Charles S Fuchs

Publications (327)2960.44 Total impact

• Article: Localized Colon Cancer, Version 3.2013.

  Al B Benson, Tanios Bekaii-Saab, Emily Chan, Yi-Jen Chen, Michael A Choti, Harry S Cooper, Paul F Engstrom, Peter C Enzinger, Marwan G Fakih, Moon J Fenton, [......], Leonard Saltz, Sunil Sharma, David Shibata, John M Skibber, William Small, Constantinos T Sofocleous, Alan P Venook, Christopher G Willett, Kristina M Gregory, Deborah A Freedman-Cass
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  ABSTRACT: The NCCN Clinical Practice Guidelines in Oncology for Colon Cancer begin with the clinical presentation of the patient to the primary care physician or gastroenterologist and address diagnosis, pathologic staging, surgical management, perioperative treatment, patient surveillance, management of recurrent and metastatic disease, and survivorship. The NCCN Colon Cancer Panel meets annually to review comments from reviewers within their institutions and to reevaluate and update their recommendations. In addition, the panel has interim conferences as new data necessitate. These NCCN Guidelines Insights summarize the NCCN Colon Cancer Panel's discussions regarding the treatment of localized disease for the 2013 update of the guidelines.
  Journal of the National Comprehensive Cancer Network: JNCCN 05/2013; 11(5):519-528. · 4.41 Impact Factor
• Article: Gastric Cancer, Version 2.2013.

  Jaffer A Ajani, David J Bentrem, Stephen Besh, Thomas A D'Amico, Prajnan Das, Crystal Denlinger, Marwan G Fakih, Charles S Fuchs, Hans Gerdes, Robert E Glasgow, [......], Aaron R Sasson, Walter J Scott, Vivian E Strong, Thomas K Varghese, Graham Warren, Mary Kay Washington, Christopher Willett, Cameron D Wright, Nicole R McMillian, Hema Sundar
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  ABSTRACT: The NCCN Clinical Practice Guidelines in Oncology for Gastric Cancer provide evidence- and consensus-based recommendations for a multidisciplinary approach for the management of patients with gastric cancer. For patients with resectable locoregional cancer, the guidelines recommend gastrectomy with a D1+ or a modified D2 lymph node dissection (performed by experienced surgeons in high-volume centers). Postoperative chemoradiation is the preferred option after complete gastric resection for patients with T3-T4 tumors and node-positive T1-T2 tumors. Postoperative chemotherapy is included as an option after a modified D2 lymph node dissection for this group of patients. Trastuzumab with chemotherapy is recommended as first-line therapy for patients with HER2-positive advanced or metastatic cancer, confirmed by immunohistochemistry and, if needed, by fluorescence in situ hybridization for IHC 2+.
  Journal of the National Comprehensive Cancer Network: JNCCN 05/2013; 11(5):531-546. · 4.41 Impact Factor
• Article: Physical Activity, Tumor PTGS2 Expression, and Survival in Patients with Colorectal Cancer.

  Mai Yamauchi, Paul Lochhead, Yu Imamura, Aya Kuchiba, Xiaoyun Liao, Zhi Rong Qian, Reiko Nishihara, Teppei Morikawa, Kaori Shima, Kana Wu, Edward Giovannucci, Jeffrey A Meyerhardt, Charles S Fuchs, Andrew T Chan, Shuji Ogino
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  ABSTRACT: BACKGROUND: Higher levels of physical activity are associated with lower colorectal cancer incidence and mortality, perhaps through influencing energy balance, cellular prostaglandin biosynthesis and systemic inflammation. Although evidence suggests interactive effects of energetics, sedentary lifestyle, and tumor CTNNB1 (beta-catenin) or CDKN1B (p27) status on colon cancer prognosis, interactive effects of physical activity and tumor PTGS2 (the official symbol for cyclooxygenase-2) status on clinical outcome remain unknown. METHODS: Utilizing molecular pathological epidemiology database of 605 stage I-III colon and rectal cancers in two prospective cohort studies (the Nurse's Health Study and the Health Professionals Follow-up Study), we examined patient survival according to post-diagnosis physical activity and tumor PTGS2 status (with 382 PTGS2-positive and 223 PTGS2-negative tumors by immunohistochemistry). Cox proportional hazards models were used to calculate colorectal cancer-specific mortality hazard ratio (HR), adjusting for clinical and other tumor variables including microsatellite instability status. RESULTS: Among PTGS2-positive cases, compared with the least active first quartile, the multivariate HRs (95% confidence interval) were 0.30 (0.14-0.62) for the second, 0.38 (0.20-0.71) for the third, and 0.18 (0.08-0.41) for the fourth quartile of physical activity level (Ptrend=0.0002). In contrast, among PTGS2-negative cases, physical activity level was not significantly associated with survival (Ptrend =0.84; Pinteraction=0.024, between physical activity and tumor PTGS2 status). CONCLUSIONS: Post-diagnosis physical activity is associated with better survival among patients with PTGS2-positive tumors, but not among patients with PTGS2-negative tumors. Impact: Immunohistochemical PTGS2 expression in colorectal carcinoma may serve as a predictive biomarker in pathology practice, which may predict stronger benefit from exercise.
  Cancer Epidemiology Biomarkers &amp Prevention 04/2013; · 4.12 Impact Factor
• Article: Multicenter Phase II Study of Tivozanib (AV-951) and Everolimus (RAD001) for Patients With Refractory, Metastatic Colorectal Cancer.

