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Romanian Journal of Oncology & Hematology, recunoscută şi pe plan internaţional Această primăvară a fost cu adevărat una bogată pentru Romanian Journal of Oncology and Hematology!

Este posibil ca acum să citiţi această revistă la Întrunirea Medicală Internaţională Translaţională şi Interdisciplinară HPV - de la biologie moleculară la clinic. Poate aţi primit revista direct la spital sau acasă, în calitate de membru al Societăţii Naţionale de Oncologie Medicală din România sau al Societăţii Române de Hematologie. Este posibil să fi citit şi numărul trecut la Congresul Bienal de Cancer Mamar sau la Conferinţa “Abordarea Multidisciplinară în Cancer în 2014” din luna mai.

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Valentin Rădoi Editor-in-Chief Romanian Journal of Oncology and Hematology University of Medicine and Pharmacy “Carol Davila”

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O n c o l o g y & H e m at o l o g y Issue 2 I Volume 2 I June 2014 PUBLISHED UNDER THE AUSPICES OF THE NATIONAL SOCIETY FOR MEDICAL ONCOLOGY IN ROMANIA; THE ROMANIAN HEMATOLOGICAL SOCIETY; THE ROMANIAN CANCER SOCIETY “VASILE PACURAR”; THE ROMANIAN ASSOCIATION FOR THE STUDY OF PAIN

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Senior Editors Prof. Dr. Florin Bădulescu (Universitatea de Medicină şi Farmacie Craiova, Craiova, România) Prof. Dr. Anca Roxana Lupu (Universitatea de Medicină şi Farmacie "Carol Davila", Bucureşti, România) Şef Lucrări Dr. Lucia Stănculeanu (Universitatea de Medicină şi Farmacie "Carol Davila", Bucureşti, România) Şef Lucrări Dr. Simona Mihuţiu (Universitatea de Medicină şi Farmacie Oradea, Oradea, România) Cerc. St. Gr. I. Dr. Grigorescu Alexandru (Institutul oncologic Prof. Dr. Alexandru Trestiorean, Bucureşti, România)

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International Editorial Board Prof. Dr. med. Anca-L. Grosu (Klinik für Strahlenheilkunde, Universität Freiburg, Freiburg, Germany) Prof. Dr. Shibo Li (University of Oklahoma Health Sciences Center, Oklahoma City, USA) Prof. Dr. Mariusz Z. Ratajczak (University of Louisville, Louisville, USA) Prof. Dr. Arnold Ganser (Hannover Medical School, Hanover, Germany) Prof. Dr. Saverio Bettuzzi (University of Parma Via Volturno, Parma, Italy) Prof. Dr. Lodovico Balducci (Moffitt Cancer Center, Tampa, USA) Prof. Dr. Leonard Wartofsky (Georgetown University School of Medicine, Washington, USA) Prof. Dr. Robert Amato (Memorial Hermann Cancer Center, Texas, USA) Prof Dr. Kevin R. Loughlin (Harvard University, Cambridge, USA) Prof. Dr. Maureen Markman (Drexel University College of Medicine, Philadelphia, USA) Prof. Dr. Stephen P. Hunger (University of Colorado School of Medicine, Colorado, USA) Prof. Dr. M.W.M. van den Brekel (Academic Medical Center Amsterdam, Amsterdam, Netherlands) Prof. Dr. M Sitki Copur (University of Nebraska Medical Center, Nebraska, USA) Prof. Dr. Derek Raghavan (UNC School of Medicine, Levine Cancer Institute, Charlotte, NC, USA) Prof. Dr. Richard J. Ablin (University of Arizona, Arizona, USA) Prof. Dr. Florian Strasser (Cantonal Hospital St. Gallen, Switzerland) Prof. Dr. Michel Rigaud (Scientific advisor - IRST, Meldola, Italy) Associate Prof. Dr. Mishu Popa McKiver (Massachusetts General Hospital, Massachusetts, USA) Assistant Prof. Dr. Alina Mihai (Univ Pittsburgh School Medicine, Pittsburgh, USA) Assistant Prof. Dr. Doru Paul (Hofstra North Shore-LIJ School of Medicine, New York, USA) Assistant Prof. Dr. Bruno Vincenzi (University Campus Bio-Medico, Rome, Italy Assistant Prof. Dr. Elizabeta C. Popa (Weill Cornell Medical College, NY, USA) Assistant Prof. Dr. Gabriela Oprea (Emory University, Atlanta, USA) Dr. Wainer Zoli (Director of the Bioscience Laboratory, IRST, Meldola, Italy) Dr. Ciprian Enachescu (Centre Hospitalier Lyon Sud, Lyon, France) Dr. Javier Martín Broto (Son Espases Hospital, Palma de Mallorca Spain) Dr. David Gómez Almaguer (Universidad Autónoma de Nuevo León, Monterrey, México) Dr. Sankalp Yadav (General Duty Medical Officer-II, Chest Clinic Moti Nagar, North Delhi Municipal Corporation, New Delhi, India)

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Editorial

NOVEL TREATMENT FOR MUSCLE INVASIVE BLADDER CARCINOMA [en] Sankalp Yadav

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Scientific Events [en]

Review

DEEPLY INVASIVE (T2-T4) BLADDER CANCER: OPTIMAL TREATMENT IN 2014 [en] Raghavan Derek

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THE ENDOCRINE PHENOTYPE IN OVARIAN TUMORS [en] Mara Carsote, Valentin Radoi, Catalina Poiana

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MOLECULAR MECHANISMS IMPLICATED IN CITOSTATIC RESISTANCE IN CANCER CELLS FROM METASTATIC BREAST CANCER [ro] Daniela Zob, Dana Lucia Stanculeanu, Iuliana Gruia

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RISK OF NON MELANOMA SKIN CANCER IN PSORIASIS PATIENTS WITH BIOLOGIC THERAPY (UP TO DATE) [ro] Ana Livia Duta, Cristina Medeleanu, Cristiana Voicu, Madalina Maftei, Victor Gabriel Clatici

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Editorial

Novel treatment for muscle invasive bladder carcinoma

Novel treatment for muscle invasive bladder carcinoma Sankalp Yadav* Chest Clinic Moti Nagar Corresponding author: Dr. Sankalp Yadav MMBS, PGDEM Chest Clinic Moti Nagar, New Delhi, PIN-110015 Tel.: +918 447 11 25 32 E-mail: drsankalpyadav@gmail.com

Open Access Article

Keywords: Cystectomy, muscle-invasive bladder cancer, radiotherapy, neoadjuvant chemotherapy Bladder cancer is a global health problem with the worldwide age standardized incidence rate (ASR) for bladder cancer being 10.1 per 100,000 for males and 2.5 per 100,000 for females.(1,2) It accounts for 4.1% of male and 1.8% of female deaths per year from cancer and is the second most common urinary tract cancer.(3) In males, after prostate, lung and colorectal cancer, it is the fourth most commonly diagnosed cancer.(4) Bladder cancer is common in geriatric age groups with the median age of diagnosis being 73 years. 70% of patients aged 65 or older are diagnosed with bladder carcinoma, and out of these, nearly one half of diagnoses occur in patients older than 75 years.(5) Urothelial cell carcinoma formerly known as transitional cell carcinoma (TCC) accounts for more than 90% of all the bladder cancers out of which 70% are non-muscle invasive bladder cancer (NMIBC) at diagnosis.(6-9) However, the NMIBC can also progress to muscle invasive bladder cancer (MIBC).(2) Also, the chance of developing invasive bladder cancer increases with age.(10) The deeply invasive bladder carcinoma (T2-T4) is a cancer with a 50% cure rate.(11) In recent years, rapid and continuing advances in our knowledge and the use of newer techniques and treatments have transformed our understanding for finding a suitable cure for this global health problem, but still the best treatment modality has not been definitively established. In this editorial, I discuss the treatment options available for muscle invasive bladder cancer.

Treatment options in muscle invasive bladder cancer Cite this article: Yadav S. Novel treatment for muscle invasive bladder carcinoma. Rom J Oncol Hematol. 2014; 2(2):60-62.

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Several therapeutic options are available to patients with muscle-invasive bladder cancer (MIBC). Presently, the available treatments involve radical cystectomy with or without concurrent chemoradiation followed by perioperative

chemotherapy. The treatment options are also dependent on the extent of the disease i.e. whether the cancer is localized or metastasized. A number of studies involving the use of neoadjuvant chemotherapy are underway to find the best treatment for invasive bladder cancer but the progress is relatively slow.

In localized invasive bladder cancer, radical cystectomy with lymphadenectomy has been the gold standard of treatment and has been used extensively in the USA. The cure rate is determined by a number of factors.(11) Radical cystectomy can be used in both young and old patients, but the study by Gray PJ et al. (2013) suggested that, in older patients, this technique has not been extensively used.(16) Although the data obtained from various studies reveals that cystectomy is generally safe and effective in highly selected older patients (17,18), the relapse rate for T3-4 MIBC is at least 50%, with most relapses occurring at distant sites, suggesting the presence of occult micro-metastases at initial presentation.(11) Radical cystectomy has its limitation like the physical and emotional impact it has on the patient.

As a result of the mental and physical side effects of radical cystectomy, patients are inclining towards bladder preservation transurethral surgeries but the level of local control of the tumor is very limited with this approach.(11,19) The use of these surgeries is mainly dependent on the size, site of the lesion and absence of deep infiltrating tumors, but even in these conditions, only partial cystectomy is possible.(11,20) Alternatively, radiotherapy is also used in those who are not willing to undergo radical cystectomy and the results are impressive in those studies that used a higher dosage especially those cumulatively greater than 60-65 Gy.(21-27) However, these studies had some limitations as the patients treated were characteristically older and less

Sankalp Yadav

robust than those subjected to cystectomy.(11) In patients with more extended tumors (greater than or equal to T3b) and those older than 75 years of age radiation therapy alone cannot cure the disease. In such cases palliative treatment modalities should be considered, particularly if cisplatin-based chemotherapy is not practically possible.(28) So far, whether radical cystectomy is superior to radiotherapy or vice versa is not proven. Radical cystectomy may give better results if performed by an expert due to more local control of the cancer.

The combination therapy involving the use of systemic chemotherapy with radiotherapy or surgery has been studied extensively in view of sparing the bladder or to improve overall surviv­al (11) However, there is the risk of delaying primary therapy and creating side effects without benefit as 30-60% of bladder cancers show some resistance to chemotherapy.(11) Classical adjuvant chemotherapy delivered after radical cystectomy has been studied but the results suggest a disease free state .(29-33) However, disease free survival cannot be considered as an indicator of success in the presence of salvage therapies.(11) Current clinical guidelines strongly recommend to consider the use of neoadjuvant cisplatinbased chemotherapy prior to cystectomy in cases of muscle-invasive bladder cancer (MIBC).(34,35) These guidelines are predicated on randomized, phase III trials showing a survival benefit with this treatment modality. (36,37) Cisplatin chemotherapy is common in present neoadjuvant chemotherapy regimens for MIBC. Although cisplatin has been used for the systemic management of bladder cancer for decades it has nephrotoxic effects.

(38,39) As a result of this, there is a certain cutoff for renal function in clinical trials evaluating cisplatinbased regimens. A common threshold in current day clinical trials is a creatinine clearance (CrCl) of 60 mL/min, below which patients are deemed ineligible.(40) However, these renal thresholds vary, with different groups utilizing thresholds of 45 and 55 mL/min.(41-43) The efficacy of neoadjuvant therapy may be based on either cytoreduction of the primary tumor, resulting in a more complete and successful surgery, or elimination of micrometastatic disease burden.

Advanced pathologic tumor stage and presence of metastasis are associated with a higher risk of death from bladder cancer. But the use of adjuvant chemotherapy is associated with improved survival, supporting the need for prospective clinical trials to assess the role of multimodal therapy in these patients.(44) Neoadjuvant cisplatinbased chemotherapy is the standard of care for muscle-invasive bladder cancer (MIBC); however, it is less frequently adopted in practice because

of concerns regarding nephrotoxicity and delay of cystectomy.(45) Waehre H et al. (1993) suggested that the survival rates improved with the use of chemotherapy in patients with deeply infiltrating (greater than or equal to T3) bladder cancer but appeared to represent an overtreatment in patients with T2 tumors.(46) The largest prospective study of squamous cell carcinoma and transitional cell carcinoma using neoadjuvant combination chemotherapy with gemcitabine/cisplatin conducted by Khaled HM et al. (2014) suggested that neoadjuvant combination chemotherapy with gemcitabine/ cisplatin did not improve survival rates in locally advanced bladder cancer over radical cystectomy alone.(47) However, they also suggested that bladder preservation was feasible, and the results in overall survival rates, in responding patients, were positive. Therefore, predictive models to select patients are needed.(47) The recent studies published involving the balloon-occluded arterial infusion (BOAI) of cisplatin/ gemcitabine, with concomitant hemodialysis and irradiation (the so-called ‘OMC [Osaka Medical College] regimen’) for bladder preservation in patients with muscle-invasive bladder cancer and lymph node metastasis have shown good results.

The OMC regimen has shown no adverse systemic effects, and it delivers an extremely high concentration of anticancer agent at the site of the tumor, as well as the pelvic area. Even in patients aged 85 years no severe toxicities were noted and therapy was completed successfully. Thus, the OMC regimen can be considered as a new option for patients with MIBC.(48) Besides, there are a number of other challenges that plague deeply invasive bladder carcinoma care.

Tomaszewski et al. suggested that patients who had care transition were more prone to treatment delay of ≥3 months, thus advocating the need to improve care transitions for better quality of care.(49) Also the skill of the surgeon and centers where the patient undergoes treatment determine the outcome.

Conclusion There are multiple treatment options for MIBC and most are governed by the stage of the cancer, extent of the disease spread and patient related factors.

However, radical cystectomy has been utilized as the gold standard in the past and even in the present day for local disease in the USA. Although various modalities like radiotherapy, chemotherapy, etc. are available, the best treatment for the particular patient is largely based on multiple factors. In the future, the treatment will be mostly determined by molecular prognostication and prediction studies. Surgery and radiation usage are definitive for local disease but the use of chemotherapy requires further advanced clinical studies. The newer treatment modalities like June 2014

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Editorial neoadjuvant chemotherapy are promising but are not extensively studied and thus a bigger number of multi-centric clinical studies will help in finding the best treatment with greater chances of survival

Novel treatment for muscle invasive bladder carcinoma

in patients suffering from deeply invasive bladder cancer.

Conflict of Interests: None.

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43. Pal SK, Ruel N, Villegas S et al. CKD-EPI and Cockcroft-Gault Equations Identify Similar Candidates for Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer. PLoS One. 2014; 9(4):e94471.

44. Clifton MM1, Psutka SP, Boorjian SA et al. Cancer-specific mortality following radical cystectomy for bladder cancer with lymph node involvement: impact of pathologic disease features and adjuvant chemotherapy. World J Urol. 2014 May 15. [Epub ahead of print] doi:10.1007/s00345-014-1319-0 45. Plimack ER, Hoffman-Censits JH, Viterbo R et al. Accelerated Methotrexate, Vinblastine, Doxorubicin, and Cisplatin Is Safe, Effective, and Efficient Neoadjuvant Treatment for MuscleInvasive Bladder Cancer: Results of a Multicenter Phase II Study With Molecular Correlates of Response and Toxicity. J Clin Oncol. 2014 May 12. [Epub ahead of print] doi:10.1200/ JCO.2013.53.2465 46. Waehre H, Ous S, Klevmark B et al. A bladder cancer multi-institutional experience with total cystectomy for muscle-invasive bladder cancer. Cancer. 1993; 72(10):3044-51.

47. Khaled HM, Shafik HE, Zabhloul MS et al. Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy for Invasive Transitional and Squamous Cell Carcinoma of the Bladder: Effect on Survival and Bladder Preservation. Clin Genitourin Cancer. 2014 May 6. [Epub ahead of print] pii:S1558-7673(14)00080-9 doi:10.1016/j.clgc.2014.04.002 48. Azuma H, Inamoto T, Takahara K et al. The novel bladder preservation therapy BOAI-CDDPradiation (OMC-regimen): a new treatment option for invasive bladder cancer patients with lymph node metastasis. Int J Oncol. 2014; 44(6):1895-903.

49. Tomaszewski JJ, Handorf E, Corcoran AT et al. Care transitions between hospitals are associated with treatment delay for patients with muscle invasive bladder cancer. J Urol. 2014 May 14. [Epub ahead of print] pii:S0022-5347(14)03556-3 doi:10.1016/j.juro.2014.05.027 This work is licensed under a Creative Commons Attribution 4 .0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/4.0/

Yadav Sankalp

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European Congress of Oncology Pharmacy 2014

8th European Scientific Oncology Conference

26 - 28 June 2014

02 - 04 July 2014

Krakow, Poland On behalf of the European Society of Oncology Pharmacy (ESOP) and the Organising Committee, we warmly welcome you to the second European Conference of Oncology Pharmacy (ECOP), in the time-honoured city of Krakow, Poland, 26-28th June 2014.

Close co-operation between oncology physicians and oncology pharmacists is essential for optimal patient care. ECOP 2014 offers a tremendous opportunity for exchange and debate between its 2,500 members, colleagues and partners worldwide.

The primary focus of this unique European Conference is to promote the highest standards of pharmaceutical care in the management and support of patients with tumours. The latest advances in research, patient management and practice are being showcased in keynote lectures, scientific symposia and poster sessions in two distinct tracks, clinical and practical.

We know that a multi-professional, multidisciplinary approach in oncology will not only ensure economic use of resources but also significantly improve patient safety.

We would like to take this opportunity to invite you to the Opening Event held in the exhibition area of the Conference venue, providing you the opportunity to meet colleagues from around the world, to network in a convivial setting and forge new links for future collaboration.

Lastly, but by no means least, our host city will match the exciting promise of the Conference itself.

Speakers, participants, guests and friends should make time to discover the wonderful city that is Krakow with its wealth of historical buildings.

We trust that you will return from the Conference inspired by colleagues from around the world and that you will have made new friends and scientific contacts that will support you in your essential work.

We are delighted to be welcoming you at what promises to be a highly educational, collaborative and successful conference.

