, Vecchio FM, Santoro L, Valentini V, et al. Restaging locally advanced rectal cancer with MR imaging after chemoradiation therapy. Radiographics 2010;30:699-721. 7. Barbaro B, Fiorucci C, Tebala C, Valentini V, Gambacorta MA, Vecchio FM, et al. Locally advanced rectal cancer: MR imaging in prediction of response after preoperative chemotherapy and radiation therapy. Radiology 2009;250:730-9. 8. Koh DM, Brown G, Temple L, Raja PA, Toomey P, Bett N, et al. Rectal cancer: mesorectal lymph nodes at MR imaging with USPIO versus histopathologic findings — initial observations. Radiology 2004;231:91-9.

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Kulkarni T, Gollins S, Maw A, Hobson P, Byrne R, Widdowson D. Magnetic resonance imaging in rectal cancer downstaged using neoadjuvant chemoradiation: accuracy of prediction of tumour stage and circumferential resection margin status. Colorectal Dis 2008;10:479-89. 2. Birbeck KF, Macklin CP, Tiffin NJ, Parsons W, Dixon MF, Mapstone NP, et al. Rates of circumferential resection margin involvement vary between surgeons and predict outcomes in rectal cancer surgery. Ann Surg 2002;235:449-57. 3. Dow-Mu K, Chau I, Tait D, Wotherspoon A, Cunningham D, Brown G. Evaluating mesorectal lymph nodes in rectal cancer before and after neoadjuvant chemoradiation using thin-section T2-weighted magnetic resonance imaging. Int J Radiat Oncol Biol Phys 2008;71:456-61. 4. O’Neill BDP, Brown G, Heald RJ, Cunningham D, Tait DM. Non-operative treatment after neoadjuvant chemoradiotherapy for rectal cancer. Lancet Oncol 2007;8:625-33. 5. Burton S, Brown G, Daniels I, Norman A, Swift I, Abulafi M, et al. MRI identified prognostic features of tumors in distal sigmoid, rectosigmoid, and upper rectum: treatment with

Correspondence to: Rodrigo Soares Napoleão do Rêgo Serviço de Coloproctologia do Hospital Felício Rocho Avenida do Contorno, 9530, Barro Preto CEP 30110-068 – Belo Horizonte (MG), Brazil. E-mail: rodrigo_snr@yahoo.com.br

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Original Article

Questionnaire assessment based on signs, symptoms and history in the prevention of colorectal cancer WALYSSON ALVES TOCANTINS DE SOUSA1, LEONARDO CARVALHO MOURA FÉ2, LORY NORONHA DE CASTRO MONTE2 1

Specialist in Coloproctology, Sociedade Brasileira de Coloproctologia; Master in Surgery; Professor of Coloproctology at Faculdade Integral Diferencial (FACID) – Teresina (PI), Brazil. 2Academician, 5th year of Medical Sciences at FACID – Teresina (PI), Brazil.

SOUSA WAT, FÉ LCM, MONTE LNC. Questionnaire assessment based on signs, symptoms and history in the prevention of colorectal cancer. J Coloproctol, 2011;31(4):339-345. Abstract: Introduction: Colorectal cancer (CRC) is an important pathology characterized by tumors in colorectal segments. Colonoscopy is the gold standard of CRC detection, but it is very expensive. Then, new methods are required for CRC screening to reduce mortality and improve the cost-benefit ratio. Objective: Evaluate the efficacy of a questionnaire (QSSA) based on signs and symptoms of CRC. Methods: The QSSA was answered by 40 patients, before the colonoscopy procedure. The patients were divided into two groups: group I, with 20 patients showing positive result in the questionnaire, and group II, with 20 people showing negative result in the questionnaire. Colonoscopy was considered positive when presenting neoplasm or its precursor. The result was statistically analyzed by Fischer’s exact test and sensitivity calculation. Results: The results showed 14 positive and 26 negative colonoscopies. Group I had 9 positive and 11 negative colonoscopies and Group II, 5 positive and 15 negative (p=0.20) colonoscopies. The questionnaire presented sensitivity of 64.2%. Conclusion: The use of this questionnaire based on signs and symptoms of CCR alone was not effective in CCR screening. Keywords: colorectal cancer; questionnaire; mass screening; diagnosis; primary prevention.

INTRODUCTION

Colonoscopy is the gold standard of CRC detection, accounting for the pathology decline8-10. However, it involves high cost and long time to perform it in the public health system in Brazil, as well as the inherent risks from the exam. Then, effective methods are required for CRC screening to reduce mortality and improve the cost-benefit ratio11,12. Almost all CRC prevention programs are based on screenings performed with fecal occult blood test (FOBT)6,11,12. Studies conducted in Denmark showed that the follow-up of patients submitted to FOBT significantly reduced the risk of mortality caused by CRC13,14. A systematic review showed that FOBT reduced the relative risk of colorectal cancer by 16% and the relative risk of death caused by CRC by 15%7.

Colorectal cancer (CRC) is a pathology characterized by tumors in the colorectal segments1. In terms of incidence, colorectal cancer is the fourth most frequent cause of cancer in the world and the second cause in developed countries2-4. In Brazil, the National Cancer Institute (INCA) estimated, in 2010, 14 new cases of CRC in each 100,000 men and 15 in each 100,000 women5. In this scenario, prevention programs have been an attractive option to reduce the incidence and mortality of CRC6,7, despite the population resistance to participate, which can influence their the program effectiveness6. Study carried out at the Faculdade Integral Diferencial – Teresina (PI), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 07/25/2011 Approved on: 09/06/2011

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Questionnaire assessment based on signs, symptoms and history in the prevention of colorectal cancer Walysson Alves Tocantins de Sousa et al.

Selvachandran et al., in two studies, demonstrated that questionnaires based on signs and symptoms can be used as a CRC screening method. Questionnaires were used in certain populations and they observed that the patients with CRC diagnosis presented higher scores than the patients without this pathology15,16. In Brazil, the possibility of incrementing the detection of colorectal cancer lesions with a questionnaire based on signs, symptoms and history was raised after a pilot study that analyzed the results of colonoscopy in patients submitted to FOBT and questionnaires of positive and negative results. The study demonstrated that most screened patients with positive results at colonoscopy were already symptomatic and/or already presented alterations at FOBT6. Considering the increasing incidence of CRC in the country, the introduction of an effective questionnaire based on signs, symptoms and history in the medical practice would help in the disease prevention. Then, the purpose of this study was to verify the effectiveness of a clinical questionnaire (QSSA) in CRC prediction, acting as an instrument of screening precursors of this neoplasm.

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comprised of the 20 first patients with negative results in the QSSA. The QSSA was considered positive when the two following criteria were fulfilled: 1. With family history of the disease, i.e., presence of at least one first-degree family member with CRC or adenomas; 2. With symptoms: a) Specific symptoms – blood in stool and/or alteration to bowel habit, such as increased frequency, aspect change (fine stool) or loss of stool for more than three months (these two symptoms alone determined positive QSSA); b) Non-specific symptoms - abdominal pain in the hypogastrium, for more than three months, anemia without defined cause, weakness, rectal pain and sensation of incomplete evacuation (in cases of non-specific symptoms, the QSSA was considered positive when presenting association of at least two symptoms). The colonoscopy procedures were performed by the same physician, with patients sedated with Midazolam at the dose of 1 to 5 mg. Olympus endoscopic equipment were used in the procedures. All exams reached the cecum. The study defined positive colonoscopy as that with neoplasm or precursors of CRC; otherwise, it was considered as negative colonoscopy. A descriptive and inferential analysis was performed through Fisher’s exact test, using Biostat 5.0 software to help in the analysis. The value of p<0.05 was considered statistically significant. In addition, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and questionnaire accuracy were calculated.

METHODS The population analyzed in this study was from a private clinic in Teresina (PI), between March and August 2010. The study included patients that would be submitted to colonoscopy and excluded those that had already been submitted to colonoscopy before, under 50 years of age or with history of pelvic radiotherapy. The patients signed an informed consent term before they start their participation in the study. The sample was constituted of 40 patients, to which a questionnaire based on signs, symptoms and history (QSSA) of colorectal cancer precursors was applied 6 (Appendix 1). The QSSA was applied immediately before the previously scheduled colonoscopy procedure was performed, with the intention of sorting the patients into two groups: group I, comprised of the 20 first patients with positive results in the QSSA, and group II,

RESULTS The study evaluated 17 (42.5%) male and 23 (57.5%) female patients. In group I, both genders presented the same number of patients. Group II had 13 female 7 male patients (Chart 1). Regarding their age, the overall mean age was 60±2 years, ranging from 50 to 90 years. 340


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DISCUSSION

In total, 14 positive and 26 negative colonoscopies were obtained. Group I presented 9 positive and 11 negative colonoscopies; while group II presented 5 positive and 15 negative colonoscopies (p=0.20) (Table 1, Chart 2) The questionnaire sensitivity was 64.2%, specificity 57.7%, PPV 45.0%, NPV 75.0% and accuracy was 60.0% (Table 2).

CRC remains as an important cause of morbimortality worldwide3,4. In Brazil, the incidence has increased each year5. Then, special attention has been dedicated to exams that diagnose CRC and its precursors. With improvements made in colonoscopy, this technique has appeared as the main method of colorectal evaluation, more effective than the radiological exam, also due to its therapeutic options17. However, this exam is inconvenient, invasive and costly. These characteristics encourage the search for other screening methods for such disease. In Brazil, the best screening method would involve low cost, easy execution, high sensitivity and social acceptance11,12. As an exam that meets all these criteria is unavailable and based on the existing resources, some methods have been discussed, especially the fecal occult blood test (FOBT), which has shown to be a very attractive option, but without fulfilling all these requirements, and questionnaire based on signs and symptoms and history. This questionnaire, still not deeply studied, has shown to be effective when used with FOBT and has an educational character in terms of disclosing its most frequent signs, symptoms and history6. Patients under 50 years of age, who constitute a population with greater risk for developing this neoplasm, were excluded, in an attempt to have a more homogeneous sample. The same objective was intended when using the other exclusion criteria. In addition, no considerable predominance was observed between the genders. Regarding the sample selection, the utilization of patients already with an indication to colonoscopy is a study bias, or possibly, a biased sample. However, this is the easiest and most economic way to conduct studies that require more invasive/or costly exams. In addition, it should be noted that many asymptomatic patients are submitted to colonoscopy as a primary

Number of patients

Gender 14 12 10 8 6 4 2 0

Male Female Group 1 Group 2 Questionnaires

Chart 1. Distribution of studied patients by gender.

Table 1. Distribution of findings by group. Group I Group II

16 14 12 10 8 6 4 2 0

Positive result in colonoscopy 9 5

Negative result in colonoscopy 11 15

Positive result in colonoscopy Negative result in colonoscopy

Group 1

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Group 2

Chart 2. Distribution of colonoscopic findings by group.

Table 2. Percentages of sensitivity, specificity, positive predictive value, negative predictive value and accuracy. QSSA +

Sensitivity 64.2%

Specificity 57.7%

PPV 45.0%

NPV 75.0%

Accuracy 60.0%

QSSA: questionnaire based on signs, symptoms and history; PPV: positive predictive value; NPV: negative predictive value.

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prevention of CRC. Then, patients with negative results in the questionnaire were relatively frequent. The statistical analysis did not show any significant difference in the findings when comparing the groups. It should be noted that most adenomas, for their reduced size, are asymptomatic, and then, not detectable or presumed using tests based on signs and symptoms. Only the family history can be detected using a questionnaire, and for this reason, the effectiveness of this strategy is questioned, especially when used alone in the prevention of CRC. An effective screening test has to present high sensitivity, even with low specificity. In this study, median values of sensitivity were obtained. The same occurred with the other diagnostic tests. It shows that, when used alone, the QSSA is not an effective screening method. Similar values were found by Altenburg et al.6.

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Then, despite the fact of being an invasive and costly test, colonoscopy remains the method of choice for screening pre-neoplastic lesions, as the QSSA showed results of low significance when used alone to detect these lesions. However, the questionnaire should be further studied and improved to help identify individuals with substantial risk for CRC. In addition, it can be used by the physician as a source of information and a way to disseminate the risk factors to the population undergoing colonoscopy. CONCLUSION The use of a questionnaire based on signs, symptoms and history, when used alone, was not effective to screen neoplastic lesions.

Resumo: Introdução: O câncer colorretal (CCR) é uma importante afecção caracterizada pela presença de tumores localizados no colón ou reto. A colonoscopia, padrão ouro na detecção do CCR, demanda alto custo. Assim, há necessidade de métodos de triagem eficazes, visando um melhor custo beneficio na diminuição da mortalidade do CCR. Objetivo: Avaliar a efetividade de um questionário de sinais, sintomas e antecedentes (QSSA) em predizer o CCR. Métodos: O QSSA foi aplicado a 40 pacientes, momentos antes da realização do exame colonoscópico, no intuito de compor dois grupos: grupo I formado pelos 20 primeiros que apresentassem o QSSA positivo, e grupo II formado pelos 20 primeiros com QSSA negativo. A colonoscopia positiva foi aquela com achado de neoplasia ou lesões precursoras do CCR. O resultado foi submetido à análise estatística através do Teste Exato de Fischer e do cálculo da sensibilidade, especificidade, acurácia e valores preditivos positivos e negativos. Resultado: Observaram-se 14 colonoscopias positivas e 26 colonoscopias negativas, assim distribuídas: grupo I, 9 positivas e 11 negativas; grupo II, 5 positivas e 15 negativas (p=0,20). O questionário apresentou sensibilidade de 64,2%. Conclusão: A utilização de um questionário de sinais, sintomas e antecedentes usado isoladamente não mostrou eficácia no rastreamento de lesões neoplásicas. Palavras-chave: câncer colorretal; questionário; programas de rastreamento; diagnóstico; prevenção primária.

REFERENCES

Estimativa de 2010: incidência de câncer no Brasil. Rio de Janeiro: INCA, 2009. 6. Altenburg FL, Biondo-Simões MLP, Bahten LCV. A pesquisa de sangue oculto nas fezes associada a um questionário de sinais e sintomas na prevenção do câncer colo retal. J Coloproctol 2009;29(1):57-64. 7. Hewitson P, Glasziou P, Watson E, Towler B, Irwig L. Cochrane systematic review of colorectal cancer screening using the fecal occult blood test (hemoccult): an update. Am J Gastroenterol 2008;103(6):1541-9. 8. Nahas SC, Marques CFS, Araújo SA, Aisaka AA, Nahas CSR, Pinto RA, et al. Colonoscopia como método diagnóstico e terapêutico das moléstias do intestino grosso: análise de 2.567 exames. Arq Gastroenterol 2005;45(2):72-82. 9. Almeida MG, Baraviera AC, Malheiros APR, Cury RM, Milman MHS, Gomes CAS, et al. Eficácia da videocolonoscopia com magnificação no diagnóstico

1. Jatobá MP, Candelária PAP, Klug WA, Fang CB, Capelhuchnik P. Pesquisa de sangue oculto nas fezes e achados colonoscópicos em 60 pacientes. J Coloproctol 2008;24(4):425-30. 2. Altenburg FL, Biondo-Simões MLP, Santiago A. Pesquisa de sangue oculto nas fezes e correlação com alterações nas colonoscopias. J Coloproctol 2007;27(3):304-9. 3. Duarte-Franco E, Franco EL. Epidemiologia e fatores de risco em câncer colorretal. In: Rossi, BM, Nakagawa WT, Ferreira FO, Aguiar Jr S, Lopes A. Câncer de cólon, reto e ânus. São Paulo: Lemar Tecmedd Editora; 2004. p. 3-21. 4. Andrade SMS, Pereira FL. Câncer colorretal sincrônico - relato de caso e revisão de literatura. J Coloproctol 2007;27(1):69-79. 5. Brasil, Ministério da saúde. Instituto Nacional do Câncer.

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diferencial dos pólipos neoplásicos e não-neoplásicos. J Coloproctol 2003;23(4):262-7. 10. Dias APTP, Gollner AM, Teixeira MTB. Neoplasias colorretais: aspectos epidemiológicos, endoscópicos e anatomopatológicos - estudo de série de casos. HU Revista 2009;35(4):305-14. 11. Perez RO, Proscurshim I, Julião GPS, Picolo M, GamaRodrigues J, Habr-Gama A. Instalação e resultados preliminares de programa de rastreamento populacional de câncer colorretal em município brasileiro. ABCD, Arq Bras Cir Gig 2008;21(1):12-15. 12. Almeida FFN, Araújo SEA, Santos FPS, Franco CJCS, Santos VR, Nahas SC, et al. Colorectal. Câncer screening. Rev Hosp Clin 2000;55(1):35-42. 13. Kronborg O, Fenger C, Olsen J, Jorgensen OD, Sondergaard O. Randomised study of screening for colorectal cancer with faecal occult blood test. Lancet 1996;348(9040):1467-71. 14. Jorgensen OD, Kronborg O, Fenger C. A randomised study screening for colorectal cancer using faecal occult blood testing: result after 13 years and seven biennial

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screening rounds. Gut 2002;50(1):29-32. 15. Selvachandran SN, Hodder RJ, Ballal MS, Jones P, Cade D. Prediction of colorectal cancer by a patient consultation questionnaire and scoring system: a prospective study. Lancet 2002;360(9329):278-83. 16. Selvachandran SN, Maw A, Ballal MS. Use of a patients consultation and weighted numerical scoring system for the prediction of colorectal cancer and other colorectal pathology in symptomatic patients: a prospective cohort validation of a Welsh population. Colorectal Dis 2010;12(5):407-14. 17. Santos CHM, Cury MS, Saad FT. Principais achados de colonoscopias realizadas em caráter de urgência e eletivas. J Coloproctol 2009;29(1):83-7. Correspondence to: Walysson Alves Tocantins de Sousa Av Lindolfo Monteiro 2801, apto. 402, Hosto CEP 64052-810 – Teresina (PI), Brazil E-mail: wtocantins@yahoo.com.br

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Appendix 1. Questionnaire based on signs, symptoms and history (QSSA) Provide your information below and answer the questions with (x) – front and back Name: __________________________________________________________ Age: ______________ Gender: _______________________________________ Address: _______________________________________________________ Telephone number: (__________) _________________________________ Height: ________ Weight (approx.): ________ 1 - Have you ever noticed blood in stool? ( ) yes ( ) no If your answer is yes, answer the questions below; otherwise, go to question 2. ( ) Bright red ( ) Dark blood ( ) Blood in the middle of stool ( ) Blood on paper, apart from stool ( ) Blood mixed with and apart from stool ( ) I can’t identify the type of bleeding How often does bleeding occur? ( ) Every day ( ) Once a week ( ) Twice a week ( ) Once a month ( ) It has happened once or it rarely occurs ( ( ( (

Bleeding started: ) One week ago or less ) One month ago ) Less than 3 months ago ) One year ago

Bleeding amount: ( ) Small amount ( ) Large amount When bleeding occurs, do you feel anything in the anus? Itching, pain or increased volume (swelling or tumoration)? ( ) Yes ( ) No 2 - What’s your usual intestinal habit like? (How often do you evacuate?). ( ) Daily ( ) Three times a week ( ) More than once a day ( ) Less than once a week ( ) Twice a week Your bowel is usually: ( ) Constipated (hard stool) ( ) Diarrhea ( ) Alternates between diarrhea and constipation Has your intestinal habit changed lately? ( ) Yes ( ) No If your answer is yes, how has it changed? ANSWER ONLY IF IT HAS CHANGED. ( ) It’s more frequent (I evacuate more often) ( ) Changed to diarrhea ( ) It’s constipated ( ) I’m losing stool ( ) It’s urgent ( ) Now I have fine stool 344


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Appendix 1. Continuation When did it change? ( ) More than 3 months ago

( ) Less than 3 months ago

3 - Do you see mucus (jelly-like substance) or pus in stool? ( ) Yes ( ) No 4 - Do you have frequent stomachache or abdominal discomfort? ( ) Yes ( ) No If you feel abdominal pain, where is the pain exactly? ( ) In lower abdomen ( ) In upper abdomen 5 - Have you felt any pain, itching, burning or increase volume (tumoration) in the anus in the last months? ( ) Yes ( ) No 6 - Have you lost appetite in the last months? ( ) Yes ( ) No 7 - Have you been submitted to any blood test that showed anemia? ( ) Yes ( ) No 8 - Have you felt constant weakness (tiredness) in the last months? ( ) Yes ( ) No 9 - Do you have nauseas and/or vomiting? ( ) Yes ( ) No 10 - Have you even been submitted to exams such as colonoscopy? ( ) Yes ( ) No 11 - Have you ever had intestinal polyps? ( ) Yes ( ) No 12 - Regarding your close family members: parents, brothers/sister and grandparents: Has any of them had cancer? ( ) Yes ( ) No Where? ( ) Bowel ( ) Breast ( ) Stomach ( ) Ovary Who had it? ( ) Parents ( ) Grandparents ( ) Brothers/Sisters ( ) Uncles/Aunts 13 - Do you: ( ) Smoke? ( ) Drink alcohol regularly? ( ) Eat fats and fried food very often? ( ) Eat greens and fruits very often? 14 - Have you ever had cancer? ( ) Yes ( ) No Where? ( ) Prostate ( ) Breast ( ) Stomach ( ) Ovary ( ) Uterus

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Original Article

Treatment of patients with colorectal cancer at a public hospital in Porto Alegre GABRIEL VOLPATO1, DENIZE SCHMITT1, CLEBER ANTÔNIO NOGUEIRA SANTOS JÚNIOR1, LUCIANO PINTO DE CARVALHO2, RUY TAKASHI KOSHIMIZU3, AFONSO CALIL MURY MALLMANN3 1

Academicians in the 7th semester of the Medical Science Course at the Universidade Luterana do Brasil (ULBRA) – Canoas (RS), Brazil. 2Physician, Service of Coloproctology, Hospital Nossa Senhora da Conceição de Porto Alegre – Porto Alegre (RS), Brazil; Assistant Professor at ULBRA – Canoas (RS), Brazil. 3Physician, Service of Coloproctology, Hospital Nossa Senhora da Conceição de Porto Alegre – Porto Alegre (RS), Brazil.

VOLPATO G, SCHMITT D, SANTOS-JR CAN, CARVALHO LP, KOSHIMIZU RT, MALLMANN ACM. Treatment of patients with colorectal cancer at a public hospital in Porto Alegre. J Coloproctol, 2011;31(4):346-350. Abstract: Objective: The purpose of this study is to demonstrate the current picture of colorectal cancer in a public hospital of Rio Grande do Sul, focusing on aspects related to diagnosis, staging and surgical therapy addressed in these patients. Methods: A descriptive and retrospective study that includes patients with colorectal cancer admitted to the Proctology Service of the Hospital Nossa Senhora da Conceição de Porto Alegre, from January 2009 to May 2011. Results: This study investigated 61 patients, 65.6% were female. Their age ranged from 40 to 84 years. Colonoscopy was performed in 58 patients; 56.9% of them had over 50% impaired colon lumen. The carcinoembryonic antigen (CEA) was collected from 59 patients, 47.5% had CEA>5 ng/mL. Distant metastases were found in 23.3% of total 60 patients. Underwent surgical treatment 58 patients, of a curative intent was 84.5%. The presence of more than 12 lymph nodes per specimen was 73.1%. All 61 patients were classified as: Stage I (9.8%), Stage II (29.5%), Stage III (29.5%) and Stage IV (31.1%). Conclusion: The profile of the patients treated at our institution indicates disease in advanced stage; however, the methods employed have provided a curative surgical treatment in our oncology patients. Keywords: colorectal neoplasms; colorectal surgery; Unified Health System.

INTRODUCTION

non-melanoma skin tumors, colorectal and rectal cancer is the third most frequent cancer in men in the South (21/100,000) and Southeast (19/100,000) regions of Brazil. In the Midwest (11/100,000) region, it is the fourth most frequent cancer. In the Northeast (5/100,000) and North (4/100.000) regions, it is the fifth. In women, it is the second most frequent cancer in the South (22/100,000) and Southeast (21/100,000) regions; the third in the Midwest (11/100,000) and Northeast (6/100,000) regions and the fifth in the North (4/100,000) region. Rio Grande do Sul has the estimated rate of 27.07 cases to each 100,000 men and 27.69 cases to each 100,000 women. Porto Alegre, the State capital, has the estimated rate of 43.59 cases to each 100,000 men and 44.45 cases to each 100,000 women3.

Colorectal cancer (CRC) is one of the most prevalent malignant neoplasms around the globe. Each year, one million new cases are diagnosed, and it is considered the third most frequent cause of cancer in the world, affecting both genders, and the second cause in developed countries1. Around 142,570 new cases of large bowel cancer are diagnosed each year in the United States, 102,900 of which are colorectal cancer and the rest refers to rectal cancer2. The number of new cases of colorectal and rectal cancer in Brazil in 2010 is estimated to be 13,310 cases in males and 14,800 in females. These numbers correspond to estimated risks of 14 new cases in each 100,000 men and 15 in each 100,000 women. Not considering

Study carried out at the Service of Coloproctology, Hospital Nossa Senhora da Conceição de Porto Alegre – Porto Alegre (RS), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 08/08/2011 Approved on: 09/09/2011

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Sporadic colorectal cancer (SCRC) accounts for 90% of all large bowel cancers that occur annually and most of them develop from an adenomatous polyp, the pre-malign phase of the anorectal adenocarcinoma4. Age is an important risk factor for SCRC. It is a rare diagnosis before 40 years of age; the incidence starts to increase considerably between 40 and 50 years of age, and the incidence rates increase at each decade and in general they are not related to genetic or environmental risk factors5. The periodic preventive exam – colonoscopy – can reduce the mean risk of death due to colorectal cancer by 90%6. In addition, most colorectal tumors, when diagnosed early, can be completely healed. Although innumerous studies have addressed the prognostic meaning of various histological and molecular types, as well as clinical characteristics, the pathological stage at the diagnosis is still the best indicator of long-term prognosis to both colon and rectal cancer. The most important characteristics are presence of distant metastases, local extension of tumor, node positivity (number of lymph nodes involved) and residual disease7. Surgery is the only curative therapy for focal colon cancer and a potentially curative option for selected patients with limited metastatic disease in the liver and/or lung. In addition, even patients that are not eligible to curative resection can benefit from palliative surgical procedures to relieve the obstruction symptoms and primary tumor bleeding8. The purpose of this study is to show the current picture of colorectal cancer at a public hospital in Rio Grande do Sul operates only through the Unified Health System (SUS), providing patients with services focused on aspects related to diagnosis, staging and surgical therapy.

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The information collected were: gender, age, carcinoembryonic antigen (CEA), primary tumor location, lesion macroscopy, colon circumference involvement during colonoscopy, the surgery performed – whether curative or palliative, involvement of adjacent organs and whether they have been resected or not and if they presented any malignancy or inflammation, tumor staging, histological type, degree of tumor differentiation, nodal positivity, number of lymph nodes per surgical specimen, presence and location of metastases. The information was entered in a database especially built for this purpose, on a spreadsheet using Microsoft Excel 2007 and later exported to SPSS v.17.0 for analysis. The quantitative variables were described using the mean value and standard deviation and the categorical variables were described through the frequency. The study was analyzed and submitted to the approval of the Research Ethics Committee (CEP) of the Hospital Nossa Senhora da Conceição. RESULTS The study investigated 61 patients, 21 were male (34.4%) and 40 were female (65.6%). The patients’ age ranged from 40 to 84 years, mean of 65.81±11.95 years. Regarding the location, most patients presented sigmoid colon tumor (n=28; 45.9%), followed by ascending colon (n=12; 19.7%), cecum (n=6; 9.8%), splenic flexure (n=5; 8.2%), descending colon (n=5; 8.2%), hepatic flexure (n=3; 4.9%) and transverse colon (n=2; 3.3%). Among the 61 analyzed patients, 58 were submitted to colonoscopy. None of them presented perforation and 28 (48.3%) had obstruction in the intestinal lumen that blocked the flow of intestinal contents. Ulcerovegetating lesions (48.3%) were the most prevalent and 56.9% of the patients showed more than 50% circumference involvement due to the lesion size (Table 1). CEA was collected from 59 patients at the pathology diagnosis; the mean value was 210.97±1401.32 ng/mL (0.22-10754 ng/mL), with 47.5% of them with CEA over 5 ng/mL (Table 2). Sixty patients were submitted to computed tomography; 14 (23.3%) of them with distant metastases, with liver as the most affected organ in 8 patients (57.1%), followed by lung in 5 cases (35.7%) and bone tissue in 1 case (7.1%).

METHODS This descriptive and retrospective study included patients with colorectal cancer admitted to the Coloproctology Service of the Hospital Nossa Senhora da Conceição, from January 2009 to May 2011. Patients with rectal cancer were excluded from the study. The patients’ data were obtained from their clinical records and histopathological reports of colonoscopy and surgical specimens. 347


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Fifty-eight patients (95.1%) were submitted to surgical procedures. The surgery was curative in 49 (84.5%) and the palliative treatment was adopted in 9 patients (15.5%). Involvement of adjacent organs was observed in 19 patients (32.8%); in 12 (63.2%) of them, the anatomopathological result confirmed the presence of malignance, 4 (21.1%) showed organ inflammation only and 3 (15.8%) did not show any alteration, with resection of 11 (57.9%) of total 19 involved organs. Table 3 shows the analysis of the 52 surgical specimens. Regarding the tumor macroscopy, 44.2%

were ulcerovegetating and 67.3% affected more than 50% of the colon lumen. The mean tumor size was 5.2±2.12 cm (1.2–12 cm). Regarding the resection margin, 51 patients (98.15%) had free margins. The mean number of lymph nodes found per specimen was 17.69±9.92 (0–59), and positivity of 50%. More than 12 lymph nodes per specimen were found in 73.1% of the surgical specimens, with 66.7% of them from patients classified as Stage II (Table 2). In relation to staging, the patients presented the following distribution: 9.8% were Stage I, 29.5% Stage II, 29.5% Stage III and 31.1% Stage IV (Table 4).

Table 1. Results of colonoscopy exams (n=58). Macroscopy Ulcerated 4 (6.9%) Vegetating 19 (32.8%) Ulcerovegetating 28 (48%) Infiltrating 1 (1.7%) Ulceroinfiltrating 6 (10%) Involvement of circumference ≤25% 8 (13.8%) ≤50% 17 (29.3%) ≤75% 5 (8.6%) ≤100% 28 (48.3%) Tumor differentiation degree Very differentiated 1 (1.7%) Moderately differentiated 55 (94.8%) Little differentiated 2 (3.4%) TU blocking the flow of intestinal contents Yes 28 (48.3%) No 30 (51.7%) Total 58 (100%)

Table 3. Pathology of surgical specimens (n=52). Macroscopy Vegetating 12 (23.1%) Ulcerovegetating 23 (44.2%) Ulcerated 8 (15.4%) Polypoid 1 (1.9%) Infiltrating 0 (0%) Ulceroinfiltrating 8 (15.4%) Involvement of circumference ≤25% 9 (17.3%) ≤50% 8 (15.4%) ≤75% 20 (38.5%) ≤100% 15 (28.8%) Involvement of margins Free 51 (98.1%) Compromised 1 (1.9%) Tumor differentiation degree Very differentiated 5 (9.6%) Moderately differentiated 39 (75%) Little differentiated 8 (15.4%) Total 52 (100%)

TU: tumor

Table 2. Characteristics of surgical prognosis regarding the patients’ staging. Staging Stage I Stage II Stage III ≥12 lymph nodes 5 (83.3%) 12 (66.7%) 15 (83.3%) <12 lymph nodes 1 (16.7%) 6 (33.3%) 3 (16.7%) Total 6 (100%) 18 (100%) 18 (100%) CEA marker >5 ng/mL 1 (16.7%) 6 (37.5%) 12 (66.7%) <5 ng/mL 5 (83.3%) 10 (62.5%) 6 (33.3%) Total 6 (100%) 16 (100%) 18 (100%) CEA: carcinoembryonic antigen.

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Stage IV 6 (60%) 4 (40%) 10 (100%)

Total 38 (73.1%) 14 (26.9%) 52 (100%)

9 (47.4%) 10 (52.6%) 19 (100%)

28 (47.5%) 31 (52.5%) 59 (100%)


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Table 4. TNM staging 2010 (n=61). Total Stage I IIA IIB IIC Total Stage II IIIA IIIB IIIC Total Stage III IVA IVB Total Stage IV

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the surgical specimens of Stage II patients had more than 12 lymph nodes and 73.1% of total analyzed specimens had more than 12 lymph nodes14. A number of serum markers has been associated with CRC, especially CEA and carbohydrate antigen (CA) 19-9. However, these markers have a low diagnostic capability to detect primary CRC due to the significant overlap with benign disease (gastritis, peptic ulcer, diverticulitis, liver disease, chronic obstructive pulmonary disease, diabetes or any acute or chronic inflammatory condition) and low sensitivity to the disease in its early phase15-18. However, the serum levels of CEA are useful to the prognosis of patients with recently diagnosed CRC. Patients with serum CEA >5 ng/mL in the preoperative period have worse prognosis than those with lower levels. In addition, higher levels of preoperative CEA that do not normalize after the surgical resection require a deeper evaluation to investigate the persistent disease. ASCO guidelines recommend that the serum levels of CEA, when obtained in the preoperative period from patients with colorectal cancer, should help in the surgical treatment preparation and planning and in the prognosis evaluation15. In our study, 47.5% of the patients that had their CEA analyzed presented serum level of >5 ng/mL at the pathological diagnosis. Around 20% of the patients have metastatic disease at the moment they search for care19. The colon cancer can spread through lymphatic and hematogenical dissemination, and through contiguous and transperitoneal pathways. The most frequent areas affected by metastasis are regional lymph nodes, liver, lung and peritoneum, and the patients can show signs or symptoms related to any of these areas. As the venous drainage of the intestinal tract is through the portal system, the first area of hematogenical dissemination is usually the liver, followed by the lungs, bones and many other sites, including the brain19. In our study, 23.3% of the patients had metastatic diseases at the moment of diagnosis, and the most affected areas were: liver (57.1%), lung (35.7%) and bone (7.1%); in agreement with the literature. Most of our patients were in advanced stages of the disease, with more than 60% of them classified as Stages III and IV, in agreement with the absence of tracking measures in our population.

6 (9.8%) 13 (21.3%) 3 (4.9%) 2 (3.3%) 18 (29.5%) 2 (3.3%) 12 (19.7%) 4 (6.6%) 18 (29.5%) 11 (18%) 8 (13.1%) 19 (31.1%)

DISCUSSION The purpose of the colon cancer surgery is to perform the complete removal of the tumor, with the main vascular pedicle of the affected segment of the colon and its lymphatic drainage area. While the segment resection is sometimes enough to remove the primary tumor, a larger resection is usually required for a satisfactory lymphadenectomy. The blood vessels should be separated at their origin point to allow wider resection and maximize the number of lymph nodes in the specimen. Block resection of adjacent structures is indicated in case of tumor ligation or adhesion to any other organ or structure. For a surgery to be oncologically correct, it prioritizes resection with free margins8. In our study, 98.1% of all resected tumors had free distal, proximal and radial margins. Regional lymphadenectomy provides important prognostic and therapeutic information that guide the adjuvant treatment. In a systematic review, the number of lymph nodes evaluated after the surgical resection was positively associated with survival of patients classified as Stage II and Stage III for colon cancer9. Established guidelines recommend that at least 12 lymph nodes should be analyzed for a proper staging10-12. The American Society of Clinical Oncology (ASCO) encourages the use of adjuvant chemotherapy in patients with colon cancer and negative lymph nodes if the surgical specimen has less than 12 lymph nodes13. Although the use of adjuvant chemotherapy has not been established in Stage II patients, in our study, 66.7% of 349


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CONCLUSION

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clude that most of them are reaching an advanced stage of the disease. However, the methods employed have provided a curative surgical treatment in our oncology patients.

After evaluating the characteristics of patients with colorectal cancer treated in our service, we con-

Resumo: Objetivo: O objetivo do presente estudo é demonstrar o panorama atual do câncer colorretal em um hospital público da capital do Rio Grande do Sul, enfocando aspectos relacionados ao diagnóstico, estadiamento e terapêutica cirúrgica abordada nesses respectivos pacientes. Métodos: Estudo descritivo e retrospectivo que inclui os pacientes com câncer colorretal internados pelo Serviço de Coloproctologia do Hospital Conceição durante o período de janeiro de 2009 a maio de 2011. Resultados: Foram estudados 61 pacientes, 65,6% mulheres. A idade variou de 40 a 84 anos. Realizaram colonoscopia 58 pacientes, desses 56,9% apresentavam mais de 50% de comprometimento da luz do cólon. O antígeno carcinoembrionário (CEA) foi coletado em 59 pacientes, 47,5% apresentavam CEA>5 ng/mL. Metástases à distância foram encontradas em 23,3% do total de 60 pacientes avaliados. Foram submetidos a tratamento cirúrgico 58 pacientes, desses a intenção curativa foi em 84,5%. A presença de mais de 12 linfonodos por peça foi de 73,1%. Os 61 pacientes estudados foram estratificados como 9,8% estádio I, 29,5% estádio II, 29,5% estádio III e 31,1% estádio IV. Conclusão: O perfil dos pacientes tratados em nossa instituição é de doença avançada; entretanto, os métodos curativos empregados têm ido ao encontro de um tratamento cirúrgico oncológico adequado. Palavras-chave: neoplasias colorretais; cirurgia colorretal; SUS.

