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Pancreatic Neoplasms: HELP
Articles by Herbert J. Zeh
Based on 101 articles published since 2010
(Why 101 articles?)
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Between 2010 and 2020, H. Zeh wrote the following 101 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5
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 Current concepts in molecular genetics and management guidelines for pancreatic cystic neoplasms: an essential update for radiologists. 2018

Kulzer, Matthew / Singhi, Aatur D / Furlan, Alessandro / Heller, Matthew T / Katabathina, Venkata S / Mcgrath, Kevin M / Zeh, Herbert J / Zureikat, Amer / Dasyam, Anil K. ·Department of Radiology, University of Pittsburgh Medical Center, Radiology Suite 200 East Wing E2051B, 200 Lothrop Street, Pittsburgh, PA, 15213, USA. · Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. · Department of Radiology, University of Texas at San Antonio, San Antonio, TX, USA. · Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. · Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. · Department of Radiology, University of Pittsburgh Medical Center, Radiology Suite 200 East Wing E2051B, 200 Lothrop Street, Pittsburgh, PA, 15213, USA. anil.dasyam@gmail.com. ·Abdom Radiol (NY) · Pubmed #29404638.

ABSTRACT: Cystic neoplasms in the pancreas are encountered frequently on imaging, often detected incidentally during evaluation for other conditions. They can have a variety of clinical and imaging presentations, and similarly, wide-ranging prognostic and treatment implications. In the majority, imaging helps in diagnosis of pancreatic cystic neoplasms (PCNs) and guides management decisions. But, a significant minority of the PCNs remain indeterminate. There have been multiple recent advances in biomarkers and molecular genetics which will likely prove helpful in risk stratification of PCNs. Several prominent national and international societies, as well as consensus groups have put forth recommendations to help guide management of PCNs. The purpose of this article is to discuss the role of imaging in evaluation of PCNs, review the recent advances in molecular genetics and pancreatic cyst fluid analysis, and analyze the pros and cons of major evidence-based and consensus guidelines for management of PCNs.

3 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.

4 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.

5 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.

6 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.

7 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.

8 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.

9 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.

10 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.

11 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.

12 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.

13 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.

14 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.

15 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.

16 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.

17 Article Assessment of Response to Neoadjuvant Therapy Using CT Texture Analysis in Patients With Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma. 2020

Borhani, Amir A / Dewan, Rohit / Furlan, Alessandro / Seiser, Natalie / Zureikat, Amer H / Singhi, Aatur D / Boone, Brian / Bahary, Nathan / Hogg, Melissa E / Lotze, Michael / Zeh, Herbert J / Tublin, Mitchell E. ·Department of Radiology, Division of Abdominal Imaging, University of Pittsburgh Medical Center, Ste 200 E Wing, 200 Lothrop St, Pittsburgh, PA 15213. · Present address: Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA. · Department of Surgery, Division of Gastrointestinal Surgical Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA. · Present address: Transplant and Hepato-Pancreato-Biliary (HPB) Institute, St. Vincent Medical Center, Los Angeles, CA. · Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA. · Present address: Department of Surgery, Division of Surgical Oncology, West Virginia University, Morgantown, WV. · Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA. · Present address: Department of Surgery, NorthShore University Hospital, Evanston, IL. · Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA. · Present address: Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX. ·AJR Am J Roentgenol · Pubmed #31799875.

ABSTRACT:

18 Article Recurrent Rearrangements in PRKACA and PRKACB in Intraductal Oncocytic Papillary Neoplasms of the Pancreas and Bile Duct. 2020

Singhi, Aatur D / Wood, Laura D / Parks, Emma / Torbenson, Michael S / Felsenstein, Matthäus / Hruban, Ralph H / Nikiforova, Marina N / Wald, Abigail I / Kaya, Cihan / Nikiforov, Yuri E / Favazza, Laura / He, Jin / McGrath, Kevin / Fasanella, Kenneth E / Brand, Randall E / Lennon, Anne Marie / Furlan, Alessandro / Dasyam, Anil K / Zureikat, Amer H / Zeh, Herbert J / Lee, Kenneth / Bartlett, David L / Slivka, Adam. ·Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Electronic address: singhiad@upmc.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland. · Carnegie Mellon University, Pittsburgh, Pennsylvania. · Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, Minnesota. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany. · Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · Department of Surgery, University of Texas Southwestern, Dallas, Texas. ·Gastroenterology · Pubmed #31678302.