Yours, Klaus Meier President of ESOP

Marbella, Málaga, Spain,

It is our pleasure to invite you to the 8th European Scientific Oncology Conference (ESOC-8) to be held in Marbella (Málaga, Spain) on 2nd- 4th July 2014. As in previous years, the ESOC meeting will highlight the best and latest findings in all areas of cancer research.

The Conference will be devoted to new promising anticancer agents in the latest pre-clinical stages or already in Phase I or II clinical studies.

The most relevant clinical investigators working on new drug development will actively participate in a very comprehensive Scientific Program, with Keynote Lectures from experts and specific Symposia devoted to the presentation and discussion of individual data from different clinical research groups.

Investigators attending the Conference will benefit from hearing about all these advances and will have the opportunity to exchange their opinion with the experts in very lively discussions.

All this in the exceptional surroundings of one of the most attractive places in the South of Spain, We look forward to seeing you in Marbella!

B. Chabner | Chairmen | H. Cortés-Funes

12th Annual Meeting of Japanese Society of Medical Oncology 17 - 19 July 2014 Fukuoka City, Japan

Dear Colleagues: We warmly welcome you to attend the 12th Annual Meeting of JSMO, which will be held in Fukuoka

from July 17 to 19 (Thursday to Saturday) 2014 in Fukuoka City, Japan. The theme of the meeting is “Comprehensive Cancer Therapy - From Translational Research and Chemotherapy to Cancer Survivorship.”

Though advances in research on cancer biology and translational research have resulted in many molecularly targeted agents and new treatment modalities, Japan and other Asian countries must deal with a rapid increase in cancer patients and survivors, especially among the elderly. The 12th Annual Meeting will discuss not only advances in cancer-targeted therapies, but also geriatric oncology and the management of cancer survivors. We expect to continue our collaboration with oncology societies from the US and EU, as well those from Asian-Pacific regions. Please join us in the international sessions to discuss issues that are vital to oncology.

Fukuoka is a wonderful city to spend time in. It is located on Kyushu Island in the southwestern part of Japan, approximately 1000 kilometers southwest of Tokyo. Fukuoka is a 90-minute flight from Tokyo, just over an hour from Seoul, 2 hours from Taipei and 4.5 hours from Beijing.

Because of its central location, Fukuoka has been Japan’s gateway to other Asian countries over the millennia, and has many interesting sites that are influenced by the Asian continent. There are also many fine restaurants within and around Fukuoka, where you can enjoy Hakata (Fukuoka) cuisine and fresh locally-sourced seafood, meats, vegetables and fruits at reasonable prices. We are certain that you will enjoy stimulating discussions and have many memorable experiences in Fukuoka during your stay. The members of the secretariat of the 12th JSMO 2014 Annual Meeting look forward to welcoming you to Fukuoka in July of next year.

Kazuo Tamura, M.D., Ph.D. Congress President, 12th Annual Meeting of JSMO Professor of Internal Medicine, Fukuoka University

Pan Pacific Lymphoma Conference 21-25 July 2014 Kohala Coast, Hawaii, USA The University of Nebraska Medical Center, Center for Continuing Education invites you to participate in the 2014 Pan Pacific Lymphoma Conference on July 21-25, 2014 at the The Fairmont Orchid, The Kohala Coast, Hawaii.

Trusted for almost two decades for its educational excellence, this international conference brings together more than 400 members of the multidisciplinary lymphoma clinical team including oncologists, hematologists, pathologists, clinical scientists, nurse practitioners, physician assistants, nurses,and pharmacists.Afull complement of research and clinical case presentations, symposiums, posters, and exhibits make this conference one of the largest gatherings of clinicians and researchers specializing in the area of lymphoma and transplantation.

The 2014 conference will include scientific sessions Monday through Friday, and two-hour symposiums throughout the conference.

OBJECTIVES At the conclusion of the conference, the attendees should be better able to: 1. Apply recent trial results with current and emerging agents and regimens to develop evidence-based clinical management strategies for Non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL).

2. Develop an algorithm for the optimal management of patients with lymphoma, inclusive of multi-modality therapies and maintenancebased regimens, across the disease continuum.

3. Personalize lymphoma treatment regimens based upon patient- and disease-specific characteristics.

4. Evaluate the optimal patient selection, timing, and regimen for stem cell transplant in patients with lymphoma.

5. Identify criteria related to the appropriate timing and patient selection for ongoing clinical trials using novel therapies.

SCOS Annual Membership Conference Diagnosis to Palliation: The Complete Spectrum of Cancer Care 01 - 02 August 2014 Charleston, SC, USA Welcome to the South Carolina Oncology Society (SCOS)! Our mission is to provide advocacy for cancer patients and to promote standards of excellence for high-quality cancer care.

SCOS is committed to adding clarity to both the clinical and business aspects of oncology care, offering our members access to meaningful, current, and helpful information and education.

6th Latin American Conference on Lung Cancer 21 – 23 August 2014 Lima, Peru.

Welcome Message Dear Colleagues, On behalf of the International Association for the Study of Lung Cancer (IASLC) and the Local June 2014

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Organizing Committee, it is a great pleasure and an honor to extend to you a warm invitation to attend the 6th Latin American Conference on Lung Cancer (LALCA 2014) to be held August 21 – 23, 2014 in Lima, Peru.

Lung Cancer is still the leading cause of death not only in Latin America but worldwide. Building on the success of the previous conferences in Chile, Argentina and Brazil, international and national speakers will discuss the science and advances in the treatment and prevention of lung cancer and thoracic malignancies worldwide and Latin America in particular.

Simultaneous translation English >< Spanish will be provided for all sessions.

With tobacco being the leading cause of morbidity and mortality worldwide and its consumption leading to respiratory and cardiovascular disease, as well as cancer, the Conference would like to support the Framework Convention for Tobacco Control and will again host a Tobacco Forum on Thursday, August 21.

We encourage physicians, nurses, other clinicians, researchers and scientists in the lung cancer field and those interested in any aspect of thoracic oncology to attend this conference. It is only through an exchange of the widest variety of research that we can offer the best program and benefits to our members and patients.

We expect more than 500 delegates from Latin America to attend this unique event and we encourage everyone to submit an abstract before the abstract submission deadline June 13, 2014.

We hope you will join us in Lima, the beautiful capital of the Republic of Peru, where you can enjoy its historical center with beautiful colonial churches and mansions; as well as its modern site with its suburbs offering a spectacular view of the Pacific Ocean. Or you might want to take a couple of extra days and enjoy an amazing journey to the center of the world Cusco with its beautiful surroundings and Inca ruins, followed by a leisurely train ride to the enigmatic citadel of Machu Picchu – one of the most amazing urban creations of the Inca Empire at 2,430m above sea-level, in the middle of a tropical mountain forest.

We look forward to welcoming you to an inspiring educational program in Lima, Peru in August 2014.

Carlos Vallejos Sologuren Luis E. Raez LALCA 2014 Conference Chair

4th International Thoracic Oncology Congress Dresden Advances through Molecular Biology in Thoracic Cancer 12 - 14 September 2014 Dresden, Germany

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Welcome!

We are pleased to invite you to the 4rd International Thoracic Oncology Congress Dresden in midSeptember, 2014 titled: Advances through Molecular Biology in Thoracic Cancer.

Our lung cancer congress will be a great opportunity for lung cancer professionals working, both, in the laboratory and in clinic, in the field of basic and translational research and in daily patient care, to share the most updated knowledge and views concerning the development of innovative therapies.

More than 50 of the most experienced lung cancer specialists including epidemiologists, molecular biologists, pathologists, pulmonologists, radiologists, surgeons, radiotherapists and medical oncologists will participate in the scientific program and their contributions will provide participants with new information on current patient care and research.

In addition to the outstanding scientific program being offered, we at the same time would like to encourage participants and guests to enjoy the great cultural opportunities of Saxony and the fabulous baroque city of Dresden.

We look forward to seeing you in Dresden on September 12th - 14th, 2014.

Nico van Zandwijk Giorgio V. Scagliotti Christian Manegold

NCCN 9th Annual Congress: Hematologic Malignancies 19 – 20 September 2014 New York, New York, USA Treatment of hematologic malignancies is increasingly complex. Issues relating to pathology, transplantation, and various new therapies require oncologists and hematologists to stay abreast of breakthrough advances. In addition, targeted therapies and oral treatments bring the latest benefits to patients. This Congress focuses on the new approaches that have been incorporated into patient management, including the use of drugs, biologics, and diagnostics.

The NCCN 8th Annual Congress: Hematologic Malignancies™ took place September 20 – 21, 2013 in New York, NY. Accredited materials from this congress are available through the NCCN Continuing Education Portal.

ESMO 2014 Congress 26 - 30 September 2014 Madrid, Spain

The theme for ESMO 2014 is ‘Precision Medicine in Cancer Care.’ Whether you are a medical or surgical oncologist, radiotherapist, immunologist or pathologist, practicing precision medicine means we are all working towards a common goal—improved patient outcomes. This is the ultimate goal of ESMO 2014.

Attendees can expect detailed exploration of the practical, political, and financial issues that stand between our ideals and the reality of implementing optimal care for every person suffering from cancer.

Invitation from the Congress President It gives me great pleasure to invite you to ESMO 2014 in Madrid 26- 30 September 2014.

I am particularly looking forward to this Congress, because it continues the powerful momentum established at our ESMO 2012 meeting in Vienna, which broke so many records for European oncology conferences: 16,394 delegates, 140 scientific and educational sessions, and a remarkable 30% rise in the number of abstract submissions – 1,238, of which 31 were latebreaking. ESMO 2012 set the standard for what a congress should be: deep, comprehensive, and up-to-the-minute. ESMO 2014 will raise that standard to a new level.

As the leading network for medical oncologists in Europe, ESMO takes very seriously its responsibility to inform, educate, and support each individual practitioner and researcher in our fast-evolving discipline.

The theme for ESMO 2014 is ‘Precision Medicine in Cancer Care’, an ideal that has rapidly shifted from “in some distant future” to “just around the corner.” We are looking forward to presentations of some of the most recent research and trials including targeted therapies and immunotherapeutic approaches, joint symposia with representatives of all cancer specialities, and robust debates on the clinical challenges of supplying genuinely personalised cancer treatment across Europe. We are also, naturally, looking forward to yet another record-breaking crop of abstracts!

ESMO is committed above all to supporting each medical oncologist with the best and most up-to-date information and educational materials. ESMO’s Clinical Practice Guidelines, OncologyPRO online educational and scientific resources, and our scientific journal Annals of

Oncology give practitioners across Europe and around the world access to the scientific and medical knowledge that supports best practice.

A congress is most of all about interaction, and ESMO 2014 will offer both the clear and efficient organization that attendees have come to expect from ESMO as well as plentiful opportunities to make new contacts, discuss new findings, learn from experts, and review presentations – both at the Congress itself and online.

All this will take place in Madrid in late summer: one of Europe’s most beautiful and vibrant cities, with a proud medical tradition and a wealth of cultural and gastronomic delights – only minutes away from the Congress venue.

Patients are waiting for delivery on the promise of precision medicine. We oncologists still have much to do to further improve cancer care. I look forward to seeing you in Madrid and helping to accelerate our profession into its next phase.

Welcome from the Committee Chairs It is now increasingly clear that cancer is a very personal disease that requires an individualized treatment approach. How can we possibly identify and effectively treat this massive collection of diseases – each sub-type with its own individual molecular makeup? For a long time, this seemed an insurmountable challenge to optimal cancer care: although the disease was clearly individual and heterogeneous, treatment was necessarily based largely on statistical collective analyses and results – a “best fit” for a population, but not necessarily for each individual sufferer.

Today, thanks to advances in molecular biology and genomics, this no longer has to be the case. As we gain greater insights into carcinogenesis, we are at the point where genuinely targeted therapy is now possible for an increasing number of cancers.

We are also rapidly moving from a ‘site of origin’ based disease classification to a genomics-based taxonomy of these complex and diverse diseases, with revolutionary implications for clinical practice, for research, and for teaching. ESMO is at the forefront of this rapidly changing landscape, a vital point of reference for the oncology profession. This is why you cannot afford to miss the 2014 ESMO Madrid Congress.

The theme for ESMO 2014 is ‘Precision Medicine in Cancer Care.’ Providing optimal treatment for patients according to individual circumstances and the molecular characteristics of their disease is also a key theme for ESMO when developing new conferences, products and services. Whether you are a medical or surgical oncologist, radiotherapist, immunologist or pathologist, practicing precision medicine means we are all working towards a common goal—improved patient outcomes. This is the ultimate goal of ESMO 2014.

ESMO 2014 will offer the chance to share that knowledge in a dynamic, peer-to-peer environment, where new ideas and new collaborations appear spontaneously at every corner. Nothing is better than face-to-face contact amongst professionals.

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In Madrid, ESMO will provide a Scientific and Educational Programme that builds on the highly successful models of ESMO 2010 in Milan and ESMO 2012 in Vienna, while extending breadth and depth. You can expect to learn about the latest results in basic, translational, and clinical research, expressing the broader concepts of precision or personalised medicine in specific treatment options.

The personalised paradigm for care demands more than ever a multidisciplinary approach: you can expect practical seminars and wide-ranging debates about how specialities can work together to achieve ever-greater precision in cancer care.

Delivering precision medicine is not just a scientific challenge: you can expect detailed exploration of the practical, political, and financial issues

that stand between our ideals and the reality of implementing optimal care for every person suffering from cancer. From the academic lab to the busy clinic, the scientific programme at ESMO 2014 aims to connect all the dots for you.

This also depends, in part, on you: the research abstracts and trials reports that you provide will help ensure that the Scientific and Education Programme is truly a conversation among peers. Your contribution will help to inspire the collaborative discussions that advance our profession – and gain you the recognition that your work deserves.

We look forward to meeting you in Madrid and to exchanging expertise. This is a remarkable time for cancer care – a time when we can all make a difference. We invite you to seize the opportunity.

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2014 PAN PACIFIC LYMPHOMA CONFERENCE

7th Africa Society For Blood Transfusion (afsbt) Biennial International Congress

21 - 25 July 2014

30 July - 2 August 2014

Hawaii, USA • Welcome message: At the conclusion of the conference, the attendees should be better able to: 1. Apply recent trial results with current and emerging agents and regimens to develop evidence-based clinical management strategies for Non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) 2. Develop an algorithm for the optimal management of patients with lymphoma, inclusive of multi-modality therapies and maintenancebased regimens, across the disease continuum 3. Personalize lymphoma treatment regimens based upon patient- and disease-specific characteristics 4. Evaluate the optimal patient selection, timing, and regimen for stem cell transplant in patients with lymphoma 5. Identify criteria related to the appropriate timing and patient selection for ongoing clinical trials for novel therapies • Event Committee Roster: James O. Armitage, MD Joe Shapiro Professor of Medicine Division of Oncology and Hematology Department of Internal Medicine University of Nebraska Medical Center Julie M. Vose, MD, MBA Neumann M. and Mildred E. Harris Professor Chief, Division of Oncology and Hematology Department of Internal Medicine University of Nebraska Medical Center

• Welcome message: The AfSBT will host its 7th AfSBT International Congress in 2014. Zimbabwe is hosting the event and the venue of the congress is Victoria Falls. The congress is organised by AfSBT through the Local Organising Committee (LOC). One of the key committees of the LOC is the Scientific Committee (SC). The Scientific Committee is composed of the International Scientific Committee (ISC) and the Local Scientific Committee (LSC). National Blood Service Zimbabwe (NBSZ) is partnering Zimbabwe Medical Association (ZiMA) and Zimbabwe Quality Assurance Programme (ZINQAP) in organising this congress. ZiMA and ZINQAP are also represented in the LOC and LSC.

Victoria Falls, Zimbabwe

26th World Congress Of The International Union Of Angiology 10 - 14 August 2014 Sydney, Australia

• Welcome message: The XXVIth World Congress of the International Union of Angiology (IUA) will take place at the Hilton Hotel, Sydney, Australia from Sunday 10th to Thursday 14th August 2014.

The IUA is a Society for Vascular Biology, Medicine, Surgery and Phlebology, with the red, blue and yellow rings of the IUA logo signifying the full spectrum of arterial, venous and lymphatic disorders which will be presented at the Sydney meeting. The Congress will be held in conjunction with the Australasian College of Phlebology 2014 Annual Scientific Meeting, and in association with the International Society for Vascular Surgery, the Australasian Society of Thrombosis and Haemostasis, the Australian and New Zealand Society of Phlebology, the Australian Wound Management Association, with participation of the Royal Society of Medicine Vascular Medicine Section, the Cochrane Peripheral Vascular Diseases Group, the French Society of Vascular Medicine, the Italian Society for Angiology and Vascular Medicine, the International Surgical Thrombosis Forum and other vascular societies and institutions affiliated with the IUA. The program will feature multidisciplinary symposia, key-note lectures, free paper sessions, consensus meetings and workshops on a wide range of topics, including arterial and venous thrombosis, anti-thrombotic and anti-platelet drugs, aortic and arterial aneurysms, cardiovascular and cerebrovascular disease, atherosclerotic risk factors and screening, prevention and management of acute stroke, hypertension, peripheral arterial disease, critical limb ischaemia, diabetes and related complications,endovascular treatment of arterial and venous disease, vascular malformations, lymphoedema, wound management, evidence based medicine, vascular imaging, prevention and management of venous thromboembolism and chronic venous disease.

This will be the first time that the biennial IUA world congress has come to this region.

Vascular physicians, angiologists, cardiologists, haematologists, vascular surgeons, phlebologists, interventional radiologists,

vascular sonographers, scientists, wound care specialists and vascular nurses are invited to visit Australia in August 2014 where Sydney will provide an ideal venue for a unique and productive multidisciplinary scientific exchange for delegates from around the world to the XXVIth World Congress of the International Union of Angiology.

Professor John Fletcher, IUA President-Elect

Iseh 2014: 43rd Annual Meeting Of The International Society For Experimental Haematology 21 - 24 August 2014 Montreal, Canada

• Welcome message: Make your plans now to attend the annual forum for the exchange and discussion of original, unpublished and significant research advances in the areas of hematology and stem cell biology.

This exclusive scientific meeting, 21-24 August 2014, willfeature leaders in the field as well as promising young scientists.

