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Pancreatic Neoplasms: HELP
Articles by Robert A. Wolff
Based on 73 articles published since 2009
(Why 73 articles?)
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Between 2009 and 2019, R. Wolff wrote the following 73 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Guideline Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. 2017

Tempero, Margaret A / Malafa, Mokenge P / Al-Hawary, Mahmoud / Asbun, Horacio / Bain, Andrew / Behrman, Stephen W / Benson, Al B / Binder, Ellen / Cardin, Dana B / Cha, Charles / Chiorean, E Gabriela / Chung, Vincent / Czito, Brian / Dillhoff, Mary / Dotan, Efrat / Ferrone, Cristina R / Hardacre, Jeffrey / Hawkins, William G / Herman, Joseph / Ko, Andrew H / Komanduri, Srinadh / Koong, Albert / LoConte, Noelle / Lowy, Andrew M / Moravek, Cassadie / Nakakura, Eric K / O'Reilly, Eileen M / Obando, Jorge / Reddy, Sushanth / Scaife, Courtney / Thayer, Sarah / Weekes, Colin D / Wolff, Robert A / Wolpin, Brian M / Burns, Jennifer / Darlow, Susan. · ·J Natl Compr Canc Netw · Pubmed #28784865.

ABSTRACT: Ductal adenocarcinoma and its variants account for most pancreatic malignancies. High-quality multiphase imaging can help to preoperatively distinguish between patients eligible for resection with curative intent and those with unresectable disease. Systemic therapy is used in the neoadjuvant or adjuvant pancreatic cancer setting, as well as in the management of locally advanced unresectable and metastatic disease. Clinical trials are critical for making progress in treatment of pancreatic cancer. The NCCN Guidelines for Pancreatic Adenocarcinoma focus on diagnosis and treatment with systemic therapy, radiation therapy, and surgical resection.

2 Guideline Pancreatic Adenocarcinoma, version 2.2012: featured updates to the NCCN Guidelines. 2012

Tempero, Margaret A / Arnoletti, J Pablo / Behrman, Stephen W / Ben-Josef, Edgar / Benson, Al B / Casper, Ephraim S / Cohen, Steven J / Czito, Brian / Ellenhorn, Joshua D I / Hawkins, William G / Herman, Joseph / Hoffman, John P / Ko, Andrew / Komanduri, Srinadh / Koong, Albert / Ma, Wen Wee / Malafa, Mokenge P / Merchant, Nipun B / Mulvihill, Sean J / Muscarella, Peter / Nakakura, Eric K / Obando, Jorge / Pitman, Martha B / Sasson, Aaron R / Tally, Anitra / Thayer, Sarah P / Whiting, Samuel / Wolff, Robert A / Wolpin, Brian M / Freedman-Cass, Deborah A / Shead, Dorothy A / Anonymous1061005. ·UCSF Helen Diller Family Comprehensive Cancer Center. ·J Natl Compr Canc Netw · Pubmed #22679115.

ABSTRACT: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pancreatic Adenocarcinoma discuss the workup and management of tumors of the exocrine pancreas. These NCCN Guidelines Insights provide a summary and explanation of major changes to the 2012 NCCN Guidelines for Pancreatic Adenocarcinoma. The panel made 3 significant updates to the guidelines: 1) more detail was added regarding multiphase CT techniques for diagnosis and staging of pancreatic cancer, and pancreas protocol MRI was added as an emerging alternative to CT; 2) the use of a fluoropyrimidine plus oxaliplatin (e.g., 5-FU/leucovorin/oxaliplatin or capecitabine/oxaliplatin) was added as an acceptable chemotherapy combination for patients with advanced or metastatic disease and good performance status as a category 2B recommendation; and 3) the panel developed new recommendations concerning surgical technique and pathologic analysis and reporting.

3 Guideline Pancreatic adenocarcinoma. 2010

Tempero, Margaret A / Arnoletti, J Pablo / Behrman, Stephen / Ben-Josef, Edgar / Benson, Al B / Berlin, Jordan D / Cameron, John L / Casper, Ephraim S / Cohen, Steven J / Duff, Michelle / Ellenhorn, Joshua D I / Hawkins, William G / Hoffman, John P / Kuvshinoff, Boris W / Malafa, Mokenge P / Muscarella, Peter / Nakakura, Eric K / Sasson, Aaron R / Thayer, Sarah P / Tyler, Douglas S / Warren, Robert S / Whiting, Samuel / Willett, Christopher / Wolff, Robert A / Anonymous3820673. · ·J Natl Compr Canc Netw · Pubmed #20876541.

ABSTRACT: -- No abstract --

4 Editorial Adjuvant therapy for pancreatic cancer: a logical strategy in search of progress. 2011

Evans, Douglas B / Wolff, Robert A. · ·Ann Surg Oncol · Pubmed #21384245.