ABSTRACT: BACKGROUND & AIMS: Intraductal oncocytic papillary neoplasms (IOPNs) of the pancreas and bile duct contain epithelial cells with numerous, large mitochondria and are cystic precursors to pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA), respectively. However, IOPNs do not have the genomic alterations found in other pancreatobiliary neoplasms. In fact, no recurrent genomic alterations have been described in IOPNs. PDACs without activating mutations in KRAS contain gene rearrangements, so we investigated whether IOPNs have recurrent fusions in genes. METHODS: We analyzed 20 resected pancreatic IOPNs and 3 resected biliary IOPNs using a broad RNA-based targeted sequencing panel to detect cancer-related fusion genes. Four invasive PDACs and 2 intrahepatic CCAs from the same patients as the IOPNs, were also available for analysis. Samples of pancreatic cyst fluid (n = 5, collected before surgery) and bile duct brushings (n = 2) were analyzed for translocations. For comparison, we analyzed pancreatobiliary lesions from 126 patients without IOPN (controls). RESULTS: All IOPNs evaluated were found to have recurring fusions of ATP1B1-PRKACB (n = 13), DNAJB1-PRKACA (n = 6), or ATP1B1-PRKACA (n = 4). These fusions also were found in corresponding invasive PDACs and intrahepatic CCAs, as well as in matched pancreatic cyst fluid and bile duct brushings. These gene rearrangements were absent from all 126 control pancreatobiliary lesions. CONCLUSIONS: We identified fusions in PRKACA and PRKACB genes in pancreatic and biliary IOPNs, as well as in PDACs and pancreatic cyst fluid and bile duct cells from the same patients. We did not identify these gene fusions in 126 control pancreatobiliary lesions. These fusions might be used to identify patients at risk for IOPNs and their associated invasive carcinomas.

19 Article Integrating next-generation sequencing to endoscopic retrograde cholangiopancreatography (ERCP)-obtained biliary specimens improves the detection and management of patients with malignant bile duct strictures. 2020

Singhi, Aatur D / Nikiforova, Marina N / Chennat, Jennifer / Papachristou, Georgios I / Khalid, Asif / Rabinovitz, Mordechai / Das, Rohit / Sarkaria, Savreet / Ayasso, M Samir / Wald, Abigail I / Monaco, Sara E / Nalesnik, Michael / Ohori, N Paul / Geller, David / Tsung, Allan / Zureikat, Amer H / Zeh, Herbert / Marsh, J Wallis / Hogg, Melissa / Lee, Kenneth / Bartlett, David L / Pingpank, James F / Humar, Abhinav / Bahary, Nathan / Dasyam, Anil K / Brand, Randall / Fasanella, Kenneth E / McGrath, Kevin / Slivka, Adam. ·Department of Pathology, University of Pittsburgh Medical Center Health System, Pittsburgh, Pennsylvania, USA. · Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Department of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. · Department of Pathology, Division of Transplant Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Department of Clinical Sciences, Surgery, University of Texas Southwestern, Dallas, Texas, USA. · Department of Surgery, West Virginia University Health Sciences Center, Morgantown, West Virginia, USA. · Department of Surgery, NorthShore University Health System, Evanston, Illinois, USA. · Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. · Department of Transplant, Thomas E Starzl Transplant Instiute University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. · Division of Hematology and Oncology, UPMC Cancer Centers, Pittsburgh, Pennsylvania, USA. · Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. ·Gut · Pubmed #30971436.