Unique with its intimate format, the ISEH 43rd Annual Scientific Meeting features more than 30 educational sessions, featuring lectures by our distinguished panel.

The New Investigators track provides those entering the field the opportunity to meet and connect with highly regarded ISEH scientists.

• Speakers: • Ben Ebert, Harvard Stem Cell Institute & Brigham and Women’s Hospital, Boston.

• Sean Morrison, UT Southwestern Medical Center, Texas.

• Scott Armstrong, Memorial Sloan Kettering Cancer Center, New York.

• David Traver, UC San Diego.

• George Daley, Harvard Stem Cell Institute and Boston Children’s Hospital.

• Guy Sauvageau, Université de Montréal.

• Connie Eaves, Terry Fox Laboratory, Vancouver.

Recipient of the 2014 ISEH Metcalf Award • Toshio Suda, Keio University, Japan.

Recipient of the 2014 ISEH Till and McCulloch Award • Emmanuelle Passegue, UC San Francisco.

New Investigator Lecturer at the 2014 ISEH Young Investigator Session • Simon Mendez-Ferrer, CNIC, Madrid June 2014

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26th European Congress Of Pathology 30 August - 3 September 2014 London, UK

• Welcome message: Dear Colleague, The 26th European Congress of Pathology (ECP 2014) will for the first time be organised as a joint venture between the European Society of Pathology and the Pathology London 2014 Ltd (a trading subsidiary of The Pathological Society of Great Britain and Ireland”).

It will be held, from 30 August to 3 September 2014 in the ExCeL Centre in London, United Kingdom.

On behalf of the European Society of Pathology and the Pathological Society of Great Britain and Ireland we would like to invite you to join us in London for a meeting that will be both exciting and involving, reflecting the rapid changes in our profession, both in unravelling disease mechanisms and in our clinical diagnostic working practice.

The motto of the Congress – Understanding Disease – is the well-known mission statement of Pathological Society of Great Britain and Ireland. And it is timely, now that we have greater understanding of many diseases arising from the ongoing revolution in genetics and other translational research methods.

Pathology is more than ever at the centre of clinical decision making, resulting in new challenges and opportunities. It is the philosophy of both the European Society of Pathology and the Pathological Society of Great Britain and Ireland that through better understanding of diseases we can improve the quality of diagnosis and treatment of patients.

The London 2014 scientific programme aims to bring science, translational research and clinical application together to provide delegates with a comprehensive forum for dissemination of research findings, exploration of modern technologies and up to date education.

In addition to providing a rewarding scientific and educational programme the London 2014 meeting will bring together pathologists and scientists from all over the world in a convivial environment providing a memorable social experience.

We are looking forward to welcoming you and spending a great time in London.

Han van Krieken President of the European Society of Pathology Ian Ellis President of the Pathological Society of Great Britain and Ireland

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• Event Committee Roster: An Ellis, UK Richard Byers, UK Adrienne Flanagan, UK Nicholas Rooney, UK Han van Krieken, The Netherlands Fred T. Bosman, Switzerland Fatima Carneiro, Portugal Michael Wells, UK

3rd World Congress On Controversies In Hematology 11 - 13 September 2014 Istanbul, Turkey

Welcome message: Dear Friends and Colleagues, We are delighted to invite you to participate in the 3rd World Congress on Controversies in Hematology (COHEM) which will take place in Istanbul, Turkey on September 11-13, 2014.

Following the success of the 1st and 2nd COHEM Congresses, which attracted almost 1,000 participants collectively from more than 60 countries, the 3rd COHEM Congress will continue the unique and successful debate format of the previous Congresses.

The 3rd COHEM Congress will share up-to-date information and provide a unique opportunity for world class leaders in the field to debate vital and contentious issues in Hematology.

This thought-provoking academic dialogue will address the most challenging current clinical and technological questions.

By allocating substantial time for discussions following each debate, audience members are encouraged to take a pro-active role in this academic dialogue. These stimulating debates will provide clinicians with state-of-the-art recommendations regarding patient care.

We invite you to attend the 3rd COHEM Congress in Istanbul and to take an active role in this innovative and interactive experience.

We look forward to welcoming you at this rewarding scientific event!

Prof. Robin Foà Prof. Rüdiger Hehlmann Prof. Emili Montserrat Prof. Eliezer Rachmilewitz Prof. Giuseppe Saglio Prof. Charles Schiffer Co-Chairpersons

The 19th International Symposium On Endoscopic Ultrasonography 18 - 20 September 2014 Chennai, India

• Welcome message: Welcome to Chennai!

It is our great pleasure to invite you on behalf of the organizing committee and outstanding faculty to attend the 19th International Symposium on Endoscopic Ultrasonography to be held in Chennai, India, from September 18-20, 2014.

EUS was once considered a “niche technology” meant for a “selected few”. Not anymore. With continual improvements in the technology, what was purely a diagnostic and staging procedure has evolved to include tissue acquisition and of late, interventions. Increased opportunities for training and the availability of educational resources have enabled an increasing number of endoscopists to acquire the requisite technical skills. These developments have facilitated the penetration of Endoscopic Ultrasound centers that were once limited to large tertiary referral institutions to smaller institutions in secondary cities and even outpatient clinics. With these changes, the technology that was once confined to Japan and to the West has made its way to the East with an increasing number of new centers being commissioned every year. This symposium, although deeply rooted in tradition, is evolving with the rapidly changing landscape of EUS. The biannual symposium that used to rotate between United States, Europe and Japan has recently been held in emerging nations such as China and Russia. In 2014 it will be in Chennai, India! Chennai is a cosmopolitan southern coastal city that is home to several multinational corporations, software and manufacturing industries. With numerous multispecialty and teaching hospitals, Chennai is a very popular destination for medical tourism and is referred to as the Mecca of Medicine in India. The city is also home to the second longest shoreline, numerous temples of historical interest and an unparalleled cuisine.

EUS 2014 will have two components: A two-day program that will include live demonstrations of basic and advanced EUS procedures combined with state-of-the art lectures and a half day program specially designed for beginners that will include practical tutorials by experts. Live demonstrations will include radial examinations, fine needle aspiration techniques interpreted in real-time by cytopathologists as

well as interventional procedures. The future environment within gastrointestinal endoscopy dictates that we not only be efficient in our practice but also remain as self-sufficient as possible. Therefore, a major focus of this symposium will be on EUS-related cytopathology to enable endosonographers to independently assess for diagnostic adequacy. We believe that this step is very important to further improve our patient outcomes.

To meet our goals and to provide a “world-class” experience we have assembled the best faculty from around the World who will enthusiastically share their knowledge, wisdom and experience. We believe that this symposium will provide you with invaluable information that will have an immediate and significant impact on your endosonography practice. We sincerely hope that you will join us in Chennai for EUS 2014!

Yours sincerely, • Event Committee Roster: Chairperson Shyam Varadarajulu USA / India Nageshwar Reddy India Secretary General K.R. Palaniswamy India

Program Committee Takao Itoi Japan Michael Levy USA Bertrand Napoleon France

Advisory Committee Paul Fockens The Netherlands Robert Hawes USA Zhendong Jin China Thomas Rösch Germany Kenjiro Yasuda Japan

Invited Faculty Amol Bapaye India Vikram Bhatia India Kenneth Binmoeller USA Kenneth Chang USA Pierre Deprez Belgium Vinay Dhir India Pramod Garg India Angels Gines Spain Lawrence Ho Singapore Atsushi Irisawa Japan Nirag Jhala USA Mouen Khashab USA Masayuki Kitano Japan Sandeep Lakhtakia India Alberto Larghi Italy Laurent Palazzo France Ian Penman UK Mathew Philip India Rajesh Puri India Vipulroy Rathod India Michael Wallace USA Aiming Yang China June 2014

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International Cytokine Society Conference 26 - 29 September 2014 Melbourne, Australia

• Welcome message: The 2014 meeting of the International Cytokine and Interferon Society is to be held in Melbourne, Australia, during October 26-29, at the state-of-theart Melbourne Convention Centre. The meeting will provide an outstanding forum for basic science and clinical researchers to present their latest data and exchange ideas relating to the broad role of cytokines and interferons in human disease, and applications to therapies.

The topics will include aspects of the biology, signal transduction and gene regulation related to cytokines, interferons and their receptors in innate and adaptive immunity, pattern recognition receptors and their role in host-pathogen interactions, infectious diseases, inflammation, cancer, autoimmunity and metabolism. Sessions will include cutting edge basic science and clinical presentations in plenary and concurrent symposia, as well as eminent keynote presentations, and are strongly supported by poster sessions.

In addition to academic basic scientists and clinical investigators, the meeting will provide strong networking opportunities for scientists in the biotechnology and pharmaceutical industries. The broad attendance and blend of senior scientists and physicians, as well as graduate students and post-doctoral fellows will help assure a vibrant and exciting conference for all.

If you would like to be updated about this conference, please add your name to the mailing list by clicking the button on the right.

• Event Committee Roster: o Shizuo Akira (Osaka University, Japan) o K Mark Ansel (University of California San Francisco, USA) o Frances Balkwill (Barts Cancer Institute, UK) o Gabrielle Belz (Walter and Eliza Hall Institute, Australia) o Jeff Babon (Walter and Eliza Hall Institute, Australia) o Andrew Brooks (University of Queensland, Australia) o Yinon Ben-Neriah (Hebrew University-Hadassah Medical Centre, Israel)

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o Zhijian James Chen (University of Texas Southwestern Medical Center, USA) o Daniel Cua (Merck Research Laboratories, USA) o Vojo Deretic (University of New Mexico, USA) o Mark Febbraio (Baker Institute, Australia) o Richard Flavell (Yale University School of Medicine, USA) o Frederic Geissman (King’s College, UK) o Florent Ginhoux (Agency for Science, Technology and Research, Singapore) o Elizabeth Hartland (University of Melbourne, Australia) o Veit Hornung (University of Bonn, Germany) o Kate Jaffrey (Harvard Medical School, USA) o Zhengfan Jiang (Peking University, China) o Simon Jones (Cardiff University, UK) o Thirumula-Devi Kanneganti (St Jude Children’s Research Hospital, USA) o Eicke Latz (University of Bonn, Germany) o Fabienne MacKay (Monash University, Australia) o Kingston Mills (Trinity College, Ireland) o Denise Monack (Stanford University, USA) o Masaaki Murakami (Osaka University, Japan) o Gabriel Nunez (University of Michigan, USA) o Keiko Ozato (National Institutes of Health (USA) o Belinda Parker (La Trobe University, Australia) o Stefan Rose-John (University of Kiel, Germany) o Chuck Samuel (University of California Santa Barbara, USA) o Feng Shao, (National Institute of Biological Sciences, China) o Mark Smyth (Queensland Institute of Medical Research, Australia) o Dale Umetsu (Genentech, USA) o Uwe Vinkemeier (University of Nottingham, UK) o Carola Vinuesa (Australia National University, Australia) o Xiao-Fan Wang (Duke University, USA) o Wolfgang Weninger (Centenary Institute, Australia) o Hua Yu (Beckman Research Institute, USA) o Elina I Zuniga (University of California San Diego, USA)

38th European Congress Of Cytology 2014 27 - 30 September 2014 Geneva, Switzerland Topics: • Gynecologic cytology • Lung • Thyroid • Liver & Pancreas • Genitourinary • Soft tissue & bone • Infectious diseases • Veterinary • Lymph node • Hematopathology • Pediatric • Salivary gland

• Head & Neck incl. ophthalmic • Central nervous system/ CSF • Breast • Fluids • Automation & quality assurance • Others

2nd International Conference On Hematology & Blood Disorders 29 September - 1 October 2014 Baltimore, USA

With the burgeoning response received for “The International Conference on Hematology & Blood Disorders” from the Editorial board, Organizing Committee members and the attendees, OMICS Group follows the same heel of success. We are overwhelmed to announce the launch of our “2nd International Conference on Hematology & Blood Disorders”. The remarkable event is to be held during September 29- October 01, 2014 at Baltimore, USA. We welcomeall the hematologists, immunologists, pathologists, oncologists, industrial professionals from biomedical and healthcare sectors, research scholars, students and all interested to be a part of our eventful event.

Hematology-2014 will witness a conglomeration of various arenas of Hematology under a single roof of knowledge. The scientific sessions of Hematology2014 has been designed on vivacious topics like Lymphocytosis, Stem cell research, Anticoagulants, Bone marrow transplants, Immunoglobulins and other plasma proteins. The meeting is sure to generate cerebrating discussions and stream out multidirectional flow of knowledge along with fostering beneficial collaborations.

With the well-organized scientific program hosting sessions on Hodgkin’s lymphoma, Thalassemia, treatments for plasma &platelet disorders, inherited blood disorders etc, along with topics like host defense and disorders, drug discovery in hematology, consultative hematology, thrombosis and Hemostasis and more, Hematology-2014 is expected to offer a better and firm platform for the researchers, students, business delegates and all attendees.

This international event is an effort to discover a weapon to fight against chronic diseases like

blood cancer ,sickle cell anemia, hemophilia, Lymphoid malignancies and myeloma, promising a better future for the progeny and a better tomorrow for the springing research.

Hematology-2014 is sure to make you ponder, raise your insights, conflate present and future and cogitate on ideas and reality. Mark your schedule, come, connect andconfer aboutyour researchat this International scientific meeting,let novel discoveries and research advancements flourish. Your rejoinder is our inspiration, right information is our aspiration. Hope to see you at Hematology-2014.

• Welcome message: Acknowledged as the leading open access publication model,OMICS Publishing Group is recognized by its authentic and consistent contributions to the scientific community.

OMICS Grouphosts over 300 leading-edge peer reviewed Open Access journals and has organized over 100 scientific conferences all over the world.OMICS Group believes that, “The Right to Information should be Universal”and with the aim of accelerating scientific discoveries, commencing from the year 2008, OMICS Group has been involved in providing a momentous platform for the world renowned scientists, researchers andtalented student community from academicinstitutions to participate in the best academic conferencesin the globe along with the collaboration initiatives with the leading entrepreneurs from industries.

OMICS Group journals possess over 3 million readers and the fame and success of the same can be attributed to the strong editorial board which contains over 30000 eminent personalities ensuring the rapid, quality and quick review processing.

With the burgeoning response ofthe “International Conference on Hematology & Blood Disorders-2013”from the Editorial board, Organizingcommittee members and the conference delegates,OMICS Groupwould like to carry forward the same heel of success and overwhelmed to announce the launchof its“2nd International Conference on Hematology & Blood Disorders”.

This astoundingevent is going to be held during September 29- October 01, 2014 at Baltimore, USA.OMICS Group International conferences always striveto unite people withdiverse expertise under a single roof of knowledge. On behalf of the organizing committee,OMICS Group welcomes all the hematologists, immunologists, pathologists, oncologists, research scholars, industrial professionals and student delegatesfrom biomedical and healthcare sectorsto be a part of the esteemed Hematology-2014. The conference will witness a conglomeration of various arenas in Hematology, sure to make you ponder, raise insights, conflate present June 2014

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Events

Scientific Events

withfuture and cogitate on ideas and reality.

Mark your schedule, come, connect and confer about your research atHematology-2014,one of the exquisitemedical meetings hosted byOMICS Group.

Hematology-2014is an attempt to explore a weapon against chronic diseases like blood cancer,hemophilia, lymphoma, myeloma, leukemia, sickle cell anemia etc., promising a better future for the progeny and a better vision for the springing research. Hematology 2014 is anticipated to be one amid the best scientific conferences in USA. The scientific sessions of this international conference on hematology has been designed on vivacious topics such as Hodgkin’s lymphoma, lymphocytosis, stem cell research, anticoagulants, bone marrow transplants, immunoglobulin and other plasma proteins.

Hematology-2014 is consisting of well-organized scientific program and effervescent speeches by the expertise.OMICS Groupscientific conferences always encouragethe young researchers and students to share their excitement and enthusiasm with world class expertise.

OMICS Groupscientific conference sareastonishing scientific events for the discussion and collaboration of the industrial personalities and medical professionals. Hematology-2014will stream the multidirectional flow of knowledge fostering beneficial partnering prospects.Hematology-2014 is going to be held in the charm city, Baltimore; participating Hematology-2014world congress would bean excellent opportunity to explore the beautiful city besides gaining knowledge. Let the novel discoveries and research advancements flourish at Hematology-2014, one of the most remarkable medical conference amidst all the OMICS Group meetings • Goal/Objective of the Event: On the Path of Identifying Novel Therapeutics for Blood Disorders • Event Committee Roster: Hematology-2014 Organization Committee Enzi Jiang Research Associate Department of Hematology and Oncology University of Southern California, USA Gouri Adel Clinical Biochemist/Head Laboratory of Medical Biochemistry IBN ZOHR Public Hospital, Algeria Paul Bajaj Professor Department of Orthopaedic Surgery David Geffen School of Medicine University of California, Los Angeles, USA Mark A. Guthridge Researcher Australian Centre for Blood Diseases Monash University, Australia Michael A. Firer

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Associate Professor Department of Chemical Engineering and Biotechnology Ariel University Center, Israel Aldo Iacono Professor Department of Pulmonary and Critical Care Medicine University of Maryland, USA Charles S Greenberg Professor Department of Medicine and Pathology Medical University of South Carolina, USA Gabriela Gheorghe Director Hematology Department of Pathology Children’s Hospital of Wisconsin USA Dr Erhabor Osaro Associate Professor of Haematology and Laboratory Medicine School of Medical Laboratory Science Usmanu Danfodio University Sokoto, Nigeria Daniel Tsun-Yee Chiu Distinguished Professor Department of Medical Biotechnology and Laboratory Science Dean of Research & Development Chang Gung University Taiwan, China Effie Liakopoulou Executive Director Partners in Personal Oncology, USA Helen Philippou Associate Professor Division of Cardiovascular and Diabetes Research University of Leeds, UK • Speakers: This international event will surely be a stream of knowledge sharing by many renowned personalities such as Dr. Daniel Tsun-Yee Chiu, Dr. Erhabor Osaro, Dr. Michael A. Firer, Dr. Dr. Effie Liakopoulou, Dr. Enzi Jiang, Dr. Mark A. Guthridge, Dr. Aldo Iacono, Dr. Charles S Greenberg, and Dr. Paul Bajaj. Scientific sessions will be chaired by the expertise from USA, UK, Japan, China, Australia and Canada.

