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2015 ANNUAL HIGHLIGHTS

The Best of the American Cancer Society Family of Journals Issue Highlights: 6 

I mpact of lung cancer screening results on participant health-related quality of life and state anxiety in the National Lung Screening Trial

11  Global cancer statistics, 2012 21 Value of combined cytology and

molecular information in the diagnosis of soft tissue tumors

23  Biospecimen repositories and cytopathology

26 

 lectronic cigarette use among E patients with cancer: Characteristics of electronic cigarette users and their smoking cessation outcomes

36 Keep up-to-date with the journals

on social media

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American Cancer Society Journals‌

Support Your Important Work in the Battle Against Cancer ACS MISSION: The American Cancer Society is the nationwide, community-based, voluntary health organization dedicated to eliminating cancer as a major health problem by preventing cancer, saving lives, and diminishing suffering from cancer, through research, education, advocacy, and service.

Cancer Cytopathology Cancer CA: A Cancer Journal for Clinicians cancercytojournal.com canceronlinejournal.com cacancerjournal.com

The American Cancer Society estimates a total of 1,658,370 new cancer cases and 589,430 cancer deaths will occur in the United States in 2015. Despite a reduction in overall cancer death rates since the early 1990s, further progress can be accelerated by applying existing cancer control knowledge across all segments of the population. Whether you are in research, clinical practice, or public health, you can depend on ACS journals to support and advance your own work. Take a look for yourself: this selection of ground-breaking articles published in ACS journals presents some of the latest emerging therapeutic strategies, evidence-based care practices, screening and prevention tools, and trends and risk factors in cancer. In short, you’ll find the information you need to do your best work in the battle against cancer.

Read On to Discover More News and Breakthroughs in Cancer Research and Care! > > >

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Contents Key

Fine-Needle Aspiration

Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) contributes to a triple-negative test in preoperative screening of pancreatic cysts ............................................................. 13 FNAB of benign thyroid nodules with papillary hyperplasia: A cytological and histological evaluation ........................................ 13 The role of cytopathology and cyst fluid analysis in the preoperative diagnosis and management of pancreatic cysts >3 cm................................................................................................ 14 Growing indication for FNA to study and analyze tumor heterogeneity at metastatic sites....................................................... 14

Gynecologic Cytopathology Breast Disease

Primary human papillomavirus screening for cervical cancer in the United States—US Food and Drug Administration approval, clinical trials, and where we are today .......................... 15

Significant clinical impact of recurrent BRCA1 and BRCA2 mutations in Mexico ............................................................................. 5

The low risk of precancer after a screening result of human papillomavirus-negative/atypical squamous cells of undetermined significance Papanicolaou and implications for clinical managementon ................................................................ 15

Screening mammography after autologous breast reconstruction is not beneficial ......................................................... 5

Chest and Lung Disease

Impact of lung cancer screening results on participant health-related quality of life and state anxiety in the National Lung Screening Trial............................................................. 6 Monitoring of epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and resistance mutations in the plasma DNA of patients with advanced non–small cell lung cancer during treatment with erlotinib............................................ 6

Influence of knowledge of human immunodeficiency virus serostatus on accuracy of cervical cytologic diagnosis ............... 16 Follow-up and clinical significance of unsatisfactory liquid-based Papanicolaou tests ....................................................... 16 Germline PTEN, SDHB-D, and KLLN alterations in endometrial cancer patients with Cowden and Cowden-like syndromes: An international, multicenter, prospective study ......................... 16

Clinical next-generation sequencing in patients with non–small cell lung cancer................................................................... 7

Head and Neck Disease

Clinical Trials

Hematologic Malignancies

Phase 2 trial of the cyclin-dependent kinase 4/6 inhibitor palbociclib in patients with retinoblastoma protein-expressing germ cell tumors .................................................................................... 7 Cancer survivors’ uptake and adherence in diet and exercise intervention trials: An integrative data analysis............................. 8

Decision-Making

Patient-centered, evidence-based, and cost-conscious cancer care across the continuum: Translating the Institute of Medicine report into clinical practice .......................................... 8

Disparities Research

Impact of state-specific Medicaid reimbursement and eligibility policies on receipt of cancer screening.......................... 9 End-of-life treatment preferences: A key to reducing ethnic/racial disparities in advance care planning? ..................... 9 Video-based educational tool improves patient comprehension of common prostate health terminology ......... 10

Epidemiology

Cancer treatment and survivorship statistics, 2014...................... 10 Cancer statistics, 2015 .......................................................................... 11 Global cancer statistics, 2012 ............................................................. 11 Interferon-γ–induced inflammatory markers and the risk of cancer: The Hordaland Health Study ................................... 12 Agent Orange exposure and cancer incidence in Korean Vietnam veterans: A prospective cohort study .............................. 12

Marital status and head and neck cancer outcomes..................... 17 Complete response to induction therapy in patients with Myc-positive and double-hit non-Hodgkin lymphoma is associated with prolonged progression-free survival................... 17 Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML............................ 18 Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia................................. 18

Hepatobiliary Disease

The clinical management of hepatocellular carcinoma in the United States, Europe, and Asia: A comprehensive and evidence-based comparison and review.......................................... 19

Immunocytochemistry

Reliability of immunostaining using pan-melanoma cocktail, SOX10, and microphthalmia transcription factor in confirming a diagnosis of melanoma on fine-needle aspiration smears................................................................................... 19 Usefulness of GATA3 and p40 immunostains in the diagnosis of metastatic urothelial carcinoma in cytology specimens................................................................................ 20 Wilms tumor 1/cytokeratin dual-color immunostaining reveals distinctive staining patterns in metastatic melanoma, metastatic carcinoma, and mesothelial cells in pleural fluids: An effective first-line test for the workup of malignant effusions..................... 20

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Contents, con’t.

Medical Oncology

Soft Tissue and Bone Sarcoma

Molecular Diagnostics and Cytogenetics

Retrospective cohort study evaluating the impact of intraperitoneal morcellation on outcomes of localized uterine leiomyosarcoma........................................................................... 29

Elevated risks of subsequent primary malignancies in patients with thyroid cancer: A nationwide, population-based study in Korea....................................................... 21 Value of combined cytology and molecular information in the diagnosis of soft tissue tumors................................................ 21 Analysis of immunocytochemical and molecular BRAF expression in thyroid carcinomas: A cytohistologic institutional experience........................................................................ 22 Comparison of urine cytology and fluorescence in situ hybridization in upper urothelial tract samples............................. 22 Multiplatform comparison of molecular oncology tests performed on cytology specimens and formalin-fixed, paraffin-embedded tissue.................................................................... 23 Available resources and challenges for the clinical annotation of somatic variations....................................................... 23 Biospecimen repositories and cytopathology................................ 23

Non-Gynecologic Cytopathology

Accuracy and risk of malignancy for diagnostic categories in urine cytology at a large tertiary institution............................... 24 Atypical urothelial tissue fragments in noninstrumented voided urine specimens are associated with low but significantly higher rates of urothelial neoplasia than benign-appearing urothelial tissue fragments...................................................................................... 24 Strategies for improving diagnostic accuracy of biliary structures..................................................................................... 25 Guidelines for pancreaticobiliary cytology from the Papanicolaou Society of Cytopathology: A review........................ 25

Outcomes Research

Electronic cigarette use among patients with cancer: Characteristics of electronic cigarette users and their smoking cessation outcomes............................................................................... 26

Pediatric Oncology

Safety and diagnostic accuracy of tumor biopsies in children with cancer............................................................................... 26

Psychosocial Oncology

When do we need to care about the caregiver? Supportive care needs, anxiety, and depression among informal caregivers of patients with cancer and cancer survivors...................................... 27 Physical, emotional, and social health differences between posttreatment young adults with cancer and matched healthy controls...................................................................................... 27

Screening and Prevention Tobacco use and cessation for cancer survivors: An overview for clinicians..................................................................... 28 Cancer screening in the United States, 2015: A review of current American Cancer Society guidelines and current issues in cancer screening..................................................... 28

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Patient-derived xenografts for individualized care in advanced sarcoma............................................................................. 29

Supportive Care

Phase III double-blind, placebo-controlled study of gabapentin for the prevention of delayed chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy, NCCTG N08C3 (Alliance).......................................... 30

Survivorship American Cancer Society prostate cancer survivorship care guidelines................................................................ 30 Oncologists and primary care physicians infrequently provide survivorship care plans......................................................................... 31 Practical clinical interventions for diet, physical activity, and weight control in cancer survivors .................................................... 31 Daughters and Mothers Against Breast Cancer (DAMES): Main outcomes of a randomized controlled trial of weight loss in overweight mothers with breast cancer and their overweight daughters ......................................................... 32

Symptom Control and Palliative Care

Early outpatient referral to palliative care services improves end-of-life care...................................................................... 32 Palliative radiotherapy at the end of life: A critical review ....................................................................................... 33 Recent progress in the treatment and prevention of cancer-related lymphedema .......................................................... 33 Clinical characteristics, pathophysiology, and management of noncentral nervous system cancer-related cognitive impairment in adults ............................. 34 Screening, evaluation, and management of cancer-related fatigue: Ready for implementation to practice? ............................................................................................. 34

Meet the Editors

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Breast Disease CA: A Cancer Journal for Clinicians | Volume 65, Issue 1, Pages 3-4, January / February 2015

Screening mammography after autologous breast reconstruction is not beneficial Mary Kay Barton

Previous studies have shown that the majority of disease recurrences after autologous reconstruction show up as an obvious abnormality, an irregularity such as swelling or dimpling, skin change, or pain. Furthermore, consensus is that screening mammography is unnecessary for patients with implant reconstruction because the implant is placed under the pectoralis muscle, displacing the entire mastectomy site, making detection easier during a physical examination (J Clin Oncol. 2009;28:173-180). However, with autologous reconstruction, the autologous tissue is placed over the pectoralis muscle, potentially making physical examination less sensitive in detection of local chest wall recurrences. Because there currently are no guidelines for screening in patients with autologous reconstruction, the authors of this study set out to investigate whether mammography is worthwhile in these patients. Freyvogel et al identified 615 patients who underwent autologous reconstruction after mastectomy at their institution between 2000 and 2009. Of these, 541 patients

had complete follow-up data and were included in the analysis. Patients with invasive (72%) or noninvasive (16%) breast cancer were included, as well as 3% of patients who had undergone prophylactic mastectomy. Most patients had a documented annual physical examination. Abnormalities found during a physical examination led to 77 biopsies being performed in 66 patients, 30 of which were found to be malignant (39%). Therefore, the yield for malignancy was much higher for biopsies performed from suspicions based on a physical examination compared with mammography findings (39% vs 8%). Furthermore, autologous breast reconstruction is safe and does not hide local recurrences during clinical examination. Researchers found that patients who underwent mastectomy and autologous tissue reconstruction do not benefit from routine mammography screening of the reconstructed breast (Ann Surg Oncol. 2014;21:3256-3260). Patient education regarding these findings can help alleviate anxiety. H

Cancer | Volume 121, Issue 3, Pages 372-378, February 1, 2015

Significant clinical impact of recurrent BRCA1 and BRCA2 mutations in Mexico Cynthia Villarreal-Garza, Rosa María Alvarez-Gómez, Carlos Pérez-Plasencia, Luis A. Herrera, Josef Herzog, Danielle Castillo, Alejandro Mohar, Clementina Castro, Lenny N. Gallardo, Dolores Gallardo, Miguel Santibáñez, Kathleen R. Blazer, and Jeffrey N. Weitzel

Frequent recurrent mutations in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 among Hispanics, including a large change in Mexican founder mutation, suggest that an ancestry-informed BRCA-testing strategy could reduce disparities and promote cancer prevention by enabling screening for hereditary breast and ovarian cancer in Mexico.

history, and the BRCA1 ex9-12del mutation explained 33% of the total. The HISPANEL mutation panel presents an opportunity for cost-effective genetic testing to enable breast and ovarian cancer prevention. H

In this study, 188 patients with cancer who were unselected for family cancer history were screened for BRCA mutations using a Hispanic mutation panel (HISPANEL) of 115 recurrent mutations. BRCA mutations were detected in 28% of patients with ovarian cancer, in 15% of patients with breast cancer overall, and in 27% of patients who had tumors that were negative for estrogen receptor, progesterone receptor, and human epithelial growth factor 2. A remarkably high prevalence of BRCA mutations was observed among patients who were not selected for family

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Chest and Lung Disease Cancer | Volume 120, Issue 21, Pages 3401-3409, November 1, 2014

Impact of lung cancer screening results on participant health-related quality of life and state anxiety in the National Lung Screening Trial Ilana F. Gareen, Fenghai Duan, Erin M. Greco, Bradley S. Snyder, Phillip M. Boiselle, Elyse R. Park, Dennis Fryback, and Constantine Gatsonis

Low-dose computed tomography (LDCT) lung screening has been associated with a 20% reduction in lung cancer mortality. This study assessed the impact of abnormal findings on health-related quality of life (HRQoL) and anxiety in the American College of Radiology (ACRIN)/National Lung Screening Trial (NLST). The NLST compared LDCT with chest X-ray screening. 2812 participants at ACRIN sites who had baseline HRQoL assessments completed the Short Form-36 and the State Trait Anxiety Inventory questionnaires to assess short-term and long-term effects of screening. False-positives were lung cancer–free at 1 year, and true-positives were not.