ABSTRACT: -- No abstract --

5 Editorial Challenges in the study of adjuvant chemoradiation after pancreaticoduodenectomy. 2010

Crane, Christopher H / Varadhachary, Gauri R / Wolff, Robert A / Fleming, Jason B. · ·Ann Surg Oncol · Pubmed #20012500.

ABSTRACT: -- No abstract --

6 Review Adjuvant or Neoadjuvant Therapy in the Treatment in Pancreatic Malignancies: Where Are We? 2018

Wolff, Robert A. ·Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard-Unit 421, Houston, TX 77030, USA. Electronic address: rwolff@mdanderson.org. ·Surg Clin North Am · Pubmed #29191281.

ABSTRACT: Since the advent of modern surgery for pancreatic cancer, clinicians have recognized this cancer's propensity to recur locally, metastasize, and cause death. Despite significant efforts to improve patient outcomes with better adjuvant therapy, only modest gains in survival have been observed. An alternative strategy of neoadjuvant therapy followed by surgery has the potential to improve patient selection and survival, and expand the pool of patients eligible for curative surgery. This article summarizes large, randomized trials of adjuvant therapy, explains the limitations imposed by up-front surgery, and suggests neoadjuvant therapy as a rational alternative to initial surgery and adjuvant therapy.

7 Review Current and Evolving Therapies for Metastatic Pancreatic Cancer: Are We Stuck With Cytotoxic Chemotherapy? 2016

Varadhachary, Gauri R / Wolff, Robert A. ·The University of Texas MD Anderson Cancer Center, Houston, TX gvaradha@mdanderson.org. · The University of Texas MD Anderson Cancer Center, Houston, TX. ·J Oncol Pract · Pubmed #27621332.

ABSTRACT: At present, front-line therapy for metastatic pancreatic ductal adenocarcinoma is combination chemotherapy, most commonly FOLFIRINOX (fluorouracil, irinotecan, and oxaliplatin) or gemcitabine and nanoparticle albumin-bound paclitaxel. Despite a better understanding of the genomic landscape and the importance of the tumor microenvironment, we have not made a seismic shift in the overall survival for this disease. Given our growing understanding of the biology of pancreatic ductal adenocarcinoma, the question remains whether novel, noncytotoxic agents will augment or even replace conventional chemotherapy. The thrust of ongoing efforts can be divided into broad categories, including exploiting the DNA damage repair phenotype, stroma and specific pathway-targeting agents, and enhancing immune destruction of pancreatic ductal adenocarcinoma. In this article, we review the current and evolving therapeutic landscape of metastatic pancreatic cancer.

8 Review Management of the Primary Tumor and Limited Metastases in Patients With Metastatic Pancreatic Cancer. 2015

Herman, Joseph M / Hoffman, John P / Thayer, Sarah P / Wolff, Robert A. · ·J Natl Compr Canc Netw · Pubmed #26158133.

ABSTRACT: New combinations of cytotoxic chemotherapy have been proven to increase response rates and survival times compared with single-agent gemcitabine for patients with metastatic pancreatic cancer. These responses have been dramatic for a subset of patients, therefore raising questions about the management of limited metastatic disease with surgery or other ablative methods. Similarly, for patients having a complete radiographic response to chemotherapy in the metastatic compartment, whether to consider local therapy in the form of radiation or surgery for the primary tumor is now an appropriate question. Therefore, collaboration among experts in surgery, medical oncology, and radiation oncology has led to the development of guiding principles for local therapies to the primary intact pancreatic tumor for patients with limited metastatic disease and those who have had a significant response after systemic therapy.

9 Review The integration of chemoradiation in the care of patient with localized pancreatic cancer. 2009

Crane, C H / Varadhachary, G / Settle, S H / Fleming, J B / Evans, D B / Wolff, R A. ·Unit 97, Department of Radiation Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, 1515, Holcombe Boulevard, Houston, 77030 Texas, USA. ccrane@mdanderson.org ·Cancer Radiother · Pubmed #19167921.

ABSTRACT: The use of chemoradiation for patients with localized pancreatic cancer is controversial. Although some randomized trials have indicated that chemoradiation improves the median survival of patients with locally advanced as well as resected pancreatic cancer, other more recent trials have called into question the role of chemoradiation and have supported the use of chemotherapy. In the adjuvant setting, the high local tumor recurrence/persistence rate in all trials probably reflects the inclusion of patients with incompletely resected tumors, whose prognosis is similar to the prognosis of patients with locally advanced who do not undergo resection, making these trials difficult to interpret. More precise clinical staging and selection of patients appropriate for surgical resection is an important goal. The keys to the successful integration of radiotherapy in the care of patients with localized pancreatic cancer are selection, sequencing and smaller treatment volumes. A strategy of initial chemotherapy followed by consolidation with a well-tolerated chemoradiation regimen both in the adjuvant and locally advanced settings maximizes benefits of both treatment options, which are in fact complementary. Herein, we discuss the rationale for this approach as well as the ongoing investigation of novel radiation approaches designed to enhance outcome through the molecular and physical targeting of disease as well as the investigation of neoadjuvant chemoradiation in radiographically resectable and borderline resectable pancreatic cancer.