  Brian M Wolpin, Kimmie Ng, Andrew X Zhu, Thomas Abrams, Peter C Enzinger, Nadine J McCleary, Deborah Schrag, Eunice L Kwak, Jill N Allen, Pankaj Bhargava, Jennifer A Chan, Wolfram Goessling, Lawrence S Blaszkowsky, Jeffrey G Supko, Meaghan Elliot, Kaori Sato, Eileen Regan, Jeffrey A Meyerhardt, Charles S Fuchs
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  ABSTRACT: BACKGROUND: Treatments that target the vascular endothelial growth factor (VEGF) pathway have efficacy in colorectal cancer. We evaluated tolerability and efficacy of tivozanib (an oral VEGF receptor-1, -2, -3 inhibitor) plus everolimus (an oral mammalian target of rapamycin inhibitor). METHODS: The phase Ib study followed a 3 + 3 dose-escalation design with three dose levels. The primary objective in the follow-on phase II study was improvement in 2-month progression-free survival (PFS) from 30% (historical benchmark) to 50% in patients with refractory, metastatic colorectal cancer. RESULTS: Dose-limiting toxicities in the phase Ib study were grade 3 fatigue and dehydration. Oral tivozanib (1 mg daily for 3 of 4 weeks) and oral everolimus (10 mg daily continuously) were advanced to a 40-patient phase II study. The most common grade 3-4 adverse events were thrombocytopenia and hypophosphatemia. The 2-month PFS rate was 50%, with 20 of 40 patients having stable disease (SD). Seven (18%) patients were treated for ≥6 months. Median PFS and overall survival (OS) times were 3.0 months (95% confidence interval [CI]: 1.9-3.6 months) and 5.6 months (95% CI: 4.4-10.6 months), respectively. Patients who developed grade 1+ hypertension had increased SD rates (65.2% vs. 29.4%) and longer OS times (10.6 vs. 3.7 months). CONCLUSIONS: The oral combination of tivozanib and everolimus was well tolerated, with stable disease achieved in 50% of patients with refractory, metastatic colorectal cancer.
  The Oncologist 04/2013; · 3.91 Impact Factor
• Article: A multi-institutional, phase II open-label study of ganitumab (AMG 479) in advanced carcinoid and pancreatic neuroendocrine tumors.

  Jonathan Strosberg, Jennifer Chan, David P Ryan, Jeffrey A Meyerhardt, Charles S Fuchs, Thomas A Abrams, Eileen M Regan, Rachel Brady, Jill Weber, Tiffany Campos, Larry Kvols, Matthew H Kulke
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  ABSTRACT: The IGF pathway has been implicated in the regulation of neuroendocrine tumor growth, and preliminary studies suggested that ganitumab (AMG 479), a human monoclonal antibody against IGF1-R, may have antitumor activity in this setting. We performed a two-cohort phase II study of ganitumab in patients with metastatic progressive carcinoid or pancreatic neuroendocrine tumors. This open-label study enrolled patients (≥18 yrs) with metastatic low and intermediate-grade carcinoid or pancreatic NETs. Inclusion criteria included evidence of progressive disease (by RECIST) within 12 months of enrollment, ECOG PS 0-2, and fasting blood sugar <160mg/dL. Prior treatments were allowed and concurrent somatostatin analog therapy was permitted. The primary endpoint was objective response. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. 60 patients (30 carcinoid, 30 pNET) were treated with ganitumab 18mg/kg every 3 weeks, among whom 54 patients were evaluable for survival and 53 patients for response. There were no objective responders by RECIST. Median PFS was 6.3 months (95% CI 4.2-12.6) for the entire cohort; 10.5 months for carcinoid patients and 4.2 months for pNET patients. The OS rate at 12 months was 66% (52%-77%) for the entire cohort. Median OS has not been reached. Grade 3/4 AEs were rare and consisted of hyperglycemia (4%), neutropenia (4%), thrombocytopenia (4%) and infusion reaction (1%). While well-tolerated, single-agent ganitumab was not found to result in major tumor responses among patients with metastatic well-differentiated carcinoid or pancreatic NET.
  Endocrine Related Cancer 04/2013; · 4.36 Impact Factor
• Article: Multi-drug inhibition of the HER pathway in metastatic colorectal cancer: Results of a phase I study of pertuzumab plus cetuximab in cetuximab-refractory patients.