REFERENCES

12. Otchy D, Hyman NH, Simmang C, Anthony T, Buie WD, Cataldo P, et al. Practice parameters for colon cancer. Dis Colon Rectum 2004;47(8):1269-84. 13. Benson AB 3rd, Schrag D, Somerfield MR, Cohen AM, Figueredo AT, Flynn PJ, et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004;22(16):3408-19. 14. Benson AB III, Schrag D, Somerfield MR, Cohen AM, Figueredo AT, Flynn PJ, et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004;22(16):3408–19. 15. Locker GY, Hamilton S, Harris J, Jessup JM, Kemeny N, Macdonald JS, et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol 2006;24(33):5313-27. 16. Macdonald JS. Carcinoembryonic antigen screening: pros and cons. Semin Oncol 1999;26(5):556-60. 17. Palmqvist R, Engarås B, Lindmark G, Hallmans G, Tavelin B, Nilsson O, et al. Prediagnostic levels of carcinoembryonic antigen and CA 242 in colorectal cancer: a matched casecontrol study. Dis Colon Rectum 2003;46(11):1538-44. 18. Van der Schouw YT, Verbeek AL, Wobbes T, Segers MF, Thomas CM. Comparison of four serum tumour markers in the diagnosis of colorectal carcinoma. Br J Cancer 1992;66(1):148-54. 19. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin 2009;59(4):225-49.

1.

Andrade SMS, Pereira FL. Câncer colorretal sincrônico - relato de caso e revisão de literatura. J Coloproctol 2007;27(1):69-79. 2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60(5):277-300. 3. INCA. Estimativa 2010 – Incidência de câncer no Brasil [cited 2011 Feb. 22]. Available from: http://www.inca.gov.br/ estimativa/2010. 4. Wills JC, Burt RW. Hereditary aspects of colon cancer. Ochsner J 2002;4:129-38. 5. Eddy DM. Screening for colorectal cancer. Ann Intern Med 1990;113(5):373-84. 6. Obrand DI, Gordon PH. Continued change in the distribution of colorectal carcinoma. Br J Surg 1998;85(2):246-8. 7. Greene FL, Page DL, Fleming ID, Fritz A, Balch CM, Haller DG, et al (Eds). AJCC (American Joint Committee on Cancer). Cancer staging manual. 6th ed. New York: Springer; 2002. p. 113. 8. Nelson H, Petrelli N, Carlin A, Couture J, Fleshman J, Guillem J, et al. Guidelines 2000 for colon and rectal cancer surgery. J Natl Cancer Inst 2001;93(8):583-96. 9. Chang GJ, Rodriguez-Bigas MA, Skibber JM, Moyer VA. Lymph node evaluation and survival after curative resection of colon cancer: systematic review. J Natl Cancer Inst 2007;99(6):433-41. 10. Compton CC, Fielding LP, Burgart LJ, Conley B, Cooper HS, Hamilton SR, et al. Prognostic factors in colorectal cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 2000;124(7):979-94. 11. McGory ML, Shekelle PG, Ko CY. Development of quality indicators for patients undergoing colorectal cancer surgery. J Natl Cancer Inst 2006;98(22):1623-33.

Correspondence to: Gabriel Volpato Travessa Vileta 230, apto 701, Jardim Botânico CEP 90690-150 – Porto Alegre (RS), Brazil E-mail: volpatinho@hotmail.com

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Original Article

Prototype system to manage data on coloproctology surgery HUEI DIANA LEE1, WILSON JUNG2, ADRIELI CRISTINA DA SILVA3, LUIZ HENRIQUE DUTRA DA COSTA2, BIANCA ESPINDOLA4, CLÁUDIO SADDY RODRIGUES COY5, JOÃO JOSÉ FAGUNDES5, FENG CHUNG WU6 Professor and Doctor at the Computer Science course and in the Post Graduation Program of Dynamic Systems and Energy engineering (PGESDE) and general coordinator at the bioinformatics laboratory (LABI) of the Universidade Estadual do Oeste do Paraná (UNIOESTE) – Foz do Iguaçu (PR), Brazil; Visiting professor in the Post Graduation Program of Surgical Sciences at the School of Medical Sciences of Universidade Estadual de Campinas (UNICAMP) – Campinas (SP), Brazil. 2 Student at PGESDE; Member of the LABI at UNIOESTE – Foz do Iguaçu (PR), Brazil. 3Member of the LABI at UNIOESTE – Foz do Iguaçu (PR), Brazil. 4Student in the Post Graduation Program of UNICAMP – Campinas (SP), Brazil. 5Professor and Doctor of the Department of Surgery, the Service of Coloproctology and the Post Graduation Program of Surgical Sciences at the School of Medical Sciences of UNICAMP – Campinas (SP), Brazil. 6Professor participating in the Post Graduation Program of Surgical Sciences of UNICAMP – Campinas (SP), Brazil; Professor and Doctor of UNIOESTE and coordinator of the Medical Department of LABI at UNIOESTE – Foz do Iguaçu (PR), Brazil. 1

LEE1 HD, JUNG W, SILVA AC, COSTA LHD, ESPINDOLA B, COY CSR, FAGUNDES JJ, WU FC. Prototype system to manage data on coloproctology surgery. J Coloproctol, 2011;31(4): 351-361. ABSTRACT: Objective: To develop a prototype system to manage data on coloproctology surgery, aiming at Data Quality (DQ) and the adoption of a DQ monitoring process, which is nonexistent in most biomedical systems. Methods: The construction of the prototype was separated into five steps: analysis of an existing system (legacy), the analysis of requirements and specifications for the new prototype, the development of the model, definition of technologies and the development of a prototype. Results: The analysis of the legacy system revealed several limitations and inconsistencies, which can result in problems concerning the DQ. Therefore, actions to prevent these problems are already being executed at the step of developing the prototype, such as the creation of interactive and more elaborate interfaces, the use of validation mechanisms on data fields and the proposal of a process to monitor inconsistencies and incompleteness in patients’ data. Conclusion: The adoption of DQ mechanisms on system development results in building a reliable and consistent database, to assist tasks such as management, scientific research and future intelligent data analysis methods. Future work includes subjective evaluations of DQ indicating the adequacy of the prototype for the users’ needs. Keywords: colorectal surgery; data collection; data analysis; information systems; data mining.

INTRODUCTION

which is the main raw material for scientific research, besides being essential for decision making. According to this point of view, in the health field it is necessary to manage information on different aspects of a patients for the performance of a surgical procedure; more specifically, in coloproctology, this specialty comprises various diseases that can be treated with surgery, such as cancer, adenomatous polypo-

Technology has been increasingly contributing by assisting the different activities in various fields, pushing the development of human knowledge. Among the different technological contributions, information systems have an important role concerning data management, since they feed databases with information,

Study carried out at the Bioinformatics Laboratory (LABI) of Universidade Estadual do Oeste do Paraná (UNIOESTE) – Foz do Iguaçu (PR), Brazil. Coloproctology Service of the School of Medical Sciences at Universidade Estadual de Campinas (UNICAMP) – Campinas (SP), Brazil. Financing source: Aid by the scholarship financing programs: National Council for Scientific and Technological Development (CNPq) and Itaupu Technological Park Foundation (FPTI-BR). Conflict of interest: nothing to declare. Submitted on: 08/08/2011 Approved on: 09/09/2011

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sis, Chron’s disease, among others1-6. Thus, an information system may significantly contribute with the management of data concerning surgery, that is, pre-, inter and postoperative periods, enabling the construction of a solid and organized database. In order to assist in a more complete analysis of the great volume of data created by the information systems, computer processes such as Data Mining (DM) can be used, since they aim to discover knowledge or interesting standards, which are not difficult to obtain when conducted by the non-automatic data analysis7. However, so that these data can be used, both for decision making and for the application of DM processes, it is important that the data that are present in the information systems be a faithful representative of the facts8. Low-quality data can harm any process that uses them, and the adoption of corrective measurements leads to high costs for the institutions9. Problems with data quality are not only characterized by data inconsistency, but also by how useful the information is(1). Therefore, Data Quality (DQ) can be defined as the information that has less inconsistencies and that is adequate to the purposes of the users10. The variety of possible DQ problems is huge. However, the problems have characteristics that allow their classification as to perspective, user and data, and to the depending or not on the context10, according to the following requirements: • Data perspective/regardless of the context: problems that may be present in any database, such as spelling mistakes, duplicated data and incorrect values; • Data perspective/depending on the context: problems that violate the specifications of the business, that is, rights and restrictions of a specific domain that define the norms of the system; • User perspective/depending on the context: problems concerning data processing, such as inaccessible, insecure data and those that are difficult to recover; • User perspective/regardless of the context: problems that indicate that data are not adequate to the purposes of the user, such as incomplete data,

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those that are irrelevant to the activities and difficult to understand. In order to assist the evaluation of DQ, there are different dimensions in literature to represent the characteristics of data11-15. Among the most cited dimensions, the accuracy characterizes the faithful representation of real world facts by data obtained by the information systems. Completeness, on the other hand, characterizes the complete representation of the states of an entity in the real world, which are necessary for the user’s needs. There is also the consistency dimension, which shows the presence of redundant data or the consistency between two related elements, such as address and postal code. Concerning data timing, the punctuality dimension shows the data that are up-to-date and available to meet the users’ needs at a proper time. As to the level of credibility and truth of the facts, it is characterized by the credibility and the relevance dimension, which characterize the level of applicability and assistance that the data can offer to meet the users’ needs. Thus, the evaluation of DQ uses the existing dimensions associated with metrics, which represents the problems with DQ to quantify the level of quality of the specific characteristics of data. Nowadays, the Coloproctology service at the School of Medical Sciences (FCM) of Universidade Estadual de Campinas (UNICAMP) uses a system developed with Microsoft Acess(2) to register the surgeries performed in this service. However, this system, which was later called the legacy system, presents limitations and inconsistencies, thus not meeting all the users’ needs, which impacts directly on the quality of the stored data. The objective of this study is to present the development of a prototype to manage data on coloproctogy surgery that offers a proper structure to the processes that use it; it also aims to create a vast data base with DQ. Thus, these data can be used for the administrative control and also for academic research; the latter is performed by the use of DM processes by health professionals, together with informatics professionals. It is interesting to point out that the proposal of this system includes a process to monitor DQ, which is still uncommon in biomedical systems, which aim to minimize the presence of wrong information in databases, thus performing the validation of fields in the

In this study, the terms data and information are indistinctively used. http://office.microsoft.com/

1 2

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interface and the emission of alerts and reports on inconsistencies and lack of patients’ data16. This study is part of the project of Intelligent Data Analysis, which is developed in a partnership between the Bioinformatics Laboratory (LABI) and Universidade Estadual do Oeste do Paraná (UNIOESTE), Foz do Iguaçu, the Coloproctology Service of FCM, in UNICAMP, The Laboratory of Computer Intelligence (LABIC), of Universidade de São Paulo (USP), São Carlos, and the Interdisciplinary Group in Data Mining and Applications (GIMDA), of Universidade Federal do ABC (UFABC), São Paulo.

3. 4. 5.

In order to develop the prototype, consolidated methods of software engineering, such as prototype and the incremental development17;18. The prototype model, as represented in Figure 1, enables the development of a system with the construction of prototypes in continuous interactions with users, thus obtaining the complete system17. The incremental model also adopts the interactive philosophy of prototype. A set of functions is added to each version of the system, which are called increments, starting with the essential elements until the system is complete, that is, after the performance of all increments18. The project of this system was organized in five main steps: 1. Analysis of the legacy system; 2. The gathering of requirements for the prototype;

Prototype’s review

Development of models and prototype screens; Definition of Technologies to be used; Development of the prototype.

In step (1), the legacy system was analyzed, thus mapping the structure of the system to identify the set of previously collected information, the existing limitations and the possible flaws that can have a negative interference in DQ. Figure 2 represents a high level vision of the legacy system. In this figure, it is possible to observe that the item patient is related with the other items of the legacy system. However, one of the limitations in the system of is that it accepts the registration of only one surgery and a set of preoperative examinations per patient. Based on the analysis of step (1), step (2) was characterized by the definition, concluded by experts in the medical and informatics fields, of the basic necessary requirements for the new system: • Control of access to the system: only authorized people can access the patients’ data; • Organization of the information: the system should have a friendly interface and provide information according to the classic elements of medical propaedeutics19; • Mobility and easy access: the system should provide mobility to the health professionals, so that the access does not depend on the geographic position or on the computer that is being used; • Data quality: the system should have mechanisms to assist the monitoring of the quality of data inserted into it.

METHODS

Review’s list

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Review’s list

Review’s list

Prototype project

Prototype system

User’s review

Prototype requirements System’s requirements

Test Delivered system

Figure 1. Prototype Modelmodified from 17.

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40 items Preoperative Examinations 14 items

6 items

Outpatient Evolution

Reoperation 19 items Patient

5 items

19 items

Hospital Evolution

Surgery 5 items Pathology Figure 2. Model of high level data in the legacy system.

other information concerning his or her origin (nationality), religion and data on blood type and RH factor. Afterwards, the occurrence section is comprised of data related to one surgery, so it is possible to register as many occurrences as necessary for each patient. The data in this section are organized in different subsections, such as: • Personal history: data on diseases, such as diabetes mellitus, hypertension and neoplasm, social and eating habits of the patient; • Diagnosis: data on coloproctological disease; • Preoperative examinations: data on laboratory, imaging and clinical examinations in the preoperative period; • Surgery: data on performed surgical procedures; • Postoperative: data on hospital and outpatient follow-up related to the respective occurrence. As mentioned, it is possible to register many occurrences for each patient, and each of them can be identified by date and time by the responsible doctor. Finally, the Family history section consists of data that identify the family characteristics of the person, such as the number of brothers, children, if there is has a twin sibling or if the person is adopted.

Besides the presented requirements, additional items were defined that were not present in the legacy system. The proposed prototype is composed of approximately 446 items (Figure 3) in comparison with the 108 items of the legacy system (Figure 2). On step (3), the models were created to represent the entities of the new system and its relations, as demonstrated in Figure 3, providing a high level view of the prototype. In this step, the screen prototype was developed, which enabled the previous definition of the structure of the system, its functions and the distribution of information. This step consisted of continuous interactions among experts in the medical and informatics field, so that all the requirements of the prototypes could be met. Thus, the information concerning the patients that is managed by the prototype is organized into three sections: • Identifying the patient; • Occurrence; • Family history. The identification section of the patient is comprised of data that allow the identification of a patient, as well as 354


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5 items

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75 items

Doctor

Postoperative

17 items 10 items Patient

Sugery

25 items Occurence

73 items Diagnosis

7 items Family History 103 items Personal History

131 items Preoperative Examinations

Figure 3. Model of high level data of the prototype.

models established in step (3). The development of the prototype was followed-up by experts in the medical field.

In step (4), the technologies used to develop the project and to make th prototype work were defined. These opensource technologies were: 1. Implementation: The Ruby programming language(3), which is a programming language focused on simplicity and productivity, and the framework for web development Ruby on Rails(4), provides the fast development of applications; 2. Application server: Apache application server(5), widely used for web applications, together with the plugin Passenger(6), which allows the installation of Ruby applications in Apache servers. 3. Database: system to manage the database (SGBD) PostgreSQL(7), which guarantees the integrity of the stored data.

RESULTS This paper led to study the viability of adopting DQ measurements during the development of a biomedical system, which is not so common in existing systems and significantly contributes with the creation and the maintenance of a quality database20-22. From a previous bibliographic analysis, it was possible to define characteristics that contribute with the DQ, and also that helps to put them into practice during the process to develop a prototype to manage data on coloproctological surgery. The system modelling was conducted by experts in the medical and informatics fields, resulting in the structure of the system represented in Figure 3; this enables the organized and loyal representation of the processes and information concerning the patients and their occurrences. In Figures 4, 5, 6 and 7, examples of prototype screens developed according to the requirements and models defined in steps (2) and (3).

In step (5), the prototype was developed with the help of Technologies presented in step (4) according to the http://www.ruby-lang.org/ http://rubyonrails.org/ 5 http://www.apache.org/ 6 http://www.modrails.com/ 7 http://www.postgresql.org/ 3 4

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Figure 4. Screen to access the system.

Figure 5. Screen for the initial registration of data.

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Figure 6. Screen to consult patients’ data.

Cirurgia indicada Hemorroidectomia clássica Esfíncterotomia Esfíncterotomia subcutânea lateral Fissurectomia posterior clássica Retopexia, operação de Delorme Colectomia direita Retossigmoidectomia (operação de Dixon) Ressecção abdomino-perineal do reto (cirurgia de Milles) Colectomia subtotal Colectomia total Cadastrar nova cirurgia Figure 7. List of possible values for the field “cirurgia indicada” (Indicated surgery).

Figure 4 shows the result of the implementation of mechanisms to control the access, so that the system can only be accessed by authorized people, thus assuring the privacy of the patients’ data. The users can only be registered by people with administrative privileges. After registering in the system, the user can access the list of patients and doctors, according to the privileg-

es given to his account by the administrator, by the fields showing on the left side of the screen. For example, in Figure 5, the screen to register the information concerning the occurrences of one patient is presented. It is important to say that these data are fictitious, used only to show the functions of the system. The style adopted for this screen is also used in the other sectios of the system. 357


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After finishing the registration, it can be consulted in the screen represented in Figure 6, which is similar to the registration screens; however, its only purpose is to show the information. In the fields in which predefined values can be inserted, as represented in Figure 7, there are mechanisms that enable the user to select the value or to register a new value, in case the wanted item is not listed.

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It is also important to point out that DQ positively influences the application of the DM process23, resulting in more reliable models and reducing the time of the data preprocessing step, which is the most difficult in the process7. Because of the presented issues and the importance of DQ for the processes that use them, steps (2) and (3) resulted in the project of a prototype to manage data on coloproctological surgery. As a guide to properly build this prototype, the Electronic Health Records Certificate (Manual de Certificação para Sistemas de Registro Eletrônico em Saúde), approved by the resolution 1821/07 of the Federal Council of Medicine24, presents several guidelines for the development of the project. Initially, it was defined that the prototype would be a web system, in order to make update and maintenance of the system easier, since they would be centralized in the server. Another advantage of choosing a web system is the mobility for the health professional, since he or she can access the system regardless of their geographical location or computer – only a web navigator would be necessary. The development of a prototype was also accompanied by medical experts, who suggested some improvements in the implemented functions, characterizing the interaction process that occurs with the prototype and the incremental development used as software process models. The programming language used to develop the prototype, as described in step (4), is the Ruby language, accompanied by the framework for the web development of Ruby on Rails. A programming language that allows the logic of the program to be developed in an understandable way, that would be later translated into computer instructions. A framework, on the other hand, can be defined as a set of library codes and mechanisms to enable the development of activities they are destined to25. The Ruby on Rails framework particularly allows the automation of different tasks during creation, installation and maintenance projects of a web system, enabling the fast development of applications26. It was built to solve 80% of the problems that are present in the web development, considering that the other 20% depend on the context of the application25. Another characteristic of this framework is the presence of mechanisms that assist the validation of graphic interface fields, establishing standards for the data to be inserted by the us-

DISCUSSION The analysis of the legacy system conducted in step (1) showed many limitations and inconsistencies that can lead to problems in DQ. The mentioned system was developed as an emergency solution to register data concerning the performed coloproctological surgeries. Thus, its modeling does not properly reflects the needs of the clinical and surgical processes represented by the data in the patients’ medical records. The data model of the legacy system, presented in Figure 2, enables to verify the relationship between the entities in this system. In this model, a patient can be only submitted to one surgery, and only one set of preoperative examinations can be registered. The item Reoperation registers patients’ recurrences, but it does not allow the registration of results of preoperative examinations related to the recurrence. Much important information that characterize the clinical picture of the patients do not have specific fields for registration, thus, it is necessary that professionals register these data in the observation fields. The data in these observation fields are in natural language, which is easy to understand; however, it is more difficult to apply the processes of analysis, like DM, besides being more prone to typos. Also, the legacy system does not have a friendly interface or security mechanisms that prevent non authorized people from accessing data; its structure is not adequate to store a great volume of data, and does not provide the possibility for the remote access to the system. Figure 3 represents the relation of the items in the proposed prototype, and it is possible to observe that, unlike the legacy system, the information on a surgery is gathered in the item Occurrence, which is also related to a doctor. Besides, the additional items enable a complete representation of the characteristics and conditions associated with the occurrences of patients, and also contribute with future applications of processes, such as DM. 358


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ers25. Besides, this framework provides mechanisms to develop test routines to assess the proper implementation of the functions of the system. Another important aspect of the project is the concern about DA in the step of prototype development [step (5)]. Thus, the functions offered by the Ruby on Rails framework also contribute with this purpose. In literature, a great part of the solutions for DQ problems are addressed to corrective methods. These methods are important because they imply high costs to the institutions. Thus, it is better to reach balance between preventive and corrective measurements9. As a preventive measurement of DQ, the project of the system also aims the implementation of processes to support the constant monitoring of the quality level of the system’s data, thus enabling the adoption of corrective measurements, if necessary, before the problems are spread and result in serious conflicts20. The monitoring process also aims to help the health professional to identify data inconsistencies, indicating records with problems. Thus, the professional can count on more reliability for decision making based on data. Another impact factor for DQ is the presence of pleasant and organized graphic interfaces in the system, so the users can easily access the system. Poor graphic interfaces may result in frustrating experiences for the users, who may leave blank or incorrect fields27. Because of this, the information will be hierarchically organized in the new system, providing an environment that is more structured to insert data. Also, mechanisms that allow to hide non used data were adopted, resulting in a cleaner and more pleasant interface, and also making the location of specific information easier. The prototype presented in this study was designed to get a larger volume of structured information to represent the patients’ characteristics. When the set of values for the fields is known, mechanisms that present the relation of possible values for that field were used, thus allowing the user to choose the proper value, as presented in Figure 7. Such mechanisms help to reduce inconsistencies and typos, contributing with DQ. If the desired value is not in the presented list, it is possible to register a new value, that will be later included in the list. It is important to say that the proposed prototype presents some special functions, aiming to facilitate

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and stimulate the use of the system. For instance, we could cite the assistance of the semiautomatic filling, with the confirmation of personal history by a health professional after the first occurrence. These data are recovered from the base of previous occurrences, so the user does not need to reinsert the information that is already in the system – it is only necessary to update the information in case there is any change. To complement the DQ solution, another important function is the registration of operations in the system by a determined user, thus helping to identify the cause of problems, if they occur. CONCLUSION Considering the impact that DQ problems can cause, the adoption of measurements that help to prevent these problems is very relevant, since it increases the reliability of the system and has a positive impact on the processes that use it. Despite the careful planning to develop the new system and its characteristics, the users also need to be aware and carefully insert the data. It is important to point out that the process of DQ monitoring enables the adoption of corrective measurements that are necessary in a proper time, before any problems can be spread, thus avoiding the origin of serious conflicts. This differential does not exist in most biomedical systems, helping to build a structured data base that can be used for simple consultations and for scientific research; for example, methods for an intelligent analysis in DM, as well as statistical analysis, can be used. In the next step, the prototype will be improved, and the data of the legacy system will migrate and be adjusted to the new system, thus minimizing the impact and becoming more pleasant to the users. Afterwards, a subjective DQ assessment of the built prototype will be performed, leading to the analysis of adapting to the needs of the users, as well as making adjustments, if necessary. ACKNOWLEDGEMENTS To the National Council for Scientific and Technological Development (CNPq) and Itaipu Technological Park Foundation (FPTI-BR), for the support by the scolarship financing. 359


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Resumo: Objetivo: Desenvolvimento de um protótipo para gerenciamento de dados de cirurgia coloproctológica, visando à Qualidade de Dados (QD), e a adoção de um processo de monitoramento da QD, inexistente na maioria dos sistemas biomédicos. Métodos: A construção do protótipo foi dividida em cinco etapas: análise de um sistema existente (legado), levantamento dos requisitos para o novo protótipo, elaboração de modelos, definição das tecnologias e desenvolvimento do protótipo. Resultados: A análise do sistema legado revelou diversas limitações e inconsistências que podem resultar em problemas de QD. Sendo assim, medidas para prevenir esses problemas estão sendo adotadas, já na etapa do desenvolvimento do protótipo, como a criação de interfaces mais elaboradas e interativas, a utilização de mecanismos de validação dos campos de dados e a proposta de um processo para monitoramento das inconsistências e incompletudes dos dados dos pacientes. Conclusão: A adoção de medidas de QD no desenvolvimento de sistemas resulta na construção de uma base de dados confiável e consistente, contribuindo com as tarefas de gerenciamento, pesquisas científicas e futuras aplicações de métodos de análise inteligente de dados. Trabalhos futuros incluem avaliações subjetivas de QD que indiquem o nível de adequação do protótipo às necessidades dos usuários. Palavras-chave: cirurgia colorretal; coleta de dados; análise de dados; sistemas de informação; mineração de dados.

REFERENCES

In: Proceedings of the 12th International Conference on Information Quality. Cambridge: MIT; 2007. p. 76-91. 11. Wand Y, Wang RY. Anchoring data quality dimensions in ontological foundations. Commun ACM 1996;39(11):86-95. 12. Lee YW, Strong DM, Kahn BK, Wang RY. AIMQ: a methodology for information quality assessment. Information & Management 2002;40(2):133-46. 13. Pipino LL, Lee YW, Wang RY. Data quality assessment. Communications of the ACM 2002;45(4):211-8. 14. Lee YW, Pipino LL, Funk JD, Wang RY. Journey to data quality. Cambridge: MIT Press; 2006. 15. Batini C, Scannapieco M. Data quality: concepts, methodologies and techniques. Berlin: Springer-Verlag; 2006. 16. Jung W, Lee HD, Silva AC, Costa LHD, Espindola B, Coy CSR, et al. Adoção de medidas de qualidade de dados para o desenvolvimento de sistemas biomédicos. In: X Conferência Brasileira de Dinâmica, Controle e Aplicações - Dincon 2011. Águas de Lindoia, Brasil; 2011. 17. Pfleeger SL. Engenharia de software: teoria e prática. 2nd ed. São Paulo: Prentice Hall; 2004. 18. Pressman RS. Engenharia de software. 5th ed. Rio de Janeiro: McGrawHill; 2002. 19. Porto CC. Exame clínico. Rio de Janeiro: Guanabara Koogan; 1982. 20. Salvador VFM, Britto M, Moura Junior LA, Almeida Junior JR. Qualidade de dados para gestão de conhecimento na área de saúde. In: Anais do X Congresso Brasileiro de Informática em Saúde. Florianópolis, Brasil; 2006. 21. Fadel FDQ, Malucelli A, Bastos LC. Prontuário eletrônico para pacientes de hanseníase via web. In: X Congresso Brasileiro de Informática em Saúde. Florianópolis, Brasil; 2006. p. 1462-7. 22. Herzberg S, Rahbar K, Stegger L, Schäfers M, Dugas M. Concept and implementation of a computer-based reminder system to increase completeness in clinical documentation. Int J Med Inform 2011;80(5):351-8. 23. Blake R, Mangiameli P. The effects and interactions of data quality and problem complexity on classification. JDIQ 2011;2(2):8.

1. Valarini R, Campos FGCM. Resultado do registro nacional brasileiro em vídeo-cirurgia colorretal em 2007. J Coloproctol 2008;28(2):145-55. 2. Martins JF, Rocha JG, Miranda EF, Sartor MC, Steckert JS, Steckert AS, et al. Análise da prevalência de entidades coloproctológicas nos pacientes idosos do serviço de coloproctologia de um Hospital Universitário. J Coloproctol 2009;29(2):145-57. 3. Torres Neto JR, Souza JRMCA, Santiago RR, Prudente ACL. Cirurgias colorretais no Hospital Universitário da Universidade Federal de Sergipe: três anos de criação do serviço de coloproctologia (série histórica). J Coloproctol 2008;28(1):77-83. 4. Prudente ACL, Torres Neto JR, Santiago RR, Mariano DR, Vieira Filho MC. Cirurgias proctológicas em 3 Anos de serviço de coloproctologia: série histórica. J Coloproctol 2009;29(1):71-6. 5. Queiroz FL, Côrtes MGW, Rocha NP, Alves AC, Freitas AHA, Lacerda Filho A, et al. Resultados do registro de cirurgias colorretais videolaparoscópicas realizadas no estado de Minas Gerais - Brasil de 1996 a 2009. J Coloproctol 2010;30(1):61-7. 6. Oliveira RG, Faria FF, Lima JRACB, Rodrigues FG, Andrade MMA, Gomes DMBM, et al. Cirurgias êntero-colorretais – abordagem cirúrgica de 129 pacientes do SUS no programa de pós-graduação Sensu Lato em coloproctologia. J Coloproctol 2010;30(3):333-43. 7. Han J, Kamber M. Data mining: concepts and techniques. 2nd ed. San Francisco: Elsevier; 2006. 8. Orr K. Data quality and systems theory. Communications of the ACM 1998;41(2):66-71. 9. Guerra-García C, Caballero I, Piattini M. A systematic literature review of how to introduce data quality requirements into a software product development. In: 5th International Conference on Evaluation of Novel Approaches to Software Engineering. Athens, Greece: 2010. 10. Ge M, Helfert M. A Review of information quality research.

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Protótipo de um sistema para gerenciamento de dados de cirurgia coloproctológica Huei Diana Lee et al.

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Correspondence to: Huei Diana Lee Laboratório de Bioinformática (LABI) Universidade Estadual do Oeste do Paraná (UNIOESTE) Parque Tecnológico Itaipu (PTI) Av. Tancredo Neves, 6731, Caixa Postal: 39 – CEP 85856-970 – Foz do Iguaçu (PR), Brazil E-mail: labi.unioeste@gmail.com

24. Conselho Federal de Medicina. Resolução CFM Nº 1.821/07 [Internet]. 2007. Available from: http://www.portalmedico. org.br/resolucoes/CFM/2007/1821_2007.htm 25. Carneiro Junior C, Al Barazi R. Beginning rails 3. Berkely: Apress; 2010. 26. Ruby S, Thomas D, Hansson DH. Agile web development with rails. 4th ed. Raleigh: Pragmatic Bookshelf; 2011. 27. Maydanchik A. Data quality assessment. Bradley Beach: Technics Publications, LLC; 2007.

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Original Article

Evaluation of quality parameters of rectal cancer surgery at the Coloproctology Unit of Hospital de Braga MAFALDA ARAÚJO PIMENTA DE CASTRO1, SANDRA FÁTIMA FERNANDES MARTINS2,3 Medical Student of the School of Health Sciences at Universidade do Minho, campus of Gualtar – Braga, Portugal. Hospital Assistant of Surgery at the Coloproctology Unit of Hospital de Braga. 3Assistant at the Life and Health Sciences Research Institute of the College of Health Sciences at Universidade do Minho, campus of Gualtar – Braga, Portugal. 1

2

CASTRO MAP, MARTINS SFF. Evaluation of quality parameters of rectal cancer surgery at the Coloproctology Unit of Hospital de Braga. J Coloproctol, 2011;31(4): 362-371. Abstract: Introduction: Rectal cancer (RC) represents 1/3 of all diagnosed colorectal cancers. After the creation of specialized units to treat RC, it became fundamental to establish criteria to assess the quality of the service. Objective: To evaluate the surgical treatment provided to RC patients at the Coloproctology Unit of Hospital de Braga (BH-CU) by means of quality parameters. Methods: We conducted an observational cross-sectional descriptive study with a convenience sample of 149 patients undergoing surgical treatment in this unit, from January 1st, 2007 to June 30, 2010. Results: We observed that the postoperative mortality rate (4%) and the global dehiscence rate (14.8%) were in accordance with recommended values. Sphincter sparing surgery rate (65.8%) was higher than the recommended minimum; however, more than 12 resected ganglia (36.6%) is inferior than what is recommended. The oncological results were analyzed by the local recurrence rate (6.7%) and the two-year survival rate (91.1%); both values are in accordance with literature. Conclusion: We conclude that the BH-CU surgical treatment has a quality level similar to that observed in literature. Keywords: rectal cancer; functional coloproctology unit; quality parameters of surgical treatment.

INTRODUCTION

the introduction of tracking programs with the population aged more than 50 years9. In Portugal, according to the National Institute of Statistics, CCR is the second most common cancer and the main cause of death due to neoplastic disease10. It is more common in urban centers, such as Lisbon, Porto and Setubal11. To the north of Portugal, data from Registro Oncológico Regional do Norte (RORENO) show that CCR was the most prevalent cancer in 2005 for both genders, and the second cause of death due to cancer, after lung cancer12,13. Rectal cancer (RC) makes up to 1/3 of the total number of diagnosed cases of CCR14. Even though the north of Portugal presents an incidence rate of 24.8/100,000 inhabitants, which is higher to the incidence in Europe (21.2/100,000 inhabitants), the five-year survival rate (53%) has a much closer value to the European mean (53.2%)12. The therapeutic approach to RC has been through significant changes in the past decades, going

Colorectal cancer (CCR) is the third most common cancer and ranks the fourth position as a cause of death by cancer worldwide1-3. Its incidence is geographically varied, and there are higher rates in North America, Australia and Western Europe. The lower rates are in developing countries4, but the incidence in these countries5 has been increasing in the past few years. According to the World Health Organization (WHO), CCR is the second most common cancer in Europe, followed by lung cancer among males and breast cancer among females6. Despite the high incidence, data from WHO from 1997 to 2007 show that mortality caused by CCR decreased7. The reduction in mortality rates was mainly due to the advances in knowledge concerning the molecular mechanisms that are responsible for the development and progression of CCR8 and for

Study carried out at the Hospital de Braga, Coloproctology Unit, Braga, Portugal. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 06/05/2011 Approved on: 06/13/2011

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from a merely surgical treatment to a multidisciplinary approach15; however, despite the aforementioned advances, surgical exeresis is still essential16, since it is the only potentially curative treatment nowadays. There are currently many therapy options related to the location of the cancer; thus, the performance of an anterior rectal resection (ARR) for superior rectal tumors is indicated; a low anterior rectal resection with coloanal anastomosis is indicated for inferior rectal tumors17. As to the latter, since this procedure has risk of dehiscence, it is established that is should be complemented with protective ileostomy18. The abdominoperineal resection (APR) is currently limited; it is recommended for tumors that present with sphincter infiltration, for cases of fecal incontinence prior to tumoral symptomatology and elderly patients with associated comorbidity that does not allow an anastomosis. The same happens with the Hartmann’s operation (HO), which is performed when there are factors that contraindicate anastomosis that would enable the preservation of the sphincters with a safe distal margin17. Also, the local transanal resection is only indicated for tumors that are limited to the mucosa and the submucosa (T1N0M0), with no lymphovascular invasion, well or moderately differentiated, with less than 3 cm in diameter and located up to 8 cm from the anal margin (AM)17. One of the great advances in the past decades, in terms of surgical treatment for CR, was the introduction of the concept of total mesorectal excision (TME). Heald et al. showed the importance of TME in the two lower thirds of the rectum, with dissection under direct visualization and preservation of the nervous plexus. The introduction of TME enabled the reduction of local recurrence rates for values of 6%, with a fiveyear survival rate of 80%, and ten-year survival rate of 78%15. The decrease in local recurrence rates was due to the fact that TME enabled the resection of RC with a negative circumferential margin19. This technique has also led to the improvement in pathological staging of cancer, as well as in the quality of life of the operated patient because of the reduction in the incidence of vesical dysfunction and sexual impotence14. The concept of margin is important to be considered in resection with a curative intent. Regarding RC, we should consider the distal, proximal and radial margins, in which the currently accepted values are 1 cm, 5 cm and 1 mm, respectively. The involvement of these margins is associated with increased locore-

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gional recurrence; more specifically, the involvement of the radial margin is associated with a recurrence risk of 56 – 80%, with a five-year survival rate, decreasing from 79 to 40%20. Another margin to be considered is the distal margin of the mesorectal dissection, which has an important prognostic value and should be 5 cm distal to the tumor, once it showed the presence of tumor niche 2 to 3 cm below the tumor17. As to the surgical treatment of RC, together with negative resection margins, a proper lymphadenectomy is the most important aspect21. In this context, it is important to perform a proper lymphadenectomy, with resection of at least 12 ganglia; besides reducing the risk of lymphatic invasion, it also prevents the substaging of the tumor22. Despite the improvements observed in the recurrence rate of the resectable RC, the local recurrence is still an issue in cases of locally advanced fixed rectal cancer. The current strategy to treat such cases is multidisciplinary23. The primary therapy enables to increase respectability, decrease the locoregional recurrence rate and improve the survival of the patient19,23. Thus, the initial treatment for locally advanced RC (T3-4 or N+) consists of the administration of chemotherapy and primary radiotherapy16,19. The creation of units that are specialized in treating RC contributed with better results, since it improved the preoperative staging by using: the pelvic magnetic resonance and endoluminal ultrasound; the primary therapy after establishing the dose and proper times of application24 in cases of locally advanced RC; the implementation of TME as a qualified technique to assess the obtained results22; and the establishment of standards concerning anatomopathological tecniques24. According to a study conducted in the United States, these changes are reflected in the decreased local recurrence rate, from 9.6 to 6.9%25. In a study group from Norway, the implementation of TME showed a decrease in the local recurrence rate, from 12% to 6%, and the survival rate after four years increased from 60% to 73%. The same happened in a randomized study conducted in the Netherlands, in which the local recurrence rate after two years was significantly lower in patients submitted to surgery and radiotherapy (2.4%) than in the group treated only with surgery (8.2%)16. Due to this evolution, many European countries, such as Germany, Sweden and Spain, showed the need to define new quality 363


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standards, with the minimum required values, which are essential for the evolution of the diagnosis, staging and treatment of RC, for beyond the ones that are usually used, such as morbidity and mortality22,24,26. By studying large samples, some indicators have been established to enable the evaluation of surgical quality concerning the RC treatment; these can be divided into general and specific criteria, and criteria that study oncologic results27. General criteria are: postoperative mortality rate, which should be inferior to 5%, ideally between 2 and 3%24,27, and the global dehiscence rate, whose required value lies between 10 and 15%22,24,27. Regarding the sphincter sparing surgery rate, it is recommended to be higher than 65%24,27, and the number of cases with more than 12 resected ganglia should be higher than 75%22; both are considered to be specific criteria. Finally, the criteria that study the oncologic results are assessed by the local recurrence rate, that should be lower than 10%22,24,27, and the ideal value for the survival rate after two years is between 70 and 80%24,25. Besides the aforementioned, these indicators enable a proper evaluation of quality in assistance, because it accounts for the final health status of the patient and its functional capacity24.