Conference Highlights Red Blood Cells Diagnosis, Treatment and Management of Blood Disorders Hematologic Malignancies Immunology and Hematology Host Defence and Disorders Stem Cell Research in Hematology Blood Transplantation Thrombosis and Hemostasis Drug Discovery in Hematology Consultative Hematology Research on Various Blood Disorders Recent Advancements in Hematology

Nume autori

June 2014

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Review

Deeply Invasive (T2-T4) Bladder Cancer: Optimal Treatment in 2014?

DEEPLY INVASIVE (T2-T4) BLADDER CANCER: OPTIMAL TREATMENT IN 2014?

Derek Raghavan President, Levine Cancer Institute Carolinas HealthCare System Charlotte, NC, USA Corresponding author: Derek Raghavan MBBS, MD, PhD, FACP, FRACP, FASCO Levine Cancer Institute, Carolinas HealthCare System, PO Box 32861, Charlotte, NC, 28232-2861 Tel.: 980 442 3115 Fax: 980 442 3101 E-mail: derek.raghavan@carolinashealthcare.org

Open Access Article

Abstract Keywords: Dasatinib, Sprycel, Large Granular Lymphocytes, Lymphocytosis, Acute Lymphoblastic Leukemia, Philadelphia Chromosome

Invasive bladder cancer has a cure rate of only 50%, when all T stages are considered. The pattern of relapse reflects systemic spread, and metastases occur despite local control. This suggests that occult metastases are present at presentation. For more than 30 years, treatment has focused on the use of systemic chemotherapy before, during or after loco-regional therapy to control occult systemic disease. More aggressive surgery and more precise radiation techniques combined with systemic chemotherapy have also been tested to improve local control. Gene analysis has been applied extensively to this clinical problem, with a focus on prediction and prognostication, but results have not translated into a defined survival benefit.

Although new agents have been tested in the neoadjuvant and adjuvant setting, no level 1 evidence has been published in the peer-reviewed literature to show that they offer benefits over the neoadjuvant approach using the MVAC or CMV regimens.

Biology of Invasive Bladder Cancer Invasive bladder cancer, representing about 20% of new cases, includes tumors that penetrate through the lamina propria into muscle and beyond. Thus about 15,000 new cases occur each year in the USA, and one must remember that some cases of non-invasive bladder cancer eventually Received: 04 March 2014 become invasive, but are not reflected in national Accepted: incidence figures. In the USA, a reasonable 04 April 2014 estimate is that more than 20,000 patients require treatment for invasive, clinically non-metastatic bladder cancer per year. Most bladder cancers Cite this article: Raghavan D. Deeply inva(90%) are urothelial carcinomas (UC), formerly sive (T2-T4) bladder cancer: termed “transitional cell carcinomas” (TCC) (1), and Optimal treatment in 2014. other cell types include squamous cell carcinoma, Rom J Oncol Hematol. adenocarcinoma, small cell carcinoma and very 2014; 2(2):76-82.

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rarely sarcoma, lymphoma, or melanoma (2,3).

Most invasive bladder tumors are moderately to poorly differentiated (1). Our xenograft studies suggested the existence of a stem cell tumor of origin in bladder cancer, explaining why urothelial carcinoma may coexist with (and perhaps give rise to) squamous and glandular patterns of cancer (4).

We have also demonstrated clonal heterogeneity, reflected in histology and ultrastructure, tumor growth kinetics, expression of growth factors and their receptors, and response to treatment (4). Thus bladder cancer is a complex cancer to treat (5).

When planning treatment of invasive disease, it is important to consider conventional predictors of outcome – stage and grade are dominant prognosticators (1,6), and solid growth pattern, large

Derek Raghavan

size, aneuploidy, lympho-vascular invasion and the presence of hydronephrosis which may also have an adverse prognostic import (1,6,7). More recently, the expression of several individual genes and gene mutations has been shown to correlate with natural history or response to treatment, including epidermal growth factor receptor (EGFR), RAS, P53, RB, P21 and several gene panels (8-17). These novel prognosticators are increasingly being factored into potential treatment algorithms for invasive bladder cancer.

EGFR expression has been shown to correlate with natural history and extent of invasion (9,10) and has also been assessed as a predictor of response to therapy. For example, the Radiation Therapy Oncology Group (RTOG) have carried out retrospective analyses of their series of cases treated with radiotherapy and cisplatinbased chemotherapy, and have demonstrated that expression of EGFR is associated with improved outcome, including response to chemo-radiotherapy, whereas expression of the HER-2-NEU gene has been shown to correlate with reduced response and survival after such treatment (18).

One controversial issue has been the clinical significance of mutation of the P53 suppressor gene as a predictor of response to systemic chemotherapy. There are conflicting data on whether mutation of P53 confers increased responsiveness or increased resistance to the impact of chemotherapy. Cote and colleagues have reported a post hoc study of immunohistochemical staining of tumor biopsies from a randomized study of adjuvant platinum-based chemotherapy (19) and suggested that tumors exhibiting mutation of P53 benefited from adjuvant chemotherapy. By contrast, those with wild-type P53 did not exhibit any benefit from adjuvant chemotherapy. The major problem with this study was the small sample size and that it was carried out on specimens obtained from a trial that was not specifically designed to answer this question.

Studies from the Memorial Sloan Kettering Cancer Center initially suggested that P53 mutation was associated with resistance to neoadjuvant chemotherapy with the methotrexate-vinblastinedoxorubicin(AdriamycinR)-cisplatin (MVAC) regimen (20). A detailed study of molecular prognosticators in patients treated with the MVAC or the cisplatin-methotrexate-vinblastine (CMV) regimens for advanced bladder cancer at Princess Margaret Hospital, Toronto, did not identify any prognostic impact from expression of P53 immunohistochemically (21).

Takata et al (22), reported a small number of patients treated with a variant of MVAC chemotherapy and identified another series of potential genetic predictors of outcome using

array techniques. The significance of their preliminary observations will require validation, but it is noted that their data also suggested that P53 gene function and mutation predict the outcomes of chemotherapy.

However, we recently published the results of a randomized trial that tested the efficacy of adjuvant MVAC chemotherapy in patients with P T1-2,No,Mo urothelial cancer, using the same laboratory that had indicated the prior positive correlation (19), but were unable to confirm the prognostic significance of P53 mutation, and also did not confirm a survival benefit from adjuvant MVAC chemotherapy (23).

While there are many potential explanations for these observations relating to trial methodology and execution, and the exclusion of P3-4 disease, the fact is that the study was negative.

Multidrug or pleiotropic resistance, in which cell surface protein complexes help to export cytotoxics from cancer cells, thus reducing their effective concentration and ability to kill the cells, may be relevant to urothelial malignancy. The demonstrable presence of multidrug resistance (MDR) proteins, including p-glycoprotein, correlates with resistance to several cytotoxics, including the taxanes, vinca alkaloids and anthracycline antibiotics. This has been found in ovarian cancer and multiple myeloma, but studies of expression of MDR in bladder cancer have been less definitive, for reasons that are not well understood. For example, our xenograft studies identified major clonal differences in response to doxorubicin and vinblastine, but we were unable to demonstrate clear and reproducible expression of p-glycoprotein in the tumor specimens. Siu et al (21) assessed patients treated with MVAC or CMV chemotherapy and did not find any prognostic impact from p-glycoprotein, although this may have been influenced by the presence of cisplatin in both regimens, an agent that is not influenced by MDR expression, or may have reflected sample size and other statistical considerations. Petrylak et al (24) showed increased p-glycoprotein in pre- and post-treatment biopsies of human tumors treated with the MVAC regimen. The highest proportion of tumor cells expressing p-glycoprotein was observed in metastases from patients treated with six or more cycles of chemotherapy. They suggested that MDR could contribute significantly to the patterns of resistance seen in the use of the MVAC regimen, although it is not clear that this translates directly to invasive, non-metastatic bladder cancer.

Definitive Local Treatment Radical surgery for invasive bladder cancer: The standard of care for most patients with invasive bladder cancer is radical cystectomy with Martie June 2014

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Deeply Invasive (T2-T4) Bladder Cancer: Optimal Treatment in 2014?

lymph node dissection (25-27). The cure rate depends on well-defined prognostic factors, including conventional indices, such as stage and grade, and the more recent correlates discussed above.

In addition, it appears that delay in cystectomy may lead to impaired survival (27), and it has been suggested that the experience of the surgeon is also critically important to optimal outcomes.

Cure is even possible from surgery alone in locally advanced stage disease, although the chance is much lower (25, 26). In experienced centers, the relapse rate for T3-4 disease is at least 50%, with most relapses occurring at distant sites, suggesting the presence of occult micro-metastases at initial presentation.

Preservation of the Bladder Some patients are not sufficiently robust to undergo radical surgery, or choose to avoid this approach because of the physical and emotional impact.

Extensive transurethral resection is occasionally used as the first surgical approach to deeply invasive bladder cancer, although the level of local control is usually inadequate (28). In carefully selected cases, with a solitary lesion on the dome of the bladder, one that is distant from the bladder neck and ureters, with at least a 2cm margin of surrounding normal bladder tissue, and absence of carcinoma-in-situ, partial cystectomy may be possible (28,29). This allows preservation of the intact bladder, albeit sometimes with a smaller capacity. When used in isolation, surgical bladder preserving techniques are associated with a higher local relapse rate.

The use of radiotherapy as an alternative to radical surgery was generally favored in parts of Europe and Canada in the past, even for medically healthy patients. When interpreting published outcome data, it should be noted that patients treated in radiation series are characteristically older and less robust than those subjected to cystectomy. The traditional approaches to radiotherapy included doses of external beam irradiation in the range of 50-70Gy, with a higher level of local control achieved in series reporting higher dose schedules, and especially those cumulatively greater than 60-65 Gy (30-36).

Whether the newer techniques of intensity modulated radiation therapy (IMRT) and image guided radiotherapy will truly improve local control and/or reduce local tissue toxicity remains to be seen (30). Although the bladder moves (physiologically) to some extent, despite the fixity of bony landmarks, with appropriate treatment planning, the movement of the bladder does not appear to affect treatment outcomes (34). Various approaches have been studied in an attempt to improve local control, to shorten the duration of treatment or to ameliorate toxicity, but without a major impact to date (35).

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After many decades of comparison, there is still no absolute proof regarding the superiority of radical cystectomy over radical radiotherapy, although my own experience is that surgery yields more reliable local control if performed by an expert. This view remains controversial and has not been proven in randomized trials.

In my clinical practice, for medically fit patients without major additional medical disorders, I usually refer patients with deeply invasive disease for radical cystectomy, reasoning that useful information is gained from surgical staging, and that local control is likely to be more certain. As discussed below, in 2014, when radiation is to be employed, the best local control, and probably survival, are achieved by a combined chemoradiation approach, as discussed below.

Combination Of Therapeutic Modalities The combination of systemic chemotherapy with radiotherapy or surgery has been studied extensively in the past few years in the hope of sparing the bladder or to improve overall survival (7) . This is based on the concept that systemic chemotherapy may reduce the extent of local tumor while controlling micro-metastases, that prospective evaluation of tumor response is enabled (especially with neoadjuvant therapy), and that chemotherapy and radiation may synergize the anti-cancer effect locally. There is, however, the risk of delaying primary therapy and creating side effects without benefit as 3060% of bladder cancers show some resistance to chemotherapy.

Of importance, the Canadian group showed, in a randomized, prospective trial, that single agent cisplatin administered during the period of radiotherapy resulted in 67% sustained pelvic tumor control compared to 45% from radiation alone (37). However, overall survival was not statistically different, despite a survival trend in favor of the combined modality therapy, but this study was not powered to demonstrate a survival benefit.

In a series dominated by clinical stage T2 bladder cancer, James et al have reported a randomized comparison of radiotherapy/5-fluorouracilmitomycin versus radiotherapy alone, and showed improved response rate, progression-free and overall survival from the combination arm (38).

Neo-Adjuvant Chemotherapy The role of neoadjuvant (first-line) systemic chemotherapy, followed by definitive radiotherapy or cystectomy has been studied in detail (7). The early, randomized trials, employing single agent chemotherapy, did not show any survival benefit compared to local treatment alone. The introduction of cisplatin-based multi-drug regimens, such as MVAC and CMV, led to modest but statistically significant

Derek Raghavan

REGIMEN

MEDIAN SURVIVAL (months)

ACTUARIAL LONG-TERM SURVIVAL (years)

PUBLISHED

Shipley (53)

CMVC-RT v C-RT

36 v 36

48% 5yr v 49% 5 yr

1998

Griffiths (40)

CMV RT/S v RT/S

44 v 37.5

35% 10 yr v 30% 10 yr

2011

Grossman (41)

MVACS v S

77 v 46

42% 10 yr v 35% 10 yr

2003

Skinner

S v S “CAP”

30 v 52

39% 5 yr v 44% 5 yr

1991

Stockle/Lehman

S v S MVEC**

~24 v ~34

19% 10 yr v 26% 10 yr

2006

Freiha

S CMV v S

63 v 36

42% 5 yr v 38% 5 yr

1996

Cognetti

SGC v S

38 v 58

44% 6.5 yr v 44% 6.5 yr

2011

SERIES NEOADJUVANT

ADJUVANT

Table 1. Results of Randomized Trials of Neoadjuvant & Adjuvant Chemotherapy for Invasive Bladder Cancer

C: cisplatin CMV: cisplatin-methotrexate-vinblastine MVAC: methotrexate-vinblastine-Adriamycin-cisplatin MVEC: methotrexate-vinblastine-epirubicin-cisplatin “CAP”: intended regimen of cyclophosphamide-Adriamycin-cisplatin, but it was modified GC: gemcitabine-cisplatin RT: radical radiotherapy S: surgery – usually radical cystectomy ** many patients in the “surgery-only” arm did not receive chemotherapy at relapse – thus this tested the utility of chemotherapy at some time, rather than purely in an adjuvant context (if asking a true adjuvant question, patients receiving surgery-only would have been treated at relapse with chemotherapy).

improvements in survival, confirmed by randomized trials and a meta-analysis (Table 1) (7,39-42).

The International trial of neoadjuvant CMV was designed to identify a 10% difference in longterm survival, but failed to do so in a cohort of nearly 1000 randomized cases (39). It did achieve a 6-7% difference survival, but was reported as a negative trial initially as it did not achieve the planned difference (39). Two years ago we reported the final results of this study, showing a sustained 6% 10 year survival benefit with a 16% reduction in death from neoadjuvant CMV, with a more obvious impact in surgical cases (40).

Although the North American Intergroup trial of neo-adjuvant MVAC revealed a substantial difference in median survival (6.4 years versus 3.8 years), the absolute improvement in longterm survival and potential cure rate was only of the order of 7-8 percent (41), consistent with the CMV study, and with a meta-analysis of published randomized trials (42). Although a modest improvement, it is real, and I believe that this approach is the state-of-the-art in 2014.

Adjuvant chemotherapy In several other cancers, classical adjuvant chemotherapy, delivered after completion

of definitive local treatment, has produced a statistically significant and clinically relevant improvement in survival. In the past quarter century, this strategy has been applied to the management of bladder cancer, in the hope of duplicating this outcome. However, randomized trials assessing the utility of combination chemotherapy regimens like the MVAC and CMV regimens or equivalent, administered after radical cystectomy for patients with pT3-4, N0-3 disease, have reportedly shown improved disease-free survival (43-47). The problem is that disease-free survival is not a sufficient parameter of success in adjuvant studies, given the potential for salvage therapy (48). In the traditional models of adjuvant chemotherapy for solid tumors, overall survival is the key outcome that indicates success (48).

The group at the University of Southern California conducted a clever study that was intended to test the utility of adjuvant cyclophosphamidedoxorubicin-cisplatin after radical cystectomy; although an apparent disease-free survival benefit was reported, the study was marred by failure to obey randomization rules, modifications of chemotherapy, a focus on disease-free survival and other procedural abnormalities (43).

Martie June 2014

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Deeply Invasive (T2-T4) Bladder Cancer: Optimal Treatment in 2014?

In another widely quoted study, conducted in Germany, there was an uneven distribution of salvage chemotherapy, making the trial a test of chemotherapy at any time after cystectomy, rather than addressing the impact of early postcystectomy chemotherapy used as classical adjuvant treatment (44-46). In this trial, patients who were randomized to cystectomy-only predominantly did not receive chemotherapy at the time of relapse, thus making the trial a test of the utility of chemotherapy per se, rather than being a test of adjuvant therapy.

The interpretation of data in this study was confounded by the addition of non-randomized cases into the follow-up analysis (45) and admixture of intent-to-treat and received-treatment analyses (46), the latter clearly being confounded by case-selection bias.

The important study reported from Stanford University was predicated on disease-free survival, and thus was closed early by its Data Safety and Monitoring Committee, and there were insufficient cases to provide a meaningful overall survival analysis (47). Unfortunately the situation has been confused by a well-publicized but flawed meta-analysis (42), which ignored the various problems of individual published and unpublished trials and grouped them together into a comparison of observed versus expected outcomes. This study erroneously concluded that there is a statistically significant survival benefit from adjuvant chemotherapy. While in the future this may be proven to be correct, this specific meta-analysis did not prove the point.

The EORTC has attempted to address this issue in a well-designed, randomized trial, in which standard local therapy has been compared to standard local therapy plus the addition of adjuvant chemotherapy.

Unfortunately this important trial closed prematurely due to lack of accrual, presumably because of preconceptions of participating clinicians (or their patients) about the true role of ancillary chemotherapy, and it will henceforth be challenging to produce level 1 data to resolve the issue.

Perhaps relevant to this issue is the study from Stadler and colleagues (23), mentioned above. While this study was not designed to address the utility of adjuvant chemotherapy per se, and was restricted to patients with mutant P53 tumors, stage pT1-2, it is noteworthy that the patients who received 3 cycles of adjuvant MVAC did not appear to have improved overall survival, compared with those who were treated with surgery alone (23). Although this may simply have reflected the population of patients with P53-mutant urothelial cancer, this study clearly did not provide any additional data to support the routine use of adjuvant chemotherapy for invasive bladder cancer. We still believe that

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a randomized trial testing the use of adjuvant chemotherapy is needed to resolve the issue, and that adjuvant chemotherapy cannot be regarded as standard-of-care in 2014.

