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Pancreatic Neoplasms: HELP
Articles by Philip R. De Reuver
Based on 9 articles published since 2010
(Why 9 articles?)
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Between 2010 and 2020, P. de Reuver wrote the following 9 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Systematic review of peri-operative prognostic biomarkers in pancreatic ductal adenocarcinoma. 2016

Petrushnko, Wilson / Gundara, Justin S / De Reuver, Philip R / O'Grady, Greg / Samra, Jaswinder S / Mittal, Anubhav. ·Upper Gastrointestinal Surgical Unit, Royal North Shore Hospital, North Shore Private Hospital, University of Sydney, St Leonards, NSW 2065, Australia. · Department of Surgery, University of Auckland, New Zealand. · Upper Gastrointestinal Surgical Unit, Royal North Shore Hospital, North Shore Private Hospital, University of Sydney, St Leonards, NSW 2065, Australia. Electronic address: anubhav.mittal@sydney.edu.au. ·HPB (Oxford) · Pubmed #27485059.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) continues to be associated with a poor prognosis. This systematic review aimed to summarize the literature regarding potential prognostic biomarkers to facilitate validation studies and clinical application. METHODS: A systematic review was performed (2004-2014) according to PRISMA guidelines. Studies were ranked using REMARK criteria and the following outcomes were examined: overall/disease free survival, nodal involvement, tumour characteristics, metastasis, recurrence and resectability. RESULTS: 256 biomarkers were identified in 158 studies. 171 biomarkers were assessed with respect to overall survival: urokinase-type plasminogen activator receptor, atypical protein kinase C and HSP27 ranked the highest. 33 biomarkers were assessed for disease free survival: CD24 and S100A4 were the highest ranking. 17 biomarkers were identified for lymph node involvement: Smad4/Dpc4 and FOXC1 ranked highest. 13 biomarkers were examined for tumour grade: mesothelin and EGFR were the highest ranking biomarkers. 10 biomarkers were identified for metastasis: p16 and sCD40L were the highest ranking. 4 biomarkers were assessed resectability: sCD40L, s100a2, Ca 19-9, CEA. CONCLUSION: This review has identified and ranked specific biomarkers that should be a primary focus of ongoing validation and clinical translational work in PDAC.

2 Clinical Trial Distal pancreatectomy, splenectomy, and celiac axis resection (DPS-CAR): common hepatic arterial stump pressure should determine the need for arterial reconstruction. 2015

Mittal, Anubhav / de Reuver, Philip R / Shanbhag, Satya / Staerkle, Ralph F / Neale, Michael / Thoo, Catherine / Hugh, Thomas J / Gill, Anthony J / Samra, Jaswinder S. ·Department of Gastrointestinal Surgery, Royal North Shore Hospital and North Shore Private Hospital, University of Sydney, Sydney, New South Wales, Australia. · Department of Surgery, University of Auckland, Auckland, New Zealand. · Department of Vascular Surgery, Royal North Shore Hospital and North Shore Private Hospital, University of Sydney, Sydney, New South Wales, Australia. · Department of Anatomical Pathology, Royal North Shore Hospital and North Shore Private Hospital, University of Sydney, Sydney, New South Wales, Australia. · Department of Gastrointestinal Surgery, Royal North Shore Hospital and North Shore Private Hospital, University of Sydney, Sydney, New South Wales, Australia; Macquarie University Hospital, Macquarie University, Sydney, New South Wales, Australia. Electronic address: jas.samra@bigpond.com. ·Surgery · Pubmed #25532436.

ABSTRACT: BACKGROUND: Tumors arising in the neck and body of the pancreas often invade the common hepatic artery and celiac axis (CA), necessitating distal pancreatectomy, splenectomy, and celiac axis resection (DPS-CAR). In these patients, the need for revascularization of the common hepatic artery (CHA) can be avoided on the basis of the pressure change in the CHA after clamping of the CA. METHODS: All patients presenting to North Shore Hospital Campus of University of Sydney with advanced pancreatic malignancy of the neck and body between 2007 and 2014 were included in the study. The pressure in the CHA was measured pre- and postclamping of the CA; a decrease of more than 25% in the mean arterial pressure necessitated vascular reconstruction of the CHA. RESULTS: Seven patients underwent a DPS-CAR between 2007 and 2014. Arterial reconstruction was required in 2 patients based on a decrease of >25% mean arterial pressure in the CHA after clamping the CA. There was no in hospital or 90-day mortality, and no patients developed ischemic hepatitis. CONCLUSION: A single-stage DPS-CAR with selective arterial reconstruction based on the CHA pressure change after clamping the CA is a safe approach.

