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Pancreatic Neoplasms: HELP
Articles by James L. Abbruzzese
Based on 87 articles published since 2009
(Why 87 articles?)
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Between 2009 and 2019, James Abbruzzese wrote the following 87 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Review Clinical Insights Into the Biology and Treatment of Pancreatic Cancer. 2016

Mettu, Niharika B / Abbruzzese, James L. ·Duke University Medical Center, Durham, NC niharika.mettu@duke.edu. · Duke University Medical Center, Durham, NC. ·J Oncol Pract · Pubmed #26759461.

ABSTRACT: Pancreatic cancer is a devastating disease with a universally poor prognosis. In 2015, it is estimated that there will be 48,960 new cases of pancreatic cancer and that 40,560 people will die of the disease. The 5-year survival rate is 7.2% for all patients with pancreatic cancer; however, survival depends greatly on the stage at diagnosis. Unfortunately, 53% of patients already have metastatic disease at diagnosis, which corresponds to a 5-year survival rate of 2.4%. Even for the 9% of patients with localized disease confined to the pancreas, the 5-year survival is still modest at only 27.1%. These grim statistics highlight the need for ways to identify cohorts of individuals at highest risk, methods to screen those at highest risk to identify preinvasive pathologic precursors, and development of effective systemic therapies. Recent clinical and translational progress has emphasized the relationship with diabetes, the role of the stroma, and the interplay of each of these with inflammation in the pathobiology of pancreatic cancer. In this article, we will discuss these relationships and how they might translate into novel management strategies for the treatment of this disease.

2 Review Consensus report of the national cancer institute clinical trials planning meeting on pancreas cancer treatment. 2009

Philip, Philip A / Mooney, Margaret / Jaffe, Deborah / Eckhardt, Gail / Moore, Malcolm / Meropol, Neal / Emens, Leisha / O'Reilly, Eileen / Korc, Murray / Ellis, Lee / Benedetti, Jacqueline / Rothenberg, Mace / Willett, Christopher / Tempero, Margaret / Lowy, Andrew / Abbruzzese, James / Simeone, Diane / Hingorani, Sunil / Berlin, Jordan / Tepper, Joel. ·Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA. philipp@karmanos.org ·J Clin Oncol · Pubmed #19858397.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality, despite significant improvements in diagnostic imaging and operative mortality rates. The 5-year survival rate remains less than 5% because of microscopic or gross metastatic disease at time of diagnosis. The Clinical Trials Planning Meeting in pancreatic cancer was convened by the National Cancer Institute's Gastrointestinal Cancer Steering Committee to discuss the integration of basic and clinical knowledge in the design of clinical trials in PDAC. Major emphasis was placed on the enhancement of research to identify and validate the relevant targets and molecular pathways in PDAC, cancer stem cells, and the microenvironment. Emphasis was also placed on developing rational combinations of targeted agents and the development of predictive biomarkers to assist selection of patient subsets. The development of preclinical tumor models that are better predictive of human PDAC must be supported with wider availability to the research community. Phase III clinical trials should be implemented only if there is a meaningful clinical signal of efficacy and safety in the phase II setting. The emphasis must therefore be on performing well-designed phase II studies with uniform sets of basic entry and evaluation criteria with survival as a primary endpoint. Patients with either metastatic or locally advanced PDAC must be studied separately.

3 Clinical Trial An Intergroup Randomized Phase II Study of Bevacizumab or Cetuximab in Combination with Gemcitabine and in Combination with Chemoradiation in Patients with Resected Pancreatic Carcinoma: A Trial of the ECOG-ACRIN Cancer Research Group (E2204). 2018

Berlin, Jordan D / Feng, Yang / Catalano, Paul / Abbruzzese, James L / Philip, Philip A / McWilliams, Robert R / Lowy, Andrew M / Benson, Al B / Blackstock, A William. ·Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. ·Oncology · Pubmed #29040974.

ABSTRACT: OBJECTIVES: Evaluate toxicity of two treatment arms, A (cetuximab) and B (bevacizumab), when combined with gemcitabine, and chemoradiation in patients with completely resected pancreatic carcinoma. Secondary objectives included overall survival (OS) and disease-free survival (DFS). METHODS: Patients with R0/R1 resection were randomized 1:1 to cetuximab or bevacizumab administered in combination with gemcitabine for two treatment cycles. Next three cycles included concurrent cetuximab/bevacizumab plus chemoradiation, followed by one cycle of cetuximab/bevacizumab. Cycles 7-12 included cetuximab/bevacizumab with gemcitabine. Cycles were 2 weeks. Frequency of specific toxicities was summarized for each treatment arm at two times during the study, after chemotherapy but prior to chemoradiation and after all therapy. RESULTS: A total of 127 patients were randomized (A, n = 65; B, n = 62). Prior to chemoradiation, the overall rate for toxicities of interest was 10% for arm A and 2% for arm B. After all therapy, the overall rates for toxicities of interest were 30 and 25% for arms A and B, respectively. Overall median OS and DFS were 17 and 11 months, respectively, which is not a significant improvement over expected survival rates for historical controls. CONCLUSIONS: Both treatments were tolerable with manageable toxicities, and were safe enough for a phase III trial had this been indicated.

4 Clinical Trial RECQ1 A159C Polymorphism Is Associated With Overall Survival of Patients With Resected Pancreatic Cancer: A Replication Study in NRG Oncology Radiation Therapy Oncology Group 9704. 2016

Li, Donghui / Moughan, Jennifer / Crane, Christopher / Hoffman, John P / Regine, William F / Abrams, Ross A / Safran, Howard / Liu, Chang / Chang, Ping / Freedman, Gary M / Winter, Kathryn A / Guha, Chandan / Abbruzzese, James L. ·Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: dli@mdanderson.org. · NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania. · Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania. · Department of Radiation Oncology, University of Maryland, Baltimore, Maryland. · Rush University Medical Center, Chicago, Illinois. · Brown University Oncology Group, Providence, Rhode Island. · Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania. · Department of Radiation Oncology, Montefiore Medical Center, Bronx, New York. · Duke University Medical Center, Durham, North Carolina. ·Int J Radiat Oncol Biol Phys · Pubmed #26725729.