Newer Approaches to Systemic Treatment Combined with Local Therapy Although some phase I-II studies focused on novel agents used in the neoadjuvant or adjuvant setting for bladder cancer have been reported, there is very little level 1 information about whether these innovations produce a real survival benefit. In clinical practice, gemcitabinecisplatin has been used widely in association with local therapy, either in a neoadjuvant or adjuvant fashion, based on the thought that the results achieved are similar to those from MVAC; in reality, the only well-powered study demonstrating this was in the metastatic setting, and revealed a hazard ratio of 1.1, slightly favoring MVAC (49).

To my knowledge, no definitive trial has proven that gemcitabine-cisplatin provides a survival benefit when added to definitive treatment in either the neoadjuvant or adjuvant setting, nor that it is equivalent to MVAC. The problems of historical, non-randomized or under-powered comparisons, including the potential for case selection bias or follow-up bias, preclude any valid statistical assessment of the published data. In fact, Cognetti and colleagues, in a randomized trial assessing the role of adjuvant gemcitabine-cisplatin in one of two schedules, reported non-significantly inferior survival from the chemotherapy arm, compared to cystectomy alone (H.R. 1.29, 95% CI 0.84-1.99, p=0.24) (50).

If I see a patient who is not sufficiently robust to tolerate the MVAC or CMV regimens, I firstly question whether that fact is likely to reflect limited potential for safe radical cystectomy. If I conclude that cystectomy is likely to be feasible and safe, and that the MVAC regimen poses too much risk because of its direct toxic side effects, I will occasionally propose neoadjuvant gemcitabinecisplatin, after explaining carefully the limitations of the published data.

Another regimen that was recently reported in a randomized comparison against MVAC for metastatic disease is the combination of gemcitabine, cisplatin and paclitaxel (GCP) (51) . Although there was a modest increment in response rate from GCP against metastatic urothelial cancer, there was no significant difference in survival. Nonetheless, a Spanish cooperative group recently reported a survival benefit from adjuvant GCP after cystectomy in a presentation at the Annual Scientific Meeting of the American Society of Clinical Oncology (52).

However, there are two important caveats to this

Derek Raghavan

observation – (a) the same group initially reported very impressive results with GCP for metastatic disease in an early report at the ASCO meeting, but subsequent follow up indicated a much less impressive true result, indicating the importance of mature follow-up and adequate sample size (53); (b) I rarely implement data presented only at clinical meetings without presentation as a peer-reviewed manuscript, and it has been some years since the initial presentation of this study without a followup peer-reviewed paper. There have been recent reports of the use of targeted therapies, such as erlotinib or lapatinib (targeting the epidermal growth factor receptor), in patients with relapsed disease, with disappointing results (54), and this concept has been extended to the neoadjuvant setting for invasive bladder cancer (55). These studies represent clinical modeling and really are not definitive, and it is not yet possible to make any recommendations about the use of targeted therapy in a neo-adjuvant context. That said, it seems reasonable to consider the neoadjuvant setting for clinical trial modeling, provided that patients are not put at risk of unnecessary or prolonged delay of definitive treatment.

Similarly, there is no published level 1 evidence that confirms the utility of gemcitabine, the taxanes, any novel platinum complexes in this context, and thus no recommendations can be made about their use, other than in the context of clinical trials, at the present time. The risk in testing such novel approaches is that an established paradigm, with defined survival benefit, will be replaced by inferior experimental therapy when cure is at stake.

The Future It seems likely that molecular prognostication and prediction will increasingly influence the selection of treatment for invasive bladder

cancer in the future. In the treatment of bladder cancer, we appear to have reached a plateau with surgical and radiation techniques to control local disease, and our progress in cytotoxic chemotherapy has been slow since the introduction of the taxanes and gemcitabine.

However, there may be potential in leveraging the panoply of targeted therapies, provided that this is done in well-structured clinical trials that are designed to avoid losing the gains that we have won since 1980.

Of importance, we must be mindful of the promiscuity of some targeted therapies in their interaction with their purported targets, and we should be cautious in the use of Bayesian randomized discontinuation designs, which may incorrectly omit agents that have modest activity, especially if it is manifested after a time lag.

Despite the failure of the “P53 trial” to achieve its goals (23), its study design may provide a useful paradigm for future research.

The idea of designing trials based on defined gene targets makes sense, but these studies may require additional patient information to improve recruitment and compliance. It also will be important to remind patients and physicians about the progress that has been made, to avoid nihilism and a return to the ways of the past, and also to emphasize the importance of randomized clinical trials in demonstrating real, but incremental, progress.

In the absence of a quantum leap forward, clinical trials will allow us to improve survival, unlike the myriad of under-powered phase I-II trials of the past 20 years.

Conflict of Interests: None.

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Review

The Endocrine Phenotype in Ovarian Tumors

The Endocrine Phenotype in Ovarian Tumors Mara Carsote1,2*, Valentin Radoi1, Catalina Poiana1,2 1. ”Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 2. Department of Pituitary and Neuroendocrine Diseases, “C.I.Parhon” National Institute of Endocrinology, Bucharest, Romania Corresponding Author: Mara Carsote MD, PhD “C.I.Parhon” National Institute of Endocrinology, Bd. Aviatorilor no. 34-36, Bucharest, Romania Tel.: 021 317 2041 E-mail: carsote_m@hotmail.com

Open Access Article

Abstract Keywords: Sertoli-Leydig cell tumor, gonadoblastoma, teratoma, ovarian tumor, ovarian carcinoid

Received: 13 May 2014 Accepted: 21 May 2014

Cite this article: Carsote M, Radoi V, Poiana C. The endocrine phenotype in ovarian tumors. Rom J Oncol Hematol. 2014; 2(2):84-89.

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The ovarian tumors represent a challenging subject in actual medicine because of the new clinical, genetic, and immunochemical features which help us better understand them. In this paper we will mainly focus on the ovarian tumors that are associated with endocrine anomalies comprising an “endocrine” phenotype. The most important are the sex cord-stromal cell tumors. They gain the enzymatic and protein equipment in order to induce an excess of estrogens that are associated with menses anomalies and uterine bleeding in menopause or androgen excess that induces the virilization syndrome. If the onset of the endocrine activity is in a juvenile population, the endocrine phenotype is dominated by precocious puberty. Another type of tumors are the germ line cell tumors, mostly the teratoma. The most interesting aspects of endocrine manifestations are the struma ovary and the ovarian carcinoid.

The gonadoblastoma associates sex reversal since the majority of the tumors associate both the presence of the Y chromosome and the female phenotype. Finally, this paper is an argument for a multidisciplinary approach in ovarian tumors.

Introduction The ovarian tumors comprise a wide area of diseases with various aggressive profiles. The endocrine involvement is related not only to the good or bad function of the ovaries, but it is also related to the complex genetic syndromes or karyotype anomalies that might bring together many endocrine disturbances, not only strictly regarding the ovarian function.

The most important aspect in this complex and dynamic field of interest is the multidisciplinary approach.A patient might be seen by a gynecologist, an endocrinologist, a surgeon, a radiologist, or an oncologist, but the most correct approach is an adequate communication and sharing of opinions

between more than one specialist. Nevertheless, the first who might come into contact with a female subject displaying an ovarian tumor might be the pediatrician, the general practitioner or the internal medicine specialist based on the large area of ages that associate ovarian tumors. After the removal of the tumor, the most important aspect that actually sets the management is the histological report.

Based on this, the endocrinologist or gynecologist, on one side, or the oncologist, on the other side, will choose the adequate strategy for the subject (Figure 1).

The classification of ovarian tumors suffered a dynamic process of being brought up to date during the last years (1). The criteria to be taken

Carsote M, Radoi V, Poiana C

Figure 1. The pyramid

with different specialists that may be involved in the management of a case with ovarian tumor

into account are mainly histological, including the malignant features (2). The term of “ovarian cancer” is classically related to the surface epithelium but all the others tumors (including those with endocrine phenotype) may embrace a malign behavior (3).

The category of the epithelial ovarian tumors (like those with mucinous, serous or endometroid cells, carcino-sarcoma mixed or undifferentiated carcinomas) includes very aggressive tumors (4).

They are correlated in various ways with all kind of risk factors, including hormonal panel such as oral contraceptives, genetic anomalies, patient’s age, and so on (5-7). Their frequency depends on the group of subjects analyzed (8,9). These tumors have less endocrine aspects on admission and this group will not be discussed in this paper (10).

The endocrine phenotype that will be taken into account in this article will be mainly focused on sex cord-stromal tumors, germ cell tumors, and also the gonadoblastoma related to the “switched” (opposite to the genetic sex) phenotype (endocrine but not only) to the karyotype. We mention that regardless of the endocrine features and the oncologic profile, each of the ovarian tumors may associate the mass syndrome caused by the tumors themselves (Figure 2).

General data

The sex cord-stromal tumors The ovarian tumors which are most frequently associated with endocrine anomalies that might become clinically manifested are sex cord-stromal tumors. They embrace a great variability of signs and symptoms, and even in the same patient the clinical appearance might change during time.

The endocrine phenotype generally includes precocious puberty, menses anomalies like uterine hemorrhage, meno-metrorrhagia, vaginal bleeding after menopause, and virilization syndrome. The adult onset masculine phenotype is mainly caused by two types of tumors: ovarian and adrenal (like adrenal carcinoma and exceptional adrenal adenoma) (11). It consists of hirsutism (evaluated based on the Ferriman-Gallwey score), alopecia, the increase of muscle mass, the change of voice, the android proportions of the body, and also biochemistry blood changes such as high levels of uric acid, increased number of red blood cells and hypercholesterolemia (12). The only external genital organ that responds to androgens after birth is the clitoris and clitoromegalia might be registered.

All the symptoms and signs related to the tumor androgens are reversible during time with different June 2014

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The Endocrine Phenotype in Ovarian Tumors

Figure 2. Abdominal mass in a 82 year old female: ovarian tumor of 19 centimeters (the histological report pointed towards a benign cyst)

timing depending on cause, organs and age of the patient. Sometimes, the secondary amenorrhea caused by hyperandrogenism that suppresses the gonatropin levels might mimic menopause (13).

Apart from the endocrine phenotype associated with the ovarian tumor, other anomalies might be registered. The risk of a second neoplasia apart from the first ovarian tumor depends on the underlying cause, the patientâ&#x20AC;&#x2122;s age, the use of oral contraceptives, radiotherapy, genetic background and so on (14). For example, we previously reported a case of thyroid cancer and androblastoma but it is difficult to appreciate if this was an incidental finding (13).

The sex cord-stromal tumors may also display non-specific features and many times the diagnostic is retrospective, after the histological examination of the removed ovary. The recent approach includes a detailed immunochemical analysis that may highlight more features of the tumor and tumorâ&#x20AC;&#x2122;s management (15). One of the most useful combination is the assay of SF1 (steroidogenic factor 1) and FOXL2 which may be positive in sex cord-stromal tumors and CK AE1/AE3 (cytokeratin) or EMA (epithelial membrane antigen) which are more suggestive for epithelium, and rather negative in sex cordstromal tumors. Nevertheless, mixed phenotypes regarding the immunochemistry panel might be registered (16-18).

The main types of sex cord-stromal tumors are the tumors associating granulosa cells, fibromas, tecomas, sclerozating stroma tumors, annular tubule tumors, tumors with Sertoli-Leydig cells, with steroid cells, and mixed or undifferentiated neoplasia (15).

The granulose cell tumors have an adult type (which represents 95% of cases) and a juvenile type (5% of cases). One of the underlying endocrine mechanisms in ovarian tumors presenting granulose cells is the Anti-Mullerian hormone (AMH) that inhibits the growth of tumor cells by activating the apoptosis after

86

the link with the AMH type II receptor from granulose cells (19). Others oncogene related proteins have been found such as YAP (yesassociated protein) (20,21). The adult group of granulose cell tumors represents the most frequent tumors from the entire group of sex cord-stromal tumors (comprising almost two thirds). The median age at diagnosis is 48 years of life. The histological features include solid or partial cystic (probably with hemorrhage) appearance. The immunochemistry might find positive reaction for calretin or CD99. The aggressive behavior is reported in some cases (recurrences or local metastases) (15,22). This makes lifelong follow-up of a patient diagnosed with such a tumor mandatory (23). The endocrine phenotype in granulose cell tumors varies from mild symptomatic cases (or even without any symptoms) to precocious puberty (in pre-pubertal state), menses anomalies due to the hyperestrogenic state in subjects of reproductive age and in post menopause endometrial hyperplasia (with secondary bleeding) is seen. Thus, the endocrine aspects are strongly related to the age of the patient. This type of tumors is regarded as the most estrogenic type of ovarian tumors (15,24).

Independent of this aspects, the tumor itself may cause an abdominal mass syndrome, or the cyst part of the tumor may cause hemoperitoneum (one tenth of cases) or even ascites (25). One in ten tumors is completely asymptomatic (regarding the mass syndrome and the endocrine anomalies) (26) . The juvenile tumors may also associate recurrences or metastases (even a case of cancer related hypercalcemia has been reported) while the endocrine phenotype is quite suggestive because of abnormal endocrine activity in early years of life: girls before menarche and young (teenager) women (15,27). The most frequent types of infantile onset in sex cord-stromal tumors were found to be, according to a meta-analysis: juvenile granulose cells tumors, sclerozating stromal tumors, Sertoli-Leydig cell tumors, and

Carsote M, Radoi V, Poiana C

fibromas (15,28). Despite the high increase of the hormonal activity in granular cell tumors, hormonal replacement therapy after the removal of the tumor (in case of bilateral ovarectomy) is necessary but even if this is applied, there are limited prospective lifelong studies regarding this issue (29).

The fibromas have a median age at onset of 42 years and may have recurrences. The histological groups are cellular fibroma and fibrosarcoma (30) . Mixed forms comprising both thecomas and fibromas have been reported (31). The thecomas may also associate an aggressive profile with recurrences or metastases; the histological forms are classical and luteinized (32,33). The endocrine phenotype in thecomas is mainly related to the excess of estrogens (like abnormal uterine bleeding including in menopause, abnormal menses and endometrial hyperplasia) and exceptional with excess of androgens (34,35).

The sclerosing stromal tumors are extremely rare and are mostly seen in the second or third decade of life. The tumors have a low aggressive profile. The symptoms are related to the mass syndrome and with anomalies of the menses. The clue of the endocrine phenotype is abnormal hormonal activity at extreme ages in pre– menopause or after menopause. The endocrine secretion is related to either excess of estrogens or of androgens (36,37).

The annular tubule ovarian tumors have two forms: one associates Peutz Jegher’s syndrome (median age at diagnosis is reported at 27 years; 1/3 of cases), and another which does not associate the Peutz syndrome and has an older age at incidence (the median age at diagnosis is reported at 34 years; 2/3 of cases). In this last situation, half of the cases embrace an endocrine phenotype with hyper-estrogenism. The signs (that are caused by an excess of estrogens) vary depending on the subject’s age (as in the case of other histological sub-types) (38-40).

The Sertoli-Leydig cell tumors have different histological types: well, medium and low differentiated, retiform type, with heterologous elements, only with Sertoli cells or stromal Leydig cells (41). The main types of cells (apart from various heterologous cells) are Sertoli cells and Leydig cells (both with virilization potential), fibroblasts or epithelial cells (possible in a net display) (Figure 3) (42). This group of tumors represents 0.5% of all ovarian tumors; they are mostly seen in the third decade of life, with a median of 35 years for the well differentiated type (43,44). One of the newest mutations reported is DICER 1 which acts as an endoribonucleasis (45). The well differentiated Sertoli-Leydig cell tumors represent one tenth of all Sertoli-Leydig tumors. Usually, they present as a solid unilateral tumor with a medium diameter

of 5 up to 6 centimeters (46). Some correlations with genital tract anomalies have been reported.

The medium or low differentiated Sertoli-Leydig cell tumors may be bilateral in 2% of cases.

Their maximum diameter has been found to be of 15 centimeters (46). The Sertoli (stromal) cell tumors have various dimensions (up to 10 centimeters). The median age of incidence of 30 years has been reported. They display mostly an estrogenic phenotype, while the androgen phenotype is seen in only 1/3 up to 1/5 of cases. The prognosis is correlated to atipia or the high number of mitoses (47). Nevertheless, the tumor might be completely asymptomatic and its diagnostic may be incidental at a routine checkup. In such cases, we encourage the term of „ovarian incidentaloma” based on an analogy with adrenal or pituitary incidentaloma. Yet, the management of the ovarian tumors is always the removal of the tumor while in pituitary incidentalomas and in selected cases of adrenal incidentaloma the adequate management is only the close follow-up of the tumor (48,49). The tumors with heterologous elements associate all kinds of cells (most frequently mucin producing epithelium, but also muscle cells or fat cells etc.) among the Sertoli-Leydig cells. They are different from teratoma because here the non-ovarian cells are fewer than in teratoma (50). The steroid cell tumors may be well or low differentiated. Four out of 10 cases associate a virilization syndrome.

Extremely rare, an estrogenic phenotype or even Cushing’s syndrome has been reported (51). The endocrine production consists in androstendion, α-hidroxyprogesteron, testosterone (52). Ten percent of Sertoli-Leydig cell tumors cannot be classified and display a non-specific endocrine and non-endocrine phenotype. These mixed forms should be evaluated based on immunochemistry and genotype such as DICER1 mutations (53).