3 Article ATRX loss is an independent predictor of poor survival in pancreatic neuroendocrine tumors. 2018

Chou, Angela / Itchins, Malinda / de Reuver, Philip R / Arena, Jennifer / Clarkson, Adele / Sheen, Amy / Sioson, Loretta / Cheung, Veronica / Perren, Aurel / Nahm, Christopher / Mittal, Anubhav / Samra, Jaswinder S / Pajic, Marina / Gill, Anthony J. ·Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia; University of Sydney, Sydney, NSW 2006, Australia; Department of Anatomical Pathology, SYDPATH, St Vincent's Hospital, Darlinghurst, NSW 2010, Australia; The Kinghorn Cancer Centre and Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia. · University of Sydney, Sydney, NSW 2006, Australia; Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. · Department of Surgery, Radboud University Medical Center, Nijmegen 6525, The Netherlands; Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. · Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. · Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. · Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. · Institute of Pathology, University of Bern, Bern 3012, Switzerland. · University of Sydney, Sydney, NSW 2006, Australia; Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. · The Kinghorn Cancer Centre and Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia. · Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia; University of Sydney, Sydney, NSW 2006, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. Electronic address: affgill@med.usyd.edu.au. ·Hum Pathol · Pubmed #30081149.

ABSTRACT: Pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms accounting for 1% to 2% of all pancreatic tumors. The biological behavior of PanNETs is heterogeneous and unpredictable, adding to the difficulties of clinical management. The DAXX (death domain associated protein) and ATRX (α-thalassemia/mental retardation syndrome X-linked) genes encode proteins involved in SWI/SNF-like chromatin remodeling. Somatic inactivating mutations in DAXX and ATRX are frequent in PanNETs, mutually exclusive, and associated with telomere dysfunction, resulting in genomic instability and alternate lengthening of telomeres. We sought to assess the clinical significance of the loss of the ATRX and DAXX proteins as determined by immunohistochemistry (IHC) in patients with PanNET. From an unselected cohort of 105 patients, we found ATRX loss in 10 tumors (9.5%) and DAXX loss in 16 (15.2%). DAXX and ATRX losses were confirmed mutually exclusive and associated with other adverse clinicopathological variables and poor survival in univariate analysis. In addition, ATRX loss was also associated with higher AJCC stage and infiltrative tumor borders. However, only ATRX loss, lymphovascular invasion, and perineural spread were independent predictors of poor overall survival in multivariate analysis. In conclusion, loss of expression of ATRX as determined by IHC is a useful independent predictor of poor overall survival in PanNETs. Given its relative availability, ATRX loss as determined by IHC may have a role in routine clinical practice to refine prognostication in patients with PanNET.

4 Article Histopathological tumour viability after neoadjuvant chemotherapy influences survival in resected pancreatic cancer: analysis of early outcome data. 2018

Townend, Phil / de Reuver, Phil R / Chua, Terence C / Mittal, Anubhav / Clark, Stephen J / Pavlakis, Nick / Gill, Anthony J / Samra, Jaswinder S. ·Department of Gastrointestinal Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia. · Discipline of Surgery, The University of Sydney, Sydney, New South Wales, Australia. · Department of Medical Oncology, Royal North Shore Hospital, Sydney, New South Wales, Australia. · Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Sydney, New South Wales, Australia. · Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia. · Deparment of Anatomical Pathology, Royal North Shore Hospital, Sydney, New South Wales, Australia. · Macquarie University Hospital, Macquarie University, Sydney, New South Wales, Australia. ·ANZ J Surg · Pubmed #28318082.