36.4% participants were false-positive, 2.2% were truepositive, 12.2% had significant related findings (SIFs), and 49.1% had negative screens. Short-term and long-term HRQoL and state anxiety did not differ from participants with false-positives, SIF, or negative screens. Short-term and long-term HRQoL were lower and anxiety was higher for true-positive participants compared to participants with falsepositives, SIF, and negative screens. Participants receiving a false-positive or SIF screen result experienced no significant difference in HRQoL or state anxiety at 1 or at 6 months after screening compared to those receiving a negative result. H

Cancer | Volume 120, Issue 24, Pages 3896–3901, December 15, 2014

Monitoring of epidermal growth factor receptor tyrosine kinase inhibitorsensitizing and resistance mutations in the plasma DNA of patients with advanced non–small cell lung cancer during treatment with erlotinib Boe S. Sorensen, Lin Wu, Wen Wei, Julie Tsai, Britta Weber, Ebba Nexo, and Peter Meldgaard

The possibility of monitoring epidermal growth factor receptor (EGFR) mutations in plasma DNA from patients with advanced non–small cell lung cancer (NSCLC) during treatment with erlotinib and its relation to disease progression was investigated. The amount of EGFR-mutant DNA was tested in plasma DNA from 23 patients with advanced NSCLC with allele-specific polymerase chain reaction tests. The data from the study showed that when a T790M mutation emerged in the blood it was accompanied by an increase in the original sensitizing EGFR mutation. When T790M was detected, it was present in all succeeding blood samples from that patient. Also, monitoring the EGFR mutations in the blood allows for the detection of the T790M mutation up to 344 days before disease progression. Ongoing monitoring of EGFR mutations in plasma DNA is feasible and may allow for the early detection of resistance mutations. These results warrant further studies to explore the clinical usefulness of such examination. H

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Chest and Lung Disease, con’t.

Cancer | Volume 121, Issue 4, Pages 631–639, February 15, 2015

Clinical next-generation sequencing in patients with non–small cell lung cancer Ian S. Hagemann, Siddhartha Devarakonda, Christina M. Lockwood, David H. Spencer, Kalin Guebert, Andrew J. Bredemeyer, Hussam Al-Kateb, TuDung T. Nguyen, Eric J. Duncavage, Catherine E. Cottrell, Shashikant Kulkarni, Rakesh Nagarajan, Karen Seibert, Maria Baggstrom, Saiama N. Waqar, John D. Pfeifer, Daniel Morgensztern, and Ramaswamy Govindan

A clinical assessment was implemented to perform nextgeneration sequencing (NGS) of genes commonly mutated in multiple cancer types. This report describes the feasibility and diagnostic yield of this examination in 381 consecutive patients with non–small cell lung cancer (NSCLC). Clinical targeted sequencing of 23 genes was performed with DNA from formalin-fixed, paraffin-embedded (FFPE) tumor tissue in a College of American Pathologists– accredited, Clinical Laboratory Improvement Amendments– certified laboratory. Single-nucleotide variants and insertion/

deletion events were reported. This analysis was performed before methods were developed to detect rearrangements by NGS. Two hundred nine of all requisitioned samples were successfully sequenced. The most common reason for not performing the sequencing was an insufficient quantity of tissue available in the blocks. NGS-based diagnostics are feasible in NSCLC and provide clinically relevant information from readily available FFPE tissue. The sample type is associated with the probability of successful testing. H

Clinical Trials Cancer | Volume 121, Issue 9, Pages 1463-1468, May 1, 2015

Phase 2 trial of the cyclin-dependent kinase 4/6 inhibitor palbociclib in patients with retinoblastoma protein-expressing germ cell tumors David J. Vaughn, Wei-Ting Hwang, Priti Lal, Mark A. Rosen, Maryann Gallagher, and Peter J. O’Dwyer

Alterations in the retinoblastoma pathway in germ cell tumors (GCTs) have been described. In the phase 1 trials of the selective cyclin-dependent kinase 4/6 inhibitor palbociclib, 3 patients with unresectable, growing, mature teratoma syndrome achieved prolonged disease stabilization. The authors conducted an open-label, phase 2 study to determine the effectiveness and safety of palbociclib in patients with incurable, refractory, retinoblastoma protein (pRB)-expressing GCTs. Patients who had incurable, refractory GCTs that demonstrated pRB expression by immunohistochemistry received oral palbociclib 125 mg daily for 21 days followed by a 7-day break. The primary endpoint was the 24-week progression-free survival (PFS) rate. A 24-week PFS rate

≥15% was considered promising, and a PFS rate ≤5% was not considered promising. Thirty patients received treatment, and 29 were evaluable for the primary endpoint. The estimated 24week PFS rate was 28% (90% exact confidence interval, 15%44%). Patients who had teratoma and teratoma with malignant transformation had significantly better PFS than patients who had nonteratomatous GCTs. Toxicity was manageable and was principally hematologic. Treatment with palbociclib was associated with a favorable 24-week PFS rate in patients with refractory, pRB-expressing GCTs. Benefit was mainly observed in patients who had unresectable teratomas and teratomas with malignant transformation. H

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Clinical Trials, con’t.

Cancer | Volume 121, Issue 1, Pages 77–83, January 1, 2015

Cancer survivors’ uptake and adherence in diet and exercise intervention trials: An integrative data analysis Rebecca N. Adams, Catherine E. Mosher, Cindy K. Blair, Denise C. Snyder, Richard Sloane, and Wendy Demark-Wahnefried

The health benefits of diet and exercise interventions for cancer survivors are documented. However, little is known regarding demographic and medical predictors of survivors’ willingness to participate in diet and exercise. Data was analyzed from 3 of the largest home-based diet and exercise intervention trials for cancer survivors. Demographic and medical factors were examined as predictors of willingness to participate, study enrollment, intervention adherence, and study completion in the pooled sample. Across trials, 11.1% of contacted survivors participated, and 5.7% were eligible

and enrolled. Among enrollees, 53.4% demonstrated ≥75% adherence to the intervention, and 91.1% completed the study. Race (Caucasian vs others), age, time since diagnosis, and cancer type predicted survivors’ willingness to participate. No significant predictors of intervention adherence or study completion were found among study enrollees. Cancer survivors’ demographic and medical characteristics predicted their interest and participation in diet and exercise intervention trials. These findings can help to guide procedures used in future trials to enhance patient representation. H

Decision-Making CA: A Cancer Journal for Clinicians | Volume 64, Issue 6, Pages 408-421, November / December 2014

Patient-centered, evidence-based, and cost-conscious cancer care across the continuum: Translating the Institute of Medicine report into clinical practice Larissa Nekhlyudov, Laura Levit, Arti Hurria, and Patricia A. Ganz

In 2013, the Institute of Medicine (IOM) concluded that cancer care in the United States is in crisis. Patients and their families are not receiving the information that they need to make informed decisions about their cancer care. Many patients do not have access to palliative care and too few are referred to hospice at the appropriate point in their disease trajectory. Simultaneously, there is a growing demand for cancer care with increases in new cancer diagnoses and the number of patients surviving cancer. Furthermore, there is a workforce shortage to care for this growing and elderly population. The IOM’s report, Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis, outlined recommendations to improve the quality of cancer care. This article provides an overview of the IOM report and highlights the recommendations that are most relevant to practicing clinicians who care for patients with cancer across the continuum. The implementation of the recommendations in clinical practice will require better patient-clinician communication, improved care coordination, targeted clinician training, effective dissemination of evidencebased guidelines and strategies for eliminating waste, and continuous quality assessment and improvement efforts. H

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Disparities Research Cancer | Volume 120, Issue 19, Pages 3016–3024, October 1, 2014

Impact of state-specific Medicaid reimbursement and eligibility policies on receipt of cancer screening Michael T. Halpern, Melissa A. Romaire, Susan G. Haber, Florence K. Tangka, Susan A. Sabatino, and David H. Howard

Although state Medicaid programs cover cancer screening, Medicaid beneficiaries are less likely to be screened for cancer and are more likely to present with tumors of an advanced stage than are those with other insurance. This study analyzed whether state Medicaid eligibility and reimbursement policies affect the receipt of breast, cervical, and colon cancer screening among Medicaid beneficiaries. Cross-sectional regression analyses of 2007 Medicaid data from 46 states and the District of Columbia examined associations between state-specific Medicaid reimbursement/ eligibility policies and receipt of cancer screening. Individuals

aged 21 years to 64 years enrolled in fee-for-service Medicaid for at least 4 months were included in the study. Increases in screening test reimbursement demonstrated mixed with the likelihood of receiving screening tests among Medicaid beneficiaries. In contrast, increased reimbursements for office visits were found to be positively associated with the odds of receiving all screening tests examined. Increased reimbursement for office visits may be an important policy tool for increasing screening among this vulnerable population. H

Cancer | Volume 120, Issue 24, Pages 3981–3986, December 15, 2014

End-of-life treatment preferences: A key to reducing ethnic/racial disparities in advance care planning? Melissa M. Garrido, Shannon T. Harrington, and Holly G. Prigerson

This study identified targets for interventions to reduce endof-life care disparities among patients with advanced cancer. The authors evaluated the degree to which end-of-life care values and preferences are associated with advance care planning within racial/ethnic minority groups. The Coping with Cancer study recruited advanced cancer patients from outpatient clinics in 5 states from 2002 to 2008. The rates of 1 type of advance care planning—do-notresuscitate (DNR) orders—in 606 patients were investigated. Associations were found among DNR order completion, religious values, and treatment preferences within racial/ ethnic groups. Non-Latino white patients were more likely to have a DNR order than blacks or Latinos. A preference against specific life-prolonging treatment was the only factor significantly associated with higher DNR order likelihood in each group, with non-Latino white patients more likely than Latino or black patients to express preferences against lifeprolonging care. Advance care planning interventions that target preferences associated with DNR orders across racial/ethnic groups may reach a broad patient population and reduce end-of-life care disparities. H

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Disparities Research, con’t.