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that did not undergo surgery, or those in which the derivative stoma was performed. Sample A convenience sample of 149 patients diagnosed with RC was used, respecting the inclusion/exclusion criteria previously established. Methods and data collection Before data collection, the work was submitted to and approved by the Ethics Committee of Hospital de Braga. A prospective database of patients diagnosed with RC was consulted; it consisted of sociodemographic data, location of the tumor, treatment of choice, number of resected ganglia, resection margins, presence of postoperative morbidity and data related to the follow-up period as the date of local recurrence and death. Statistical analysis All statistical analyses were performed with the 18.0 version of the software Package for the Social Sciences, (SPSS Inc. R, Chicago, Illinois, USA). A simple descriptive analysis of all the variables was conducted by defining the total number of cases and the absolute and relative frequencies for valid cases. As for the treatment of continuous quantitative variables (age, distance to anal margin and number of resected ganglia) central tendency (mode and mean) and dispersion (standard deviation [SD]) were measured.

OBJECTIVE To assess the surgical treatment given to patients with rectal cancer in the Coloproctology Unit of Hospital de Braga, from January 1st, 2007, and June 30, 2010, according to quality standards.

RESULTS

METHODS

Sample caracterization From January 1st, 2007, and June 30, 2010, 164 patients with RC were treated at the Coloproctology Unit of Hospital de Braga. At first, 15 patients were not eligible for the study, once they were in no conditions to be submitted to surgery (n=7) or in case they had been submitted to the isolated performance of a derivative stoma (n=9). Thus, after the establishment of exclusion criteria, 149 patients were included in the study, that is, 91% of the patients that had been initially identified. As to gender distribution, we observed that 57% of the patients (n=85) were males, and 43% (n=64) were females. Mean age was 68±12 years; among females, it was 66±13 years, and for males it was 70±11

Population The study population was comprised of patients treated for RC from January 1st, 2007, to June 30, 2010, at the Coloproctology Unit of Hospital de Braga. This study considered as “rectal cancer” all the cases of histopathological diagnosis of adenocarcinoma, located up to 15 cm from the anal margin, measured with the rigid sigmoidoscopy. Inclusion criteria were: patients with histological diagnosis of rectal adenocarcinoma submitted to surgery (local resection, anterior rectal resection, low anterior rectal resection or abdominoperineal resection). Exclusion criteria were: patients with histological diagnosis of rectal adenocarcinoma 364


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years. Mode was equal to 80 years. After observing the age group analysis, we noticed that most cases, 35.6%, occurs between the ages of 70 and 80 years (n=53) (Figure 1). The most common location of RC was the medium rectum, in 53% of the cases, followed by the lower and upper rectum, in 27.5 and 19.5% of the cases, respectively (Table 1). The mean distance to the anal margin was 8.5±4.3 cm. After staging, 27.5% (n=41) of the patients underwent primary therapy followed by surgery; out of these, chemoradiotherapy was used in 25.5% of the patients (Table 2).

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40% 35%

Percentage

30%

Evaluation of surgery quality parameters

25% 20% 15% 10%

Type of surgery Concerning the performed surgeries, 98.7% (n=147) were elective, and 93.3% (n=139) of the cases, it had a curative intent. The most common surgery was the low anterior rectal resection, 30.2% (n=45), followed by the abdominoperineal resection (22.1%) (n=33). As demonstrated in Table 3, 65.8% of the surgeries were classified as “Sphincter Sparing Surgery”.

5% 0%

30-40 40-50 50-60 60-70 70-80 80-90 Age Groups

Figure 1. Distribution of the “Age” variable by age groups.

Anastomotic dehiscence Out of the 149 studied cases, 22 presented with postoperative morbidity classified as “anastomotic dehiscence”. In this group, 9 patients needed surgical reintervention. After crossing the variables “type of surgery” and “anastomotic dehiscence”, it was possible to show that the low anterior rectal resection is the surgical procedure that presents the highest global anastomotic dehiscence rate, with 6.8% of the cases; out of these, 3.4% were conservatively treated, and the other 3.4% needed surgical reintervention (Table 4). After analyzing the global dehiscence rate along the years of the study, we observed that 2007 and 2009 presented the highest percentage, with 4.7% of the cases; in 2010, this value decreased (Figure 2). Out of the 22 patients who presented with anastomotic dehiscence, only 1 (0.7%) was submitted to primary radiotherapy.

Table 1. Characterizing the variable “Anatomical Location”. Anatomical Location Absolute N° (n) Frequency (%) Superior rectum 29 19.5 Medium rectum 79 53.0 Inferior rectum 41 27.5 Total 149 100.0

Table 2. Characterizing the variable “Primary Treatment”. Primary Treatment Absolute N° (n) Frequency (%) No primary 108 72.5 treatment CT + RT 38 25.5 CT 1 0.7 RT 2 1.3 Total 149 100

Postoperative mortality The postoperative mortality rate was 4.0% (n=6). From these patients, 3 presented with postoperative morbidity characterized as anastomotic dehiscence; two were submitted to conservative treatment, and one underwent surgery.

CT: chemotherapy; RT: radiotherapy.

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Table 3. Characterizing the variable “Type of surgery”. Type of Surgery Absolute n° (n) Frequency (%) Sphincter Sparing Surgery Low anterior rectal resection 45 30.2 65.8 % Anterior rectal resection 28 18.8 Low anterior rectal resection + ileostomy 21 14.1 Local Resection 4 2.7 Hartmann’s operation 18 12.1 34.2 % Abdominoperineal resection 33 22.1 Total 149 100.0 CT: chemotherapy; RT: radiotherapy

Percentage

Table 4. Crossing variables “Type of surgery” and “Anastomotic dehiscence”. Absolute n°(n) Dehiscence – Conservative treatment 13 Low anterior rectal resection 5 Abdominoperineal resection 5 Low anterior rectal resection + ileostomy 3 Dehiscence – Surgical treatment 9 Low anterior rectal resection 5 Abdominoperineal resection 4 Low anterior rectal resection + ileostomy 0 Total 22

Frequency (%) 8.8 3.4 3.4 2 6.0 3.4 2.6 0 14.8

Number of analyzed ganglia The mean of analyzed ganglia (gg) was 11±7 ganglia, the median was 9.5 and the mode was 6 ganglia. The analysis of 12 or more ganglia was only observed in 36.6% of the cases (n=49); in the other 63.4% (n=85), an inferior number of ganglia were analyzed. Out of the 41 cases submitted to primary therapy, 70.7% (n=29) presented a number of analyzed ganglia inferior to 12. From the 85 cases with less than 12 analyzed ganglia, 29 cases (34.1%) had primary therapy.

5.0% 4.7% 4.7% 4.5% 4.0% 4.0% 4.0% 3.5% 3.0% 2.7% 2.0% 2.5% 2.0% 2.0% 2.0% 1.4% 1.5% 0.7% 1.0% 0.7% 0.7% 0.5% 0.0% 2007 2008 2009 2010

Locoregional recurrence The global recurrence rate was 6.7% (n=10). The patients submitted to primary therapy presented an inferior recurrence rate, 1.3%, in relation to those who underwent isolated surgery (5.4%).

Dehiscence – Global Dehiscence – Surgical treatment Dehiscence – Conservative Treatment

Survival after 2 years The survival rate after 2 years was 91.9% in the studied sample.

Figure 2. Evolution of the variable “Anastomotic dehiscence”.

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DISCUSSION

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Concerning the treated patients, it was observed that males are more affected, in 57% of the cases, and that 92.4% of the cases are comprised in age groups older than 50 years, which is in accordance with literature1,3,37. As to the location of the RC, our studied showed that 53% of the cases were in the medium rectum, which is similar to findings from studies conducted in Germany, Spain and the United States of America, in which 40 to 55% of the cancers had this anatomical location22,25,38. The administration of primary therapy is currently essential to approach locally advanced RC or with ganglion invasion, since it increases the possibility of resection, decreases the locoregional recurrence rate and increases survival rates23. In this study, after staging, 27.5% (n=41) of the patients underwent primary therapy followed by surgery. Concerning the performed surgeries, 93.3% (n=139) of the cases had curative intent, which is higher than the values found in literature, that shows values such as 91.5% in Norway28, 83% in Sweden39 and 64% in the Netherlands40. This result can be due to the fact that we are located in a region with high incidence of colorectal cancer; this is why patients have been tracked for the past few years, which enabled  the early diagnosis, as well as the relation between the functional unit and the health centers; this way, patients were rapidly referred. The most common surgery in the coloproctology functional unit was the low anterior rectal resection (30.2%), which is in accordance with rates found in literature, of 39.5%38 and 47.3%23. As to the parameter “sphincter sparing surgery”, in Sweden and Spain the recommended values are higher than 70%24,39 of the performed surgery; in Norway and the Netherlands, the ideal value is between 65 and 70%28,40. The result was 65.8%, which is close to the minimum value required in these studies. This value can be explained because the ultralow anterior rectal resection is not performed with coloanal anastomosis, and also because of the high percentage of cases in comparison to other series of performed Hartmann’s operation, 12.1% (n=18). Out of these patients, only one was submitted to urgent surgery; the others underwent elective surgery, in which the “sphincter sparing” resection could be performed, but due to the old age of the patients (mode of 80 years), with comorbidities associated with sphincter malfunctions, it

The treatment of RC has progressed for the past few decades15, and this progress is mostly due to the creation of functional units that are specifically directed to this pathology24. Many European countries, such as Norway, the Netherlands, Germany, Sweden, France, Denmark and Spain, have been working to define new quality standards to establish minimum required values for the surgical treatment of RC22,24,26,28-32. The requirement for the creation of coloproctology functional units is based on many studies that demonstrate that the treatment of patients with specific diagnoses, such as RC, is better in hospitals that receive a lot of cases of this pathology; and although it might sound true, this may be more related to specific characteristics of the surgeon than to the number of cases in the hospital33,34. In Europe, it is acknowledged that the surgeon factor, especially the technique, the ability and the practice, are essential and influence the results of the treatment for RC35. Thus, the sub specialization of colorectal surgeons who are especially trained and have performed a high number of surgeries, is one of the most important predictors of quality concerning colorectal surgery33,34. In 2006, Rogers et al. suggested at least 13 rectal resections per surgeon as the minimum value required for maintaining the certificate in colorectal surgery for a period of 4 years, and in hospitals that have at least 84 surgeries of this type during this period34. In Sweden, as in this study, Martling et al. observed that the high number of surgeries is associated with better results, and defined that a group reaches such classification when each surgeon performs at least 12 rectal resections in a year36. In Portugal, there are many coloproctology functional units; however, there are few studies that evaluate quality standards. So, this study aims to audit the quality of the health care service that is present at the functional units of Hospital de Braga in order to provide a work base that allows its improvement. After analyzing the data concerning the functional units of Hospital de Braga, from January 1st, 2007, to June 30, 2010, 164 patients with RC were treated, and since the unit had three surgeons, these values are clearly above the suggested by the two aforementioned studies34,36 for the performance of RC surgery, so to offer quality standards to these patients. 367


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was chosen to perform a definitive stoma in order to avoid the high risk of fecal incontinence. The rate of abominoperineal resections performed was 22.1% (n=33), which is within the limits described in literature, from 22 and 27%41, strongly influenced by the number of patients in the center. For tumors that are under the 8 cm from the anal margin, the described values range from 44.6 to 44.8%41. This rate has been considered as one of the reliability criteria of the functional units41-43; however, such criteria are being discussed41,42, since they depend on the percentage of RC located in the inferior 1/3 of the rectum that each unit presents; in this study, it was 27.5% of the cases. Concerning the postoperative morbidity analysis, we chose to only characterize the anastomotic dehiscence since it is the main cause of morbimortality of rectal resection35. Values of 15%24 are described in Spanish studies, but other countries presented inferior numbers: 9% in Sweden39, 10% in Germany, 10% in Norway28, and 12% in the Netherlands40. The first issue we face to compare values concerning the coloproctology functional units at Hospital de Braga with data presented in literature is the definition of this concept. Except for the German study, none of the others define “anastomotic dehiscence”. This problem is registered in literature, since there are many studies related to dehiscence values; a review conducted by Bruce et al. on the incidence of anastomotic dehiscence post colorectal surgery analyzed 97 studies, in which 57 different definitions of anastomotic dehiscence were defined by the need of surgical reintervention, clinical findings or radiological criteria, thus making the comparison between studies more difficult44. In this study, the anastomotic dehiscence was defined as colorectal anastomotic failure, diagnosed by clinical or radiological criteria, with or without the need for the surgical treatment, which represents a total dehiscence rate of 14.8% (n=22); this value would decrease to 6% (n=9) in case only the patients who needed surgical reintervention were considered. When we analyze which “Type of surgery” presents the higher total dehiscence rate, we observe that the low anterior rectal resection is the highest, in 6.8% of the cases, which is in accordance with literature, since the risk of dehiscence depends on the level of anastomosis, among other factors, that is, bigger in the medium and inferior rectum45.

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Another important aspect in the data analysis is that the low anterior rectal resection with ileostomy presents the lowest total dehiscence value, 2%, and also that all the other cases (n=3) were treated without the new surgical intervention. Even though the primary therapy increases the risk of dehiscence, this study did not have enough data to establish such a relation45. Data obtained after the analysis of the evolution of the variable “anastomotic dehiscence” throughout the studied years are inconclusive. Annual values are very similar, however, a gradual increase in dehiscence cases that needed surgical reintervention was observed. This can be a result of lower anastomoses that are performed with the years, due to the accumulated experience, thus causing a higher risk of dehiscence. The lowest dehiscence value was observed in 2010, concerning the first six months of the year; although, there is a tendency to reduce such number. As to the postoperative mortality rate, according to countries like Sweden, Norway, the Netherlands and Spain, it should be around 2 and 3%24,28,39,40; however, this interval is not a consensus, and in Germany the recommendation is that it should be inferior to 5%22. In our study, the postoperative mortality rate was 4.0% (n=6) and, as described in literature, this rate is directly related to the anastomotic dehiscence rate, once it is the main cause of death at the postoperative for the colorectal patient24. Out of these six patients, three had anastomotic dehiscence, and one underwent a new surgery. Besides, other aspects are also important, especially the old age of most patients in the sample, which leads to low resistance to the intercurrences that occur during admission, as well as associated comorbidities25; thus, it was the cause of death for other 3 patients (respiratory failure, myocardial infarction and pulmonary edema). The evaluation of the ganglia involvement is essential for the staging of the RC, and significant correlations have been established between the number of analyzed ganglia and the survival of patients46. In order to study the number of analyzed ganglia, the cohort value was established based on criteria of different surgeon associations, which recommend the analysis of at least 12 negative ganglia41,46,47. This way, it is possible to confirm with 90% accuracy that the patient is free of lymphatic invasion38,48. In one of the studies conduct368


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ed in Germany, it was defined that more than 75% of the surgeries should have more than 12 analyzed ganglia; in Spain, the value presented for such indicator is around 71%22,38. In this context, the percentage of cases in which 12 or more ganglia were analyzed (36.6%) is lower than the minimum required value. Three types of factors can contribute with this value: the ones that depend on anatomy and on the biological conditions of the patient; the ones that depend on surgical technique; and the ones that depend anatomopathological technique48. Concerning the factors that depend on the patient, the anatomical factors stand out, with individual variations related to the number of lymphatic ganglia, the age of the patient, with the tendency to perform surgeries that are less aggressive in oncological terms, with the old age of the patients48 and the administration of the primary treatment, which causes the ganglia to decrease in size, thus making resection harder46. Concerning this last aspect in the analyzed study, 70% of the cases that were submitted to primary therapy presented a number of analyzed ganglia inferior to 12; however, they represent only 34.1% of the cases with less than 12 analyzed ganglia, thus, the low percentage cannot be only related to that fact. As to the surgical technique, the analysis of resection margins that led to the observation that out of the 164 operated patients, only one presented with radial margin invasion; with this, we concluded that a proper total mesorectal excision was performed, and that the lymphatic ganglia that were present in the mesorectum were completely removed; they might or might not have been accounted for. In literature, abominoperineal resection is described as the surgery with the lowest number of ganglia48. Since this surgery ranks in second place in our series as to the most performed surgeries, this might have contributed with the obtained results. Finally, these results can be justified by the anatomopathological technique, since this unit is still based on the classical model of visual identification and ganglion palpation, which is a slow and delicate process, and also, in 70% of the cases, ganglia have less than 5 mm in diameter and could easily go unnoticed during the resection process48. The locoregional recurrence of RC is one of the most feared situations, since it is usually inoperable and the patient could die slowly and painfully43. As 55 to 80% of the recurrence cases happen in the first two

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years after surgery49, the local recurrence rate in this period is one of the main indicators of the oncological results. The maximum value established for that rate is 10%, and it is presented by the Spanish series24; however, in decreasing order, we found the following values: 9% in the Netherlands40, 6% in Sweden28,39, and 4% in Norway28. In these three countries, this limit is lower for patients submitted to the primary treatment, and the minimum required value is between 1.5% and 2.4%28,39,40. In this area, the studied unit presents good numbers, with a local recurrence rate of 6.8%, subdivided into 6.1% of recurrence without primary treatment and 0.7% with primary treatment. CONCLUSION The periodic evaluation of quality standards concerning the surgery of RC is important in any coloproctology functional unit, since it enables internal monitoring, identifies the key points as to how to intervene for better results, and yet, at the same time, it enables to inform the patients in the unit about the expected results at the institution, instead of those in literature. In this study, quality standards were classified as: general, specific and those that study oncological results. Concerning general criteria, the postoperative mortality rate, 4%, and the global dehiscence rate, 14.8%, are within the values recommended in literature. In the category of specific criteria, the rate of sphincter sparing surgeries, 65.8%, was higher than the recommended limit; however, the rate concerning more than 12 resected ganglia, 36.6%, is lower than recommended. Finally, the analysis of oncological results was conducted by a local recurrence rate, 6.7%, and survival rate after two years, 91.1%, both within recommended values. With this study, we can observe that the values in this unit are within the values recommended in literature for most of the quality criteria. The exception, and one of the items that should receive short term investments, is the improvement of the anatomopathological characterization of the number of assessed ganglia. However, it is important to emphasize that with the rapid therapeutic advances, it is necessary to discuss and regularly rethink the minimum required values, as well as to define a limit of standards that are easy to calculate, so that the evaluation of the results by each of the surgeons in the unit can be a simple and periodic process. 369


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Resumo: Introdução: O câncer do reto (CR) constitui cerca de 1/3 da totalidade dos casos de câncer colorretal diagnosticados. Após a criação de unidades especializadas no tratamento do CR, tornou-se fundamental estabelecer critérios que permitam avaliar a qualidade do tratamento prestado. Objetivo: Avaliar, segundo parâmetros de qualidade, o tratamento cirúrgico prestado aos doentes com CR, na Unidade Funcional de Coloproctologia (UFC) do Hospital de Braga (HB). Métodos: Realizou-se um estudo observacional, transversal e descritivo com uma amostra de conveniência constituída por 149 doentes operados de CR entre 1º de Janeiro de 2007 e 30 de Junho de 2010. Resultados: Observou-se que a taxa de mortalidade pós-operatória (4%) e a taxa global de deiscência (14,8%) se encontram dentro dos valores recomendados. A taxa de realização de cirurgia poupadora de esfíncteres (65,8%) foi superior ao limite mínimo aconselhado; no entanto, a taxa de número de gânglios ressecados superior a 12 (36,6%), encontra-se aquém do exigível. Os resultados oncológicos foram analisados através da taxa de recidiva local, 6,7%, e da taxa de sobrevida aos 2 anos, 91,1%, ambos dentro dos valores propostos na literatura. Conclusão: Concluímos que o tratamento cirúrgico prestado na UFC do HB apresenta um nível de qualidade semelhante ao globalmente recomendado. Palavras-chave: câncer do reto; unidade funcional coloproctologia; parâmetros de qualidade do tratamento cirúrgico.

REFERÊNCIAS

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1. Svagzdys S, Lesauskaite V, Pavalkis D, Nedzelskiene I, Pranys D, Tamelis A. Microvessel density as new prognostic marker after radiotherapy in rectal cancer. BMC Cancer 2009;9:95. 2. Des Guetz G, Uzzan B, Nicolas P, ,Cucherat M, Morere JF, Benamouzig R, et al. Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Metaanalysis of the literature. Br J Cancer 2006;94(12):1823-32. 3. Brenner H, Hoffmeister M, Haug U. Should colorectal cancer screening start at the same age in European countries? Contributions from descriptive epidemiology. Br J Cancer 2008;99(3):532-5. 4. Center MM, Jemal A, Smith RA, Ward E. Worldwide variations in colorectal cancer. CA Cancer J Clin 2009;59(6):366-78. 5. Aljebreen AM. Clinico-pathological patterns of colorectal cancer in Saudi Arabia: younger with an advanced stage presentation. Saudi J Gastroenterol 2007;13(2):84-7 6. Neagoe A, Molnar AM, Acalovschi M, Seicean A, Serban A. Risk factors for colorectal cancer: an epidemiologic descriptive study of a series of 333 patients. Rom J Gastroenterol 2004;13(3):187-93. 7. Bosetti C, Levi F, Rosato V, Bertuccio P, Lucchini F, Negri E, et al. Recent trends in colorectal cancer mortality in Europe. Int J Cancer 2011;129(1):180-91. 8. Nagy VM. Updating the management of rectal cancer. J Gastrointestin Liver 2008;17(1):69-74. 9. Wilson JA. Colon cancer screening in the elderly: when do we stop? Trans Am Clin Climatol Assoc 2010;121:94-103. 10. Chaves FC. Rastreio e prevenção de tumores malignos. Lisboa: Permanyer Portugal; 2005. 11. Pereira CA, Henriques J. Cirurgia - Patologia e Clínica. 2a ed. Lisboa: Mc Graw-Hill; 2006. 12. Instituto Português de Oncologia do Porto. RORENO – Registo Oncológico Regional do Norte 2005. [Cited 2010 Sep 15]. Available from: http://www.ipoporto.minsaude.pt/NR/rdonlyres/C2A78C3F-1009-4F29-B9702D1A69F40DCE/15264/Roreno_05.pdf).

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Gastroenterol Hepatol 2005;28(7):417-25. 25. Phang PT, McGahan CE, McGregor G, MacFarlane JK, Brown CJ, Raval MJ, et al. Effects of change in rectal cancer management on outcomes in British Columbia. Can J Surg 2010;53(4):225-31. 26. Pahlman L, Bohe M, Cedermark B, Dahlberg M, Lindmark G, Sjödahl R, et al. The Swedish rectal cancer registry. Br J Surg 2007;94(10):1285-92. 27. Hortiz H. Standards of quality and instrumentation required for the laparotomic approach in the surgery of the lower rectum. Cir Esp 2003;74(6):321-4. 28. Wibe A, Moller B, Norstein J, Carlsen E, Wiig JN, Heald RJ, et al. A national strategic change in treatment policy for rectal cancer--implementation of total mesorectal excision as routine treatment in Norway. A national audit. Dis Colon Rectum, 45(7):857-66. 29. Phelip JM, Milan C, Herbert C, Grosclaude P, Arveux P, Raverdy N, et al. Evaluation of the management of rectal cancers before and after the consensus conference in France. Eur J Gastroenterol Hepatol 2004;16(10):1003-9. 30. Nesbakken A, Nygaard K, Westerheim O, Mala T, Lunde OC.. Local recurrence after mesorectal excision for rectal cancer. Eur J Surg Oncol 2002;28(2):126-34. 31. Iversen LH, Norgaard M, Jepsen P, Jacobsen J, Christensen MM, Gandrup P, et al. Trends in colorectal cancer survival in northern Denmark: 1985-2004. Colorectal Dis 2007;9(3):210-7. 32. Grossmann I, de Bock GH, van de Velde CJ, Kievit J, Wiggers T. Results of a national survey among Dutch surgeons treating patients with colorectal carcinoma. Current opinion about follow-up, treatment of metastasis, and reasons to revise follow-up practice. Colorectal Dis 2007;9(9):787-92. 33. Merlino J. Defining the volume-quality debate: is it the surgeon, the center, or the training? Clin Colon Rectal Surg 2007;20(3):231-6. 34. Rogers SO, Wolf RE, Zaslavsky AM, Wright WE, Ayanian JZ.. Relation of surgeon and hospital volume to processes and outcomes of colorectal cancer surgery. Ann Surg 2006;244(6):1003-11. 35. Codina-Cazador A, Espin E, Biondo S, Lujan J, de Miguel M, Alós R, et al. Audited teaching program for the treatment of rectal cancer in Spain: results of the first year. Cir Esp 2007;82(4):209-13. 36. Martling A, Cedermark B, Johansson H, Rutqvist LE, Holm T. The surgeon as a prognostic factor after the introduction of total mesorectal excision in the treatment of rectal cancer. Br J Surg 2002;89(8):1008-13. 37. Zavoral M, Suchanek S, Zavada F, Dusek L, Muzik J, Seifert B, et al. Colorectal cancer screening in Europe. World J Gastroenterol 2009;15(47):5907-15. 38. Sancho C, Villalba FL, Garcia-Coret MJ, Vazquez A, Safont MJ, Hernández A, et al. Self-evaluation of a clinical pathway to improve the results of rectal cancer. Cir Esp

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2010;87(4):231-8. 39. Martling AL, Holm T, Rutqvist LE, Moran BJ, Heald RJ, Cedemark B. Effect of a surgical training programme on outcome of rectal cancer in the County of Stockholm. Stockholm Colorectal Cancer Study Group, Basingstoke Bowel Cancer Research Project. Lancet 2000;356(9224):93-6. 40. Kapiteijn E, Putter H, van de Velde CJ. Impact of the introduction and training of total mesorectal excision on recurrence and survival in rectal cancer in The Netherlands. Br J Surg 2002;89(9):1142-9. 41. Rodriguez-Cuellar E, Ruiz Lopez P, Romero Simo M, Landa Garcia JI, Roig Vila JV, Ortiz Hurtado H. Analysis of the quality of surgical treatment of colorectal cancer, in 2008. A national study. Cir Esp 2010;88(4):238-46. 42. Ptok H, Marusch F, Kuhn R, Gastinger I, Lippert H. Influence of hospital volume on the frequency of abdominoperineal resection and long-term oncological outcomes in low rectal cancer. Eur J Surg Oncol 2007;33(7):854-61. 43. Simunovic M, To T, Baxter N, Balshem A, Ross E, Cohen Z, et al. Hospital procedure volume and teaching status do not influence treatment and outcome measures of rectal cancer surgery in a large general population. J Gastrointest Surg 2000;4(3):324-30. 44. Bruce J, Krukowski ZH, Al-Khairy G, et al. Systematic review of the definition and measurement of anastomotic leak after gastrointestinal surgery. Br J Surg. 2001;88:1157-1168. 45. Ferenschild FT, Dawson I, de Wilt JH, de Graaf EJ, Groenendijk RP, Tetteroo GW. Total mesorectal excision for rectal cancer in an unselected population: quality assessment in a low volume center. Int J Colorectal Dis 2009;24(8):923-9. 46. Sprenger T, Rothe H, Homayounfar K, Beissbarth T, Ghadimi BM, Becker H, et al. Preoperative chemoradiotherapy does not necessarily reduce lymph node retrieval in rectal cancer specimens--results from a prospective evaluation with extensive pathological work-up. J Gastrointest Surg 2010;14(1):96-103. 47. Wong SL. Lymph node counts and survival rates after resection for colon and rectal cancer. Gastrointest Cancer Res 2009;3(2 Suppl):S33-5. 48. Martinez-Ramos D, Escrig-Sos J, Miralles-Tena JM, Rivadulla-Serrano I, Salvador-Sanchís JL. Is there a minimum number of lymph nodes that should be examined after surgical resection of colorectal cancer? Cir Esp 2008;83(3):108-17. 49. Wiig JN, Odd S. Locoregional recurrence of rectal cancer, In: Surgical Treatment: Evidence-Based and ProblemOriented. Holzheimer RG, Mannick JA (Eds). Munique: Zuckschwerdt; 2001. Correspondence to: Sandra Martins Rua Monsenhor Ferreira, 28, 3º Esq 4710-407 – Braga, Portugal. E-mail: sandramartins@ecsaude.uminho.pt

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Case Report

Chagasic megacolon and large bowel neoplasms: case series and literature review MAXWEL CAPSY BOGA RIBEIRO1, RAQUEL FRANCO LEAL2, CLÁUDIO SADDY RODRIGUES COY3, PRISCILLA DE SENE PORTEL OLIVEIRA4, DÉBORA HELENA GONÇALVES ROSSI5, JOÃO JOSÉ FAGUNDES6, MARIA DE LOURDES SETSUKO AYRIZONO2 Resident of Digestive System Surgery in the School of Medical Sciences of Universidade Estadual de Campinas (UNICAMP) – Campinas (SP), Brazil. 2Doctor Professor of the Coloproctology Group in the subject of diseases of the digestive system in the School of Medical Sciences of UNICAMP – Campinas (SP), Brazil; Permanent at the Brazilian Society of Coloproctology. 3 Associate Professor and Coordinator of the subject of diseases of the Digestive System in the School of Medical Sciences of UNICAMP – Campinas (SP), Brazil; Permanente in the Brazilian Society of Coloproctology. 4Medical Assistant of the Coloproctology Group in the subject of diseases of the digestive system in the school of Medical Sciences of UNICAMP – Campinas (SP), Brazil; Associated to the Brazilian Coloproctology Society. 5Medical Assistant of the Coloproctology Group in the subject of diseases of the digestive system in the school of Medical Sciences of UNICAMP – Campinas (SP), Brazil. 6 Associate Professor of the Coloproctology Group in the subject of diseases of the digestive system in the School of Medical Sciences of UNICAMP Campinas (SP), Brazil; Permanent at the Brazilian Society of Coloproctology. 1

RIBEIRO MCB, LEAL RF, COY CSR, OLIVEIRA PSP, ROSSI DHG, FAGUNDES JJ, AYRIZONO MLS. Chagasic megacolon and large bowel neoplasms: case series and literature review. J Coloproctol, 2012;31(4): 372-377. Abstract: There is a clear association between chagasic megaesophagus and the esophageal cancer. On the other hand, the association between chagasic megacolon and intestinal neoplasm is uncommon. There are only a few cases described in literature. We selected two cases of colorectal adenocarcinoma associated with adenoma from 2000 to 2011, which are added to the four patients already described by this group. The mean age of the patients, was 68.5 years. Both had been submitted to surgical resection of the neoplasm. Survival rates ranged and were directly related to tumor staging at the time of diagnosis. In this context, we report our case series and reviwed the corresponding literature, especially the clinical and epidemiological aspects of this rare association. Keywords: megacolon; Chagas disease; adenocarcinoma.

Such association seems to be invalid, and even negative, for large intestine neoplasm and chagasic colopathy, due to the few described cases5,7,10,12. In endemic regions for Chagas disease, the incidence of colorectal cancer is about 0.1%1. From 1984 to 2011, in the Coloproctology Service of Hospital de Clínicas of Universidade Estadual de Campinas (UNICAMP), six cases of this rare association were described, the largest case series known, and four

INTRODUCTION The association between esophageal cancer and chagasic megaesophagus is very clear, indexes that range from 22.4 to 9.2%1-10. Chronic esophagitis secondary to eating cholestasis and the prolonged exposure of the esophageal mucosa to carcinogens that are present in the diet would be predisposing factors for this relation11.

Study carried out at the Coloproctology Service in the subject of Diseases of the Digestive System in the Department of Surgery of the School of Medical Sciences of Universidade Estadual de Campinas (UNICAMP) – Campinas (SP), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 07/27/2011 Approved on: 09/16/2011

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located in the rectosigmoid transition. The patient was submitted to total colectomy. The AP of the surgical piece showed 20 polyps distributed in the colon with no malignancy (Figure 3). She presented with postoperative evolution without intercurrences, and remains in outpatient follow-up, without intestinal complaints.

had already been reported12. We bring two cases that occurred in the last decade, their clinical and epidemiological aspects, besides the corresponding literature review. CASE REPORT Patient n° 1 A 58 year-old black woman with positive serology and medical record for Chagas disease reported history of intestinal constipation for 15 years, with many episodes of fecaloma. Thirty six months before, she complained of intermittent and painless enterorrhagia. She underwent enema, which showed megarectum and megasigmoid (Figure 1). Colonoscopy showed many polyps, and six were resected (Figure  2). The anatomopathological test (AP) showed intramucosal adenocarcinoma in one of the polyps,

Figure 2. Colonoscopy showing many polyps. Endoscopic resection for the anatomopathological study.

Figure 1. Enema demonstrating megarectum and megasigmoid.

Figure 3. Surgical piece with megacolon and many polyps.

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Chagasic megacolon and large bowel neoplasms: case series and literature review Maxwel Capsy Boga Ribeiro et al.

Patient n° 2 A 79 year-old white man with positive serology and medical record for Chagas disease reported history of intestinal constipation for a year, associated with recurring abdominal pain and poorly characterized. He also reported losing 11 pounds in this period. The colonoscopy showed ulcerative lesions in descending colon. The biopsy showed a moderately differentiated adenocarcinoma. The abdominal computed tomography showed dilated rectum and sigmoid, with a great amount of feces and image suggesting descending colon neoplasm, besides multiple hepatic lesions compatible with metastasis. Due to the bowel subocclusion, he was submitted to a segmental colectomy and primary anastomosis (Figures 4 and 5). He had a mixed shock (cardiogenic and pulmonary sepsis), leading to death on the 34th postoperative day due to multiple organ failure. Cases reported in literature concerning the association between chagasic megacolon and large intestine neoplasm are demonstrated in Table 1.

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Figure 4. Surgical piece with megasigmoid.

DISCUSSION The relation between chagasic megacolon and large intestine neoplasm is a paradox and also intriguing. First, fecal stasis would lead to chronic bowel irritation and to the prolonged exposure of the mucosa to the carcinogenic factors in the diet. On the other hand, the incidence of chagasic megacolon cancer in endemic regions for Chagas disease is only 0.1%1. Garcia and Garcia et al.13,14 experimentally induced megacolon with the topic application of benzalkonium chloride in the intestinal serosa of Wistar rats, and observed that these animals presented a lower incidence of tumors after being exposed to dimethylhydrazine. Oliveira and Oliveira et al.8,15 observed that Wistar rats chronically infected by Tripanossoma cruzi presented a lower frequency of benign and malignant chemically induced neoplastic colics. Studies with necropsies and surgical specimens confirmed these findings. Meneses et al.16 found only one case of colorectal cancer in 198 necropsies of patients with chagasic megacolon, and no cases in 129 surgical pieces from patients with chagasic colopathy. Garcia13, on the other hand, found one rectal adenocarcinoma out of the 802 studied surgical specimens.

Figure 5. Detail of the colic tumor adjacent to the dilated segment.

374


N.R. N.R.