ABSTRACT: BACKGROUND: Neoadjuvant therapy is increasingly recognized as an effective strategy prior to pancreatoduodenectomy. We investigate the role of neoadjuvant chemotherapy (NAC) followed by surgery and the predictive role of viable residual tumour cells histopathologically on outcomes. METHODS: The study population comprised of 195 consecutive patients with pancreatic adenocarcinoma who were treated with either NAC or a surgery-first (SF) strategy. Histopathological viable tumour cells were examined in the NAC patients and clinicopathological factors were correlated with overall survival. RESULTS: Forty-two patients (22%) were treated with NAC and 153 patients (78%) underwent SF. NAC was associated with higher estimated blood loss during surgery (928 mL versus 615 mL; P = 0.004), fewer (<15) excised lymph nodes (37% versus 17%; P = 0.015) and lower rates of lymphovascular invasion (65% versus 45%; P = 0.044) when compared with SF. Two-year survival of patients undergoing NAC was 63% and 51% in patients undergoing SF (P = 0.048). The 2-year survival of patients who had >65% residual tumour cells was 45% and 90% in patients who had <65% residual tumour cells (P = 0.022). Favourable responders (<65% viable tumour cells) were observed to have shorter operation time (<420 min) (55% versus 13%; P = 0.038), trend towards negative lymph node status (38% versus 10%; P = 0.067) and greater lymph node harvest in node positive patients (≥4 positive lymph nodes) (77% versus 37%; P = 0.045). CONCLUSION: The improved survival of patients undergoing NAC indicates effective management of micrometastatic disease and is an effective option requiring further investigation. Histopathological viable tumour cells after NAC was a surrogate marker for survival.

5 Article Circulating and disseminated tumor cells in pancreatic cancer and their role in patient prognosis: a systematic review and meta-analysis. 2017

Stephenson, David / Nahm, Christopher / Chua, Terence / Gill, Anthony / Mittal, Anubhav / de Reuver, Philip / Samra, Jaswinder. ·Sydney Medical School, University of Sydney, Camperdown, Sydney, Australia. · Upper GI Surgical Unit, Department of Gastrointestinal Surgery, Royal North Shore Hospital, St. Leonards, Sydney, Australia. · Cancer Diagnosis and Pathology, Kolling Institute, Royal North Shore Hospital, St. Leonards, Sydney, Australia. · Department of Surgery, Radboud University Medical Centre, Nijmegen, The Netherlands. ·Oncotarget · Pubmed #29291024.

ABSTRACT: Background: Disseminated tumor cells (DTCs) and circulating tumor cells (CTCs) have been postulated to seed metastases and contribute to poorer patient outcomes in many types of solid cancer. To date, no systematic reviews have examined the role of both DTCs and CTCs in pancreatic cancer. We aimed to determine the prognostic value of DTCs/CTCs in pancreatic cancer using a systematic review and meta-analysis. Materials and Methods: A comprehensive literature search identified studies examining DTCs and CTCs in the bone marrow and blood of pancreatic cancer patients at diagnosis with follow-up to determine disease-free/progression-free survival (DFS/PFS) and overall survival (OS). Statistical analyses were performed to determine the hazard ratio (HR) of DTCs/CTCs on DFS/PFS and OS. Results: The literature search identified 16 articles meeting the inclusion criteria. The meta-analysis demonstrated statistically significant HR differences in DFS/PFS (HR = 1.93, 95% CI 1.19-3.11, Conclusion: The detection of DTCs/CTCs at diagnosis is associated with poorer DFS/PFS and OS in pancreatic cancer.

6 Article Immunoregulatory Forkhead Box Protein p3-Positive Lymphocytes Are Associated with Overall Survival in Patients with Pancreatic Neuroendocrine Tumors. 2016

de Reuver, Philip R / Mehta, Shreya / Gill, Preetjote / Andrici, Juliana / D'Urso, Lisa / Clarkson, Adele / Mittal, Anubhav / Hugh, Thomas J / Samra, Jaswinder S / Gill, Anthony J. ·Department of Gastrointestinal Surgery, Royal North Shore Hospital and North Shore Private Hospital, University of Sydney, New South Wales, Australia. Electronic address: Philipdereuver@gmail.com. · Department of Gastrointestinal Surgery, Royal North Shore Hospital and North Shore Private Hospital, University of Sydney, New South Wales, Australia. · Department of Anatomical Pathology, Royal North Shore Hospital, Cancer Diagnosis and Pathology Group Kolling Institute of Medical Research, University of Sydney, New South Wales, Australia. · Department of Gastrointestinal Surgery, Royal North Shore Hospital and North Shore Private Hospital, University of Sydney, New South Wales, Australia; Macquarie University Hospital, Macquarie University, New South Wales, Australia. ·J Am Coll Surg · Pubmed #26809747.