Cancer | Volume 121, Issue 5, Pages 733–740, March 1, 2015

Video-based educational tool improves patient comprehension of common prostate health terminology Daniel S. Wang, Ashesh B. Jani, Musu Sesay, Caroline G. Tai, Daniel K. Lee, Katharina V. Echt, Michael G. Goodman, Kerry E. Kilbridge, and Viraj A. Master

Health care providers often share treatment options with patients using medical terminology. However, studies show lack of understanding, particularly in underserved populations. It was hypothesized that a video-based educational tool would significantly improve the understanding of key terms related to prostate health in these populations. A video-based educational tool providing animations to promote understanding of terms related to urinary, bowel, and sexual function was created by experts, including urologists and human-computer interaction specialists. Patients from 2 low-income safety net clinics viewed the application, where

a previously developed survey was administered to determine before and after levels of comprehension. Fifty-six patients completed the study. Comprehension did increase after viewing the video, with notable improvements including the terms incontinence, bowels, and impotence. Their understanding of the function of the prostate and their ability to locate the prostate on anatomic drawings improved too. This educational tool is an effective method for overcoming incomprehension of prostate health terminology among patients, enhancing patient participation in shared and informed decision for prostate cancer education. H

Epidemiology CA: A Cancer Journal for Clinicians | Volume 64, Issue 4, Pages 252-271, July/August 2014

Cancer treatment and survivorship statistics, 2014 Carol E. DeDantis, Chun Chieh Lin, Angela B. Mariotto, Rebecca L. Siegel, Kevin D. Stein, Joan L. Kramer, Rick Alteri, Anthony S. Robbins, and Ahmedin Jemal

The number of cancer survivors continues to increase due to the aging and growth of the population and improvements in early detection and treatment. In order for the public health community to better serve these survivors, the American Cancer Society and the National Cancer Institute collaborated to estimate the number of current and future cancer survivors using data from the Surveillance, Epidemiology, and End Results (SEER) program registries. In addition, current treatment patterns for the most common cancer types are described based on information in the National Cancer Data Base and the SEER and SEER-Medicare linked databases; treatment-related side effects are also briefly described. Nearly 14.5 million Americans with a history of cancer were alive on January 1, 2014; by January 1, 2024, that number will increase to nearly 19 million.

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The 3 most common prevalent cancers among males are prostate cancer (43%), colorectal cancer (9%), and melanoma (8%), and those among females are cancers of the breast (41%), uterine corpus (8%), and colon and rectum (8%). The age distribution of survivors varies substantially by cancer type. For example, the majority of prostate cancer survivors (62%) are aged 70 years or older, whereas less than one-third (32%) of melanoma survivors are in this older age group. It is important for clinicians to understand the unique medical and psychosocial needs of cancer survivors and to proactively assess and manage these issues. There are a growing number of resources that can assist patients, caregivers, and health care providers in navigating the various phases of cancer survivorship. H


Epidemiology, con’t.

CA: A Cancer Journal for Clinicians | Volume 65, Issue 1, Pages 5-29, January / February 2015

Cancer statistics, 2015

Rebecca L. Siegel, Kimberley D. Miller, and Ahmedin Jemal

Each year the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States for the current year and compiles the most recent data on cancer incidence, mortality, and survival.

Incidence data were collected by the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. A total of 1,658,370 new cancer cases and 589,430 cancer deaths are projected for the United States in 2015. During the most recent 5 years for which there are data (20072011), delay-adjusted cancer incidence rates (13 oldest SEER

registries) declined by 1.8% per year in men and were stable in women, while cancer death rates nationwide decreased by 1.8% per year in men and by 1.4% per year in women. The overall cancer death rate decreased from 215.1 (per 100,000 population) in 1991 to 168.7 in 2011, a total relative decline of 22%. However, the magnitude of the decline varied by state, and was generally lowest in the South (~15%) and highest in the Northeast (≼20%). For example, there were declines of 25% to 30% in Maryland, New Jersey, Massachusetts, New York, and Delaware, which collectively averted 29,000 cancer deaths in 2011 as a result of this progress. Further gains can be accelerated by applying existing cancer control knowledge across all segments of the population.H

CA: A Cancer Journal for Clinicians | Volume 65, Issue 2, Pages 87-108, March / April 2015

Global cancer statistics, 2012

Lindsey A. Torre, Freddie Bray, Rebecca L. Siegel, Jacques Ferlay, Joannie Lortert-Tieulent, and Ahmedin Jemal

countries, and has surpassed breast cancer as the leading cause of cancer death among females in more developed countries; breast cancer remains the leading cause of cancer death among females in less developed countries.

Cancer constitutes an enormous burden on society in more and less economically developed countries alike. The occurrence of cancer is increasing because of the growth and aging of the population, as well as an increasing prevalence of established risk factors such as smoking, overweight, physical inactivity, and changing reproductive patterns associated with urbanization and economic development. Based on GLOBOCAN estimates, about 14.1 million new cancer cases and 8.2 million deaths occurred in 2012 worldwide. Over the years, the burden has shifted to less developed countries, which currently account for about 57% of cases and 65% of cancer deaths worldwide. Lung cancer is the leading cause of cancer death among males in both more and less developed

Other leading causes of cancer death in more developed countries include colorectal cancer among males and females and prostate cancer among males. In less developed countries, liver and stomach cancer among males and cervical cancer among females are also leading causes of cancer death. Although incidence rates for all cancers combined are nearly twice as high in more developed than in less developed countries in both males and females, mortality rates are only 8% to 15% higher in more developed countries. This disparity reflects regional differences in the mix of cancers, which is affected by risk factors and detection practices, and/or the availability of treatment.

Risk factors associated with the leading causes of cancer death include tobacco use (lung, colorectal, stomach, and liver cancer), overweight/obesity and physical inactivity (breast and colorectal cancer), and infection (liver, stomach, and cervical cancer). A substantial portion of cancer cases and deaths could be prevented by broadly applying effective prevention measures, such as tobacco control, vaccination, and the use of early detection tests. H

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Epidemiology, con’t.

Cancer | Volume 120, Issue 21, Pages 3370-3377, November 1, 2014

Interferon-γ–induced inflammatory markers and the risk of cancer: The Hordaland Health Study Hui Zuo, Grethe S. Tell, Stein E. Vollset, Per M. Ueland, Ottar Nygård, Øivind Midttun, Klaus Meyer, Arve Ulvik, and Simone J.P.M. Eussen

It has been reported that interferon-γ (IFN-γ)–induced inflammatory markers, such as circulating neopterin and kynurenine-to-tryptophan ratio (KTR), are increased in patients with cancer and are also a predictor of poor prognosis. This prospective analysis, the Hordaland Health Study, included 6594 adults without known cancer at baseline between April 1998 and June 1999. Hazard ratios and 95% confidence intervals were calculated using multivariate Cox proportional hazards regression models. A total of 971 incident cancer cases were identified over a median follow-up

time of 12 years. Baseline plasma neopterin, KTR, and C-reactive protein (CRP) were associated with an increased risk of overall cancer in models adjusted for covariates. The associations between the inflammatory markers and risk of major specific cancer types were also provided. These findings indicate that plasma neopterin, KTR, and CRP are associated with a significantly increased risk of overall cancer, revealing new evidence regarding the role of IFN-γ–induced inflammation in human carcinogenesis. H

Cancer | Volume 120, Issue 23, Pages 3699–3706, December 1, 2014

Agent Orange exposure and cancer incidence in Korean Vietnam veterans: A prospective cohort study Sang-Wook Yi and Heechoul Ohrr

During the Vietnam War, US and allied military sprayed approximately 77 million liters of tactical herbicides including Agent Orange, contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Few studies to date have examined the association between Agent Orange exposure and cancer incidence among the Korean veterans. An Agent Orange exposure index, based on the proximity of the veteran’s military unit to the area that was sprayed with Agent Orange, was developed using a geographic information system-based model. Cancer incidence was followed for 180,251 Vietnam veterans from 1992 through 2003. After adjustment for age and military rank, high exposure to Agent Orange was found to significantly increase the risk of all cancers combined. Exposure to Agent Orange several decades earlier may increase the risk of cancers in all sites combined, as well as several specific cancers, among Korean veterans of the Vietnam War, including some cancers that were not found to be clearly associated with exposure to Agent Orange in previous cohort studies primarily based on Western populations. H

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Fine-Needle Aspiration Cancer Cytopathology | Volume 122, Issue 6, Pages 412-419, June 2014

Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) contributes to a triple-negative test in preoperative screening of pancreatic cysts Roseann I. Wu, Won Jae Yoon, William R. Brugge, Mari Mino-Kenudson, and Martha B. Pitman

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of pancreatic cysts obtains cyst fluid for cytologic and biochemical analysis, determining mucinous and malignance. This study assessed the effectiveness of EUS-FNA in a unit of small pancreatic cysts that were benign on imaging studies. All pancreatic cysts undergoing initial EUS-FNA in 2006 and 2007 were retrospectively analyzed. Ninety-two patients with pancreatic cysts met the inclusion criteria; those with high-risk features on imaging studies were excluded. Cytology, histology, and cyst fluid analysis data was collected.

EUS-FNA supported a diagnosis of a mucinous cyst in 41% patients. Cytology showed an absence of high-grade atypia (HGA) in 97% of patients. The mean follow-up was 4.4 years, during which 6 cysts were surgically resected, and 16 cysts were resampled by at least 1 subsequent EUS-FNA. EUS-FNA contributes to a triple-negative test for pancreatic cysts—no high-risk stigmata, no worrisome features, and no HGA on cytology—providing a negative predictive value of 99% for conservative management. H

Cancer Cytopathology | Volume 122, Issue 9, Pages 666-677, September 2014

FNAB of benign thyroid nodules with papillary hyperplasia: A cytological and histological evaluation Marc P. Pusztaszeri, Jeffrey F. Krane, Edmund S. Cibas, Gilbert Daniels, and William C. Faquin

BTN-PH for 44 patients was evaluated to identify the causes of diagnostic error and to better define its cytologic criteria. The available cytological and histological slides were reviewed and scored for 10 cytomorphological features. Fifteen FNAB cases of standard PTC were reviewed for comparison. These were the diagnoses: benign, 18; suspicious for malignancy (S-PTC), 12; atypia of undetermined significance/follicular lesion of undetermined significance, 10; follicular neoplasm, 5; malignant (PTC), 2; and nondiagnostic, 1. All cases diagnosed as S-PTC/PTC had focal nuclear atypia, including grooves, enlargement and crowding, and chromatin pallor and pseudoinclusions; however, the extent of nuclear atypia was significantly less than in the control group of PTCs. Benign thyroid nodules with papillary hyperplasia (BTN-PH) are sometimes misinterpreted cytologically as papillary thyroid carcinoma (PTC). A total of 48 fine-needle aspiration biopsy (FNAB) series of historically confirmed

BTN-PH represents a significant pitfall in thyroid FNABs in which it can be misinterpreted as S-PTC/PTC. Cytologic clues to this pitfall include limited and variable nuclear atypia, small nuclear size, and cytoplasmic pigment. H

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Fine-Needle Aspiration, con’t.

Cancer Cytopathology | Volume 122, Issue 11, Pages 804-809, November 2014

The role of cytopathology and cyst fluid analysis in the preoperative diagnosis and management of pancreatic cysts >3 cm Ivan Chebib, Kurt Yaeger, Mari Mino-Kenudson, and Martha B. Pitman

Pancreatic cyst size >3 cm is worrisome rather than high-risk for malignancy, based on the 2012 International Guidelines for the management of mucinous cysts. Over a 7-year period, 93 pancreatic cysts >3 cm were resected, assessing for clinical, radiologic, and pathologic information. Performance of cytology for the detection of malignancy and surgical triage compared with imaging was evaluated. Cytology/cyst fluid analysis had the highest specificity compared with imaging; magnetic resonance imaging (MRI) showed the highest sensitivity. MRI had the highest predictive value for mucinous versus nonmucinous cysts.

MRI and EUS were able to predict malignancy from the presence of high-risk imaging features. Some benign cases also showed high-risk imaging features on MRI, computed tomography, and EUS. Cytology correctly classified 5 of 6 cysts with high-risk imaging as benign. Preoperative evaluation of pancreatic cysts >3 cm is warranted, as many are nonmucinous cysts and not highgrade. Cytology is more specific than imaging for the detection of malignancy in cysts >3 cm. H

Cancer Cytopathology | Volume 122, Issue 7, Pages 504-511, July 2014

Growing indication for FNA to study and analyze tumor heterogeneity at metastatic sites Francisco Beca and Fernando Schmitt

In routine practice, suspected metastases in patients with cancer are only occasionally biopsied. However, biopsies of metastatic lesions can be valuable, not only in confirming the presence of metastatic disease but also in revealing unsuspected benign disease or secondary malignancies. Also, such biopsies also assess biomarkers that might differ from those on primary tumor cells, and can thereby facilitate selection of the optimal treatment. Because of the increasing recognition of clonal and phenotypic heterogeneity of tumors, in the near future, biopsying of metastatic lesions may constitute a standard-of-care practice, allowing assessment of molecular differences between the primary tumor and metastatic lesions. The authors conclude that fine-needle aspiration is currently the best method for making repeated biopsies to monitor the tumor: it is minimally invasive, safe, and cost effective and can be coupled with modern ancillary techniques. H

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Gynecologic Cytopathology Cancer Cytopathology | Volume 122, Issue 10, Pages 720-729, October 2014

Primary human papillomavirus screening for cervical cancer in the United States—US Food and Drug Administration approval, clinical trials, and where we are today RItu Nayar, Robert A. Goulart, Patricia G. Tiscornia-Wasserman, and Diane Davis Davey

About 70% of cancers and 54% of high-grade lesions are attributable to HPV. The high sensitivity of clinically validated HPV tests and issues with establishing quality cytology services led to the evaluation of primary HPV testing as a screening modality for cervical cancer.

looked for the detection of HPV that was initially approved for use with cervical cytology. RMS stated that the addition of a negative Pap result to a negative HR-HPV result at baseline added little benefit and increased the colposcopy rate only slightly.