The germ cell tumors The class of germ cell tumors includes tumors with unipotent germinal cells (disgerminomas) and pluripotent germinal cells (teratoma, yolk sac tumor, embryonal carcinoma, choriocarcinoma, polyembryoma or mixed tumors) (54). Disgerminomas represent 1% of ovarian cancers and may be bilateral. They are mostly seen at extreme ages. Ten percent of these tumors are hCG producers. Endocrine anomalies are estrogen or androgen excess (55) . The neuroendocrine markers are LDH and neuron specific enolase. Extremely rare, they are associated with high levels of calcium or prolactin (56) . Teratomas may be mature or immature (benign or malign). They are most frequently seen in young females. The clinical phenotype may be absent or related to the heterologous June 2014

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elements (57). As pointed by the Greek word “teratos” meaning bizarre they behave in surprising ways. For example, the peritoneal gliomatosis is the implant of neural adult cells from an ovary immature glial cell teratoma (58). The struma ovari represents teratomas with thyroid tissue. They are usually benign, unilateral tumors (59-61) . Mostly, these are seen in the fifth decade of life. The mass syndrome is registered in one fifth of the cases (59-61). Fifteen percent of teratomas may associate thyroid tissue but, in struma ovari, by definition, 50% of the tumor is comprised of thyroid cells. The thyroid pattern is follicular, papilar or mixed. Thyroid cancer in this tissue is very rare. Most of the times the thyroid tissue is hypofunctional and rarely hyperfunctional (5961) . The ovarian carcinoid is very rare. The true carcinoid syndrome is very rare. The heterologous elements are neuroendocrine cells. The pattern is insular, trabecular, mucinous or mixed. Usually the tumors are very aggressive, as pointed by the Ki67 proliferation marker (62-64).

The gonadoblastoma The gonadoblastoma is a mixed tumor with germinal cells, sex cord-stromal cells etc.

Some genetic syndromes have been reported in association with gonadoblastoma such as Apert or Fraiser. The clue in understanding the gonadoblastoma is that in 90% of cases the Y chromosome is present. The clinical (nevertheless) phenotype is switched to the karyotype meaning that 4 out of 5 cases have a female phenotype while the Y chromosome is present in Turner mosaicism (such as 45 X0/46 XY) or Swyer syndrome (the mutation of the SRY gene) (65,66).

Figure 3. The types of cells in Sertoli-Leydig tumors

Conclusion The area of ovarian tumors underlying endocrine anomalies is related to the sex cordstromal tumors that associate an estrogenic or androgenic phenotype, both with effects in puberty. In very young ages, the “endocrine” germ line cell tumors are struma ovary and ovarian carcinoid. We would also mention the “inversed” phenotype in gonadoblastoma which associates the Y chromosome and the female phenotype.

Conflict of Interests: None.

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Molecular mechanisms implicated in citostatic resistance in cancer cells fro m metastatic breast cancer

Molecular mechanisms implicated in citostatic resistance in cancer cells from metastatic breast cancer Mecanisme moleculare implicate în rezistenţa la chimioterapie în celulele neoplazice din cancerul mamar metastatic Daniela Zob¹*, Dana Lucia Stănculeanu¹, Iuliana Gruia² 1. Medical Oncology I, Institute of Oncology, Bucharest, Romania 2. Research, Institute of Oncology, Bucharest, Romania Corresponding Author: Daniela Zob Medical Oncology I, Institute of Oncology, Bucharest, Romania, Fundeni Street, no. 252, Sector 2, Bucharest, Romania Tel: +40 021 227 10 00 Fax: 40 021 318 32 62 E-mail: danielazob@yahoo.com

Open Access Article

Abstract Keywords: breast cancer, chemotherapy, resistance, molecular mechanisms

Received: 13 February 2014 Reviewed: 05 May 2014 Accepted: 28 May 2014

Cite this article: Zob D, Stănculeanu DL, Gruia I. Molecular mechanisms implicated in citostatic resistance in cancer cells from metastatic breast cancer.

Rom J Oncol Hematol.

2014; 2(2):90-97.

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The purpose of chemotherapy is to prevent cancer cells from multiplying, invading and metastasizing. The majority of cytotoxic drugs are active on multiplying cells - cancer cells and normal dividing cells. Chemotherapy could be used with curative intent, but, in clinical practice, curative intent is limited by citostatic drug resistance and toxicity to normal tissues.

Chemotherapy resistance could be divided in intrinsic resistance - resistance that appears before any exposure to chemotherapy, and extrinsec resistance - resistance developed during the treatment, or inductible resistance in which cancer cells suffer genetic and epigenetic modifications that lead to chemoresistance. Resistance can be related to: pharmacological factors such as absorption, improper activation, metabolisation and rapid excretion of cytotoxic drugs or alteration of transport proteins - (resulting in a low level of the drug); and physiological factors: metastasis in “sanctuaries”; and cellular factors: a decrease in drug accumulation (low influx, high efflux), alteration of cellular metabolism (increase in degradation, low activation); citoplasmatic-nuclear inactivation (glutathione, metalotionine, proteins?), DNA repair, alteration in cellular targets.

Although cellular mechanisms implied in citostatic resistance have been elucidated in culture cells, their clinical relevance is less clear.

In this article we intend to present a short review of recent data from the literature regarding molecular and cellular mechanisms with a less known clinical relevance compared to the pharmacological one in relation with chemotherapy resistance.

Zob D, Stănculeanu DL, Gruia I

Rezumat Cuvinte-cheie: Cancer mamar, chimioterapie, rezistenţă, mecanisme moleculare

Scopul tratamentului citostatic este prevenirea multiplicării celulelor canceroase şi a fenomenului de invazie şi metastazare. Majoritatea agenţilor citostatici îşi exercită efectul asupra celulelor în diviziune, afectând cu preponderenţă celulele tumorale, dar şi celulele normale aflate în diviziune. Deşi aparent chimioterapicele ar avea acţiune curativă, în practica curentă, acţiunea curativă este diminuată de prezenţa rezistenţei la tratament şi de toxicitatea asupra ţesuturilor normale.

Rezistenţa la chimioterapie poate fi divizată în rezistenţă intrinsecă – rezistenţa apărută înaintea oricărei expuneri la citostaticul respectiv, sau extrinsecă - rezistenţa dezvoltată pe parcursul tratamentului, sau inductibilă - în care celulele canceroase suferă modificări genetice sau epigenetice, care duc la chimiorezistenţă. Rezistenţa poate fi legată de factori farmacologici precum absorbţia, activarea deficitară, metabolizarea şi excreţia rapidă a citostaticului sau alterarea proteinelor de transport, (rezultând în nivel scăzut de medicament), fiziologici - metastazarea în “sanctuare“ şi factori celulari: scăderea acumulării citostaticului (influx scăzut, eflux crescut), alterarea metabolismului celular (creşterea degradării, scăderea activării), inactivarea citoplasmatic-nucleară (glutation, metalotionine, proteine?), repararea ADN, alterarea ţintei celulare.

Chiar dacă mecanismele celulare implicate în rezistenţa la chimioterapie sunt elucidate pe culturi celulare, relevanţa clinică este mai puţin clară. În cele ce urmează vom prezenta o actualizare a principalilor factori celulari şi moleculari implicaţi în rezistenţa la chimioterapie, cu relevanţă clinică mai puţin cunoscută comparativ cu cea farmacologică.

Abreviations: Fasl - ligand FAS FasR - CD 95-receptor Fas Bak - antagonist “killer” Bcl2 omolog (Bcl-2 monologus antagonist killer) Bax - proteina x asociată Bcl (Bcl associated x protein) Cyt C - citocrom C SMAC/DIABLO - homolog Diablo IAPs - proteina inhibitoare a apoptozei (inhibitor of apoptosis proteins) C9 - caspaza 9 C3 - caspaza 3 C7 - caspaza 7 NFkB - nuclear factor Kappa- (light chain enhancer of activated B cells; face parte din categoria factorilor de transcripţie cu acţiune rapidă) STAT - factor de transcripţie (signal transducer activator of transcription) GADD45 - gena - implicată în răspunsul la stres (Growth Arrest and DNA Damage) P21/WAF1 - inhibitor kinazic ciclin dependent (cyclin dependent kinase inhibitor) ADN - acid dezoxiribonucleic ATP - adenozin trifosfat ADP - adenozin difosfat ABC - caseta care leagă ATP (ATP binding cassette) Pgp - P-glicoproteina MRPs - proteine de rezistenţă multimedicament (multidrug resistance proteins)

ABCA - caseta care leagă ATP (ABCG-ATP binding cassette A-G) TMD - domeniu transmembranar (transmembranar domain) NBD - domeniu de legare a nucleotidelor (nucleotide binding domain) GSH - glutation MRP1- proteină de rezistenţă multimedicament 1 (multidrug resistance protein 1) BCRP - proteină de rezistenţă în cancerul mamar (breast cancer resistance protein) MDR - rezistenţă multimedicament (multidrug resistance) Non ABC protein MDR - proteine MDR transportoare, altele decât ABC implicate în rezistenţa multimedicament RhoGTP-aze - este o familie de proteine G mici de semnalizare, GTP-aze şi este o subfamilie a superfamiliei Ras HSF - regiune colorantă omogenă (homogenous staining region) DHR - dihidrofolat reductază (dihidrofolat reductase) ARNm - ARN mesager VP16 - vepesid BSO - aminoacid butionin sulfoximă sintetic mTHF - acid levomefolic (methyltetrahydrofolate) 5FdUMP - monofosfat fluorodeoxiuridin (fluorodeoxyuridine monophosfhate) 5FTP - flourouridin trifosfat (flourouridine triphosphate) June 2014

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Molecular mechanisms implicated in citostatic resistance in cancer cells fro m metastatic breast cancer

c-myc - gena reglatoare c-Myc localizată pe cromozomul 8 Bcl2 - familia Bcl 2; proteine reglatoare ale apoptozei (B–cell lymphoma 2) Bcl-XI - moleculă transmembranară în mitocondrie, membru al familiei de proteine Bcl-2 (B-cell lymphoma-extralarge) P53 - proteina supresoare tumorală numită p53 TP53 - gena care codifică p53 P14 - regulator pozitiv p53 Akt - regulator negativ p53 ATM - mutaţie ataxie-telangiectazie (ataxia telangiectasia mutation) ART - ATM şi Rad 3 legate

ADN-PK – protein-kinaza ADN dependentă (DNA-protein kinase) Gena mdm2 - este un regulator negativ al p53 (mouse double minute 2 homolog) Bax - proteină care iniţiază direct apoptoza SAPK – protein-kinaza activată de stres (stress activated protein-kinase) numită şi JNK (c-jun N terminal protein-kinase a cărei activare este necesară pentru moartea celulară) MAPK – protein-kinaza activată mitogen (mitogen activated protein-kinase) ERK - kinază reglată de stimulul extracelular (extracellular stimulus regulated kinase)

Cancerul mamar este neoplazia cu incidenţa cea mai mare la sexul feminin în România, conform estimărilor WHO (International Agency for Research on Cancer- EUCAN) 2012 (25,22% din toate neoplaziile diagnosticate anual sunt cancere mamare) şi cu cea mai mare mortalitate (16,74% în România în 2012). Incidenţa brută în Uniunea Europeană este de 94.2/100.000 femei, iar mortalitatea este de 23.1/100.000 femei. În ciuda faptului că prognosticul cancerului mamar s-a ameliorat simţitor în ultimii ani, un număr mare de paciente prezintă evoluţie de boală, rezistenţa la diferitele citostatice reprezentând principala cauză de eşec terapeutic în cazul majorităţii pacientelor cu cancer mamar metastatic.

Scopul tratamentului citostatic este prevenirea multiplicării celulelor canceroase, a fenomenului de invazie şi metastazare (1,2). Majoritatea agenţilor citostatici îşi exercită efectul asupra celulelor în diviziune, afectând cu preponderenţă celulele tumorale cu diviziune necontrolată, dar şi celule normale aflate în diviziune.

Deşi aparent chimioterapicele ar avea acţiune curativă, în practica curentă, acţiunea curativă este diminuată de prezenţa rezistenţei la tratament şi de toxicitatea asupra ţesuturilor normale. De aici apar obstacolele în utilizarea tratamentului citostatic: rezistenţa la medicament şi toxicitatea asupra ţesuturilor normale.

Didactic, rezistenţa la chimioterapie poate fi divizată în rezistenţa intrinsecă - înaintea oricărei expuneri la citostaticul respectiv, sau extrinsecă - dobândită pe parcursul tratamentului, sau inductibilă - în care celulele canceroase suferă modificări genetice sau epigenetice, care duc la chimiorezistenţă. Rezistenţa poate fi legată de factori farmacologici precum absorbţia (1), activarea deficitară, metabolizarea (3) şi excreţia rapidă a citostaticului (4) sau alterarea proteinelor de transport, fiziologici - metastazarea în “sanctuare“ (5) şi factori celulari: scăderea acumulării citostaticului (influx scăzut (6), eflux crescut (7)), alterarea metabolismului celular (creşterea degradării, scăderea activării), inactivarea citoplasmaticnucleară (glutation, metalotionine, proteine?), repararea ADN, alterarea ţintei celulare (figura 1).

În cele ce urmează vom prezenta o actualizare a principalilor factori celulari şi moleculari, cu relevanţă clinică mai puţin cunoscută comparativ cu cea farmacologică. Chiar dacă mecanismele au fost clarificate în culturile celulare, relevanţa acestora în practica clinică e mai puţin clară.

Excluderea: 1.a. Sechestrarea - Sechestrarea intracitoplas­ matică a citostaticelor a fost corelată cu prezenţa “citoplastelor”. Acestea sunt vezicule intracelulare cu membrană proprie, în care sunt concentrate şi sechestrate anumite citostatice în celulele tumorale (ex. doxorubicina). Antraciclinele şi alcaloizii de vinca (baze slabe) pot fi captate de vezicule endozomale şi lipozomale cu un pH acid şi apoi eliminate prin fuziune cu membrana plasmatică. Acest mecanism determină imposibilitatea efectuării activităţii citotoxice a citostaticelor respective.

1.b. Exportul activ sau creşterea efluxului celular. Creşterea activităţii pompelor de eflux dependente ATP determină scăderea concentraţiei intracelulare a anumitor citostatice (doxorubicin, daunorubicin, vinblastine, vincristine şi paclitaxel).

Medicamente precum antraciclinele şi taxanii, care intră în celulă prin difuziune pasivă, pot fi exportate activ transmembranar via transporteri “ATP binding cassette” (ABC), transporteri care includ Pgp (P-glicoproteina) şi MRPs (multi drug resistance proteins) (8,9).

Transporterii ABC utilizează energia rezultată din hidroliza ATP-ului pentru realizarea efluxului şi pot fi divizaţi în trei categorii funcţionale: 1.

“Importeri”- mediază influxul nutrienţilor în celulă ex. aminoacizi, glucide şi ioni; 2. “Efluxeri” - pompe care exportă toxine şi medicamente din celulă; 3. Transporteri implicaţi în procesul de translaţie şi reparare a ADN-ului. Până în prezent au fost identificate 49 de gene ABC divizate în 7 subfamilii (ABCA- ABCG) (tabelul 1).

Proteinele familiei ABC sunt caracterizate prin două domenii distincte: domeniul transmembranar

Zob D, Stănculeanu D, Gruia I

Figura 1. Principalele mecanisme implicate in rezistenta la chimioterapie. Adaptat după (17)

(TMD- transmembranar domain), cunoscut şi ca “membrane spanning domain”, şi domeniul care leagă nucleotidele (NBD - nucleotide binding domain). TMD recunoaşte o varietate de substraturi şi suferă modificări conformaţionale pentru a le transporta transmembranar. Secvenţa aminoacizilor şi structura TMD sunt variabile, reflectând diversitatea chimică a substraturilor ce pot fi translocate. NBD sau “ATP - binding cassette” (ABC) este localizat în citoplasmă şi are o secvenţă şi structură fixă unde se produce legarea de ATP (11).

P - glicoproteina (PGP)/ ABCB1 PGP are o distribuţie tisulară largă (12) şi a fost primul transportor ABC identificat ca fiind supraexprimat în liniile celulare de cancer mamar MDR (multidrug resistance). Gena care codifică Pgp este “multidrug resistence 1” MDR1 - denumită şi ABCB1 (13). PGP are 12 domenii transmembranare şi două situsuri de legare a ATP. Alţi transporteri cu structura similară sunt MDR4, MRP4, MRP5 şi MRP7. Este localizată la nivelul membranei apicale a celulelor epiteliale şi este implicată în exportul transmembranar al compuşilor neutri şi cationici hidrofobi, precum: vinblastin, vincristin, doxorubicin, daunorubicin, etoposid şi paclitaxel. Pentru transportul transmembranar via PGP, extracţia citostaticului apare frecvent direct din partea citoplasmatică a dublului strat lipidic (14).

Proteina asociată MDR (MRP1) este exprimată în multe organe şi tipuri celulare (vezi tabelul 1), iar studiile au demonstrat că supraexpresia MDR1 face celula rezistentă la o varietate de substanţe citostatice, printre care şi doxorubicin(15).

Pentru multe medicamente, transportul mediat MRP1 este stimulat de prezenţa glutationului.

Spre deosebire de PGP, care are tendinţa de a fi localizată la nivelul membranei apicale a celulelor epiteliale, MRP1 este localizată bazolateral. MRP 1

are o structură similară cu PGP şi are nevoie de două molecule ATP ca sursă energetică, dar situsurile de legare a nucleotidelor 1 şi 2 (NBD1 şi NBD2) diferă în afinitate pentru ART. Substratul se leagă de domeniul transmembranar MRP1, cauzând o modificare conformaţională a proteinei, care iniţial induce legarea ATP de NBD1. Următoarele modificări conformaţionale cresc legarea ATP la NBD2. Când ambele NBD1 şi NBD2 sunt ocupate, substratul legat este transportat extracelular. ATP legat la NBD2 este hidroxilat şi se eliberează subsecvent ADP de la NBD2 şi întoarce parţial MRP1 la conformaţia originală, facilitând eliberarea legării ATP şi completarea ciclului NBD1 (7).

“Breast Cancer Resistance Protein” (BCRP)/ ABCG2 este exprimată într-o varietate de tumori şi este asociată cu rezistenţa la o varietate de agenţi: mitoxantronă, camptotecin, antracicline şi antifolaţi (16) . Spre deosebire de PGP şi MRP1, proteina BCRP conţine numai un domeniu transmembranar şi un domeniu de legare a nucleotidului. Mecanismul de transport facilitat de BCRP nu a fost investigat în detaliu. Unele dintre celulele stem şi celulele tumorale în mediu hipoxic ar putea fi protejate de agenţii citostatici prin creşterea expresiei BCRP indusă de hipoxie.

