Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Pancreatic Neoplasms: HELP
Articles by Williams G. Hawkins
Based on 56 articles published since 2009
(Why 56 articles?)
||||

Between 2009 and 2019, W. Hawkins wrote the following 56 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Guideline Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. 2017

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

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

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

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

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

3 Guideline Pancreatic adenocarcinoma. 2010

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

ABSTRACT: -- No abstract --

4 Review Therapeutic targeting of pancreatic cancer utilizing sigma-2 ligands. 2012

Hornick, John R / Spitzer, Dirk / Goedegebuure, Peter / Mach, Robert H / Hawkins, William G. ·Department of Surgery, Harvard Medical School, Boston, MA, USA. ·Surgery · Pubmed #22763259.

ABSTRACT: One major barrier in the development of pancreas cancer therapeutics is the selective delivery of the drugs to their cellular targets. We have previously developed several sigma-2 ligands and reported the discovery of a component of the receptor for these ligands. Several sigma-2 ligands have been shown to trigger apoptosis in pancreas cancer cells. More importantly, sigma-2 ligands are internalized rapidly by the cancer cells and are capable of delivering other small-molecule therapeutics. Here we review sigma-2 ligands and conjugates as a potential novel therapy suitable for investigation in patients with pancreatic cancer.

5 Review Myeloid-derived suppressor cells: general characteristics and relevance to clinical management of pancreatic cancer. 2011

Goedegebuure, P / Mitchem, J B / Porembka, M R / Tan, M C B / Belt, B A / Wang-Gillam, A / Gillanders, W E / Hawkins, W G / Linehan, D C. ·Department of Surgery and Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA. goedegep@wustl.edu ·Curr Cancer Drug Targets · Pubmed #21599634.

ABSTRACT: Recent studies describe a heterogeneous population of cells of the myeloid lineage, termed myeloid derived suppressor cells (MDSC), which are observed with increased prevalence in the peripheral blood and tumor microenvironment of cancer patients, including pancreatic cancer. Accumulation of MDSC in the peripheral circulation has been related to extent of disease, and correlates with stage. MDSC have primarily been implicated in promoting tumor growth by suppressing antitumor immunity. There is also compelling evidence MDSC are also involved in angiogenesis and metastatic spread. Two main subsets of MDSC have been identified in cancer patients: a monocytic subset, characterized by expression of CD14, and a granulocytic subset characterized by expression of CD15. Both subsets of MDSC actively suppress host immunity through a variety of mechanisms including production of reactive oxygen species and arginase. Just as in humans, accumulation of monocytic and granulocytic MDSC has been noted in the bone marrow, spleen, peripheral circulation, and tumors of tumor bearing mice. Successful targeting of MDSC in mice is associated with improved immune responses, delayed tumor growth, improved survival, and increased efficacy of vaccine therapy. By further elucidating mechanisms of MDSC recruitment and maintenance in the tumor environment, strategies could be developed to reverse immune tolerance to tumor. We discuss here what is currently known about MDSC as well as some potential strategies targeting MDSC in the context of our work on pancreatic cancer and recent literature. Due to the number of new reports on MDSC, the most pertinent ones have been selected.

6 Review Potential targets for pancreatic cancer immunotherapeutics. 2011

Dodson, Lindzy F / Hawkins, William G / Goedegebuure, Peter. ·Washington University School of Medicine, Department of Surgery, Saint Louis, MO 63110, USA. lfriend@wustl.edu ·Immunotherapy · Pubmed #21463193.

ABSTRACT: Pancreatic adenocarcinoma is the fourth leading cause of cancer death with an overall 5-year survival of less than 5%. As there is ample evidence that pancreatic adenocarcinomas elicit antitumor immune responses, identification of pancreatic cancer-associated antigens has spurred the development of vaccination-based strategies for treatment. While promising results have been observed in animal tumor models, most clinical studies have found only limited success. As most trials were performed in patients with advanced pancreatic cancer, the contribution of immune suppressor mechanisms should be taken into account. In this article, we detail recent work in tumor antigen vaccination and the recently identified mechanisms of immune suppression in pancreatic cancer. We offer our perspective on how to increase the clinical efficacy of vaccines for pancreatic cancer.

7 Clinical Trial Interferon-based chemoradiation followed by gemcitabine for resected pancreatic adenocarcinoma: long-term follow-up. 2017

Ohman, Kerri A / Liu, Jingxia / Linehan, David C / Tan, Marcus C / Tan, Benjamin R / Fields, Ryan C / Strasberg, Steven M / Hawkins, William G. ·Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA. · Division of Public Health Sciences, Section of Oncologic Biostatistics, Washington University School of Medicine, St. Louis, MO, USA. · Department of Surgery, University of Rochester Medical Center, Rochester, NY, USA. · Department of Surgery, University of South Alabama Health System, Mobile, AL, USA. · Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA. · Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA; Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital, and Washington University School of Medicine, St. Louis, MO, USA. · Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA; Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital, and Washington University School of Medicine, St. Louis, MO, USA. Electronic address: hawkinsw@wudosis.wustl.edu. ·HPB (Oxford) · Pubmed #28162923.

ABSTRACT: To report long-term follow up of a phase II, single-arm trial of resectable pancreatic ductal adenocarcinoma (PDAC) treated with adjuvant interferon-based chemoradiation followed by gemcitabine to determine survival, recurrence, and complications. METHODS: From 2002 to 2005, 53 patients with PDAC underwent pancreaticoduodenectomy and received adjuvant interferon-based chemoradiation consisting of external-beam irradiation and simultaneous 3-drug chemotherapy of continuous daily 5-fluorouracil infusion, weekly intravenous bolus cisplatin, and subcutaneous interferon-α, followed by two months of weekly intravenous gemcitabine. RESULTS: Actual overall survival for the 5- and 10-year periods were 26% and 10%, respectively, with a median overall survival of 25 months (95% CI: 16.4-38.5). Adverse prognostic factors on multivariate analysis were positive tumor margin (p < 0.035), lymphovascular invasion (p < 0.015), and perineural invasion (p < 0.026). Median time to recurrence was 11 months. Positive tumor margin was associated with lymph node involvement (p < 0.005), portal vein resection (p < 0.038), and metastases (p < 0.018). Late complications were frequent and predominated by gastrointestinal and infectious complications. CONCLUSIONS: Adjuvant interferon-based chemoradiation for PDAC improves long-term survival compared to standard therapy. However, recurrence rates and long-term complications remain high, thus further studies are indicated to assess patient characteristics that indicate a favorable treatment profile.