  Douglas A Rubinson, Howard S Hochster, David P Ryan, Brian M Wolpin, Nadine Jackson McCleary, Thomas A Abrams, Jennifer A Chan, Syma Iqbal, Heinz J Lenz, Dean Lim, Jeffrey Rose, Tanios Bekaii-Saab, Helen X Chen, Charles S Fuchs, Kimmie Ng
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  ABSTRACT: Purpose Resistance to cetuximab, a monoclonal antibody against the epithelial growth factor receptor (EGFR), in colorectal cancer (CRC) may result from compensatory signaling through ErbB receptors, ErbB2/neu/HER2 (HER2) and ErbB3/HER3 (HER3). Pertuzumab is a monoclonal antibody that blocks HER2 hetero-dimerization; thus the combination of pertuzumab and cetuximab could possibly overcome cetuximab resistance. Patients and methods This single-arm, open-label, multicenter phase I/II study was designed to assess the safety and efficacy of pertuzumab and cetuximab in patients with cetuximab-resistant KRAS wild type metastatic CRC. Thirteen patients were enrolled and received cetuximab in combination with pertuzumab at several dose levels in a 3 + 3 design. Patients were assessed for dose-limiting toxicity (DLT) during the first cycle. A phase II portion was planned, but not initiated due to toxicity. Results Six of the thirteen patients (46 %) experienced DLTs, therefore the study was terminated early. Grade 3 or higher DLTs included dermatitis with desquamation and/or acneiform rash (n = 6), mucositis or stomatitis (n = 5), and diarrhea (n = 2). There was one Grade 5 event (myocardial infarction) attributed to underlying disease. Among the 13 patients, seven (54 %) were evaluable for response. The objective response rate was 14 %: one patient had a partial response lasting 6 months. Two patients had stable disease (29 %), and four had progressive disease (57 %). Median progression free survival was 2.1 months (95 % CI, 1.5-4.9) and median overall survival was 3.7 months (95 % CI, 1.6-7.9). Conclusion Combination pertuzumab and cetuximab in refractory CRC was associated with potential antitumor activity; however, the combination was not tolerable due to overlapping toxicities.
  Investigational New Drugs 04/2013; · 3.36 Impact Factor
• Article: Effect of vitamin d supplementation on blood pressure in blacks.

  John P Forman, Jamil B Scott, Kimmie Ng, Bettina F Drake, Elizabeth Gonzalez Suarez, Douglas L Hayden, Gary G Bennett, Paulette D Chandler, Bruce W Hollis, Karen M Emmons, Edward L Giovannucci, Charles S Fuchs, Andrew T Chan
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  ABSTRACT: Blacks have significantly higher rates of hypertension than whites, and lower circulating levels of 25-hydroxyvitamin D. There are few data about the effect of vitamin D3 (cholecalciferol) supplementation on blood pressure in blacks. During 2 winters from 2008 to 2010, 283 blacks (median age, 51 years) were randomized into a 4-arm, double-blind trial for 3 months of placebo, 1000, 2000, or 4000 international units of cholecalciferol per day. At baseline, 3 months, and 6 months, systolic and diastolic pressure and 25-hydroxyvitamin D were measured. The 3-month follow-up was completed in 250 (88%) participants. The difference in systolic pressure between baseline and 3 months was +1.7 mm Hg for those receiving placebo, -0.66 mm Hg for 1000 U/d, -3.4 mm Hg for 2000 U/d, and -4.0 mm Hg for 4000 U/d of cholecalciferol (-1.4 mm Hg for each additional 1000 U/d of cholecalciferol; P=0.04). For each 1-ng/mL increase in plasma 25-hydroxyvitamin D, there was a significant 0.2-mm Hg reduction in systolic pressure (P=0.02). There was no effect of cholecalciferol supplementation on diastolic pressure (P=0.37). Within an unselected population of blacks, 3 months of oral vitamin D3 supplementation significantly, yet modestly, lowered systolic pressure. Future trials of vitamin D supplementation on blood pressure are needed to confirm these promising results, particularly among blacks, a population for whom vitamin D deficiency may play a more specific mechanistic role in the pathogenesis of hypertension.
  Hypertension 04/2013; 61(4):779-85. · 6.21 Impact Factor
• Article: Inflammatory Plasma Markers and Pancreatic Cancer Risk: a Prospective Study of 5 U.S. Cohorts.

  Ying Bao, Edward Giovannucci, Peter Kraft, Zhi Rong Qian, Chen Wu, Shuji Ogino, John Michael Gaziano, Meir J Stampfer, Jing Ma, Julie E Buring, Howard Sesso, I-Min Lee, Nader Rifai, Michael N Pollak, Li Jiao, Lawrence S Lessin, Barbara B Cochrane, Joann E Manson, Charles S Fuchs, Brian M Wolpin
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  ABSTRACT: BACKGROUND: Chronic inflammation may play a role in the development of pancreatic cancer. However, few prospective studies have examined the association between plasma inflammatory markers and pancreatic cancer risk. METHODS: In a prospective, nested case-control study of 470 cases and 1094 controls from Health Professionals Follow-up Study, Nurses' Health Study, Physicians' Health Study, Women's Health Initiative, and Women's Health Study, we investigated the association of prediagnostic circulating C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α-receptor II (TNF-αR2) with subsequent pancreatic cancer risk. The median follow-up time of cases was 7.2 years (range 1-26 years). RESULTS: No association was observed between plasma CRP, IL6, and TNF-αR2 and risk of pancreatic cancer. Comparing extreme quintiles, the multivariate ORs were 1.10 (95% CI, 0.74-1.63; Ptrend= 0.81) for CRP, 1.19 (95% CI, 0.81-1.76; Ptrend = 0.08) for IL6, and 0.88 (95% CI, 0.58-1.33; Ptrend = 0.57) for TNF-αR2. CONCLUSIONS: Pre-diagnostic levels of circulating CRP, IL6, and TNF-αR2 were not associated with risk of pancreatic cancer. Impact: Systemic inflammation as measured by circulating inflammatory factors is unlikely to play a major role in the development of pancreatic cancer.
  Cancer Epidemiology Biomarkers &amp Prevention 03/2013; · 4.12 Impact Factor
• Article: Prospective cohort studies of bowel movement frequency and laxative use and colorectal cancer incidence in US women and men.