The US Food and Drug Administration recently approved the additional indication of Primary Screening for the Roche cobas human papillomavirus test, the Addressing the Need for Advanced HPV Diagnostics (ATHENA). This test

The long-term performance of HPV primary screening compared with other screening methods, including opposition, is not yet known, because the ATHENA trial has only 3 years of follow-up. H

Cancer Cytopathology | Volume 122, Issue 11, Pages 842-850, November 2014

The low risk of precancer after a screening result of human papillomavirusnegative/atypical squamous cells of undetermined significance Papanicolaou and implications for clinical management Julia C. Gage, Hormuzd A. Katki, Mark Schiffman, Philip E. Castle, Barbara Fetterman, Nancy E. Poitras, Thomas Lorey, Li C. Cheung, Catherine Behrens, Abha Sharma, Fang-Hui Zhao, Jack Cuzick, Zi Hua Yang, and Walter K. Kinney

Different US practice guidelines have conflicting recommendations for when women should return after a human papillomavirus (HPV)-negative test result—either three or five years. One way to determine management is to compare the risk of precancer/cancer after an HPV-negative result with the risks after other negative screening results. For example, if the risk after an HPV-negative result was similar to the risk after a negative Pap test, a 3-year return would be preferred because guidelines agree that women with negative Pap test results should return in three years. Alternatively, if the risk after an HPV-negative result is similar to that after a cotest-negative result (HPV negative/Pap test negative), a 5-year return would be preferred because guidelines agree that women testing cotest negative should return in five years.

cancer among women aged 30 years to 64 years at Kaiser Permanente Northern California with the following test results from 2003 through 2012: 17,191 women testing HPV negative; 980,268 women testing Pap test negative (regardless of HPV result); and 892,882 women testing cotest negative. The 5-year CIN3+ and cancer risks after an HPV-negative result were closer to the risks after a negative Pap test result. Women testing HPV negative were found to have precancer/ cancer risks that were more closely aligned with women with negative Pap test results, suggesting that women testing HPV negative should be managed similarly to women testing negative on Pap tests with a 3-year return for screening. H

The authors compared risks of cervical intraepithelial neoplasia of grade 3 or higher (CIN3+) and cervical

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Gynecologic Cytopathology, con’t.

Cancer Cytopathology | Volume 122, Issue 12, Pages 909-913, December 2014

Influence of knowledge of human immunodeficiency virus serostatus on accuracy of cervical cytologic diagnosis Louis-Jacques van Bogaert

Women infected with the human immunodeficiency virus (HIV) are at high risk of human papillomavirus-persistent infections. This study investigated whether, in South Africa, the accuracy of abnormal cytology confirmed by a histological diagnosis using loop electrosurgical excision procedure (LEEP) is affected by knowledge of the woman’s HIV serostatus. A total 0f 7648 biopsy specimens were taken. The overall prevalence of preinvasive lesions was 73.9% in HIV-infected women compared with 50.3% in women not infected with HIV. The concordance and discordance rates between

cytology and histology were similar in uninfected and infected women. Among HIV-infected women, 79.1% of discordant results were due to cytological overdiagnosis; among HIV-negative women, 86.5% of discordant results were due to underdiagnosis. The finding of a higher prevalence of preinvasive lesions combined with the knowledge of a patient’s HIV-positive serostatus prompts more cytological overdiagnosis, thereby resulting in avoidable LEEP interventions. H

Cancer Cytopathology | Volume 123, Issue 1, Pages 59-65, January 2015

Follow-up and clinical significance of unsatisfactory liquid-based Papanicolaou tests Christopher L. Owens, Diana S.M. Buist, Daniel Peterson, Aruna Kamineni, Sheila Weinmann, Tyler Ross, Andrew E Williams, Azadeh Stark, Kenneth F. Adams, Chyke A. Doubeni, and Terry S. Field

Few studies to date have examined adherence to recommended guidelines for follow-up and outcomes after an unsatisfactory Papanicolaou (Pap) test (UPT) with liquidbased technologies. Within 4 US health plans, the median time to follow-up and the percentage of patients with follow-up testing by 120 days was calculated after a UPT. This study compared the risk of a diagnosis of cervical intraepithelial neoplasia of type 2 or

worse (CIN2+) after a UPT with the risk after a satisfactory Pap test. In this study, 634,644 Pap tests were evaluated. Of 1442 UPTs, 53.4% had follow-up testing within 120 days. This study found that various clinical factors associated with the risk of CIN2+ appear to influence the receipt of follow-up after a UPT. HPV test results in patients with UPTs might be used in follow-up strategies; specifically, a negative test result might reduce the urgency for repeat Pap testing. H

Cancer | Volume 121, Issue 5, Pages 688–696, March 1, 2015

Germline PTEN, SDHB-D, and KLLN alterations in endometrial cancer patients with Cowden and Cowden-like syndromes: An international, multicenter, prospective study Haider Mahdi, Jessica L. Mester, Emily A. Nizialek, Joanne Ngeow, Chad Michener, and Charis Eng

Endometrial cancer has been recognized only recently as a major component of Cowden syndrome (CS). This study aimed at identifying the prevalence and clinicopathologic predictors of germline phosphatase and tensin homolog (PTEN_mut+), succinate dehydrogenase (SDHx_var+), and killin (KLLN_Me+) in CS and Cowden syndrome–like (CSL) patients presenting with endometrial cancer. PTEN and SDHB-D mutation and KLLN promoter methylation analyses were performed for 371 prospectively enrolled patients (2005-2011). PTEN protein was analyzed 16 American Cancer Society Family of Journals

from patient-derived lymphoblast lines. The PTEN Cleveland Clinic (CC) score is a weighted, regression-based risk calculator giving the a priori risk for PTEN_mut+. Clinical predictors of PTEN and KLLN variations, but not SDHx_var+, were identified. These predictors should alert the treating physician to potential hereditary risks and the need for referral to genetic professionals. High-risk cancer observation and prophylactic surgery of the uterus may be considered for KLLN_Me+ patients similarly to PTEN_mut+ patients. H


Head and Neck Disease Cancer | Volume 121, Issue 8, Pages 1273–1278, April 15, 2015

Marital status and head and neck cancer outcomes Gino Inverso, Brandon A. Mahal, Ayal A. Aizer, R. Bruce Donoff, Nicole G. Chau, and Robert I. Haddad

This study examined the effects of marital status on stage at presentation, receipt of treatment, and survival in patients with head and neck cancer. The Surveillance, Epidemiology, and End Results database was used to analyze 51,272 patients who were diagnosed with HNC from 2007 to 2010. The impact of marital status on cancer stage at presentation, receipt of definitive treatment, and HNC-specific mortality was determined using multivariable logistic and Fine and Gray competing-risks regression models, as appropriate. Marriage had a protective effect against metastatic presentation of oral and laryngeal cancers but not against oropharyngeal, hypopharyngeal, or nasopharyngeal cancers.

Among patients with nonmetastatic disease, married patients were more likely to receive definitive treatment and had a lower risk of head and neck cancer-specific mortality; these associations remained significant across all head and neck cancer sites. Among patients with oral and laryngeal cancers, those who are married are less likely to present with metastatic disease. Also, married patients are more likely to receive definitive treatment and less likely to die from head and neck cancer sites. This suggests that spousal support may have a role in the observation of visual and symptomatic head and neck cancer sites types and leads to higher rates of treatment and better survival. H

Hematologic Malignancies Cancer | Volume 120, Issue 11, Pages 1677–1685, June 1, 2014

Complete response to induction therapy in patients with Myc-positive and double-hit non-Hodgkin lymphoma is associated with prolonged progression-free survival Jonathon B. Cohen, Susan M. Geyer, Gerard Lozanski, Weiqiang Zhao, Nyla A. Heerema, Nathan C. Hall, Veena A. Nagar, Jessica A. Hemminger, Jeffrey A. Jones, Pierluigi Porcu, Beth A. Christian, Robert A. Baiocchi, Kami J. Maddocks, Joseph M. Flynn, Steven M. Devine, and Kristie A. Blum

Myc-positive B-cell non-Hodgkin lymphoma (NHL) with or without a B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL2) rearrangement is associated with lower progressionfree survival (PFS) and overall survival (OS). This study reviewed the outcomes of patients with myc-positive and double-hit NHL at The Ohio State University. All patients who had non-Burkitt, aggressive B-cell NHL from 2008 to 2011 were assessed for the translocation and for v-myc avian myelocytomatosis viral oncogene homolog (CMYC) rearrangements at diagnosis, and all myc-positive patients were included in this study. Associations with

clinical characteristics were described, and univariable and multivariable models were used to assess connections between clinical variables and outcomes. Of 49 myc-positive patients, 29 patients also had BCL2 rearrangements (double-hit NHL). This study discovered that the achievement of a CR with front-line therapy is associated with a prolonged PFS and OS in patients with myc-positive NHL, even after adjusting for type of initial therapy, histology, age, IPI, or the presence of a concurrent BCL2 translocation. H

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Hematologic Malignancies, con’t.

Cancer | Volume 121, Issue 2, Pages 234–242, January 15, 2015

Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML Jorge E. Cortes, Stuart L. Goldberg, Eric J. Feldman, David A. Rizzeri, Donna E. Hogge, Melissa Larson, Arnaud Pigneux, Christian Recher, Gary Schiller, Krzysztof Warzocha, Hagop Kantarjian, Arthur C. Louie, and Jonathan E. Kolitz

CPX-351 is a liposome-encapsulated fixed-molar-ratio formulation of cytarabine and daunorubicin that uses molar ratio–dependent drug-drug synergy to enhance antileukemic effectiveness. This phase II study randomized 125 patients 2:1 to CPX-351. Patients with acute myeloid leukemia (AML) in first relapse after initial Complete Remission (CR) lasting ≥1 month were stratified per the European Prognostic Index (EPI) into favorable, intermediate, and poor-risk groups based on duration of first CR, cytogenetics, age, and transplant history. Survival at 1 year was the primary effective end point.

Patient characteristics were well balanced between the 2 study arms. Improvements in useful outcomes were observed following CPX-351, but did not meet the criteria for 1-year survival improvement in the overall population. Subset analyses of the EPI-defined poor-risk strata demonstrated higher response rates and improvements in event-free and overall survival. Also, 60-day mortality was lower in the CPX-351 study arm for poor-risk patients. This data suggests possible improved outcomes in CPX-351treated first relapse AML patients with EPI-defined poorrisk disease. H

Cancer | Volume 121, Issue 4, Pages 556–561, February 15, 2015

Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia Jean-Pierre Issa, Guillermo Garcia-Manero, Xuelin Huang, Jorge Cortes, Farhad Ravandi, Elias Jabbour, Gautam Borthakur, Mark Brandt, Sherry Pierce, and Hagop M. Kantarjian

Hypomethylating agents have demonstrated activity in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Preclinical and single-arm trials have suggested that adding histone deacetylase (HDAC) inhibitors may synergize the epigenetic variation of hypomethylating agents and improve treatment results.

study. Patients were randomized in a Bayesian responseadaptive design to receive intravenous decitabine 20 mg/m2 daily for 5 days or decitabine plus oral valproic acid 50 mg/ kg daily for 7 days, repeated every 4 to 6 weeks. Overall, 34% of patients achieved complete remission, and 55% had an objective response.