10 Clinical Trial Phase I Trial of Consolidative Radiotherapy with Concurrent Bevacizumab, Erlotinib and Capecitabine for Unresectable Pancreatic Cancer. 2016

Chadha, Awalpreet S / Skinner, Heath D / Gunther, Jillian R / Munsell, Mark F / Das, Prajnan / Minsky, Bruce D / Delclos, Marc E / Chatterjee, Deyali / Wang, Huamin / Clemons, Marilyn / George, Geena / Singh, Pankaj K / Katz, Matthew H / Fleming, Jason B / Javle, Milind M / Wolff, Robert A / Varadhachary, Gauri R / Crane, Christopher H / Krishnan, Sunil. ·Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. · Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. ·PLoS One · Pubmed #27336466.

ABSTRACT: PURPOSE: To determine the safety, tolerability and maximum tolerated dose (MTD) of addition of erlotinib to bevacizumab and capecitabine-based definitive chemoradiation (CRT) in unresectable pancreatic cancer. METHODS: Seventeen patients with CT-staged, biopsy-proven unresectable pancreatic cancer were enrolled between 3/2008 and 10/2010. Prior chemotherapy was permitted. Two patients each were enrolled at dose levels (DLs) 1-4 and 9 patients at DL 5. All patients received 50.4 Gy (GTV only) in 28 fractions with concurrent capecitabine, bevacizumab and erlotinib. Dose of each drug was escalated in 5 DLs using the continual reassessment method. Bevacizumab was escalated from 5mg/Kg q2weeks (DLs 1-4) to 10mg/Kg q2weeks (DL 5); daily erlotinib from 100mg/day (DLs 1-2) to 150 mg/Kg (DLs 3-5); and capecitabine from 400mg/m2 twice daily on days of radiation (DL 1) to 650mg/m2 (DLs 2-3) to 825 mg/m2 (DLs 4-5). Reassessment for potential resection was performed 6-8 weeks later. RESULTS: Sixteen patients received gemcitabine-based chemotherapy prior to CRT. With a median clinical follow-up of 10 months, no grade 3 toxicities were observed in DLs 1-4. Three (33%) patients at DL 5 developed a grade 3 acute toxicity (2 diarrhea, 1 rash). No grade 4 or 5 toxicities were seen. DL 4 was selected as the MTD; therefore, the recommended doses in combination with radiation are: bevacizumab, 5mg/Kg q2weeks; erlotinib, 150 mg/Kg daily; and capecitabine, 825mg/m2 BID. Median survival was 17.4 months. Of the five patients who underwent resection, 4 were originally deemed locally advanced and 1 was borderline resectable. Three patients had excellent pathological response (2 complete response and 20% viable tumor) at surgery, and the 2 patients with complete response are still alive at 61 and 67 months of follow up with no local or distant failures. CONCLUSIONS: This chemoradiation regimen at the recommended dose levels is safe and tolerable for patients with unresectable pancreatic cancer and merits further evaluation.

11 Clinical Trial Neoadjuvant therapy is associated with a reduced lymph node ratio in patients with potentially resectable pancreatic cancer. 2015

Roland, Christina L / Yang, Anthony D / Katz, Matthew H G / Chatterjee, Deyali / Wang, Huamin / Lin, Heather / Vauthey, Jean N / Pisters, Peter W / Varadhachary, Gauri R / Wolff, Robert A / Crane, Christopher H / Lee, Jeffrey E / Fleming, Jason B. ·Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. ·Ann Surg Oncol · Pubmed #25352267.

ABSTRACT: BACKGROUND: The use of neoadjuvant therapy (NAC) for the treatment of potentially resectable pancreatic cancer remains controversial. In this study, we sought to evaluate cancer-specific endpoints in patients undergoing a NAC versus a surgery-first (SF) approach with specific emphasis on lymph node metastases. METHODS: A total of 222 patients who underwent NAC and 85 patients who underwent SF were identified from 1990 to 2008 and compared for cancer-related endpoints. Peripancreatic lymph nodes from 135 neoadjuvant therapy patients were evaluated for histologic tumor regression. RESULTS: Patients who underwent NAC followed by surgery had improved overall survival and time to local recurrence compared with the SF approach. NAC patients were less likely to have lymph node metastases (p = 0.001), lymphovascular invasion (LVI), and had smaller tumors. On multivariate analysis, lymph node positivity was associated with SF, tumor size, and the presence of LVI. NAC patients with N0 disease had equivalent outcomes to patients with a low-LNR (0.01-0.15), whereas patients with a LNR >0.15 had reduced survival, and time to local and distant recurrence. Ten of 135 (7.4 %) NAC patients had evidence of tumor regression in at least one lymph node. CONCLUSIONS: Patients with potentially resectable PDAC selected to undergo NAC had improved survival and longer time to recurrence. Although some of these differences may be related to improvements in multimodality therapy completion rates, tumor regression in lymph node metastases exists and may demonstrate a biologic benefit of NAC compared with a SF approach.