ABSTRACT: PURPOSE: To confirm whether a previously observed association between RECQ1 A159C variant and clinical outcome of resectable pancreatic cancer patients treated with preoperative chemoradiation is reproducible in another patient population prospectively treated with postoperative chemoradiation. METHODS AND MATERIALS: Patients were selected, according to tissue availability, from eligible patients with resected pancreatic cancer who were enrolled on the NRG Oncology Radiation Therapy Oncology Group 9704 trial of 5-fluorouacil (5-FU)-based chemoradiation preceded and followed by 5-FU or gemcitabine. Deoxyribonucleic acid was extracted from paraffin-embedded tissue sections, and genotype was determined using the Taqman method. The correlation between genotype and overall survival was analyzed using a Kaplan-Meier plot, log-rank test, and multivariate Cox proportional hazards models. RESULTS: In the 154 of the study's 451 eligible patients with evaluable tissue, genotype distribution followed Hardy-Weinberg equilibrium (ie, 37% had genotype AA, 43% AC, and 20% CC). The RECQ1 variant AC/CC genotype carriers were associated with being node positive compared with the AA carrier (P=.03). The median survival times (95% confidence interval [CI]) for AA, AC, and CC carriers were 20.6 (16.3-26.1), 18.8 (14.2-21.6), and 14.2 (10.3-21.0) months, respectively. On multivariate analysis, patients with the AC/CC genotypes were associated with worse survival than patients with the AA genotype (hazard ratio [HR] 1.54, 95% CI 1.07-2.23, P=.022). This result seemed slightly stronger for patients on the 5-FU arm (n=82) (HR 1.64, 95% CI 0.99-2.70, P=.055) than for patients on the gemcitabine arm (n=72, HR 1.46, 95% CI 0.81-2.63, P=.21). CONCLUSIONS: Results of this study suggest that the RECQ1 A159C genotype may be a prognostic or predictive factor for resectable pancreatic cancer patients who are treated with adjuvant 5-FU before and after 5-FU-based chemoradiation. Further study is needed in patients treated with gemcitabine to determine whether an association exists.

5 Clinical Trial Transport properties of pancreatic cancer describe gemcitabine delivery and response. 2014

Koay, Eugene J / Truty, Mark J / Cristini, Vittorio / Thomas, Ryan M / Chen, Rong / Chatterjee, Deyali / Kang, Ya'an / Bhosale, Priya R / Tamm, Eric P / Crane, Christopher H / Javle, Milind / Katz, Matthew H / Gottumukkala, Vijaya N / Rozner, Marc A / Shen, Haifa / Lee, Jeffery E / Wang, Huamin / Chen, Yuling / Plunkett, William / Abbruzzese, James L / Wolff, Robert A / Varadhachary, Gauri R / Ferrari, Mauro / Fleming, Jason B. · ·J Clin Invest · Pubmed #24614108.

ABSTRACT: BACKGROUND: The therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC) is partly ascribed to ineffective delivery of chemotherapy to cancer cells. We hypothesized that physical properties at vascular, extracellular, and cellular scales influence delivery of and response to gemcitabine-based therapy. METHODS: We developed a method to measure mass transport properties during routine contrast-enhanced CT scans of individual human PDAC tumors. Additionally, we evaluated gemcitabine infusion during PDAC resection in 12 patients, measuring gemcitabine incorporation into tumor DNA and correlating its uptake with human equilibrative nucleoside transporter (hENT1) levels, stromal reaction, and CT-derived mass transport properties. We also studied associations between CT-derived transport properties and clinical outcomes in patients who received preoperative gemcitabine-based chemoradiotherapy for resectable PDAC. RESULTS: Transport modeling of 176 CT scans illustrated striking differences in transport properties between normal pancreas and tumor, with a wide array of enhancement profiles. Reflecting the interpatient differences in contrast enhancement, resected tumors exhibited dramatic differences in gemcitabine DNA incorporation, despite similar intravascular pharmacokinetics. Gemcitabine incorporation into tumor DNA was inversely related to CT-derived transport parameters and PDAC stromal score, after accounting for hENT1 levels. Moreover, stromal score directly correlated with CT-derived parameters. Among 110 patients who received preoperative gemcitabine-based chemoradiotherapy, CT-derived parameters correlated with pathological response and survival. CONCLUSION: Gemcitabine incorporation into tumor DNA is highly variable and correlates with multiscale transport properties that can be derived from routine CT scans. Furthermore, pretherapy CT-derived properties correlate with clinically relevant endpoints. TRIAL REGISTRATION: Clinicaltrials.gov NCT01276613. FUNDING: Lustgarten Foundation (989161), Department of Defense (W81XWH-09-1-0212), NIH (U54CA151668, KCA088084).

6 Clinical Trial Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4(Dpc4) immunostaining with pattern of disease progression. 2011

Crane, Christopher H / Varadhachary, Gauri R / Yordy, John S / Staerkel, Gregg A / Javle, Milind M / Safran, Howard / Haque, Waqar / Hobbs, Bridgett D / Krishnan, Sunil / Fleming, Jason B / Das, Prajnan / Lee, Jeffrey E / Abbruzzese, James L / Wolff, Robert A. ·Dept of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX. ccrane@mdanderson.org ·J Clin Oncol · Pubmed #21709185.

ABSTRACT: PURPOSE: This phase II trial was designed to assess the efficacy and safety of cetuximab, gemcitabine, and oxaliplatin followed by cetuximab, capecitabine, and radiation therapy in locally advanced pancreatic cancer (LAPC). PATIENTS AND METHODS: Treatment-naive eligible patients (n = 69) received intravenous gemcitabine (1,000 mg/m(2)) and oxaliplatin (100 mg/m(2)) every 2 weeks for four doses, followed by radiation (50.4 Gy to the gross tumor only) with concurrent capecitabine (825 mg/m(2) twice daily on radiation treatment days). Cetuximab (500 mg/m(2)) was started on day 1 of chemotherapy and was continued every 2 weeks during chemotherapy and chemoradiotherapy. Diagnostic cytology specimens were immunostained for Smad4(Dpc4) expression. RESULTS: Median overall survival time was 19.2 months (95% CI, 14.2 to 24.2 months), and 1-year, 2-year, and 4-year actuarial overall survival rates were 66.0%, 25.02%, and 11.3%, respectively. Acneiform rash correlated with improved survival (P = .001), but initial CA19-9, borderline resectable initial stage, and surgical resection (n = 7) did not. The 1-year and 2-year radiographic local progression rates were 22.8% and 61.0%, respectively. The worst acute toxic effects were GI toxicity (32% and 10% for grades 2 and 3, respectively); fatigue (26% and 6% for grades 2 and 3, respectively); sensory neuropathy (9% and 1% for grades 2 and 3, respectively); and acneiform rash (54% and 3% for grades 2 and 3, respectively). Smad4(Dpc4) expression correlated with a local rather than a distant dominant pattern of disease progression (P = .016). CONCLUSION: This regimen appears effective and has acceptable toxicity. The primary end point (1-year overall survival rate > 45%) was met, with encouraging survival duration. Smad4(Dpc4) immunostaining correlated with the pattern of disease progression. Prospective validation of Smad4(Dpc4) expression in cytology specimens as a predictive biomarker is warranted and may lead to personalized treatment strategies for patients with localized pancreatic cancer.