This study evaluated the possible benefit of adding valproic acid, an HDAC inhibitor, to decitabine in the treatment of MDS and AML.

Adding valproic acid to decitabine was not associated with an improved outcome. Future therapies may consider combining hypomethylating agents with better HDAC inhibitors and using different schedules. H

A total of 149 patients with higher risk MDS or with AML aged ≥60 years (median age of 69 years) were treated for the

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Hepatobiliary Disease Cancer | Volume 120, Issue 18, Pages 2824–2838, September 15, 2014

The clinical management of hepatocellular carcinoma in the United States, Europe, and Asia: A comprehensive and evidence-based comparison and review Zhi Ven Fong and Kenneth K. Tanabe

Hepatocellular carcinoma (HCC), the most common primary malignancy of the liver, represents 1 of the leading causes of cancer deaths in the world. There are many treatment options for HCC involving several specialties in the multidisciplinary care of the patient. Vast heterogeneity in management tendencies has been observed. This report reviewed and compared guidelines on the management of HCC from the United States (National Comprehensive Cancer Network), Europe (European Association for the Study of the Liver-European Organization for Research and Treatment of Cancer), and Asia (consensus statement from the 2009 Asian Oncology Summit). Only some differences in observation and treatment allocation recommendations were found. The geographic differences in tumor biology and resources make it impractical to have a globally universal guideline for all patients. Recommendations from the 3 groups are influenced by geographic differences in the prevalence and biology of the disease and available resources. Both physicians and policy makers should include these considerations when treating patients with HCC and structuring policies and guidelines. H

Immunocytochemistry Cancer Cytopathology | Volume 122, Issue 10, Pages 779-785, October 2014

Reliability of immunostaining using pan-melanoma cocktail, SOX10, and microphthalmia transcription factor in confirming a diagnosis of melanoma on fine-needle aspiration smears Jessica Clevenger, Cicily Joseph, Marilyn Dawlett, Ming Guo, and Yun Gong

This study included 50 FNA cases with a definitive diagnosis of melanoma. Twenty-nine cases were epithelioid type (group 1), and 21 cases were predominantly spindle cell type with or without an epithelioid component (group 2). Each case was immunostained using pan-melanoma cocktail, SOX10, and MITF. Staining intensity and the percentage of positive cells were recorded. Accurate fine-needle aspiration (FNA) diagnosis of metastatic melanoma is of therapeutic and prognostic significance and often requires ancillary studies. The reliability of immunostaining using a pan-melanoma cocktail, Sryrelated HMG-BOX gene 10 (SOX10), and microphthalmia transcription factor (MITF) in confirming a diagnosis of melanoma on FNA smears has not been studied.

SOX10 had the highest overall detection rate, followed by MITF and pan-melanoma cocktail. The pan-melanoma cocktail and SOX10 performed equally well for groups 1 and 2, and MITF had a higher detection rate in group 1. Overall, SOX10 and MITF appeared superior to the pan-melanoma cocktail and SOX10 seemed better than MITF in confirming melanoma in FNA smears. H American Cancer Society Family of Journals

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Immunocytochemistry, con’t.

Cancer Cytopathology | Volume 122, Issue 6, Pages 468-473, June 2014

Usefulness of GATA3 and p40 immunostains in the diagnosis of metastatic urothelial carcinoma in cytology specimens Tamar C. Brandler, Mohamed S. Aziz, Lisa M. Rosen, Tawfiqul A. Bhuiya, and Oskana Yaskiv

GATA3 (GATA-binding protein 3) appearance in urothelial carcinoma (UC) and mammary carcinomas has been recently reported. Delta Np63 (p40) has been shown to be expressed highly selectively in squamous cell carcinomas (SCCs), but the literature concerning the expression of p40 in UC is limited and controversial. This study evaluated the usefulness of GATA3 and p40 in the diagnosis of metastatic UC MUC in cytology specimens. Thirty-two MUC cytology cases and 44 controls (22 UC cases and 22 SCC cases) were stained for GATA3, p40, and p63

and nuclear staining intensity and the percentage of positive cells were recorded and compared. This study demonstrated that GATA3 is useful in confirming the diagnosis of MUC in cytology specimens and in distinguishing between MUC and SCC. p40 is a valuable adjunct to GATA3 in the diagnosis of MUC in cytology specimens, especially when SCC is not part of the clinical differential diagnosis. H

Cancer Cytopathology | Volume 122, Issue 8, Pages 586-595, August 2014

Wilms tumor 1/cytokeratin dual-color immunostaining reveals distinctive staining patterns in metastatic melanoma, metastatic carcinoma, and mesothelial cells in pleural fluids: An effective first-line test for the workup of malignant effusions James R. Conner, Edmund S. Cibas, Jason L. Hornick, and Xiohua Qian

The workup of a malignant effusion usually requires immunostaining with a panel of markers. Although nuclear Wilms tumor 1 (WT1) expression is widely used to detect tumors of ovarian and mesothelial origin, it is less well known that WT1 is also expressed in the cytoplasm of melanomas and mesenchymal tumors. The usefulness of a WT1/AE1/ AE3 dual-color immunostain in the workup of malignant effusions was evaluated. Eighty-six pleural effusions, including 17 metastatic melanomas, 31 metastatic adenocarcinomas, 10 malignant mesotheliomas, 10 lymphoproliferative disorders, 5 metastatic sarcomas, and 13 benign specimens, were immunostained using a peroxidase-based brown chromogen for WT1 and an alkaline phosphatase-based red chromogen for AE1/AE3 on cell block sections. The majority of malignant effusions stained in 1 of 4 distinctive patterns. This study showed that a WT1/AE1/ AE3 dual-color immunostain can reliably identify malignancy in pleural effusions and group malignant cells into discrete subsets, thereby narrowing the differential diagnosis. This simple double stain can be a cost-effective, first-line test in the workup of patients with malignant discharges. H

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Medical Oncology Cancer | Volume 121, Issue 2, Pages 259–268, January 15, 2015

Elevated risks of subsequent primary malignancies in patients with thyroid cancer: A nationwide, population-based study in Korea Yoon Young Cho, Jiwon Lim, Chang-Mo Oh, Junsun Ryu, Kyu-Won Jung, Jae Hoon Chung, Young-Joo Won, and Sun Wook Kim

Thyroid cancer affects young adults, and survival is excellent. With long life expectancy, successive cancers is an important concern for survivors of thyroid cancer. This study investigated the incidence and types of second primary malignancies in Korean patients with thyroid cancer.

Among 178,844 patients with thyroid cancer, 2895 were diagnosed with subsequent second primary malignancies. The overall risks of a second primary cancer were elevated by 6% in patients who had thyroid cancer compared with the general population during the same period.

The study group included 178,844 registrants with thyroid cancer from the Korea Central Cancer Registry (KCCR) database between 1993 and 2010. Standardized incidence ratios (SIRs) were calculated using a statistical software program (SEER*Stat 8.0.4).

This is the largest, standardized, population-based study to date using nationwide data from the entire Korean population. The risks of several cancers were elevated significantly during follow-up, thus alerting physicians to pay special attention in their care of patients with thyroid cancer and long-term survivors. H

Molecular Diagnostics and Cytogenetics Cancer Cytopathology | Volume 123, Issue 3, Pages 141-151, March 2015

Value of combined cytology and molecular information in the diagnosis of soft tissue tumors Jerzy Klijanienko, Gaelle Pierron, Xavier Sastre-Garau, and Stamatios Theocharis

The diagnosis of a soft tissue tumor (STT) is a complex process that requires a multidisciplinary team consisting of a medical oncologist, a radiologist, a pathologist, and a molecular biologist. The combination of this information gives highly accurate results. Fine-needle aspiration in this setting is one of the most performed techniques for obtaining, in a noninvasive way, ideal material for morphological, immunohistochemical, and molecular purposes. The recently published 2013 World Health Organization classification, which contains 128 different entities, highlights the role of combined morphology and molecular information in accurate STT diagnoses. An accurate tumor finding is a dynamic process, as evidenced by the constant modifications of international accepted classifications, which are more and more based on molecular abnormalities. In the future, STT classification will certainly be a hybrid of morphology and molecular data and, consequently, will be very “useful” for cytology. H

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Molecular Diagnostics and Cytogenetics, con’t.

Cancer Cytopathology | Volume 122, Issue 7, Pages 527-535, July 2014

Analysis of immunocytochemical and molecular BRAF expression in thyroid carcinomas: A cytohistologic institutional experience Esther Diana Rossi, Maurizio Martini, Sara Capodimonti, Tonia Cenci, Patrizia Straccia, Basilio Angrisani, Costantino Ricci, Paola Lanza, Celestino Pio Lombardi, Alfredo Pontecorvi, Luigi Maria Larocca, and Guido Fadda

It has been demonstrated that the valine-to-glutamic acid substitution at position 600 (V600E) in the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) gene is an effective diagnostic/prognostic marker for papillary thyroid carcinoma (PTC) — detected by using using DNA-based techniques. However, monoclonal V600E antibody (clone VE1) could be an alternative strategy for detection purposes. This study investigated molecular and immunocytohistochemical BRAF analyses in a prospective series of samples. Fifty-five prospective cytohistologic samples that were diagnosed as PTC were studied using both DNA BRAF testing and the VE1 antibody. The intensity of VE1 expression was graded from 0 (negative) to 3+ (strong). All diagnoses were histologically confirmed. Thirty-seven samples with mutated BRAF and 18 samples with wild-type BRAF were reported with 100% cytohistologic concordance. The VE1 antibody represents a feasible first-line approach for evaluating BRAF mutation status and may be a valid tool

in the selection of samples for molecular analysis. This study highlights the statistically significant difference between molecular and VE1 positivity in PTC. H

Cancer Cytopathology | Volume 122, Issue 6, Pages 459-467, June 2014

Comparison of urine cytology and fluorescence in situ hybridization in upper urothelial tract samples Jordan P. Reynolds, Jesse S. Voss, Benjamin R. Kipp, R. Jeffrey Karnes, Aziza Nassar, Amy C. Clayton, Michael R. Henry, Thomas J. Sebo, Jun Zhang, and Kevin C. Halling

The performance of cytology and FISH in the presence or absence of concomitant bladder cancer within 2 years was compared in 61 patients (112 samples). The performance of near-tetrasomy versus hypertetrasomy was also compared. Biopsy confirmation of UTUC in 21 patients was considered the gold standard.

The cytologic diagnosis of urothelial carcinoma (UC) of the upper urothelial tract (UT) is challenging. Using the UroVysion probe set adds diagnostic value for the detection of bladder cancer in voided urine. In instrumented UT specimens, this study encountered positive UT cytology and fluorescence in situ hybridization (FISH) cases that did not demonstrate subsequent UT carcinoma. 22 American Cancer Society Family of Journals

Cytology alone was found to be poorly sensitive but highly specific for the detection of UTUC. Tetrasomy FISH resulted in many false-positive cases. Other false-positive FISH results were likely due to the presence of bladder cancer cells contaminating the UT specimen. The combination of cytology and FISH appears to have good specificity while maintaining good sensitivity in evaluating UTUC when using modified scoring criteria for the appropriate patient. H


Molecular Diagnostics and Cytogenetics, con’t.