  Xuehong Zhang, Kana Wu, Eunyoung Cho, Jing Ma, Andrew T Chan, Xiang Gao, Walter C Willett, Charles S Fuchs, Edward L Giovannucci
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  ABSTRACT: PURPOSE: The associations between bowel movement frequency, laxative use, and colorectal cancer incidence remain uncertain. No published studies have accounted for potential latency between these factors and colorectal cancer onset. METHODS: We prospectively examined these associations among 88,173 women in the Nurses' Health Study (NHS, 1982-2010) and 23,722 men in the Health Professionals Follow-up Study (HPFS, 2000-2010). Cox proportional hazards regression models were used to estimate multivariable hazard ratios (HRs, 95 % CIs). We conducted time lagged analyses to evaluate the potential latency in the NHS. RESULTS: We documented 2,012 incident colorectal cancer cases. The HRs (95 % CIs) for infrequent bowel movement relative to daily were 0.86 (95 % CI 0.71-1.04) in women and 0.81 (95 % CI 0.48-1.37) in men. The HRs for weekly to daily relative to never laxative use were 0.98 (95 % CI 0.81-1.20) in women and 1.41 (95 % CI 0.96-2.06) in men. In women, the HRs for every 3 days or less bowel movement relative to daily were 0.87 (95 % CI 0.59-1.27) for colorectal cancers that developed within 10 years of assessment, 1.03 (95 % CI 0.85-1.26) for 11-18 years after assessment, and 0.73 (95 % CI 0.54-1.01) for 19-28 years after assessment. The corresponding HRs for weekly to daily relative to never laxative use were 0.93 (95 % CI 0.63-1.37), 1.03 (95 % CI 0.74-1.44), and 0.98 (95 % CI 0.71-1.35), respectively. CONCLUSION: Bowel movement frequency and laxative use appear not to be associated with colorectal cancer risk in this study.
  Cancer Causes and Control 03/2013; · 2.88 Impact Factor
• Article: Early life factors and risk of inflammatory bowel disease in adulthood.

  Hamed Khalili, Ashwin N Ananthakrishnan, Leslie M Higuchi, James M Richter, Charles S Fuchs, Andrew T Chan
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  ABSTRACT: : Early life factors have been postulated to play a role in development of immune tolerance and intestinal microbiome, which in turn may influence the risk of inflammatory bowel disease. : We conducted a prospective cohort study of 60,186 U.S. women enrolled since 1976 in the Nurses Health Study (NHS) I and 86,495 women enrolled since 1989 in the NHS II with no history of ulcerative colitis (UC) or Crohn's disease (CD). Information about breastfeeding, birth weight, and preterm birth were collected in 1992 in NHS I and 1991 in NHS II. Diagnoses of CD and UC were confirmed through review of medical records. We used Cox proportional hazards models to calculate hazard ratios and 95% confidence intervals. : Among 146,681 women over 3,373,726 person-years of follow-up, we documented 248 cases of CD and 304 cases of UC through 2007 in NHS II and 2008 in NHS I. The median age of diagnosis was 51 for CD and 49 for UC. Compared with women who were not breastfed, women who were breastfed had multivariate-adjusted hazard ratios of 0.99 (95% confidence interval, 0.76-1.30) for CD and 1.03 (95% confidence interval, 0.81-1.32) for UC. Similarly, low or high birth weight and preterm birth were not significantly associated with risk of UC or CD. : In 2 large prospective cohorts of U.S. women, we did not observe a significant association between early life factors including having been breastfed, birth weight, preterm birth, and risk of adult-onset UC and CD.
  Inflammatory Bowel Diseases 03/2013; 19(3):542-7. · 4.86 Impact Factor
• Article: Prospective Analysis of Body Mass Index, Physical Activity, and Colorectal Cancer Risk Associated with β-Catenin (CTNNB1) Status.