7 Clinical Trial Bevacizumab plus gemcitabine and oxaliplatin as first-line therapy for metastatic or locally advanced pancreatic cancer: a phase II trial. 2011

Fogelman, David / Jafari, Mehrdad / Varadhachary, Gauri R / Xiong, Henry / Bullock, Susie / Ozer, Harold / Lin, E / Morris, Jeffrey / Cunningham, Patti / Bennett, Bronwyn / Abbruzzese, James L / Wolff, Robert A. ·MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 426, Houston, TX 77030, USA. dfogelman@mdanderson.org ·Cancer Chemother Pharmacol · Pubmed #21479635.

ABSTRACT: PURPOSE: The gemcitabine and oxaliplatin (GEMOX) has yielded among the longest progression-free survival durations in patients with advanced pancreatic cancer (APC). We postulated that adding bevacizumab would increase the effectiveness of GEMOX. METHODS: Eligible patients had stage III or IV pancreatic cancer, ECOG PS 0-2, and no prior gemcitabine. Treatment included 1,000 mg/m(2) intravenous gemcitabine over 100 min on day 1, 10 mg/kg intravenous bevacizumab on day 1, and 100 mg/m(2) oxaliplatin given on day 2. Cycles were repeated every 2 weeks. CT imaging was performed every 6 weeks. RESULTS: Fifty patients were enrolled: 14 had stage III disease, the remainder stage IV. Median age was 59 years. Fourty-five patients were ECOG 0-1. The grade 3-4 toxicity rate was 94%; fatigue (47%) and nausea (40%) were frequent. One patient died after a bowel perforation; a second died of a CVA. The median PFS was 4.9 months; median survival was 11.9 months; 1 year survival was 42%. Locally advanced patients lived 12.8 months; metastatic patients lived 10.2 months. Patients developing grade 3 hypertension were more likely to have a radiologic response (P = .012); survival among the top and bottom quintiles of hypertension was 14.7 and 6.2 months, respectively. Survival correlated with baseline CA 19-9 (P = .004) and radiologic response. The overall response rate was 36%; 34% demonstrated stable disease. CONCLUSIONS: The GEMOX/bevacizumab regimen demonstrated an excellent median overall survival but did not meet our objective of a 14 month median survival. Toxicity was significant. We do not recommend further evaluation of this regimen.

8 Clinical Trial A randomized phase II study of PX-12, an inhibitor of thioredoxin in patients with advanced cancer of the pancreas following progression after a gemcitabine-containing combination. 2011

Ramanathan, Ramesh K / Abbruzzese, James / Dragovich, Tomislav / Kirkpatrick, Lynn / Guillen, Jose M / Baker, Amanda F / Pestano, Linda A / Green, Sylvan / Von Hoff, Daniel D. ·Virgina G Piper Cancer Center, TGen, Scottsdale, AZ, 85259, USA. rramanathan@tgen.org ·Cancer Chemother Pharmacol · Pubmed #20461382.

ABSTRACT: PURPOSE: This study evaluated PX-12, a novel small molecule inhibitor of the proto-oncogene (Trx-1), in patients with previously treated advanced pancreatic cancer (APC). METHODS: PX-12 (54 or 128 mg/m²) was administered by 3-hour IV infusion daily × 5 days every 21 days (n = 17). Patients were randomized to either 54 or 128 mg/m² and then stratified based on CA 19-9 level (≥ 1,000 vs. < 1,000 U/ml) and SUV values on PET scans (≥ 7.0 vs. <7.0). The primary endpoint was based on a progression-free survival (PFS) at 4 months in ≥ 40% of patients, and required 40 patients in each arm. An amendment required elevated Trx-1 levels (> 18 ng/ml) as an entry criteria after the first 17 patients were accrued. RESULTS: Plasma Trx-1 levels were elevated in 3/28 (11%) patients screened for study. The grade of the expired metabolite odor was higher in the 128 mg/m² arm. Therapy was well tolerated, and Grade ≥ 3 adverse events were uncommon. The best response was stable disease in 2 patients. There was no consistent decrease in SUV, Trx-1 levels or CA 19-9 levels with therapy. No patients had a PFS of >4 months. Median PFS and survival were 0.9 months (95% CI 0.5-1.2) and 3.2 months (95% CI 2.4-4.2), respectively. CONCLUSIONS: Due to the lack of significant antitumor activity and unexpectedly low baseline Trx-1 levels, the study was terminated early. PX-12 does not appear to be active in unselected patients with previously treated APC.

9 Clinical Trial A phase II study of isoflavones, erlotinib, and gemcitabine in advanced pancreatic cancer. 2011

El-Rayes, Bassel Fuad / Philip, Philip A / Sarkar, Fazlul H / Shields, Anthony F / Ferris, Ann Marie / Hess, Kenneth / Kaseb, Ahmad O / Javle, Milind M / Varadhachary, Gauri R / Wolff, Robert A / Abbruzzese, James L. ·Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA. belraye@emory.edu ·Invest New Drugs · Pubmed #20107864.

ABSTRACT: BACKGROUND: The EGFR/Akt/NF-κB signalling pathway is frequently deregulated in pancreatic cancer and contributes to cell growth, metastasis and chemoresistance. An isoflavone, genistein, inactivates Akt and NF-κB and enhances the anti-tumor activity of erlotinib and gemcitabine in experimental systems of pancreas cancer. This phase II study was undertaken to determine the effects of adding isoflavone to a regimen of gemcitabine and erlotinib on survival in patients with advanced pancreatic cancer. METHODS: Eligibility included previously untreated patients with advanced pancreatic adenocarcinoma. Patients received gemcitabine 1,000 mg/m² on days 1, 8, and 15, and erlotinib 150 mg once daily P.O. on day 1 to day 28. Soy isoflavones (Novasoy®) were administered at a dose of 531 mg twice daily P.O. starting day -7 until the end of study participation. RESULTS: Twenty patients with advanced pancreas cancer were enrolled (median age 57.9 years). Sixteen patients had stage IV disease. The median number of cycles was 2 per patient. The median survival time was 5.2 months (95% CI, 4.6-N/A months). The probability of survival at 6 months was 50% (95% CI, 32-78%). CONCLUSIONS: The addition of soy isoflavones to gemcitabine and erlotinib did not appear to increase the survival of patients with advanced pancreatic cancer.