ABSTRACT: OBJECTIVE: Despite improvements in imaging, serum CA19-9 and pathological evaluation, differentiating between benign and malignant bile duct strictures remains a diagnostic conundrum. Recent developments in next-generation sequencing (NGS) have opened new opportunities for early detection and management of cancers but, to date, have not been rigorously applied to biliary specimens. DESIGN: We prospectively evaluated a 28-gene NGS panel (BiliSeq) using endoscopic retrograde cholangiopancreatography-obtained biliary specimens from patients with bile duct strictures. The diagnostic performance of serum CA19-9, pathological evaluation and BiliSeq was assessed on 252 patients (57 trainings and 195 validations) with 346 biliary specimens. RESULTS: The sensitivity and specificity of BiliSeq for malignant strictures was 73% and 100%, respectively. In comparison, an elevated serum CA19-9 and pathological evaluation had sensitivities of 76% and 48%, and specificities of 69% and 99%, respectively. The combination of BiliSeq and pathological evaluation increased the sensitivity to 83% and maintained a specificity of 99%. BiliSeq improved the sensitivity of pathological evaluation for malignancy from 35% to 77% for biliary brushings and from 52% to 83% for biliary biopsies. Among patients with primary sclerosing cholangitis (PSC), BiliSeq had an 83% sensitivity as compared with pathological evaluation with an 8% sensitivity. Therapeutically relevant genomic alterations were identified in 20 (8%) patients. Two patients with CONCLUSIONS: The combination of BiliSeq and pathological evaluation of biliary specimens increased the detection of malignant strictures, particularly in patients with PSC. Additionally, BiliSeq identified alterations that may stratify patients for specific anticancer therapies.

20 Article Results from a Phase IIb, Randomized, Multicenter Study of GVAX Pancreas and CRS-207 Compared with Chemotherapy in Adults with Previously Treated Metastatic Pancreatic Adenocarcinoma (ECLIPSE Study). 2019

Le, Dung T / Picozzi, Vincent J / Ko, Andrew H / Wainberg, Zev A / Kindler, Hedy / Wang-Gillam, Andrea / Oberstein, Paul / Morse, Michael A / Zeh, Herbert J / Weekes, Colin / Reid, Tony / Borazanci, Erkut / Crocenzi, Todd / LoConte, Noelle K / Musher, Benjamin / Laheru, Dan / Murphy, Aimee / Whiting, Chan / Nair, Nitya / Enstrom, Amanda / Ferber, Sandy / Brockstedt, Dirk G / Jaffee, Elizabeth M. ·The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. dle@jhmi.edu. · Virginia Mason Medical Center, Seattle, Washington. · University of California San Francisco, San Francisco, California. · University of California Los Angeles, Los Angeles, California. · University of Chicago Medical Center, Chicago, Illinois. · Washington University School of Medicine in St. Louis, St. Louis, Missouri. · Columbia University Medical Center, New York, New York. · Duke University Medical Center, Durham, North Carolina. · University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · University of Colorado Cancer Center, Aurora, Colorado. · University of San Diego Moores Cancer Center, La Jolla, California. · HonorHealth, Tgen, Scottsdale, Arizona. · Providence Cancer Center, Portland, Oregon. · University of Wisconsin Carbone Cancer Center, Madison, Wisconsin. · Baylor College of Medicine, Houston, Texas. · The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. · Aduro Biotech, Berkeley, California. · Array Biostatistics, LLC, Chicago, Illinois. ·Clin Cancer Res · Pubmed #31126960.

ABSTRACT: PURPOSE: Limited options exist for patients with advanced pancreatic cancer progressing after 1 or more lines of therapy. A phase II study in patients with previously treated metastatic pancreatic cancer showed that combining GVAX pancreas (granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated PATIENTS AND METHODS: Patients with previously treated metastatic pancreatic adenocarcinoma were randomized 1:1:1 to receive Cy/GVAX + CRS-207 (arm A), CRS-207 (arm B), or physician's choice of single-agent chemotherapy (arm C). The primary cohort included patients who had failed ≥2 prior lines of therapy, including gemcitabine. The primary objective compared OS between arms A and C in the primary cohort. The second-line cohort included patients who had received 1 prior line of therapy. Additional objectives included OS between all treatment arms, safety, and tumor responses. RESULTS: The study did not meet its primary efficacy endpoint. At the final study analysis, median OS [95% confidence interval (CI)] in the primary cohort ( CONCLUSIONS: The combination of Cy/GVAX + CRS-207 did not improve survival over chemotherapy. (ClinicalTrials.gov ID: NCT02004262)

21 Article A Combination of Robotic Approach and ERAS Pathway Optimizes Outcomes and Cost for Pancreatoduodenectomy. 2019

Kowalsky, Stacy J / Zenati, Mazen S / Steve, Jennifer / Esper, Stephen A / Lee, Kenneth K / Hogg, Melissa E / Zeh, Herbert J / 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. · Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA. ·Ann Surg · Pubmed #31082913.

