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Pancreatic Neoplasms: HELP
Articles by Herbert J. Zeh
Based on 89 articles published since 2008
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Between 2008 and 2019, H. Zeh wrote the following 89 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Guideline Potentially Curable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. 2017

Khorana, Alok A / Mangu, Pamela B / Berlin, Jordan / Engebretson, Anitra / Hong, Theodore S / Maitra, Anirban / Mohile, Supriya G / Mumber, Matthew / Schulick, Richard / Shapiro, Marc / Urba, Susan / Zeh, Herbert J / Katz, Matthew H G. ·Alok A. Khorana and Marc Shapiro, Cleveland Clinic, Cleveland, OH · Pamela B. Mangu, American Society of Clinical Oncology, Alexandria, VA · Jordan Berlin, Vanderbilt University, Nashville, TN · Anitra Engebretson, Pancreatic Cancer Action Network, Manhattan Beach, CA · Theodore S. Hong, Massachusetts General Hospital, Boston, MA · Anirban Maitra and Matthew H.G. Katz, The University of Texas MD Anderson Cancer Center, Houston, TX · Supriya G. Mohile, University of Rochester, Rochester, NY · Matthew Mumber, Harbin Clinic, Rome, GA · Richard Schulick, University of Colorado at Denver, Denver, CO · Susan Urba, University of Michigan, Ann Arbor, MI · and Herbert J. Zeh, University of Pittsburgh, Pittsburgh, PA. ·J Clin Oncol · Pubmed #28398845.

ABSTRACT: Purpose To update the Potentially Curable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline published on May 31, 2016. The October 2016 update focuses solely on new evidence that pertains to clinical question 4 of the guideline: What is the appropriate adjuvant regimen for patients with pancreatic cancer who have undergone an R0 or R1 resection of their primary tumor? Methods The recently published results of a randomized phase III study prompted an update of this guideline. The high quality of the reported evidence and the potential for its clinical impact prompted the Expert Panel to revise one of the guideline recommendations. Results The ESPAC-4 study, a multicenter, international, open-label randomized controlled phase III trial of adjuvant combination chemotherapy compared gemcitabine and capecitabine with gemcitabine monotherapy in 730 evaluable patients with resected pancreatic ductal adenocarcinoma. Median overall survival was improved in the doublet arm to 28.0 months (95% CI, 23.5 to 31.5 months) versus 25.5 months (95% CI, 22.7 to 27.9 months) for gemcitabine alone (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = .032). Grade 3 and 4 adverse events were similar in both arms, although higher rates of hand-foot syndrome and diarrhea occurred in patients randomly assigned to the doublet arm. Recommendations All patients with resected pancreatic cancer who did not receive preoperative therapy should be offered 6 months of adjuvant chemotherapy in the absence of medical or surgical contraindications. The doublet regimen of gemcitabine and capecitabine is preferred in the absence of concerns for toxicity or tolerance; alternatively, monotherapy with gemcitabine or fluorouracil plus folinic acid can be offered. Adjuvant treatment should be initiated within 8 weeks of surgical resection, assuming complete recovery. The remaining recommendations from the original 2016 ASCO guideline are unchanged.

2 Review Autophagy Inhibition in Pancreatic Adenocarcinoma. 2018

Boone, Brian A / Zeh, Herbert J / Bahary, Nathan. ·Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA. · Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA. Electronic address: baharyn@upmc.edu. ·Clin Colorectal Cancer · Pubmed #29223362.

ABSTRACT: Although some progress has been made in recent years with the development of more effective chemotherapy regimens, new treatment approaches are needed to improve outcomes for patients with pancreatic adenocarcinoma. The cellular process of autophagy, a cell survival mechanism that allows cancer cells to survive the hazardous conditions of the tumor microenvironment and treatment, has emerged as a viable target in pancreatic cancer. We review the mechanism of autophagy, its role in pancreatic carcinogenesis, the preclinical and clinical evidence supporting targeting autophagy in patients with pancreatic adenocarcinoma, and areas of future investigation that hold promise for improving this treatment approach.

3 Review Minimally Invasive Approaches to Pancreatic Surgery. 2016

Magge, Deepa / Zureikat, Amer / Hogg, Melissa / Zeh, Herbert J. ·Division of GI Surgical Oncology, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA. Electronic address: maggedr@upmc.edu. · Division of GI Surgical Oncology, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA. · Division of GI Surgical Oncology, University of Pittsburgh Medical Center, 5150 Centre Avenue, Suite 417, Pittsburgh 15232, PA, USA. ·Surg Oncol Clin N Am · Pubmed #27013364.

ABSTRACT: Minimally invasive techniques have the potential to revolutionize the surgical management of pancreatic disease in the setting of benign and malignant processes. Pancreatic surgery, in particular, may be aided significantly by minimal access surgery given the high morbidity associated with traditional open pancreatic procedures. This article presents a review of two minimally invasive techniques for distal pancreatectomy and pancreaticoduodenectomy, focusing on metrics of technique, safety, morbidity, and oncologic outcomes and potential benefits.

4 Review The chemokine receptors CXCR4/CXCR7 and their primary heterodimeric ligands CXCL12 and CXCL12/high mobility group box 1 in pancreatic cancer growth and development: finding flow. 2015

Shakir, Murtaza / Tang, Daolin / Zeh, Herbert J / Tang, Siu Wah / Anderson, Carolyn J / Bahary, Nathan / Lotze, Michael T. ·From the *Department of Surgery, University of Pittsburgh Cancer Institute; †Hillman Cancer Center, University of Pittsburgh Cancer Institute; and ‡Molecular Imaging Laboratory, Department of Radiology, and §Department of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, PA. ·Pancreas · Pubmed #25872129.

ABSTRACT: Novel therapies need to be developed for patients with pancreatic cancer because of the poor outcomes of current regimens. Pancreatic cancer cells respond to the C-X-C chemokine receptor type 4 (CXCR4)/C-X-C chemokine receptor type 7 (CXCR7)/C-X-C motif chemokine 12 (CXCL12)/high-mobility group box 1 signaling axis and this axis presents a novel target for therapy. C-X-C motif chemokine 12 stimulates CXCR4/CXCR7-bearing cells in a paracrine manner. C-X-C chemokine receptor type 4 and CXCR7 are transmembrane G protein-coupled receptors that, upon interaction with ligand CXCL12, activate downstream protein kinases that promote a more aggressive behavior. C-X-C chemokine receptor type 4 is expressed on most pancreatic cancer cells, whereas CXCR7 is primarily expressed on tumor-associated endothelium. High-mobility group box 1 promotes the CXCR4 and CXCL12 interaction, promoting angiogenesis and lymphangiogenesis. Hypoxia-inducible factor 1 is a potent stimulator of CXCR4 and CXCL12 expression, promoting more aggressive behavior. This receptor/ligand interaction can be disrupted by CXCR4 antagonists available and in clinical use to harvest bone marrow stem cells. Novel imaging strategies are now being developed at several centers to evaluate response to therapy and identify early recurrence. Thus, the CXCR4/CXCR7/CXCL12 interaction plays a critical role in cancer cell progression, proliferation, invasion, as well as metastasis and is a suitable target for therapy, imaging, as well as development of novel diagnostics.