12 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).

13 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.

14 Clinical Trial Survival and quality of life of patients with resected pancreatic adenocarcinoma treated with adjuvant interferon-based chemoradiation: a phase II trial. 2011

Katz, Matthew H G / Wolff, Robert / Crane, Christopher H / Varadhachary, Gauri / Javle, Milind / Lin, E / Evans, Douglas B / Lee, Jeffrey E / Fleming, Jason B / Pisters, Peter W T. ·Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, USA. ·Ann Surg Oncol · Pubmed #21701927.

ABSTRACT: PURPOSE: We conducted a phase II trial to assess the survival duration and quality of life of patients who received adjuvant interferon-based chemoradiation for pancreatic adenocarcinoma after pancreaticoduodenectomy. METHODS: Patients with a performance status of 0 or 1 were enrolled to receive interferon-alfa-2b (3 million units MWF), cisplatin (30 mg/m(2), 6 doses) and 5-fluorouracil (5-FU; 175 mg/m(2)/day), concurrent with external-beam radiation (50.4 Gy) and followed by 2 courses of systemic 5-FU. The protocol was modified to include an optional 9 day break in the middle of chemoradiation. Quality of life was assessed by use of validated instruments. RESULTS: Twenty-eight patients were eligible for analysis. The operation of 15 (54%) patients was performed at other institutions. All patients had T3 tumors, 22 (79%) had positive lymph nodes and 4 (14%) had positive (R1) margins. 24 (86%) patients completed therapy. In all, 25 (89%) patients experienced grade 3 toxicity and 3 (11%) patients were hospitalized. The most common grade 3 events were leukopenia (15, 54%) and neutropenia (12, 43%). No grade 4 toxicity occurred. Overall quality of life decreased during chemoradiation but returned to baseline thereafter and was stable throughout surveillance. 19 patients have died; the median follow-up of the 9 survivors is 62 months. The median OS duration of treated patients was 42.3 (95% confidence interval 30.5-54.2) months. CONCLUSIONS: Adjuvant interferon-based chemoradiation can be delivered safely and tolerably-though with substantial reversible toxicity-to patients of good performance status at an experienced cancer center. Therapy may be associated with an improvement in overall survival.

15 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.

16 Clinical Trial Phase 1 clinical trials in 83 patients with pancreatic cancer: The M. D. Anderson Cancer Center experience. 2011

Vaklavas, Christos / Tsimberidou, Apostolia-Maria / Wen, Sijin / Hong, David / Wheler, Jennifer / Ng, Chaan S / Naing, Aung / Uehara, Cynthia / Wolff, Robert A / Kurzrock, Razelle. ·Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. ·Cancer · Pubmed #20737567.

ABSTRACT: BACKGROUND: The outcomes of patients with pancreatic cancer treated on early phase clinical trials have not been systematically analyzed. The purpose of this study was to report the presenting characteristics and outcomes of patients with locally advanced or metastatic pancreatic cancer treated on phase 1 clinical trials at a single institution. METHODS: The authors reviewed the records of consecutive patients with metastatic pancreatic cancer who were treated in the Phase I Clinical Trials Program at The University of Texas M. D. Anderson Cancer Center from November 2004 to March 2009. Data recorded and analyzed included survival, response, and disease characteristics. RESULTS: Eighty-three patients were identified. The median age was 62 years (range, 39-81 years). Of 78 patients evaluable for response, 2 (3%) had a partial response (PR), and 10 (13%) had stable disease (SD) for ≥ 4 months. With a median follow-up for survivors of 3.7 months, the median survival from presentation in the phase 1 clinic was 5.0 months (95% confidence interval [CI], 3.3-6.2). The median overall survival from diagnosis was 22.1 months (95% CI, 17.9-26.5). The median time to treatment failure was 1.5 months (95% CI, 1.3-1.8). Independent factors associated with lower rates of PR/SD were liver metastases (P = .001) and performance status >0 (P = .01). Independent factors associated with shorter survival were liver metastases (P = .007), low calcium level (P = .015), and elevated CEA level (>6 ng/mL) (P = .005). CONCLUSIONS: Our results suggest that phase 1 clinical trials offer a reasonable therapeutic approach for patients with advanced pancreatic cancer.

17 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.

18 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.