“Non ABC protein MDR” este un alt transporter conjugat GSH, “Ral-binding protein 1” (RLIP76/ RALBP1), o proteină Ral reglată care aparţine familiei Rho GTPaze. RLIP76 membranară funcţionează ca o pompă de eflux multispecifică pentru agenţii antitumorali - alcaloizii de vinca şi antracicline (9- REDOX). RLIP 76 pare să fie o proteină de răspuns la stres, care oferă protecţie împotriva stresului oxidativ indus de aceşti compuşi. Multe rapoarte au descris asocierea proteinei rezistente pulmonare (LRP - lung resistance protein) cu June 2014

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Gena

Proteina

Ţesutul

Citostaticele exportate de transporter

ABCB1

PGP/ MDR1

Intestine, ficat, rinichi, placentă, barieră hematoencefalică, majoritatea ţesuturilor

ADR, VP 16, VBL, PTXl

ABCC1

MRP1

Toate ţesuturile

ADR, VCR, VP16, MTX

ABCC4

MRP4

Prostată, testicul, ovar, intestine, pancreas, plămân, rinichi, majoritatea ţesuturilor

ABCC5

MRP5

Majoritatea ţesuturilor

6-mercaptopurină, 6-tioguanină şi metaboliţii şi MTX 6-mercaptopurină şi 6-tioguanină şi metaboliţii

ABCC10

MRP7

ABCC11

MRP8

ABCC12

MRP9

Sân, testicul, creier, os, ovar

Necunoscute

ABCG2

BCRP

Ficat, sân

DOX, IRI, MTX

Expresie scăzută în toate ţesuturile cu excepţia pancreasului Expresie scazută în toate ţesuturile cu excepţia rinichiului, splină, colon, creier

5-flourouracil

Tabelul 1. Transporterii ABC şi implicarea lor în rezistenţa la citostatice prin scăderea concentraţiei intracelulare (10) fenotipul MDR non Pgp mediat în linii celulare canceroase umane.

1.c. Scăderea influxului - prin mutaţii inactivatoare sau scăderea expresiei moleculelor carrier (17).

Influxul celular al citostaticelor hidrosolubile apare de-a lungul membranei plasmatice şi este produs de carrieri cunoscuţi a transporta nutrienţi sau alte molecule esenţiale cu greutate moleculară mică şi de procesul de endocitoză nespecifică (18) sau mediată de receptor (pinocitoză). Selecţia celulelor rezistente la citostaticele care intră în celulă via receptori sau transporteri rezultă din mutaţiile care elimină/modifică aceste molecule de suprafaţă celulară, ca de exemplu rezistenţa la metotrexat prin mutaţie şi/sau scăderea transporterilor de folaţi: folate binding protein, rezistenţa la analogii de nucleozide, prin mutaţii ale unor transporteri specifici de nucleozide. Unii dintre agenţii citostatici noi ca imunotoxinele care se leagă de receptorii de pe suprafaţa celulei nu pot omorî celula dacă nu sunt internalizaţi mai ales pe calea endocitozei receptor-mediată. Citostaticele hidrosolubile au o afinitate crescută pentru transportatori carrier de nutrient şi rar se acumulează celular - exemplu cisplatinul, 8-azaguanida şi 5-fluorouracilul.

Modificarea ţintei citostaticului. Modificări ale situsului de legare a citostaticelor (19) apar în cazul rezistenţelor la taxani, metotrexat, antracicline.

Rezistenţa la taxani poate apărea atât prin creşterea efluxului celular via Pgp, cât şi prin alterarea expresiei proteinelor asociate microtubulilor, mutaţii ale tubulinei sau expresia alterată a isoformei β a tubulinei, mutaţii ale β tubulinei, supraexpresia βIII tubulinei sau alterarea situsului de legare. Supraexpresia βIII tubulinei a fost asociată cu rezistenţa intrinsecă şi dobândită la taxani în diferite linii celulare (20, 21).

Celulele rezistente la Metotrexat prezintă cro­ mozomi minusculi (“double-minute”) sau HSR

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(homogenous staining regions) ca mărturie a amplificării genice (mecanism de activare a protooncogenelor) a enzimei dihidrofolat-re­ duc­tază (DHFR), care este ţinta atacului pentru metotrexaţi. Se pot cita şi alte exemple de modificări enzimatice care reprezintă alterări cantitative ale timidilat-sintetazei (enzimă implicată în rezistenţa la 5-fluorouracil) sau ale topoizomerazelor.

Topoizomerazele sunt enzime nucleare care catalizează modificări în structura secundară, terţiară şi cuaternară a ADN, catalizând clivarea tranzitorie monocatenară (topoizomeraza I) sau bicatenară (topoizomeraza II) a ADN. Citostaticele antitopoizomerazice permanentizează complexele clivabile ADN-proteină, perturbând repararea, replicarea şi transcrierea ADN. Topoizomeraza II este ţinta antraciclinelor, care se leagă de enzimă şi stabilizează intermediarul topoizomeraza IIADN. O creştere a expresiei topoizomerazei II este însoţită de creşterea sensibilităţii la antracicline.

S-a raportat existenţa unei legături între expresia ARNm a topoizomerazei II şi răspunsul la antracicline (6). Gena pentru topoizomeraza II poate fi amplificată în tumorile mamare primitive (22).

Sistemul topoizomeraza II generează un alt model de rezistenţă multimedicament, numit impropriu rezistenţă pleiotropică atipică sau MDR atipic, ceea ce creează confuzii cu sistemul Pgp-170, în care mutaţiile pot afecta rezistenţa la MDR. Rezistenţa tip AT-II (antitopoizomeraza II) interesează agenţii intercalanţi: antraciclinele, antracendiona (mitoxantron), acridine (mAMSA), dactinomicina şi neintercalanţi- VP 16 (23). Există studii care corelează modificările calitative cu apariţia unei rezistenţe selective la intercalanţi. Scăderea fiziologică a nivelului Topo II în celulele care nu sunt în diviziune explică rezistenţa relativă la AT-II a unor tumori solide care conţin o fracţie importantă de celule

Zob D, Stănculeanu DL, Gruia I

în G0. Activitatea topoizomerazei II este afectată de mai multe citostatice şi determină o primă alterare a funcţiei ADN prin rupturile intercatenare şi dublucatenare. Numeroase citostice stabilizează cuplul ADN-enzima care blochează în al II-lea timp realipirea lanţurilor ADN, iniţial clivate. Complexele citostatic-enzimă-ADN sunt reversibile, permiţând eliberarea citostaticului.

3. Detoxifiere prin activarea sistemelor de detoxifiere - respectiv citocromul p450 - cu funcţie mixtă de oxidază, prin creşterea nivelurilor moleculelor sulfhidril (glutationul - GSH şi metalotioninele) şi a enzimelor corelate.

Glutationul (GSH) şi metalotioninele par a juca un rol major în rezistenţa la cisplatin şi agenţii alkilanţi.

Acestea pot lega medicamentele în citoplasmă sau nucleu, prevenind astfel interacţiunea lor cu ADN sau prevenind “ADN crosslink”-area.

Totuşi, mecanismul prin care moleculele sulfhidril influenţează citotoxicitatea nu este elucidat.

Glutationul - nivelul glutationului pare a fi important în rezistenţa la citostatice. În unele studii s-au detectat niveluri crescute de GSH în liniile celulare ovariene selectate pentru rezistenţă la cisplatin in vitro. Depleţia GSH prin privare nutritivă sau pretratament cu aminoacidul sintetic butionin sulfoximină (BSO) - un inhibitor ireversibil al GSH (synthesis enzyme gamma glutamylcysteine synthetase) - creşte in vitro citotoxicitatea la cisplatin, melfalan şi iradiere, mai ales în cazul liniilor celulare umane de cancer ovarian (24).

Metalotioninele sunt proteine mici bogate în thiol, care aparent participă la detoxifierea metalelor grele. S-a observat o slabă corelare între expresia ARN-ului mesager al metalotioninei II şi rezistenţa la cisplatin în câteva linii celulare umane de cancer ovarian. Transfecţia genei metalotioninelor în celule murine cu cancer ovarian conferă rezistenţă la anumiţi agenţi alkilanţi. Metalotioninele pot contribui la rezistenţa la agenţii alkilanţi şi iradiere.

Expresia metalotioninelor poate fi corelată astfel cu prognosticul în cancerul mamar (25).

Modificări ale metabolismului citostaticelor: Activarea intracelulară este necesară în cazul unor antimetaboliţi (rezistenţa la antipurinice şi antipirimidinice fiind mediate prin niveluri reduse ale kinazelor fosforiboziltransferazelor) şi ale unor alkilanţi (ex. ciclofosfamidă). Rezistenţa poate să apară prin inactivarea expresivă (ex. dezaminarea antimetaboliţilor) sau alterarea unor cofactori (ex.

5-10 mTHF care creşte inhibiţia timidilat-sintetazei de către FdUMP). De exemplu 5-fluorouracilul este convertit de către celulă la compuşii fosforilaţi 5-FdUMP şi 5-FTP. FdUMP se leagă de timidilat sintetaza, “rate limiting enzyme” în sinteza timidin trifosfatului şi replicarea ADN este inhibată.

Astfel, expresia timidilat sintetazei poate modula sensibilitatea la 5-fluorouracil. Este discutabil dacă amplificarea genelor pentru dihidrofolat reductază şi timidilat sintetază reprezintă un mecanism de

rezistenţă, aşa cum a fost experimentat pe linii celulare tumorale animale. Până acum, majoritatea studiilor pe celule tumorale umane a indicat faptul că expresia crescută poate fi un factor de rezistenţă, dar nu este sinonim cu amplificarea genică.

4. Evitarea morţii celulare: Blocarea/supresia semnalelor apoptozei (26) Rezistenţa la apoptoză reprezintă cea mai puternică formă de rezistenţă la chimioterapie.

Apoptoza este reglată de protooncogene şi gene supresoare tumorale (27). Poate fi crescută de C-myc şi scăzută de Bcl2 şi este reglată inclusiv de gena supresoare tumorală p53. Proteina supresoare tumorală p53 joacă un rol central în reglarea ciclului celular şi moartea celulară. Gena care codifică p53, TP53, este cel mai frecvent mutantă în cancerele mamare, circa 50% din toate tumorile fiind estimate a fi purtătoare de mutaţie. În tumorile p53 “wild-type”, activitatea lui p53 poate fi compromisă de inactivarea activităţii regulatorilor pozitivi ai p53, precum p14 sau supraactivarea regulatorilor negativi ai activităţii p53 precum Akt (28, 29). Lezarea ADN-ului rezultă în activarea kinazelor “upstream” precum ATM (ataxia-telangiectazia mutated), ATR (ATM şi Rad-3 legate) şi ADN-PK (protein-kinaza ADN dependentă), care pot activa direct sau indirect p53. Studii pe linii celulare au evidenţiat experimental că alterarea funcţiei p53 rezultă în creşterea rezistenţei la diferiţi agenţi care lezează ADN (30, 31). Într-un sumar al 11 studii care au inclus 603 pacienţi cu cancer mamar, 143 (24%) au prezentat alterarea genei p53 (32). Produsul genei mdm-2 inactivează p53. Amplificarea sau expresia alterată a acestei gene poate fi un mecanism adiţional prin care p53 este inactivată. Proteina care iniţiază direct apoptoza este numită Bax, iar proteina codificată de bcl-2 îşi exercită efectele antiapoptotice prin formarea unor heterodimeri cu proteina Bax. Bcl-2 conferă rezistenţă la citostatice.

Când apoptoza este blocată, nici un citostatic sau asociaţie de citostatice, indiferent de doză, nu pot determina eradicarea completă a celulelor maligne. Supraexpresia proteinelor Bcl-2, Bcl-Xl poate fi o altă modalitate de suprimare a apoptozei şi de câştigare a unui fenotip celular cu rezistenţă la agenţii care lezează ADN. O altă modalitate de influenţare a apoptozei este prin intermediul căii proteinkinazei activate de stres (SAPK). Ca răspuns la tratamentele citostatice/genotoxice, se declanşează o cascadă intracitoplasmatică de transducţie a semnalului în care intervine MAPK (mitogen-activated protein kinase) şi ERK (extracellular stimulus regulated kinase). Din această categorie de kinaze face parte şi SAPC (stress activated protein kinase), numită şi JNK (c-jun N terminal protein kinase). Activarea SAPK este necesară pentru moartea celulară în cazul unor categorii de stres celular, aşa cum este şi chimioterapia. Inhibarea activării SAPK are rol protector asupra celulelor tumorale chimiotratate June 2014

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Figura 2. Interacţiunile între căile de transmitere a semnalelor pro-apoptotice şi pro-supravieţuire pot juca un rol important în determinarea răspunsului la chimioterapie (6)

cu antracicline sau etoposid. Mecanismul exact al implicării SAPK este necunoscut (33). Coexpresia p53 şi PGP este frecvent asociată cu prognostic nefavorabil (34, 35) în cancerul mamar (figura 2).

Apoptoza este controlată prin calea extrinsecă – care implică receptori ai unei superfamilii TNF, şi calea intrinsecă, care implică mitocondriile şi este controlată de proteine care aparţin Bcl2. Aceste două căi duc la activarea v-caspazelor (proteaze care conţin cisteină) responsabile de expunerea fosfatidil-serinei la suprafaţa membranei celulare, încetarea diviziunii şi fragmentarea nucleului şi citoscheletului cu formarea de corpi apoptotici.

Calea intrinsecă este activată ca răspuns la lezarea ADN-ului. În mod normal, proteinele pro­apoptotice sunt eliberate din mitocondrie pentru activarea caspazelor şi iniţierea apoptozei. Marea familie a proteinelor aparţinând Bcl2 joacă un rol major în reglarea apoptozei, prin reglarea permeabilităţii

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membranei mitocondriale cu aju­to­rul modulării anumitor caspaze, în special cas­paza 9, care împiedică eliberarea de către mito­condrie a citocromului C. Bcl 2 şi BclXL inhibă for­marea complexelor APAF1/citocrom C/ caspaza9necesare apoptozei.Mitocondriile joacă un rol-cheie în reglarea apoptozei. Într-adevăr, în faza efectoare a apoptozei se deschid porii de tranziţie ai permeabilităţii mitocondriilor.

Aceşti pori sunt canale oligoproteice constituite la nivelul membranei externe de către VDAC (Voltage Dependent Anion Channel), iar la nivelul membranei interne, de către ANT (Adenine Nuclotide Trans­ locator). În urma deschiderii acestor pori, se eliberează molecule pro-apoptice, ca citocrom C, caspazele 2, 3 şi 9, precum şi factorul de inducere a apoptozei (AIF - Apoptosis Inducing Factor). AIF este una din moleculele proapoptotice eliberate de mitocondriile localizate în spaţiul dintre membranele mitocondriale. Proteinele AIF, citocromul C, anumite

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caspaze, endonucleza G şi alţi factori sunt eliberaţi în citosol, iniţiind faza de degradare celulară.

Calea extrinsecă: mecanismul de activare a receptorului Fas - Apoptosis Stimulating Fragment (cunoscut şi ca Apo1 sau CD95), joacă un rol esenţial în apoptoză. Semnalele emise de Fas recrutează un complex format din FADD (molecula adaptoare - Fas Associated Death Domain) şi din procaspaza 8. Formarea acestui complex antrenează clivajul caspazei 8 produsă sub forma sa activă dimerică, precum şi cascada de activare secvenţială a diverselor caspaze, printre care şi caspaza 3. Exista două căi de transducţie a semnalelor Fas, depinzând de tipul celulei: în celulele de tip I (timocite), caspaza 8 activează direct caspaza 3, în celulele de tip II (hepatocite), caspaza activeaza Bid - o proteină proapoptotică (BH3 interacting domanin death agonist), provocând eliberarea citocromului

C. Asocierea dintre citocromul C şi APAF1 (Apoptotic Peptidase Activating Factor) activează caspaza 9, care la rândul ei activează caspaza 3. În concluzie, rezistenţa la chimioterapie este o problemă majoră în oncologie şi mecanismele de la baza ei sunt multifactoriale (36). Nu este cunoscut care mecanism de rezistenţă este dominant la un anumit pacient. Potenţialele beneficii clinice ale mecanismului de reversie a rezistenţei la chimioterapie sunt enorme. Rezistenţa apare nu doar la chimioterapia tradiţională, dar şi la terapia ţintită, precum tamoxifenul, care ţinteşte receptorul de estro­gen în cancerul mamar (37), imatinibul, care ţinteşte activ­itatea kinazică a BCR-ABL translocat în CML(38) sau gefitinib, care inhibă EGFR kinaza(36,39).Fără îndoială, vor mai fi descoperite mecanisme de rezistenţă pe măsură ce apar medicamente noi şi descoperim noi ţinte tera­peutice.

Conflict of Interests: None.

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Risk of Non Melanoma Skin Cancer in psoriasis patients with biologic therapy (up to date) Riscul de non-melanoma skin cancer asociat terapiei biologice din psoriasis (up to date) Ana Livia Duta1, Cristina Medeleanu1, Cristiana Voicu1, Madalina Maftei1, Victor Gabriel Clatici2* 1. Dermatology Clinic, Elias Emergency University Hospital, Bucharest, Romania 2. University of Medicine and Pharmacy ,,Carol Davila”, Bucharest, Romania Corresponding Author: Victor Gabriel Clătici Dermatology Clinic, Elias Emergency University Hospital, 17 bd. Marasti Street, Sector 1, Bucharest, Romania Tel.: 0213.161.600–190.224 Fax: 0213.173.052 E-mail: claticiv@yahoo.com

Open Access Article

Abstract Keywords: non-melanoma skin cancer, basal cell carcinoma, squamous cell carcinoma, psoriasis, biologic therapy, prevention

Received: 16 April 2014 Accepted: 10 June 2014

Rezumat Cuvinte-cheie:

non-melanoma skin cancer, carcinom Cite this article: bazocelular, carcinom Duta AL, Medeleanu C, spinocelular, psoriazis, Voicu C, Maftei M, Clatici VG. Risk of Non Melanoma terapie biologică, prevenţie Skin Cancer in psoriasis patients with biologic therapy (up to date). Rom J Oncol Hematol. 2014; 2(2):98-102.