5 Review The utility of the robot in pancreatic resections. 2014

Zureikat, Amer H / Hogg, Melissa E / Zeh, Herbert J. · ·Adv Surg · Pubmed #25293609.

ABSTRACT: Robotic pancreatic resections have been established as safe alternatives to the open and laparoscopic approaches. The platform has proven to be versatile, and discriminable, allowing an increasing number of surgeons to perform complex pancreatic resections in minimally invasive fashion. To date, the realized advantages of the robotic technique are decreased blood loss, and fewer conversions to laparotomy. Although these are 2 very important metrics, larger experiences comparing robotics to open and/or laparoscopic surgery are ultimately needed if the true potential of robotic pancreatic resections are to be realized.

6 Review Sweating the small stuff: microRNAs and genetic changes define pancreatic cancer. 2013

Tang, Siuwah / Bonaroti, Jillian / Unlu, Sebnem / Liang, Xiaoyan / Tang, Daolin / Zeh, Herbert J / Lotze, Michael T. ·Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA. ·Pancreas · Pubmed #23774697.

ABSTRACT: MicroRNAs (miRNAs) are 18- to 22-nucleotide-long, single-stranded, noncoding RNAs that regulate important biological processes including differentiation, proliferation, and response to cellular stressors such as hypoxia, nutrient depletion, and traversion of the cell cycle by controlling protein expression within the cell. Many investigators have profiled cancer tissue and serum miRNAs to identify potential therapeutic targets, understand the pathways involved in tumorigenesis, and identify diagnostic tumor signatures. In the setting of pancreatic cancer, obtaining pancreatic tissue is invasive and impractical for early diagnosis. Several groups have profiled miRNAs that are present in the blood as a means to diagnose tumor progression and predict prognosis/survival or drug resistance. Several miRNA signatures found in pancreatic tissue and the peripheral blood, as well as the pathways that are associated with pancreatic cancer, are reviewed here in detail. Three miRNA biomarkers (miR-21, miR-155, and miR-200) have been repetitively identified in both pancreatic cancer tissue and patients' blood. Those miRNAs regulate and are regulated by the central genetic and epigenetic changes observed in pancreatic cancer including p53, transforming growth factor β, p16(INK4A), BRCA1/2, and Kras. These miRNAs are involved in DNA repair, cell cycle, and cell invasion and also play important roles in promoting metastases.

7 Review Robotic-assisted major pancreatic resection. 2011

Zeh, H J / Bartlett, David L / Moser, A James. ·Division of Surgical Oncology, Department of Surgery, University of Pittsburgh School of Medicine, Suite 417, UPMC Cancer Pavilion, 5150 Center Avenue, Pittsburgh, PA 15232, USA. zehh@upmc.edu ·Adv Surg · Pubmed #21954697.

ABSTRACT: Robotic-assisted major pancreatic resections allow recreation of time-tested open surgical procedures on a minimally invasive platform. Early outcomes from robotic-assisted major pancreatic resections are comparable with those of laparoscopic and open approaches. Robotic assistance has the potential to bring the well-recognized advantages of minimally invasive surgery to major pancreatic resections. Technological innovations and increased surgeon familiarity with this approach will improve, likely leading to greater adoption and acceptance.

8 Review Multi-institutional tumor banking: lessons learned from a pancreatic cancer biospecimen repository. 2010

Demeure, Michael J / Sielaff, Timothy / Koep, Larry / Prinz, Richard / Moser, A James / Zeh, Herb / Hostetter, Galen / Black, Jodi / Decker, Ardis / Rosewell, Sandra / Bussey, Kimberly J / Von Hoff, Daniel. ·Scottsdale Healthcare Cancer Surgery, Scottsdale, AZ, USA. mdemeure@tgen.org ·Pancreas · Pubmed #20861694.

ABSTRACT: Clinically annotated pancreatic cancer samples are needed for progress to be made toward developing more effective treatments for this deadly cancer. As part of a National Cancer Institute-funded program project, we established a biospecimen core to support the research efforts. This article summarizes the key hurdles encountered and solutions we found in the process of developing a successful multi-institution biospecimen repository.

9 Clinical Trial FOLFIRINOX Versus Gemcitabine/Nab-Paclitaxel for Neoadjuvant Treatment of Resectable and Borderline Resectable Pancreatic Head Adenocarcinoma. 2018

Dhir, Mashaal / Zenati, Mazen S / Hamad, Ahmad / Singhi, Aatur D / Bahary, Nathan / Hogg, Melissa E / Zeh, Herbert J / Zureikat, Amer H. ·Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, USA. · Department of Biostatistics and Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. · Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. · Department of Medical Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. · Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. zureikatah@upmc.edu. · Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. zureikatah@upmc.edu. ·Ann Surg Oncol · Pubmed #29761331.

ABSTRACT: BACKGROUND: Both FOLFIRINOX and gemcitabine/nab-paclitaxel (G-nP) are used increasingly in the neoadjuvant treatment (NAT) of pancreatic ductal adenocarcinoma (PDA). This study aimed to compare neoadjuvant FOLFIRINOX and G-nP in the treatment of resectable (R) and borderline resectable (BR) head PDA. METHODS: A single-institution retrospective review of R and BR patients undergoing pancreaticoduodenectomy after NAT with FOLFIRINOX or G-nP was performed. Comparative analysis was performed using inverse-probability-weighted (IPW) estimators. The end points of the study were overall survival (OS) and an 80% reduction in CA19-9 with NAT. RESULTS: In this study, 193 patients were analyzed, with 73 patients receiving FOLFIRINOX and 120 patients receiving G-nP. The median OS was 38.7 months for FOLFIRINOX versus 28.6 months for G-nP (p = 0.214). The patients who received FOLFIRINOX were younger and had fewer comorbidities, more BR disease, and larger tumors than those treated with G-nP (all p < 0.05). The two regimens were equally effective in achieving an 80% decline in CA19-9 (p = 0.8). The R0 resection rates were similar (80%), but FOLFIRINOX was associated with a reduction in pN1 disease (56% vs. 72%; p = 0.028). The receipt of adjuvant therapy was similar (74 vs. 75%; p = 0.79). In the Cox regression analysis with adjustment for baseline and treatment-related variables (FOLFIRINOX vs. G-nP, age, gender, computed tomography (CT) tumor size, BR vs. R, pre-NAT CA19-9), regimen type was not associated with a survival benefit. In the IPW analysis of 166 patients, however, the average treatment effect of FOLFIRINOX was to increase OS by 4.9 months compared with G-nP (p = 0.012). CONCLUSIONS: Both FOLFIRINOX and G-nP are viable options for neoadjuvant treatment of PDA. In this study, neoadjuvant FOLFIRINOX was associated with a 4.9-month improvement in survival compared with G-nP after adjustment for covariates.