10 Clinical Trial Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies. 2010

Javle, Milind M / Shroff, Rachna T / Xiong, Henry / Varadhachary, Gauri A / Fogelman, David / Reddy, Shrikanth A / Davis, Darren / Zhang, Yujian / Wolff, Robert A / Abbruzzese, James L. ·Department of Gastrointestinal Medical Oncology, UT-M D Anderson Cancer Center, Houston, TX, USA. mjavle@mdanderson.org ·BMC Cancer · Pubmed #20630061.

ABSTRACT: BACKGROUND: The phosphoinositide 3-kinase (PI3K)/Akt pathway is constitutively activated in pancreatic cancer and the mammalian target of rapamycin (mTOR) kinase is an important mediator for its signaling. Our recent in vitro studies suggest that prolonged exposure of pancreatic cancer cells to mTOR inhibitors can promote insulin receptor substrate-PI3K interactions and paradoxically increase Akt phosphorylation and cyclin D1 expression in pancreatic cancer cells (negative feedback loop). The addition of erlotinib to rapamycin can down-regulate rapamycin-stimulated Akt and results in synergistic antitumor activity with erlotinib in preclinical tumor models. METHODS: Two studies prospectively enrolled adult patients with advanced pancreatic cancer, Eastern Cooperative Oncology Group performance status 0-1, adequate hematologic, hepatic and renal parameters and measurable disease. In Study A, temsirolimus was administered intravenously at 25 mg weekly. In Study B, everolimus was administered orally at 30 mg weekly and erlotinib was administered at 150 mg daily. The primary endpoint in both studies was overall survival at 6 months. Secondary endpoints included time to progression, progression-free survival, overall survival, response rate, safety and toxicity. Pretreatment tumor biopsies were analyzed by immunofluorescence and laser scanning cytometry for the expression of pmTOR/mTOR, pAkt/Akt, pErk/Erk, pS6, p4EBP-1 and PTEN. RESULTS: Five patients enrolled in Study A; Two patients died within a month (rapid disease progression and hemorrhagic stroke, respectively). One patient developed dehydration and another developed asthenia. Sixteen patients enrolled in Study B.: 12 males, all ECOG PS = 1. Median cycles = 1 (range 1-2). Grade 4 toxicity: hyponatremia (n = 1), Grade 3: diarrhea (n = 1), cholangitis (n = 3), hyperglycemia (n = 1), fatigue (n = 1). Grade 2: pneumonia (n = 2), dehydration (n = 2), nausea (n = 2), neutropenia (n = 1), mucositis (n = 2) & rash (n = 2). Four patients were hospitalized. Progressive disease occurred in 15 and 1 was non-evaluable. Pretreatment biopsies revealed a higher pAkt/Akt ratio in tumor specimens that in nonmalignant pancreatic tissue. No such trends were noted for the other biomarkers. CONCLUSIONS: Neither study with mTOR inhibitors demonstrated objective responses or disease stability. The negative feedback loop resulting from mTOR inhibition may account for the disease progression and toxicity noted in these studies. Future strategies should aim for a broader targeting of the PI3K pathway in pancreatic cancer. STUDY A: NCT 0075647. STUDY B: NCT00640978.

11 Clinical Trial Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. 2010

Philip, Philip A / Benedetti, Jacqueline / Corless, Christopher L / Wong, Ralph / O'Reilly, Eileen M / Flynn, Patrick J / Rowland, Kendrith M / Atkins, James N / Mirtsching, Barry C / Rivkin, Saul E / Khorana, Alok A / Goldman, Bryan / Fenoglio-Preiser, Cecilia M / Abbruzzese, James L / Blanke, Charles D. ·Wayne State University, Karmanos Cancer Institute, GI Oncology, Detroit, MI 48201, USA. philipp@karmanos.org ·J Clin Oncol · Pubmed #20606093.

ABSTRACT: PURPOSE: Patients with advanced pancreas cancer present with disease that is poorly responsive to conventional therapies. Preclinical and early clinical evidence has supported targeting the epidermal growth factor receptor (EGFR) signaling pathway in patients with pancreas cancer. This trial was conducted to evaluate the contribution of an EGFR-targeted agent to standard gemcitabine therapy. Cetuximab is a monoclonal antibody against the ligand-binding domain of the receptor. PATIENTS AND METHODS: Patients with unresectable locally advanced or metastatic pancreatic adenocarcinoma were randomly assigned to receive gemcitabine alone or gemcitabine plus cetuximab. The primary end point was overall survival. Secondary end points included progression-free survival, time to treatment failure, objective response, and toxicity. RESULTS: A total of 745 eligible patients were accrued. No significant difference was seen between the two arms of the study with respect to the median survival time (6.3 months for the gemcitabine plus cetuximab arm v 5.9 months for the gemcitabine alone arm; hazard ratio = 1.06; 95% CI, 0.91 to 1.23; P = .23, one-sided). Objective responses and progression-free survival were similar in both arms of the study. Although time to treatment failure was longer in patients on gemcitabine plus cetuximab (P = .006), the difference in length of treatment was only 2 weeks longer in the combination arm. Among patients who were studied for tumoral EGFR expression, 90% were positive, with no treatment benefit detected in this patient subset. CONCLUSION: In patients with advanced pancreas cancer, the anti-EGFR monoclonal antibody cetuximab did not improve the outcome compared with patients treated with gemcitabine alone. Alternate targets other than EGFR should be evaluated for new drug development.