19 Clinical Trial Phase II study of bevacizumab with concurrent capecitabine and radiation followed by maintenance gemcitabine and bevacizumab for locally advanced pancreatic cancer: Radiation Therapy Oncology Group RTOG 0411. 2009

Crane, Christopher H / Winter, Kathryn / Regine, William F / Safran, Howard / Rich, Tyvin A / Curran, Walter / Wolff, Robert A / Willett, Christopher G. ·Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. ccrane@mdanderson.org ·J Clin Oncol · Pubmed #19636002.

ABSTRACT: PURPOSE: The primary objective of this study was to assess the 1-year survival of patients with locally advanced, unresectable pancreatic cancer treated with the combination of bevacizumab, capecitabine, and radiation. Secondary end points were toxicity, progression-free survival (PFS), and response rate (RR). PATIENTS AND METHODS: Patients with locally advanced pancreatic cancer without duodenal invasion were treated with 50.4 Gy per 28 fractions to the gross tumor with concurrent capecitabine 825 mg/m(2) orally twice daily on days of radiation and bevacizumab 5 mg/kg on days 1, 15, and 29 followed by maintenance gemcitabine 1 g/m(2) weekly for 3 weeks and bevacizumab 5 mg/kg every 2 weeks, both in 4-week cycles until progression. Treatment plans were reviewed for quality assurance (QA). RESULTS: Between January 2005 and February 2006, 82 eligible patients were treated. The median and 1-year survival rates were 11.9 months (95% CI, 9.9 to 14.0 months) and 47% (95% CI, 36% to 57%). Median PFS was 8.6 months (95% CI, 6.9 to 10.5), and RR was 26%. Overall, 35.4% of patients had grade 3 or greater treatment-related gastrointestinal toxicity (22.0% during chemoradiotherapy, 13.4% during maintenance chemotherapy). Unacceptable radiotherapy protocol deviations (ie, inappropriately generous volume contoured) correlated with grade 3 or greater gastrointestinal toxicity during chemoradiotherapy (45% v 18%; adjusted odds ratio, 3.7; 95% CI, 0.98 to 14.1; P = .05). CONCLUSION: The addition of bevacizumab to chemoradiotherapy followed by bevacizumab and gemcitabine resulted in a similar median survival to previous Radiation Therapy Oncology Group studies in patients with locally advanced pancreatic cancer. Prospective QA may help limit toxicity in future trials.

20 Article First-Line Gemcitabine and Nab-Paclitaxel Chemotherapy for Localized Pancreatic Ductal Adenocarcinoma. 2019

Gulhati, Pat / Prakash, Laura / Katz, Matthew H G / Wang, Xuemei / Javle, Milind / Shroff, Rachna / Fogelman, David / Lee, Jeffrey E / Tzeng, Ching-Wei D / Lee, Jeffrey H / Weston, Brian / Tamm, Eric / Bhosale, Priya / Koay, Eugene J / Maitra, Anirban / Wang, Huamin / Wolff, Robert A / Varadhachary, Gauri R. ·Hematology/Oncology Fellowship Program, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Division of Surgery, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 426, Houston, TX, 77030, USA. · Division of Internal Medicine, Department of Gastroenterology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Division of Diagnostic Imaging, Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Division of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Division of Pathology/Lab Medicine, Department of Anatomic Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 426, Houston, TX, 77030, USA. gvaradha@mdanderson.org. ·Ann Surg Oncol · Pubmed #30324485.

ABSTRACT: BACKGROUND: Preoperative chemotherapy provides early treatment of micro-metastases and guaranteed delivery of all components of multimodality therapy for localized pancreatic ductal adenocarcinoma (PDAC). For locally advanced (LA) PDAC, induction chemotherapy is the standard of care. This study evaluated the use of gemcitabine and nab-paclitaxel (Gem/nab-P) as first-line therapy for localized PDAC. METHODS: Clinicopathologic features, treatment, and outcomes were evaluated for 99 patients with localized PDAC. The patients were staged using previously published criteria as follows: potentially resectable (PR), borderline type A (BR-A) (anatomy amenable to vascular resection), BR-B (biology suspicious for metastatic disease including high CA19-9), BR-C (comorbidities requiring medical optimization), and LA. RESULTS: The 99 patients (PR/BR/LA: 45/14/40) were treated with Gem/nab-P. Clinical staging showed that 20 patients had PR or BR-A disease, whereas 39 patients had BR-B or BR-C disease. The BR-B+C cases included one or more of the following: age of 80 years or older (13%), Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 or more (13%), moderate to severe comorbidities (55%), CA19-9 of 1000 or higher (28%), and suspicion for metastases (21%). The majority of the patients received biweekly Gem/nab-P dosing, which was well tolerated. Pancreatectomy was performed for 12 (60%) of 20 patients with PR+BR-A, 2 (5%) of 39 patients with BR-B+C, and 1 (3%) of 40 patients with LA disease. During a median follow-up period of 26 months, the median overall survival (OS) period was 18 months (95% confidence interval [CI], 15.6-20.5 months) for all the patients, 17 months (95% CI, 14.6-19.5 months) for the unresected patients, and not reached for the resected patients (p = 0.028 for resected vs unresected patients). CONCLUSIONS: A significant number of patients with radiographically resectable PDAC albeit aggressive biology (BR-B), medically inoperable conditions (BR-C), or both received biweekly first-line Gem/nab-P. The resection rates were lower for the BR-B/BR-C patients than for the PR/BR-A patients (hazard ratio [HR], 0.43; 95% CI, 0.19-1.00; p = 0.05).