Cancer Cytopathology | Volume 123, Issue 1, Pages 30-39, January 2015

Multiplatform comparison of molecular oncology tests performed on cytology specimens and formalin-fixed, paraffin-embedded tissue Michael P. Gailey, Aaron A. Stence, Chris S. Jensen, and Deqin Ma

Molecular oncology testing is important for patient management, and requests for the molecular analysis of cytology specimens are increasing. Formalin-fixed, paraffinembedded (FFPE) cell blocks of such specimens have been routinely used for molecular diagnosis. However, the inability to assess cellularity before cell block preparation is a pitfall of their use. In this study, cytologic preparations were tested with molecular test platforms, and the results were compared with paired FFPE tissue. Seventy-seven cytology cases, including fine-needle aspiration smears, touch preparations, and SurePath thin-layer

preparations, were selected. Areas of interest were removed from the slide with a matrix capture solution. DNA was evaluated by mutation analysis for BRAF, epidermal growth factor receptor (EGFR), RAS, and a 50-gene panel with various testing platforms. Thirty-eight tumors with FFPE tissue were tested in parallel. Cytologic preparations were a reliable source for molecular oncology testing. DNA derived from cytology samplings performed well on multiple platforms, and 100% concordance was observed between cytology specimens and FFPE tissue. H

Cancer Cytopathology | Volume 122, Issue 10, Pages 730-736, October 2014

Available resources and challenges for the clinical annotation of somatic variations Catherine I. Dumur

Next-generation sequencing (NGS) has become an important tool for identifying clinically relevant variants in both inherited disorders and oncology. Alternative explanation that enables the creation of meaningful clinical reports often requires withdrawing multiple publicly available databases. There are a number of such resources that have been designed to catalog and remove an overabundance of germline variants or mutations. When analyzing tumor specimens in clinical settings, different or ancillary resources may be needed that are specific for somatic deviations or actionable mutations

that may have clinical or treatment implications. The purpose of this review is to review the state of the art of somatic variation databases. The current need for collecting various annotation sources into one-stop solutions to facilitate faster query execution and better integration into existing laboratory information systems are discussed. A resource with links to other databases containing additional information would be desirable. The creation of such a resource will require the constant submission of all available data for each variant. H

Cancer Cytopathology | Volume 123, Issue 3, Pages 152-161, March 2015

Biospecimen repositories and cytopathology Savitri Krishnamurthy

Biospecimen storage areas are important for the advancement of biomedical research. Literature on the potential for biobanking of fine-needle aspiration, gynecologic, and nongynecologic cytology specimens is very limited. The potential for biobanking of these specimens as valuable additional resources to surgically removed tissues appears to be excellent. The cervicovaginal specimens that can be used for biobanking include Papanicolaou-stained monolayer preparations and left over material from liquid-based cytology preparations. Different types of specimen preparations of fine-needle

aspiration and nongynecologic specimens, including Papanicolaou-stained and Diff-Quik–stained smears, cell blocks, and dedicated excess/remaining material from fineneedle aspiration stored frozen in a variety of solutions, can be used for biobanking. Because of several gaps in knowledge regarding the standard of operative procedures for the procurement, storage, and quality assessment of cytology specimens, further studies as well as national conferences and workshops are needed not only to create awareness but also to facilitate the use of cytopathology specimens for biobanking. H American Cancer Society Family of Journals

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Non-Gynecologic Cytopathology Cancer Cytopathology | Volume 123, Issue 1, Pages 10-18, January 2015

Accuracy and risk of malignancy for diagnostic categories in urine cytology at a large tertiary institution Karen Chau, Lisa Rosen, Constantinos Coutsouvelis, Maly Fenelus, Ryan Brenkert, Melissa Klein, Gary Stone, Stephen Raab, Mohamed Aziz, and Rubina Cocker

Benchmarks for the accuracy and risk of malignancy per urine cytology diagnostic category at a high-volume center were provided. The additive sensitivity for the determination of the residual risk of disease was calculated to determine the performance of cytology and optimal triage, including the number of urine samples, before the detection of malignancy in surveillance patients. A 2-year laboratory information system–based search generated 587 subjects with histological follow-up. The sensitivity and specificity of cytology for urothelial malignancy,

the risk of malignancy per diagnostic category, the additive sensitivity, and the time for conversion from a negative to a positive initial cytology result were examined. The findings suggest that atypia favoring malignancy is being appropriately flagged. Further definition of the atypical category is needed to increase specificity with a better qualitative or measurable morphological algorithm. This study provides a risk of malignancy for each category for benchmarking and clinical triage. Follow-up should include at least 4 consecutive urine specimens over a period of 22.2 months. H

Cancer Cytopathology | Volume 123, Issue 3, Pages 186-192, March 2015

Atypical urothelial tissue fragments in noninstrumented voided urine specimens are associated with low but significantly higher rates of urothelial neoplasia than benign-appearing urothelial tissue fragments Irem Onur, Dorothy L. Rosenthal, and Christopher J. VandenBussche

The interpretation of urothelial tissue fragments (UTF) in voided urine (VU) specimens is controversial. If UTF contain cytomorphologically atypical cells, the diagnosis often becomes more challenging. The outcome of patients with benignappearing UTF in 274 noninstrumented VU specimens was previously studied. In this study, noninstrumented VU specimens containing UTF with atypical cytomorphological features (AUTF) were evaluated and compared with the previous results. The Johns Hopkins Hospital electronic pathology database was searched for VU cases containing UTF over a 5-year period. A total of 170 noninstrumented VU specimens containing AUTF were identified. Twenty-four specimens had subsequent or coincidental surgical pathology specimens. The presence of AUTF in noninstrumented VU was found to be associated with low rates of urothelial neoplasia but had a

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statistically higher risk of urothelial neoplasia than the presence of BUTF. In particular, the rate of high-grade urothelial carcinoma was significantly higher in noninstrumented VU specimens containing AUTF than those containing BUTF. Urolithiasis was associated with AUTF in a substantial percentage of noninstrumented VU specimens. H


Non-Gynecologic Cytopathology, con’t.

Cancer Cytopathology | Volume 123, Issue 4, Pages 244-252, April 2015

Strategies for improving diagnostic accuracy of biliary structures Marcela Salomao, Tamas A. Gonda, Elizabeth Margolskee, Vasco Egula, Helen Remotti, John M. Poneros, Amrita Sethi, and Anjali Saqi

Brush cytology is the initial intervention when evaluating biliary strictures. Biliary brush cytology is known for its low sensitivity (but high specificity) and may be accompanied by biopsies and/or fluorescent in situ hybridization (FISH) to improve diagnostic yield. This study aimed to identify features to enhance cytological sensitivity and assess which sampling method(s) improved identification of pancreatobiliary adenocarcinomas.

cells with foamy cytoplasm, drunken honeycomb, and single vacuolated malignant cells improves sensitivity. Also, a sampling of stromal tissue may enable a pancreatobiliary adenocarcinomas diagnosis. Concurrent biopsies and FISH are helpful in enhancing the diagnostic yield of pancreatobiliary adenocarcinomas. H

Seventy-three biliary stricture cases were retrieved (38 pancreatobiliary adenocarcinomas and 35 control benign strictures). Biliary brushings, FISH, and biopsies were reviewed. Cytology specimens were evaluated for cellularity and presence of drunken honeycomb, loosely cohesive clusters of round cells, large atypical cells with foamy cytoplasm, and single vacuolated malignant cells. Biopsies were examined for the presence of stromal invasion. This study found that the low sensitivity of biliary brushings results from limited cellularity. Identification of large atypical

Cancer Cytopathology | Volume 122, Issue 6, Pages 399-411, June 2014

Guidelines for pancreaticobiliary cytology from the Papanicolaou Society of Cytopathology: A review Martha B. Pitman and Lester J. Layfield

The newest installment on state-of-the-art standards of practice in cytopathology from the Papanicolaou Society of Cytopathology (PSC) focuses on the pancreaticobiliary system. Similar to the National Cancer Institute recommendations for aspiration cytology of the thyroid, the PSC guidelines for pancreaticobiliary cytology addresses suggestions, techniques, terminology and vocabulary, ancillary studies, and postprocedure management. Each committee was composed of a multidisciplinary group of experts in diagnosing, managing, and treating patients with pancreaticobiliary disease. Draft documents were posted on an interactive Web-based forum hosted by the PSC Web

site (www.papsociety.org) and the topics of terminology, ancillary testing, and management were presented at national and international meetings over an 18-month period for discussion and feedback from practicing pathologists around the world. This review provides a synopsis of these guidelines. The PSC Guidelines for Pancreatobiliary Cytology provides general recommendations regarding the signals for biopsy, the techniques of sampling, a new proposed terminology plan, ancillary techniques and postprocedure treatment, and management recommendations for each of the proposed diagnostic categories. H

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Outcomes Research Cancer | Volume 120, Issue 22, Pages 3527–3535, November 15, 2014

Electronic cigarette use among patients with cancer: Characteristics of electronic cigarette users and their smoking cessation outcomes Sarah P. Borderud, Yuelin Li, Jack E. Burkhalter, Christine E. Sheffer, and Jamie S. Ostroff

Since continued smoking after a cancer diagnosis increases the risk of adverse health outcomes, patients with cancer are strongly advised to quit. However, electronic cigarettes (E-cigarettes) are becoming increasingly popular. This article provides the first published clinical data regarding E-cigarette use and cessation (stopping) outcomes among patients with cancer.

population. These findings raise doubts concerning the usefulness of E-cigarettes for stopping smoking among patients with cancer. Further research is needed to evaluate the safety and effectiveness of E-cigarettes for patients to quit smoking with cancer. H

A total of 1074 participants included smokers (patients with cancer) who recently enrolled in a tobacco treatment program at a comprehensive cancer center. A 3-fold increase in E-cigarette use was observed from 2012 to 2013. E-cigarette users were more nicotine dependent than nonusers, had more prior quit attempts, and were more likely to be diagnosed with thoracic and head or neck cancers. The high rate of E-cigarette usage found in this study coincides with the increased E-cigarette use in the general

Pediatric Oncology Cancer | Volume 121, Issue 7, Pages 1098–1107, April 1, 2015

Safety and diagnostic accuracy of tumor biopsies in children with cancer Rodrigo B. Interiano, Amos H.P. Loh, Nathan Hinkle, Fazal N. Wahid, Alpin D. Malkan, Armita Bahrami, Jesse J. Jenkins, Shenghua Mao, Jianrong Wu, Kimberly Proctor, Victor M. Santana, Alberto S. Pappo, Robert E. Gold, and Andrew M. Davidoff

Tumor biopsies are central to the diagnosis and management of cancer and are critical to efforts in personalized medicine and targeted therapeutics. In this study, the safety and accuracy of biopsies in children with cancer were evaluated. All biopsies performed with a suspected or established diagnosis of cancer from 2003 – 2012 were reviewed. Patient characteristics and disease-related and procedure-related factors were compared with procedure-related complications and diagnostic accuracy. A total of 1073 biopsies were performed in 808 patients. Of 1025 biopsies with adequate follow-up, 79 were associated

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with an adverse event, 35 were minor, and 32 were major. Eleven deaths occurred within 30 days after the procedure, but the procedure may have contributed to the outcome in only 2 cases. A total of 926 biopsies provided definitive histologic diagnoses. Tumor biopsies in children with cancer are associated with a low incidence of complications and a high rate of diagnostic accuracy. The predictive factors identified for adverse outcomes may aid in risk assessment and preprocedural counseling. H


Psychosocial Oncology Cancer | Volume 121, Issue 9, Pages 1513–1519, May 1, 2015

When do we need to care about the caregiver? Supportive care needs, anxiety, and depression among informal caregivers of patients with cancer and cancer survivors Halina Sklenarova, Arne Krümpelmann, Markus W. Haun, Hans-Christoph Friederich, Johannes Huber, Michael Thomas, Eva C. Winkler, Wolfgang Herzog, and Mechthild Hartmann

Cancer not only affects patients but also their caregivers. The objective of this study was to assess the unmet needs of cancer caregivers and to identify possible predictors of their supportive care needs. In a cross-sectional survey, 188 dyads of patients diagnosed with lung, urological, or gastrointestinal cancer and their primary caregivers were engaged. Caregivers were asked to complete the Supportive Care Needs Survey selfreport questionnaire (for partners and caregivers); patients completed the corresponding questionnaire. Both groups provided information regarding their distress (National Comprehensive Cancer Network Distress Thermometer), anxiety, and depression (Patient Health Questionnaire-4). Clinical characteristics were obtained from medical records. The mean age of the caregivers was 57.8 years, and the average age was 62.5 years. Approximately 72.3% were female, and 33.0% were male.