12 Article Three novel genetic variants in NRF2 signaling pathway genes are associated with pancreatic cancer risk. 2019

Yang, Wenjun / Liu, Hongliang / Duan, Bensong / Xu, Xinyuan / Carmody, Dennis / Luo, Sheng / Walsh, Kyle M / Abbruzzese, James L / Zhang, Xuefeng / Chen, Xiaoxin / Wei, Qingyi. ·Key Laboratory of Fertility Preservation and Maintenance, School of Basic Medicine and the General Hospital, Ningxia Medical University, Yinchuan, China. · Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham. · Duke Cancer Institute, Duke University Medical Center, Durham. · Department of Population Health Sciences, Duke University School of Medicine, Durham. · Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham. · Department of Neurosurgery, Duke University School of Medicine, Durham. · Department of Medicine, Population Health Sciences, Duke University School of Medicine, Durham. · Department of Pathology, Duke University School of Medicine, Durham. ·Cancer Sci · Pubmed #30972876.

ABSTRACT: Pancreatic cancer (PanC) is one of the most lethal solid malignancies, and metastatic PanC is often present at the time of diagnosis. Although several high- and low-penetrance genes have been implicated in PanC, their roles in carcinogenesis remain only partially elucidated. Because the nuclear factor erythroid2-related factor2 (NRF2) signaling pathway is involved in human cancers, we hypothesize that genetic variants in NRF2 pathway genes are associated with PanC risk. To test this hypothesis, we assessed associations between 31 583 common single nucleotide polymorphisms (SNP) in 164 NRF2-related genes and PanC risk using three published genome-wide association study (GWAS) datasets, which included 8474 cases and 6944 controls of European descent. We also carried out expression quantitative trait loci (eQTL) analysis to assess the genotype-phenotype correlation of the identified significant SNP using publicly available data in the 1000 Genomes Project. We found that three novel SNP (ie, rs3124761, rs17458086 and rs1630747) were significantly associated with PanC risk (P = 5.17 × 10

13 Article Obesogenic high-fat diet heightens aerobic glycolysis through hyperactivation of oncogenic KRAS. 2019

Wang, Dan / Bi, Yawei / Hu, Lianghao / Luo, Yongde / Ji, Juntao / Mao, Albert Z / Logsdon, Craig D / Li, Ellen / Abbruzzese, James L / Li, Zhaoshen / Yang, Vincent W / Lu, Weiqin. ·Division of Gastroenterology and Hepatology, Department of Medicine, Stony Brook of University School of Medicine, Stony Brook, New York, 11794, USA. · Department of Gastroenterology, Changhai Hospital, Shanghai, China. · School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China. · Centeer BioTherapeutics Ltd Co, Houston, TX, USA. · Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina, USA. · Division of Gastroenterology and Hepatology, Department of Medicine, Stony Brook of University School of Medicine, Stony Brook, New York, 11794, USA. weiqin.lu@stonybrookmedicine.edu. ·Cell Commun Signal · Pubmed #30819189.

ABSTRACT: Oncogenic KRAS plays a vital role in controlling tumor metabolism by enhancing aerobic glycolysis. Obesity driven by chronic consumption of high-fat diet (HFD) is a major risk factor for oncogenic KRAS-mediated pancreatic ductal adenocarcinoma (PDAC). However, the role of HFD in KRAS-mediated metabolic reprogramming has been obscure. Here, by using genetically engineered mouse models expressing an endogenous level of KRAS

14 Article Measurement of Reactive Oxygen Species by Fluorescent Probes in Pancreatic Cancer Cells. 2019

Luo, Yongde / Wang, Dan / Abbruzzese, James L / Lu, Weiqin. ·Center for Cancer and Metabolism Research, Institute for Life Science, Wenzhou University, Zhejiang, China. yluo99@centeerbiotherapeutics.com. · School of Pharmaceutical Science, Wenzhou Medical University, Zhejiang, China. yluo99@centeerbiotherapeutics.com. · Proteomics and Nanotechnology Laboratory, Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, USA. yluo99@centeerbiotherapeutics.com. · Center BioTherapeutics Ltd. Co., Houston, TX, USA. yluo99@centeerbiotherapeutics.com. · Division of Gastroenterology and Hepatology, Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY, USA. · Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, NC, USA. · Division of Gastroenterology and Hepatology, Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY, USA. Weiqin.Lu@stonybrookmedicine.edu. ·Methods Mol Biol · Pubmed #30378057.

ABSTRACT: Pancreatic cancer is a highly lethal disease and is projected to become the second leading cause of cancer-related death by 2020. Among the different subtypes, pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. The genetic landscape of PDAC shows nearly ubiquitous mutations of KRAS. However, expression of KRAS somatic mutants alone is insufficient to drive PDAC. Redox deregulation may contribute significantly to KRAS-mediated PDAC. Thus, measurement of cellular reactive oxygen species (ROS) levels is essential to determine how oxidative stress affects mutant KRAS and modulates intracellular signaling pathways leading to the change of cellular functions and the development of PDAC. Here we describe the protocol for comparative measurement of several key forms of ROS, including intracellular and mitochondrial levels of superoxide as well as extracellular H

15 Article Genetic variants in the platelet-derived growth factor subunit B gene associated with pancreatic cancer risk. 2018

Duan, Bensong / Hu, Jiangfeng / Liu, Hongliang / Wang, Yanru / Li, Hongyu / Liu, Shun / Xie, Jichun / Owzar, Kouros / Abbruzzese, James / Hurwitz, Herbert / Gao, Hengjun / Wei, Qingyi. ·Department of Gastroenterology, Institute of Digestive Diseases, Tongji Hospital, Tongji University School of Medicine, Shanghai, China. · Duke Cancer Institute, Duke University Medical Center, Durham, NC. · Department of Medicine, Duke University School of Medicine, Durham, NC. · Department of Gastroenterology, Shenyang Northern Hospital, Shenyang, Liaoning, China. · Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China. · Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC. · National Engineering Center for Biochip at Shanghai, Shanghai, China. · Department of Population Health Sciences, Duke University School of Medicine, Durham, NC. ·Int J Cancer · Pubmed #29168174.

ABSTRACT: The platelet-derived growth factor (PDGF) signaling pathway plays important roles in development and progression of human cancers. In our study, we aimed to identify genetic variants of the PDGF pathway genes associated with pancreatic cancer (PC) risk in European populations using three published genome-wide association study datasets, which consisted of 9,381 cases and 7,719 controls. The expression quantitative trait loci (eQTL) analysis was also performed using data from the 1000 Genomes, TCGA and GTEx projects. As a result, we identified two potential susceptibility loci (rs5757573 and rs6001516) of PDGFB associated with PC risk [odds ratio (OR) = 1.10, 95% confidence interval (CI) = 1.05-1.16, and p = 4.70 × 10

16 Article Diabetes, Pancreatogenic Diabetes, and Pancreatic Cancer. 2017

Andersen, Dana K / Korc, Murray / Petersen, Gloria M / Eibl, Guido / Li, Donghui / Rickels, Michael R / Chari, Suresh T / Abbruzzese, James L. ·Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD. · Division of Endocrinology, Department of Medicine, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, and Indiana University Melvin and Bren Simon Cancer Center and Pancreatic Cancer Signature Center, Indianapolis, IN. · Department of Health Sciences Research, Mayo Clinic, Rochester, MN. · Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA. · Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX. · Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. · Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN. · Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC james.abbruzzese@duke.edu. ·Diabetes · Pubmed #28507210.