  Teppei Morikawa, Aya Kuchiba, Paul Lochhead, Reiko Nishihara, Mai Yamauchi, Yu Imamura, Xiaoyun Liao, Zhi Rong Qian, Kimmie Ng, Andrew T Chan, Jeffrey A Meyerhardt, Edward Giovannucci, Charles S Fuchs, Shuji Ogino
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  ABSTRACT: Dysregulation of the WNT/β-catenin (CTNNB1) signaling pathway is implicated in colorectal carcinoma and metabolic diseases. Considering these roles and cancer prevention, we hypothesized that tumor CTNNB1 status might influence cellular sensitivity to obesity and physical activity. In clinical follow-up of 109,046 women in the Nurses' Health Study and 47,684 men in the Health Professionals Follow-up Study, there were 861 incident rectal and colon cancers with tissue immunohistochemistry data on nuclear CTNNB1 expression. Using this molecular pathological epidemiology database, we conducted Cox proportional hazards regression analysis using data duplication method to assess differential associations of body mass index (BMI) or exercise activity with colorectal cancer risk according to tumor CTNNB1 status. Greater BMI was associated with a significantly higher risk of CTNNB1-negative cancer [multivariate HR = 1.34; 95% confidence interval (CI), 1.18-1.53 for 5.0 kg/m increment; P = 0.0001] but not with CTNNB1-positive cancer risk (multivariate HR = 1.07; 95% CI, 0.92-1.25 for 5.0 kg/m increment; P = 0.36; P = 0.027, between CTNNB1-negative and CTNNB1-positive cancer risks). Physical activity level was associated with a lower risk of CTNNB1-negative cancer (multivariate HR = 0.93; 95% CI, 0.87-1.00 for 10 MET-h/wk increment; P = 0.044) but not with CTNNB1-positive cancer risk (multivariate HR = 0.98; 95% CI, 0.91-1.05 for 10 MET-h/wk increment; P = 0.60). Our findings argue that obesity and physical inactivity are associated with a higher risk of CTNNB1-negative colorectal cancer but not with CTNNB1-positive cancer risk. Furthermore, they suggest that energy balance and metabolism status exerts its effect in a specific carcinogenesis pathway that is less likely dependent on WNT/CTNNB1 activation. Cancer Res; 73(5); 1600-10. ©2012 AACR.
  Cancer Research 03/2013; 73(5):1600-10. · 7.86 Impact Factor
• Article: Preoperative Cetuximab, Irinotecan, Cisplatin, and Radiation Therapy for Patients with Locally Advanced Esophageal Cancer.

  Michael S Lee, Harvey J Mamon, Theodore S Hong, Noah C Choi, Panagiotis M Fidias, Eunice L Kwak, Jeffrey A Meyerhardt, David P Ryan, Raphael Bueno, Dean M Donahue, Michael T Jaklitsch, Michael Lanuti, David W Rattner, Charles S Fuchs, Peter C Enzinger
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  ABSTRACT: Purpose. To determine the efficacy and toxicity of weekly neoadjuvant cetuximab combined with irinotecan, cisplatin, and radiation therapy in patients with locally advanced esophageal or gastroesophageal junction cancer.Methods and Materials. Patients with stage IIA-IVA esophageal or gastroesophageal junction cancer were enrolled in a Simon's two-stage phase II study. Patients received weekly cetuximab on weeks 0-8 and irinotecan and cisplatin on weeks 1, 2, 4, and 5, with concurrent radiotherapy (50.4 Gy on weeks 1-6), followed by surgical resection.Results. In the first stage, 17 patients were enrolled, 16 of whom had adenocarcinoma. Because of a low pathologic complete response (pCR) rate in this cohort, the trial was discontinued for patients with adenocarcinoma but squamous cell carcinoma patients continued to be enrolled; two additional patients were enrolled before the study was closed as a result of poor accrual. Of the 19 patients enrolled, 18 patients proceeded to surgery and 16 patients underwent an R0 resection. Three patients (16%) had a pCR. The median progression-free survival interval was 10 months and the median overall survival duration was 31 months. Severe neutropenia occurred in 47% of patients, and severe diarrhea occurred in 47% of patients. One patient died preoperatively from sepsis, and one patient died prior to hospital discharge following surgical resection.Conclusions. This schedule of cetuximab in combination with irinotecan, cisplatin, and radiation therapy was toxic and did not achieve a sufficient pCR rate in patients with localized esophageal adenocarcinoma to undergo further evaluation.
  The Oncologist 02/2013; · 3.91 Impact Factor
• Article: Metastatic Colon Cancer, Version 3.2013: Featured Updates to the NCCN Guidelines.

  Al B Benson, Tanios Bekaii-Saab, Emily Chan, Yi-Jen Chen, Michael A Choti, Harry S Cooper, Paul F Engstrom, Peter C Enzinger, Marwan G Fakih, Moon J Fenton, [......], Leonard Saltz, Sunil Sharma, David Shibata, John M Skibber, William Small, Constantinos T Sofocleous, Alan P Venook, Christopher G Willett, Kristina M Gregory, Deborah A Freedman-Cass
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  ABSTRACT: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer begin with the clinical presentation of the patient to the primary care physician or gastroenterologist and address diagnosis, pathologic staging, surgical management, perioperative treatment, patient surveillance, management of recurrent and metastatic disease, and survivorship. The NCCN Colon Cancer Panel meets annually to review comments from reviewers within their institutions and to reevaluate and update their recommendations. In addition, the panel has interim conferences as new data necessitate. These NCCN Guidelines Insights summarize the NCCN Colon Cancer Panel's discussions surrounding metastatic colorectal cancer for the 2013 update of the guidelines. Importantly, changes were made to the continuum of care for patients with advanced or metastatic disease, including new drugs and an additional line of therapy.
  Journal of the National Comprehensive Cancer Network: JNCCN 02/2013; 11(2):141-152. · 4.41 Impact Factor
• Article: Efficacy, safety, pharmacokinetics and biomarkers of cediranib monotherapy in advanced hepatocellular carcinoma: A phase II study.