10 Clinical Trial Results of a prospective phase 2 clinical trial of induction gemcitabine/capecitabine followed by stereotactic ablative radiation therapy in borderline resectable or locally advanced pancreatic adenocarcinoma. 2018

Quan, Kimmen / Sutera, Philip / Xu, Karen / Bernard, Mark E / Burton, Steven A / Wegner, Rodney E / Zeh, Herbert / Bahary, Nathan / Stoller, Ronald / Heron, Dwight E. ·Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. · Department of Radiation Medicine, University of Kentucky, Lexington, Kentucky. · Department of Surgical Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. · Department of Medical Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. · Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Electronic address: herond2@upmc.edu. ·Pract Radiat Oncol · Pubmed #29291966.

ABSTRACT: PURPOSE: Stereotactic ablative radiation therapy's (SABR's) great conformity and short duration has become an attractive treatment modality. We report a phase 2 clinical trial to evaluate efficacy and safety of induction chemotherapy (ICT) followed by SABR in patient with borderline resectable (BR) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC). METHODS AND MATERIALS: Patients with biopsy-proven BR or LA PDAC were treated with four 21-day cycles of intravenous gemcitabine and oral capecitabine. Patients were restaged within 4 weeks after ICT by computed tomography and treated by 3-fraction SABR if no metastasis or progressive disease was identified. Patients were restaged 4 weeks following SABR to determine resectability. Tumor response was assessed with carbohydrate antigen 19-9. RESULTS: Thirty-five patients (19 BR/16 LA) were enrolled. The median age was 71.8 years (range, 50.6-81.1). ICT was completed in 91.4% (n = 32) of patients. All patients who completed ICT completed SABR. Of those 32 patients, 34.3% (n = 12: 10 BR, 2 LA) underwent pancreaticoduodenectomy and 11 of 12 (91.7%) received R0 resection. Median overall survival was 18.8, 28.3, and 14.3 months for the entire cohort, BR, and LA, respectively. The 2-year local progression-free survival (LPFS) was 44.9%, 40%, and 52% for the entire cohort, BR, and LA, respectively. For BR patients, multivariate analysis showed surgery was associated with better overall survival and LPFS. One-year LPFS for patients with surgery was 80% and 44% without surgery. Within the 15.4-month follow-up, no grade 3+ toxicity from SABR was observed. No significant quality of life change was observed before and after ICT, SABR, or surgery for BR or LA patients. CONCLUSIONS: This is the first prospective phase 2 study to investigate the feasibility and efficacy of a 12-week gemcitabine/capecitabine ICT followed by SABR for BR or LA PDAC. The results suggest excellent tolerability, high R0 resection rates, and acceptable posttreatment complications.

11 Clinical Trial Safety and Biologic Response of Pre-operative Autophagy Inhibition in Combination with Gemcitabine in Patients with Pancreatic Adenocarcinoma. 2015

Boone, Brian A / Bahary, Nathan / Zureikat, Amer H / Moser, A James / Normolle, Daniel P / Wu, Wen-Chi / Singhi, Aatur D / Bao, Phillip / Bartlett, David L / Liotta, Lance A / Espina, Virginia / Loughran, Patricia / Lotze, Michael T / Zeh, Herbert J. ·Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. · Institute for Hepatobiliary and Pancreatic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. · Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA. · Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA. · Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. lotzemt@upmc.edu. · Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. zehxhx@upmc.edu. ·Ann Surg Oncol · Pubmed #25905586.

ABSTRACT: PURPOSE: Autophagy is a cell survival mechanism that plays a critical role in pancreatic carcinogenesis. Murine studies have previously demonstrated that treatment with the late-autophagy inhibitor chloroquine in combination with chemotherapy limited tumor growth. METHODS: In this phase 1/2 trial, we examined treatment with hydroxychloroquine (HCQ) and gemcitabine for patients with pancreatic adenocarcinoma. The primary endpoints were safety and tolerability, evaluated by Storer's dose escalation design. Secondary endpoints were CA 19-9 biomarker response, R0 resection rates, survival, and correlative studies of autophagy. RESULTS: Thirty-five patients were enrolled. There were no dose-limiting toxicities and no grade 4/5 events related to treatment. Nineteen patients (61 %) had a decrease in CA 19-9 after treatment. Twenty-nine patients (94 %) underwent surgical resection as scheduled, with a 77 % R0 resection rate. Median overall survival was 34.8 months (95 % confidence interval, 11.57 to not reached). Patients who had more than a 51 % increase in the autophagy marker LC3-II in circulating peripheral blood mononuclear cells had improvement in disease-free survival (15.03 vs. 6.9 months, p < 0.05) and overall survival (34.83 vs. 10.83 months, p < 0.05). No outcome differences were demonstrated in the 81 % of patients with abnormal p53 expression assessed by immunohistochemistry in the resected specimens. CONCLUSIONS: Preoperative autophagy inhibition with HCQ plus gemcitabine is safe and well tolerated. Surrogate biomarker responses (CA 19-9) and surgical oncologic outcomes were encouraging. p53 status was not associated with adverse outcomes.

12 Clinical Trial Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. 2015

Le, Dung T / Wang-Gillam, Andrea / Picozzi, Vincent / Greten, Tim F / Crocenzi, Todd / Springett, Gregory / Morse, Michael / Zeh, Herbert / Cohen, Deirdre / Fine, Robert L / Onners, Beth / Uram, Jennifer N / Laheru, Daniel A / Lutz, Eric R / Solt, Sara / Murphy, Aimee Luck / Skoble, Justin / Lemmens, Ed / Grous, John / Dubensky, Thomas / Brockstedt, Dirk G / Jaffee, Elizabeth M. ·Dung T. Le, Beth Onners, Jennifer N. Uram, Daniel A. Laheru, Eric R. Lutz, Sara Solt, and Elizabeth M. Jaffee, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore · Tim F. Greten, National Cancer Institute, Bethesda, MD · Andrea Wang-Gillam, Siteman Cancer Center, Washington University, St Louis, MO · Vincent Picozzi, Virginia Mason Medical Center, Seattle, WA · Todd Crocenzi, Providence Portland Medical Center, Portland, OR · Gregory Springett, Moffitt Cancer Center, Tampa, FL · Michael Morse, Duke University Medical Center, Durham, NC · Herbert Zeh, University of Pittsburgh, Pittsburgh, PA · Deirdre Cohen, New York University Langone Medical Center · Robert L. Fine, Columbia University Medical Center, New York, NY · and Aimee Luck Murphy, Justin Skoble, Ed Lemmens, John Grous, Thomas Dubensky Jr, and Dirk G. Brockstedt, Aduro BioTech, Berkeley, CA. ·J Clin Oncol · Pubmed #25584002.