21 Article Circulating Nucleic Acids Are Associated With Outcomes of Patients With Pancreatic Cancer. 2019

Bernard, Vincent / Kim, Dong U / San Lucas, F Anthony / Castillo, Jonathan / Allenson, Kelvin / Mulu, Feven C / Stephens, Bret M / Huang, Jonathan / Semaan, Alexander / Guerrero, Paola A / Kamyabi, Nabiollah / Zhao, Jun / Hurd, Mark W / Koay, Eugene J / Taniguchi, Cullen M / Herman, Joseph M / Javle, Milind / Wolff, Robert / Katz, Matthew / Varadhachary, Gauri / Maitra, Anirban / Alvarez, Hector A. ·Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea. · Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: Haalvarez@mdanderson.org. ·Gastroenterology · Pubmed #30240661.

ABSTRACT: BACKGROUND & AIMS: We aimed to investigate the clinical utility of circulating tumor cell DNA (ctDNA) and exosome DNA (exoDNA) in pancreatic cancer. METHODS: We collected liquid biopsy samples from 194 patients undergoing treatment for localized or metastatic pancreatic adenocarcinoma from April 7, 2015, through October 13, 2017 (425 blood samples collected before [baseline] and during therapy). Additional liquid biopsy samples were collected from 37 disease control individuals. Droplet digital polymerase chain reaction was used to determine KRAS mutant allele fraction (MAF) from ctDNA and exoDNA purified from plasma. For the longitudinal analysis, we analyzed exoDNA and ctDNA in 123 serial blood samples from 34 patients. We performed analysis including Cox regression, Fisher exact test, and Bayesian inference to associate KRAS MAFs in exoDNA and ctDNA with prognostic and predictive outcomes. RESULTS: In the 34 patients with potentially resectable tumors, an increase in exoDNA level after neoadjuvant therapy was significantly associated with disease progression (P = .003), whereas ctDNA did not show correlations with outcomes. Concordance rates of KRAS mutations present in surgically resected tissue and detected in liquid biopsy samples were greater than 95%. On univariate analysis, patients with metastases and detectable ctDNA at baseline status had significantly shorter times of progression-free survival (PFS) (hazard ratio [HR] for death, 1.8; 95% CI, 1.1-3.0; P = .019), and overall survival (OS) (HR, 2.8; 95% CI, 1.4-5.7; P = .0045) compared with patients without detectable ctDNA. On multivariate analysis, MAFs ≥5% in exoDNA were a significant predictor of PFS (HR, 2.28; 95% CI, 1.18-4.40; P = .014) and OS (HR, 3.46; 95% CI, 1.40-8.50; P = .007). A multianalyte approach showed detection of both ctDNA and exoDNA MAFs ≥5% at baseline status to be a significant predictor of OS (HR, 7.73, 95% CI, 2.61-22.91, P = .00002) on multivariate analysis. In the longitudinal analysis, an MAF peak above 1% in exoDNA was significantly associated with radiologic progression (P = .0003). CONCLUSIONS: In a prospective cohort of pancreatic cancer patients, we show how longitudinal monitoring using liquid biopsy samples through exoDNA and ctDNA provides both predictive and prognostic information relevant to therapeutic stratification.

22 Article Surfaceome profiling enables isolation of cancer-specific exosomal cargo in liquid biopsies from pancreatic cancer patients. 2018

Castillo, J / Bernard, V / San Lucas, F A / Allenson, K / Capello, M / Kim, D U / Gascoyne, P / Mulu, F C / Stephens, B M / Huang, J / Wang, H / Momin, A A / Jacamo, R O / Katz, M / Wolff, R / Javle, M / Varadhachary, G / Wistuba, I I / Hanash, S / Maitra, A / Alvarez, H. ·Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA. · The University of Texas MD Anderson Cancer UTHealth Graduate School of Biomedical Sciences, Houston, USA. · Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, USA. · ContinuumDx, Houston, USA. · McCombs Institute for the Early Detection and Treatment of Cancer, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, USA. ·Ann Oncol · Pubmed #29045505.