  Andrew X Zhu, Marek Ancukiewicz, Jeffrey G Supko, Dushyant V Sahani, Lawrence S Blaszkowsky, Jeffrey A Meyerhardt, Thomas A Abrams, Nadine Jackson McCleary, Pankaj Bhargava, Alona Muzikansky, Susan Sheehan, Eileen Regan, Eamala Vasudev, Michelle Knowles, Charles S Fuchs, David P Ryan, Rakesh K Jain, Dan G Duda
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  ABSTRACT: PURPOSE: We performed a single-arm phase II study of cediranib, a pan-VEGFR tyrosine kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC). Patients and Methods: Patients with histologically-confirmed measurable advanced HCC and adequate hematologic, hepatic, and renal functions received cediranib 30-mg orally once daily (4 weeks/cycle). The primary endpoint was progression-free survival (PFS) rate at 3 months. Other endpoints included response rates, overall survival (OS), pharmacokinetics (PK) and biomarkers for cediranib. RESULTS: Cediranib treatment resulted in an estimated 3-month-PFS rate of 77% [60%, 99%]. Median PFS was 5.3 [3.5,9.7] months, stable disease was seen in 5/17 patients (29%), and median OS was 11.7 [7.5-13.6] months. Grade 3 toxicities included hypertension (29%), hyponatremia (29%) and hyperbilirubinemia (18%). Cediranib PK were comparable to those seen in cancer patients with normal hepatic function. Plasma levels of VEGF and PlGF increased and sVEGFR1, sVEGFR2 and Ang-2 decreased after cediranib treatment. PFS was inversely correlated with baseline levels of VEGF, sVEGFR2, and bFGF and with on-treatment levels of bFGF and IGF-1, and directly associated with on-treatment levels of IFN-γ. OS was inversely correlated with baseline levels of sVEGFR1, Ang-2, TNF-α, CAIX and CD34+CD133+CD45dim circulating progenitor cells and on-treatment levels of sVEGFR2. CONCLUSIONS: Despite the limitations of primary endpoint selection, cediranib at 30-mg daily showed a high incidence of toxicity and preliminary evidence of antitumor activity in advanced HCC. Hepatic dysfunction did not appear to affect the steady-state PK of cediranib. Exploratory studies suggested pro-angiogenic and inflammatory factors as potential biomarkers of anti-VEGF therapy in HCC.
  Clinical Cancer Research 01/2013; · 7.74 Impact Factor
• Article: Prediagnostic plasma vitamin B6 (pyridoxal 5'-phosphate) and survival in patients with colorectal cancer.

  Youjin Je, Jung Eun Lee, Jing Ma, Xuehong Zhang, Eunyoung Cho, Bernard Rosner, Jacob Selhub, Charles S Fuchs, Jeffrey Meyerhardt, Edward Giovannucci
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  ABSTRACT: PURPOSE: Higher plasma pyridoxal 5'-phosphate (PLP) levels are associated with a decreased incidence of colorectal cancer, but the influence of plasma PLP on survival of patients with colorectal cancer is unknown. We prospectively examined whether prediagnostic plasma PLP levels are associated with mortality among colorectal cancer patients. METHODS: We included 472 incident cases of colorectal cancer identified in the Nurses' Health Study, the Health Professionals Follow-up Study, and the Physicians' Health Study from 1984 to 2002. The patients provided blood samples two or more years before cancer diagnosis. Stratified Cox proportional hazards models were used to calculate hazard ratios (HR) with 95 % confidence intervals (CI) adjusted for other risk factors for cancer survival. RESULTS: Higher plasma PLP levels were not associated with a significant reduction in colorectal cancer-specific (169 deaths) or overall mortality (259 deaths). Compared with patients who had less than 45 pmol/ml of plasma PLP (median: 33.6 pmol/ml), those who had 110 pmol/ml or higher levels (median: 158.8 pmol/ml) had multivariable HRs of 0.85 (95 % CI 0.50-1.45, p trend = 0.37) and 0.87 (95 % CI 0.56-1.35, p trend = 0.24) for colorectal cancer-specific and overall mortality. Higher plasma PLP levels, however, seemed to be associated with better survival among patients who had lower circulating 25-hydroxyvitamin D(3) levels (<26.5 ng/ml) (p interaction ≤.005). CONCLUSIONS: Higher prediagnostic plasma PLP levels were not associated with an improvement on colorectal cancer survival overall. Further research is needed to clarify the influence of vitamin B6 on colorectal cancer progression and survival.
  Cancer Causes and Control 01/2013; · 2.88 Impact Factor
• Article: Polymorphisms in genes related to one-carbon metabolism are not related to pancreatic cancer in PanScan and PanC4.