ABSTRACT: PURPOSE: GVAX pancreas, granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells, induces T-cell immunity to cancer antigens, including mesothelin. GVAX is administered with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells. CRS-207, live-attenuated Listeria monocytogenes-expressing mesothelin, induces innate and adaptive immunity. On the basis of preclinical synergy, we tested prime/boost vaccination with GVAX and CRS-207 in pancreatic adenocarcinoma. PATIENTS AND METHODS: Previously treated patients with metastatic pancreatic adenocarcinoma were randomly assigned at a ratio of 2:1 to two doses of Cy/GVAX followed by four doses of CRS-207 (arm A) or six doses of Cy/GVAX (arm B) every 3 weeks. Stable patients were offered additional courses. The primary end point was overall survival (OS) between arms. Secondary end points were safety and clinical response. RESULTS: A total of 90 patients were treated (arm A, n = 61; arm B, n = 29); 97% had received prior chemotherapy; 51% had received ≥ two regimens for metastatic disease. Mean number of doses (± standard deviation) administered in arms A and B were 5.5 ± 4.5 and 3.7 ± 2.2, respectively. The most frequent grade 3 to 4 related toxicities were transient fevers, lymphopenia, elevated liver enzymes, and fatigue. OS was 6.1 months in arm A versus 3.9 months in arm B (hazard ratio [HR], 0.59; P = .02). In a prespecified per-protocol analysis of patients who received at least three doses (two doses of Cy/GVAX plus one of CRS-207 or three of Cy/GVAX), OS was 9.7 versus 4.6 months (arm A v B; HR, 0.53; P = .02). Enhanced mesothelin-specific CD8 T-cell responses were associated with longer OS, regardless of treatment arm. CONCLUSION: Heterologous prime/boost with Cy/GVAX and CRS-207 extended survival for patients with pancreatic cancer, with minimal toxicity.

13 Clinical Trial First-in-man study of western reserve strain oncolytic vaccinia virus: safety, systemic spread, and antitumor activity. 2015

Zeh, Herbert J / Downs-Canner, Stephanie / McCart, J Andrea / Guo, Zong Sheng / Rao, Uma N M / Ramalingam, Lekshmi / Thorne, Stephen H / Jones, Heather L / Kalinski, Pawel / Wieckowski, Eva / O'Malley, Mark E / Daneshmand, Manijeh / Hu, Kang / Bell, John C / Hwang, Tae-Ho / Moon, Anne / Breitbach, Caroline J / Kirn, David H / Bartlett, David L. ·Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada. · Department of Pathology, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. · 1] Department of Pharmacology, Pusan National University, Busan, South Korea [2] SillaJen, Inc., Seoul, South Korea. · SillaJen, Inc., Seoul, South Korea. ·Mol Ther · Pubmed #25292189.

ABSTRACT: Oncolytic viral therapy utilizes a tumor-selective replicating virus which preferentially infects and destroys cancer cells and triggers antitumor immunity. The Western Reserve strain of vaccinia virus (VV) is the most virulent strain of VV in animal models and has been engineered for tumor selectivity through two targeted gene deletions (vvDD). We performed the first-in-human phase 1, intratumoral dose escalation clinical trial of vvDD in 16 patients with advanced solid tumors. In addition to safety, we evaluated signs of vvDD replication and spread to distant tumors, pharmacokinetics and pharmacodynamics, clinical and immune responses to vvDD. Dose escalation proceeded without dose-limiting toxicities to a maximum feasible dose of 3 × 10(9) pfu. vvDD replication in tumors was reproducible. vvDD genomes and/or infectious particles were recovered from injected (n = 5 patients) and noninjected (n = 2 patients) tumors. At the two highest doses, vvDD genomes were detected acutely in blood in all patients while delayed re-emergence of vvDD genomes in blood was detected in two patients. Fifteen of 16 patients exhibited late symptoms, consistent with ongoing vvDD replication. In summary, intratumoral injection of the oncolytic vaccinia vvDD was well-tolerated in patients and resulted in selective infection of injected and noninjected tumors and antitumor activity.

14 Clinical Trial Phase II study of induction fixed-dose rate gemcitabine and bevacizumab followed by 30 Gy radiotherapy as preoperative treatment for potentially resectable pancreatic adenocarcinoma. 2013

Van Buren, George / Ramanathan, Ramesh K / Krasinskas, Alyssa M / Smith, Ryan P / Abood, Gerard J / Bahary, Nathan / Lembersky, Barry C / Shuai, Yongli / Potter, Douglas M / Bartlett, David L / Zureikat, Amer H / Zeh, Herbert J / Moser, A James. ·Division of Surgical Oncology, UPMC Pancreatic Cancer Center, Pittsburgh, PA, USA. ·Ann Surg Oncol · Pubmed #23904005.

ABSTRACT: BACKGROUND: Eighty percent of patients with resected pancreatic ductal carcinoma (PDC) experience treatment failure within 2 years. We hypothesized that preoperative fixed-dose rate (FDR) gemcitabine (GEM) combined with the angiogenesis inhibitor bevacizumab (BEV) and accelerated 30 Gy radiotherapy (RT) would improve outcomes among patients with potentially resectable PDC. METHODS: This phase II trial tested induction FDR GEM (1,500 mg/m(2)) plus BEV (10 mg/kg IV) every 2 weeks for three cycles followed by accelerated RT (30 Gy in 10 fractions) plus BEV directed at gross tumor volume plus a 1-2 cm vascular margin. Subjects underwent laparoscopy and resection after day 85. Therapy was considered effective if the complete pathologic response rate exceeded 10 % and the margin-negative resection rate exceeded 80%. RESULTS: Fifty-nine subjects were enrolled; 29 had potential portal vein involvement. Two grade 4 (3.4%) and 19 grade 3 toxicities (32.8%) occurred. Four subjects manifested radiographic progression, and 10 had undetected carcinomatosis. Forty-three pancreatic resections (73%) were performed, including 19 portal vein resections (44%). Margin-negative outcomes were observed in 38 (88%, 95% confidence interval [CI] 75-96), with one complete pathologic response (2.3%; 95% CI 0.1-12). There were seven (6 grade 3; 1 grade 4) wound complications (13%). Median overall survival for the entire cohort was 16.8 months (95% CI 14.9-21.3) and 19.7 months (95% CI 16.5-28.2) after resection. CONCLUSIONS: Induction therapy with FDR GEM and BEV, followed by accelerated BEV/RT to 30 Gy, was well tolerated. Although both effectiveness criteria were achieved, survival outcomes were equivalent to published regimens.

15 Clinical Trial Phase II study of gemcitabine and erlotinib as adjuvant therapy for patients with resected pancreatic cancer. 2011

Bao, Philip Q / Ramanathan, Ramesh K / Krasinkas, Alyssa / Bahary, Nathan / Lembersky, Barry C / Bartlett, David L / Hughes, Steven J / Lee, Kenneth K / Moser, A James / Zeh, Herbert J. ·Department of Surgery, Stony Brook University Hospital, Stony Brook, NY, USA. ·Ann Surg Oncol · Pubmed #21104328.

ABSTRACT: BACKGROUND: There is currently no consensus about the most effective adjuvant therapy for adenocarcinoma of the pancreas. Both gemcitabine and erlotinib have been demonstrated to improve survival in patients with metastatic disease. This study was designed to evaluate the efficacy of gemcitabine and erlotinib as adjuvant therapy, and to explore potential biomarkers associated with response. METHODS: An institutional review board-approved single-center phase II trial of adjuvant biweekly fixed-dose rate gemcitabine (1500 mg/m(2)) and daily erlotinib (150 mg/day) for 4 months followed by maintenance erlotinib (150 mg/day) over 8 months was initiated. Primary end point was recurrence-free survival (RFS). Epidermal growth factor receptor (EGFR) expression in the resected tumors was assessed by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). RESULTS: The study completed planned accrual of 25 patients. Median follow-up was 18.2 (range 11.6-23.5) months. Recurrences were observed in 17 subjects (68%). Median RFS was 14.0 months (95% confidence interval [95% CI], 8.2-24.5) with 1-year and 2-year RFS of 56% (95% CI, 35-73) and 26% (95% CI, 6-52), respectively. Median overall survival was not reached. Estimated 1-year and 2-year overall survival was 84% (95% CI, 63-94) and 53% (95% CI, 22-76), respectively. Nine patients (36%) had a grade 3 event and only 1 (4%) had a grade 4 (neutropenia). Most toxicities were dermatologic, gastrointestinal, and constitutional. There were nonsignificant trends to longer RFS and lower recurrence rates while receiving therapy in subjects with fluorescence in situ hybridization-positive tumors and greater immunohistochemistry expression. CONCLUSIONS: Our phase II results suggest that adjuvant gemcitabine and erlotinib is a promising regimen that merits further investigation.