1988 N.R.

1988 N.R.

1988 N.R.

1989 N.R.

1997

Rezende9

Lima16

Pucci16

Meneses et al.16

Oliveira et al.8

60

1999

375

64

2011

Presente trabalho Descending colon

Rectosigmoid

Sigmoid

Transverse colon

Rectosigmoid

Descending colon

Sigmoid

Sigmoid

Cecum

Transverse colon

Transverse colon

Rectum

Sigmoid

Rectosigmoid

Ascending colon

Location

Exploratory laparotomy

Hartman

Hartman

Right hemicolectomy

N.R.

N.R.

1 polyp in rectosigmoid

20 polyps in the colon

1 adenoma in sigmoid

1 adenoma in descending colon

TisN0M0

T1N0M0

T4N0M0

rectosigmoidectomy T3N1M1

Total colectomy

Duhamel-Haddad

Total colectomy

T4N3M1

T4N3M1

T4N1M0

Dukes C

Dukes C

T2N0M0

T2N0M0

N.R.

N.R.

N.R.

Necropsy finding

N.R.

N.R.

Staging

N.R.

N.R.

Surgery

5 adenomas in the Duhamel-Haddad left colon

No

No

No

No

No

No

No

Familial adenomatous polyposis

2 villous adenomas

N.R.

Association with adenoma

34 days

Much after 60 months

Much after 12 months

Much after 48 months

8 months

3 months

Much after 20 months

Much after 24 months

N.R.

9 months

7 months

N.R.

N.R.

N.R.

Survival

Presente série

8

3

7

11

26

21

21

21

21

Referência

Chagasic megacolon and large bowel neoplasms: case series and literature review Maxwel Capsy Boga Ribeiro et al.

N.R.: non reported; M: male; F: demale. The studies by Lima and Pucci were reported by Meneses et al.16

M

M

74

79

F

60

M

M

47

2002

Fagundes et al.12

58

F

60

2002

M

M

M

Adad et al.1

Crema et al.19

84

F

57

Gabriel-Neto et al.18 1998

M

64

N.R.

N.R.

Year Age Gender

Author

Table 1. Cases of association between chagasic megacolon and large intestine tumor. Journal of Coloproctology October/December, 2011 Vol. 31 Nº 4


Journal of Coloproctology October/December, 2011

Chagasic megacolon and large bowel neoplasms: case series and literature review Maxwel Capsy Boga Ribeiro et al.

Changes in the bacterial flora and intestinal pH, as well as in the composition of the affected intestinal wall that would lead to changes in the neurotransmitter and neuropeptide levels, have been studied as protective factors to the occurrence of neoplasms in these patients13,14,17,18. Concerning the described case series, mean age of our patients was 68.5 years, very close to that observed by Fagundes et al.12, in 2002; it is also close to the age group of colorectal cancer incidence in non-chagasic patients. Men were prevalent in the sample of the service. As to location, we observed that the distal large bowel was mostly affected, and one case was in descending colon, and the other in the sigmoid. Both described adenocarcinomas presented concomitant adenomas. A literature review showed a 36% incidence of adenoma in patients with chagasic megacolon and colorectal neoplasm12. Thus, adenoma seems to be also a risk factor for colorectal cancer in these patients. The surgery was related to the tumor location and staging. For patient 1, due to the high number of polyps distributed in the colon, the choice was total colectomy. In case 2, because of the presence of disseminated hepatic metastasis, as well as the clinical

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performance of the patient, the choice was a palliative partial colectomy. Generally, literature relates the worst prognosis to intestinal neoplasms that are incident in the chagasic megacolon. This would be related to the late diagnosis in these patients, once the colic dilatation could slow the appearance of obstructive symptoms. We still question if such tumors could not present more aggressive genetics, once they occur in an apparently inhospitable environment for the development of neoplasms. CONCLUSION The rarity of large intestine neoplasms in patients with chagasic megacolon does not justify the additional colonoscopic monitoring or the performance of enema in patients whose symptomatology does not indicate it. A high level of suspicion is demanded with the occurrence of any change in the clinical picture of patients with chagasic colopathy. Finally, more studies are necessary to clear up the factors that are really involved in the relation between chagasic megacolon and colorectal carcinogenesis.

Resumo: Há uma clara associação entre megaesôfago por doença de Chagas e o câncer esofágico. Ao contrário, tal relação, entre megacólon chagásico e neoplasias do intestino grosso é, reconhecidamente, incomum. Existem poucos casos relatados na literatura. Destacamos, entre 2000 e 2011, dois casos, sendo ambos adenocarcinomas colorretais e associados a adenomas, que se somam aos outros quatro já descritos por este grupo. A média de idade dos pacientes, foi de 68,5 anos. Todos foram submetidos à ressecção cirúrgica da neoplasia. A sobrevida foi variável e diretamente relacionada ao estádio do tumor no momento do diagnóstico. Dentro desse contexto, relatamos essa série de casos e revisamos a literatura correlata, com relação aos aspectos clínicos e epidemiológicos dessa rara associação. Palavras-chave: megacólon; doença de Chagas; adenocarcinoma.

REFERENCES

4.

Huggins D. Carcinoma do esôfago associado ao megaesôfago chagásico (relato de um caso). An Inst Hig Med Trop 1976;4:57-62. 5. Livstone EM, Skinner DB. Tumors of the esophagus. In: Berr JE (ed). Bockus Gastroenterology. 4th ed. Philadelphia: WB Saunders Co; 1985. p.814-840. 6. Lopes ER. Megaesôfago, megacólon e câncer. Rev Soc Bras Med Trop 1988;21:91-4. 7. Lustig ES, Puricelli L, Lansetti JC. Association of Chagas’ disease and cancer. Medicina 1980;40:43-6. 8. Oliveira EC. Associação entre infecção crônica pelo Trypanosoma cruzi e câncer de cólon. Estudo experimental em

1.

Adad SJ, Etchebehere RM, Araújo JR, Madureira AB, Lima VGF, Silva AA, et al. Association of chagasic megacolon and cancer of the colon: case report and review of the literature. Rev Soc Bras Med Trop 2002;35:63-8. 2. Abreu RB, Quaglieri P, Ribeiro MF, Corsi PR, Castro LT, Gagliardi D, et al. Megaesôfago: doença precursora do câncer de esôfago. Rev Bras Cirur 1990;80:91-4. 3. Brandalise NA, Andreollo NA, Leonardi LS, Callejas Neto F. Carcinoma associado a megaesôfago chagásico. Rev Col Bras Cir 1985;12:196-9.

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Chagasic megacolon and large bowel neoplasms: case series and literature review Maxwel Capsy Boga Ribeiro et al.

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SB, Luquetti AO, et al. Chronic Trypanosoma cruzi infection associated with low incidence of 1,2-dimethylhydrazineinduced colon cancer in rats. Carcinogenesis 2001;22:737-40. 16. Meneses ACO, Lopes MAB, Rocha A, Fatureto MC, Lopes GP, Lopes ER, et al. Megas e câncer. Câncer de intestino grosso em chagásicos com megacólon. Arq Gastroenterol 1989;26:13-6. 17. Gabella G. Size of neurons and glial cells in the intramural ganglia of the hypertrophic intestine of the guinea-pig. J Neurocyt 1984;13:73-84. 18. Gabriel-Neto S, Oliveira EC, Carmo FV, Conceição DC, Mendonça GG, Leite MSB, et al. Megacólon chagásico associado à adenocarcinoma de cólon. Rev Soc Bras Med Trop 1998;31:46-9. 19. Crema E, Lima VGF, Madureira AB, Adad SJ, Silva AA, Oliveira CB, et al. Associação de neoplasia obstrutiva com megacólon chagásico. J Coloproctol 1999;19:87-9.

ratos [Dissertação de Mestrado]. Goiânia (GO): Universidade Federal de Goiás; 1998. 9. Rezende JM, Rosa H, Vaz MGM, Andrade-Sá N, Porto JD, Neves Neto J, et al. Endoscopia no megaesôfago. Estudo prospectivo de 600 casos. Arq Gastroenterol 1985;22:53-62. 10. Rocha A, Almeida HO, Esper FE, Moraes DM, Santos EP, Teixeira VPA. Associação entre megaesôfago e carcinoma de esôfago. Rev Soc Bras Med Trop 1983;16:94-7. 11. Pinotti HW, Pollara WM, Gemperi R, Raia AA. O problema do câncer no megaesôfago. Rev Ass Méd Bras 1980;26:379-81. 12. Fagundes JJ, Góes JRN, Coy CSR, Ayrizono MLS, Mochizuki M, Chadu M, et al. Associação entre megacólon chagásico e câncer do intestino grosso: apresentação de casos e revisão da literatura. J Coloproctol 2002;22:252-6. 13. Garcia SB. O câncer no megacólon: estudos da incidência no homem e experimental em ratos [Tese de Doutorado]. Ribeirão Preto (SP): Faculdade de Medicina da Universidade de São Paulo; 1995. 14. Garcia SB, Oliveira JSM, Pinto LZ, Muccillo G, Zucoloto S. The relationship between megacolon and carcinoma of the colon: an experimental approach. Carcinogenesis 1996;17:1777-96. 15. Oliveira EC, Leite MSB, Miranda JA, Andrade AL, Garcia

Correspondence to: Maxwel Capsy Boga Ribeiro Av. Romeu Tórtima, 359, Cidade Universitária CEP 13000-001 – Campinas (SP), Brazil E-mail: maxwelboga@yahoo.com.br

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Case Report

Non-Hodgkin lymphoma as a cause of acute intestinal obstruction/perforation in patients with adenocarcinoma of the sigmoidcolon: a case report MARCELO PANDOLFI BASSO¹, ADRIANA BORGONOVI CHRISTIANO¹, LETÍCIA VIEIRA GUERRER², FRANCISCO DE ASSIS GONÇALVES-FILHO³, JOÃO GOMES NETINHO4 ¹Resident, Coloproctology, Hospital de Base da Faculdade de Medicina de São José do Rio Preto (FAMERP) – São José do Rio Preto (SP), Brazil. ²Resident, General Surgery, Hospital de Base da FAMERP – São José do Rio Preto (SP), Brazil. ³Assistant Physician, Coloproctology, Hospital de Base da FAMERP – São José do Rio Preto (SP), Brazil. 4Head of Coloproctology, Hospital de Base da FAMERP – São José do Rio Preto (SP), Brazil.

BASSO MP, CHRISTIANO AB, GUERRER LV, GONÇALVES-FILHO FA, NETINHO JG. Non-Hodgkin lymphoma as a cause of acute intestinal obstruction/perforation in patients with adenocarcinoma of the sigmoidcolon: a case report. J Coloproctol, 2011;31(4):378-381. Abstract: Report of a rare case of an 83-year-old patient with lymphoma of the terminal ileum causing obstructive/perforated acute abdomen synchronous with sigmoid colon adenocarcinoma and review of literature data about small bowel malignancies, particularly lymphomas. It seems to correspond to a rare disease (2% of all bowel cancers), more prevalent in elderly and immunocompromised patients, whose symptoms are vague and early diagnosis is difficult, often making it impossible to establish the correct therapy. Keywords: gastrointestinal neoplasm; lymphoma; adenocarcinoma; intestinal obstruction; intestinal perforation.

INTRODUCTION

ileum) as causes of low obstruction, both in order of decreasing frequency2. Perforated acute abdomen is the perforation of any hollow viscera resulting from inflammatory, infectious and/or neoplastic processes. In addition, it can have traumatic causes, including iatrogenesis. The main intra-abdominal places of gastrointestinal tract perforation are the stomach and duodenum, followed by colons and other small bowel regions3. Perforation of small bowel segments is considered a complication of intestinal inflammatory diseases, especially in the Crohn’s disease. This complication is more common in patients with ileitis or ileocolitis, with incidence of around 23%. The infectious causes (such as tuberculosis in its intestinal form) and neoplasms (1–5% of all gastrointestinal tumors) should also be taken into account4.

Acute abdomen refers to the group of signs and symptoms, especially pain, of an intra-abdominal disease, for which the surgical treatment is most indicated1. Obstructive acute abdomen is an urgent or emerging clinical situation caused by interrupted gastrointestinal flow. This condition is one of the most frequent acute abdominal diseases, associated with high morbidity and mortality rates, especially in case of late diagnosis or treatment start, and, in these circumstances, it may reach 20% mortality2. The main causes of intestinal obstruction vary with the level of obstruction, with brides and adhesions, internal hernia and large stomach tumors as causes of high obstruction, and colorectal diseases, volvulus and stenosis from intestinal inflammatory disease (terminal

Study carried out at the Hospital de Base da Faculdade de Medicina de São José do Rio Preto – São José do Rio Preto (SP), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted: 07/14/2012 Approved on: 08/03/2010

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Linfoma não-Hodgkin como causa de abdome agudo obstrutivo/perfurativo em paciente com adenocarcinoma de sigmoide: relato de caso Marcelo Pandolfi Basso et al.

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In patients with non-Hodgkin lymphoma, perforation or obstruction has been described, especially in the terminal ileum. However, this situation is uncommon2,4. CASE REPORT A.A.O., male, 83 years old, white, retired farm worker, formerly a smoker, was receiving multidisciplinary outpatient care due to systemic arterial hypertension, coronary artery disease, chronic kidney disease and chronic obstructive pulmonary disease. He had history of abdominal surgery to correct an aorta aneurism. The patient was admitted to another outpatient care in June 2008, due to a subocclusive acute abdomen, with improved conditions after a non-surgical treatment during the hospitalization, as well as episodes of hematochezia that started in January 2009. Without following the recommendations to investigate intestinal bleeding, the patient returned to the Emergency Service of the Hospital de Base in May 2009, reporting, one day before admission, strong abdominal pain in the mesogastric region, associated with vomiting, hyporexia, non-quantified weight loss, intestinal constipation, as well as occasional episodes of hematochezia, which had started 6 months before. The patient had with him the result of a recent colonoscopy made at another service, which showed a vegetative injury in the sigmoid colon, with no biopsy result. Three days after the symptoms appeared, the patient presented intense abdominal pain, abdominal distension and fecaloid vomiting (obstructive acute abdomen from probable neoplastic etiology), and was submitted to an emergency exploratory laparotomy. It showed neoplasm in rectum-sigmoid transition with macroscopic invasion of urinary bladder, without upstream colon distension, as well as presence of injury probably from the secondary graft in the terminal ileum, at approximately 15 cm from the ileocecal valve, associated with the obstruction, distension of the loops of small intestine and blocked perforation. The selected treatment was right-side enterocolectomy (Figures 1 to 3) and production of a Mickulicz ileotransversostomy, as well as exhaustive wash of the peritoneal cavity with physiological solution. The rectumsigmoid transition injury was not addressed due to the patient’s emergency situation, bladder size and invasion and as it was not the cause of the acute abdomen observed. The patient to the Intensive Care Unit in the immediate postop-

Figure 1. Resected terminal ileum segment, with apparent area of secondary graft.

Figure 2. Region of previously blocked perforation.

Figure 3. Intraluminal aspect of the injury.

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risk factor to be considered is the immunosuppression, especially the one caused by the human immunodeficiency virus (HIV), chemotherapies and/or corticotherapy. In addition, celiac disease presents increased risk for the development of primary lymphomas3,5. The intestinal invasion by lymphomas may not present specific symptoms and remain silent for a long time. Their initial manifestation can be obstruction or perforation (25%). In general, they present vague symptoms, common to other histopathological types: unclear abdominal pain, nauseas, alteration to the intestinal rhythm, anorexia and weight loss7. Gastrointestinal tract lymphomas are most of non-Hodgkin type. The diffuse lymphoma of large B cells corresponds to the most frequent histopathological and immunohistochemical type8, more prevalent in people in their 70s and older. The preoperative diagnosis is difficult, considering the insidious clinical manifestations that many times cause late search for specialized medical attention. In addition, given the similar symptoms and signs to other common diseases in the digestive tract, the correct diagnosis can only be obtained after the histomorphological and immunohistochemical analysis of the injury, many times after the patient is submitted to a surgical procedure. In contrast, the distinction between primary lymphomas and the secondary infiltration of the gastrointestinal tract can be made through a biopsy of the bone marrow or other organs under suspicion of being affected by the disease. When this procedure is not possible, the consolidated and accurate criteria of Dawson9 can be used: non-palpable peripheral lymphadenopathy, normal thorax radiography, leukometry with differential showing no alterations, injury affecting particularly the gastrointestinal tract – only regional lymph nodes, and not the liver or spleen. The presence of these four criteria indicates the primary origin of lymphomas. The case reported refers to an elderly patient with intermittent symptoms, suggesting a malign intestinal disease, confirmed through complementary exams (colonoscopy with biopsies). Emergency laparotomy showed the disease already well advanced locally in the sigmoid colon, as well as injury suggesting distance metastasis (terminal ileum), with signs of intestinal obstruction and perforation. The

erative period, progressed with clinical decompensation of comorbidities and died on the second postoperative day. The anatomopathological exam of the vegetating injury of the sigmoid observed in the colonoscopy showed a very differentiated and ulcerated tubular adenocarcinoma and the anatomopathological and immunohistochemical exams (Figure 4) of the injury in the distal ileum showed diffuse large B-cell lymphoma expressing immunophenotyping (CD20+). DISCUSSION The small bowel is rarely the place of neoplastic injuries, which represent only 1 to 5% of all gastrointestinal tract tumors4. The incidence of malign neoplasm is even lower, around 1 to 2%5. The terminal ileum is where malign injuries occur more frequently (50%), with the others equally occurring between the duodenum and the jejune. In contrast, the frequency of benign tumors seems to increase starting at the duodenum towards the ileum4,6. Only 10% of the large intestine tumors are symptomatic and the frequency of benign injuries is ten times the frequency of malign injuries4. Lymphomas are some of the malign neoplasms of the small bowel (7–25%). Primary lymphomas correspond to less than 2% of all intestinal tumors, with prevalence of intestine infiltration by neoplastic cells from other locations. The terminal ileum is the most common place of lymphoma occurrence, due to the higher concentration of lymphoid tissue associated with the intestine. The main

Figure 4. Histopathological aspect of the lymphoma in the terminal ileum.

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Linfoma não-Hodgkin como causa de abdome agudo obstrutivo/perfurativo em paciente com adenocarcinoma de sigmoide: relato de caso Marcelo Pandolfi Basso et al.

anatomopathological analysis of the resected intestinal segment showed a terminal ileum lymphoma synchronous with adenocarcinoma of the sigmoid colon. With no proper time for further investigations of the patient’s conditions and with the criteria of Dawson described above, we concluded that the lymphoma in the reported case was a primary lymphoma of the gastrointestinal tract, since it fulfilled all criteria established, and was synchronous with the neoplasms presented by the patient. Synchronization between intestinal neoplasms is frequent, especially in the case of sigmoid colon adenocarcinoma, and it should always be investigated10,11. The incidence of a second synchronous neoplasm with sigmoid colon adenocarcinoma, regardless of the histological type and the location in

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the gastrointestinal tract, ranges between 1 and 6.8% in general population10. CONCLUSION Small bowel neoplasms are rare, and the benign type is more frequent. Gastrointestinal tract lymphomas are among the malign injuries, primary or secondary to a neoplastic infiltration. The most frequent place of incidence is the terminal ileum, considering its histological peculiarities. Signs and symptoms are vague and unspecific, which makes early diagnosis and accurate treatment more difficult. However, these diseases should always be remembered and considered in the differential diagnosis of the various intestinal syndromes.

Resumo: Relato de caso raro de um paciente de 83 anos, com linfoma de íleo terminal causador de abdome agudo obstrutivo/perfurativo sincrônico à adenocarcinoma de cólon sigmoide e revisão dos dados disponíveis na literatura acerca das neoplasias de intestino delgado, em especial os linfomas. Constata-se que corresponde a uma afecção rara (2% de todas as neoplasias intestinais), mais predominante em pacientes idosos e imunodeprimidos, cuja sintomatologia é vaga e o diagnóstico precoce difícil, fato que impossibilita muitas vezes a instituição da terapêutica correta. Palavras-chave: neoplasia gastrointestinal; linfoma; adenocarcinoma; obstrução intestinal; perfuração intestinal.

REFERENCES

7. Rangel MF, Silva MVM, Fernandes MJC, Ferreira MAS, Nóbrega LPS, Souza MG. Tumores malignos do intestino delgado. Rev Col Bras Cir 2000;27(6):385-8. 8. Silva FE, Scofano V, Ascoly MH, Arakaki Jr N, Reis OCA, Silva Sá MAG. Fístula êntero-vesical como complicação de linfoma intestinal. J Coloproctol 2003;23(3):200-4. 9. Dawson IMP, Comes JS, Morson BC. Primary malignant lymphoid tumours of the intestinal tract. Report of 37 cases with study of factors influencing prognosis. Br J Surg 1983;49:80-9. 10. Jara RLS, Santos CHM, Alves LP, Miiji LNO. Tumor de reto e cárdia sincrônicos. Relato de caso e revisão da literatura. J Coloproctol 2007;27(1):80-2. 11. Santos CHM, Silva CN, Miiji LNO. Adenocarcinoma de cólon e carcinoma espinocelular de canal anal concomitante. Relato de caso e revisão da literatura. J Coloproctol 2005;25(2):162-4.

1. Postier RG, Squires RA. Abdome agudo. In: Townsend Jr CM, Beauchamp RD, Evers BM, Mattox KL, editors. Sabinston Tratado de cirurgia. 19a ed. Rio de Janeiro: Elsevier; 2009. p. 1108-25. 2. Sallum EA. Abdome agudo obstrutivo. In: Gama-Rodrigues JJ, Machado MCC, Rasslan S, editors. Clínica cirúrgica. Barueri (SP): Manole; 2008. p. 1071-8. 3. Silva AL, Barbosa CA. Obstrução intestinal aguda. In: Lopes AC, editor. Tratado de clínica médica. São Paulo: Roca; 2006. p. 1092-109. 4. Steinman E. Perfuração de víscera oca. In: Gama-Rodrigues JJ, Machado MCC, Rasslan S (Eds). Clínica cirúrgica. Barueri (SP): Manole; 2008. p. 1079-94. 5. Evers BM. Intestino delgado. In: Townsend Jr CM, Beauchamp RD, Evers BM, Mattox KL, editors. Sabinston - Tratado de cirurgia. 19a ed. Rio de Janeiro: Elsevier; 2009. p. 1201-51. 6. Torricelli FCM, Lopes RI, Dias AR, Marchini GS, Bonafe WW, Lopes JM, et al. Linfoma ileal primário como uma causa de intussuscepção ileocecal recorrente. J Coloproctol 2008;28(2):246-50.

Correspondence to: João Gomes Netinho Rua San Francisco, 481, Condomínio Débora Cristina CEP 15093-030 – São José do Rio Preto (SP), Brazil E-mail: jgnetinho@riopreto.com.br

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Case Report

Treatment of rectal leiomyoma by endoscopic resection RAFAEL DENADAI PIGOZZI SILVA1, ROGÉRIO SAAD-HOSSNE2, RAFAEL ALICEDA FERRAZ1, MARCUS DE MEDEIROS MATSUSHITA3, ROBERTO FALZONI4, FÁBIO VIEIRA TEIXEIRA5 Academicians, Medical School of Universidade de Marília – Marília (SP), Brazil. 2Assistant Professor, Physician at the Department of Surgery and Orthopedics of the Medical School of Universidade Estadual Paulista (UNESP) – Botucatu (SP), Brazil. 3Doctor and Professor, Department of Pathology of the Medical School of Universidade de Marília; Pathologist at the Associação Beneficente Hospital Universitário da Universidade de Marília (ABHU) – Marília (SP), Brazil. 4Technical Director, Service of Surgical Pathology of the Division of Anatomical Pathology at the Clinical Hospital of the Medical School of Universidade de São Paulo (HC-FMUSP) – São Paulo (SP), Brazil. 5Guest Professor, Doctor at the Department of Surgery and Orthopedics, Medical School of UNESP – Botucatu (SP), Brazil; Physician at UNIGASTRO – Marília (SP), Brazil. 1

SILVA RDP; SAAD-HOSSNE R; FERRAZ RA; MATSUSHITA MM; FALZONI R; TEIXEIRA FV. Treatment of rectal leiomyoma by endoscopic resection. J Coloproctol, 2011;31(4):382-386. ABSTRACT: Leiomyomas of the rectum are rare, with low reported incidence in literature. In most cases, patients are asymptomatic, and are often incidental endoscopic findings. The difficult distinction from leiomyosarcomas, associated with the possibility of recurrence, implies the absence of a standard treatment. Endoscopic resection, if well indicated, may be a therapeutic option. In this study, we report two cases of asymptomatic leiomyoma of the rectum in two patients, discovered incidentally during a routine colonoscopy, removed by conventional polypectomy and discuss its diagnostic and therapeutic aspects based on a literature review. Keywords: rectal neoplasm; leiomyoma; colonoscopy.

IntroduCTION

blood vessel walls4,12,16. They occur especially in the distal two-thirds of the rectum13,15 and tend to present intraluminal growth7. Most cases are asymptomatic1,9,10,17,18, and for this reason, found incidentally while performing endoscopic procedures1,3,5,9,10,16,18,19. The difficult distinction from leiomyosarcoma, associated with the possibility of recurrence, implies the absence of a standard treatment9,11. The purpose of this study was to report the authors’ experience with endoscopic resection in two cases of leiomyoma of the rectum found incidentally during a colonoscopy and discuss its diagnostic and therapeutic aspects based on a literature review.

Leiomyoma and leiomyosarcoma, tumors of smooth muscle, can occur in the whole gastrointestinal tract1-3, affecting more frequently organs such as the stomach (65%) and small bowel (25%)4 and rarely found in the rectum1,5-14. Leiomyoma of the rectum occurs in approximately 1 out of 2,000-3,000 rectal tumors4,8 and, although such occurrence is rare, many cases have been reported in the literature1,4-14 since its first histopathological confirmation described by Malassez in 18724. These tumors are originated in the smooth muscle fibers of mucosa or muscular fibers of the circular and longitudinal layers of the rectal wall4,8,12,15,16 or

Study carried out at the Service of Endoscopy, Digestive Tract Surgery and Coloproctology at UNIGASTRO, Associação Beneficente Hospital Universitário (ABHU) – Marília (SP), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 08//11/2010 Approved on: 10/27/2010

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Treatment of rectal leiomyoma by endoscopic resection Rafael Denadai Pigozzi Silva et al.

CASE REPORTS

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were elongated and regular, with delicate and evenly distributed chromatin, without evidence of necrosis. The second presented crossed-over bundles of smooth muscle cells in the submucosa, individually uniform, with elongated nuclei and smooth margins, located in the cell nuclei, with no areas of necrosis. In both dissected specimens, the margins did not present neoplasm, and no mitosis was observed in ten high-resolutions fields. At the immunohistochemical analysis, the tumors were positive for smooth muscle actin and desmin and negative for CD117 (c-kit) (Figures 2A-D). Both patients are now receiving outpatient care, with no symptoms and signs of local recurrence, as well as no colon lesions in colonoscopy examinations made in the follow-up period.

Report 1 A 39-year-old male patient, was sent for investigation of a lower gastrointestinal bleeding that had started one year before. He reported that the bleeding was sporadic after evacuating, noticed during anal cleansing, with streaks of blood on the toilet paper, without any other associated symptom. General and abdominal examinations showed no alteration. The proctologic examination showed firstdegree hemorrhoid. No tumor was evidenced with digital rectal examination. To better elucidate the situation, the patient was submitted to colonoscopy, which detected a sessile polypoid lesion, of smooth surface, around 4 mm diameter, with no alterations to the mucosa and no signs of lower rectal bleeding (Figure 1A). A loop polypectomy was performed, without complications. The patient was discharged one day after the procedure.

Polyp

Polyp

Report 2 A 56-year-old male patient came in with rectal pain at evacuation for 6 months. He reported burning sensation of moderate intensity, caused by evacuation and relieved after passing stool. He denied any history of bleeding or other associated symptoms. General and abdominal examinations showed no alteration. The proctologic examination showed a chronic anal fissure in the posterior midline. The digital rectal examination did not detect any tumor. Colonoscopy showed a sessile polyp of 5 mm diameter, smooth surface, no alterations to the mucosa and no signs of upper rectal bleeding (Figure 1B). The endoscopic resection of the lesion (loop polypectomy) was performed, without complications. The patient was discharged one day after the procedure. The two dissected specimens were submitted to an anatomopathological analysis. Macroscopically, they presented uniform whitish color and consistency. No area with necrosis or cystic alterations were observed. In both lesions, both showed in microscopy mucosa of colonic pattern without interruption. In the first, the glass plate showed proliferating smooth muscle cells, with relatively abundant cytoplasm, and arranged in crossed-over bundles. The nuclei

Lower rectum

A

B

Figure 1. Colonoscopy showing: (A) sessile polypoid lesion in the lower rectum, of smooth surface and around 4 mm diameter, with no alterations to the mucosa and no signs of bleeding; (B) sessile polyp in the upper rectum, of 5 mm diameter, smooth surface, with no alterations to the mucosa and no signs of bleeding.

A

C

B

D

Figure 2. Immunohistochemical blades of specimens endoscopically resected via rectum showing positivity for smooth muscle actin (case 1 - A and case 2 - B) and negativity for CD117 (c-kit) (case 1 - C and case 2 - D).

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DiscussION

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(size, number and layer it originated)1,7,11,14,18,21. It can also help distinguish benign from malign disease (rupture of normal tissue planes, cystic degeneration and lymphadenopathy)7,11,14,19. Differential diagnosis includes schwannomas, carcinoid tumors, neurofibroma, hemangioma, endometriosis, lipomas, melanoma, and especially gastrointestinal stromal tumors (GISTs) and leiomyosarcoma6,16,27. The distinction of these lesions is essential, as it affects the proper therapy selection14,19,27, as each lesion has specific clinical and pathological characteristics6,27. Histologically, leiomyomas differ from GISTs due to their uniform positivity in immunohistochemistry for smooth muscle actin and desmin and their negativity for CD34 and CD117 (c-kit), unlike the GISTs1,5,6,14,16,19,27. On the other hand, differing leiomyomas from leiomyosarcomas is often difficult2,7-9,13,14-16,19,21,25-28. In histology, leiomyosarcomas present differentiated smooth muscle cells6,14; most of them of high-degree type, with focal pleomorphism and increased mitotic activity6,27, and presenting the same immunohistochemical pattern as that of leiomyomas6,27. However, no criteria have been established to determine the malignity of these tumors19,21. Then, certain characteristics suggest the malignity degree, including the tumor size (>5 cm), histological aspect (necrosis of tumor cells, ulceration and cell atypia), and the number of mitotic figures per 10 high-power fields1,8,14,15,18,19,27,28. From these, the latter is the most important malignity criterion7,14,16; tumors of less than two mitoses per 10 fields offer good prognosis; however, if two or more mitoses are found, the tumor is usually considered as malign7,19. Therefore, a complete analysis of the resected specimens is essential for malignity diagnosis and correct selection of treatment plans27. Due to the difficult distinction between benign and malign tumors 2,7-9,13-16,19,21,27, possibility of recurrence7-9,11-13,16,19,21,25,29 and insensitivity of these tumors to adjuvant therapies7,8,14-16,18,19,28, most authors recommend the surgical removal of the tumor3,7,8,11-19,29-31, either through open15,16,18,21 or endoscopic procedure1,2,5,10,12,21,32,33. The surgical treatment should ensure tumor-free margins1,18. The options include transanal excision,

Leiomyoma of the rectum represents only 3% of all gastrointestinal leiomyoma1, and less than 0.1% of rectal tumors1,4,8. So far, the most important compilation of anorectal tumors of smooth muscle (432 leiomyoma and 480 leiomyosarcoma) found in worldwide literature has been that published by Hatch et al.7, in 2000. In Brazil, few cases of smooth muscle tumors of the rectum have been described15,16,18,20-24. In general, these tumors occur more predominantly in individuals between 40 and 59 years old7. This study investigated two male patients and, in the case compilation made by Hartch et al.7, the probability that men will develop anorectal benign and malign tumors of smooth muscle was a little higher than in women7. Regarding the wall location, there seems to be no significant difference when comparing leiomyoma and leiomyosarcoma7. The clinical manifestations vary with the size, location and direction of the tumoral growth1. Most patients are asymptomatic1,9,10,17,18; discomfort or local pain, associated or not with defecation, palpable mass, sensation of a strange body, changes in intestinal habit and rectal bleeding1,3,9,15,16,18 are sporadically reported in the literature1,9,25,26. Usually, when symptomatic, the tumors are diagnosed within one year of symptom onset7. As in the cases reported in this study, most tumors are intraluminal and sessile1,5,6 and may occasionally present a pedicle1,5,10. In both cases described here, the patients had proctologic complaints - the first was related hemorrhoid and the second to a chronic anal fissure -, and these findings are similar to those in the literature, where most lesions are incidentally diagnosed, through digital rectal examination or endoscopy1,3,5,9,16-19, before the patients had any complaint1,5,17. Besides colonoscopy, some examinations can help in the lesion diagnosis and staging: opaque enema, colonoscopy, computed tomography, magnetic resonance and endoanal ultrasound1,9,11,15,16,18. Therefore, the histopathological analysis will determine the sure diagnosis and the distinction between benign and malign lesions11,16,21. Particularly when the lesion is in the rectum, the endoanal ultrasound can help define the lesion extent 384


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Treatment of rectal leiomyoma by endoscopic resection Rafael Denadai Pigozzi Silva et al.

endoscopic resection, lower anterior resection or abdominoperineal amputation7,9,15,19. In both cases, endoscopic resection of the lesion was considered a therapeutic procedure, as the margins were free of neoplasm, and the tumors were smaller than 5 cm, without necrosis, ulceration and cell atypia, and the number of mitoses per 10 highpower fields was less than two1,8,14-15,19,27,28. Some cases using endoscopic resection of rectal leiomyoma have been described2,10,12,32,33. This approach is a valid alternative to invasive surgery when the complete removal of the lesion is ensured5,32. However, it may lead to hemorrhage and perforation1,2,32,34. Therefore, endoscopic resection is improper to leiomyosarcoma and leiomyoma of ≥2 cm diameter or originated in the muscularis propria, due to the risk of hemorrhage and perforation32. Thus, it is extremely important to determine the layer of lesion origin32. In this context, endoscopic ultrasound will help decide about the proper surgical procedure1,7,11,14,18,34, as the distinction from the lesion origin layer is important for

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the proper surgical planning2,11,14,34. Usually, leiomyomas originated in the muscularis mucosa can be endoscopically resected, while for those originated in the muscularis propria, this procedure should be avoided34. Unfortunately, this procedure was not performed in the patients of this study. Prognosis is uncertain for these tumors25, due to the recurrence rate7-9,11-13,16,19,21,25,29, and the short follow-up period for the cases reported above5,7,15,21,25. Then, extended follow-up is important to confirm a disease-free status2,5,7,14,15,18,19,21. The postoperative follow-up can include tomography, flexible digestive endoscopy and endoanal ultrasound4,14,19,21. We have concluded that leiomyoma in the rectum is rare, usually asymptomatic, and that it should be distinguished from GISTs and leiomyosarcoma. For this purpose, histological and immunohistochemical analyses of the whole specimen should be performed by a pathologist with experience in this type of lesion. Endoscopic resection is an therapeutic option, since it enables the complete removal of the tumor.

RESUMO: Os leiomiomas de reto são raros, com baixa incidência relatada na literatura; na maioria dos casos os pacientes são assintomáticos, sendo que em muitos casos são achados incidentais endoscópicos. A dificuldade de distinguí-los dos leiomiossarcomas, aliada a possibilidade de recorrência, implica na inexistência de um tratamento padrão. A ressecção endoscópica desde que bem indicada pode ser uma opção terapêutica. Reportamos dois casos de leiomioma de reto assintomáticos em dois pacientes, descobertos casualmente durante exame colonoscópico de rotina, removidos por polipectomia convencional e discutimos seus aspectos diagnósticos e terapêuticos, através de uma revisão da literatura. Palavras-chave: neoplasia retal; leiomioma; colonoscopia.