  Max Leenders, Samsiddhi Bhattacharjee, Paolo Vineis, Victoria Stevens, H Bas Bueno-de-Mesquita, Xiao-Ou Shu, Laufey Amundadottir, Myron Gross, Geoffrey S Tobias, Jean Wactawski-Wende, [......], Kari G Rabe, Elio Riboli, Anne Tjønneland, Dimitrios Trichopoulos, Jarmo Virtamo, Kala Visvanathan, Joanne W Elena, Herbert Yu, Anne Zeleniuch-Jacquotte, Rachael Z Stolzenberg-Solomon
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  ABSTRACT: PURPOSE: The evidence of a relation between folate intake and one-carbon metabolism (OCM) with pancreatic cancer (PanCa) is inconsistent. In this study, the association between genes and single-nucleotide polymorphisms (SNPs) related to OCM and PanCa was assessed. METHODS: Using biochemical knowledge of the OCM pathway, we identified thirty-seven genes and 834 SNPs to examine in association with PanCa. Our study included 1,408 cases and 1,463 controls nested within twelve cohorts (PanScan). The ten SNPs and five genes with lowest p values (<0.02) were followed up in 2,323 cases and 2,340 controls from eight case-control studies (PanC4) that participated in PanScan2. The correlation of SNPs with metabolite levels was assessed for 649 controls from the European Prospective Investigation into Cancer and Nutrition. RESULTS: When both stages were combined, we observed suggestive associations with PanCa for rs10887710 (MAT1A) (OR 1.13, 95 %CI 1.04-1.23), rs1552462 (SYT9) (OR 1.27, 95 %CI 1.02-1.59), and rs7074891 (CUBN) (OR 1.91, 95 %CI 1.12-3.26). After correcting for multiple comparisons, no significant associations were observed in either the first or second stage. The three suggested SNPs showed no correlations with one-carbon biomarkers. CONCLUSIONS: This is the largest genetic study to date to examine the relation between germline variations in OCM-related genes polymorphisms and the risk of PanCa. Suggestive evidence for an association between polymorphisms and PanCa was observed among the cohort-nested studies, but this did not replicate in the case-control studies. Our results do not strongly support the hypothesis that genes related to OCM play a role in pancreatic carcinogenesis.
  Cancer Causes and Control 01/2013; · 2.88 Impact Factor
• Article: Molecular pathological epidemiology of epigenetics: emerging integrative science to analyze environment, host, and disease.

  Shuji Ogino, Paul Lochhead, Andrew T Chan, Reiko Nishihara, Eunyoung Cho, Brian M Wolpin, Jeffrey A Meyerhardt, Alexander Meissner, Eva S Schernhammer, Charles S Fuchs, Edward Giovannucci
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  ABSTRACT: Epigenetics acts as an interface between environmental/exogenous factors, cellular responses, and pathological processes. Aberrant epigenetic signatures are a hallmark of complex multifactorial diseases (including neoplasms and malignancies such as leukemias, lymphomas, sarcomas, and breast, lung, prostate, liver, and colorectal cancers). Epigenetic signatures (DNA methylation, mRNA and microRNA expression, etc) may serve as biomarkers for risk stratification, early detection, and disease classification, as well as targets for therapy and chemoprevention. In particular, DNA methylation assays are widely applied to formalin-fixed, paraffin-embedded archival tissue specimens as clinical pathology tests. To better understand the interplay between etiological factors, cellular molecular characteristics, and disease evolution, the field of 'molecular pathological epidemiology (MPE)' has emerged as an interdisciplinary integration of 'molecular pathology' and 'epidemiology'. In contrast to traditional epidemiological research including genome-wide association studies (GWAS), MPE is founded on the unique disease principle, that is, each disease process results from unique profiles of exposomes, epigenomes, transcriptomes, proteomes, metabolomes, microbiomes, and interactomes in relation to the macroenvironment and tissue microenvironment. MPE may represent a logical evolution of GWAS, termed 'GWAS-MPE approach'. Although epigenome-wide association study attracts increasing attention, currently, it has a fundamental problem in that each cell within one individual has a unique, time-varying epigenome. Having a similar conceptual framework to systems biology, the holistic MPE approach enables us to link potential etiological factors to specific molecular pathology, and gain novel pathogenic insights on causality. The widespread application of epigenome (eg, methylome) analyses will enhance our understanding of disease heterogeneity, epigenotypes (CpG island methylator phenotype, LINE-1 (long interspersed nucleotide element-1; also called long interspersed nuclear element-1; long interspersed element-1; L1) hypomethylation, etc), and host-disease interactions. In this article, we illustrate increasing contribution of modern pathology to broader public health sciences, which attests pivotal roles of pathologists in the new integrated MPE science towards our ultimate goal of personalized medicine and prevention.Modern Pathology advance online publication, 11 January 2013; doi:10.1038/modpathol.2012.214.
  Modern Pathology 01/2013; · 4.79 Impact Factor
• Article: Feasibility of Computer-Based Self-Administered Cancer-Specific Geriatric Assessment in Older Patients With Gastrointestinal Malignancy.