16 Article Outcomes and Risk Score for Distal Pancreatectomy with Celiac Axis Resection (DP-CAR): An International Multicenter Analysis. 2019

Klompmaker, Sjors / Peters, Niek A / van Hilst, Jony / Bassi, Claudio / Boggi, Ugo / Busch, Olivier R / Niesen, Willem / Van Gulik, Thomas M / Javed, Ammar A / Kleeff, Jorg / Kawai, Manabu / Lesurtel, Mickael / Lombardo, Carlo / Moser, A James / Okada, Ken-Ichi / Popescu, Irinel / Prasad, Raj / Salvia, Roberto / Sauvanet, Alain / Sturesson, Christian / Weiss, Matthew J / Zeh, Herbert J / Zureikat, Amer H / Yamaue, Hiroki / Wolfgang, Christopher L / Hogg, Melissa E / Besselink, Marc G / Anonymous2651208. ·Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. · Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA. · Department of Surgery, University of Utrecht Medical Center, Utrecht, The Netherlands. · Department of Surgery, Pancreas Institute University of Verona, Verona, Italy. · Division of General and Transplant Surgery, University of Pisa, Pisa, Italy. · Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany. · Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, Halle, Saale, Germany. · Second Department of Surgery, Wakayama Medical University, Wakayama, Japan. · Department of Surgery and Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France. · The Pancreas and Liver Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. · Center of General Surgery and Liver Transplant, Fundeni Clinical Institute, Bucharest, Romania. · Department of HPB and Transplant Services, National Health Service, Leeds, UK. · Department of HPB Surgery, Hôpital Beaujon, APHP, University Paris VII, Clichy, France. · Division of Surgery, Department for Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden. · Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA. · Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. · Department of Surgery, Northshore University HealthSystem, Chicago, IL, USA. · Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. m.g.besselink@amc.nl. ·Ann Surg Oncol · Pubmed #30610560.

ABSTRACT: BACKGROUND: Distal pancreatectomy with celiac axis resection (DP-CAR) is a treatment option for selected patients with pancreatic cancer involving the celiac axis. A recent multicenter European study reported a 90-day mortality rate of 16%, highlighting the importance of patient selection. The authors constructed a risk score to predict 90-day mortality and assessed oncologic outcomes. METHODS: This multicenter retrospective cohort study investigated patients undergoing DP-CAR at 20 European centers from 12 countries (model design 2000-2016) and three very-high-volume international centers in the United States and Japan (model validation 2004-2017). The area under receiver operator curve (AUC) and calibration plots were used for validation of the 90-day mortality risk model. Secondary outcomes included resection margin status, adjuvant therapy, and survival. RESULTS: For 191 DP-CAR patients, the 90-day mortality rate was 5.5% (95 confidence interval [CI], 2.2-11%) at 5 high-volume (≥ 1 DP-CAR/year) and 18% (95 CI, 9-30%) at 18 low-volume DP-CAR centers (P = 0.015). A risk score with age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, multivisceral resection, open versus minimally invasive surgery, and low- versus high-volume center performed well in both the design and validation cohorts (AUC, 0.79 vs 0.74; P = 0.642). For 174 patients with pancreatic ductal adenocarcinoma, the R0 resection rate was 60%, neoadjuvant and adjuvant therapies were applied for respectively 69% and 67% of the patients, and the median overall survival period was 19 months (95 CI, 15-25 months). CONCLUSIONS: When performed for selected patients at high-volume centers, DP-CAR is associated with acceptable 90-day mortality and overall survival. The authors propose a 90-day mortality risk score to improve patient selection and outcomes, with DP-CAR volume as the dominant predictor.

17 Article Incidence and comparative outcomes of periampullary cancer: A population-based analysis demonstrating improved outcomes and increased use of adjuvant therapy from 2004 to 2012. 2019

Hester, Caitlin A / Dogeas, Epameinondas / Augustine, Mathew M / Mansour, John C / Polanco, Patricio M / Porembka, Matthew R / Wang, Sam C / Zeh, Herbert J / Yopp, Adam C. ·Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, Dallas, Texas. · Department of Veterans Affairs North Texas Health Care System, Dallas, Texas. ·J Surg Oncol · Pubmed #30561818.

ABSTRACT: BACKGROUND AND OBJECTIVES: Periampullary adenocarcinoma (PAC) is stratified anatomically: ampullary adenocarcinoma (AA), distal cholangiocarcinoma (DCC), duodenal adenocarcinoma (DA), and pancreatic ductal adenocarcinoma (PDAC). We aimed to determine differences in incidence, prognosis, and treatment in stage-matched PAC patients in a longitudinal study. METHODS: PAC patients were identified in The National Cancer Database from 2004 to 2012. Clinicopathological variables were compared between subtypes. Covariate-adjusted treatment use and OS were compared. RESULTS: The 116 705 patients with PAC were identified: 1320 (9%) AA, 3732 (3%) DCC, 7142 (6%) DA, and 95 511 (82%) PDAC. DA, DCC, and PDAC were associated with worse survival compared with AA (hazard ratio [HR], 1.10; 95% CI, 1.1-1.1; HR, 1.50; 95% CI, 1.4-1.6, and HR, 1.90; 95% CI, 1.8-1.9). Among resected patients, DA was associated with improved survival compared with AA (HR, 0.70; 95% CI, 0.67-0.75); DCC and PDAC were associated with worse survival (HR, 1.41; 95% CI, 1.31-1.53 and HR, 2.041; 95% CI, 1.07-2.12). Resected AA, PDAC, and DA, but not DCC, demonstrated significantly improved survival over the studied period. While all patients had increased adjuvant therapy (AT) receipt over time (P < 0.001), only patients with PDAC had increased neoadjuvant therapy (NAT) receipt ( P < 0.001). CONCLUSION: Resected PDAC, AA, and DA were associated with clinically significant improved survival over time, mirroring a concurrent associated increased receipt of AT.

18 Article Inhibition of endoplasmic-reticulum-stress-mediated autophagy enhances the effectiveness of chemotherapeutics on pancreatic cancer. 2018

Thakur, Prakash C / Miller-Ocuin, Jennifer L / Nguyen, Khanh / Matsuda, Rina / Singhi, Aatur D / Zeh, Herbert J / Bahary, Nathan. ·Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Cancer Institute, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. · Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. · Smilow Cancer Hospital, Yale School of Medicine, New Haven, CT, USA. · University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA. · Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. · Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Cancer Institute, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. bahary@pitt.edu. ·J Transl Med · Pubmed #29986726.