ABSTRACT: OBJECTIVE: To determine the impact of enhanced recovery after surgery (ERAS) pathway implementation on outcomes, and cost of robotic and open pancreatoduodenectomy. BACKGROUND: ERAS pathways have shown benefit in open pancreatoduodenectomy (OPD). The impact of ERAS on robotic pancreatoduodenectomy (RPD) is unknown. METHODS: Retrospective review of consecutive RPD and OPDs in the pre-ERAS (July, 2014-July, 2015) and ERAS (July, 2015-July, 2016) period. Univariate and multivariate logistic regression was used to determine impact of ERAS and operative approach alone, or in combination (pre-ERAS + OPD, pre-ERAS + RPD, ERAS + OPD, ERAS + RPD) on length of hospital stay (LOS) and overall cost. RESULTS: In all, 254 consecutive pancreatoduodenectomies (RPD 62%, OPD 38%) were analyzed (median age 67, 47% female). ERAS patients had shorter LOS (6 vs 8 days; P = 0.004) and decreased overall cost (USD 20,362 vs 24,277; P = 0.001) compared with non-ERAS patients, whereas RPD was associated with decreased LOS (7 vs 8 days; P = 0.0001) and similar cost compared with OPD. On multivariable analysis (MVA), RPD was predictive of shorter LOS [odds ratio (OR) 0.33, confidence interval (CI) 0.16-0.67, P = 0.002), whereas ERAS was protective against high cost (OR 0.57, CI 0.33-0.97, P = 0.037). On MVA, when combining operative approach with ERAS pathway use, a combined ERAS + RPD approach was associated with reduced LOS and optimal cost compared with other combinations (pre-ERAS + OPD, pre-ERAS + RPD, ERAS + OPD). CONCLUSION: ERAS implementation is independently associated with cost savings for pancreatoduodenectomy. A combination of ERAS and robotic approach synergistically decreases hospital stay and overall cost compared with other strategies.

22 Article The platelet NLRP3 inflammasome is upregulated in a murine model of pancreatic cancer and promotes platelet aggregation and tumor growth. 2019

Boone, Brian A / Murthy, Pranav / Miller-Ocuin, Jennifer L / Liang, Xiaoyan / Russell, Kira L / Loughran, Patricia / Gawaz, Meinrad / Lotze, Michael T / Zeh, Herbert J / Vogel, Sebastian. ·Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Surgery, West Virginia University, Morgantown, WV, USA. · Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University Tübingen, Tübingen, Germany. · Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA. · Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. sebastian.vogel@nih.gov. · Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University Tübingen, Tübingen, Germany. sebastian.vogel@nih.gov. · Department of Perioperative Medicine, Pediatric Anesthesiology and Critical Care Section, National Institutes of Health Clinical Center, NIH, 10 Center Drive, Building 10 Room B1B50, Bethesda, MD, 20814, USA. sebastian.vogel@nih.gov. ·Ann Hematol · Pubmed #31020347.

ABSTRACT: Platelets are activated in solid cancers, including pancreatic ductal adenocarcinoma (PDA), a highly aggressive malignancy with a devastating prognosis and limited therapeutic options. The mechanisms by which activated platelets regulate tumor progression are poorly understood. The nucleotide-binding domain leucine-rich repeat containing protein 3 (NLRP3) inflammasome is a key inflammatory mechanism recently identified in platelets, which controls platelet activation and aggregation. In an orthotopic PDA mouse model involving surgical implantation of Panc02 murine cancer cells into the tail of the pancreas, we show that the NLRP3 inflammasome in circulating platelets is upregulated in pancreatic cancer. Pharmacological inhibition or genetic ablation of NLRP3 in platelets resulted in decreased platelet activation, platelet aggregation, and tumor progression. Moreover, interfering with platelet NLRP3 signaling significantly improved survival of tumor-bearing mice. Hence, the platelet NLRP3 inflammasome plays a critical role in PDA and might represent a novel therapeutic target.

23 Article Robotic pancreatoduodenectomy with vascular resection: Outcomes and learning curve. 2019

Beane, Joal D / Zenati, Mazen / Hamad, Ahmad / Hogg, Melissa E / Zeh, Herbert J / Zureikat, Amer H. ·University of Pittsburgh Medical Center, Division of Surgical Oncology, PA. · NorthShore University Health System, Evanston, IL. · University of Texas Southwestern Medical Center, Dallas, TX. · University of Pittsburgh Medical Center, Division of Surgical Oncology, PA. Electronic address: zureikatah@upmc.edu. ·Surgery · Pubmed #30905468.