REFERENCES

leiomyomas that should be separated from gastrointestinal stromal tumors-a clinicopathologic and immunohistochemical study of eighty-eight cases. Mod Pathol 2001;14(10):950-6. 6. Miettinen M, Kopczynski J, Makhlouf HR, Sarlomo-Rikala M, Gyorffy H, Burke A, et al. Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the duodenum: a clinicopathologic, immunohistochemical, and molecular genetic study of 167 cases. Am J Surg Pathol 2003;27(5):625-41. 7. Hatch KF, Blanchard DK, Hatch GF 3rd, Wertheimer-Hatch L, Davis GB, Foster RS Jr, et al. Tumors of the rectum and anal canal. World J Surg 2000;24(4):437-43. 8. Saunders RN, Pattenden C, Agarawal PK. Heavy rectal bleeding secondary to the passage of a rectal leiomyoma per anus. Ann R Coll Surg Engl 2004;86(6):W44-6. 9. Zerilli M, Lotito S, Scarpini M, Mingazzini PL, Meli C, Lombardi A, et al. Recurrent leiomyoma of the rectum

1. De Palma GD, Rega M, Masone S, Siciliano S, Persico M, Salvatori F, et al. Lower gastrointestinal bleeding secondary to a rectal leiomyoma. World J Gastroenterol 2009;15(14):1769-70. 2. Ishiguro A, Uno Y, Ishiguro Y, Munakata A. Endoscopic removal of rectal leiomyoma: case report. Gastrointest Endosc 1999;50(3):433-6. 3. Gómez NA, Cozzarelli R, Alvarez LR, Fabre E, Vargas PE, Zapatier JA. Rectum leiomyoma in a 10-month-old female. Pediatr Surg Int 2003;19(1-2):104-5. 4. Serra J, Ruiz M, Lloveras B, Guillaumes S, Garriga J, Trias R. Surgical outlook regarding leiomyoma of the rectum. Report of three cases. Dis Colon Rectum 1989;32(10):884-7. 5. Miettinen M, Sarlomo-Rikala M, Sobin LH. Mesenchymal tumors of muscularis mucosae of colon and rectum are benign

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treated by endoscopic transanal microsurgery. G Chir 1997;18(8-9):433-6. 10. Zurac S, Tudose I, Micu G, Bastian A, Gamada E, Stăniceanu F, et al. Rectal leiomyoma-report of two cases originating in muscularis mucosae. Rom J Intern Med 2009;47(1):97-100. 11. Hsieh JS, Huang CJ, Wang JY, Huang TJ. Benefits of endorectal ultrasound for management of smooth-muscle tumor of the rectum: report of three cases. Dis Colon Rectum 1999;42(8):1085-8. 12. Martín Fernández J, Carbajo Vicente M, García Rojo M, Martín Dávila F, Pardo García R, Hernández Calvo J. Tumors originating in the muscularis mucosae of the recto-sigma. Rev Esp Enferm Dig 1996;88(12):868-72. 13. Sasaki K, Gotoh Y, Nakayama Y, Hayasaka H, Ishiyama Y, Miyashita H. Leiomyoma of the rectum. Int Surg 1985;70(2):149-52. 14. Bahadursingh AM, Vagefi PA, Howell A, Prather C, Longo WE. Spindle cell tumor of the distal rectum. Dig Dis Sci 2005;50(1):37-41. 15. Kock KS. Leiomioma retal - relato de caso e revisão de literatura. J Coloproctol 2004;24(2):170-3. 16. Marzán L, Pupo Neto JA, Bottino AMCF, Lacombe DLP. Análise crítica da classificação e estudo imuno-histoquímico dos tumores da camada muscular do cólon e reto - revisão de 11 Casos. J Coloproctol 2003;23(4):244-55. 17. Tanaka M, Fujishima H, Chijiiwa Y, Nawata H, Eguchi T, Kinjo M. Endoscopic ultrasonographic findings in rectal leiomyoma. J Gastroenterol Hepatol 1995;10(1):103-5. 18. Campos FG, Leite AF, Araújo SE, Atuí FC, Seid V, HabrGama A, et al. Anorectal leiomyomas: report of two cases with different anatomical patterns and literature review. Rev Hosp Clin Fac Med Sao Paulo 2004;59(5):296-301. 19. Edwards MA, Beatty JS, Shah MB, Bittner JG 4th. An unusual presentation of rectal leiomyoma. Am Surg 2008;74(5):448-50. 20. Moraes SP, Quilici F, Reis Neto JA, Gabriele, JF, Alves TMI, Trivino MB. Leiomiossarcoma retal: relato de caso. J Coloproctol 2002;22(3):3. 21. Ferreira JJ, Gonçalvez RO, Marques TC. Leiomioma de reto tratado por ressecção transretal. J Coloproctol 2000;20(4):243-5. 22. Ramos JR, Pinho M, Ramos RP, Magalhães KMC, Baptista AS. Leiomiossarcoma do reto - relato de um caso. J Coloproctol 1987;7(3):107-9.

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23. Kiss DR, Iwasso S, Tessler S, de Castro JV, Iriya Y. Leiomyosarcoma of the rectum. Report of a case. Rev Assoc Med Bras 1979;25(2):59-60. 24. Souza GA. Leiomiossarcoma perianorretal. Relato de um caso operado. J Coloproctol 1983;3(4):143-5. 25. Le Borgne J, Guiberteau-Canfrere V, Lehur PA, Bitar O, Serraz H, Thoulouzan E, et al. Leiomyoma of the rectum. Chirurgie 1993-1994;119(4):212-5. 26. Chou FF, Eng HL, Sheen-Chen SM. Smooth muscle tumors of the gastrointestinal tract: analysis of prognostic factors. Surgery 1996;119(2):171-7. 27. Ponsaing LG, Kiss K, Hansen MB. Classification of submucosal tumors in the gastrointestinal tract. World J Gastroenterol 2007;13(24):3311-5. 28. Wang TK, Chung MT. Anorectal leiomyosarcomas. J Gastroenterol 1998;33(3):402-7. 29. Vorobyov GI, Odaryuk TS, Kapuller LL, Shelygin YA, Kornyak BS. Surgical treatment of benign, myomatous rectal tumors. Dis Colon Rectum 1992;35(4):328-31. 30. Odariuk TS, Vorob’ev GI, Kapuller LL, Shelygin IuA, Korniak BS. The surgical treatment of benign smooth-muscle tumors of the rectum. Khirurgiia (Mosk) 1992;3:62-6. 31. Tarasidis G, Brown BC, Skandalakis LJ, Mackay G, Lauer RC, Gray SW, et al. Smooth muscle tumors of the rectum and anus: a collective review of the world literature. J Med Assoc Ga 1991;80(12):685-99. 32. Zhou XD, Lv NH, Chen HX, Wang CW, Zhu X, Xu P, et al. Endoscopic management of gastrointestinal smooth muscle tumor. World J Gastroenterol 2007;13(36):4897-902. 33. Nakase H, Ide M, Yazumi S, Watanabe N, Itoh T, Matsuura M, et al. Rectal leiomyoma with fibromuscular obliteration mimicking adematous lesion. Endoscopy 2002;34(3):241. 34. Xu GQ, Zhang BL, Li YM, Chen LH, Ji F, Chen WX, et al. Diagnostic value of endoscopic ultrasonography for gastrointestinal leiomyoma. World J Gastroenterol 2003;9(9):2088-91. Correspondence to: Fábio Vieira Teixeira Serviço de Endoscopia, Cirurgia do Aparelho Digestivo e Coloproctologia – UNIGASTRO Rua Dr. Próspero Cecílio Coimbra, 80, Cidade Universitária CEP 17525-160 – Marilia (SP), Brazil E-mail: fabioteixeira@unimedmarilia.com.br

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Case Report

Laparoscopic left lateral segmentectomy for metachronic metastases of small intestine adenocarcinoma: a case report Sergio Renato Pais-Costa1, Sergio Luiz Melo Araujo2, Olímpia Alves Teixeira Lima3, Marcio Almeida Paes4, Sandro José Martins5 In Doctor’s Degree Program, Universidade Federal de São Paulo (UNIFESP) – São Paulo (SP), Brazil; Oncologic Surgeon Physician, Hospital Santa Lucia – Brasília (DF), Brazil. 2Specialist in General Surgery; General Surgeon and Physician of the Hospital Santa Lucia – Brasília (DF), Brazil. 3Assistant Professor of Surgery at the Universidade de Brasília (UNB) – Brasilia (DF), Brazil; General Surgeon and Physician of the Hospital Santa Lucia – Brasília (DF), Brazil. 4Head of the Clinical Oncology Service of the Hospital de Base do Distrito Federal – Brasília (DF), Brazil; Oncologist at the Hospital Santa Lucia – Brasília (DF), Brazil. 5Adjunct Professor of Oncology at the Universidade de Brasilia (UNB); Oncologist at the Hospital Santa Lucia – Brasília, (DF), Brazil. 1

Pais-Costa SR; Araujo SLM; Lima OAT; Paes MA; Martins SJ. Laparoscopic left lateral segmentectomy for metachronic metastases of small intestine adenocarcinoma: a case report. J Coloproctol, 2011;31(4):387-392. Abstract: Hepatectomy has been the standard treatment for metachronic metastases of non-colorectal (NCR) origin, mainly when the disease-free interval is more than two years. Laparoscopic hepatectomy has become the golden standard mainly for left side resections, due to lower morbidity, shorter hospital stay, early recovery and good cosmetic outcome. The authors report the case of a female patient with two metachronic metastases (ten years of disease-free survival), of non-colorectal origin (adenocarcinoma of small intestine), treated by laparoscopic left lateral segmentectomy (left hepatic lobectomy) with success. The postoperative progress was satisfactory. To date, the patient has presented no tumoral recurrence (six months of follow-up period). Laparoscopic left lateral segmentectomy can be satisfactorily performed in selected cases of hepatic metastasis. This approach presents low morbidity and good cosmetic result. The lack of alternative treatments and the poor prognosis of untreated cases have justified surgical resection in order to increase overall survival. Nevertheless, this approach should be performed by hepatic surgery expertise teams trained on advanced laparoscopic procedures. Keywords: laparoscopy; colorectal neoplasm; hepatectomy; neoplasm metastasis; liver neoplasm/surgery; liver neoplasm/secondary; survival rate.

INTRODUCTION

deeper knowledge of anatomy and surgery technique, combined with the increasingly improved support conditions, both in the intraoperative and postoperative periods, has lead to substantially reduced mortality in this operation1. In parallel, due to developments in hepatic surgery, hepatectomy has been freely indicated for the treatment of CR metastases, where resection is the only way of healing or extended survival1-7. More recently, several series in the literature have also demonstrated

Hepatectomy has been selected as the curative treatment of choice for metastases of colorectal (CR) origin. In a systematic review recently published by Simmonds et al.1, the survival rates in 5 years in 16 series, including R0 resection only, range from 15 to 67%, median of 30%. In the same study, postoperative mortality ranged from 0 to 6.6%, median of 3%. Then, the

Study carried out at the Hospital Santa Lucia – Brasília (DF), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 09/30/2010 Approved on: 10/21/2011

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Laparoscopic left lateral segmentectomy for metachronic metastases of small intestine adenocarcinoma: a case report Sergio Renato Pais-Costa et al.

satisfactory results in the resection of non-colorectal (NCR) metastases. The results, when the NCR metastases resection is performed in selected cases, are similar to those observed in CR metastases resection, with rates in a 5-year survival ranging from 20 up to 45%8-13. In our community, the author of this study, in a prior study that compared CR and NCR metastases, observed similar survival, of around 20%, in a 5-year survival for the two groups7. Literature shows that this practice has been more freely adopted, especially when the disease remains exclusively confined to the liver, limited to one lobe, and mainly when the disease-free survival (DFS) between the primary tumor treatment and the distant lesion presentation is more than two years8-13. Today, laparoscopic resection of metastases has become a reality, especially for lesions in the left hepatic lobe, as it is technically easier to be performed using this access. Laparoscopic hepatectomy (LH) offers many advantages in relation to the open surgery, such as lower morbidity, shorter hospital stay, reduced postoperative pain, reduced bleeding, reduced transfusion, early return to habitual activities, early feeding and good cosmetic outcome. Recent studies show that, in an oncologic perspective, LH does not show any difference in terms of recurrence, margins or survival when compared to the open technique if the principles of radicality are maintained14-29.

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The authors describe the case of a young female patient with two metachronic metastases (ten years of disease-free survival) in the left hepatic lobe (segments II-III), originated from an adenocarcinoma of small intestine (terminal ileum), who was submitted to a laparoscopic left lateral segmentectomy (left hepatic lobectomy – segments II+III) with success. The postoperative progress was excellent, with six-month disease-free survival so far. CASE REPORT A 42-year-old female patient was submitted to a partial enterectomy in the terminal ileum (20-cm resection) with primary entero-entero anastomosis due to an adenocarcinoma of small intestine (TNM staging – T2N0M0) ten years before. No adjuvant treatment was performed at the time, with periodic examinations. In the routine exams, the abdominal control computed tomography showed two 3 cm metastases in the left hepatic lobe (segments II-III). The patient was in excellent conditions in general, with no sign of clinical or radiological extrahepatic dissemination. Staging was complemented with magnetic resonance of the abdomen, which showed these lesions only (Figure  1). A PET-SCAN (positron emission tomography) was also performed, which confirmed an exclusively hepatic disease. The serum dosage of carcinoembryonic antigen was 41.2 ng/mL. As the patient had two small metastases confined to the left lobe and she presented a long disease-free period (ten years between the enterectomy and the presentation of hepatic lesions), the surgical resection was proposed. The laparoscopic procedure was suggested, which has been the medical team’s choice to treat lesions in the left hepatic lobe. Five trocars were used, and their sites are illustrated in Figure 2. In the abdominal cavity evaluation, no sign of distant dissemination was observed. Laparoscopic left lateral segmentectomy was then successfully performed, without interoccurrences, using the intrahepatic Glissonian access technique, as described by Machado et al.29. No clamping of the liver hilum (Pringle maneuver) was performed. A hemostatic 10 mm LigaSure jaw (Valleylab, USA) for parenchyma sectioning and a white-loaded endoscopic stapler, of vascular type (Endogia 45 mm, Ethicon), for the left hilar elements and left hepatic vein.

Figure 1. Nuclear magnetic resonance of the abdomen showing two lesions of 3 cm in the left lobe, segments II-III.

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The specimen was removed into an endobag, closed and without contamination, through a small median incision at the previous surgery site (Figures 2 and 3). The patient was fed on the same day (12 hours after the surgery). She did not receive blood, only dipyrone, as an analgesic substance. She presented good progress, without interoccurrences and was discharged from hospital on the third day after the surgery. The histopathological exam showed only two lesions with metastatic adenocarcinoma and neoplasm-free margins. No adjuvant treatment was indicated, only periodic exams. Six months after the surgery, the patient showed no symptoms and no disease recurrence. DISCUSSION The resection of NCR metastases has been considered the standard curative treatment in selected cases. Several series have shown the benefit of resection when compared to alternative palliative treatments, such as systemic chemotherapy. Only resection can offer the real chance of healing or extended survival. However, the proper selection seems to be the main rationale of resection. Then, factors such as: patientâ&#x20AC;&#x2122;s good conditions in general; proper nutritional and hepatic reserves; exclusively hepatic lesion; long disease-free survival between the primary tumor treatment and the presentation of metastases; and the NCR metastases etiology itself, seem to be the most important prognostic criteria for long-time survival observed in the literature7-13. Laurent et al.12, when evaluating a series of 39 patients submitted to surgery due to NCR metastases with zero mortality, observed global survival of 35% in the 8-year period. Only the disease-free survival (DFS) over 24 months was a positive prognostic factor for long-term survival at the multivariate analysis (MVA). The primary tumor origin, such as gastrointestinal tract (GIT), genitourinary tract (GUT) or others (sarcomas, breast, melanoma, etc.), was not a criterion of poor prognosis through the MVA. Weitz et al.9, in a study that analyzed a series of 141 patients from the Memorial Sloan Kettering Cancer Center, in New York (zero mortality and 33% morbidity), observed that the main factors of good prognosis at the MVA were DFS over 24 months and primary tumor etiology

Figure 2. Sites of trocar utilization. Incision for specimen removal.

Figure 3. Left lateral sectorectomy. Note the two metastases in segments II-III (2 cm margin).

(tumor of reproductive system). However, Hemming et al.13, in Toronto, Canada, evaluating a series a 37 patients whose postoperative mortality was also zero, reported 45% survival in a 5-year period; at the MVA, no statistically significant difference was observed when compared to the DFS over 36 months. The only two predictive factors of better survival were: origin of non-gastrointestinal primary tumor (NGIT) and neoplasm-free margins. 389


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Ercolani et al.11, in an Italian study that analyzed 83 cases of resection, observed 34% survival in a 5-year period, also with zero postoperative mortality, while morbidity was 20%. At the MVA, they found only the tumor volume as a prognostic factor for recurrence (metastasis volume larger than 125 cc), although the DFS over one year showed a tendency towards that, but without significance due to the sample size. Specifically when the subgroup of operated primary tumor was analyzed, a statistically significant different was observed between metastases from GIT versus GUT tumors, sarcomas or even breast. For GIT tumors, survival was lower than in the others, with 17.3% in 3 years, and 8.4% in 5 years, respectively. In our community, the author of this study, in a previously published case that analyzed ten patients submitted to resection of metachronic metastases of NCR (DFS over one year), observed 50% survival in a 3-year period, with zero mortality in the hepatectomies performed8. In another previous study of the same author, in which ten patients with NCR metastasis were compared to a similar contemporaneous cohort of 20 patients with NCR metastasis, all of them submitted to hepatic resection (all cases operated by the same medical team), no statistically significant difference was observed for survival between the two groups. The criteria of poor prognosis at the MVA in both groups (CR and NCR metastases) were: lymph node involvement (in hepatic hilum or primary tumor) and more than one metastasis7. Finally, in the study of greater number of cases found in the literature (although multicenter and retrospective), Adam et al.10, when evaluating 1,452 patients submitted to resection due to NCR metastases, observed 36% overall survival in a 5-year period (23% in 10-year survival), associated with 2.3% overall mortality and 21.5% morbidity. They found, at the MVA, the following factors of poor prognosis: age over 60 years, primary tumor that is not breast or melanoma cancer, squamous cells in the histological study (epidermoid carcinoma), DFS lower than one year, extra-hepatic disease, resection with positive margin and larger hepatectomy. These authors also described a score, with a mathematical model, that can predict survival based on these prognostic factors. In addition, they sorted the

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patients according to the MVA and evaluated their long-term survival. Then, the patients were classified according to this score as: low risk (score 0–3, 46% survival in a 5-year period), medium risk (score 4–6, 33% survival in a 5-year period) and high risk (score over 6, survival in a 5-year period lower than 10%). When applying this mathematical model to this case, the patient would be classified as low risk, combined with her excellent nutritional condition, absence of comorbidities and good hepatic reserve, facts that influenced the selection of resection. With the development in laparoscopic surgery in general, laparoscopic hepatectomy (LH) has been more freely indicated for the treatment of both benign and malign hepatic neoplasms. Advantages, such as reduced intraoperative bleeding, lower morbidity, shorter hospital stay, early recovery and good cosmetic outcome, have been constantly observed14-29. For left-side resections, recently published controlled studies have suggested laparoscopy as the favorite method especially of experienced surgeons in laparoscopic hepatic surgery15,16. This fact also influenced the decision on the access method used in this study, as 20 LHs have been performed by the medical team (for both benign and malign tumors) in the last four years30. On the other hand, regarding the treatment of malign neoplasm, recent studies have suggested that there is no difference between LH and open hepatectomy to treat metastases in portals, margins, localsystemic recurrence or long-term survival20,22,23,26,27. In our community, Machado et al.24, in a small series of four patients with CR metastasis submitted to LH, have already demonstrated the benefit of LH, which was performed with effectiveness and safety. In a review in the national literature, however, no case of LH used in the treatment of NCR metastasis has been found to date. This case shows that, when well indicated and performed by a team with expertise in hepatic surgery, particularly in laparoscopic procedures, LH can be an excellent therapeutic option. LH offers innumerous advantages (lower morbidity, reduced postoperative pain, early recovery and good cosmetic outcome), without compromising the oncologic radicality. 390


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CONCLUSION

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treatments and the poor prognosis of untreated cases of NCR metastasis have justified surgical resection in order to increase overall survival. Nevertheless, this approach should be performed by hepatic surgery expertise teams trained on advanced laparoscopic procedures.

Laparoscopic left lateral segmentectomy (left hepatic lobectomy) can be satisfactorily performed in selected cases of hepatic metastasis, with lower morbidity and good cosmetic result. The lack of alternative

Resumo: A hepatectomia tem sido o tratamento padrão para metástase de origem não colorretal (NCR) metacrônica, principalmente quando o intervalo livre de doença é maior do que dois anos. A hepatectomia por laparoscopia tem se tornado padrão principalmente para as ressecções à esquerda, haja vista a menor morbidade, menor tempo de internação, reabilitação precoce e melhor resultado estético. Os autores relatam um caso de paciente com duas metástases metacrônicas (10 anos de sobrevida livre de doença), de etiologia não colorretal (adenocarcinoma de intestino delgado), tratada com segmentectomia lateral esquerda (lobectomia hepática esquerda) laparoscópica. Paciente apresentou boa evolução pós-operatória sem recidiva (seis meses de seguimento). Segmentectomia lateral esquerda laparoscópica pode ser satisfatoriamente realizada em casos selecionados de metástases hepáticas, acarretando menor morbidade e melhor resultado estético. A falta de tratamentos alternativos e o prognóstico reservado nos casos de metástases NCR não operadas justificam a ressecção com o objetivo de prolongar a sobrevida. No entanto, essa abordagem deve ser realizada por equipe especializada em cirurgia hepática com treinamento em procedimentos laparoscópicos avançados. Palavras-chave: laparoscopia; neoplasias colorretais; hepatectomia; metástase neoplásica; neoplasias hepáticas/cirurgia; neoplasias hepáticas/secundário; taxa de sobrevida.

REFERENCES

8. Costa SRP, Horta SHC, Miotto MJ, Costas MC, Henriques AC, Speranzini M. Ressecção hepática para o tratamento de metástases não-colorretais e não-neuroendócrinas: indicações e resultados em 10 pacientes operados. Einstein 2008;6(1):56-62. 9. Weitz J, .Blumgart LH, Fong Y, Jarnargin WR, Dangelica M, Harrison LE, et al. Partial hepatectomy for metastases from noncolorectal, nonneuroendocrine carcinoma. Ann Surg 2005;241(2):269-76. 10. Adam R, Chiche L, Aloia T, Elias D, Salmon R, Rivoire M, et al. Hepatic resection for noncolorectal nonendocrine liver metastasis: analysis of 1452 patients and development of prognostic model. Ann Surg 2006;244(4):534-35. 11. Ercolani G, Grazi GL, Ravaioli M, Ramacciato G, Cescon M, Varotti G, et al. The role of liver resection for noncolorectal, nonneuroendocrine metastases: experience with 142 observed cases. Ann Surg Oncol 2005;12(6):1-8. 12. Laurent C, Rullier E, Feyle R, Masson B, Saric J. Resection of noncolorectal and nonnneuroendocrine liver metastases: late metastases are the only chance of cure. World J Surg 2001;25:1532-6. 13. Hemming AW, Sielaff TD, Gallinger S, Cattral MS, Taylor BR, Greig PD, et al. Hepatic resection of noncolorectal nonneuroendocrine metastases. Liver Transpl 2000;6(1):97-101. 14. Ardito F, Tayar C, Laurent A, Karoui M, Loriau J, Cherqui D. Laparoscopic liver resection for benign disease. Arch Surg 2007;142(12):1188-93. 15. Campos RR, Hernández CM, Conesa AL, Abellán B, Pérez PP, Paricio PP. La ressección laparoscópica de los segmentos del lóbulo izquierdo debe ser el abordaje inicial em centros com experiência. Cir Esp 2009;85(4):214-21.

1. Simmonds PC, Primrose JN, Colquitt JL, Garden OJ, Poston GJ, Rees M. Surgical resection of metastases from colorectal cancer: a systematic review of published studies. Br J Cancer 2006;94:982-99. 2. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230(3):309-21. 3. Adam R. Tratamento das metástases hepáticas do câncer colorretal. In: Correia MM, Mello ElR, Santos CER (Eds). Cirurgia do câncer hepatobiliar. Rio de Janeiro: Revinter; 2003. p. 139-46. 4. Choi EA, Rodgers SE, Ahmad SA, Abdalla EK. In: Feig BW, Berger DH, Fuhrman GM (Eds.) The M.D. Anderson Surgical Oncology Handbook. 4th ed. Philadelphia: Lippincott & Wilkins; 2006. p. 238-47. 5. Minagawa M, Makuuchi M, Torzilli G, Takayama T, Kawasaki S, Kosuge T, et al. Extension of the frontiers of surgical indications in the treatment of liver metastases from colorectal cancer. Ann Surg 2000;231(4):487-99. 6. Scheele J, Altendorf-Hofmann A. Surgical treatment of liver metastases. In: Blumgart LH, Fong Y (Eds.) Surgery of the liver and biliary tract. 3th ed. Edinburgh: WB Saunders; 2000. p. 1475-502. 7. Costa SRP, Horta SHC, Henriques AC, Waisberg J, Speranzini MB. Hepatectomia para o tratamento de metástases colorretais e não-colorretais: análise comparativa em 30 casos operados. J Coloproctol 2009;29(2):216-25.

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Laparoscopic left lateral segmentectomy for metachronic metastases of small intestine adenocarcinoma: a case report Sergio Renato Pais-Costa et al.

16. Carswell KA, Sagias FG, Murgatroyd B, Rela M, Heaton N, Patel AG. Laparoscopic versus open left lateral segmentectomy. BMC Surgery 2009;9(14):1-9. 17. Cho JY, Han HS, Yoon YS, Shin SH. Outcomes of laparoscopic liver resection for lesions located in the right side of the liver. Arch Surg 2009;144(1):25-9. 18. Cugat E, Marco C. Cirugía laparoscópica del hígado. Una opción madura? Cir Esp 2009;85(4):193-5. 19. Dulucq JL, Wintringer P, Stabilini C, Berticelli J, Mahajna A. Laparoscopic liver resections: a single center experience. Surg Endosc 2005;19:886-91. 20. Gagner M, Rogula T, Selzer D. Laparoscopic liver resection: benefits and controversies. Surg Clin North Am 2004;84:451-62. 21. Gigot JF, Gilneur D, Azagra JS, Goergen M, Ceuterik M, Morino M, et al. Auspices of the hepatobiliary and pancreatic section of the Royal Belgian Society of Surgery and the Belgian Group for Endoscopic Surgery. Laparoscopic liver resection for malignant liver tumours: preliminary results of a multicenter European study. Ann Surg 2002;236(1):90-7. 22. Kofron AJ, Auffenberg BS, Kung R, Abecassis M. Evaluation of 300 minimally invasive liver resections at a single institution. Ann Surg 2007;246(3):385-94. 23. Lee KF, Cheung YS, Chong CN, Tsang YYY, Ng WWC, Ling E, et al. Laparoscopic versus open hepatectomy for liver tumours: a case control study. Hong Kong Med J 2007;13(6):442-8. 24. Machado MAC, Makdissi FF, Almeida FAR, Luiz-Neto M, Martins ACA, Machado MCC. Hepatectomia laparoscópica

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no tratamento das metástases hepáticas. Arq Gastroenterol 2008;45(4):330-2. 25. Zhang L, Chen YJ, Shang CZ, Zhang HW, Huang ZJ. Total laparoscopic liver resection in 78 patients. World J Gastroenterol 2009;15(45):5727-31. 26. Pilgrim CHC, To H, Usatoff V, Evans PM. Laparoscopic hepatectomy is a safe procedure for cancer patients. HPB 2009;11:247-51. 27. Nguyen KV, Geller DA. Is laparoscopic liver resection safe and comparable to open liver resection for hepatocellular carcinoma? Ann Surg Oncol 2009;16:1765-7. 28. Machado MAC, Makdissi FF, Galvão FH, Machado MCC. Intrahepatic Glissonian approach for laparoscopic right segmental liver resections. Am J Surg 2008;196:e38-e42. 29. Machado MAC, Makdissi FF, Surjan RC, Herman P, Teixeira AR, Machado MCC. Laparoscopic resection of left liver segments using intrahepatic Glissonian approach. Surg Endosc 2009;23:2615-9. 30. Pais-Costa SR, Araujo SLM, Lima AOT, Chartuni A. Laparoscopic hepatectomy from hepatic tumors: a series of twenty resectable cases. Ann Oncol 2011;22(Suppl 5): 67.

Correspondence to: Sergio Renato Pais-Costa SGAS 710/910, Sala 330 CEP 70390-100 – Brasília (DF), Brazil E-mail: srenatopaiscosta@hotmail.com

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Fungal Colitis by Paracoccidioides brasiliensis: a case report CARLOS JOSÉ GALEAZZI1, CÁSSIA FERNANDA ESTOFOLETE2, ANTÔNIO CARLOS SOARES DE MORAES FILHO1, ANDERSON LUBITO SIMONI3, FRANCISCO DE ASSIS GONÇALVES-FILHO4, JOÃO GOMES NETINHO5 Resident physicians, Service of Coloproctology of the Hospital de Base at the Faculdade de Medicina de São José do Rio Preto (FAMERP) – São José do Rio Preto (SP), Brazil. 2Academician, Medical School at FAMERP – São José do Rio Preto (SP), Brazil. 3Resident physician, Service of General Surgery of the Hospital de Base da FAMERP – São José do Rio Preto (SP), Brazil. 4Professor physician, Service of Coloproctology of the Hospital de Base at FAMERP – São José do Rio Preto (SP), Brazil. 5Head of the Service of Coloproctology of the Hospital de Base ay FAMERP – São José do Rio Preto (SP), Brazil. 1

GALEAZZI CJ, ESTOFOLETE CF, MORAES-FILHO ACS, SIMONI AL, GONÇALVES-FILHO FA, NETINHO JG. Colitis by Paracoccidioides brasiliensis: a case report. J Coloproctol, 2011;31(4): 393-396. Abstract: Paracoccidioidomycosis (PBM) is an infection caused by a dimorphic fungus called Paracoccidioides brasiliensis. It occurs in Latin America, with incidence of 1 to 3 per 100,000 inhabitants in endemic areas. The digestive tract is usually not affected, but when it occurs, it may lead to events similar to colorectal neoplasm and inflammatory bowel disease (IBD). This is a case report of a 68-year-old female patient, with diarrhea without blood or mucus for 6 months, weight loss of 8 kg over the period. Abdominal ultrasonography showed some mass in the right colon, suggestive of cancer and liver perihilar lymph node. Colonoscopy showed lesions suggestive of Crohn’s disease. Biopsy showed chronic granulomatous colitis of fungal etiology: Paracoccidioidomycosis. The patient did not tolerate oral treatment with itraconazole and subsequently sulfadiazine, requiring hospital admission for the treatment with amphotericin B. The presence of Paracoccidioidomycosis in the digestive tract may be associated with bloody diarrhea, mucus, rectal hemorrhage, abdominal pain, malabsorption syndrome. Histopathological studies show the fungus and a chronic inflammatory infiltrate and granulation tissue. The differential diagnoses are tuberculosis, colorectal cancer and inflammatory bowel disease. The treatment is oral antifungal (itraconazole, sulfadiazine) or intravenous (amphotericin B) based. The case has caused diagnostic confusion between colon cancer (clinical and US) and Crohn’s disease (colonoscopy). Keywords: Paracoccidioides; mycoses; colitis; amphotericin B.

INTRODUCTION

Brazilian blastomycosis, Lutz-Splendore-Almeida disease and Lutz’s mycosis3. PBM is considered the most important fungal infection in Latin America, with the incidence of 1 to 3 per 100,000 inhabitants in endemic areas2, occurring from Southern Mexico to Northern Argentina7. Individuals affected by the disease are mostly men who live and/or develop activities in rural areas1,8, between 30 and 59 years old4-6,9. The social and economic costs incurred with the debilitation of individuals in their most productive phase and extended treatment, as well as the

Paracoccidioidomycosis (PBM) is a granulomatous systemic mycosis of subacute or chronic progress, caused by a dimorphic fungus called Paracoccidioides brasiliensis1-7, known due to its microscopic aspect of a “pilot’s wheel”. The disease was first described in 1908 by Adolfo Lutz; in 1930, Floriano Paulo de Almeida named it Paracoccidioides brasiliensis. Only in 1971 it was named Paracoccidioidomycosis, and it is also known as Lutz’s disease, South American blastomycosis,

Study carried out at the Service of Coloproctology of the Hospital de Base, at the Faculdade de Medicina de São José do Rio Preto (FAMERP) – São José do Rio Preto (SP), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 02/01/2011 Approved on: 11/23/2011

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frequent sequelae that can lead to early death when not opportunely diagnosed and treated10,11, ensure high epidemiological relevance to this pathology. The infection by Paracoccidioides brasiliensis affects primarily the lungs, through inhalation of the fungus, and can spread to several organs and systems, originating lesions in mucosae, lymph nodes, skin and adrenal glands1-3,8, and it may present general symptoms, including fever, weight loss, weakness and prostration1,8. The digestive tract is usually not affected2,8, around 2.7% of the cases of PBM, but when it occurs, it may lead to manifestations similar to colorectal neoplasm2 and inflammatory bowel disease (IBD)1. The fungus identification is through an anatomopathological analysis of the exudate tissues or culture2. The purpose of this study is to report a case of bowel infection by Paracoccidioidomycosis and present a literature review.

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(Figure 1), without alterations; small bowel flow with evidence of anal stenosis in the ileocecal valve. Colonoscopy showed lesions suggestive of Crohn’s disease. (Figure  2). The anatomopathological analysis showed chronic granulomatous colitis of fungal etiology: Paracoccidioidomycosis (Figures 3 and 4). The patient was then submitted to an oral treatment, initially with itraconazole, and afterwards, with sulfadiazine, but neither medication was well tolerated. For this reason, the patient had to be hospitalized for the treatment with amphotericin B.

CASE REPORT A 68-year-old female patient, for six months complaining of diarrhea without blood or mucus. She reported weight loss of 8 kg over the period. A prior investigation through abdominal ultrasonography performed by another service showed some mass in the right colon, suggestive of cancer and liver perihilar lymph node. Thorax and abdomen radiography and abdominal computed tomography were performed for investigation

Figure 2. Colonoscopy suggestive of IBD.

Figure 1. Computed tomography of abdomen without alterations.

Figure 3. Histological cut of cecum with intense inflammatory process. Color: Silver; 100X.

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er, experimental studies could not reproduce the lesions after fungus inoculation in the intestinal lumen. Today, the respiratory way has been accepted and proven as the main access to the fungus, with the creation of a primary pulmonary complex, followed by lymphatic and hematogenic dissemination to other organs and systems, including bowel lymph nodes and lymphoid tissues of Peyer’s patches, which can affect the intestinal mucosa14. The diagnosis of Paracoccidioidomycosis is based on several techniques: direct methods, which include histological preparations, fresh mounts or culture exam; the indirect methods, which provide diagnosis of some level of certainty; and the imaging methods, such as tomography and magnetic resonance, widely used in the diagnostic investigation4. Radiography and tomography can present unspecific images, but that can suggest PBM, such as calcification of abdominal lymph anal stenosis2. Colonoscopy shows the global lesion of the colon with rigid wall, flat erosions with irregular edges and dispersed nodes across the congested and friable mucosa of the colon8,15. The anatomopathological analysis, recommended for a definitive diagnosis, shows the presence of fungus and a chronic inflammatory infiltrate, associated with granulation tissue1,8. However, in the last years, the progress in the diagnosis of Paracoccidioidomycosis has been strongly based on the development of serological essays. With them, it is possible to have the diagnosis and effectively determine the antifungal therapy during and after the treatment4. The differential diagnosis should be performed with tuberculosis, colorectal cancer and inflammatory bowel disease. Even after the investigation, the diagnostic conclusion may be difficult, as in the reported case. Although the clinical condition and US suggested colorectal cancer, colonoscopy showed lesions that suggested Crohn’s disease. The evidence of fungus in the tissue was essential for the successful case management. The treatment of Paracoccidioidomycosis consists of two phases: attack, aiming at the immediate control of signs and symptoms of the disease and the reduction of worm burden, and the maintenance, conducted until healing criteria are obtained, seeking to reduce the risk of recurrence. The effective drugs against Paracoccidioidomycosis are from three different groups: amphotericin B, from the group of polyene antibiotics; sulfadiazine and other sulfanilamide compounds; and the group of azole drugs with systemic action3,16, prescribed according to specific indication.

Figure 4. Detail of Paracoccidioides brasiliensis (arrow) on bowel tissue. Color: Silver, 400X.