8 Clinical Trial Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. 2016

Nywening, Timothy M / Wang-Gillam, Andrea / Sanford, Dominic E / Belt, Brian A / Panni, Roheena Z / Cusworth, Brian M / Toriola, Adetunji T / Nieman, Rebecca K / Worley, Lori A / Yano, Motoyo / Fowler, Kathryn J / Lockhart, A Craig / Suresh, Rama / Tan, Benjamin R / Lim, Kian-Huat / Fields, Ryan C / Strasberg, Steven M / Hawkins, William G / DeNardo, David G / Goedegebuure, S Peter / Linehan, David C. ·Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA; Alvin J Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO, USA. · Division of Oncology, Washington University School of Medicine, Saint Louis, MO, USA; Alvin J Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO, USA. · Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA. · Department of Surgery, University of Rochester Medical Center, Rochester, NY, USA; Center for Tumor Immunology, University of Rochester Medical Center, Rochester, NY, USA; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA. · Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA; Division of Public Health Sciences, Washington University School of Medicine, Saint Louis, MO, USA; Alvin J Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO, USA. · Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, USA; Alvin J Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO, USA. · Division of Oncology, Washington University School of Medicine, Saint Louis, MO, USA; Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA; Alvin J Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO, USA. · Department of Surgery, University of Rochester Medical Center, Rochester, NY, USA; Center for Tumor Immunology, University of Rochester Medical Center, Rochester, NY, USA; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA. Electronic address: david_linehan@urmc.rochester.edu. ·Lancet Oncol · Pubmed #27055731.

ABSTRACT: BACKGROUND: In pancreatic ductal adenocarcinoma, the CCL2-CCR2 chemokine axis is used to recruit tumour-associated macrophages for construction of an immunosuppressive tumour microenvironment. This pathway has prognostic implications in pancreatic cancer, and blockade of CCR2 restores anti-tumour immunity in preclinical models. We aimed to establish the safety, tolerability, and recommended phase 2 oral dose of the CCR2 inhibitor PF-04136309 in combination with FOLFIRINOX chemotherapy (oxaliplatin and irinotecan plus leucovorin and fluorouracil). METHODS: We did this open-label, dose-finding, non-randomised, phase 1b study at one centre in the USA. We enrolled treatment-naive patients aged 18 years or older with borderline resectable or locally advanced biopsy-proven pancreatic ductal adenocarcinoma, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1, and normal end-organ function. Patients were allocated to receive either FOLFIRINOX alone (oxaliplatin 85 mg/m(2), irinotecan 180 mg/m(2), leucovorin 400 mg/m(2), and bolus fluorouracil 400 mg/m(2), followed by 2400 mg/m(2) 46-h continuous infusion), administered every 2 weeks for a total of six treatment cycles, or in combination with oral PF-04136309, administered at a starting dose of 500 mg twice daily in a standard 3 + 3 dose de-escalation design. Both FOLFIRINOX and PF-04136309 were simultaneously initiated with a total treatment duration of 12 weeks. The primary endpoints were the safety, tolerability, and recommended phase 2 dose of PF-04136309 plus FOLFIRINOX, with an expansion phase planned at the recommended dose. We analysed the primary outcome by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01413022. RESULTS: Between April 19, 2012, and Nov 12, 2014, we treated 47 patients with FOLFIRINOX alone (n=8) or with FOLFIRINOX plus PF-04136309 (n=39). One patient had a dose-limiting toxic effect in the dose de-escalation group receiving FOLFIRINOX plus PF-04136309 at 500 mg twice daily (n=6); this dose was established as the recommended phase 2 dose. We pooled patients in the expansion-phase group (n=33) with those in the dose de-escalation group that received PF-04136309 at the recommended phase 2 dose for assessment of treatment-related toxicity. Six (75%) of the eight patients receiving FOLFIRINOX alone were assessed for treatment toxicity, after exclusion of two (25%) patients due to insurance coverage issues. The median duration of follow-up for treatment toxicity was 72·0 days (IQR 49·5-89·0) in the FOLFIRINOX alone group and 77·0 days (70·0-90·5) in the FOLFIRINOX plus PF-04136309 group. No treatment-related deaths occurred. Two (5%) patients in the FOLFIRINOX plus PF-04136309 group stopped treatment earlier than planned due to treatment-related toxic effects. Grade 3 or higher adverse events reported in at least 10% of the patients receiving PF-04136309 included neutropenia (n=27), febrile neutropenia (n=7), lymphopenia (n=4), diarrhoea (n=6), and hypokalaemia (n=7). Grade 3 or higher adverse events reported in at least 10% of patients receiving FOLFIRINOX alone were neutropenia (n=6), febrile neutropenia (n=1), anaemia (n=2), lymphopenia (n=1), diarrhoea (n=2), hypoalbuminaemia (n=1), and hypokalaemia (n=3). Therapy was terminated because of treatment-related toxicity in one (17%) of the six patients receiving FOLFIRINOX alone. 16 (49%) of 33 patients receiving FOLFIRINOX plus PF-04136309 who had undergone repeat imaging achieved an objective tumour response, with local tumour control achieved in 32 (97%) patients. In the FOLFIRINOX alone group, none of the five patients with repeat imaging achieved an objective response, although four (80%) of those patients achieved stable disease. INTERPRETATION: CCR2-targeted therapy with PF-04136309 in combination with FOLFIRINOX is safe and tolerable. FUNDING: Washington University-Pfizer Biomedical Collaborative.

9 Clinical Trial A phase I study of IMP321 and gemcitabine as the front-line therapy in patients with advanced pancreatic adenocarcinoma. 2013

Wang-Gillam, Andrea / Plambeck-Suess, Stacey / Goedegebuure, Peter / Simon, Peter O / Mitchem, Jonathan B / Hornick, John R / Sorscher, Steven / Picus, Joel / Suresh, Rama / Lockhart, Albert C / Tan, Benjamin / Hawkins, Williams G. ·Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. ·Invest New Drugs · Pubmed #22864469.