ABSTRACT: BACKGROUND: Endoplasmic reticulum (ER) stress and its consequent unfolded protein response (UPR) are believed to be associated with progression, survival and chemoresistance of a variety of tumor cells through multiple cellular processes, including autophagy. Therefore, the ER stress-autophagy pathway presents a potential molecular target for therapeutic intervention. The objective of this study was to evaluate the therapeutic efficacy of ER stress and autophagy modulators in the context of pancreatic ductal adenocarcinoma (PDAC). METHODS: We first targeted IRE1α, an important regulator of the UPR, through STF-083010 treatment in PDAC cell lines in vitro. Chloroquine was then used to target autophagy and an optimal combination treatment was developed using chloroquine, sunitinib and gemcitabine. Apoptosis was analyzed using TUNEL assay, autophagy was estimated using lysotracker staining and electron microscopy, and UPR was analyzed using anti-GRP78 immunostaining and XBP1 splicing. Transplantation of PDAC derived KPCP1 and Panc02 cells in mouse pancreas were performed to study treatment efficacy in vivo. RESULTS: Suppression of the IRE1α by STF-083010 alone resulted in increased lysosomes and reduced viability of PDAC cells. Chloroquine treatment alone inhibited downstream autophagy but was insufficient in reducing PDAC cell growth. However, combining STF-083010 and chloroquine had additive anti-tumor efficacy when used with gemcitabine. Sunitinib alone caused abnormal maturation of the autolysosomes with increased intracellular multivesicular bodies and increased apoptosis evident in PDAC cells. Sunitinib showed a synergistic effect with chloroquine in reducing in vitro PDAC cell viability and significantly increased the efficacy of gemcitabine in human and murine PDAC cell lines. The anti-proliferative effect of gemcitabine was significantly increased when used in combination with sunitinib and/or chloroquine in both in vitro and in vivo PDAC models. The addition of sunitinib and/or chloroquine to gemcitabine, resulted in a significantly increased survival of the animals without noticeably increased toxicity. Sunitinib, gemcitabine and chloroquine treated mice showed a significant reduction of GRP78 expression, reduced cell proliferation and increased apoptosis in pancreas, compatible with a tumor response. CONCLUSIONS: Sunitinib combined with chloroquine reduces tumor growth through suppression of autophagy and increased apoptosis. Co-administration of modulators of ER stress-mediated autophagy with chemotherapy presents a novel therapeutic approach in PDAC.

19 Article Chloroquine reduces hypercoagulability in pancreatic cancer through inhibition of neutrophil extracellular traps. 2018

Boone, Brian A / Murthy, Pranav / Miller-Ocuin, Jennifer / Doerfler, W Reed / Ellis, Jarrod T / Liang, Xiaoyan / Ross, Mark A / Wallace, Callen T / Sperry, Jason L / Lotze, Michael T / Neal, Matthew D / Zeh, Herbert J. ·Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. booneba@upmc.edu. · UPMC Cancer Pavilion, University of Pittsburgh, Suite 417, 5150 Centre Ave, Pittsburgh, PA, 15232, USA. booneba@upmc.edu. · Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. · Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA. · Departments of Thoracic Surgery, University of Pittsburgh, Pittsburgh, PA, USA. · Immunology, University of Pittsburgh, Pittsburgh, PA, USA. · Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA. ·BMC Cancer · Pubmed #29929491.

ABSTRACT: BACKGROUND: The hypercoagulable state associated with pancreatic adenocarcinoma (PDA) results in increased risk of venous thromboembolism, leading to substantial morbidity and mortality. Recently, neutrophil extracellular traps (NETs), whereby activated neutrophils release their intracellular contents containing DNA, histones, tissue factor, high mobility group box 1 (HMGB1) and other components have been implicated in PDA and in cancer-associated thrombosis. METHODS: Utilizing an orthotopic murine PDA model in C57/Bl6 mice and patient correlative samples, we studied the role of NETs in PDA hypercoagulability and targeted this pathway through treatment with the NET inhibitor chloroquine. PAD4 and RAGE knockout mice, deficient in NET formation, were used to study the role of NETs in platelet aggregation, release of tissue factor and hypercoagulability. Platelet aggregation was assessed using collagen-activated impedance aggregometry. Levels of circulating tissue factor, the initiator of extrinsic coagulation, were measured using ELISA. Thromboelastograms (TEGs) were performed to assess hypercoagulability and changes associated with treatment. Correlative data and samples from a randomized clinical trial of preoperative gemcitabine/nab-paclitaxel with and without hydroxychloroquine were studied and the impact of treatment on venous thromboembolism (VTE) rate was evaluated. RESULTS: The addition of NETs to whole blood stimulated platelet activation and aggregation. DNA and the receptor for advanced glycation end products (RAGE) were necessary for induction of NET associated platelet aggregation. PAD4 knockout tumor-burdened mice, unable to form NETs, had decreased aggregation and decreased circulating tissue factor. The NET inhibitor chloroquine reduces platelet aggregation, reduces circulating tissue factor and decreases hypercoagulability on TEG. Review of correlative data from patients treated on a randomized protocol of preoperative chemotherapy with and without hydroxychloroquine demonstrated a reduction in peri-operative VTE rate from 30 to 9.1% with hydroxychloroquine that neared statistical significance (p = 0.053) despite the trial not being designed to study VTE. CONCLUSION: NETs promote hypercoagulability in murine PDA through stimulation of platelets and release of tissue factor. Chloroquine inhibits NETs and diminishes hypercoagulability. These findings support clinical study of chloroquine to lower rates of venous thromboembolism in patients with cancer. TRIAL REGISTRATION: This study reports correlative data from two clinical trials that registered with clinicaltrials.gov, NCT01128296 (May 21, 2010) and NCT01978184 (November 7, 2013).

20 Article CA19-9 on Postoperative Surveillance in Pancreatic Ductal Adenocarcinoma: Predicting Recurrence and Changing Prognosis over Time. 2018

Rieser, Caroline J / Zenati, Mazen / Hamad, Ahmad / Al Abbas, Amr I / Bahary, Nathan / Zureikat, Amer H / Zeh, Herbert J / Hogg, Melissa E. ·Department of Surgical Oncology, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Medical Oncology, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Surgical Oncology, University of Pittsburgh, Pittsburgh, PA, USA. hoggme@upmc.edu. ·Ann Surg Oncol · Pubmed #29786131.