ABSTRACT: INTRODUCTION: The safety, efficacy, and learning curve for robotic pancreatoduodenecomy has been reported; however, the outcomes and learning curve of robotic pancreatoduodenecomy with vascular resections remain unknown. Our aim was to evaluate the outcomes of robotic pancreatoduodenecomy with vascular resections compared with robotic pancreatoduodenecomy without vascular resection and to identify the learning curve and benchmarks for improved performance during robotic pancreatoduodenecomy with vascular resections. METHODS: A retrospective review of consecutive patients who underwent robotic pancreatoduodenecomy with vascular resections and robotic pancreatoduodenecomy between 2011 and 2017. Patients were analyzed consecutively, and a cumulative sum analysis was performed to detect improvements in performance over time. RESULTS: Of 380 consecutive robotic pancreatoduodenecomy patients, 50 (13%) underwent robotic pancreatoduodenecomy with vascular resections. Compared with robotic pancreatoduodenecomy, robotic pancreatoduodenecomy with vascular resections were more likely to have had pancreatic adenocarcinoma (84% vs 42%) and had received neoadjuvant therapy (35% vs 65%, P < .01). Robotic pancreatoduodenecomy with vascular resections operative time revealed a steady, significant decrease (Rho = -0.38, p = .006) with marked initial improvement after the first 8 cases and maturation of the learning curve after 35 cases. A significant decrease in duration of the hospital stay was observed throughout the experience (Rho = -0.528, P < .0001), whereas margin status, pancreatic fistula, major morbidity, and mortality remained constant and comparable to robotic pancreatoduodenecomy alone. CONCLUSION: Robotic pancreatoduodenectomy with vascular resections is safe and feasible. For surgeons who have surpassed the learning curve of robotic pancreatoduodenectomy, it appears that improvements in performance of robotic pancreatoduodenecomy with vascular resections can be observed after 35 cases.

24 Article Risk of Venous Thromboembolism for Patients with Pancreatic Ductal Adenocarcinoma Undergoing Preoperative Chemotherapy Followed by Surgical Resection. 2019

Boone, Brian A / Zenati, Mazen S / Rieser, Caroline / Hamad, Ahmad / Al-Abbas, Amr / Zureikat, Amer H / Hogg, Melissa E / Neal, Matthew D / Zeh, Herbert J. ·Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. Brian.boone@hsc.wvu.edu. · Division of Surgical Oncology, Department of Surgery, West Virginia University, Morgantown, WV, USA. Brian.boone@hsc.wvu.edu. · Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Surgery, UT Southwestern, Dallas, TX, USA. ·Ann Surg Oncol · Pubmed #30652227.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is associated with a hypercoagulable state, resulting in a high risk of venous thromboembolism (VTE). Risk of VTE is well established for patients receiving chemotherapy for advanced disease and during the perioperative period for patients undergoing surgical resection. However, data are lacking for patients undergoing neoadjuvant treatment followed by resection, who may have a unique risk of VTE because of exposure to both chemotherapy and surgery. METHODS: The study included patients with PDA who underwent neoadjuvant therapy followed by surgery from 2007 to June 2017. Development of VTE was evaluated from the start of treatment through the 90-day postoperative period. Risk factors including demographic, treatment, and laboratory variables were evaluated. RESULTS: The study investigated 426 patients receiving neoadjuvant therapy before surgical resection. Of these patients, 20% had a VTE within 90 days postoperatively (n = 87), and 70% of the VTE occurred during the postoperative period. The VTE included pulmonary embolism (30%), deep vein thrombosis (33%), and thrombosis of the portal vein (PV)/superior mesenteric vein (SMV) (40%). A pretreatment hemoglobin level lower than 10 g/dL and a platelet count higher than 443 were independently associated with VTE during neoadjuvant treatment. The independent predictors of postoperative VTE were a body mass index higher than 35 kg/m CONCLUSIONS: Venous thromboembolism during neoadjuvant therapy and the subsequent perioperative period is common and has a significant impact on outcome. Further study into novel thromboprophylaxis measures or protocols during neoadjuvant treatment and the perioperative period is warranted.

25 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 / Anonymous4750974. ·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.

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