  Nadine J McCleary, Devin Wigler, Donna Berry, Kaori Sato, Thomas Abrams, Jennifer Chan, Peter Enzinger, Kimmie Ng, Brian Wolpin, Deborah Schrag, Charles S Fuchs, Arti Hurria, Jeffrey A Meyerhardt
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  ABSTRACT: Background. The Cancer-Specific Geriatric Assessment (CSGA) is a primarily self-administered paper survey of validated measures.Methods. We developed and tested the feasibility of a computer-based CSGA in patients ≥70 years of age who were receiving treatment for gastrointestinal malignancies at the Dana-Farber Cancer Institute. From December 2009 to June 2011, patients were invited to complete the CSGA at baseline (start of new treatment) and follow-up (at the first of 4 months later or within 4 weeks of completing treatment). Feasibility endpoints were proportion of eligible patients consented, proportion completing CSGA at baseline and follow-up, time to complete CSGA, and proportion of physicians reporting CSGA results that led to a change in clinical decision-making.Results. Of the 49 eligible patients, 38 consented (76% were treatment naive). Median age was 77 years (range: 70-89 years), and 48% were diagnosed with colorectal cancer. Mean physician-rated Karnofsky Performance Status was 87.5 at baseline (SD 8.4) and 83.5 at follow-up (SD 8). At baseline, 92% used a touchscreen computer; 97% completed the CSGA (51% independently). At follow-up, all patients used a touchscreen computer; 71% completed the CSGA (41% independently). Mean time to completion was 23 minutes at baseline (SD 8.4) and 20 minutes at follow-up (SD 5.1). The CSGA added information to clinical assessment for 75% at baseline (n = 27) and 65% at follow-up (n = 17), but it did not alter immediate clinical decision-making.Conclusion. The computer-based CSGA feasibility endpoints were met, although approximately half of patients required assistance. The CSGA added information to clinical assessment but did not affect clinical decision-making, possibly due to limited alternate treatment options in this subset of patients.
  The Oncologist 01/2013; · 3.91 Impact Factor
• Article: A Resequence Analysis of Genomic Loci on Chromosomes 1q32.1, 5p15.33, and 13q22.1 Associated With Pancreatic Cancer Risk.

  Hemang Parikh, Jinping Jia, Xijun Zhang, Charles C Chung, Kevin B Jacobs, Meredith Yeager, Joseph Boland, Amy Hutchinson, Laura Burdett, Jason Hoskins, Harvey A Risch, Rachael Z Stolzenberg-Solomon, Stephen J Chanock, Brian M Wolpin, Gloria M Petersen, Charles S Fuchs, Patricia Hartge, Laufey Amundadottir
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  ABSTRACT: OBJECTIVE: The objective of this study was to fine-map common pancreatic cancer susceptibility regions. METHODS: We conducted targeted Roche-454 resequencing across 428 kb in 3 genomic regions identified in genome-wide association studies (GWAS) of pancreatic cancer, on chromosomes 1q32.1, 5p15.33, and 13q22.1. RESULTS: An analytical pipeline for calling genotypes was developed using HapMap samples sequenced on chr5p15.33. Concordance to 1000 Genomes data for chr5p15.33 was greater than 96%. The concordance for chr1q32.1 and chr13q22.1 with pancreatic cancer GWAS data was greater than 99%. Between 9.2% and 19.0% of variants detected were not present in 1000 Genomes for the respective continental population. The majority of completely novel single-nucleotide polymorphisms (SNPs) were less common (minor allele frequency [MAF], ≤5%) or rare (MAF, ≤2%), illustrating the value of enlarging test sets for discovery of less common variants. Using the data set, we examined haplotype blocks across each region using a tag SNP analysis (r > 0.8 for MAF of ≥5%) and determined that at least 196, 243, and 63 SNPs are required for fine-mapping chr1q32.1, chr5p15.33, and chr13q22.1, respectively, in European populations. CONCLUSIONS: We have characterized germline variation in 3 regions associated with pancreatic cancer risk and show that targeted resequencing leads to the discovery of novel variants and improves the completeness of germline sequence variants for fine-mapping GWAS susceptibility loci.
  Pancreas 01/2013; · 2.39 Impact Factor
• Article: Pre-diagnostic leukocyte genomic DNA methylation and the risk of colorectal cancer in women.

  Hongmei Nan, Edward L Giovannucci, Kana Wu, Jacob Selhub, Ligi Paul, Bernard Rosner, Charles S Fuchs, Eunyoung Cho
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  ABSTRACT: Abnormal one-carbon metabolism may lead to general genomic (global) hypomethylation, which may predispose an individual to the development of colorectal neoplasia. We evaluated the association between pre-diagnostic leukocyte genomic DNA methylation level and the risk of colorectal cancer in a nested case-control study of 358 colorectal cancer cases and 661 matched controls within the all-female cohort of the Nurses' Health Study (NHS). Among control subjects, we further examined major plasma components in the one-carbon metabolism pathway in relation to genomic DNA methylation level. Liquid chromatography/tandem mass spectrometry was used to examine leukocyte genomic DNA methylation level. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) using logistic regression. Overall genomic DNA methylation level was not associated with the risk of colorectal cancer (p for trend, 0.45). Compared with women in the lowest quintile of methylation, the multivariate OR of colorectal cancer risk was 1.32 (95% CI, 0.82-2.13) for those in the highest quintile. We did not find significant associations between major plasma components of one-carbon metabolism or risk factors for colorectal cancer and genomic DNA methylation level (all p for trend >0.05). Also, neither one-carbon metabolism-related plasma components nor well-known risk factors for colorectal cancer modified the association between genomic DNA methylation level and the risk of colorectal cancer (all p for interaction >0.05). We found no evidence that hypomethylation of leukocyte genomic DNA increases risk of colorectal cancer among women. Additional studies are needed to investigate the association between pre-diagnostic genomic DNA methylation level and colorectal cancer risk among diverse populations.
  PLoS ONE 01/2013; 8(4):e59455. · 4.09 Impact Factor