Caregivers were more distressed and exhibited higher anxiety scores compared with patients. Approximately 14.4% of caregivers reported no unmet need and 43.6% had at least 10 needs that were unmet. Main caregiver concerns were regarding health care service and information needs followed by emotional and psychological needs. To some degree, unmet needs in patients and caregivers’ anxiety predicted unmet caregiver needs. Sociodemographic and clinical variables were not found to be significant predictors. A substantial percentage of caregivers have unmet needs for support, mainly with regard to fears concerning the patient’s condition, receiving disease-related information, and emotional support for themselves. Prediction of unmet needs in caregivers from other clinical and psychological variables was rather poor. Therefore, by means of the frequency and inconsistency of caregivers unmet needs, they should be thoroughly evaluated to offer specific approaches. H

Cancer | Volume 120, Issue 15, Pages 2247–2254, August 1, 2014

Physical, emotional, and social health differences between posttreatment young adults with cancer and matched healthy controls John M. Salsman, Sofia F. Garcia, Betina Yanez, Stacy D. Sanford, Mallory A. Snyder, and David Victorson

Young adults (YAs; ages 18-39 years) with cancer face interrupted developmental milestones and increased stressors that can adversely influence psychosocial adjustment. Transitioning from active treatment to posttreatment survivorship can be particularly challenging. The purpose of this study is to describe the health-related quality of life (HRQL) and psychological adaptation of YAs after treatment, relative to young adults without cancer. Three cohorts of YAs of mixed cancer diagnoses and an age-, education-, sex-, and partner status–matched group of healthy control participants (HCs) were recruited via an online research panel.

YAs reported poorer physical and emotional well-being but better social well-being, and they reported comparatively stable scores for posttraumatic growth compared to HCs, who reported greater posttraumatic growth across groups. Findings underscore the negative and positive sequelae for YAs and highlight the need for comprehensive assessment among YA survivors. A matched, HC group allows the HRQL and psychological adaptation of YAs to be placed in context, enabling a more precise determination of the impact of cancer. H

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Screening and Prevention CA: A Cancer Journal for Clinicians | Volume 64, Issue 4, Pages 272-290, July / August 2014

Tobacco use and cessation for cancer survivors: An overview for clinicians Maher Karam-Hage, Paul M. Cinciripini, and Ellen R. Gritz

Approximately 30% of all cancer deaths in the United States are caused by tobacco use and smoking. Cancers of eighteen sites have been causally linked to smoking, the most common of which are the lung, head and neck, bladder, and esophagus. While quit rates and quit attempt rates are relatively high shortly after a cancer diagnosis, the recidivism rates are also high. Therefore, screening, treating, and preventing relapse to tobacco use is imperative among patients with and survivors of cancer. To date, research has consistently shown that a combination of pharmacologic and behavioral interventions is needed to achieve the highest smoking cessation rates, with a recent emphasis on individualized treatment as a most promising approach.

treatments and to increase the risk of complications and of developing secondary cancers. The authors recommend that oncology providers screen all patients for tobacco use and refer users to specialized treatment when available. Alternatively, oncology clinicians can provide basic advice on tobacco use cessation and pharmacotherapy and/or referral to outside resources (eg, quitlines). Herein, the authors summarize the current knowledge on tobacco use and its treatment, with a focus on the related available evidence for patients with and survivors of cancer.H

Challenges in health care systems, including the lack of appropriate resources and provider training, have slowed the progress in addition to important clinical considerations relevant to the treatment of tobacco dependence (eg, a high degree of comorbidity with psychiatric disorders and other substance use disorders). However, continued tobacco use has been shown to limit the effectiveness of major cancer

CA: A Cancer Journal for Clinicians | Volume 65, Issue 1, Pages 30-54, January / February 2015

Cancer screening in the United States, 2015: A review of current American Cancer Society guidelines and current issues in cancer screening Robert A. Smith, Deana Manassaram-Baptiste, Durado Brooks, Mary Doroshenk, Stacey Fedewa, Debbie Saslow, Otis W. Brawley, and Richard Wender

Each year, the American Cancer Society (ACS) publishes a summary of its guidelines for early cancer detection along with a report on data and trends in cancer screening rates and select issues related to cancer screening. In this issue of the journal, the current ACS cancer screening guidelines are

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summarized. The latest data on utilization of cancer screening from the National Health Interview Survey (NHIS) is also described, as are several issues related to screening coverage under the Affordable Care Act, including the expansion of the Medicaid program. H


Soft Tissue and Bone Sarcoma Cancer | Volume 120, Issue 13, Pages 2006–2015, July 1, 2014

Patient-derived xenografts for individualized care in advanced sarcoma Justin Stebbing, Keren Paz, Gary K. Schwartz, Leonard H. Wexler, Robert Maki, Raphael E. Pollock, Ronnie Morris, Richard Cohen, Arjun Shankar, Glen Blackman, Victoria Harding, David Vasquez, Jonathan Krell, Daniel Ciznadija, Amanda Katz, and David Sidransky

Patients with advanced, metastatic sarcoma have a poor prognosis, and the overall benefit from the few standard-ofcare therapeutics available is small. The rarity of this tumor leads to difficulties in conducting clinical trials. The authors previously reported the outcome of patients with common solid tumors who received treatment with drug regimens who were first tested in patient-derived xenografts using the TumorGrafts method. Tumors taken from 29 patients with sarcoma were implanted into immunodeficient mice, identifying drug targets and drugs for clinical use. The results were used to personalize cancer treatment. Twenty-two were successfully engrafted, permitting the identification of treatment regimens. Although 6 patients died before the completion of TumorGraft testing, a correlation between TumorGraft results and clinical outcome was observed in 81% of the remaining mice. No patients progressed during the TumorGraft-predicted therapy. This data supports the use of the personalized TumorGraft model as an investigational platform for therapeutic decision-making that can guide treatment for rare tumors. A randomized phase 3 trial versus physician’s choice is warranted. H

Cancer | Volume 120, Issue 20, Pages 3154–3158, October 15, 2014

Retrospective cohort study evaluating the impact of intraperitoneal morcellation on outcomes of localized uterine leiomyosarcoma Suzanne George, Constance Barysauskas, César Serrano, Titilope Oduyebo, Jose A. Rauh-Hain, Marcela G. Del Carmen, George D. Demetri, and Michael G. Muto

Uterine leiomyosarcoma (ULMS) is identified in 0.1% to 0.2% of hysterectomy specimens of presumed leiomyoma. No preoperative technique reliably differentiates ULMS from uterine leiomyoma. Increasing use of minimally invasive approaches for the management of leiomyomas may result in inadvertently morcellated ULMS with resulting intraperitoneal dissemination of the tumor. This study assessed the impact of intraperitoneal morcellation on the outcomes of patients with ULMS. In this reexamining group study, all patients with ULMS who attended the authors’ institutions from 2007 to 2012

were reviewed. Demographics and outcomes were compared between those who underwent morcellation or total abdominal hysterectomy (TAH) for their first surgery. Fiftyeight patients were identified, including 39 who underwent TAH and 19 who underwent intraperitoneal morcellation. Intraperitoneal morcellation of presumed leiomyoma was found to worsen the outcome of women with ULMS. Because there are no reliable preoperative techniques to distinguish ULMS from benign leiomyoma, all efforts to minimize intraperitoneal uterine morcellation should be considered. H

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Supportive Care Cancer | Volume 120, Issue 22, Pages 3575–3583, November 15, 2014

Phase III double-blind, placebo-controlled study of gabapentin for the prevention of delayed chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy, NCCTG N08C3 (Alliance) Debra L. Barton, Gita Thanarajasingam, Jeff A. Sloan, Brent Diekmann, Jyotsna Fuloria, Lisa A. Kottschade, Alan P. Lyss, Anthony J. Jaslowski, Miroslaw A. Mazurczak, Scott C. Blair, Shelby Terstriep, and Charles L. Loprinzi

Despite targeted antiemetics, data support an unmet need related to the management of delayed nausea and vomiting (NV). Promising pilot data informed this phase III trial evaluating gabapentin for delayed NV from highly emetogenic chemotherapy (HEC). Four hundred thirty patients received prophylactic treatment with 20 mg of dexamethasone and a 5HT3 receptor antagonist (RA) on the day of chemotherapy, followed by gabapentin 300 mg twice a day and dexamethasone (dex) or placebo

and dex after HEC. Gabapentin/placebo was started the day of chemotherapy and continued through day 5 for the first chemotherapy cycle, whereas dex was gradually adjusted down on days 2-4. The primary end point was complete response (CR), defined as no vomiting and no use of rescue medications on days 2-6, using an NV diary. Patients were in turn satisfied with the control of their nausea and vomiting irrespective of arm with 5HT3 RA and dexamethasone providing good control of nausea and vomiting for most patients. H

Survivorship CA: A Cancer Journal for Clinicians | Volume 64, Issue 4, Pages 225-249, July / August 2014

American Cancer Society prostate cancer survivorship care guidelines Ted A. Skolarus, Andrew M.D. Wolf, Nicole L. Erb, Durado D. Brooks, Brian M. Rivers, Willie Underwood III, Andrew L. Salner, Michael J. Zelefsky, Jeanny B. Aragon-Ching, Susan F. Slovin, Daniela A. Wittmann, Michael A. Hoyt, Victoria J. Sinibaldi, Gerard Chodak, Mandi L. Pratt-Chapman, and Rebecca L. Cowens-Alvarado

Prostate cancer survivors approach 2.8 million in the United States. While guidelines exist for timely treatment and observation for a recurrent disease, there is limited availability of guidelines that facilitate the provision of posttreatment clinical follow-up care, addressing the effects that survivors face. Based on recommendations set forth by a National Cancer Survivorship Resource Center expert panel, the American Cancer Society developed clinical follow-up care guidelines to facilitate the provision of posttreatment care by primary care clinicians. These guidelines were developed using a combined approach of evidence synthesis and expert consensus. Existing guidelines for health promotion, surveillance, and screening for second primary cancers were referenced when available. 30 American Cancer Society Family of Journals

To promote comprehensive follow-up care and optimal health and quality of life for the posttreatment survivor, the guidelines address health promotion, surveillance for prostate cancer recurrence, screening for second primary cancers, long-term and late effects assessment and management, psychosocial issues, and care coordination among the oncology team, primary care clinicians, and nononcology specialists. A key challenge to the development of these guidelines was the limited availability of published evidence for management of prostate cancer survivors after treatment. Much of the evidence relies on studies with small sample sizes and retrospective analyses of facility-specific and population databases. H


Survivorship, con’t.

CA: A Cancer Journal for Clinicians | Volume 64, Issue 5, Pages 291-292, September / October 2014

Oncologists and primary care physicians infrequently provide survivorship care plans Mary Kay Barton

The Institute of Medicine recommends that, after primary treatment, all cancer survivor patients receive a survivorship care plan (SCP) that includes a treatment summary and an individualized follow-up plan making clear which physician is responsible. Danielle Blanch-Hartigan, PhD, MPH, a cancer prevention fellow at the National Cancer Institute in Rockville, Maryland, and colleagues used data from the Survey of Physician Attitudes Regarding the Care of Cancer Survivors, a 2009 national poll of 1020 primary care physicians and 1130 oncologists, for the current study of whether they provide patients with an SCP. This study found that 64% of oncologists reported always/ almost always discussing survivorship care. About one-half of oncologists said that they always/almost always discussed which physician would provide the follow-up services for cancer care, and 42% discussed which physician would handle other medical issues. Only about one-third of oncologists reported that they discussed both the survivorship care plan

and provider responsibility with a patient. Slightly less than 10% said they always/almost always provided a written SCP to their patients, and less than 5% said they regularly did all three items. Answers from primary care physicians revealed that 21% reported always/almost always recommended survivorship care, 34% reported always/almost always discussed who would follow-up with the patient for their cancer care, and 33% reported always/almost always discussed which physician would take care of other medical issues. Only 12% of primary care physicians reported always/almost always discussing all three issues. This study has shown that most primary care physicians and oncologists do not consistently provide SCPs to cancer survivors (J Clin Oncol. 2014;32:1578-1585). The authors suggest that the factors that they found to be associated with behaviors could provide areas for improving survivorship care, specifically physician training and care coordination. Both medical education and increased communication between providers could address these concerns. H

CA: A Cancer Journal for Clinicians | Volume 65, Issue 3, Pages 167-189, May / June 2015

Practical clinical interventions for diet, physical activity, and weight control in cancer survivors Wendy Denmark-Wahnefried, Laura Q. Rogers, Catherine M. Alfano, Cynthia A. Thomson, Kerry S. Courneya, Jeffrey A. Meyerhardt, Nicole L. Stout, Elizabeth Kvale, Heidi Ganzer, and Jennifer A. Ligibel

The importance of expanding cancer treatment to include the promotion of overall long-term health is emphasized in the Institute of Medicine report on delivering quality oncology care. Weight management, physical activity, and a healthy diet are key components of tertiary prevention but may be areas in which the oncologist and/or the oncology care team may be less familiar. This article reviews current diet and physical activity guidelines, the evidence supporting those recommendations, and provides an overview of practical interventions that have

resulted in favorable improvements in lifestyle behavior change in cancer survivors. It also describes current lifestyle habits among cancer survivors and the role of the oncologist in helping cancer patients and survivors embark upon changes in lifestyle behaviors, and it calls for the development of partnerships between the oncology providers, primary care providers, and experts in nutrition, exercise science, and behavior change to help positively orient cancer patients toward longer and healthier lives. H

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Survivorship, con’t.