ABSTRACT: The relationships between diabetes and pancreatic ductal adenocarcinoma (PDAC) are complex. Longstanding type 2 diabetes (T2DM) is a risk factor for pancreatic cancer, but increasing epidemiological data point to PDAC as also a cause of diabetes due to unknown mechanisms. New-onset diabetes is of particular interest to the oncology community as the differentiation of new-onset diabetes caused by PDAC as distinct from T2DM may allow for earlier diagnosis of PDAC. To address these relationships and raise awareness of the relationships between PDAC and diabetes, a symposium entitled Diabetes, Pancreatogenic Diabetes, and Pancreatic Cancer was held at the American Diabetes Association's 76th Scientific Sessions in June 2016. This article summarizes the data presented at that symposium, describing the current understanding of the interrelationships between diabetes, diabetes management, and pancreatic cancer, and identifies areas where additional research is needed.

17 Article Sequential Validation of Blood-Based Protein Biomarker Candidates for Early-Stage Pancreatic Cancer. 2017

Capello, Michela / Bantis, Leonidas E / Scelo, Ghislaine / Zhao, Yang / Li, Peng / Dhillon, Dilsher S / Patel, Nikul J / Kundnani, Deepali L / Wang, Hong / Abbruzzese, James L / Maitra, Anirban / Tempero, Margaret A / Brand, Randall / Firpo, Matthew A / Mulvihill, Sean J / Katz, Matthew H / Brennan, Paul / Feng, Ziding / Taguchi, Ayumu / Hanash, Samir M. ·Departments of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · International Agency for Research on Cancer (IARC) Lyon, France. · Division of Medical Oncology, Duke University, Durham, NC, USA. · Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Pancreas Center, University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA · Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA. · Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. ·J Natl Cancer Inst · Pubmed #28376157.

ABSTRACT: Background: CA19-9, which is currently in clinical use as a pancreatic ductal adenocarcinoma (PDAC) biomarker, has limited performance in detecting early-stage disease. We and others have identified protein biomarker candidates that have the potential to complement CA19-9. We have carried out sequential validations starting with 17 protein biomarker candidates to determine which markers and marker combination would improve detection of early-stage disease compared with CA19-9 alone. Methods: Candidate biomarkers were subjected to enzyme-linked immunosorbent assay based sequential validation using independent multiple sample cohorts consisting of PDAC cases (n = 187), benign pancreatic disease (n = 93), and healthy controls (n = 169). A biomarker panel for early-stage PDAC was developed based on a logistic regression model. All statistical tests for the results presented below were one-sided. Results: Six out of the 17 biomarker candidates and CA19-9 were validated in a sample set consisting of 75 PDAC patients, 27 healthy subjects, and 19 chronic pancreatitis patients. A second independent set of 73 early-stage PDAC patients, 60 healthy subjects, and 74 benign pancreatic disease patients (combined validation set) yielded a model that consisted of TIMP1, LRG1, and CA19-9. Additional blinded testing of the model was done using an independent set of plasma samples from 39 resectable PDAC patients and 82 matched healthy subjects (test set). The model yielded areas under the curve (AUCs) of 0.949 (95% confidence interval [CI] = 0.917 to 0.981) and 0.887 (95% CI = 0.817 to 0.957) with sensitivities of 0.849 and 0.667 at 95% specificity in discriminating early-stage PDAC vs healthy subjects in the combined validation and test sets, respectively. The performance of the biomarker panel was statistically significantly improved compared with CA19-9 alone (P < .001, combined validation set; P = .008, test set). Conclusion: The addition of TIMP1 and LRG1 immunoassays to CA19-9 statistically significantly improves the detection of early-stage PDAC.

18 Article Preoperative Therapy and Pancreatoduodenectomy for Pancreatic Ductal Adenocarcinoma: a 25-Year Single-Institution Experience. 2017

Cloyd, Jordan M / Katz, Matthew H G / Prakash, Laura / Varadhachary, Gauri R / Wolff, Robert A / Shroff, Rachna T / Javle, Milind / Fogelman, David / Overman, Michael / Crane, Christopher H / Koay, Eugene J / Das, Prajnan / Krishnan, Sunil / Minsky, Bruce D / Lee, Jeffrey H / Bhutani, Manoop S / Weston, Brian / Ross, William / Bhosale, Priya / Tamm, Eric P / Wang, Huamin / Maitra, Anirban / Kim, Michael P / Aloia, Thomas A / Vauthey, Jean-Nicholas / Fleming, Jason B / Abbruzzese, James L / Pisters, Peter W T / Evans, Douglas B / Lee, Jeffrey E. ·Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1484, Houston, TX, 77030, USA. · Department of Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Gasteroenterology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Diagnostic Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC, USA. · University Health Network, Toronto, ON, Canada. · Division of Surgical Oncology, Department of Surgery, The Medical College of Wisconsin, Milwaukee, WI, USA. · Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1484, Houston, TX, 77030, USA. jelee@mdanderson.org. ·J Gastrointest Surg · Pubmed #27778257.

ABSTRACT: BACKGROUND: The purpose of this study was to evaluate a single-institution experience with delivery of preoperative therapy to patients with pancreatic ductal adenocarcinoma (PDAC) prior to pancreatoduodenectomy (PD). METHODS: Consecutive patients (622) with PDAC who underwent PD following chemotherapy and/or chemoradiation between 1990 and 2014 were retrospectively reviewed. Preoperative treatment regimens, clinicopathologic characteristics, operative details, and long-term outcomes in four successive time periods (1990-1999, 2000-2004, 2005-2009, 2010-2014) were evaluated and compared. RESULTS: The average number of patients per year who underwent PD following preoperative therapy as well as the proportion of operations performed for borderline resectable and locally advanced (BR/LA) tumors increased over time. The use of induction systemic chemotherapy, as well as postoperative adjuvant chemotherapy, also increased over time. Throughout the study period, the mean EBL decreased while R0 margin rates and vascular resection rates increased overall. Despite the increase in BR/LA resections, locoregional recurrence (LR) rates remained similar over time, and overall survival (OS) improved significantly (median 24.1, 28.1, 37.3, 43.4 months, respectively, p < 0.0001). CONCLUSIONS: Despite increases in case complexity, relatively low rates of LR have been maintained while significant improvements in OS have been observed. Further improvements in patient outcomes will likely require disruptive advances in systemic therapy.