ABSTRACT: Background: Detection of circulating tumor DNA can be limited due to their relative scarcity in circulation, particularly while patients are actively undergoing therapy. Exosomes provide a vehicle through which cancer-specific material can be enriched from the compendium of circulating non-neoplastic tissue-derived nucleic acids. We carried out a comprehensive profiling of the pancreatic ductal adenocarcinoma (PDAC) exosomal 'surfaceome' in order to identify surface proteins that will render liquid biopsies amenable to cancer-derived exosome enrichment for downstream molecular profiling. Patients and methods: Surface exosomal proteins were profiled in 13 human PDAC and 2 non-neoplastic cell lines by liquid chromatography-mass spectrometry. A total of 173 prospectively collected blood samples from 103 PDAC patients underwent exosome isolation. Droplet digital PCR was used on 74 patients (136 total exosome samples) to determine baseline KRAS mutation call rates while patients were on therapy. PDAC-specific exosome capture was then carried out on additional 29 patients (37 samples) using an antibody cocktail directed against selected proteins, followed by droplet digital PCR analysis. Exosomal DNA in a PDAC patient resistant to therapy were profiled using a molecular barcoded, targeted sequencing panel to determine the utility of enriched nucleic acid material for comprehensive molecular analysis. Results: Proteomic analysis of the exosome 'surfaceome' revealed multiple PDAC-specific biomarker candidates: CLDN4, EPCAM, CD151, LGALS3BP, HIST2H2BE, and HIST2H2BF. KRAS mutations in total exosomes were detected in 44.1% of patients undergoing active therapy compared with 73.0% following exosome capture using the selected biomarkers. Enrichment of exosomal cargo was amenable to molecular profiling, elucidating a putative mechanism of resistance to PARP inhibitor therapy in a patient harboring a BRCA2 mutation. Conclusion: Exosomes provide unique opportunities in the context of liquid biopsies for enrichment of tumor-specific material in circulation. We present a comprehensive surfaceome characterization of PDAC exosomes which allows for capture and molecular profiling of tumor-derived DNA.

23 Article Open Pancreaticoduodenectomy Case Volume Predicts Outcome of Laparoscopic Approach: A Population-based Analysis. 2018

Kutlu, Onur C / Lee, Jeffrey E / Katz, Matthew H / Tzeng, Ching-Wei D / Wolff, Robert A / Varadhachary, Gauri R / Vauthey, Jean-Nicolas / Fleming, Jason B / Conrad, Claudius. ·Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL. · Department of Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX. · Department of Surgical Oncology, University of Kentucky, Lexington, KY. · Department of Gastrointestinal Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX. ·Ann Surg · Pubmed #28045744.

ABSTRACT: OBJECTIVE: To determine if laparoscopic pancreaticoduodenectomy (LPD) is safe and offers benefits over open pancreaticoduodenectomy (OPD) at institutions with lower pancreaticoduodenectomy (PD) volume. BACKGROUND: Although a hospital-based case volume-outcome relationship for morbidity, mortality, and oncologic quality has been reported for OPD, comparative trends for LPD have yet to be investigated. METHODS: A total of 4739 patients with complete data were identified in National Cancer Data Base between 2010 and 2011; 4309 patients had OPD and 430 patients had LPD. Institutions were categorized into quartiles based on PD case volume. For the entire cohort and within each quartile, LPD and OPD were compared for 30-day and 90-day mortality, length of hospital stay, 30-day unplanned readmission rate, and margin status. Binary logistic regression, linear regression, and propensity score matching was performed. RESULTS: Hospitals with low PD case volume (≤25 PDs per year; 91% of all hospitals in the US and 25% of cases) had the highest 30- and 90-day mortality, highest margin positivity rates, and lowest lymph node counts. These trends were more pronounced in the LPD group. Only in the highest-volume hospitals was LPD associated with shorter hospital stay and lower readmission compared with OPD. CONCLUSIONS: These findings confirm that risks of postoperative mortality and suboptimal oncologic surgical quality following PD are higher in low-volume hospitals. Furthermore, these risks are more profound with LPD compared with OPD. These data suggest that the putative benefits of LPD are unlikely to be observed in institutions performing ≤25 PDs per year.

24 Article Prognostic Significance of Tumor-Infiltrating Lymphocytes in Patients With Pancreatic Ductal Adenocarcinoma Treated With Neoadjuvant Chemotherapy. 2017

Nejati, Reza / Goldstein, Jennifer B / Halperin, Daniel M / Wang, Hua / Hejazi, Nazila / Rashid, Asif / Katz, Matthew H / Lee, Jeffrey E / Fleming, Jason B / Rodriguez-Canales, Jaime / Blando, Jorge / Wistuba, Ignacio I / Maitra, Anirban / Wolff, Robert A / Varadhachary, Gauri R / Wang, Huamin. ·From the Departments of *Pathology, †Gastrointestinal Medical Oncology, ‡Surgical Oncology, and §Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX. ·Pancreas · Pubmed #28902789.