Cancer | Volume 120, Issue 16, Pages 2522–2534, August 15, 2014

Daughters and Mothers Against Breast Cancer (DAMES): Main outcomes of a randomized controlled trial of weight loss in overweight mothers with breast cancer and their overweight daughters Wendy Demark-Wahnefried, Lee W. Jones, Denise C. Snyder, Richard J. Sloane, Gretchen G. Kimmick, Daniel C. Hughes, Hoda J. Badr, Paige E. Miller, Lora E. Burke, and Isaac M. Lipkus

Few studies to date have used the cancer diagnosis as a teachable moment to promote healthy behavior changes in survivors of cancer and their family members. This study explored the possibility of mother-daughter weight loss. A randomized controlled trial of weight loss intervention was undertaken among 68 mother-daughter pairs, each comprised of a survivor of breast cancer and her adult biological daughter. All women had body mass indices ≥ 25 kg/m2 and underwent in-person assessments at baseline, 6, and 12 months, with accelerometry and exercise capacity performed on a subset

of individuals. All women received a personalized workbook and 6 newsletters, promoting weight loss, exercise, and a diet program. Significant differences occurred in mothers for body mass index, weight, and waist circumference (WC); significant differences were observed in the WC of corresponding daughters. Improvements in lifestyle behaviors and health outcomes are possible with tailored print interventions. More research is needed to expand this work beyond the motherdaughter pair. H

Symptom Control and Palliative Care CA: A Cancer Journal for Clinicians | Volume 64, Issue 4, Pages 223-224, July / August 2014

Early outpatient referral to palliative care services improves end-of-life care Mary Kay Barton

Previous studies have shown that palliative care improves end-of-life care over routine oncologic care alone. In this retrospective group study, researchers set out to evaluate how the timing and setting of initial palliative care referral affects the quality of end-of-life care. David Hui, MD, MSc, assistant professor in the department of palliative care at The University of Texas MD Anderson Cancer Center in Houston, Texas, and his colleagues performed a secondary analysis of an earlier study that examined the pattern of palliative care at their institution. This analysis included adult patients who died of advanced cancer between September 1, 2009, and February 28, 2010, who were in contact with The University of Texas MD Anderson Cancer Center within the last three months of their life, and had received a palliative care referral. A total of 366 patients were included in the analysis whom received their first palliative care referral as an outpatient or inpatient.

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This study demonstrated that early involvement of palliative care was associated with significantly fewer emergency department visits, hospital admissions, and hospital deaths compared with a late referral. Further analysis demonstrated that outpatient referral was associated with fewer emergency room visits, hospital admissions, hospital deaths, and ICU admissions, as well as shorter hospital stays in the last month of life. Also, the complex end-of-life care score was also lower in the outpatient referral group. The main point of the study is that patients who were referred to palliative care earlier and as outpatients had better end-oflife care compared with those referred later or as inpatients, and this study has shown that for patients with cancer, referral to outpatient palliative care services improves the quality of their end-of-life care compared with those who were referred as inpatients. H


Symptom Control and Palliative Care, con’t.

CA: A Cancer Journal for Clinicians | Volume 64, Issue 5, Pages 295-310, September / October 2014

Palliative radiotherapy at the end of life: A critical review Joshua A. Jones, Stephen T. Lutz, Edward Chow, and Peter A. Johnstone

When delivered with palliative intent, radiotherapy can help to alleviate a multitude of symptoms related to advanced cancer. In general, time to symptom relief is measured in weeks to months after the completion of radiotherapy. Over the past several years, an increasing number of studies have explored rates of radiotherapy use in the final months of life and have found variable rates of radiotherapy use. The optimal rate is unclear, but would incorporate anticipated efficacy in patients whose survival allows it and minimize overuse among patients with expected short survival. Clinician prediction has been shown to overestimate the length of survival in repeated

studies. Prognostic indices can provide assistance with estimations of survival length and may help to guide treatment decisions regarding palliative radiotherapy in patients with potentially short survival times. This review explores the recent studies of radiotherapy near the end of life, examines general prognostic models for patients with advanced cancer, describes specific clinical circumstances when radiotherapy may and may not be beneficial, and addresses open questions for future research to help clarify when palliative radiotherapy may be effective near the end of life. H

CA: A Cancer Journal for Clinicians | Volume 65, Issue 1, Pages 55-81, January / February 2015

Recent progress in the treatment and prevention of cancer-related lymphedema Simona F. Shaitelman, Kate D. Cromwell, John C. Rasmussen, Nicole L. Stout, Jane M. Armer, Bonnie B. Lasinski, and Janice N. Cormier

This article provides an overview of the recent developments in the diagnosis, treatment, and prevention of cancer-related lymphedema. Lymphedema incidence by tumor site is evaluated. Measurement techniques and trends in patient education and treatment are also reviewed to include current trends in

therapeutic and surgical treatment options as well as longerterm management. Finally, an overview of the policies related to insurance coverage and reimbursement is discussed, giving the clinician an overview of important trends in the diagnosis, treatment, and management of cancer-related lymphedema. H

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Symptom Control and Palliative Care, con’t.

CA: A Cancer Journal for Clinicians | Volume 65, Issue 2, Pages 123-138, March / April 2015

Clinical characteristics, pathophysiology, and management of noncentral nervous system cancer-related cognitive impairment in adults Jeffrey S. Wefel, Shelli R. Kesler, Kyle R. Noll, and Sanne B. Schagen

Over the past few decades, a body of research has emerged confirming what many adult patients with noncentral nervous system cancer have long reported—that cancer and its treatment are frequently associated with cancer-related cognitive impairment (CRCI). The severity of CRCI varies, and symptoms can emerge early or late in the disease course. CRCI is typically mild to moderate. Animal models and novel neuroimaging techniques have begun to unravel the pathophysiologic mechanisms underlying CRCI, including the role of inflammatory cascades, direct

neurotoxic effects, damage to progenitor cells, white matter abnormalities, and reduced functional connectivity, among others. Given the lack of research on CRCI with other cancer populations, this review synthesizes the current literature with a deliberate focus on CRCI within the context of breast cancer. A hypothetical case-study approach is used to illustrate how CRCI often presents clinically and how current science can inform practice. While the literature regarding intervention for CRCI is growing, behavioral and pharmacologic approaches are discussed. H

CA: A Cancer Journal for Clinicians | Volume 63, Issue 3, Pages 190-211, May / June 2015

Screening, evaluation, and management of cancer-related fatigue: Ready for implementation to practice? Ann M. Berger, Sandra A. Mitchell, Paul B. Jacobsen, and William F. Pirl

Evidence regarding cancer-related fatigue (fatigue) has accumulated sufficiently such that recommendations for screening, evaluation, and/or management have been released recently by 4 leading cancer organizations. These evidence-based fatigue recommendations are available for clinicians, and some have patient versions; but barriers at the patient, clinician, and system levels hinder dissemination and implementation into practice. The underlying biologic mechanisms for this debilitating symptom have not been elucidated completely, hindering the development of mechanistically driven interventions. However, significant progress has been made toward methods for screening and comprehensively evaluating fatigue and other common symptoms using reliable and valid self-report measures. Limited data exist to support the use of any pharmacologic agent; however, several nonpharmacologic interventions

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have been shown to be effective in reducing fatigue in adults. Never before have evidence-based recommendations for fatigue management been disseminated by 4 premier cancer organizations (the National Comprehensive Cancer, the Oncology Nursing Society, the Canadian Partnership Against Cancer/Canadian Association of Psychosocial Oncology, and the American Society of Clinical Oncology). Clinicians may ask: Are we ready for implementation into practice? The reply: A variety of approaches to screening, evaluation, and management are ready for implementation. To reduce fatigue severity and distress and its impact on functioning, intensified collaborations and close partnerships between clinicians and researchers are needed, with an emphasis on system-wide efforts to disseminate and implement these evidence-based recommendations. H


Meet the Editors Celeste N. Powers, MD, PhD Well known throughout the international cytopathology community, Celeste N. Powers is Editor-in-Chief of Cancer Cytopathology, dedicated to advancing cytopathology research for early cancer diagnosis and prevention. Dr. Powers is also the Chair of the Division of Anatomic Pathology at Virginia Commonwealth University Medical Center. Among her many national duties, she has served as President of the American Society of Cytopathology and is currently President of the United States and Canadian Academy of Pathology. In recognition of her dedication to the field of cytopathology, Dr. Powers was presented with the Papanicolaou Award in 2008, the highest award given by the American Society of Cytopathology.

Submit to the journal at mc.manuscriptcentral.com/cancercyto

Fadlo R. Khuri, MD Dr. Fadlo R. Khuri is Professor and Chairman of the Department of Hematology and Medical Oncology and Executive Associate Dean of Research at Emory University School of Medicine. He also serves as Deputy Director for the Winship Cancer Institute. Dr. Khuri holds the Roberto C. Goizueta Distinguished Chair for Cancer Research. He is a Professor of Otolaryngology, Medicine, and Pharmacology, and he also serves as Editor-in-Chief of the journal Cancer. He was recently elected the 16th President of the American University of Beirut. His research focuses on the development of molecular, prognostic, therapeutic, and chemopreventative approaches to improve the standard of care for patients with tobaccorelated cancers. His research has been supported by peer-reviewed grants from the National Cancer Institute, Department of Defense, and American Cancer Society. Dr. Khuri is the recipient of numerous awards, including the 2006 Naji Sahyoun Memorial Award from the Middle East Medical Assembly, the 2010 Waun Ki Hong Award from the University of Texas MD Anderson Cancer Center, and the 2013 Richard and Hilda Rosenthal Memorial Award from the American Association for Cancer Research. He was inducted into the American Society for Clinical Investigation and is listed among America’s Top Doctors and the Marquis Who’s Who in the World.

Submit to the journal at mc.manuscriptcentral.com/cancer

Otis Webb Brawley, MD Otis Webb Brawley is the Chief Medical and Scientific Officer and Executive Vice President of the American Cancer Society. He is also Editor-in-Chief of CA: A Cancer Journal for Clinicians. He is responsible for promoting cancer prevention, early detection, and quality treatment through cancer research and education, championing a variety of efforts, including initiatives to decrease smoking, improve diet, and enhance the ACS’ advocacy programs. Moreover, he is a leader in the Society’s efforts to eliminate disparities in access to quality cancer care. Dr. Brawley also serves as Professor of Hematology, Oncology, Medicine, and Epidemiology at Emory University.

Ted Gansler, MD, MBA, MPH As Director of Medical Content at the American Cancer Society, Ted Gansler heads the ACS Continuing Professional Education program, serves as Editor of CA: A Cancer Journal for Clinicians, and provides medical and scientific review of information for patients and the general public. He is also a member of the ACS Epidemiology Research Department. Prior to joining the ACS, Dr. Gansler directed the Cytopathology Laboratory Fellowship Program at Emory University, where he is currently an Adjunct Professor of Pathology.

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CA: A Cancer Journal for Clinicians Continuing Education activities FREE CME / CNE activities for physicians and nurses CA provides continuing professional education in cancer prevention, early detection, diagnosis, treatment, survivorship, and other topics relevant to decreasing cancer incidence and mortality and improving quality of life for cancer survivors. With ANCC and ACCME-accredited activities, you can receive flexible credit ranging from 1-2 hours/credits.

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