19 Article The effects of curcumin (diferuloylmethane) on body composition of patients with advanced pancreatic cancer. 2016

Parsons, Henrique A / Baracos, Vickie E / Hong, David S / Abbruzzese, James / Bruera, Eduardo / Kurzrock, Razelle. ·Department of Medicine/Division of Palliative Care, University of Ottawa, Ontario, Canada. · Department of Oncology/Division of Palliative Care Medicine, University of Alberta, Edmonton, Alberta, Canada. · Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. · Department of Medicine/Division of Oncology Duke University School of Medicine, Durham, North Carolina, USA. · Department of Palliative Care and Rehabilitation Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. · Division of Hematology & Oncology and Center for Personalized Cancer Therapy, Moores Cancer Center, University of California San Diego, San Diego, California, USA. ·Oncotarget · Pubmed #26934122.

ABSTRACT: BACKGROUND: Curcumin is a natural product that is often explored by patients with cancer. Weight loss due to fat and muscle depletion is a hallmark of pancreatic cancer and is associated with worse outcomes. Studies of curcumin's effects on muscularity show conflicting results in animal models. METHODS AND RESULTS: Retrospective matched 1:2 case-control study to evaluate the effects of curcumin on body composition (determined by computerized tomography) of 66 patients with advanced pancreatic cancer (22 treated,44 controls). Average age (SEM) was 63(1.8) years, 30/66(45%) women, median number of prior therapies was 2, median (IQR) time from advanced pancreatic cancer diagnosis to baseline image was 7(2-13.5) months (p>0.2, all variables). All patients lost weight (3.3% and 1.3%, treated vs. control, p=0.13). Treated patients lost more muscle (median [IQR] percent change -4.8[-9.1,-0.1] vs. -0.05%[-4.2, 2.6] in controls,p<0.001) and fat (median [IQR] percent change -6.8%[-15,-0.6] vs. -4.0%[-7.6, 1.3] in controls,p=0.04). Subcutaneous fat was more affected in the treated patients. Sarcopenic patients treated with curcumin(n=15) had survival of 169(115-223) days vs. 299(229-369) sarcopenic controls(p=0.024). No survival difference was found amongst non-sarcopenic patients. CONCLUSIONS: Patients with advanced pancreatic cancer treated with curcumin showed significantly greater loss of subcutaneous fat and muscle than matched untreated controls.

20 Article ABO non-O type as a risk factor for thrombosis in patients with pancreatic cancer. 2015

Li, Donghui / Pise, Mayurika N / Overman, Michael J / Liu, Chang / Tang, Hongwei / Vadhan-Raj, Saroj / Abbruzzese, James L. ·Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. ·Cancer Med · Pubmed #26275671.

ABSTRACT: ABO blood type has previously been identified as a risk factor for thrombosis and pancreatic cancer (PC). The aim of the study is to demonstrate the associations between ABO blood type and other clinical factors with the risk of thromboembolism (TE) in patients with PC. We conducted a retrospective study in 670 patients with pathologically confirmed pancreatic adenocarcinoma at the University of Texas MD Anderson Cancer Center. Clinical information was retrieved from medical records. ABO blood type was determined serologically and/or genetically. Logistic regression models, Kaplan-Meier plot, log-rank test, and Cox proportional hazard regression models were employed in data analysis. The incidence of TE was 35.2% in 670 patients who did not have TE prior to cancer diagnosis. Pulmonary embolism (PE) and deep vein thrombosis (DVT) consisted 44.1% of the TE events. Non-O blood type, pancreatic body/tail tumors, previous use of antithrombotic medication, and obesity (body mass index >30 kg/m(2) ) were significant predictors for TE in general. Blood type A and AB, low hemoglobin level (≤ 10 g/dL), obesity, metastatic tumor, and pancreatic body/tail tumors were significant predictors for PE and DVT. Patients with metastatic tumor or pancreatic body/tail tumors had a much higher frequency of early TE events (≤ 3 months after cancer diagnosis); and early TE occurrence was a significant independent predictor for increased risk of death. These observations suggest that ABO non-O blood type is an independent predictor for TE in PC. A better understanding of the risk factors for TE in PC may help to identify patients who are most likely to benefit from prophylactic anticoagulation therapy.

21 Article Family history as a marker of platinum sensitivity in pancreatic adenocarcinoma. 2015

Fogelman, David / Sugar, Elizabeth A / Oliver, George / Shah, Neeraj / Klein, Alison / Alewine, Christine / Wang, Huamin / Javle, Milind / Shroff, Rachna / Wolff, Robert A / Abbruzzese, James L / Laheru, Daniel / Diaz, Luis A. ·Department of G.I. Medical Oncology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 426, Houston, TX 77030, USA. · University of Texas/M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 426, Houston, TX 77096, USA. · Sidney Kimmel Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA. · Departments of Biostatistics and Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA. · Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Room E3537, Baltimore, MD 21205, USA. · 6300 Harry Hines Blvd. Ste 265, Dallas, TX 75235, USA. · Staten Island University Hospital, 475 Seaview Avenue, Staten Island, NY 10305, USA. · Departments of Pathology and Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 1650 Orleans St., Rm G89, Baltimore, MD 21231-1000, USA. · Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, USA. · Johns Hopkins Bloomberg School of Public Health, 1650 Orleans Street, CRB I Room 590, Baltimore, MD 21231, USA. · Department of Medical Oncology, NCI-National Cancer Institute, 10 Center Dr, Bldg 10/12N226, Bethesda, MD 20892, USA. · 1515 Holcombe Blvd., Unit 0085, Houston, TX 77030, USA. · Division of Medical Oncology, Duke University, 10 Searle Drive, 445 Seeley G Mudd Building, Durham, NC 27710, USA. · Swim Across America Laboratory, Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins, 1650 Orleans Street, CRB I Room 590, Baltimore, MD 21231, USA. ·Cancer Chemother Pharmacol · Pubmed #26126726.