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Biologic therapy represented an important step in the treatment of immune-mediated diseases and patients with moderate or severe psoriasis may benefit from this. In general, biologic agents are well tolerated, with mild side effects, but the immunosuppression they cause may favor the occurrence of malignancies, with an increased incidence of non-melanoma skin cancer (NMSC). However, data are confronted with the concomitant or previous use of other therapies with increased risk of NMSC. Since it is a very common and easily diagnosed malignancy in its early stages, the management of NMSC in patients treated with biologic therapy consists mainly in prevention and continuous monitoring. A diagnosed NMSC does not require treatment discontinuation and excision is indicated, although the therapeutic decision should be primarily based on the relative risk/benefit ratio.

Terapia biologică a reprezentat un pas important pentru tratamentul afecțiunilor mediate imun, iar pacienții cu psoriazis moderat sau sever pot beneficia de aceasta. În general, agenții biologici utilizați sunt bine toleraţi, cu reacții adverse ușoare, dar imunosupresia cauzată poate favoriza apariţia neoplaziilor, observându-se o incidenţă crescută a non-melanoma skin cancer (NMSC). Datele din literatura de specialitate sunt însă confruntate de utilizarea, concomitentă sau în trecut, a altor terapii cu risc pentru NMSC. Având în vedere faptul că este o neoplazie foarte frecventă şi uşor diagnosticabilă în stadii incipiente, managementul NMSC la pacienţii aflaţi sub terapie biologică este în mare parte unul preventiv şi de monitorizare continuă. Un NMSC diagnosticat nu impune întreruperea tratamentului şi are indicaţie de excizie, dar decizia terapeutică trebuie să se bazeze în principal pe relevanţa utilităţii beneficiului în detrimentul riscului.

Duta AL, Medeleanu C, Voicu C, Maftei M, Clatici VG

Introducere

Tratamentul psoriazisului

Psoriazisul este o afecțiune cutanată cronică, mediată imun, caracterizată prin hiperproliferare și turnover epidermic modificat, ceea ce duce la un proces de cheratinizare defectuos (1). Studii observaționale estimează că psoriazisul afectează între 1% și 3% din populație (2,3). În SUA, în cadrul unui studiu efectuat din 2009 până în 2010 au fost diagnosticați 7,4 milioane de adulți, cu o prevalență de 3,2%, care a rămas însă stabilă de la jumătatea anilor 2000 (4). Având în vedere faptul că pacienții se confruntă cu o boală cronică, manifestată prin prezenţa unor plăci eritematoase acoperite de scuame groase, este inevitabilă apariția implicațiilor psihosociale și se vorbește din ce în ce mai des despre calitatea vieții mult diminuată (5,6). Dizabilitatea este comparabilă cu cea a pacienților cu diverse alte boli cronice, precum afecțiuni cardiovasculare, diabet zaharat, cancer sau depresie (5,7).

Tratamentul psoriazisului folosește în principal agenți antiinflamatori și antiproliferativi, iar alegerea schemei de tratament depinde de multipli factori. Forma de psoriazis, severitatea afecțiunii, dorința pacientului, comorbiditățile sau toleranța la medicamente sunt factori care trebuie luați în considerare, iar pentru simplificarea deciziei, American Academy of Dermatology ne propune un ghid (22). Astfel, pentru psoriazisul în formă limitată se recomandă tratament topic sau fototerapie, iar pentru formele extinse sau non-responsive, UVB, PUVA (psoralen-UVA), tratament sistemic sau terapie biologică. Terapiile disponibile în prezent includ corticosteroizi topici, analogi de vitamină D3, fototerapie UVB și PUVA, metotrexat, ciclosporină, retinoizi (acitretin) și agenți biologici (23).

Factorii predispozanți ai psoriazisului Există multipli factori de risc incriminați în dezvoltarea și agravarea leziunilor de psoriazis.

Predispoziția genetică are un rol important, fiind descrisă asocierea cu alelele HLA-CW6 (PSORS1), dar şi cu multe alte locusuri genetice (8-10) , iar acest aspect este puternic susținut și de istoricul familial pozitiv, mai ales la rudele de gradul I (11). Fumatul este asociat cu severitatea clinică și crește nivelul de IL 17 și IL 22, interleukine care intervin în exacerbarea leziunilor (12). S-a observat că obezitatea apare de obicei după debutul psoriazisului și că nu există o cauzalitate unidirecțională, ci probabil ambele derivă dintr-o fiziopatologie comună (11,13). Un studiu prospectiv indică faptul că obezitatea și adipozitatea abdominală sunt factori de risc semnificativi pentru femei, astfel încât scăderea în greutate ar putea fi o ţintă pentru prevenția și managementul psoriazisului (14).

Traumatismul este considerat un trigger local, evidențiat prin fenomenul Koebner, şi se manifestă prin exacerbarea leziunilor după stimuli traumatici (fizici, chimici, electrici, chirur­ gicali, infecțioși) (15). Stresul psihogen este asociat cu debutul bolii și, de asemenea, cu agravarea leziunilor preexistente, care apar frecvent la un interval de săptămâni sau luni de zile (11,16).

Infecțiile, și mai ales infecțiile recente de căi respiratorii superioare, pot declanșa apariția psoriazisului, notându-se relația importantă dintre infecția streptococică și psoriazisul gutat (17,18).

Multiple medicamente sunt incriminate ca factori agravanți, iar în managementul comorbidităţilor asociate ar trebui evitate în principal anumite antibiotice, antimalaricele, beta-blocantele, litiul, inhibitorii de enzimă de conversie şi preparatele antiinflamatorii nesteroidiene (19-21).

Terapia biologică utilizată în psoriazis Există dovezi certe că psoriazisul este o afecțiune mediată imun și că limfocitele T, în principal Th1 și Th17, au un rol important prin citokinele pe care le secretă (TNF alfa, IFN alfa) (24,25). Terapia biologică a revoluționat tratamentul psoriazisului și constă practic în utilizarea unor agenți care acționează la nivel genetic sau la nivelul procesului imun care stă la baza fiziopatologiei unei boli. Există patru agenți biologici disponibili, adalimumab, infliximab, etanercept și ustekinumab, aprobați pentru tratamentul psoriazisului în SUA, Uniunea Europeană și alte regiuni ale lumii (22,26-29). În România, începând cu anul 2008, pacienții cu psoriazis moderat sau sever pot beneficia de aceștia prin intermediul “Programului naţional pentru tratamentul pacienţilor cu psoriazis vulgar de severitate medie şi gravă”.

Infliximabul este un anticorp monoclonal himeric (murinic și uman), primul din clasa anti-TNF alfa folosit în practica medicală. Mecanismul de acțiune constă în legarea de molecula solubilă de TNF alfa din plasmă, dar și de receptorii TNF de la nivelul membranei celulare, blocând astfel efectul acestei citokine.

Adalimumabul este un anticorp monoclonal uman cu același mecanism de acțiune ca și infliximabul şi se administrează în injecții subcutanate, fiind foarte eficace și în artrita psoriazică (30).

Etanerceptul este o proteină de fuziune care se leagă de subunitatea Fc a receptorului TNF, având ca scop final neutralizarea efectului TNF de vasodilatație, activare a keratinocitelor și a migrării leucocitare.

Eficacitatea și siguranța acestor trei antagoniști ai TNF utilizați pentru tratamentul psoriazisului moderat și sever au fost evidențiate în studii randomizate (31-34). Evidențele arată că infliximabul ar fi cel mai eficace, adalimumabul ar avea eficiență intermediară, iar etanerceptul ar avea cea mai slabă eficacitate (35).

Ustekinumabul este un anticorp uman mono­ clonal care se leagă de subunitatea p40 a IL12 și June 2014

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IL23, blocând astfel acțiunea acestor interleukine și, la rândul lui, și-a demonstrat eficacitatea atât pe termen scurt, cât și pe termen lung (36).

O metaanaliză din ianuarie 2014 susține ca infliximabul și ustekinumabul sunt cele mai eficace, în schimb, adalimumabul prezintă cel mai bun raport cost/eficacitate, urmat de ustekinumab și infliximab (37).

Efecte adverse ale terapiei biologice Terapia cu agenți anti-TNF reprezintă un pas important în tratamentul psoriazisului, dar manipularea acestei citokine poate avea consecințe negative pentru pacient, care impun întreruperea tratamentului. În general este bine tolerată, cu reacții adverse ușoare și limitate, care permit continuarea tratamentului (38). Cel mai frecvent, pacienții acuză cefalee, infecții de căi respiratorii, sinuzită, celulită sau reacție acută la perfuzie, manifestată prin prurit și urticarie în timpul perfuziei sau în următoarele două ore de la finalizarea acesteia (32,34,39,40).

Complicațiile infecțioase au fost evidențiate iniţial pe studii cu animale, ducând chiar la reactivarea tuberculozei latente (41,42). Astfel, pacienții cu risc crescut de tuberculoză sau cu tuberculoză latentă trebuie să primească tratament profilactic înainte de începerea terapiei biologice și toți bolnavii trebuie atent monitorizați pe parcursul tratamentului (38). S-au raportat și cazuri rare de infecții oportuniste, infecții granulomatoase la pacienții trataţi cu infliximab și etanercept, printre care histoplasmoza, listerioza şi altele (43).

Paradoxal, tratamentul anti-TNF poate fi implicat în apariția de novo a psoriazisului, iar acest fenomen a fost raportat pentru infliximab şi adalimumab (44).

Infliximabul se foloseşte cu precauție la bolnavii cu insuficiență cardiacă, dat fiind faptul că, folosit în doze de 10 mg/kg, se asociază cu agravarea insuficienței cardiace congestive și cu mortalitate (45) . Un studiu realizat în 2008 a observat că pacienții au dezvoltat Ac anti-ADN ds, cel mai frecvent de tip IgM, în 10-12% din cazuri la adalimumab, 15% la etanercept şi 20% la infliximab şi că DILE (druginduced lupus erythematosus) ar putea fi mai degrabă un efect de clasă (46). Foarte rar, agenții anti-TNF pot declanșa afecţiuni demielinizante sau limfoproliferative (47,48).

Un studiu recent arată că reacțiile adverse cutanate sunt strâns corelate cu sexul feminin, cu folosirea infliximabului sau a terapiei concomitente cu corticosteroizi, iar dintre acestea, psoriazisul și herpesul zoster sunt cel mai frecvent întâlnite (49). Se consideră că ustekinumabul este un factor de risc pentru dezvoltarea de herpes zoster și se recomandă vaccinarea înainte de iniţierea tratamentului (50,51).

TNF joacă un rol important în controlul ma­ lignităților, iar blocarea efectului său prin terapia biologică se corelează cu risc crescut de neoplazii (52) . O metaanaliză realizată în 2011 a analizat 74 de

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studii randomizate în care s-au folosit agenți antiTNF pentru cel puțin 4 săptămâni și a concluzionat că riscul relativ al neoplaziilor este de 0,99, dar crește la 2,02 după analiza incidenței nonmelanoma skin cancer (NMSC) (53).

Non-melanoma skin cancer (NMSC) NMSC, incluzând carcinomul bazocelular (BCC) și carcinomul spinocelular (SCC), este cea mai frecventă formă de cancer în medicină (54, 55) și reprezintă aproximativ 95% din patologia oncologică cutanată (56). Incidența NMSC este de două ori mai mare la bărbați, crește substanțial cu vârsta și crește anual la nivel global cu un procent de până la 8%, (57) existând o preponderență mai mare a BCC față de SCC (58).

Zonele fotoexpuse sunt cele mai predispuse, fiind certă implicarea expunerii la soare sau la surse artificiale de radiații UV, iar subțierea stratului de ozon accentuează efectul nefavorabil prin creşterea nivelul de UVB de-a lungul anului (59). Fototipul deschis, folosirea preparatelor fotosensibilizante (60), factorii ocupaționali (61, 62) , şi expunerea la arsenic (63) sunt, de asemenea, strâns corelate cu apariția BCC și SCC şi, în plus, pentru SCC, un rol activ îl joacă fumatul, atât prin efectul toxic, cât și prin efectul termic (64). Imunosupresia de diverse cauze, infecția cu virusul HPV (65,66), infecția HIV (67), limfomul de tip non-Hodgkin (66) sau imunosupresia iatrogenă (69-72) contribuie toate la dezvoltarea NMSC.

Terapia biologică și riscul NMSC Imunosupresia sub anti-TNF determină variații ale prevalenței NMSC de la 0,3 la 1,4% (73). În teorie, terapia biologică crește riscul de malignitate prin alterarea controlului imunitar, dar datele sunt confruntate de folosirea concomitentă sau în trecut a tiopurinelor și a fototerapiei (74). În plus, pacienții cu psoriazis prezintă diverse comorbidități și pot fi tratați în același timp cu imunosupresoare și alte terapii care cresc riscul de NMSC (35).

Un studiu realizat în anul 2006 asupra infliximabului şi adalimumabului la pacienții cu artrită reumatoidă a evidențiat faptul că terapia cu anti-TNF este asociată cu un risc semnificativ de NMSC și alte tipuri de malignități (74). Cu toate acestea, o altă metaanaliză din 2009 a concluzionat că folosirea acestora, în dozele aprobate, nu se asociază cu risc crescut de NMSC și că datele diferă prin excluderea rezultatelor unor studii mai vechi, realizate pentru doze inadecvate (75). Recent s-a observat că utilizarea agenților biologici pe o perioadă scurtă (< 90 zile) sau persistentă (> 365 zile) în monoterapie dublează riscul de NMSC (76).

Folosirea ustekinumabului pentru tratamentul psoriazisului relevă un profil de siguranță mai bun în ceea ce privește dezvoltarea NMSC, incidența fiind similară cu cea din populația generală (50,77). În ciuda datelor obținute în urma unor trei mari studii randomizate (PHOENIX I (29), PHOENIX II (78), ACCEPT (79)),

Duta AL, Medeleanu C, Voicu C, Maftei M, Clatici VG

au fost recent raportate două cazuri de SCC multifocal la pacienții expuși la ustekinumab, acest lucru indicând totuși necesitatea controalelor de rutină (77).

Concluzii Managementul NMSC la pacienții aflați sub terapie biologică este în mare parte unul preventiv şi de monitorizare continuă. Prevenția primară constă în aplicarea unor măsuri de combatere a factorilor de risc, iar pacienții ar trebui să fie consultați de rutină și să fie consiliați privind măsurile de fotoprotecție. Comportamentul individual de fotoprotecție, aplicat corect încă din copilărie, este cea mai importantă modalitate de prevenție și poate scădea incidența cancerului de piele cu până la 80% (80-82), iar utilizarea regulată a cremelor fotoprotectoare și-a demonstrat eficacitatea în prevenția NMSC invazive (83).

Cancerul de piele este ușor diagnosticabil în stadiu incipient și se recomandă screeningul pacienților pentru stabilirea diagnosticului precoce, ca prevenție secundară, ținând seama de istoricul de neoplazie, deoarece aceștia sunt mult

mai expuși la NMSC. Un NMSC diagnosticat are indicație de excizie, iar întreruperea tratamentului biologic nu se indică de rutină (84). Ca ultimă etapă, prevenția terțiară constă în monitorizarea regulată a pacienților diagnosticați cu NMSC, prin consult dermatologic al întregii suprafețe corporale. Șansele de a dezvolta aceste efecte adverse sunt mult mai mici, comparativ cu rata de succes la tratament, astfel încât sunt necesare decizii raționale în ceea ce privește prescrierea agentului biologic în psoriazis. Decizia trebuie să fie bazată în principal pe relevanța utilității beneficiului în detrimentul riscului, lucru care trebuie individualizat pentru fiecare persoană în parte (35). Toţi pacienții trebuie să fie consiliați cu privire la riscurile acestei terapii și, deopotrivă, la eficacitatea de care mulți alții beneficiază. Cancerele de piele reprezintă cea mai frecventă formă de cancer în medicină (55), așadar, un pacient care sub terapie biologică ar avea un beneficiu minor, dar risc crescut de a dezvolta diverse neoplazii, nu reprezintă un bun candidat.

Conflict of Interests: None.

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Nume autori

“Îndrumar pentru examenul practic în specialitatea ORL și chirurgie cervico-facială” Apariție: 2013 Autori: Prof. Dr. Romeo Călărașu, Dr. Tiberiu Dimitriu, Dr. Daniela Safta Coautori: Dr. Ileana Linaru și Dr. Loredana Mitran Adresare: medici primari și specialiști ORL, chirurgi, studenți, rezidenți “Numeroasele examene şi concursuri pe care trebuie să le susţină fiecare medic după terminarea facultăţii solicită din partea fiecărui cadru medical o susţinută şi continuă documentare. În sprijinul acestora, periodic s-au publicat diferite materiale, ce au folosit la buna desfăşurare a acestor examene.

În acest context, ne-am gândit să venim în ajutorul colegilor mai tineri, cu experienţa noastră, acumulată în decursul anilor, în activitatea clinică, dar şi în pregătirea pe care noi înşine a trebuit să o facem, când am fost nevoiţi să susţinem diferite examene şi concursuri.

Tematica, stabilită de minister,

pe specialităţile cu profil chirurgical, implică, obligatoriu, o probă practică, cu diferite operaţii, ce trebuie susţinută şi practicată de către candidat.”

Prof. Dr. Romeo Călăraşu, Dr. Daniela Safta, Dr. Tiberiu Dimitriu

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Conform Legii nr. 677/2001, beneficiaţi de dreptul de acces, de intervenţie asupra datelor, dreptul de a nu fi supus unei decizii individuale.

Aveţi dreptul să vă opuneţi prelucrării datelor personale care vă privesc şi să solicitaţi ştergerea datelor. Pentru exercitarea acestor drepturi, vă puteţi adresa cu o cerere scrisă, datată şi semnată la sediul social din Calea Rahovei nr. 266-268 corp 2 etaj 2 camerele 22-23, București.

De asemenea, vă este recunoscut dreptul de a vă adresa justiţiei. Media Systems Communication este înregistrată la Autoritatea Națională de Supraveghere a Prelucrării Datelor cu Caracter Personal sub numărul 29878/7.11.2013.

Nume autori

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