ABSTRACT: PURPOSE: This phase I study was conducted to determine the safety profile and maximum tolerated dose (MTD) of IMP321, a soluble lymphocyte activation gene-3 (LAG-3) Ig fusion protein and MHC Class II agonist, combined with gemcitabine in patients with advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: Patients with advanced pancreatic adenocarcinoma were treated with gemcitabine (1,000 mg/m(2))(level 1), gemcitabine (1,000 mg/m(2)) plus IMP 321 at 0.5 mg (level 2) and 2.0 mg (level 3), respectively. Safety, toxicity, and immunological markers at baseline and post treatment were assessed. RESULTS: A total of 18 patients were enrolled to the study, and 17 were evaluable for toxicity. None of the 6 patients who received 0.5 mg IMP321 experienced IMP321-related adverse events. Of the 5 patients who received IMP321 at the 2 mg dose level, 1 experienced rash, 1 reported hot flashes and 2 had mild pain at the injection sites. No severe adverse events previously attributed to IMP321 were observed. No significant differences were observed when comparing pre- and post-treatment levels of monocytes (CD11b+CD14+), conventional dendritic cells (CD11c+) or T cell subsets (CD4, CD8). CONCLUSIONS: IMP321 in combination with gemcitabine is a well-tolerated regimen. IMP321 did not result in any severe adverse events. No incremental activity observed for the additional IMP 321 to gemcitabine at the dose levels evaluated, likely due to sub-optimal dosing. Immunological markers suggested that higher dose levels of IMP321 are needed for future clinical studies.

10 Article Residual Tumor Index: A Prognostically Significant Pathologic Parameter in Neoadjuvant-treated Pancreatic Ductal Adenocarcinoma. 2018

Panni, Roheena Z / Gonzalez, Ivan / Hartley, Christopher P / Williams, Gregory A / Liu, Jingxia / Hawkins, William G / Chatterjee, Deyali. ·Department of Surgery, Division of HPB and GI surgery. · Departments of Pathology and Immunology. · Surgery, Division of Public Health, Section of Oncologic Biostatistics, Washington University in St. Louis, St. Louis, MO. ·Am J Surg Pathol · Pubmed #30179901.

ABSTRACT: In the setting of neoadjuvant therapy (NAT) for pancreatic ductual adenocarcinoma (PDAC), accurate measurement of tumor size, and consequently, staging based on AJCC eighth edition, is difficult. Attempts to address the limitations of tumor size in the NAT setting have included correlation of residual tumor percent with survival. However, only cases with complete pathologic response or minimal residual disease have shown better prognosis compared with all other groups. To date, no studies have simultaneously evaluated the prognostic value of tumor size and tumor regression in the setting of PDAC status post NAT (NAT-PDAC). Our aim was to study the prognostic value of residual tumor index (RTI), a metric combining residual tumor percent and tumor bed size as an interaction term (% residual tumor×tumor bed size [cm]). In a cohort of 105 cases of NAT-PDAC, we show that RTI supersedes the prognostic value of AJCC eighth edition T staging via multivariate cox regression. At a binary cutoff of 0.35 for RTI, the hazard ratio for recurrence-free survival is 3.26 (95% confidence interval, 1.51-7.04), P<0.01. We further identified cutoffs of ≤0.2, 0.2 to 2 and >2 that stratified our cases into 3 groups via RTI, which were statistically significant in Kaplan-Meier curve analysis of recurrence-free survival (P<0.01) and overall survival (P<0.01). RTI represents a novel metric for combining the prognostic value of tumor size and residual tumor in NAT-PDAC.

11 Article Breast and pancreatic cancer interrupt IRF8-dependent dendritic cell development to overcome immune surveillance. 2018

Meyer, Melissa A / Baer, John M / Knolhoff, Brett L / Nywening, Timothy M / Panni, Roheena Z / Su, Xinming / Weilbaecher, Katherine N / Hawkins, William G / Ma, Cynthia / Fields, Ryan C / Linehan, David C / Challen, Grant A / Faccio, Roberta / Aft, Rebecca L / DeNardo, David G. ·Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. · Department of Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA. · Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, USA. · Department of Surgery, University of Rochester Medical Center, Rochester, NY, 14642, USA. · Section of Stem Cell Biology, Division of Oncology, Washington University School of Medicine, St. Louis, MO, 63110, USA. · Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA. · John Cochran St. Louis Veterans Administration Hospital, St. Louis, MO, 63106, USA. · Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. ddenardo@wustl.edu. · Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, USA. ddenardo@wustl.edu. · Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA. ddenardo@wustl.edu. ·Nat Commun · Pubmed #29593283.

ABSTRACT: Tumors employ multiple mechanisms to evade immune surveillance. One mechanism is tumor-induced myelopoiesis, whereby the expansion of immunosuppressive myeloid cells can impair tumor immunity. As myeloid cells and conventional dendritic cells (cDCs) are derived from the same progenitors, we postulated that myelopoiesis might impact cDC development. The cDC subset, cDC1, which includes human CD141

12 Article The Hand-Assisted Laparoscopic Approach to Resection of Pancreatic Mucinous Cystic Neoplasms: An Underused Technique? 2018

Postlewait, Lauren M / Ethun, Cecilia G / McInnis, Mia R / Merchant, Nipun / Parikh, Alexander / Idrees, Kamran / Isom, Chelsea A / Hawkins, William / Fields, Ryan C / Strand, Matthew / Weber, Sharon M / Cho, Clifford S / Salem, Ahmed / Martin, Robert C G / Scoggins, Charles / Bentrem, David / Kim, Hong J / Carr, Jacquelyn / Ahmad, Syed / Abbott, Daniel / Wilson, Gregory C / Kooby, David A / Maithel, Shishir K. · ·Am Surg · Pubmed #29428029.

ABSTRACT: Pancreatic mucinous cystic neoplasms (MCNs) are rare tumors typically of the distal pancreas that harbor malignant potential. Although resection is recommended, data are limited on optimal operative approaches to distal pancreatectomy for MCN. MCN resections (2000-2014; eight institutions) were included. Outcomes of minimally invasive and open MCN resections were compared. A total of 289 patients underwent distal pancreatectomy for MCN: 136(47%) minimally invasive and 153(53%) open. Minimally invasive procedures were associated with smaller MCN size (3.9 vs 6.8 cm; P = 0.001), lower operative blood loss (192 vs 392 mL; P = 0.001), and shorter hospital stay(5 vs 7 days; P = 0.001) compared with open. Despite higher American Society of Anesthesiologists class, hand-assisted (n = 46) had similar advantages as laparoscopic/robotic (n = 76). When comparing hand-assisted to open, although MCN size was slightly smaller (4.1 vs 6.8 cm; P = 0.001), specimen length, operative time, and nodal yield were identical. Similar to laparoscopic/robotic, hand-assisted had lower operative blood loss (161 vs 392 mL; P = 0.001) and shorter hospital stay (5 vs 7 days; P = 0.03) compared with open, without increased complications. Hand-assisted laparoscopic technique is a useful approach for MCN resection because specimen length, lymph node yield, operative time, and complication profiles are similar to open procedures, but it still offers the advantages of a minimally invasive approach. Hand-assisted laparoscopy should be considered as an alternative to open technique or as a successive step before converting from total laparoscopic to open distal pancreatectomy for MCN.