DISCUSSION The first bowel commitment by Paracoccidioidomycosis was described by Viana in 196812. Unlike other types of mycosis, it is not usually related to immunodepressant diseases, although cases have been observed in association with infection by HIV, neoplasms and, more rarely, transplantation of organs5. The disease presents a wide spectrum of clinical manifestations, from benign local disease to multifocal systemic conditions, of difficult treatment and potentially life threatening7. The digestive tract is usually not affected by this disease, but when it occurs, it may be associated with bloody diarrhea, mucus, rectal hemorrhage, abdominal pain, malabsorption syndrome with protein loss enteropathy8. The manifestations of bowel PBM can be similar to both colorectal neoplasm2 and inflammatory bowel disease1, which may lead to diagnostic confusion. Controversial assumptions have been discussed in relation to the fungus access to bowel, as there are many proposed contamination ways, including skin, mucosae, lung and the gastrointestinal tract itself. Some authors believe that the fungus would access the digestive tract from direct contamination of the intestinal mucosa13. Anorectal PBM cases support this assumption, where the contamination occurred in individuals accustomed to performing anal hygiene with vegetal leaves. Howev395


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Resumo: Paracoccidioidomicose (PBM) é uma infecção causada por um fungo dimórfico: Paracoccidioides brasiliensis. Ocorre na América Latina, com incidência de 1 a 3 por 100.000 habitantes em áreas endêmicas. O acometimento do trato digestivo é infrequente, sendo que pode levar a manifestações semelhantes à neoplasia colorretal e doença inflamatória intestinal (DII). Relatamos o caso da paciente feminina, 68 anos, com diarreia sem sangue ou muco há seis meses, com perda ponderal de 8 kg no período. Ultrassom abdominal evidenciou massa em cólon direito sugestiva de neoplasia e linfonodomegalia peri-hilar hepática. A colonoscopia evidenciou lesões sugestivas de doença de Crohn. A biopsia mostrou colite crônica granulomatosa de etiologia fúngica: Paracoccidioidomicose. A paciente não tolerou tratamento oral com itraconazol e, posteriormente, sulfadiazina. Necessitou de internação para tratamento com anfotericina B. O acometimento da PBM no trato digestivo pode cursar com diarreia muco-sanguinolenta, retorragia, dor abdominal e síndrome de má absorção. O estudo histopatológico mostra o fungo e um infiltrado inflamatório crônico com tecido de granulação. Os diagnósticos diferenciais são tuberculose, câncer colorretal e doença inflamatória intestinal. O tratamento é feito com antifúngicos orais (itraconazol, sulfadiazina) ou endovenosos (anfotericina B). O caso levou à confusão diagnóstica entre câncer de cólon (US e quadro clínico) e doença de Crohn (colonoscopia). Palavras-chave: Paracoccidioides; micoses; colite; anfotericina B.

REFERENCES

11. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância Epidemiológica. Guia de vigilância epidemiológica/Ministério da Saúde, Secretaria de Vigilância em Saúde, Departamento de Vigilância Epidemiológica. 7 ed. Brasília: Ministério da Saúde; 2009. 816 p. (Série A. Normas e Manuais Técnicos). 12. Viana GO. Blastomicose sul-americana. Contribuição ao seu estudo no Estado de Goiás [dissertation]. Goiás: Universidade Federal de Goiás; 1968. 13. Machado Filho J, Miranda JL. Considerações relativas à blastomicose sul-americana. Localizações, sintomas iniciais, vias de penetração e disseminação em 313 casos consecutivos. Hospital (Rio de Janeiro) 1960;58:99-137. 14. Fonseca LC, Mignone C. Paracoccidioidomicose do intestino delgado. Aspectos anátomo-clínicos e radiológicos de 125 casos. Rev Hosp Clin Fac Med Sao Paulo 1976;31(3): 199-207. 15. Fernández JA, Rosales TC, Naupari MO, Ayala L, Caller A, Del Aguila RP. South American blastomycosis. Diagnosis by colonoscopy. Arq Gastroenterol 1979;16(1):24-9. 16. Visbal G, San-Blas G, Murgich J, Franco H. Paracoccidioides brasiliensis, paracoccidioidomycosis and antifungal antibiotics. Curr Drug Targets Infect Disord 2005;5(3): 211-26.

1. Penna JF. Blastomycosis of the colon resembling clinically ulcerative colitis. Gut 1979;20(10):896-9. 2. Chojniak R, Vieira RA, Lopes A, Silva JC, Godoy CE. Intestinal paracoccidiodomycosis simulating colon cancer. Rev Soc Bras Med Trop 2000;33(3):309-12. 3. Palmeiro M, Cherubini K, Yurgel L. Paracoccidioidomicose – Revisão da Literatura. Scientia Medica 2005;15(4):274-8. 4. Anastácio VM, Passeto MPA, Góngora DVN, Soares MMCN, Almeida MTG. Paracoccidioidomicose: Correlação entre achados clínicos elaboratoriais na região de São José do Rio Preto. Arq Ciênc Saúde 2007;14(3):181-5. 5. Rassi TNO, Passos RRB, Kumagai KM, Soranz Filho JE, Freitas JAH. Paracoccidioidomicose crônica multifocal tendo como primeira manifestação o envolvimento palpebral: relato de caso. Arq Bras Oftalmol 2009;72(6):822-5. 6. Forjaz MHH, Fischman O, Camargo ZP, Vieira Filho JPB, Colombo AL. Paracoccidioidomicose em índios brasileiros da tribo Suruí: estudo clínico-laboratorial de 2 casos. Rev Soc Bras Med Trop 1999;32(5):571-5. 7. Marques SA. Paracoccidioidomicose é esporotricose associada a imunossupressão. Med Cut Iber Lat Am 2009;37(4): 159-170. 8. Azevedo AN, Fernandes AC, Silva AG, Moreira MAR, Leite ACA, Moreira H. Diagnóstico por colonoscopia da blastomicose sul-americana. J Coloproctol 2000;20(2):103-6. 9. Bittencourt JI, de Oliveira RM, Coutinho ZF. Paracoccidioidomycosis mortality in the State of Paraná, Brazil, 1980/1998. Cad Saude Publica 2005;21(6):1856-64. 10. Daher RR, Vasconcelos WM, Cardoso VM. Fígado e blastomicose sul-americana. J Bras Med 1973;25:83-90.

Correspondence to: Carlos José Galeazzi Serviço de Coloproctologia do Hospital de Base da Faculdade de Medicina de São José do Rio Preto Rua Noruega, 345 – Jardim Alto Rio Preto CEP 15020-230 – São José do Rio Preto (SP), Brazil E-mail: cjgaleazzi@yahoo.com.br

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Case Report

Complication related to colostomy orifice: intestinal evisceration Valdemir José Alegre Salles1, Eduardo Saba2, Endrigo Rodrigues Pissinin3, Eduardo Rubens Francisco Arguello3, Hugo Nunes Machado Filho3 Assistant Professor; Doctor at the Universidade de Taubaté (UNITAU); Associate Member of Sociedade Brasileira de Coloproctologia – São Paulo (SP); General Surgeon at the Hospital Regional do Vale do Paraíba – Taubaté (SP), Brazil. 2General Surgeon fo the Hospital Regional do Vale do Paraíba – Taubaté (SP); Assistant Professor at UNITAU – Taubaté (SP), Brazil. 3General Surgeons at the Hospital Regional do Vale do Paraíba – Taubaté (SP), Brazil. 1

Salles VJA, Saba E, Pissinin ER, Arguello ERF, Machado Filho HN. Complication related to colostomy orifice: intestinal evisceration. J Coloproctol, 2011;31(4):397-400. Abstract: Intestinal evisceration at the site of a stoma is a rare event, with high morbimortality. Its clinical manifestation often occurs between the sixth and seventh days after surgery. The risk factors most frequently related to evisceration are: increased intra-abdominal pressure, digestive tract cancer surgery, emergency surgery and stomas in the surgical incision. The authors report the case of a male patient, aged 62, suffering from adenocarcinoma of the rectum with obstructive acute abdomen, who underwent loop transversotomy for decompression. On the fourth day after surgery, he had a bronchospasm crisis, with evisceration of ileum and colon through the colostomic hole. The association of some triggering factors, such as emergency surgery, colorectal malignant neoplasm, increased intraabdominal pressure and technical failure of colostomy were decisive in the development of this rare peri-colostomy complication. Keywords: dehiscence; evisceration; colostomy; wound closure techniques; complications.

INTRODUCTION

CASE REPORT

Complications at the colostomy site show variable incidence, with the most frequent of them occurring in the immediate postoperative period, such as: necrosis, colocutaneous fixation dehiscence, retraction, hemorrhage, cellulitis and abscess1-4, with no difference if appearing 30 days after the surgery, when complications usually occur in approximately 39% of the cases5. Local factors that influence the incidence of complications include: stoma topography, involvement of rectus abdominis muscle, preoperative demarcation, stoma diameter, transposition on intra- or extraperitoneal plane with fascia fixation, aponeurotic closure, emergency surgery and stoma type6, as well as higher predominance associated with females and obesity7. Due to the low frequency of this type of complication, but associated with high morbidity, the authors decided to report this case, discussing the factors predisposing to intestinal evisceration and the adopted therapeutic option.

A 62-year-old male patient was admitted to the emergency sector of the Hospital Regional do Vale do Paraíba with obstructive acute abdomen and was submitted to loop transversotomy for decompression. He had middle rectum adenocarcinoma and was taking an oncologic neoadjuvant treatment. His comorbidity was chronic obstructive pulmonary disease associated with systemic arterial hypertension, both under proper clinical control. On the fourth post-operative day, with functional colostomy and without relevant clinical alterations, the patient had a bronchospasm crisis with intermittent cough and intense pain at the colostomy site. Despite the clinical measures adopted, his respiratory condition was worsened, requiring a mechanical ventilation support, and he was transferred to the Intensive Care Unit (ICU). During this respiratory decompensation, he presented evisceration of ileum and colon

Study carried out at the Hospital Regional do Vale do Paraíba – Taubaté (SP), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 03/05/11 Approved on: 28/11/11

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DISCUSSION

through the colostomic hole (Figure 1), although he remained with the colocutaneous fixation tube in the intestinal segment (Figure 2). He was then submitted to an urgency surgery, with surgical approach through the colostomy site, and the peritoneumaponeurotic hole diameter was corrected, reducing it by using simple suturing, with separate stitches of unabsorbable wire (zero nylon©). In surgical exploration, microperfurations were observed in a restricted area of eviscerated colon, which determined the partial resection of transverse colon followed by terminal colostomy and mucosa fistula. The patient presented satisfactory clinical progress and was discharged from the hospital, with scheduled elective rectosigmoidectomy.

Intestinal evisceration at the site of a stoma is a rare event, with few reports in the literature of this complication8,9, which presents high morbimortality and incidence between 2 and 3.5%10. General morbidity associated with colostomy may vary between 20 and 30% and mortality, around 1%8. Acute dehiscence of surgical incision, also called evisceration, has incidence in adults ranging from 0.4 to 3.0%11 and it may present early clinical manifestation due to a number of factors, leading to ineffective healing12. Total evisceration occurs through complete rupture of aponeurosis and, in partial evisceration, the involvement is restricted to skin and subcutaneous tissue13. Its clinical manifestation often occurs between the sixth and seventh days after surgery14,15. The approximate interval of 30 days is considered the most critical, as in this period, the surgical wound tension is maintained mostly by the surgical synthesis material, which constitutes the main factor for proper healing maintenance16. The risk factors most frequently related to evisceration are: anemia, increased intra-abdominal pressure (due to ascites, cough, adynamic ileum, acute urine retention and vomiting), improper healing, digestive tract cancer surgery, emergency surgery, low vitamin or zinc level, malnutrition, diabetes mellitus, advanced age – over 65 years old, multiple organ failure, fever, digestive fistulas, systemic arterial hypertension, hypoproteinemia, jaundice, shock, surgical wound infection, peritonitis, drainage holes or stomas in the surgical incision, surgical reintervention, surgery duration over three hours, inadequate suture material, uremia, corticotherapy, chemotherapy and/or radiotherapy, mechanical ventilation and technical failure, among others10,14-18. To prevent evisceration, the surgeon should correct the triggering factors and, in the surgery, use proper incisions, handle tissues carefully and perform the surgical incision closure following the tissue planes12,15,19,20. When performing colostomy, some basic concepts should be taken into account, such as: location, which should be far from the surgical incision; prior demarcation; hole size, whose extension should be close to two to three fingers (around 5 cm); proper bowel mobilization, free of tension and with good blood cir-

Figure 1. Voluminous intestinal evisceration through the colostomic site.

Figure 2. Colocutaneous fixation tube fixed to the intestinal segment.

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Complication related to colostomy orifice: intestinal evisceration Valdemir José Alegre Salles et al.

culation1. In cases of low-level bowel obstruction, the colostomy approach through the abdominal cavity is usually performed in the right upper quadrant, far from bony prominences, with the extension of transverse cutaneous incision extension of around 8 cm8. After defining the aponeurotic cutaneous hole diameter, the muscle plane is accessed through a transrectal approach. After opening the peritoneal cavity, the colon segment to be extruded is determined and, after colostomy is performed, the colon is fixed to the skin at the mucocutaneous junction, which should be made with inabsorbable suture, such as prolene 3–0 or 4–0, our absorbable suture, such as catgut 2–020-22. This case report involved some triggering factors, such as: urgency surgery, malignant colorectal neoplastic disease and increased intra-abdominal pressure, due

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to the chronic obstructive pulmonary disease, factors associated with the technical failure to perform colostomy, as the hole diameter of stoma was larger than required for colon extrusion, due to the large transverse colon distension observed in the episode of acute intestinal obstruction. In the surgical approach for intestinal evisceration, the surgical practice can be defined by exploratory laparotomy combined with the creation of a new stoma or an intervention restricted to the colostomic site23. The method adopted in this study, with resection of the eviscerated loop and new colostomy performed through the prior colostomic hole, was based the patient’s clinical condition of severe respiratory failure for being less aggressive, as, in the opinion of the surgical team, large exploratory laparotomy could increase the patient’s morbimortality.

Resumo: A evisceração intestinal desenvolvida no sítio de um estoma é um evento raro, tendo elevada morbimortalidade. Sua manifestação clínica ocorre frequentemente entre o sexto e o sétimo dias de pós-operatório. Os fatores de risco mais frequentemente relacionados à evisceração são: aumento da pressão intra-abdominal, câncer do aparelho digestório, cirurgia de urgência e estomias na incisão cirúrgica. Os autores relatam o caso de um paciente do sexo masculino, com 62 anos, portador de adenocarcinoma do reto médio com abdômen agudo obstrutivo, sendo submetido à transversostomia em alça, com finalidade descompressiva. No quarto dia de pós-operatório com crise de broncoespasmo, apresentou evisceração do cólon e íleo pelo orifício abdominal colostômico. A associação de alguns fatores desencadeantes, como a cirurgia de urgência, a doença neoplásica colorretal maligna, o aumento da pressão intra-abdominal e a falha técnica na confecção da colostomia, foram determinantes para o desenvolvimento desta rara complicação pericolostômica. Palavras-chave: deiscência; evisceração; colostomia; técnicas de fechamento de ferimentos; complicações.

REFERENCES

nationwide prospective audit of stoma complications within 3 weeks of surgery. Colorectal Dis 2007;9(9):834-8. 8. Hines JR, Harris GD. Colostomy and colostomy closure. Surg Clin North Am 1977;57(6):1379-92. 9. Corsi PR, Lanterno G, Pereira CSB, Rasslan S. Evisceração Transcolostômica – Relato de Caso. J Coloproctol 1991;11(3):98-100. 10. Salvador A, Villalba F, Galindo P, Enguix MJ, Iglesias R, Mir J, et al. La evisceración como complicación de la cirugía abdominal. Cir Esp 2003;74(Suppl 1):86. 11. Col C, Soran A, Col M. Can postoperative abdominal wound dehis­cence be predicted? Tokai J Exp Clin Med 1998;23:123-7. 12. Rodríguez-Hermosa JI, Codina-Cazador A, Ruiz B, Roig J, Gironès J, Pujadas M, et al. Factores de riesgo de dehiscencia aguda de la pared abdominal trás laparotomia en adultos. Cir Esp 2005;77(5):280-6. 13. Álvarez J. Evisceración. In: Álvarez J, Porrero JL, Dávilla D, editores. Cirugía de la pared abdominal. Madrid: Arán Ediciones; 2002. p. 55-60.

1.

Hoffman MS, Barton DPJ, Gates J, Roberts WS, Fiorica JV, Finan MA, et al. Complications of colostomy performed on gynecologic cancer patients. Gynecol Oncol 1992;44:231-4. 2. Londono-Schimmer EE, Leong APK, Phillips RKS. Life table analysis of stomal complications following colostomy. Dis Colon Rectum 1994;37:916-20. 3. Nour S, Beck J, Stringer MD. Colostomy complications: infants and children. Ann R Coll Surg Engl 1996;78:526-30. 4. Park JJ, Del Pino A, Orsay CP, Nelson RL, Pearl RK, Cintron JR, et al. Stoma complications. Dis Colon Rectum 1999;42:1575-80. 5. Duchesne JC, Wang YZ, Weintraub SL, Boyle M, Hunt JP. Stoma complications: a multivariate analysis. Am Surg 2002;68(11):961-6. 6. Szczepkowski M, Gil G, Kobus A. Parastomal hernia repair – Bielañski Hospital experience. Acta Chir Iugosl 2006;53(2):99-102. 7. Cottam J, Richards K, Hasted A, Blackman A. Results of a

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Complication related to colostomy orifice: intestinal evisceration Valdemir José Alegre Salles et al.

14. Fagniez PL, Hay JM, Lacaine F, Thomsen C. Abdominal midline in­cision closure. A multicentric randomized prospective trial of 3135 patients, comparing continuous vs interrupted polyglycolic acid su­tures. Arch Surg 1985;120:1351-3. 15. Wissing J, Van Vroonhoven TJ, Schattenkerk ME, Veen HF, Ponsen RJ, Jeekel J. Fascia closure after midline laparotomy: results of a randomized trial. Br J Surg 1987;74:738-41. 16. Carter D. The surgeon as a risk factor. BMJ 2003;326:832-3. 17. Docobo-Durantez F, Sacristán-Pérez C, Flor-Civera B, Liedó-Matoses S, Kreisler E, Biondo S. Estúdio clínico aleatorizado entre sutura de polidioxanona y de nylon en el cierre de laparotomía en pacientes de riesgo. Cir Esp 2006;79(5):305-9. 18. Portilla F, Flikier B, Espinosa E, Utreta A, Rada R, Vega J, et al. Estudo aleatorizado sobre la utilización de mallas reabsorbibles para la prevención de la evisceración en la cirugía colorrectal. Cir Esp 2008;83(1):12-7. 19. Riou JP, Cohen JR, Johnson H Jr. Factors influencing wound dehis­cence. Am J Surg 1992;163:324-30.

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20. Webster C, Neumayer L, Smout R, Horn S, Daley J, Henderson W, et al. Prognostic models of abdominal wound dehiscence after lapa­rotomy. J Surg Res 2003;109:130-7. 21. Bouillot JL, Aouad K. Traitement chirurgical des complications des colostomies. In: Encyclopedie MédicoChirurgicale. Techniques chirurgicales – Appareil digestif, 40-545, Paris: Techniques; 2002. 12p. 22. Keighley MRB. Estomas. In: Keighley MRB, Pemberton JH, Fazio VW, Parc R. Atlas de Cirurgia Colorretal. Rio de Janeiro: Revinter; 1999, p 61-91. 23. Gallot D. Traitement chirurgical des complications des colostomies. In: Encyclopedie Médico-Chirurgicale. Techniques chirurgicales – Appareil digestif, 40-545, Paris: Techniques; 1990. 10p. Correspondence to: Valdemir José Alegre Salles Rua José Bonani, 199, Independência CEP 12031-260 – Taubaté (SP), Brazil E-mail: vjasia@gmail.com

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Case Report

Superior mesenteric artery compression syndrome - case report PAULO ROCHA FRANÇA NETO1, RODRIGO DE ALMEIDA PAIVA2, ANTÔNIO LACERDA FILHO3, FÁBIO LOPES DE QUEIROZ1, TEON NORONHA2 Master in Medical Sciences, Universidade Federal de Minas Gerais (UFMG); Member of the Coloproctologic Clinic, Hospital Felício Rocho – Belo Horizonte (MG), Brazil. 2Member of the Coloproctologic Clinic, Hospital Felício Rocho – Belo Horizonte (MG), Brazil. 3Doctor in Medical Sciences, UFMG; Member of the Coloproctologic Clinic, Hospital Felício Rocho – Belo Horizonte (MG), Brazil. 1

NETO PRF, PAIVA RDA, FILHO AL, QUEIROZ FLD, NORONHA T. Superior mesenteric artery compression syndrome - case report. J Coloproctol, 2011;31(4): 401-404. Abstract: Superior mesenteric artery syndrome is an entity generally caused by the loss of the intervening mesenteric fat pad, resulting in compression of the third portion of the duodenum by the superior mesenteric artery. This article reports the case of a patient with irremovable metastatic adenocarcinoma in the sigmoid colon, that evolved with intense vomiting. Intestinal transit was carried out, which showed important gastric dilation extended until the third portion of the duodenum, compatible with superior mesenteric artery syndrome. Considering the patient’s nutritional condition, the medical team opted for the conservative treatment. Four months after the surgery and conservative measures, the patient did not present vomiting after eating, maintaining previous weight. Superior mesenteric artery syndrome is uncommon and can have unspecific symptoms. Thus, high suspicion is required for the appropriate clinical adjustment. A barium examination is required to make the diagnosis. The treatment can initially require gastric decompression and hydration, besides reversal of weight loss through adequate nutrition. Surgery should be adopted only in case of clinical treatment failure. Keywords: superior mesenteric artery syndrome; diagnosis; abdominal pain; duodenum, radiography.

INTRODUCTION

CLINICAL CASE

The superior mesenteric artery syndrome was described for the first time by Von Rokitansky in 18611, and later studied by Wiekie 2, who detailed most clinical findings in early 20 th century. It is a rare entity, caused by compression of the third portion of the duodenum by the superior mesenteric artery, resulting in an obstruction in this segment. This article reports a case of this disease in a patient that presented fast weight loss due to colon neoplasm.

A 40-year-old female patient, previously healthy, for six months with intestinal constipation and evacuation discomfort. Her weight was 35 kg at the first appointment and she also reported frequent vomiting. In addition, she reported considerable weight loss of 30 kg in 6 months. Clinical examination The patient was very thin, without abdominal distention and with palpable mass in the left iliac fossa.

Study carried out at the Clínica de Coloproctologia do Hospital Felício Rocho – Belo Horizonte (MG), Brazil. Financing source: Coloproctologic Clinic, Hospital Felício Rocho. Conflict of interest: nothing to declare. Submitted on: 07/22/2009 Approved on: 09/01/2009

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Figure 1. Intestinal transit showing important gastric dilation. The arrows show the contract progression interruption point.

Figure 2. Gastric dilation extended to the third portion of the duodenum.

Colonoscopy Colonoscopy was performed reaching the sigmoid, where the equipment light was narrowed, blocking the equipment progression. Biopsies of the region showed normal colonic mucosa.

sigmoid, with invasion of ureter and iliac vessels in their left portion. Biopsy of implants and loop colostomy in transverse colon were performed. Two days after the surgery and with restart of oral food intake, the patient started to present frequent vomiting, but reporting significant improvement in general. Her abdomen remained flat, raising the suspcion of proximal obstruction or gastroparesis. Intestinal transit was carried out (Figures 1, 2 and 3), which showed important gastric dilation until the third portion of the duodenum, compatible with superior mesenteric artery syndrome. Considering the patientâ&#x20AC;&#x2122;s nutritional condition, the medical team opted for conservative measures (small food portions in more frequent intakes and left lateral decubitus position after meals). Four months after the surgery and conservative measures, the patient did not present vomiting anymore, with considerable weight gain of 8 kg.

Abdomen and pelvis tomography Tomography was suggestive of hepatic metastasis, pyelocalyceal dilation and suspicion of iliac vessel invasion. Thorax tomography This tomography was suggestive of bilateral pulmonary metastases. Treatment performed Exploratory laparotomy was performed, which showed ascites, irremovable hepatic metastases, peritoneal implants and voluminous tumoral lesion in the 402


Journal of Coloproctology October/December, 2011

Superior mesenteric artery compression syndrome - case report Paulo Rocha França Neto et al.

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dominal pain (59 to 81% of the cases), which is relieved when changing the position, as well as vomiting, nauseas and anorexia6,9. This condition makes food intake impossible, leading to worsened clinical conditions. The post-operative confirmation diagnosis is difficult; but, once the suspicion exists, a contrast study of the duodenum can provide a number of signs compatible with superior mesenteric artery syndrome, including: dilation of the first and second portions of the duodenum; compression of duodenal arc, with difficult or interrupted transit of contrast medium; stasis of the contrast medium at the gastrointestinal level for more than four hours; obstruction disappears when changing to left lateral decubitus or ventral position10-12. In some patients, computed tomography of abdomen is required, which can show the duodenal obstruction and its relation with aorta and superior mesenteric artery. More invasive exams, such as arteriography and angioresonance, are not indicated when contrast radiography does not suggest the diagnosis13-15. The differential diagnosis of superior mesenteric artery syndrome includes other causes of small bowel obstruction, as well as diseases associated with duodenal dysmotility (megaduodenum), including diabetes, collagen diseases, scleroderma and chronic idiopathic intestinal pseudo-obstruction16. The clinical treatment is initially indicated, which consists in the introduction of a nasogastric probe for stomach decompression, correction of hydroelectrolytic disorders and acid-base balance. If possible, small amounts of food and in short intervals should be adopted, as well as change to left lateral decubitus position. In more severe cases, total parenteral nutrition may be necessary. When these measures are successful, the need for a surgical treatment may be reduced from 70 to 14%17. The surgical treatment is recommended in case of clinical treatment failure, in symptomatic patients. It consists in duodenojejunostomy in most cases, with 80% success rate18,19. Lee et al.20 concluded that duodenojejunostomy presented better results in severe cases, when compared to gastrojejunostomy and Strong’s operation (division of the ligament of Treitz).

Figure 3. Intestinal transit compatible with superior mesenteric artery syndrome.

DISCUSSION Retroperitoneal fat tends to keep the mesenteric root and the superior mesenteric artery far from the aorta. The angle between the two arteries varies from 25 to 60° in normal individuals and the radiographic distance between them ranges from 10 to 28 mm3-5. The reduction in angle to 6–16° and in the aortomesenteric distance to 2–8 mm causes duodenal obstruction. Around two thirds of patients with this syndrome are female, 75% between 10 and 39 years of age. In general population, the estimated prevalence ranges from 0.013 to 0.3%6-8. The main causes of this syndrome are severe cranioencephalic trauma, long period in dorsal decubitus position on bed, immobilization in hyperextension device, considerable weight loss accentuated by consumptive disease, eating disorders, among others. The main symptoms are: intermittent post-prandial epigastric ab-

CONCLUSION The superior mesenteric artery syndrome is a rare entity that does not enable proper food intake. 403


Journal of Coloproctology October/December, 2011

Superior mesenteric artery compression syndrome - case report Paulo Rocha França Neto et al.

The post-operative confirmation diagnosis is difficult; but, once the suspicion exists, a contrast study of the duodenum can provide a number of signs compatible with superior mesenteric artery syndrome. In some patients, computed tomography of abdomen is

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required to confirm the diagnosis. The clinical treatment is initially indicated, as it was successfully performed in the studied patient. The surgical treatment is recommended in case of clinical treatment failure, in symptomatic patients.

Resumo: A síndrome da artéria mesentérica superior é uma entidade clínica causada geralmente pela perda do tecido adiposo mesentérico, resultando na compressão da terceira porção do duodeno pela artéria mesentérica superior. Esse artigo relata o caso clínico de uma paciente portadora de adenocarcinoma de cólon sigmoide metastático irressecável, que evoluiu com vômitos incoercíveis. Realizou-se, então, trânsito intestinal que evidenciou dilatação gástrica importante, que se prolongava até a terceira porção duodenal, quadro radiológico compatível com pinçamento da artéria mesentérica superior. Diante da condição nutricional da paciente, foi optado por iniciar medidas conservadoras (porções alimentares pequenas e mais frequentes, além de decúbito lateral esquerdo após as refeições). Quatro meses após a cirurgia e as medidas conservadoras, a paciente não apresentava mais vômitos pós-prandiais, nem emagrecimento. A síndrome da artéria mesentérica inferior é incomum e os sintomas podem ser inespecíficos. Sendo assim, um índice elevado de suspeita é exigido no ajuste clínico apropriado. O diagnóstico é feito, habitualmente, através de exame radiológico contrastado. O tratamento pode, inicialmente, exigir a descompressão gástrica e a reposição volêmica, além da reversão da perda de peso com nutrição adequada. A cirurgia deve ser reservada para os casos de falha do tratamento clínico. Palavras-chave: síndrome da artéria mesentérica superior; diagnóstico; dor abdominal; duodeno; radiografia.

REFERENCES

11. Gustafsson L, Falk A, Lukes PJ, Gamklou R. Diagnosis and treatment of superior mesenteric artery syndrome. Br J Surg 1984;71:499-501. 12. Burgener FA, Kormano M. Differential diagnosis in conventional radiology. New York: Thieme, 1985. 13. Ahmed AR, Taylor I. Superior mesenteric artery syndrome. Postgrad Med J 1997;73:776-8. 14. Hunnicutt KL. A 6-year-old child with abdominal pain. Clin Pediatr (Phila) 2001;40:563-4. 15. Burrington JD. Superior mesenteric artery syndrome in children. Am J Dis Child. 1976;130:1367-70. 16. Superior mesenteric artery compression syndrome, 2009 [cited 2009 June 02]. Available from: http://www.uptodate.com. 17. Laffer LC. Acute dilatation of the stomach and acute arteriomesenteric ileus. Ann Surg 1908;47:94-7. 18. Barner HB, Sherman CD Jr: Vascular compression of the duodenum. Int Abstr Surg 1963;117:103-18. 19. Lundell L, Thulin A. Wilkie’s syndrome – a rarity? Br J Surg 1980;67:604-6. 20. Lee CS, Mangla JC. Superior mesenteric artery compression syndrome. Am J Gastroenterol 1978;70:141-50.

1.

Von Rokitansky C. Lehrbuch der pathologischen Anatomie. Vienna: Braumuller & Seidel; 1861. 2. Wilkie DP. Chronic duodenal ileus. Am J Med Sci 1927;173:643-9. 3. Derric JR, Fadhli HA. Surgical anatomy of the superior mesenteric artery. Am Surg 1965;31:545-7. 4. Wayne ER, Burrington JD. Duodenal obstruction by the superior mesenteric artery in children. Surgery 1972;72:762-8. 5. Barnes J, Lee M. Superior mesenteric artery syndrome in an intravenous drug abuser after rapid weight loss. South Med J. 1996;89:331-4. 6. Ylinen P, Kinnunen J, Hockerstedt K. Superiormesenteric artery syndrome. A followup study of 16 operated patients. J Clin Gastroenterol 1989;11:386-91. 7. Goin LS, Wilk SP: Intermittent arteriomesenteric occlusion of the duodenum. Radiology 1956;67:729-37. 8. Nugent FW, Braasch JW, Epstein H. Diagnosis and surgical treatment of arteriomesenteric obstruction of the duodenum. JAMA 1966;196:1091-3. 9. Biank V, Werlin S. Superior mesenteric artery syndrome in children: a 20-year experience. J Pediatr Gastroenterol Nutr 2006;42:522-5. 10. Cohen LB, Field SP, Sachar DB. The superior mesenteric artery syndrome the disease that isn’t, or is it? J Clin Gastroenterol 1985;7:113-6.

Correspondence to: Paulo Rocha França Neto Rua Cônego Rocha Franco 252, Bairro Gutierrez CEP 30430-000 – Belo Horizonte (MG), Brazil E-mail: paulinho.med@ig.com.br

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Special Session

Intestinal spirochetosis LUIS ROBERTO MANZIONE NADAL1, SIDNEY ROBERTO NADAL2 4th year resident in General Surgery at Hospital do Servidor Público Estadual - São Paulo (SP), Brazil; Titular in the Brazilian Society of Coloproctology (TSBCP). 2Associate Professor at the Department of Surgery at the School of Medical Sciences of Santa Casa de São Paulo – São Paulo (SP), Brazil; Supervisor of the technical team of Proctology at Instituto de Infectologia Emílio Ribas – São Paulo (SP), Brazil; TSBCP. 1

NADAL LRM; NADAL SR. Intestinal spirochetosis. J Coloproctol, 2011;31(4): 405-407. Abstract: The intestinal spirochetosis (IS) is a histologically defined by the presence of spirochetal microorganisms connected to the apical cell membrane of the colorectal epithelium. The disease is caused by a heterogeneous group of bacteria. In humans, Brachyspira aalborgi and Brachyspira pilosicoli are prevalent. The incidence ranges from 1% in developed countries to 34% in poorer areas. It affects 62.5% of colonized areas, as well as men who have intercourse with men (MSM) and those with the human immunodeficiency virus (HIV) infected. Clinical significance of such colonization is still not clear. Most infected people are asymptomatic. At the presence of gastrointestinal symptoms, treatment with metronidazole is effective. Due to unknown reasons, MSM and HIV-positive men are more likely to be symptomatic. Treponema pallidum infection must be excluded, since this agent may cause serious and permanent complications, and because the treatment is different. Keywords: spirochaetales infections; colitis, microscopic; intestinal bacterial invasion; HIV infections.

TheAcquired Immunodeficiency Syndrome (AIDS) brought a new set of conditions created by previously known opportunistic agents, in some cases considered as commensal or saprophytes1, to the clinical practice. In the coloproctological service, we are faced with diarrheas of obscure etiological diagnosis, and sometimes of complex control. The colonoscopy, important test in these cases, and the colonic mucosa biopsies are essential to treat these patients2. The cytomegalovirus, the herpes virus and, recently, bacteria from the Spirochaetaceae family, as well as the one that causes syphilis, are some of these findings. Recognizing these agents and the proper treatment ensures a better quality of life for the patient. First acknowledged by van Leeuvenhoek in the 17th century, and described in 1967 by Harland and Lee, as cited in literature3, the intestinal spirochetosis is defined as the colonization of the colon mucosal and the appendix apical membrane by gram-negative bacteria of the Spirochaetaceae family, usually Brachyspira aalborgi and Brachyspira pilosicoli3-6. The genders Leptospira and Treponema, in the same family, have histological similarities, but important differences concerning DNA and RNA3.

The microorganism spreads by the fecal-oral route, and colonization depends on sanitation, diet, behavior and immunological status. Chronic fecal stasis also favors multiplication3,4. Fecal colonization with spirochaeta, however, is not common3,5 in the population, and its incidence ranges from 1% in developed countries to 34% in the developing countries, affecting up to 62.5% of men who have intercourse with HIV positive men3,5. There seems to be no relation between the degree of immunodeficiency and the extension of the infection3. The increased incidence in this specific population suggests the sexual transmission of the agents3, besides the previously described routes. The method of choice for diagnosis is the colorectal mucosa biopsy4. The colonoscopic appearance varies from normal to moderate edema, erythema, erosions or small ulcers4. Hematoxylin eosin staining shows a thick layer or basophilic organisms covering the mucous surface, thus generating a false brush border3. There is rarely the invasion of the lamina propria. Colonization is not associated with a significant inflammation. Microorganisms can be revealed by using the periodic acid-Schiff

Study carried out at the technical team of Proctology at Instituto de Infectologia Emílio Ribas – São Paulo (SP), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 10/27/2011 Approved on: 10/28/2011

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Journal of Coloproctology October/December, 2011

Intestinal spirochetosis Luis Roberto Manzione Nadal et al.

(PAS), Giemsa, Crocotts and silver4. Immunohistochemical tests with anti-Treponema pallidum antibodies, which present a cross reaction with Brachyspira spp, have been used to identify the agent7. The polymerase chain reaction (PCR) and in situ hybridization detect bacteria in the stool and in the biopsy specimens. Generally, it is asymptomatic and detected by the colorectal mucosa biopsy3-7. A few patients present with aqueous diarrhea, weight loss, abdominal pain and rectal bleeding. The increased incidence of spirochaeta was observed in appendicectomy specimens of patients who had typical symptoms and signs of acute appendicitis, however, with no inflammation at histopathological evaluation4. The clinical significance of intestinal spirochetosis is little known, and widely reported in veterinary studies. Bacteria of the Spirochaetaceae family are considered as commensal in humans, and are usually incidentally found in intestinal mucosal biopsies, thus not being related to the referred symptoms3. However, asymptomatic patients can be safely followed-up, but the symptomatic and immunodepressed ones can be

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treated with metronidazole 500 mg three times a day, or clarithromycin 800 mg every day, for ten days. Most report relief of symptoms and recurrence is rare3,4. Secondary syphilis may cause similar symptoms. The intestinal mucosa biopsy shows granulomatous colitis7. Personal history can show unprotected sex and other forms of the disease in the skin (roseola syphilitica) or anogenital lesions (primary or secondary). Syphilis is known as the “great impersonator”, and may simulate different impacts on all the organs and  systems7. Proper diagnosis, treatment and follow-up prevent complications. For the HIV-positive patients, it causes the increase of viral load and the decrease of T CD4 lymphocytes, which are reversed after treatment with penicillin8. Colitis caused by spirochaeta is rare, but should be part of the differential diagnosis of infectious diarrhea in immunocompromised patients, especially among those who have anal sex. Secondary syphilis with colorectal location should be ruled out for presenting similar symptoms, because the treatment is different and the complications of the untreated disease are severe, permanent and disabling.