ABSTRACT: BACKGROUND: Serum carbohydrate antigen 19-9 (CA19-9) correlates with response to therapy and overall survival (OS) for patients with pancreatic ductal adenocarcinoma (PDAC). This study aimed to define the chronologic relationship between CA19-9 elevation and radiographic recurrence to develop a model that can predict the risk of recurrence (RFS) and prognosis during interval surveillance for patients with resected PDAC. METHODS: A retrospective review examined patients undergoing surgery for pancreatic adenocarcinoma from January 2010 to May 2016. Their CA19-9 levels were classified at diagnosis, after surgery, and at 6-month surveillance intervals. Recurrence was defined by radiographic evidence. The CA19-9 levels were correlated with RFS and OS at every time point using multivariate analysis. RESULTS: The study examined 525 patients. Five patterns of CA19-9 were identified: normal ("nonsecretors," 18.5%), always elevated, and high at diagnosis but normal after resection involving three patterns with varied behavior during surveillance. These five patterns had implications for RFS and OS. When elevation of CA19-9, as assessed at 6-month intervals, was analyzed relative to detection of radiographic disease, CA19-9 had poor positive predictive value (average, 35%) but high negative predictive value (average, 92%) for radiographic recurrence. Conditional RFS showed that CA19-9 elevation did not equal radiographic recurrence but predicted subsequent RFS. Additionally, conditional OS showed that CA19-9 elevation alone was predictive at each time point. CONCLUSION: This study showed that CA19-9 patterns beyond the post-resection period predict RFS and OS. High CA19-9 frequently is discordant with recurrence on imaging and may precede it by more than 6 months. At each surveillance interval, CA19-9 is predictive of prognosis, which may help in counseling patients and could be used to direct protocols of salvage chemotherapy.

21 Article Health Disparities Impact Expected Treatment of Pancreatic Ductal Adenocarcinoma Nationally. 2018

Lutfi, Waseem / Zenati, Mazen S / Zureikat, Amer H / Zeh, Herbert J / Hogg, Melissa E. ·Scaife Hall, Pittsburgh, 15261, USA. · Scaife Hall, Pittsburgh, 15261, USA. hoggme@upmc.edu. ·Ann Surg Oncol · Pubmed #29691733.

ABSTRACT: BACKGROUND AND PURPOSE: National adherence to treatment guidelines for pancreatic ductal adenocarcinoma (PDAC) is a concern. This study aims to evaluate national expected treatment (ET) adherence for all PDAC stages. We hypothesized that both patient and hospital demographics are associated with national ET disparities for PDAC. METHODS: Clinical stage I through IV PDAC patients were evaluated using the National Cancer Data Base from 2004 to 2013. ET was defined as surgery for stage I/II, chemotherapy or radiation for stage III, and chemotherapy for stage IV. Unexpected treatment (UT) was defined as no surgery for stage I/II, surgery for stage III, and radiation or surgery for stage IV. No treatment is denoted by NT. RESULTS: 171,351 patients were identified, of whom 56,589 (33.0%) were stage I/II, 23,459 (13.7%) were stage III, and 91,303 (53.3%) were stage IV. Of patients, 48.4% received ET, 14.7% received UT, and 36.9% received NT. ET rates were 41.1% for stage I/II, 65.4% for stage III, and 48.5% for stage IV patients. On multivariable analysis, older age, non-White race, lower socioeconomic status, being uninsured or Medicaid, increased comorbidities, nonacademic centers, and low-volume hospitals were independent negative predictors of receiving ET (P < 0.01). On subgroup analysis, high-volume academic centers had similar negative predictors of ET despite higher ET adherence overall (P < 0.01). CONCLUSIONS: Patient and hospital factors impact ET of PDAC on a national level. These treatment disparities for PDAC are concerning, even at high-volume academic centers. Future studies need to identify the causes of treatment disparities for PDAC with intervention measures aimed to relieve treatment disparities.

22 Article RAGE-specific single chain Fv for PET imaging of pancreatic cancer. 2018

Kim, Hye-Yeong / Wang, Xiaolei / Kang, Rui / Tang, Daolin / Boone, Brian A / Zeh, Herbert J / Lotze, Michael T / Edwards, W Barry. ·Molecular Imaging Laboratory, Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. · Department of Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America. · Department of Bioengineering, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America. · Department of Immunology, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America. ·PLoS One · Pubmed #29529089.

ABSTRACT: Noninvasive detection of both early pancreatic neoplasia and metastases could enhance strategies to improve patient survival in this disease that is notorious for an extremely poor prognosis. There are almost no identifiable targets for non-invasive diagnosis by positron emission tomography (PET) for patients with pancreatic ductal adenocarcinoma (PDAC). Over-expression of the receptor for advanced glycation end products (RAGE) is found on the cell surface of both pre-neoplastic lesions and invasive PDAC. Here, a RAGE-specific single chain (scFv) was developed, specific for PET imaging in syngeneic mouse models of PDAC. An anti-RAGE scFv conjugated with a sulfo-Cy5 fluorescence molecule showed high affinity and selectivity for RAGE expressing pancreatic tumor cells and genetically engineered KRASG12D mouse models of PDAC. An in vivo biodistribution study was performed with the 64Cu-radiolabled scFv in a syngeneic murine pancreatic cancer model, demonstrating both the feasibility and potential of an anti-RAGE scFv for detection of PDAC. These studies hold great promise for translation into the clinic.

23 Article Loss of Chromatin-Remodeling Proteins and/or CDKN2A Associates With Metastasis of Pancreatic Neuroendocrine Tumors and Reduced Patient Survival Times. 2018

Roy, Somak / LaFramboise, William A / Liu, Ta-Chiang / Cao, Dengfeng / Luvison, Alyssa / Miller, Caitlyn / Lyons, Maureen A / O'Sullivan, Roderick J / Zureikat, Amer H / Hogg, Melissa E / Tsung, Allan / Lee, Kenneth K / Bahary, Nathan / Brand, Randall E / Chennat, Jennifer S / Fasanella, Kenneth E / McGrath, Kevin / Nikiforova, Marina N / Papachristou, Georgios I / Slivka, Adam / Zeh, Herbert J / Singhi, Aatur D. ·Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri. · Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania. · Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Electronic address: zehxhx@upmc.edu. · Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Electronic address: singhiad@upmc.edu. ·Gastroenterology · Pubmed #29486199.

ABSTRACT: Despite prognostic grading and staging systems, it is a challenge to predict outcomes for patients with pancreatic neuroendocrine tumors (PanNETs). Sequencing studies of PanNETs have identified alterations in death domain-associated protein (DAXX) and alpha-thalassemia/mental retardation X-linked chromatin remodeler (ATRX). In tumors, mutations in DAXX or ATRX and corresponding loss of protein expression correlate with shorter times of disease-free survival and disease-specific survival of patients. However, DAXX or ATRX proteins were lost in only 50% of distant metastases analyzed. We performed whole-exome sequencing analyses of 20 distant metastases from 20 patients with a single nonsyndrome, nonfunctional PanNET. We found distant metastases contained alterations in multiple endocrine neoplasia type 1 (MEN1) (n = 8), ATRX (n = 5), DAXX (n = 5), TSC2 (n = 3), and DEP domain containing 5 (DEPDC5) (n = 3). We found copy number loss of cyclin dependent kinase inhibitor 2A (CDKN2A) in 15 metastases (75%) and alterations in genes that regulate chromatin remodeling, including set domain containing 2 (SETD2) (n = 4), AT-rich interaction domain 1A (ARID1A) (n = 2), chromodomain helicase DNA binding protein 8 (CHD8) (n = 2), and DNA methyl transferase 1 (DNMT1) (n = 2). In a separate analysis of 347 primary PanNETs, we found loss or deletion of DAXX and ATRX, disruption of SETD2 function (based on loss of H3 lysine 36 trimethylation), loss of ARID1A expression or deletions in CDKN2A in 81% of primary PanNETs with distant metastases. Among patients with loss or deletion of at least 1 of these proteins or genes, 39% survived disease-free for 5 years and 44% had disease-specific survival times of 10 years. Among patients without any of these alterations, 98% survived disease-free for 5 years and 95% had disease-specific survival times of 10 years. Therefore, primary PanNETs with loss of DAXX, ATRX, H3 lysine 36 trimethylation, ARID1A, and/or CDKN2A associate with shorter survival times of patients. Our findings indicate that alterations in chromatin-remodeling genes and CDKN2A contribute to metastasis of PanNETs.