ABSTRACT: OBJECTIVES: The aim of this study was to examine tumor-infiltrating lymphocytes (TILs) and their prognostic value in patients with pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy. METHODS: Intratumoral CD4, CD8, and FOXP3 lymphocytes were examined by immunohistochemistry using a computer-assisted quantitative analysis in 136 PDAC patients who received neoadjuvant therapy and pancreaticoduodenectomy. The results were correlated with clinicopathological parameters and survival. RESULTS: High CD4 TILs in treated PDAC were associated with high CD8 TILs (P = 0.003), differentiation (P = 0.04), and a lower frequency of recurrence (P = 0.02). Patients with high CD4 TILs had longer disease-free survival and overall survival (OS) than did patients with low CD4 TILs (P < 0.01). The median OS of patients with a high CD8/FOXP3 lymphocyte ratio (39.5 [standard deviation, 6.1] months) was longer than that of patients with a low CD8/FOXP3 lymphocyte ratio (28.3 [standard deviation, 2.3] months; P = 0.01). In multivariate analysis, high CD4 TILs were an independent prognostic factor for disease-free survival (hazard ratio, 0.49; 95% confidence interval, 0.30-0.81; P = 0.005) and OS (hazard ratio, 0.54; 95% confidence interval, 0.33-0.89; P = 0.02). CONCLUSIONS: High level of CD4 lymphocytes is associated with tumor differentiation and lower recurrence and is an independent prognostic factor for survival in PDAC patients treated with neoadjuvant therapy.

25 Article Association of Clinical Factors With a Major Pathologic Response Following Preoperative Therapy for Pancreatic Ductal Adenocarcinoma. 2017

Cloyd, Jordan M / Wang, Huamin / Egger, Michael E / Tzeng, Ching-Wei D / Prakash, Laura R / Maitra, Anirban / Varadhachary, Gauri R / Shroff, Rachna / Javle, Milind / Fogelman, David / Wolff, Robert A / Overman, Michael J / Koay, Eugene J / Das, Prajnan / Herman, Joseph M / Kim, Michael P / Vauthey, Jean-Nicolas / Aloia, Thomas A / Fleming, Jason B / Lee, Jeffrey E / Katz, Matthew H G. ·Department of Surgical Oncology; University of Texas MD Anderson Cancer Center, Houston. · Department of Pathology; University of Texas MD Anderson Cancer Center, Houston. · Department of Gastrointestinal Medical Oncology; University of Texas MD Anderson Cancer Center, Houston. · Department of Radiation Oncology; University of Texas MD Anderson Cancer Center, Houston. ·JAMA Surg · Pubmed #28700784.

ABSTRACT: Importance: We previously demonstrated that a major pathologic response to preoperative therapy, defined histopathologically by the presence of less than 5% viable cancer cells in the surgical specimen, is an important prognostic factor for patients with pancreatic ductal adenocarcinoma. However, to our knowledge, the patients most likely to experience a significant response to therapy are undefined. Objective: To identify clinical factors associated with major pathologic response in a large cohort of patients who underwent preoperative therapy and pancreatectomy for pancreatic ductal adenocarcinoma. Design, Setting, and Participants: Retrospective review of a prospectively maintained database at University of Texas MD Anderson Cancer Center. The study included 583 patients with histopathologically confirmed pancreatic ductal adenocarcinoma who received preoperative therapy prior to pancreatectomy between 1990 and 2015. Exposures: Preoperative therapy consisted of systemic chemotherapy alone (n = 38; 6.5%), chemoradiation alone (n = 261; 44.8%), or both (n = 284; 48.7%) prior to pancreatoduodenectomy (n = 514; 88.2%), distal pancreatectomy (n = 62; 10.6%), or total pancreatectomy (n = 7; 1.2%). Main Outcomes and Measures: Clinical variables associated with a major pathologic response (pathologic complete response or <5% residual cancer cells) were evaluated using logistic regression. Results: Among all patients, the mean (SD) age was 63.7 (9.2) years, and 53.0% were men. A major pathologic response was seen in 77 patients (13.2%) including 23 (3.9%) who had a complete pathologic response. The median overall survival duration was significantly longer for patients who had a major response than for those who did not (73.4 months vs 32.2 months, P < .001). On multivariate logistic regression, only age younger than 50 years, baseline serum cancer antigen 19-9 level less than 200 U/mL, and gemcitabine as a radiosensitizer were associated with a major response. The number of these positive factors was associated with the likelihood of a major response in a stepwise fashion (0, 7.5%; 1, 12.7%; 2, 16.9%; 3, 35.7%; P = .009). Conclusions and Relevance: Although a major pathologic response occurs infrequently following preoperative therapy for pancreatic ductal adenocarcinoma, it is associated with a significantly improved prognosis. Of the patient- and treatment-related factors we analyzed, only young age, low baseline cancer antigen 19-9, and gemcitabine as a radiosensitizer were associated with a major pathologic response. Given its association with long-term survival, better predictors of response and more effective preoperative regimens should be aggressively sought.

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