Resumo: A espiroquetose intestinal está definida histologicamente como a presença de micro-organismos da família spirochetaceae ligadas ao ápice das células do epitélio cólico. A doença pode ser provocada por um grupo heterogêneo de bactérias. Em humanos, a Brachyspira aalborgi e a Brachyspira pilosicoli predominam. A incidência varia desde 1%, nos países desenvolvidos, até 34% nas áreas mais pobres, atingindo taxas de colonização de 62,5%, em homens que fazem sexo com homens (HSH) e vírus da imunodeficiência humana (HIV) positivo. O significado clínico dessa colonização ainda é incerto e a maioria dos infectados permanece assintomática. Quando há sintomas gastrointestinais, o tratamento com metronidazol é efetivo. Por razões desconhecidas, HSH positivos para o HIV, apresentam mais infestação sintomática. A infecção pelo Treponema pallidum dever ser excluída, pois os tratamentos são diferentes e as complicações por essa última são mais graves e definitivas. Palavras-chave: infecções por spirochaetales; colite microscópica; invasão bacteriana intestinal; infecções por HIV.

REFERENCES 1. Nadal SR, Calore EE, Manzione CR, Horta SHC, Ferreira AF, Almeida LV. Hypertrofic herpes simplex simulating neoplasias in AIDS patients. Dis Colon Rectum 2005;48(12):2289-93. 2. Manzione CR, Nadal SR, Calore EE, Manzione TS. Achados colonoscópicos e histológicos em doentes HIV+ com diarréia crônica. J Coloproctol 2003;23(4):256-61. 3. Tsinganou E, Gebbers JO. Human intestinal spirochetosis – a review. GMS Ger Med Sci 2010;8:Doc 01. 4. Panackel C, Sebastian B, Mathai S, Thomas R. Intestinal spirochaetosis. Indian J Pathol Microbiol 2010;53(4):902-3. 5. Zubiaurre L, Zapata E, Castiella A, Rodríguez J, Zaldumbide L. Intestinal spirochetosis. Gastroenterol Hepatol 2011;34(1):58-9. 6. Schmiedel D, Epple HJ, Loddenkemper C, Ignatius R, Wagner

7.

8.

J, Hammer B, et al. Rapid and accurate diagnosis of human intestinal spirochetosis by fluorescence in situ hybridization. J Clin Microbiol 2009;47(5):1393–1401. Gaspari V, D’Antuono A, Misciali C. Secondary syphilis with intestinal involvement: description of a case. G Ital Dermatol Venereol 2008;143(1):79-82. Kofoed K, Gerstoft J, Mathiesen LR, Benfield T. Syphilis and human immuno- deficiency virus (HIV)-1 coinfection: influence on CD4 T-cell count, HIV-1 viral load, and treatment response. Sex Transm Dis 2006;33(3):143-8.

Correspondence to: Luis Roberto Manzione Nadal Rua Mateus Grou, 130 – Pinheiros CEP 05415-040 – São Paulo (SP), Brazil E-mail: clinicamn@gmail.com

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Special Session

Crohn’s Disease: Current state of biological therapy Doença de Crohn: Estado atual da terapia biológica Júlio César Monteiro Santos Júnior, TSBP1 Department of Surgery at the Coloproctology Section of Hospital Maternidade Frei Galvão – Guaratinguetá (SP), Brazil; Full Member of the Brazilian Society of Coloproctology.

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Santos Júnior JCM. Crohn’s Disease: Current state of biological therapy. J Coloproctol, 2011;31(4):408-419. Abstract: The inflammatory bowel diseases (IBD) are defined as nonspecific chronic intestinal inflammations with possible systemic involvement. IBD have unknown etiology. The inflammatory process is complex and heterogeneous, both as to the characterization of the disease that affects the digestive tract, without an intelligible pattern of revelation and balance, and in its different systemic damages when including the extensive and severe extraintestinal symptoms. Aparently, the natural history of the disease is irregular in relation to the offending agent system and the attacked system, both in the intestinal and extraintestinal teguments. Isolated aspects showing irregularity in this balance gives us the notion that IBD, especially Crohn’s disease, can be caused by the stimulation of an immune response caused by damaging agents (intestinal bacteria), but mediated by inadequate genetic factors, whose expressions determine different individual susceptibilities. These observations have been shown in genetic studies that emphasize the importance of pathological interaction between host and bacteria subsidized by a genomic region that contains genes producing proteins (NOD2 - nucleotide-binding oligomerization domain containing 2) participating in an enhanced defense response by the tissue. Increased numbers and the activation of these cells in the intestinal mucosa elevate local levels of tumor necrosis factor α (TNF-α), interleukin1β, interferon-γ, and cytokines of the interleukin-23–Th17 pathway. So, it can be assumed that the susceptibility, which is a result of genetic alterations, is connected to an exaggerated response in the pro-inflammatory phase because of a dysfunction in the intestinal immune system. The identification of tumor necrosis factor (TNF-α) as the active element in the pro-inflammatory inadequate response gave rise to the heightened production of biological substances that could block TNF-α, at different levels, opening a large field of view to new treatment of IBD. Keywords: Crohn’s disease; tumor necrosis factor-alpha; monoclonal antibody.

INTRODUCTION

This study focuses on Crohn’s disease (CD) and the current state of biological therapy. CD was first mentioned by Charles Combe and William Saunders, in 18061; they described some observations resulting from necroscopic examinations of specimens in which the lesion was characterized by stenosis, affecting the distal ileum and with colon involvement; in this segment, constriction zones measuring approximately 7 cm each were observed and separated by preserved parts.

Inflammatory bowel diseases (IBD) are defined as unspecified chronic inflammation of the digestive tract with skin and articular manifestations of unknown etiology. Concerning this subject, most authors mention proctocolitis and Crohn disease. These are different diseases, whose clinical common aspects are usually abdominal pain, diarrhea, bleeding, anemia and weight loss.

Study carried out at the Department of Surgery at the Coloproctology Section of Hospital Maternidade Frei Galvão – Guaratinguetá (SP), Brazil. Financing source: none. Conflict of interest: nothing to declare. Submitted on: 08/07/2011 Approved on: 08/15/2011

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The ileal serosa of the stenosed segment, as well as in the colon, thickened due to the inflammatory process. In 1859, Samuel Wilks2 observed similar cases. However, Crohn et al. conducted the first well-documented series of the disease in 1932, at Mount Sinai Hospital, in NewYork1. CD has been known for more than 200 years, but is still subject of scientific speculations; so far, its etiology has not been clarified. The inflammatory process is complex and heterogeneous, be it in the characterization of the disease, which compromises the digestive tract and does not follow an intelligible pattern of manifestation and balance, be it in its different systemic expressions3, when they relate to extensive and severe extraintestinal manifestations4. Significant systemic signals and symptoms of CD can be observed when it compromises children (infants or preschoolers). As to these patients, remarkable systemic damage is caused by growth disorders. Also, growth and height deficiency is relevant for children, since it can be the first manifestation of CD 5. Fever of unknown origin, loss of appetite, pain and weight loss can precede the factors related to more objective manifestations of the disease5,6. Relevant extraintestinal changes that are common to CD affect organs and systems simultaneously, with varied degrees of severity4. The spectrum of extraintestinal changes demonstrates the unspecified characterization of the disease with etiopathogenic basis connected to the system of origin that is common to other chronic inflammatory diseases; this brings out its condition of systemic disease4. Anterior uveitis (iridocyclitis), for instance, is one of the extraintestinal complications of CD, and is also related to a great number of autoimmune and autoinflammatory diseases7. In this sense, rheumatic diseases appear (seronegative spondyloarthritis, whose group is characterized by inflammations of one or more joints, big or small, and tendons and muscularscheletic insertions). Among these, sacroiliitis and ankylosing spondylitis8-10 are common for CD, and much more frequent than it is observed in practice, since early changes that cannot always be shown by imaging resources can be asymptomatic, thus going unnoticed10,11.

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Articular manifestations stand out due to pain of varied intensity, according to the extension of the inflammatory process, with the risk to lose mobility or even the articular function11. On the other hand, besides the endocrinological changes that have an impact on the immune system12, there are external integumentary lesions, such as erythema nodosum and pyoderma gangrenosum. Although the cause of erythema nodosum is usually unknown in about 30 to 50% of the time, it can also be connected with a variety of autoimmune diseases, like Crohn’s and Behçet, as well as infections caused by streptococcus, tuberculosis, mycoplasmal, diseases related to the Epstein-Barr virus and other herpetic lesions13. The pyoderma gangrenosum, which is a neutrophilic dermatosis of unspecific etiology14-18 and whose necrosis and deep ulcers make the lesion look very unpleasant and painful, is an integumentary disease regarding a dysfunction in the immune system, which has a relation with Crohn’s disease19. Observing the immunologic response and aiming to understand a bit more about CD in order to explain its etiopathogeny20,21, there are speculations as to the immune response of the intestine, since is mediation occurs by factors such as: mucus barrier, mucus architecture and integrity, cellular components and their specific functions, and circulating cells of tissue defense. The balance of intestinal immunity is present at birth; afterwards, it expands with the definition of the intestinal flora until the establishment of the system’s homeostasis, that is, a balanced and healthy interaction between host and the luminal microecosystem. Isolated or connected aspects that demonstrate some irregularity in this balance give us the notion that the IBDs, especially CD, may be caused by the stimulation of an immune response provoked by aggressive agents (intestinal bacteria, for example), but inadequately mediated by genetic factors. Their expressions define different individual susceptibilities20, which are not only seen in the extension the intestinal mucosa compromise, but also by the dimension and nature of transmural changes. They are also caused by local vascular changes, involved in the inflammatory process; by the manifestations and systemic associations with other immune diseases; by the responses to 408


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clinical conventional treatments; and, finally, by other data that characterize the natural history of the disease and its specificities, for each person15,16. These observations have been analyzed in genetic studies that demonstrate the importance of the pathological interaction between host and bacteria21 – almost exclusively because of the host, rather than the bacteria – subsidized by a genomic region that contains genes that produce proteins (nucleotide oligomerization double-domain protein – NOD2) and participates in the response of tissue defense by signaling the activation of the immune response system; by autophagy genes and by reaction paths with interleukin-23 components competing with T lymphocytes (Th-17)22-26. In the NOD2 gene, the protein’s role is related to the response of the host defense by signaling the activation of caspase (family of intracellular cysteine endopeptidases that help regulate the inflammation and the apoptosis) and of the system of protein kinase signaling, activated by mitogens (MAP-kinases), a system of intracellular signaling which involves the MAP-kinases cascade – subfamily of enzymes that respond to the extracellular stimulation and regulate the activities of gene expressions, mitosis, differentiation, cellular survival and apoptosis. Usually, the protein codified by the gene NOD2 works as an intracellular sensor of murein, which is a polyssacharide (peptidoglycan) of the cell wall of the bacteria. The most susceptible association with CD23,27 was made with changes in the NOD2. Three gene polymorphous that codify the nucleotide oligomerization of the domain 2 of the protein with flaws are known to harm the responses that are sensitive to murein28,29. Usually, the secretion of proinflammatory cytokines by the antigen cells that are present in the intestinal wall is minimal, since the invading bacteria are destroyed. This results in the power of defense of the immune system against the elements of the intestinal microecosystem without causing tissue lesion30. However, with the aforementioned genetic polymorphism, among other homeostatic changes of the intestinal immune system that occur on patients who have CD, especially that characterized by the higher cellular presence that mediates an ineffective activity against peptidoglycan in the cell wall of the bacteria, it is easy to increase the production of cytokines (such as the tumoral necrosis factor – TNF – and interleukin-1β) and

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antimicrobial peptides27, 31. Thus, there is an exaggerated secretion of proinflammatory cytokines. This process involving the contribution of the NOD2 gene polymorphism to the intestinal inflammation observed at CD is complex and not completely understood27 – there are over 30 genomic locus involved in the genetics of CD33,34. However, the general idea is that the active stage of the inflammatory process is characterized by the lamina propria of the mucosa with defense cells (neutrophils, macrophages, dendritic cells and T-killer leukocytes), without the presence of an increased invasion of microbes. Under these conditions, the susceptibility caused by gene changes may be connected to an exaggerated response in the proinflammatory phase, as a result of a dysfunction in the intestinal immune system21. BIOLOGICAL THERAPY The biological therapy, which is under analysis in this study, will result in the biological response modifiers of the intestine, with special attention to the blockage of specific cytokines that modulate the inflammatory process at the existence of genetic pleomorphism21,27,35. Genetic aspects involving CD have been known since the past century, usually due to epidemiological studies addressed to etiological and pathogenetic factors36-40. However, the genetic perspective was only established after the first gene related to CD was described41, and successfully confirmed42-44. The pathogenesis of CD and its genetic link is partly subsidized by the complicated interaction between immune, innate and adaptive cells, involving the vascular blood and the lymphatic intestinal systems, as well as local tissue immunity. There is the participation of cytokines and genetically controlled modulators, which provides more or less balance as to the tolerance of the organism to the intestinal “microbiota”, expressed by proinflammatory responses, which may be inadequate21,35,45,46. The observations of these inadequate responses and of proper genetic studies led to the acknowledgement of the association between CD and NOD2 gene polymorphism, as aforementioned. This gene is relatively common among CD patients coming from Eu409


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rope, is absent among Asians and rare among African American people with the disease26,27,29,47. Estimates show that approximately 30% of the patients with CD coming from Europe have at least one of the three NOD polymorphism genes. Those who carry the polymorphism gene are more prone to presenting ileal disease, with a complication related to stenosis and the need for surgical resection, when compared to those who do not carry it31; heterozygotes have increased risk of CD (factor 1.75 to 4), while homozygotes have a much higher risk (factor 11 to 27)30. However, the NODS polymorphism gene alone is not sufficient to cause CD, which demonstrate the complex aspects of the multifactorial disease, that is yet to be fully understood21,48. In the process of proinflammatory activity, among the different cytokines that are produced, the tumoral necrosis factor stands out (TNF-α), which is a model of proinflammatory cytokine with multiple effects on the innate and adaptive immune system cells, as well as on the vascular endothelium of microcirculation49,50. The tumoral necrosis factor stimulates the stage of acute inflammation, as well as apoptosis. It also increases the production of cytokines and the cytokines of small peptides; it increases the secretion of elastase and collagenase; it increases the properties of molecular adhesion to the vascular endothelium; and promotes the accumulation of leukocytes in the tissue51. These multiple actions define the pleiotropic feature of TNF- α, turning it into a specific target for the treatment of intestinal bowel disease50. The interpretation of this fact, which is not only related to CD, but also to other autoimmune inflammatory diseases, led to the conduction of research plans with the objective to create substances that should be completely produced by the host, and at the same time able to block the unwanted actions of active proteins that impact the proinflammatory stage. However, it should present low specificity for the invading antigen with harmful effects for the host. Current information taken from studies concerning the association of genetics with the clinical aspects and the results of animal experiments about the inflammatory bowel phenomenon have gathered elements to interpret that the etiopathogenesis of CD may be at least partly dependent on a innate genetic

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error, which promotes the unbalance of the intestinal immune system. The disorder that appears during the proinflammatory stage expresses itself by the exaggerated production of cytokines (TNF and interleukin-1β) and antimicrobial peptides27,52. Among these cytokines, TNF-α has been considered as the key element49,51,53,54, thus becoming the target for the development of new therapy strategies for CD55-59. Monoclonal antibodies In 1901, Paul Ehrlich and Johan Morgenroth used the term “self-toxic horror” to express their “concern for the destruction that an autoimmune reaction could cause in relation to the inflammatory response, which is so necessary to protect the organism”. The formation of tissue autotoxin, result of the defense process, however, could be a real threat to the living being60. Such concept became the basis for future knowledge regarding autoimmune diseases, the systemic inflammatory reaction and multiple organ failure. As to IBD, the importance of TNF-α and its pleiotropic aspects for the triggering of tissue changes and the emerging challenge related to the idea of specific agonist block, connected to knowledge regarding immunotherapy (the discovery of the antibody structure and the development of hybridoma) and the subsequent production of monoclonal antibodies, led to the first intention to create the proteins “originating from different genes and species” (chimeric* proteins = obtained by means of genetic modifications, linking factors from two species, for example: mouse-human). Thus, as a monoclonal antibody, it is possible to oppose to the action of TNF-α. The terms chimeric and “humanized” – referring to monoclonal antibodies – are used to express the combination of sources coming from human and mouse DNA in the process of recombination, which leads to the formation of the antibody61. Infliximab The first monoclonal antibody to be therapeutically used for autoimmune human diseases that interested CD therapy was infliximab, which was first administrated for the treatment of rheumatoid arthritis62,63. 410


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Created in the 1990s, infliximab is a monoclonal antibody (IgC1) of human nature (constant region – 75%) and murine (variable region – 25%), which binds to human TNF (TNF-α) and neutralizes its biological action. Originally, the antibody was believed to obstruct the link between the cytokine and its natural receptor64,65. However, the observation that another blocker, called etanercept – which is not a monoclonal antibody, but blocks the action of TNF-α by binding with the receptor without producing any biological effect over CD, or causing a situation that is worse than the placebo66 –, led to other speculations about the pharmacological action of infliximab. As a result, it was demonstrated that the action of the monoclonal antibody is extended to the lymphocytes of the peripheral blood and to the lamina propria T-lymphocytes, inducing both to apoptosis66-68. The first relevant studies were published by the end of the 1990s55-58,69, with promising results as to the action of infliximab on CD, specially the fistulizing effect involving multicentric cooperation. Along the past ten years, more than 50 publications addressed to the treatment of IBD, including CD in its different forms, prove the positive results of the long and medium term therapy with the chimeric monoclonal antibody, including for infants70-78. The first promising responses for 61% of the treated patients versus 17% on placebo come from double prospective study (placebo-medicine) conducted with more than 100 patients with CD refractory to the conventional treatment, with high levels of disease activity, using different doses of infliximab (5, 10 and 20 mg/kg). Clinical responses were registered on week 2, similar to the 70-point drop in CD activity index (CDAI). Besides this answer, this stage also demonstrated clinical remission in 27% of the treated patients, against 8% in the placebo group55. Non-controlled studies conducted in a short period to compare clinical results with population studies were developed afterwards79,80. In Italy, the experience was registered in a project with 63 patients; some had refractory CD (31 patients) and others had fistulizing CD (32 patients). In order to assess the results, clinical remission for the group with refractory CD, analyzed on week 0, 2 and 6, was defined by the authors as CDAI≤150, and clinical response was determined with a 70-point drop or

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more in the initial score. For the group with fistulizing CD, the complete response was defined as the fistula closure observed in the evaluation performed on week 10, or as the partial response in situations in which the number, size and drainage of the fistulae decreased on the same week79. In this study, clinical response on week 2 was observed in 42.5% of the patients with refractory CD, while clinical remission was observed in 31.3% of the patients. More precise data were noticed on week 10, with clinical response in 80.6% and remission in 71% of the patients. Among patients with fistulizing CD, 47% presented full responses, 25% had partial responses and 28% showed no responses whatsoever until the end of the treatment. Side effects were present in 16% of the patients, and were interpreted by the authors as a result of the immunomodulator therapy used as adjuvant79. In Hungary, the results of a multicentric experience involving 363 patients for 6 years in a geographically extensive and long-lasting study were reported. The group had patients with refractory CD (31.4%), patients with fistulizing CD (53.7%), steroid-dependent CD patients (7.2%) and patients with both situations – refractory and fistulizing CD (4.4%)80. In the global scenario, response to therapy was 86.2%. The most significant positive results were observed in patients who had been recently diagnosed, and among those who have had concomitant immunomodulator therapy. Adverse effects were allergic reactions (9.4%), late hypersensitivity (4.7%), infection (4.4%) and malignant neoplasm (0.8%). These results were considered as good, but there was the suggestion of the concomitant effect of immunodepression80. As for infants, infliximab was also tested as to safety and effectiveness. The project Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry, that aims to evaluate the long-term therapy, included 729 children in a multicentric study (approximate age of 16 years)75. Patients who had infliximab – a group of 202 children – presented clinical history and diagnosis of the disease for a period that ranged from 1 year, one to two years, and older than two years (62, 23 and 15%, respectively). Immunomodulators and steroids were used as an adjuvant therapy among children who needed a prolonged treatment. Treatment with infliximab lasted less than one year, up to three years, and children remained with the inactive disease, 411


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without other medications or surgical treatment75. Despite the exciting benefits75,81, and before the top down approach to the treatment with infliximab81,82 is established, the case reports that explain the effects of remission caused by the monoclonal antibody should be emphasized, especially regarding infants. That is why it is important to review the duration and the meaning of benefic effects in this population, especially by observing that prolonged use was followed by “loss of response”, with limited duration of the effect, since 50% of the patients lose the benefits after five years under maintenance treatment. This forces the doses to be adjusted so the prior levels of therapy effectiveness could be reached, thus substantially increasing the time of submission to the medicine. Besides this lack of efficiency, such exposure for patients who initially needed continuous infusions and adjustments for a longer period increases the chances of unwanted side effects, thus leading to the search for new therapy strategies for the infants with CD83. Similar aspects have been observed in the adult population: 25 to 40% of the patients who presented clinical responses to early therapy stopped responding effectively to the medication. In this case, they needed to have their doses and intervals readjusted; sometimes, the medication needed to be discontinued for a significant number of patients because it completely lost its efficiency, or due to side effects76,84-86. This sudden loss of action is probably related to the high concentration of antibodies against infliximab87,88 in a patient who used staggered doses of monoclonal antibody for an efficient therapy response, probably induced by the murine fraction of infliximab89-91.

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is simple, and the application is subcutaneous, which facilitates its use. The recommendation for CD, especially in the most complicated cases, is 160 mg as the induction dose on the first day, followed by 80 mg on the 14th and 40 mg on the 28th day. The history of this new antibody begins with the publication of clinical trials concerning the action on rheumatoid arthritis, in 199992. In 2002, ADA was approved by FDA to treat rheumatoid arthritis and, in 2007-2008, it was subsidized by the studies of Hanauer et al.95 and Sandborn et al.96, respectively. It did not only prove its efficiency and safety to induce the remission of the disease in patients who have not used a monoclonal antibody95, but also tested its action as to maintenance of response96, including in patients who had been treated with infliximab97; it also demonstrated balance as to prolonged use98. These results gave new directions for the treatment of CD, especially due to the “purity” of ADA and by the growing number of patients for whom the failed response to infliximab showed something similar to what had been observed with other drugs used to treat CD. The results of the treatment with ADA were beneficial for 60% of the patients for an average period of 2 years, not only favoring those who had been under monoclonal antibody, but also for those who were using it for the first time. However, after a while and with the growing number of patients included in the studies, for a relevant number of people (28%)99 the antibody also lost its effect due to immunological intolerance99,100. The population involved had twice as many patients who had received anti-TNF in relation to those who were being treated for the first time (22 versus 8% per patient per year of treatment). For those patients who presented with the extraintestinal manifestation of CD, the risk of losing efficiency is even higher101. In spite of that, the initially surprising results have been interpreted as a rich and suggestive experience – for example, in the infant population – that can guide the “early introduction of the monoclonal antibody with the hope to change the natural course of CD in this population”81,82,102, thus inducing the idea of “top-down” therapy. On the other hand, an interesting point observed in investigations that comprise groups on drugs and placebo groups, even if the difference among them is not mathematically defined, is that the positive results in the placebo group are not negligible. In the study about the induction of remis-

Adalimumab Adalimumab (ADA) – result of a joint research (BASF Bioresearch Corporation and Cambridge Antibody Technology) that initiated din 199392 – is a monoclonal antibody, just like infliximab, type IgG1, but its composition is 100% human. It is the third substance directed to TNF after infliximab and etanercept, and the second monoclonal developed for humans with the goal to act the same as the first, but with the likely advantage not to cause the unwanted effects of reaction to hypersensitivity93,94. Thus, it is useful to treat CD in a patient who is “resistant” to infliximab59. The posology 412


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sion using ADA, it was observed that, among the 301 patients who completed the investigation – 159 in the group on drugs and 166 in the placebo group –, 21% of those who had drugs and 7% of those who were in the placebo group presented clinical remission on week 4. When the result was assessed by the CD activity index (CDAI)103 for 70 points, comparison values between group on drugs and placebo group were 52 and 34%, respectively. In both circumstances, the differences were statistically confirmed97. It is a known fact that remission in CD can be spontaneous. If we could remove these values spontaneously generated in the treated group, the difference between groups would certainly not be 14.2% for clinical remission, nor 17.8% for the points given by CDAI. The loss of response and the need to intensify the dose involve medical and economic interests that may cause unwanted repercussions for the patients. With the profile of a substance that is able to cause the remission of CD both in patients who had not been treated with a monoclonal antibody and in those who were victims of infliximab95,104, ADA was used with the expectation that the results could be superior to those observed with infliximab, especially concerning prolonged use and no loss of activity. This is because other effects, whose frequencies may range from 1 to 26% (1, 11 and 26%, including dose adjustment, temporary discontinuation and permanent withdrawal, respectively), are sometimes negligible, but of variable severity, such as mere allergic reactions (cutaneous rash, pruritus, difficulty breathing, constrictive chest pain, although, under some circumstances, they may be severe105-107 and fatal108, which requires a criterious selection of patients110). The loss of response that corresponds to 18.2% means 20.3% of risk per patient a year. The average number of patients who needed to reinforce the dose among primary users was 37%, with a risk of 24.8% per patient/year. Considering the ones who primarily presented good response to ADA and those who did not respond well, the mean percentage of patients who needed to progressively increase their dose was 21.4%, with annual risk of 24.4% per patient/year. On the other hand, the group who required reinforcement recovered the response in 71.4% of the cases, and showed remission in 40%111. The same study that showed these data demonstrated the possibility to predict loss of response

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or the need for the staggered increase of the dose, especially concerning the following factors: male, smokers, family history of IBD, disease restricted to the colon, extraintestinal manifestations, induction with a 40/80 mg dose, long term condition, prior use of monoclonal antibody (infliximab), no good response111,112. Actually, one out of five patients experiments loss of response and needs a dose reinforcement111. Relevant aspects resulting from these facts have recently been approached by Dretzk et al.111 in a systematic review about the benefit-cost involving two monoclonal antibodies, with emphasis for the following conclusions: a. “therapy with adalimumab and infliximab may be beneficial in comparison with the conventional treatment, when the results are measured at induction and maintenance”; b. for induction both have benefits that compensate for the cost when compared to the conventional treatment applied on severe CD; the same is true for ADA in relation to moderate CD, but not for infliximab; c. based on this review, “none of the two drugs is profitable as a maintenance therapy, be it for severe or moderate CD”. CONCLUSION The new formal knowledge about etiopathogeny of CD, especially when it depends on genetic changes and the relation between the proinflammatory activity of TNF-α in the mechanism of tissue lesions, enabled the development of monoclonal antibodies, which were profusely used due to the belief that it would be possible to change the natural history of the disease. This way, the dream to offer an unprecedented benefit-cost treatment could come true. However, the association between CD and NOD2 polymorphism gene is variable among populations, being relatively common among patients with CD from Europe, but is absent among Asians, and rare among African Americans with the disease26,27,29,47. This gives CD a multifactorial etiologic character, with or without the genetic implication. These facts could involve data to explain the more or less efficient action of the monoclonals. For now, the most effective procedure involving the biological therapy should meet some criteria that should be at least defined to choose the candidates for treatment with monoclonal antibodies. 413


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munosuppressors) and was planned for a definite time of 12 months, or earlier, if the treatment fails; 4. The treatment with adalimumab or infliximab should only continue if it becomes clear that the disease is active by clinical symptoms, biological markers, endoscopic tests, if necessary; 5. For its purpose, CD is considered severe when the general health status is significantly compromised, associated with one or more symptoms, such as: weight loss, fever, severe and frequent abdominal pain (3-4 times or more per day), daily diarrhea, regardless of presenting extraintestinal manifestations or fistula. This definition corresponds to CDAI103 of 300, or a Harvey-Bradshaw index lower than 8-9; 6. Treatment with infliximab or adalimumab should be administered and assessed by doctors who have experience with TNF-α inhibitors and with the treatment of patients with CD.

So, the National Institute for Health and Clinical Excellence (UK) brings about some items whose interest and relevance enable to transcript six of them114: 1. Infliximab and adalimumab are recommended for adult patients who have severe CD and do not respond to conventional therapy (including steroids and immunosuppressors), or for those who do not tolerate medicines or present factors that contraindicate the use of conventional therapy. Infliximab or adalimumab should be in accordance with a treatment plan in which the administration will be continued until there is no response, or 12 months after the beginning, or less, if there is any problems; 2. Treatment should be initiated with cheaper drugs, considering the cost of administration, the necessary doses and the price per dose; 3. Infliximab was released to treat fistulizing CD after not responding to conventional treatment (including antibiotics, surgical drainage and im-

Resumo: As doenças intestinais inflamatórias (DII), definidas como inflamação crônica inespecífica dos intestinos, com eventual comprometimento sistêmico, são de etiologia desconhecida. O processo inflamatório é complexo e heterogêneo, tanto na caracterização da doença que atinge o trato digestório, onde não obedece a um padrão inteligível de revelação e de equilíbrio, como em seus variados danos sistêmicos, quando englobam os extensos e graves sintomas extraintestinais. Tudo indica que, na história natural da doença, há uma notável irregularidade entre agente agressor e sistema agredido, tanto a nível intestinal, como nos tegumentos extraintestinais. Aspectos isolados ou de conjunto que denotam irregularidade nesse equilíbrio dão-nos a noção de que as DII, sobretudo a doença de Crohn, podem ser originadas pela estimulação de uma resposta imune, provocada por agentes agressores (bactérias intestinais, por exemplo), mas mediadas de forma inadequada por fatores genéticos, cujas expressões determinam diferentes susceptibilidades individuais. Essas observações têm sido realçadas em estudos genéticos, que destacam a importância da interação patológica entre hospedeiro e bactéria, subsidiados por uma região genômica que contém genes produtores de proteínas (proteína de dois domínios de oligomerização de nucleotídeos - NOD2), com participação na resposta de defesa tecidual pela sinalização da ativação do sistema de resposta imune; por genes autofágicos e por vias de reações com componentes de interleucinas-23 com a concorrência de linfócitos-T (Th-17). Nessas condições, o que pode ser suposto é que a susceptibilidade, que decorre de alterações gênicas, esteja ligada a uma exagerada resposta na fase pró-inflamatória, decorrente de uma disfunção do sistema imune intestinal. A identificação do fator de necrose tumoral (TNF-α) como o elemento ativo na resposta pró-inflamatória inadequada e exacerbada ensejou a produção de substâncias biológicas que fossem capazes de bloquear o TNF-α, em diferentes níveis, abrindo um campo grande de perspectiva para novo tipo de tratamento das DII. Palavras-chave: doença de Crohn; fator de necrose tumoral alfa; anticorpo monoclonal.

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O’ Keefe SJ. Nutrition and gastrointestinal disease. Scand J Gastroenterol Suppl 1996;220:52-9. 7. McGonagle D, Aziz A, Dickie LJ, McDermott MF. An integrated classification of pediatric inflammatory diseases, based on the concepts of autoinflammation and the immunological disease continuum. Pediatr Res 2009;65(5 Pt 2):38R-45R. 8. Dekker-Saeys BJ, Meuwissen SG, Van Den Berg-Loonen EM, De Haas WH, Agenant D, Tytgat GN. Ankylosing spondylitis and inflammatory bowel disease. II. Prevalence of peripheral arthritis, sacroiliitis, and ankylosing spondylitis im patients suffering from inflammatory bowel disease. Ann Rheum Dis 1978;37:33-5. 9. Lanna CCD, Ferrari MLA, Carvalho MAP, Cunha AS. Manifestações articulares em pacientes com doença de Crohn e retocolite ulcerativa. Rev Bras Reumatol 2006;4(S1):45-51. 10. Bandinelli F, Milla M, Genise S, Giovannini L, Bagnoli S, Candelieri A, et al. Ultrasound discloses entheseal involvement in inactive and low active inflammatory bowel disease without clinical signs and symptoms of spondyloarthropathy. Rheumatology (Oxford) 2011;50(7):1275-9. 11. Orchard TR, Wordsworth BP, Jewell DP. Peripheral arthropathies in inflammatory bowel disease: their articular distribution and natural history. Gut 1998;42(3):387-91. 12. Hayes CE, Nashold FE, Spach KM, Pedersen LB. The immunological functions of the vitamin D endocrine system. Cell Mol Biol (Noisy-le-grand) 2003;49(2):277-300. 13. Mert A, Ozaras R, Tabak F, Pekmezci S, Demirkesen C, Ozturk R. Erythema nodosum: an experience of 10 years. Scand J Infect Dis 2004;36(6-7):424-7. 14. Bhat RM. Management of pyoderma gangrenosum--an update. Indian J Dermatol Venereol Leprol 2004;70(6):329-35. 15. Hayes RC, Curtis A. Pyoderma gangrenosum with a contiguous erosion of the distal ulna. J Cutan Med Surg 2004;8(3):162-5. 16. Horner B, El-Muttardi N, Mercer D. Pyoderma gangrenosum complicating bilateral breast reduction. Br J Plast Surg 2004;57(7):679-81. 17. Joshi A, Mamta. Behcet’s syndrome with pyodermagangrenosum-like lesions treated successfully with dapsone monotherapy. J Dermatol 2004;31(10):806-10. 18. Menachem Y, Gotsman I. Clinical manifestations of pyoderma gangrenosum associated with inflammatory bowel disease. Isr Med Assoc J 2004;6(2):88-90. 19. Freeman HJ. Erythema nodosum and pyoderma gangrenosum in 50 patients with Crohn’s disease. Can J Gastroenterol 2005;19(10):603-6. 20. Shanahan F. Host-flora interactions in inflammatory bowel disease. Inflamm Bowel Dis 2004;10(S1):S16-24. 21. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med 2009;361(21):2066-78. 22. Yamazaki K, McGovern D, Ragoussis J, Paolucci M, Butler H, Jewell D, et al. Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn’s disease. Hum Mol Genet 2005;14:499-506.