13 Article Multifunctional thiosemicarbazones and deconstructed analogues as a strategy to study the involvement of metal chelation, Sigma-2 (σ 2018

Pati, Maria Laura / Niso, Mauro / Spitzer, Dirk / Berardi, Francesco / Contino, Marialessandra / Riganti, Chiara / Hawkins, William G / Abate, Carmen. ·Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Via Orabona 4, I-70125 Bari, Italy; Department of Surgery, Division of Hepatobiliary, Pancreatic, and Gastrointestinal Surgery, Washington University School of Medicine, St. Louis, MO, USA. · Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Via Orabona 4, I-70125 Bari, Italy. · Department of Surgery, Division of Hepatobiliary, Pancreatic, and Gastrointestinal Surgery, Washington University School of Medicine, St. Louis, MO, USA. · Dipartimento di Oncologia, Università degli Studi di Torino, via Santena 5/bis, I-10153 Torino, Italy. · Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Via Orabona 4, I-70125 Bari, Italy. Electronic address: carmen.abate@uniba.it. ·Eur J Med Chem · Pubmed #29287249.

ABSTRACT: The aggressiveness of pancreatic cancer urgently requires more efficient treatment options. Because the sigma-2 (σ

14 Article Targeting both tumour-associated CXCR2 2018

Nywening, Timothy M / Belt, Brian A / Cullinan, Darren R / Panni, Roheena Z / Han, Booyeon J / Sanford, Dominic E / Jacobs, Ryan C / Ye, Jian / Patel, Ankit A / Gillanders, William E / Fields, Ryan C / DeNardo, David G / Hawkins, William G / Goedegebuure, Peter / Linehan, David C. ·Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA. · Alvin J Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri, USA. · Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA. · Tumor Biology Program, University of Rochester Medical Center, Rochester, New York, USA. · Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA. · Department of Medicine, Oncology Division, Washington University School of Medicine, St. Louis, Missouri, USA. · Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, USA. ·Gut · Pubmed #29196437.

ABSTRACT: OBJECTIVE: Chemokine pathways are co-opted by pancreatic adenocarcinoma (PDAC) to facilitate myeloid cell recruitment from the bone marrow to establish an immunosuppressive tumour microenvironment (TME). Targeting tumour-associated CXCR2 METHODS: Blood, bone marrow and tumours were analysed from PDAC patients and controls. Treatment response and correlative studies were performed in mice with established orthotopic PDAC tumours treated with a small molecule CCR2 inhibitor (CCR2i) and CXCR2 inhibitor (CXCR2i), alone and in combination with chemotherapy. RESULTS: A systemic increase in CXCR2 CONCLUSION: Dual targeting of CCR2

15 Article Tissue-Resident Macrophages in Pancreatic Ductal Adenocarcinoma Originate from Embryonic Hematopoiesis and Promote Tumor Progression. 2017

Zhu, Yu / Herndon, John M / Sojka, Dorothy K / Kim, Ki-Wook / Knolhoff, Brett L / Zuo, Chong / Cullinan, Darren R / Luo, Jingqin / Bearden, Audrey R / Lavine, Kory J / Yokoyama, Wayne M / Hawkins, William G / Fields, Ryan C / Randolph, Gwendalyn J / DeNardo, David G. ·Department of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA; ICCE Institute, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA. · Department of Rheumatology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA. · Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA. · Department of Surgery, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA. · Division of Biostatistics, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA. · Department of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA. · Department of Rheumatology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA; Howard Hughes Medical Institute, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA. · Siteman Cancer Center, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA; Department of Surgery, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA. · Department of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA. · Department of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA; ICCE Institute, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA. Electronic address: ddenardo@wustl.edu. ·Immunity · Pubmed #28813661.

ABSTRACT: Tumor-associated macrophages (TAMs) are essential components of the cancer microenvironment and play critical roles in the regulation of tumor progression. Optimal therapeutic intervention requires in-depth understanding of the sources that sustain macrophages in malignant tissues. In this study, we investigated the ontogeny of TAMs in murine pancreatic ductal adenocarcinoma (PDAC) models. We identified both inflammatory monocytes and tissue-resident macrophages as sources of TAMs. Unexpectedly, significant portions of pancreas-resident macrophages originated from embryonic development and expanded through in situ proliferation during tumor progression. Whereas monocyte-derived TAMs played more potent roles in antigen presentation, embryonically derived TAMs exhibited a pro-fibrotic transcriptional profile, indicative of their role in producing and remodeling molecules in the extracellular matrix. Collectively, these findings uncover the heterogeneity of TAM origin and functions and could provide therapeutic insight for PDAC treatment.

16 Article The diagnosis of pancreatic mucinous cystic neoplasm and associated adenocarcinoma in males: An eight-institution study of 349 patients over 15 years. 2017

Ethun, Cecilia G / Postlewait, Lauren M / McInnis, Mia R / Merchant, Nipun / Parikh, Alexander / Idrees, Kamran / Isom, Chelsea A / Hawkins, William / Fields, Ryan C / Strand, Matthew / Weber, Sharon M / Cho, Clifford S / Salem, Ahmed / Martin, Robert C G / Scoggins, Charles R / Bentrem, David / Kim, Hong J / Carr, Jacquelyn / Ahmad, Syed A / Abbott, Daniel E / Wilson, Gregory / Kooby, David A / Maithel, Shishir K. ·Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, Georgia. · Division of Surgical Oncology, Department of Surgery, University of Miami, Miami, Florida. · Division of Surgical Oncology, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Surgery, Washington University School of Medicine, St Louis, Missouri. · Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. · Department of Surgery, University of Michigan, Ann Arbor, Michigan. · Division of Surgical Oncology, Department of Surgery, University of Louisville, Louisville, Kentucky. · Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois. · Division of Surgical Oncology, Department of Surgery, University of North Carolina, Chapel Hill, North Carolina. · Division of Surgical Oncology, Department of Surgery, University of Cincinnati Cancer Institute, Cincinnati, Ohio. ·J Surg Oncol · Pubmed #28211072.