24 Article Postoperative narcotic use is associated with development of clinically relevant pancreatic fistulas after distal pancreatectomy. 2018

Kowalsky, Stacy J / Zenati, Mazen S / Dhir, Mashaal / Schaefer, Eric G / Dopsovic, Andrew / Lee, Kenneth K / Hogg, Melissa E / Zeh, Herbert J / Vollmer, Charles M / Zureikat, Amer H. ·Division of Surgical Oncology, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA. · Division of Biostatistics, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA. · Pharmacy Department, University of Pittsburgh Medical Center, Pittsburgh, PA. · University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. · Division of Surgical Oncology, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA. Electronic address: zureikatah@upmc.edu. ·Surgery · Pubmed #29269087.

ABSTRACT: BACKGROUND: Various strategies to decrease postoperative pancreatic fistula after a distal pancreatectomy have proved unsuccessful. Because narcotics can cause spasm of the sphincter of Oddi and thereby increase pressure within the pancreatic duct stump, we hypothesized that increased narcotic use would be associated with increased occurrence of clinically relevant postoperative pancreatic fistula after distal pancreatectomy. METHODS: Retrospective analysis of consecutive distal pancreatectomies (2011-2016) was performed. Postoperative narcotic use was calculated in morphine equivalents. Postoperative pancreatic fistula was graded according to the International Study Group on Pancreatic Surgery. Perioperative variables were evaluated using multivariate logistic regression with clinically relevant postoperative pancreatic fistula as the dependent outcome. RESULTS: In the study, 310 distal pancreatectomies were analyzed (61% robotic, 20% open, 19% laparoscopic). Average age was 62 (53% female), and median total dose of morphine equivalents was 424 mg (interquartile range 242-768). Clinically relevant postoperative pancreatic fistula occurred in 21.6%. Clinically relevant postoperative pancreatic fistula and not clinically relevant postoperative pancreatic fistula cohorts were similar in most demographics and operative variables, but clinically relevant postoperative pancreatic fistula patients had fewer stapled transections (80 vs 90%, P=.025), less pancreatic cancers (11 vs 35%, P<.001), and greater median total morphine equivalents (577 vs 403 mg, P < .009). On univariate analysis, clinically relevant postoperative pancreatic fistula was associated with body mass index, nonstapled transection, suture ligation of the PD, a nonpancreatic cancer pathology, prophylactic octreotide, and total morphine equivalents >424 (cohort median). On multivariate analysis, only pancreatic cancer pathology was protective against a clinically relevant postoperative pancreatic fistula (odds ratio 0.24, confidence interval, 0.10-0.50, P=.001), while increasing total morphine equivalents were predictive of a clinically relevant postoperative pancreatic fistula (odds ratio 1.13, confidence interval, 1.01-1.27, P=.035) with a 13% increased risk for every approximate ≈100 mg increase in total morphine equivalents. CONCLUSION: In this retrospective analysis, postoperative narcotic use was associated with the development of clinically relevant postoperative pancreatic fistula after distal pancreatectomy. Limiting narcotic use may be one of the few available mitigating strategies against the development of a clinically relevant postoperative pancreatic fistula after distal pancreatectomy.

25 Article JTC801 Induces pH-dependent Death Specifically in Cancer Cells and Slows Growth of Tumors in Mice. 2018

Song, Xinxin / Zhu, Shan / Xie, Yangchun / Liu, Jiao / Sun, Lingyi / Zeng, Dexing / Wang, Pengcheng / Ma, Xiaochao / Kroemer, Guido / Bartlett, David L / Billiar, Timothy R / Lotze, Michael T / Zeh, Herbert J / Kang, Rui / Tang, Daolin. ·The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, Guangdong, 510510, China; Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. · The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, Guangdong, 510510, China. · Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. · Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. · Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania. · Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Institut National de la Santé et de la Recherche Médicale, Paris, France; Université Pierre et Marie Curie, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden. · The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, Guangdong, 510510, China; Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: tangd2@upmc.edu. ·Gastroenterology · Pubmed #29248440.

ABSTRACT: BACKGROUND & AIMS: Maintenance of acid-base homeostasis is required for normal physiology, metabolism, and development. It is not clear how cell death is activated in response to changes in pH. We performed a screen to identify agents that induce cell death in a pH-dependent manner (we call this alkaliptosis) in pancreatic ductal adenocarcinoma cancer (PDAC) cells and tested their effects in mice. METHODS: We screened a library of 254 compounds that interact with G-protein-coupled receptors (GPCRs) to identify those with cytotoxic activity against a human PDAC cell line (PANC1). We evaluated the ability of JTC801, which binds the opiod receptor and has analgesic effects, to stimulate cell death in human PDAC cell lines (PANC1, MiaPaCa2, CFPAC1, PANC2.03, BxPc3, and CAPAN2), mouse pancreatic cancer-associated stellate cell lines, primary human pancreatic ductal epithelial cells, and 60 cancer cell lines (the NCI-60 panel). Genes encoding proteins in cell death and GPCR signaling pathways, as well as those that regulate nuclear factor-κB (NF-κB) activity, were knocked out, knocked down, or expressed from transgenes in cancer cell lines. JTC801 was administered by gavage to mice with xenograft tumors, C57BL/6 mice with orthographic pancreatic tumors grown from Pdx1-Cre;KRas RESULTS: Exposure of human PDAC cell lines (PANC1 and MiaPaCa2) to JTC801 did not induce molecular markers of apoptosis (cleavage of caspase 3 or poly [ADP ribose] polymerase [PARP]), necroptosis (interaction between receptor-interacting serine-threonine kinase 3 [RIPK3] and mixed lineage kinase domain like pseudokinase [MLKL]), or ferroptosis (degradation of glutathione peroxidase 4 [GPX4]). Inhibitors of apoptosis (Z-VAD-FMK), necroptosis (necrosulfonamide), ferroptosis (ferrostatin-1), or autophagy (hydroxychloroquine) did not prevent JTC801-induced death of PANC1 or MiaPaCa2 cells. The cytotoxic effects of JTC801 in immortalized fibroblast cell lines was not affected by disruption of genes that promote apoptosis (Bax CONCLUSIONS: In a screen of agents that interact with GPCR pathways, we found JTC801 to induce pH-dependent cell death (alkaliptosis) specifically in cancer cells such as PDAC cells, by reducing expression of CA9. Levels of CA9 are increased in human cancer tissues. JTC801 might be developed for treatment of pancreatic cancer.

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