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23. McCarroll SA, Huett A, Kuballa P, Chilewski SD, Landry A, Goyette P, et al. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn’s disease. Nat Genet 2008;40:1107-12. 24. Parkes M, Barret JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA, et al. Sequence variants in the autophagy gene IRGM and multiple other repicanting loci contribute to Crohn’s disease susceptibility. Nat Genet 2007;39:830-32. 25. Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, et al. Genome-wide association study identifies new susceptibility loci for Crohn’s disease and implicates autophagy in disease pathogenesis. Nat Genet 2007;39:596-604. 26. Cho JH, Weaver CT. The genetics of inflammatory bowel disease. Gastroenterology 2007;133:1327-39. 27. Abraham C, Cho JH. Functional consequences of NOD2 (CARD15) mutations. Inflamm Bowel Dis 2006;12(7):641-50. 28. Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L, et al. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol 2003;4(7):702-7. 29. Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 2003;278(11):8869-72. 30. Economou M, Trikalinos TA, Loizou KT, Tsianos EV, Ioannidis JP. Differential effects of NOD2 variants on Crohn’s disease risk and phenotype in diverse populations: a metaanalysis. Am J Gastroenterol 2004;99(12):2393-404. 31. Lesage S, Zouali H, Cezard JP, Colombel JF, Belaiche J, Almer S, et al. CARD15/NOD2 mutational analysis and genotypephenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet 2002;70(4):845-57. 32. Cho JH, Weaver CT. The genetics of inflammatory bowel disease. Gastroenterology 2007;133(4):1327-39. 33. Barrett JC, Hansoul S, Nicolae DL, , Cho JH, Duerr RH, Rioux JD, et al. Genome-wide assocition defines more tha 30 distinct susceptibility loci for Crohn’s disease. Nat Genet 2008;40:955-62. 34. Cho JH, Abraham C. Inflammatory bowel disease genetics: Nod2. Annu Rev Med 2007;58:401-16. 35. Abraham C, Cho JH. IL-23 and autoimmunity: new insights into the pathogenesis of inflammatory bowel disease. Annu Rev Med 2009;60:97-110. 36. Maraka Z. Pathogenesis and aetiology of inflammatory bowel disease. In: Dombal FT, Myren J, Bouchier IAD, Watkinson G, editors. Inflammatory Bowel Disease - Some international data and reflections. Oxford: Oxford University Press; 1986. p.29-65. 37. Bayless TM, Tokayer AZ, Polito JM 2nd, Quaskey SA, Mellits ED, Harris ML. Crohn’s disease: concordance for site and clinical type in affected family members--potential hereditary influences. Gastroenterology 1996;111(3):573-9. 38. Polito JM 2nd, Childs B, Mellits ED, Tokayer AZ, Harris ML, Bayless TM. Crohn’s disease: influence of age at diagnosis

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on site and clinical type of disease. Gastroenterology 1996;111(3):580-6. 39. Polito JM 2nd, Rees RC, Childs B, Mendeloff AI, Harris ML, Bayless TM. Preliminary evidence for genetic anticipation in Crohn’s disease. Lancet 1996;347(9004):798-800. 40. Lee JC, Bridger S, McGregor C, Macpherson AJ, Jones JE. Why children with inflammatory bowel disease are diagnosed at a younger age than their affected parent. Gu. 1999;44(6):808-11. 41. Hugot JP, Laurent-Puig P, Gower-Rousseau C, Olson JM, Lee JC, Beaugerie L, et al. Mapping of a susceptibility locus for Crohn’s disease on chromosome 16. Natur. 1996;379(6568):821-3. 42. Cavanaugh J. International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16. Am J Hum Genet 2001;68(5):1165-71. 43. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 2001 31;411(6837):603-6. 44. Gasche C, Grundtner P. Genotypes and phenotypes in Crohn’s disease: do they help in clinical management? Gut 2005;54(1):162-7. 45. Abraham C, Cho J. Interleukin-23/Th17 pathways and inflammatory bowel disease. Inflamm Bowel Dis 2009;15(7):1090-100. 46. Ardizzone S, Bianchi Porro G. Inflammatory bowel disease: new insights into pathogenesis and treatment. J Intern Med 2002;252(6):475-96. 47. Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn’s disease. J Biol Chem 2003;278(8):5509-12. 48. Shanahan F. Crohn’s disease. Lancet 2002;359(9300):62-9. 49. Van Deventer SJ. Tumour necrosis factor and Crohn’s disease. Gut 1997;40(4):443-8. 50. Shah B, Mayer L. Current status of monoclonal antibody therapy for the treatment of inflammatory bowel disease. Expert Rev Clin Immunol 2010;6(4):607-20. 51. Danese S, Semeraro S, Marini M, Roberto I, Armuzzi A, Papa A, et al. Adhesion molecules in inflammatory bowel disease: therapeutic implications for gut inflammation. Dig Liver Dis 2005;37(11):811-8. 52. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 2005;307(5710):731-4. 53. Braegger CP, Nicholls S, Murch SH, Stephens S, MacDonald TT. Tumour necrosis factor alpha in stool as a marker of intestinal inflammation. Lancet 1992;339(8785):89-91. 54. Breese EJ, Michie CA, Nicholls SW, Murch SH, Williams CB, Domizio P, et al. Tumor necrosis factor alpha-producing cells in the intestinal mucosa of children with inflammatory

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bowel disease. Gastroenterology 1994;106(6):1455-66. 55. Targan SR, Hanauer SB, Van Deventer SJ, Mayer L, Present DH, Braakman T, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 1997;337(15):1029-35. 56. Present DH. Review article: the efficacy of infliximab in Crohn’s disease--healing of fistulae. Aliment Pharmacol Ther 1999;13(S4):23-8. 57. Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, Van Hogezand RA, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999;340(18):1398-405. 58. Rutgeerts P, D’Haens G, Targan S, Vasiliauskas E, Hanauer SB, Present DH, et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn’s disease. Gastroenterology 1999;117(4):761-9. 59. Nakamura K, Honda K, Mizutani T, Akiho H, Harada N. Novel strategies for the treatment of inflammatory bowel disease: Selective inhibition of cytokines and adhesion molecules. World J Gastroenterol 2006;12(29):4628-35. 60. Baue AE. The horror autotoxicus and multiple-organ failure. Arch Surg 1992;127(12):1451-62. 61. Chadd HE, Chamow SM. Therapeutic antibody expression technology. Curr Opin Biotechnol 2001;12(2):188-94. 62. Elliott MJ, Maini RN. New directions for biological therapy in rheumatoid arthritis. Int Arch Allergy Immunol 1994;104(2):112-25. 63. Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 1994;344(8930):1105-10. 64. Knight DM, Trinh H, Le J, Siegel S, Shealy D, McDonough M, et al. Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol 1993;30(16):1443-53. 65. Scallon BJ, Moore MA, Trinh H, Knight DM, Ghrayeb J. Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine 1995;7(3):251-9. 66. Van den Brande JM, Braat H, Van den Brink GR, Versteeg HH, Bauer CA, Hoedemaeker I, et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease. Gastroenterology 2003;124(7):1774-85. 67. Suenaert P, Bulteel V, Lemmens L, Noman M, Geypens B, Van Assche G, et al. Anti-tumor necrosis factor treatment restores the gut barrier in Crohn’s disease. Am J Gastroentero. 2002;97(8):2000-4. 68. Di Sabatino A, Pender SL, Jackson CL, Prothero JD, Gordon JN, Picariello L, et al. Functional modulation of Crohn’s disease myofibroblasts by anti-tumor necrosis factor

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antibodies. Gastroenterology 2007;133(1):137-49. 69. Van Dullemen HM, Van Deventer SJ, Hommes DW, Bijl HA, Jansen J, Tytgat GN, et al. Treatment of Crohn’s disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 1995;109(1):129-35. 70. Wenzl HH, Reinisch W, Jahnel J, Stockenhuber F, Tilg H, Kirchgatterer A, et al. Austrian infliximab experience in Crohn’s disease: a nationwide cooperative study with long-term follow-up. Eur J Gastroenterol Hepatol 2004;16(8):767-73. 71. Wewer V, Riis L, Vind I, Husby S, Munkholm P, Paerregaard A. Infliximab dependency in a national cohort of children with Crohn’s disease. J Pediatr Gastroenterol Nutr 2006;42(1):40-5. 72. Caviglia R, Ribolsi M, Rizzi M, Emerenziani S, Annunziata ML, Cicala M. Maintenance of remission with infliximab in inflammatory bowel disease: efficacy and safety long-term follow-up. World J Gastroenterol 2007;13(39):5238-44. 73. Moss AC, Fernandez-Becker N, Jo Kim K, Cury D, Cheifetz AS. The impact of infliximab infusion reactions on longterm outcomes in patients with Crohn’s disease. Aliment Pharmacol Ther 2008;28(2):221-7. 74. Rudolph SJ, Weinberg DI, McCabe RP. Long-term durability of Crohn’s disease treatment with infliximab. Dig Dis Sci 2008;53(4):1033-41. 75. Hyams JS, Lerer T, Griffiths A, Pfefferkorn M, Kugathasan S, Evans J, et al. Long-term outcome of maintenance infliximab therapy in children with Crohn’s disease. Inflamm Bowel Dis 2009;15(6):816-22. 76. Schnitzler F, Fidder H, Ferrante M, Noman M, Arijs I, Van Assche G, et al. Long-term outcome of treatment with infliximab in 614 patients with Crohn’s disease: results from a single-centre cohort. Gut 2009;58(4):492-500. 77. Schnitzler F, Fidder H, Ferrante M, Noman M, Arijs I, Van Assche G, et al. Mucosal healing predicts long-term outcome of maintenance therapy with infliximab in Crohn’s disease. Inflamm Bowel Dis 2009;15(9):1295-301. 78. Malheiros APR, Teixeira MG, Scanavini Neto A, Silva Filho EV, Rodrigues LCO, Thierry R, et al. Treatment of Crohn’s disease with infliximb: first choice? ABCD Arq Bras Cir Dig 2009;22(2):101-4. 79. Ardizzone S, Colombo E, Maconi G, Bollani S, Manzionna G, Petrone MC, et al. Infliximab in treatment of Crohn’s disease: the Milan experience. Dig Liver Dis 2002;34(6):411-8. 80. Miheller P, Lakatos PL, Horvath G, Molnar T, Szamosi T, Czegledi Z, et al. Efficacy and safety of infliximab induction therapy in Crohn’s Disease in Central Europe-a Hungarian nationwide observational study. BMC Gastroenterol 2009;9:66. 81. Parashette KR, Makam RC, Cuffari C. Infliximab therapy in pediatric Crohn’s disease: a review. Clin Exp Gastreonterol 2010;3:57-63. 82. Lee JS, Lee JH, Lee HJ, Kim MJ, Choe YH. Efficacy of early treatment with infliximab in pediatric Crohn’s disease. World

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J Gastroenterol 2010;16(14):1776-81. 83. De Bie CI, Hummel TZ, Kindermann A, Kokke FT, Damen GM, Kneepkens CM, et al. The duration of effect of infliximab maintenance treatment in paediatric Crohn’s disease is limited. Aliment Pharmacol Ther 2011;33(2):243-50. 84. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359(9317):1541-9. 85. Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004;350(9):87685. 86. Van Assche G, Magdelaine-Beuzelin C, D’Haens G, Baert F, Noman M, Vermeire S, et al. Withdrawal of immunosuppression in Crohn’s disease treated with scheduled infliximab maintenance: a randomized trial. Gastroenterology 2008;134(7):1861-8. 87. Haraoui B, Cameron L, Ouellet M, White B. Anti-infliximab antibodies in patients with rheumatoid arthritis who require higher doses of infliximab to achieve or maintain a clinical response. J Rheumatol 2006;33(1):31-6. 88. Wolbink GJ, Vis M, Lems W, Voskuyl AE, Groot E, Nurmohamed MT, et al. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum 2006;54(3):711-5. 89. Farrell RJ, Alsahli M, Jeen YT, Falchuk KR, Peppercorn MA, Michetti P. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology 2003;124(4):917-24. 90. Baert F, Noman M, Vermeire S, Van Assche G, D’ Haens G, Carbonez A, et al. Influence of immunogenicity on the longterm efficacy of infliximab in Crohn’s disease. N Engl J Med 2003;348(7):601-8. 91. Hanauer SB, Wagner CL, Bala M, Mayer L, Travers S, Diamond RH, et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn’s disease. Clin Gastroenterol Hepatol 2004;2(7):542-53. 92. Kempeni J. Preliminary results of early clinical trials with the fully human anti-TNFalpha monoclonal antibody D2E7. Ann Rheum Dis 1999;58(S1):I70-2. 93. Youdim A, Vasiliauskas EA, Targan SR, Papadakis KA, Ippoliti A, Dubinsky MC, et al. A pilot study of adalimumab in infliximab-allergic patients. Inflamm Bowel Dis 2004;10(4):333-8. 94. Sandborn WJ, Hanauer S, Loftus EV Jr., Tremaine WJ, Kane S, Cohen R, et al. An open-label study of the human anti-TNF monoclonal antibody adalimumab in subjects with prior loss of response or intolerance to infliximab for Crohn’s disease. Am J Gastroenterol 2004;99(10):1984-9. 95. Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh D, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the

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CLASSIC-I trial. Gastroenterology 2006;130(2):323-33. 96. Sandborn WJ, Hanauer SB, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh DG, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut 2007;56(9):1232-9. 97. Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Colombel JF, Panaccione R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007;146(12):829-38. 98. Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 2007;132(1):52-65. 99. Bartelds GM, Krieckaert CL, Nurmohamed MT, Van Schouwenburg PA, Lems WF, Twisk JW, et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA 2011;305(14):1460-8. 100. Kamiris K, Paintaud G, Noman M, Magdelaine-Beuzelin C, Ferrante M, Degenne D, et al. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn’s disease. Gastroenterology 2009;137(5):1628-40. 101. Chaparro M, Panes J, Garcia V, Merino O, Nos P, Domenech E, et al. Long-term durability of response to adalimumab in Crohn’s disease. Inflamm Bowel Dis 2011. 102. Kim MJ, Choe YH. Change in the treatment strategy for pediatric Crohn’s disease. Korean J Pediatr 2010;53(9):830-3. 103. Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn’s disease activity index. National cooperative Crohn’s disease study. Gastroenterology 1976;70(3):439-44. 104. Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Colombel JF, Panaccione R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007;146(12):829-38. 105. Gupta A, Pendyala P, Arora P, Sitrin MD. Development of the nephrotic syndrome during treatment of Crohn’s disease with adalimumab. J Clin Gastroenterol 2011;45(3):e30-3. 106. Vannucchi V, Grazzini M, Pieralli F, Giannotta M, Biagioni C, Nozzoli C. Adalimumab-induced lupus erythematosus with central nervous system involvement in

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a patient with Crohn’s disease. J Gastrointestin Liver Dis 2011;20(2):201-3. 107. Leblanc S, Lloret Linares C, Cacheux W, Mouthon L, Chaussade S. Aortic thrombosis in young women with Crohn’s disease receiving adalimumab: report of two cases. Inflamm Bowel Dis 2011;17(3):862-3. 108. Frank KM, Hogarth DK, Miller JL, Mandal S, Mease PJ, Samulski RJ, et al. Investigation of the cause of death in a gene-therapy trial. N Engl J Med 2009;361(2):161-9. 109. Anderson PJ. Tumor necrosis factor inhibitors: clinical implications of their different immunogenicity profiles. Semin Arthritis Rheum 2005;34(5 Suppl1):19-22. 110. FDA. Medication guide Humira® (Hu-MARE-ah) (adalimumab) injection [Internet] 2011. Available from: http://www.rxabbott.com/pdf/humira_medguide.pdf. 111. Billioud V, Sandborn WJ, Peyrin-Biroulet L. Loss of response and need for adalimumab dose intensification in Crohn’s disease: a systematic review. Am J Gastroenterol 2011;106(4):674-84. 112. Cohen RD, Lewis JR, Turner H, Harrell LE, Hanauer SB, Rubin DT. Predictors of adalimumab dose escalation in patients with crohn’s disease at a tertiary referral center. Inflamm Bowel Dis 2011. 113. Dretzke J, Edlin R, Round J, Connock M, Hulme C, Czeczot J, et al. A systematic review and economic evaluation of the use of tumour necrosis factor-alpha (TNF-alpha) inhibitors, adalimumab and infliximab, for Crohn’s disease. Health Technol Assess 2011;15(6):1-244. 114. NICE. National Institute for Health and Clnical Excellence - Infleximab (review) and adalimumab for the treatmenf of Crohn’s disease. London: NICE; 2011. 115. Harvey RF, Bradshaw JM. A simple index of Crohn’s-disease activity. Lancet 1980;1(8167):514. 116. Abraham C, Cho J. Inflammatory bowel disease - Current review on the pathogenesis of inflammatory bowel disease (IBD). New Engl J Med 2009;361(21):2066-78. Correspondence to: Júlio César M Santos Jr Av. Min Urbano Marcondes, 516 CEP 12515-230 – Guaratinguetá (SP), Brazil E-mail: instmed@provale.com.br

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ALACP REPORT

ALACP Board 2011-2013 President: José Victor Rodrigues Mendoza (El Salvador) 1st Vice-President: Ricardo Alfonzo Nunes (Venezuela) 2nd Vice-President: Ricardo Fretes (Paraguai) Secretary-General: Eduardo de Paula Vieira (Brazil) Vice-Secretary: Viviane Castro Souza Passos (Brazil) Treasurer: Andrés Pessôa Pandelo (Brazil) 1st Vice-Treasurer: Andréa Povedano  (Brazil)

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• The XXII Congress of the Latin American Association of Coloproctology was held in Mendoza – Argentina, from August 8 to 11, 2011, showing high scientific level. It counted on the expressive presence of experts, including from Brazil. • The next congress will be held in El Salvador, from July 8 to 11, 2013. The link will be shortly published in this page.

ALACP Secretariat Av. Marechal Câmara, 160 /916 – Ed. Orly 20020-080 – Rio de Janeiro – RJ – Brazil Tel: 55 (21) 2240-8927 / Fax: 55 (21) 2220-5803 Eduardo de Paula Vieira Secretary-General

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Services accredited by SBCP for the improvement in coloproctology Hospital Universitário C. Fraga Filho - UFRJ Reg. Mec. 124 Av. Brigadeiro Trompowsky - Ilha do Fundão 21941-590 - Rio de Janeiro - RJ Tel: (21) 2562-2010 - ramal 2719

Fundação Ensino Superior Vale do Sapucai Hospital das Clínicas Samuel Libânio Rua Comendador José Garcia, 777 36540-000 - Pouso Alegre - MG Tel: (35) 3422-2345

Hospital Universitário Pedro Ernesto - UERJ Reg. Mec 153 Av. 28 de Setembro, 77 20551-030 - Rio de Janeiro - RJ Tel: (21) 2587-6100

Hospital Ernesto Dornelles Av. Ipiranga, 1801 96160-093 - Porto Alegre - RS Tel: (51) 3217-2002 Hospital Nossa Senhora da Conceição Av. Francisco Trein, 596 91350-200 - Porto Alegre - RS Tel: (51) 3341-1300

Hospital de Ipanema Reg. Mec 156 Rua Antonio Parreiras, 69 - Ipanema 22411-020 - Rio de Janeiro - RJ Tel: (21) 3111-2379

Hospital Barão de Lucena Av. Caxangá, 3860 - Iputinga 50731-000 - Recife - PE Tel: (81) 3453-3566

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Hospital das Clínicas - UFCE Rua Capitão Francisco Pedro, 1290 60430-370 - Fortaleza - CE Tel: (85) 3243-9117

Hospital da Lagoa Reg. Mec 162 Rua Jardim Botânico, 501 22470-050 - Rio de Janeiro - RJ Tel.: (21) 3111-5100

Irmandade da Santa Casa da Misericórdia de São Paulo Departamento de Cirurgia Rua Cesário Mota Junior, 112 01221-020 - São Paulo - SP Tel.: (11)224-0122

Hospital Naval Marcílio Dias Reg. Mec 171 Rua César Zama, 185 - Lins de Vasconcelos 20725-090 - Rio de Janeiro - RJ Tel: (21) 2599-5599 - ramal 5648 / 5428

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Hospital Heliópolis Reg. Mec 210 Rua Cônego Xavier, 276 Vila Heliópolis 04231-030 - São Paulo - SP Tel. (11) 2274-7600 (ramal 244)

Hospital Municipal Miguel Couto - Rio Rua Mário Ribeiro, 157 - Leblon 22430-160 - Rio de Janeiro - RJ Tel. (21) 2274-6050 Santa Casa de Belo Horizonte Grupo de Colo-Proctologia de Belo Horizonte Av. Francisco Sales, Praça Hugo Werneck, s/nº 30150-300 - Belo Horizonte - MG Tel. (31) 3238-8131

Hospital Universitário da Faculdade de Medicina PUC RS - Serviço de Coloproctologia Av. Ipiranga, 6690 90610-000 - Porto Alegre - RS Informações: COREME tel. 3339-1322 Ramal 2378 Tel: (51) 3320-3000 Hospital Clínicas da Universidade Federal do Paraná Rua Gal. Carneiro, s/n 80060-150 - Curitiba - PR Tel: (41) 3360-1800

Hospital das Clínicas Faculdade de Medicina da Universidade de São Paulo - SP Av. Dr. Eneas de Carvalho Aguiar, 255 Cerqueira Cesar 05403-000 - São Paulo - SP Tel. (11)3069-6000 420


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Services accredited by SBCP for the improvement in coloproctology

Hospital do Andaraí Rua Leopoldo, 280 - 2º andar -Andaraí 20541-170 - Rio de Janeiro - RJ (21) 2562-2719

Hospital de Base do Distrito Federal S M H S , 101 BL. A Setor Hospitalar Sul 70335-900 - Brasília - DF Tel. (61) 3325-5050

Hospital Municipal São José Av. Getúlio Vargas, 233 89202-001 - Joinville - SC (47) 3441-6666

Real e Benemérita Sociedade Portuguesa de Beneficência Hospital São Joaquim Rua Maestro Cardim, 769 01323-001 - São Paulo - SP Tel: (11) 3253-5022

Hospital Geral de Goiânia Dr. Alberto Rassi Av. Anhanguera , 6379 - Setor Oeste 74043-011 - Goiânia - GO Tel: (62) 3221-6031

Hospital Universitário Evangélico de Curitiba Al. Augusto Stellfeld, 1908 80730-150 - Curitiba - PR Tel. (41) 3222-0727 / 3322-4141

Santa Casa de Misericórdia - Fortaleza - CE Serviço de Coloproctologia Rua Barão do Rio Branco, 1816 60025-061 - Fortaleza - CE Tel: (85) 3211-1911

Hospital do Servidor Público Estadual de São Paulo – “FMO” Serviço de Gastroenterologia Cirúrgica e Coloproctologia Rua Pedro de Toledo, 1800 - 11º andar - Ala Central 04029-000 - São Paulo - SP Tel. (11) 5088-8117 / 5088-8119

Hospital do Serviço Público Municipal - SP Serviço de Coloproctologia Rua Castro Alves nº 60 - Liberdade 01532 - São Paulo - SP Tel: (11) 3208-2211

Hospital Geral Roberto Santos MEC/CNRM - PARECER Nº 98/99 Est. do Saboeiro, S/N - Cabula 41180-780 - Salvador - BA Tel. (71) 3372-2849

Hospital Nossa Senhora das Graças Serviço de Coloproctologia Rua Alcides Munhoz, 433 - Mêrces 80810-040 Curitiba - PR Tel: (41) 3240-6706 Fax. (41) 3240-6500

Centro de Colo-Proctologia do Ceará Av. Pontes Vieira, 2551 (2º andar) 60130-241 - Fortaleza - CE Tel. (85) 3257-6588 - 257-7728

Serviço de Coloproctologia Hospital das Clínicas da Faculdade de Medicina Universidade Federal de Goiás 1ª Avenida, s/nº 74650-050 - Goiânia - GO Tel.: (62) 3202-1800 ramal 1094 - COREME Tel.: (62) 3202-4443

Hospital de Base da Faculdade de Medicina de São José do Rio Preto Av. Brigadeiro Faria Lima, 5416 15090-000 - São José do Rio Preto - SP Tel. (17) 3201-5000 Hospital Felício Rocho Av. Contorno, 9.530 30110-130 - Belo Horizonte - MG Tel. (31) 3339-7142

Hospital Universitário Prof. Alberto Antunes Av. Lourival Melo Mota, s/n Tabuleiro do Martins 57072-900 - Maceió - AL Tel.: (82) 3322-2494

Hospital de Jacarepaguá Av. Menezes Cortes, 3245 20715-190 - Rio de Janeiro - RJ Tel. (21) 2425-2255 - R. 200 Hospital Sírio Libanês CNRN / MEC Nº 23/2002 Rua Dona Adma Jafet, 91 01308-050 - São Paulo - SP Tel. (11) 3155-0200

Vol. 31 Nº 4

Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP Av. Bandeirantes, 3900 14048-900 - Ribeirão Preto - SP Tel. (16) 3602-1000 / 3602-2509 421


Journal of Coloproctology October/December, 2011

Services accredited by SBCP for the improvement in coloproctology

Hospital Universitário da Universidade Federal de Sergipe Rua Cláudio Batista s/nº Sanatório 49060-100 - Aracajú - SE Tel. (79) 3218-1738

Hospital São Rafael Serviço de Coloproctologia Av. São Rafael, 2152 - São Marcos 41256-900 - Salvador - BA Tel.: (71) 3281-6400

Hospital das Clínicas -UFMG Instituto Alfa de Gastroenterologia Av. Prof. Alfredo Balena, 110 , 2º andar Sta. Efigênia 30130-100, Belo Horizonte, MG Tel. (31) 3248-9403 / (31) 3248-9251

Vitória Apart Hospital Serviço de Coloproctologia Rod. BR 101 Norte Km 2 - Carapina 29101-900 - Serra - ES Tel.: (27) 3201-5555

Vol. 31 Nº 4

Hospital Municipal Dr. Mário Gatti Serviço de Coloproctologia Av. Prefeito Faria Lima, 340 - Parque Itália 13036-902 - Campinas - SP Tel.: (19) 3772-5700

Clínica Reis Neto Rua General Osório, 2273 12025-155 - Cambuí - Campinas - SP Tel.: (19) 3252-5611 Hospital Universitário Cajuru - Serviço de Coloproctologia Reg. Mec. Parecer 43/06 Av. São José, 300 80050-350 - Cristo Rei - Curitiba - PR Tel.: (41) 3271-3009

Serviço de Coloproctologia Hospital de Clínicas de Porto Alegre Universidade Federal do Rio Grande do Sul Rua Ramiro Barcelos, 2.350 / sala 600 CEP: 90035-903 - Porto Alegre - RS Tel.: (51) 3359-8232

We require the Coloproctology services that have medical residency or internships related to this specialty to send their program and schedule to the Society, so they can be publicized. This section will be available to publicize rules and dates of selection. Minimum program to be accredited by the Brazilian Society of Coloproctology Staff – Participation of at least two full members of SBCP. Surgeries – Monthly mean of at least three colorectal surgeries and six anoperineal surgeries. Ambulatory – Monthly mean of at least 50 appointments. Endoscopies – Monthly mean of at least 20 rectosigmoidoscopies and five colonoscopies. Available supporting units: Radiology, pathological anatomy, endoscopy, clinical analysis laboratory, ICU, Oncology, Radiotherapy, Statistical and Medical Files. Teaching – a) Weekly meetings of the service to discuss cases and also published articles; b) To estimulate the production of scientific papers to be presented at the annual congress of the Brazilian Society of Coloproctology and possible publication in the SBCP journal; c) To send at least one original article per year for possible publication in the SBCP journal. 422


remissive index October - December Index by author A Abreu Filho, J. G. de Accetta, A. F. Accetta, I. Adad, S. J. Akamatsu, F. E. Albuquerque, E. F. de Albuquerque, I. C. de  Alcantara, P. S. M. Almeida, M. G. de Alvarenga, I. M.   Alves Filho, V. Andrade, M. F. C. de Andrade, M. M. de A. Arantes T. de S. Araujo, S. L. M. Arguello, E. R. F. Ayrizono, M. de L. S. Azevedo, M. A.

31(3): 276 31(2): 165 31(2): 165 31(2): 205 31(4): 311 31(3): 294 31(1): 85 31(2): 120 31(2): 120 31(2): 155 31(1): 44 31(2): 169 31(2): 184 31(4): 334 31(4): 311 31(1): 44 31(2): 120 31(4): 387 31(4): 397 31(4): 372 31(3): 225

B Balestrim Filho, A. Balsamo, F. Basso, M. P.  Batista, R. R.   Bertollo, L. A. Biazon, A. C. B. Biffi, R. Borba, M. R. Bortolfi, V. T. Braga T. A. Braga, A. C. G.   Branco Filho, A. J. Brochado, M. C. R. T. Bromberg, S. H.

31(2): 197 31(1): 39 31(2): 231 31(4): 378 31(1): 64 31(1): 85 31(2): 210 31(3): 241 31(3): 291 31(1): 26 31(2): 120 31(3): 241 31(2): 197 31(1): 44 31(2): 169 31(2): 184 31(3): 291 31(2): 120 31(1): 77

C Cabral, M. M. D. A. Calore, E. E. Camara, C. A. C. R. Cantarelli Junior, J. C. Capelhuchmik, P.

31(1): 17 31(1): 71 31(2): 205 31(3): 301 31(3): 257

Carmo Jr. J.  Carmona, M. Z. Carvalho, E Carvalho, L. P. da Carvalho, L. P. de Castro, C. A. T. de Castro, E. V. Castro, M. A. P. de Cenciarelli, S. Cesar, M. A. P.   Christiano, A. B. Constantino, J. R. M.   Cordeiro, F. Cortez, K. C. D . Costa, B. X. M. da  Costa, L. H. D . da Costa, L. H. D. da Costa, L. M. P.   Coutinho, C. P.  Coy, C. S. R.   Cristiano, A. B. Cruz, G. M. G. da   Cueto G. D . Cunha, F. L. da Cunrath, G. S.

Fagundes, J. J. Fagundes, R. B. Falzoni, R. Fang, C. B. Faria, F. F.  Fayad, J. B.  Fe, L. C. M. Feres, O. Fernandes, C. K. M. Fernandes, I. L.  Ferraz, R. A. Ferraz, R. A. Ferreira, R. M. R. S.   Ferreira, S. Ferrero, C. A. Figueira, M. de S. Fonseca, C. B. Fonseca, L. M. da  Fonseca, M. F. M. Formiga, G. J. S.    Franรงa Neto, P. R. Franรงa, P. R. Francisco Neto, P. R. Franco, M. I. F. Freitas, A. H. A. Freitas, C. D . Froehner Junior, I.

31(2): 205 31(4): 334 31(3): 299 31(4): 346 31(2): 147 31(1): 39 31(1): 81 31(4): 372 31(1): 26 31(2): 126 31(3): 257 31(3): 294 31(4): 378 31(1): 44 31(2): 169 31(2): 184 31(1): 58 31(3): 248 31(4): 330 31(4): 334 31(1): 1 31(4): 351 31(1): 44 31(2): 169 31(2): 184 31(2): 169 31(2): 184 31(1): 1 31(4): 351 31(4): 372 31(2): 131 31(1): 44 31(2): 169 31(2): 184 31(2): 165 31(2): 155 31(2): 131

G

D Demario, L. A. Denadai, R.  Diniz, F.

Galeazzi, C. J. 31(4): 393 Ghezzi, T. 31(1): 26 Gomes, D. M. B. M. 31(1): 44 Gonรงalves Filho, F. de A. 31(4): 378  31(4): 393 Goulart, R. de A. 31(1): 32 Guerrer, L. V. 31(4): 378

31(2): 213 31(1): 32 31(4): 325 31(3): 268 E

Espinola, B. Estofolete, C. F.

31(4): 351 31(4): 393

Helene Junior, A. Horta, Sergio H. C. Hosse, R. S.

31(1): 1

423

J Jacomo, A. L. Jung, W.

31(4): 311 31(4): 351 K

Klug, W. A. Koppe, D. C. Koshimizu, R. T.  Kotze, L. M. da S. Kotze, P. G.  

31(3): 257 31(2): 147 31(2): 147 31(4): 346 31(3): 233 31(3): 233 31(3): 268 31(3): 325

L Lacerda Filho, A.  Lacerda Filho, A.  Lacome, D. Lameiro, T. M. do M. Lamounier, P. C. de C.  Lanna, D. de    Leal, R. F. Lee, H. D.  Leite, J. M. Leite, S. M. O.    Lima Junior, A. C. B.   Lima, D. L. Lima, O. A. T. Lima, R. F. C. Lima, T. M. de A. Lira, E. F. de Luca, F. Luz, M. M. P. da

31(1): 17 31(1): 89 31(4): 330 31(4): 401 31(2): 165 31(2): 155 31(4): 330 31(4): 401 31(1): 44 31(2): 169 31(2): 184 31(4): 372 31(1): 1 31(4): 351 31(2): 126 31(1): 44 31(2): 169 31(2): 184 31(2): 200 31(1): 44 31(2): 169 31(2): 184 31(3): 299 31(4): 387 31(1): 64 31(2): 120 31(3): 276 31(1): 26 31(1): 17

M

H

F Fagundes J. J.

31(4): 372 31(3): 301 31(4): 382 31(3): 257 31(1): 44 31(2): 184 31(1): 107 31(2): 217 31(4): 339 31(2): 197 31(1): 89 31(2): 139 31(3): 285 31(1): 32 31(4): 382 31(1): 44 31(2): 169 31(2): 184 31(1): 8 31(1): 1 31(3): 248 31(3): 301 31(1): 17 31(1): 81 31(1): 64 31(1): 39 31(1): 64 31(1): 85 31(2): 210 31(1): 189 31(4): 330 31(4): 401 31(1): 77 31(1): 81 31(3): 268 31(3): 268

31(2): 213 31(1): 71 31(4): 325

Machado Filho, H. N. 31(4): 397 Machado, R. B. 31(1): 1 Machado, S. P. 31(1): 71


Remissive Index

Journal of Coloproctology October/December, 2011

Madeira, H. 31(1): 81 Mader, A. M. A. A. 31(3): 225 Maggi, D. C. 31(3): 241 Mallmann, A. C. M. 31(2): 147 Mallmann, A. C. M. 31(4): 346 Manzione, C. R. 31(1): 71 Manzione, L. R. 31(4): 405 Manzione, T. da S. 31(1): 71 Marciano, M. R. 31(2): 131 Margarido, N. F. 31(4): 311 Maria Junior, C. L. S. 31(2): 200 Marianelli, R. 31(1): 94 Mariano, D. R. 31(3): 262 Marques, G. C. de S. 31(2): 197 Marques, L. H. S. 31(2): 155 Martinez, C. A. R. 31(2): 155 Martinez, C. A. R. 31(4): 311 Martins, L. C. 31(3): 225 Martins, S. F. F. 31(4): 362 Martins, S. J. 31(4): 387 Matos, D. 31(1): 8 Matsushita, M. de M. 31(4): 382 Mattos, B. M. R. de 31(2): 197 Mattosinho - Fraรงa, L. C. 31(1):77 Mello, D. F. 31(2): 213 Mendonรงa, S. 31(1): 58 Mendonรงa, S. de S. 31(3): 248 Menezes, A. P. A. de 31(3): 262 Micheletti, A. M. R. 31(2): 205 Miranda, L. E. C. 31(3): 299 Miszputen, S. J. 31(4): 325 Monte, L. N. de C. 31(4): 339 Moraes Filho, A. C. S. 31(4): 393 Motta, G. L. 31(3): 301 Motta, M. M. da 31(2): 139  31(3): 285 Moura, A. R. 31(2): 115  31(2): 139  31(3): 262  31(3): 285 Muziz, R. C. C. 31(2): 126 N Nadal, Si. R.   Netinho, J. G.  

31(1): 71 31(1): 94 31(4): 405 31(2): 131 31(4): 378 31(4): 393

Neves, P. M.   Nogueira, V. F. P. Noronha, T.

 Rego, R. S. N. de  Ribeiro, M. C. B. Rocha, J. J. R. da Rodrigues, F. G.    Rossi, D. H. G.

31(1): 44 31(2): 169 31(2): 186 31(1): 58 31(4): 401

O Oliveira, J. P. de B. Oliveira, P. S. P. Oliveira, R. G.  Ortiz, J. A.  Otoch, J. P.

31(1): 58 31(4): 372 31(1): 44 31(1):184 31(2): 126 31(3): 257 31(2): 120

Saad-Hossne, R. 31(1): 32 Saad-Hossne, R. 31(4): 382 Saba, E. 31(4): 397 Salem, J. B. 31(3): 233 Salles, V. J. A. 31(4): 397 Santana, L. O. 31(2): 139  31(3): 285 Santana, R. M. de 31(2): 115 Santos Jr., J. C. M. 31(1): 98 Santos Junior, C. A. N. 31(4): 346 Santos Junior, J. C. M. 31(4): 408 Santos, G. de A. 31(2): 169  31(2): 184 Schimedt, J. 31(2): 147 Schmitt, D. 31(4): 346 Seid, V. E. 31(1): 71 Serra, M. M. P. 31(4): 311 Silva, A. C. da 31(4): 351 Silva, C. M. G. da 31(2): 155 Silva, E. G. V. V. 31(2): 169  31(2): 184 Silva, F. P. A. da 31(3): 294 Silva, I. G. da 31(1): 44  31(2): 169  31(2): 184 Silva, L. C. 31(1): 89 Silva, L. C. 31(4): 334 Silva, R. D. P. 31(4): 382 Silva, R. G. da 31(1): 17 Silva-Junior, J. B. 31(2): 139  31(3): 285 Silveira, A. M. 31(2): 200 Simoni, A. L. 31(4): 393 Soares, P. C. 31(1): 8 Sobrado Junior, C. W. 31(3): 233 Sousa, W. A. T. de 31(4): 339 Souza, B. D. 31(3): 225 Steckert-Filho, A. 31(3): 268

31(4): 387 31(4): 387 31(4): 330 31(4): 401 31(3): 306 31(3): 291 31(3): 294 31(2): 155 31(4): 311 31(2): 205 31(4): 397 31(1): 26 31(1): 39 31(2):210 31(2): 139 31(3): 285 31(3): 241 31(2): 165

Q Queiroz, F. L. de   Quites, L. V.

31(4): 334 31(4): 330 31(4): 334 31(4): 372 31(2): 197 31(1): 44 31(2): 169 31(2): 184 31(4): 372

S

P Paes, M.A. Pais-Costa, S. R. Paiva, R. de A.  Pandini, L. C. Patricio, S. C. de O. Paula, P. R. de Pereira, J. A. Pereira, J. A. Pereira, J. M. Pissinin, E. R. Pozzi, S. Pozzobon, B. H. Z.  Prudente, A. C. L.  Pukanski, M. F. Pupo Neto, J. de A.

Vol. 31 Nยบ 4

31(4): 330 31(4): 334 31(4): 401 31(1): 17

R Ramaciotti Filho, P. R. 31(1): 39 Ramos, L. A. G. 31(1): 89 Rampazzo, A. 31(3): 301 Rebelo, F. E. F. 31(4): 330

424

T Teixeira, F. R.

31(3): 262

Teixeira, F. V.  Teixeira, R. G.  Todinov, L. R. Toledo, P. S. de Torres Neto, J. da R.     Torres, F. A. do P. Torres, J. A. do P.

31(1): 32 31(4): 382 31(1): 44 31(2): 184 31(1): 64 31(1): 85 31(2): 115 31(2): 139 31(3): 262 31(3): 285 31(2): 115 31(2): 115

U Umana, D.

31(1): 26 V

Valarini, S. B. M. Valle Junior, H. N.   Valvo, M. Vasconcelos, R. Vieira, A. Villa, L. L. Volpato, G.

31(3): 241 31(1): 44 31(2): 169 31(2): 184 31(1): 26 31(2): 165 31(3): 233 31(1): 8 31(4): 346

W Waisberg, J. Wassano, N. S. Wu, Feng C. 

31(3): 225 31(3): 241 31(1): 1 31(4): 351 Y

Yamaguchi, N.

31(1): 77 Z

Zampieri, J. C. Zandonรก, B.

31(1): 77 31(2): 147


Coloproctologia v31n4