ABSTRACT: BACKGROUND: Per WHO, 2000 classification, pancreatic mucinous cystic neoplasms (MCN) are defined by presence of ovarian stroma, and are primarily located in the pancreatic body/tail of females. The incidence of MCN and associated malignancy in males, since, standardization of MCN diagnostic-criteria is unknown. METHODS: MCN resections from 2000 to 2014 at eight institutions of the Central-Pancreas-Consortium were included, and divided into early (2000-2007) and late (2008-2014) time-periods. Primary aim was to characterize MCN and associated adenocarcinoma/high-grade-dysplasia (AC/HGD) in males versus females over time. RESULTS: Of 1667 resections for pancreatic cystic lesions, 349 pts (21%) had MCNs: 310 (89%) female, 39 (11%) male. Patients were equally divided between early (n = 173) and late (n = 176) time-periods. MCN in male-patients decreased over time (early: 15%, late: 7%; P = 0.036), as did pancreatic head/neck location (early: 22%, late: 11%; P = 0.01). MCN-associated AC/HGD was more frequent in males versus females (39 vs. 12%; P < 0.001). The overall rate of MCN-associated AC/HGD remained stable (early: 17%, late: 13%; P = 0.4), and was identical in males (39%) over both time-periods. Males with AC/HGD had more LN-positive disease versus females (57 vs. 22%; P = 0.039). CONCLUSIONS: As the diagnostic-criteria of MCN have standardized over time, MCN diagnosis has decreased in males and head/neck location. Despite this, MCN-associated adenocarcinoma/high-grade dysplasia has been stable and remains high in males. Any male with suspected MCN, regardless of location, should undergo resection.

17 Article The Targeted SMAC Mimetic SW IV-134 is a strong enhancer of standard chemotherapy in pancreatic cancer. 2017

Hashim, Yassar M / Vangveravong, Suwanna / Sankpal, Narendra V / Binder, Pratibha S / Liu, Jingxia / Goedegebuure, S Peter / Mach, Robert H / Spitzer, Dirk / Hawkins, William G. ·Department of Surgery, Barnes-Jewish Hospital and Washington University School of Medicine St. Louis, 660 S. Euclid Ave, Box 8109, Saint Louis, MO, 63110, USA. · Present Address: Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, 8215-NT, Los Angeles, CA, 90048, USA. · Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA. · Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Washington University School of Medicine, St Louis, MO, USA. · Division of Public Health Sciences, Section of Oncologic Biostatistics, Washington University School of Medicine, St. Louis, MO, USA. · Alvin J. Siteman Cancer Center, St. Louis, MO, USA. · Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA. · Department of Surgery, Barnes-Jewish Hospital and Washington University School of Medicine St. Louis, 660 S. Euclid Ave, Box 8109, Saint Louis, MO, 63110, USA. hawkinsw@wudosis.wustl.edu. · Alvin J. Siteman Cancer Center, St. Louis, MO, USA. hawkinsw@wudosis.wustl.edu. ·J Exp Clin Cancer Res · Pubmed #28095907.

ABSTRACT: BACKGROUND: Pancreatic cancer is a lethal malignancy that frequently acquires resistance to conventional chemotherapies often associated with overexpression of inhibitors of apoptosis proteins (IAPs). We have recently described a novel means to deliver second mitochondria-derived activator of caspases (SMAC) mimetics selectively to cancer cells employing the sigma-2 ligand/receptor interaction. The intrinsic death pathway agonist SMAC offers an excellent opportunity to counteract the anti-apoptotic activity of IAPs. SMAC mimetics have been used to sensitize several cancer types to chemotherapeutic agents but cancer-selective delivery and appropriate cellular localization have not yet been considered. In our current study, we tested the ability of the sigma-2/SMAC drug conjugate SW IV-134 to sensitize pancreatic cancer cells to gemcitabine. METHODS: Using the targeted SMAC mimetic SW IV-134, inhibition of the X-linked inhibitor of apoptosis proteins (XIAP) was induced pharmacologically and its impact on cell viability was studied alone and in combination with gemcitabine. Pathway analyses were performed by assessing caspase activation, PARP cleavage and membrane blebbing (Annexin-V), key components of apoptotic cell death. Single-agent treatment regimens were compared with combination therapy in a preclinical mouse model of pancreatic cancer. RESULTS: The sensitizing effect of XIAP interference toward gemcitabine was confirmed via pharmacological intervention using our recently designed, targeted SMAC mimetic SW IV-134 across a wide range of commonly used pancreatic cancer cell lines at concentrations where the individual drugs showed only minimal activity. On a mechanistic level, we identified involvement of key components of the apoptosis machinery during cell death execution. Furthermore, combination therapy proved superior in decreasing the tumor burden and extending the lives of the animals in a preclinical mouse model of pancreatic cancer. CONCLUSION: We believe that the strong sensitizing capacity of SW IV-134 in combination with clinically relevant doses of gemcitabine represents a promising treatment option that warrants clinical evaluation.

18 Article Sigma-2 receptor agonist derivatives of 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) induce cell death via mitochondrial superoxide production and caspase activation in pancreatic cancer. 2017

Pati, Maria Laura / Hornick, John R / Niso, Mauro / Berardi, Francesco / Spitzer, Dirk / Abate, Carmen / Hawkins, William. ·Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Via Orabona 4, I-70125, Bari, Italy. · Department of Surgery, Division of Hepatobiliary, Pancreatic, and Gastrointestinal Surgery, Washington University School of Medicine, St. Louis, MO, USA. · Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Via Orabona 4, I-70125, Bari, Italy. carmen.abate@uniba.it. ·BMC Cancer · Pubmed #28086830.