ABSTRACT: PURPOSE: Metastatic pancreatic adenocarcinoma is considered a uniformly fatal disease with a median survival of 1 year with modern chemotherapy. While a subset of patients achieve prolonged survival, few of the factors that define this group of patients are known. METHODS: For the determination of overall survival (OS), 549 patients with histologically confirmed metastatic pancreatic adenocarcinoma were evaluated. Emphasis was placed on treatment history and family history of breast, ovarian, and pancreatic cancers. To ensure a uniform metastatic population, patients treated with prior locoregional therapies (i.e., surgery or radiotherapy) were excluded as were patients with a prior history of stage I-III disease. RESULTS: Patients with family history or pedigree history of cancer had superior OS. This was especially true in patients with three or more relatives with either breast, ovarian, or pancreatic cancers [hazard ratio (HR) 0.49, 95 % confidence interval (CI) 0.30-0.80, p = 0.003]. First-line platinum chemotherapy was associated with a poor survival (hazard ratio for death 1.74, 95% CI 1.12-2.71, p = 0.01) for patients without a family history of these cancers but not for those without such a history (p = 0.31). In fact, as the number of relatives with these cancers increased, the OS survival improved for individuals receiving first-line platinum therapy (HR 0.76, 95 % CI 0.65-0.89, p = 0.0004), which was not the case for those receiving other therapies (p = 0.98). CONCLUSIONS: Treatment with platinum chemotherapy in patients with a family history of breast, ovarian, or pancreatic cancers was associated with a longer survival, whereas platinum use in patients without such a family history of cancer was associated with poor survival. These findings suggest that family history may serve as a predictive marker for platinum use in patients with metastatic pancreatic adenocarcinoma.

22 Article Cyclopamine-loaded core-cross-linked polymeric micelles enhance radiation response in pancreatic cancer and pancreatic stellate cells. 2015

Zhao, Jun / Wu, Chunhui / Abbruzzese, James / Hwang, Rosa F / Li, Chun. ·‡Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, China. · ∥Division of Medical Oncology, Duke School of Medicine, Durham, North Carolina 27710, United States. ·Mol Pharm · Pubmed #25936695.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Cyclopamine (CPA), a potent inhibitor for sonic hedgehog pathway (SHH), shows great promises in PDAC treatment, including the disruption of tumor-associated stroma, and enhancement of radiation therapy. However, CPA is insoluble in water and therefore requires a nanometric delivery platform to achieve satisfactory performance. We herein encapsulated CPA in a core-cross-linked polymeric micelle system (M-CPA). M-CPA was combined with Cs-137 radiation and evaluated in vitro in PDAC cell lines and a human pancreatic stellate cell line. The results showed that M-CPA had higher cytotoxicity than CPA, abolished Gli-1 expression (a key component of SHH), and enhanced the radiation therapy of Cs-137. M-CPA radiosensitization correlated with its ability to disrupt the repair of radiation-induced DNA damage. These findings indicate that the combination therapy of M-CPA and radiation is an effective strategy to simultaneously treat pancreatic tumors and tumor-associated stroma.

23 Article Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer. 2014

Koay, Eugene J / Baio, Flavio E / Ondari, Alexander / Truty, Mark J / Cristini, Vittorio / Thomas, Ryan M / Chen, Rong / Chatterjee, Deyali / Kang, Ya'an / Zhang, Joy / Court, Laurence / Bhosale, Priya R / Tamm, Eric P / Qayyum, Aliya / Crane, Christopher H / Javle, Milind / Katz, Matthew H / Gottumukkala, Vijaya N / Rozner, Marc A / Shen, Haifa / Lee, Jeffrey E / Wang, Huamin / Chen, Yuling / Plunkett, William / Abbruzzese, James L / Wolff, Robert A / Maitra, Anirban / Ferrari, Mauro / Varadhachary, Gauri R / Fleming, Jason B. ·Division of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA. ·Phys Biol · Pubmed #25427073.

ABSTRACT: There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of therapeutic outcome.

24 Article New option for the initial management of metastatic pancreatic cancer? 2014

Abbruzzese, James L / Hess, Kenneth R. ·Duke Cancer Institute, Durham, NC james.abbruzzese@duke.edu. · University of Texas MD Anderson Cancer Center, Houston, TX. ·J Clin Oncol · Pubmed #24982449.

ABSTRACT: -- No abstract --

25 Article Solid pseudopapillary neoplasm of the pancreas: clinicopathologic and survival analyses of 64 cases from a single institution. 2014

Estrella, Jeannelyn S / Li, Lei / Rashid, Asif / Wang, Hua / Katz, Matthew H / Fleming, Jason B / Abbruzzese, James L / Wang, Huamin. ·Departments of *Pathology ‡Gastrointestinal Medical Oncology §Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX †Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China. ·Am J Surg Pathol · Pubmed #24418850.

ABSTRACT: Although solid pseudopapillary neoplasms (SPNs) are considered tumors of low malignant potential, patients may present with aggressive disease (ie, liver metastasis/invasion into adjacent organs) and, rarely, die from disease. Although the clinicopathologic features associated with aggressive SPNs have been reported, important prognostic factors of survival remain unclear. We systematically reviewed 64 cases of SPN resected at our institution for tumor size, extent of invasion, margin status, presence of lymphovascular, muscular vessel, and perineural invasion, and lymph node and distant metastases. Clinicopathologic characteristics were correlated with the presence of metastasis/recurrence and disease-specific survival. Five (8%) patients presented with stage IV disease. During follow-up, 5 (13%) of 39 patients with stage I-II disease had recurrences. Patients with metastatic/recurrent SPNs had significantly larger tumor size (P<0.001) and more frequent tumor invasion into muscular vessels (P=0.02). In a median follow-up of 76 months, only 2 died of disease (1 who presented with extensive peritoneal tumor involvement who died 2.5 mo after surgery, and 1 unusual case who presented with multiple liver metastasis and peritoneal seeding who died 19 mo after surgery), and 5 were alive with disease. The 10-year disease-specific survival rate was 96%. Muscular vessel invasion (P=0.001), tumor (T) stage by European Neuroendocrine Tumors Society (ENETS) classification (P<0.001), ENETS stage grouping (P<0.001), and stage grouping by the American Joint Committee on Cancer (AJCC stage, P<0.001) were important predictors of disease-specific survival in patients with SPN. Our study highlights the importance of pathologic evaluation in risk assessment in patients with SPNs.

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