ABSTRACT: BACKGROUND: Despite considerable efforts by scientific research, pancreatic cancer is the fourth leading cause of cancer related mortalities. Sigma-2 receptors, which are overexpressed in several tumors, represent promising targets for triggering selective pancreatic cancer cells death. METHODS: We selected five differently structured high-affinity sigma-2 ligands (PB28, PB183, PB221, F281 and PB282) to study how they affect the viability of diverse pancreatic cancer cells (human cell lines BxPC3, AsPC1, Mia PaCa-2, and Panc1 and mouse Panc-02, KCKO and KP-02) and how this is reflected in vivo in a tumor model. RESULTS: Important cytotoxicity was shown by the compounds in the aggressive Panc02 cells, where cytotoxic activity was caspase-3 independent for four of the five compounds. However, both cytotoxicity and caspase-3 activation involved generation of Reactive Oxygen Species (ROS), which could be partially reverted by the lipid antioxidant α-tocopherol, but not by the hydrophilic N-acetylcysteine (NAC) indicating crucial differences in the intracellular sites exposed to oxidative stress induced by sigma-2 receptor ligands. Importantly, all the compounds strongly increased the production of mitochondrial superoxide radicals except for PB282. Despite a poor match between in vitro and the in vivo efficacy, daily treatment of C57BL/6 mice bearing Panc02 tumors resulted in promising effects with PB28 and PB282 which were similar compared to the current standard-of-care chemotherapeutic gemcitabine without showing signs of systemic toxicities. CONCLUSIONS: Overall, this study identified differential sensitivities of pancreatic cancer cells to structurally diverse sigma-2 receptor ligands. Of note, we identified the mitochondrial superoxide pathway as a previously unrecognized sigma-2 receptor-activated process, which encourages further studies on sigma-2 ligand-mediated cancer cell death for the targeted treatment of pancreatic tumors.

19 Article Pattern of Venous Collateral Development after Splenic Vein Occlusion in an Extended Whipple Procedure (Whipple at the Splenic Artery) and Long-Term Results. 2017

Rosado, Ismael Dominguez / Bhalla, Sanjeev / Sanchez, Luis A / Fields, Ryan C / Hawkins, William G / Strasberg, Steven M. ·Section of Hepato-Pancreato-Biliary Surgery, Washington University in Saint Louis School of Medicine, Siteman Cancer Center, and Barnes-Jewish Hospital, 4990 Children's Place, Suite 1160, (Campus Box 8109), St Louis, MO, 63110, USA. · Department of Surgery, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Vasco de Quiroga 15 Col, Tlalpan, 14000, Mexico City, Mexico. · Mallinckrodt Institute of Radiology, Washington University in Saint Louis School of Medicine, Siteman Cancer Center, and Barnes-Jewish Hospital, 660 S Euclid Ave Campus Box 8131, St Louis, MO, 63110, USA. · Section of Vascular Surgery, Washington University in Saint Louis School of Medicine, Siteman Cancer Center, and Barnes-Jewish Hospital, 660 S Euclid Ave Campus Box 8109, St Louis, MO, 63110, USA. · Section of Hepato-Pancreato-Biliary Surgery, Washington University in Saint Louis School of Medicine, Siteman Cancer Center, and Barnes-Jewish Hospital, 4990 Children's Place, Suite 1160, (Campus Box 8109), St Louis, MO, 63110, USA. strasbergs@wustl.edu. ·J Gastrointest Surg · Pubmed #27921207.

ABSTRACT: BACKGROUND: Extended Whipple procedures may require division of the splenic vein (SV). Controversy exists regarding the risk of sequelae of sinistral portal hypertension when the SV is ligated without reimplantation. The aim of this study was to identify postoperative venous collateral patterns and sequelae of SV ligation, as well as long-term results in an extended Whipple procedure. STUDY DESIGN: Patients who had an extended Whipple procedure (Whipple at the Splenic Artery or WATSA) were entered in an institutional database. Evaluation of the venous collaterals was performed at least 5 months postoperatively by imaging. Spleen size and platelet counts were measured before and after operation. RESULTS: Fifteen patients were entered from 2009 to 2014. SV was not reconstructed and the IMV-SV junction was always resected. Two collateral routes developed. An inferior route was present 14/15 patients. It connected the residual SV to the SMV via intermediate collateral veins in the omentum and along the colon. A superior route, present in 10/15 patients connected the residual SV to the portal vein via gastric, perigastric, and coronary veins. Gastrointestinal bleeding did not occur. Mean platelet count and spleen size were not affected significantly. Procedures were long, but few severe complications developed. In 12 patients with adenocarcinoma, the median survival has not been reached. CONCLUSIONS: Patients who have SV ligation in an extended Whipple are protected against sequelae of sinestral portal hypertension by inferior collateral routes. The omentum and marginal veins of the colon are key links in this pathway.

20 Article Utility of a multidisciplinary tumor board in the management of pancreatic and upper gastrointestinal diseases: an observational study. 2017

Brauer, David G / Strand, Matthew S / Sanford, Dominic E / Kushnir, Vladimir M / Lim, Kian-Huat / Mullady, Daniel K / Tan, Benjamin R / Wang-Gillam, Andrea / Morton, Ashley E / Ruzinova, Marianna B / Parikh, Parag J / Narra, Vamsi R / Fowler, Kathryn J / Doyle, Majella B / Chapman, William C / Strasberg, Steven S / Hawkins, William G / Fields, Ryan C. ·Department of Surgery, Barnes-Jewish Hospital and the Alvin J. Siteman Cancer Center at Washington University School of Medicine, Saint Louis, MO, USA. · Department of Medicine, Barnes-Jewish Hospital and the Alvin J. Siteman Cancer Center at Washington University School of Medicine, Saint Louis, MO, USA. · Department of Pathology and Immunology, Barnes-Jewish Hospital and the Alvin J. Siteman Cancer Center at Washington University School of Medicine, Saint Louis, MO, USA. · Department of Radiation Oncology, Barnes-Jewish Hospital and the Alvin J. Siteman Cancer Center at Washington University School of Medicine, Saint Louis, MO, USA. · Mallinckrodt Institute of Radiology, Barnes-Jewish Hospital and the Alvin J. Siteman Cancer Center at Washington University School of Medicine, Saint Louis, MO, USA. · Department of Surgery, Barnes-Jewish Hospital and the Alvin J. Siteman Cancer Center at Washington University School of Medicine, Saint Louis, MO, USA. Electronic address: fieldsr@wudosis.wustl.edu. ·HPB (Oxford) · Pubmed #27916436.

ABSTRACT: BACKGROUND & OBJECTIVES: Multidisciplinary tumor boards (MDTBs) are frequently employed in cancer centers but their value has been debated. We reviewed the decision-making process and resource utilization of our MDTB to assess its utility in the management of pancreatic and upper gastrointestinal tract conditions. METHODS: A prospectively-collected database was reviewed over a 12-month period. The primary outcome was change in management plan as a result of case discussion. Secondary outcomes included resources required to hold MDTB, survival, and adherence to treatment guidelines. RESULTS: Four hundred seventy cases were reviewed. MDTB resulted in a change in the proposed plan of management in 101 of 402 evaluable cases (25.1%). New plans favored obtaining additional diagnostic workup. No recorded variables were associated with a change in plan. For newly-diagnosed cases of pancreatic ductal adenocarcinoma (n = 33), survival time was not impacted by MDTB (p = .154) and adherence to National Comprehensive Cancer Network guidelines was 100%. The estimated cost of physician time per case reviewed was $190. CONCLUSIONS: Our MDTB influences treatment decisions in a sizeable number of cases with excellent adherence to national guidelines. However, this requires significant time expenditure and may not impact outcomes. Regular assessments of the effectiveness of MDTBs should be undertaken.

21 Article Association of Preoperative Risk Factors With Malignancy in Pancreatic Mucinous Cystic Neoplasms: A Multicenter Study. 2017

Postlewait, Lauren M / Ethun, Cecilia G / McInnis, Mia R / Merchant, Nipun / Parikh, Alexander / Idrees, Kamran / Isom, Chelsea A / Hawkins, William / Fields, Ryan C / Strand, Matthew / Weber, Sharon M / Cho, Clifford S / Salem, Ahmed / Martin, Robert C G / Scoggins, Charles / Bentrem, David / Kim, Hong J / Carr, Jacquelyn / Ahmad, Syed / Abbott, Daniel E / Wilson, Gregory C / Kooby, David A / Maithel, Shishir K. ·Winship Cancer Institute, Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, Georgia. · Division of Surgical Oncology, Department of Surgery, University of Miami, Miami, Florida. · Division of Surgical Oncology, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Surgery, Washington University School of Medicine, St Louis, Missouri. · Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison. · Division of Surgical Oncology, Department of Surgery, University of Louisville, Louisville, Kentucky. · Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois. · Division of Surgical Oncology, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill. · Division of Surgical Oncology, Department of Surgery, University of Cincinnati Cancer Institute, Cincinnati, Ohio. ·JAMA Surg · Pubmed #27760255.

ABSTRACT: Importance: Pancreatic mucinous cystic neoplasms (MCNs) harbor malignant potential, and current guidelines recommend resection. However, data are limited on preoperative risk factors for malignancy (adenocarcinoma or high-grade dysplasia) occurring in the setting of an MCN. Objectives: To examine the preoperative risk factors for malignancy in resected MCNs and to assess outcomes of MCN-associated adenocarcinoma. Design, Setting, and Participants: Patients who underwent pancreatic resection of MCNs at the 8 academic centers of the Central Pancreas Consortium from January 1, 2000, through December 31, 2014, were retrospectively identified. Preoperative factors of patients with and without malignant tumors were compared. Survival analyses were conducted for patients with adenocarcinoma. Main Outcomes and Measures: Binary logistic regression models were used to determine the association of preoperative factors with the presence of MCN-associated malignancy. Results: A total of 1667 patients underwent resection of pancreatic cystic lesions, and 349 (20.9%) had an MCN (310 women [88.8%]; mean (SD) age, 53.3 [14.7] years). Male sex (odds ratio [OR], 3.72; 95% CI, 1.21-11.44; P = .02), pancreatic head and neck location (OR, 3.93; 95% CI, 1.43-10.81; P = .01), increased radiographic size of the MCN (OR, 1.17; 95% CI, 1.08-1.27; P < .001), presence of a solid component or mural nodule (OR, 4.54; 95% CI, 1.95-10.57; P < .001), and duct dilation (OR, 4.17; 95% CI, 1.63-10.64; P = .003) were independently associated with malignancy. Malignancy was not associated with presence of radiographic septations or preoperative cyst fluid analysis (carcinoembryonic antigen, amylase, or mucin presence). The median serum CA19-9 level for patients with malignant neoplasms was 210 vs 15 U/mL for those without (P = .001). In the 44 patients with adenocarcinoma, 41 (93.2%) had lymph nodes harvested, with nodal metastases in only 14 (34.1%). Median follow-up for patients with adenocarcinoma was 27 months. Adenocarcinoma recurred in 11 patients (25%), with a 64% recurrence-free survival and 59% overall survival at 3 years. Conclusions and Relevance: Adenocarcinoma or high-grade dysplasia is present in 14.9% of resected pancreatic MCNs for which risks include male sex, pancreatic head and neck location, larger MCN, solid component or mural nodule, and duct dilation. Mucinous cystic neoplasm-associated adenocarcinoma appears to have decreased nodal involvement at the time of resection and increased survival compared with typical pancreatic ductal adenocarcinoma. Indications for resection of MCNs should be revisited.

22 Article Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. 2016

Jiang, Hong / Hegde, Samarth / Knolhoff, Brett L / Zhu, Yu / Herndon, John M / Meyer, Melissa A / Nywening, Timothy M / Hawkins, William G / Shapiro, Irina M / Weaver, David T / Pachter, Jonathan A / Wang-Gillam, Andrea / DeNardo, David G. ·Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA. · Integrating Communications within the Cancer Environment (ICCE) Institute, Washington University School of Medicine, St. Louis, Missouri, USA. · Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA. · Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA. · Verastem Inc., Needham, Massachusetts, USA. · Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA. ·Nat Med · Pubmed #27376576.

ABSTRACT: Single-agent immunotherapy has achieved limited clinical benefit to date in patients with pancreatic ductal adenocarcinoma (PDAC). This may be a result of the presence of a uniquely immunosuppressive tumor microenvironment (TME). Critical obstacles to immunotherapy in PDAC tumors include a high number of tumor-associated immunosuppressive cells and a uniquely desmoplastic stroma that functions as a barrier to T cell infiltration. We identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as an important regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlated with high levels of fibrosis and poor CD8(+) cytotoxic T cell infiltration. Single-agent FAK inhibition using the selective FAK inhibitor VS-4718 substantially limited tumor progression, resulting in a doubling of survival in the p48-Cre;LSL-Kras(G12D);Trp53(flox/+) (KPC) mouse model of human PDAC. This delay in tumor progression was associated with markedly reduced tumor fibrosis and decreased numbers of tumor-infiltrating immunosuppressive cells. We also found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to T cell immunotherapy and PD-1 antagonists. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and renders tumors responsive to immunotherapy.

23 Article Conjugation to the sigma-2 ligand SV119 overcomes uptake blockade and converts dm-Erastin into a potent pancreatic cancer therapeutic. 2016

Ohman, Kerri A / Hashim, Yassar M / Vangveravong, Suwanna / Nywening, Timothy M / Cullinan, Darren R / Goedegebuure, S Peter / Liu, Jingxia / Van Tine, Brian A / Tiriac, Herve / Tuveson, David A / DeNardo, David G / Spitzer, Dirk / Mach, Robert H / Hawkins, William G. ·Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA. · Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA. · Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital, and Washington University School of Medicine, St. Louis, MO, USA. · Division of Public Health Sciences, Section of Oncologic Biostatistics, Washington University School of Medicine, St. Louis, MO, USA. · Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA. · Cold Spring Harbor Laboratory, New York, NY, USA. · Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. · Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA. ·Oncotarget · Pubmed #27244881.

ABSTRACT: Cancer-selective drug delivery is an important concept in improving treatment while minimizing off-site toxicities, and sigma-2 receptors, which are overexpressed in solid tumors, represent attractive pharmacologic targets. Select sigma-2 ligands have been shown to be rapidly internalized selectively into cancer cells while retaining the capacity to deliver small molecules as drug cargoes. We utilized the sigma-2-based drug delivery concept to convert Erastin, a clinically underperforming drug, into a potent pancreatic cancer therapeutic. The Erastin derivative des-methyl Erastin (dm-Erastin) was chemically linked to sigma-2 ligand SV119 to create SW V-49. Conjugation increased the killing capacity of dm-Erastin by nearly 35-fold in vitro and reduced the size of established tumors and doubled the median survival in syngeneic and patient-derived xenograft models when compared to non-targeted dm-Erastin. Mechanistic analyses demonstrated that cell death was associated with robust reactive oxygen species production and could be efficiently antagonized with antioxidants. Mass spectrometry was employed to demonstrate selective uptake into pancreatic cancer cells. Thus, targeted delivery of dm-Erastin via conjugation to the sigma-2 ligand SV119 produced efficient tumor control and prolonged animal survival with minimal off-target toxicities, and SW V-49 represents a promising new therapeutic with the potential to advance the fight against pancreatic cancer.

24 Article Single institution results of radical antegrade modular pancreatosplenectomy for adenocarcinoma of the body and tail of pancreas in 78 patients. 2016

Grossman, Julie G / Fields, Ryan C / Hawkins, William G / Strasberg, Steven M. ·Section of Hepato-Pancreato-Biliary Surgery, Department of Surgery, Washington University in St. Louis, Barnes-Jewish Hospital and Siteman Cancer Center, 4990 Children's Place, Suite 1160, Box 8109, St. Louis, MO, 63110, USA. ·J Hepatobiliary Pancreat Sci · Pubmed #27207482.

ABSTRACT: BACKGROUND: The purpose of this report is to present results of the radical antegrade modular pancreatosplenectomy (RAMPS) procedure in 78 patients from a single center. METHODS: Seventy-eight patients had RAMPS procedure over 13 years. A database dealing with RAMPS for adenocarcinoma of the pancreas was constructed so that it could be converted into a set of tables. Each table covered one element of the subject. The database was populated from clinical records of patients who had a RAMPS procedure from 1999 to 2013. RESULTS: Fifty-six patients had anterior RAMPS and 22 had posterior RAMPS. Negative tangential margins were obtained in 94% of specimens. Overall the R0 rate was 85%. Mean lymph node count was 20. There were no 30-day or in-hospital mortalities but two patients died within 90 days. Pancreatic fistula and need for postoperative transfusion were the most common complications. Median survival was 24.6 months and 5-year overall actuarial survival was 25.1%. CONCLUSIONS: The RAMPS technique resulted in high negative tangential margin rates and good lymph node retrieval. The long-term survival result in 78 patients is probably an accurate reflection of what is possible with this tumor using this technique at this time.

25 Article Perception Is Reality: quality metrics in pancreas surgery - a Central Pancreas Consortium (CPC) analysis of 1399 patients. 2016

Abbott, Daniel E / Martin, Grace / Kooby, David A / Merchant, Nipun B / Squires, Malcolm H / Maithel, Shishir K / Weber, Sharon M / Winslow, Emily R / Cho, Clifford S / Bentrem, David J / Kim, Hong Jin / Scoggins, Charles R / Martin, Robert C / Parikh, Alexander A / Hawkins, William G / Ahmad, Syed A. ·Department of Surgery, University of Cincinnati, Cincinnati, OH, United States. Electronic address: abbottdl@ucmail.uc.edu. · Department of Surgery, University of Cincinnati, Cincinnati, OH, United States. · Department of Surgery, Emory University, Atlanta, GA, United States. · Department of Surgery, Miami University, Miami, FL, United States. · Department of Surgery, University of Wisconsin, Madison, WI, United States. · Department of Surgery, Northwestern University, Chicago, IL, United States. · Department of Surgery, University of North Carolina, Chapel Hill, NC, United States. · Department of Surgery, University of Louisville, Louisville, KY, United States. · Department of Surgery, Vanderbilt University, Nashville, TN, United States. · Department of Surgery, Washington University, St Louis, MO, United States. ·HPB (Oxford) · Pubmed #27154811.

ABSTRACT: INTRODUCTION: Several groups have defined pancreatic surgery quality metrics that identify centers delivering quality care. Although these metrics are perceived to be associated with good outcomes, their relationship with actual outcomes has not been established. METHODS: A national cadre of pancreatic surgeons was surveyed regarding perceived quality metrics, which were evaluated against the Central Pancreas Consortium (CPC) database to determine actual performance and relationships with long-term outcomes. RESULTS: The most important metrics were perceived to be participation in clinical trials, appropriate clinical staging, perioperative mortality, and documentation of receipt of adjuvant therapy. Subsequent analysis of 1399 patients in the CPC dataset demonstrated that a R0 retroperitoneal and neck margin was obtained in 79% (n = 1109) and 91.4% (n = 1278) of cases, respectively. 74% of patients (n = 1041) had >10 lymph nodes harvested, and LN positivity was 65% (n = 903). 76% (n = 960) of eligible patients (surgery first approach) received adjuvant therapy within 60 days of surgery. Multivariate analysis demonstrated margin status, identification of >10 lymph nodes, nodal status, tumor grade and delivery of adjuvant therapy within 60 days to be associated with improved overall survival. CONCLUSIONS: These analyses demonstrate that systematic monitoring of surgeons' perceived quality metrics provides critical prognostic information, which is associated with patient survival.

Next