ABSTRACT: BACKGROUND: Forkhead box protein p3-positive (FoxP3(+)) regulatory T cells (Tregs) suppress host T-cell-mediated immune responses, limit surveillance against cancers, and have been associated with a poor prognosis. STUDY DESIGN: This study aims to identify the prognostic significance of FoxP3(+) Tregs in pancreatic neuroendocrine tumors (PNETs). Patients diagnosed with PNETs between 1992 and 2014 (n = 101) were included in this retrospective analysis. Clinical data, histopathology, and expression of FoxP3(+) Tregs and Ki-67 by immunohistochemistry were assessed. The association of these factors with survival was tested by log-rank test and in additional multivariable analysis. RESULTS: A total of 101 patients were included in this study. Mean age was 58.0 years (range 18 to 87 years) and median tumor size was 25 mm (range 8 to 160 mm). The degree of infiltration of tumor by FoxP3(+) Tregs was graded as 0 (n = 75), 1 (n = 15), or 2 (n = 11). Median follow-up was 50 months (interquartile range 123 months; Q1 = 20 months and Q3 = 123 months). In univariate analyses, patient age older than 57 years, TNM stage III or IV, tumor size >25 mm, Ki-67 labeling index >20, and a high number of FoxP3(+) tumor-infiltrating lymphocytes were significantly associated with poorer overall survival. In multivariable analyses, FoxP3(+) expression score of 2 (hazard ratio = 6.9; 95% CI 1.4-34.4) was the only statistically significant predictor for overall mortality. CONCLUSIONS: FoxP3(+) Treg expression is an independent prognostic factor in patients with PNETs, associated with statistically significant shorter overall survival. There is a role for additional research into the immune-mediated role of FoxP3(+) Tregs in PNETs.

7 Article Transverse closure of mesenterico-portal vein after vein resection in pancreatoduodenectomy. 2016

Chua, T C / de Reuver, P R / Staerkle, R F / Neale, M L / Arena, J / Mittal, A / Shanbhag, S T / Gill, A J / Samra, J S. ·Department of Gastrointestinal Surgery, Royal North Shore Hospital, St Leonards, NSW, Australia; Discipline of Surgery, University of Sydney, Sydney, NSW, Australia. Electronic address: terence.c.chua@gmail.com. · Department of Gastrointestinal Surgery, Royal North Shore Hospital, St Leonards, NSW, Australia; Discipline of Surgery, University of Sydney, Sydney, NSW, Australia. · Department of Vascular Surgery, Royal North Shore Hospital, St Leonards, NSW, Australia; Discipline of Surgery, University of Sydney, Sydney, NSW, Australia. · Department of Gastrointestinal Surgery, Royal North Shore Hospital, St Leonards, NSW, Australia; Discipline of Surgery, University of Sydney, Sydney, NSW, Australia; Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, University of Sydney, Australia. · Department of Surgery, Auckland City Hospital, Auckland, New Zealand. · Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW, Australia; Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, University of Sydney, Australia. · Department of Gastrointestinal Surgery, Royal North Shore Hospital, St Leonards, NSW, Australia; Discipline of Surgery, University of Sydney, Sydney, NSW, Australia; Macquarie University Hospital, Macquarie University, NSW, Australia. Electronic address: jas.samra@bigpond.com. ·Eur J Surg Oncol · Pubmed #26456791.

ABSTRACT: BACKGROUND: Resection of the involved mesenteric-portal vein (MPV) is increasingly performed in pancreatoduodenectomy. The primary aim of this study is to assess the rate of R0 resection in transverse closure (TC) versus segmental resection with end-to-end (EE) closure and the secondary aims are to assess the short-term morbidity and long-term survival of TC versus EE. METHODS: Patients undergoing pancreatoduodenectomy with MPV resection were identified from a prospectively database. The reconstruction technique were examined and categorized. Clinical, pathological, short-term and long-term survival outcomes were compared between groups. RESULTS: 110 patients underwent PD with MPV resection of which reconstruction was performed with an end-to-end technique in 92 patients (84%) and transverse closure technique in 18 patients (16%). Patients undergoing transverse closure tended to have had a shorter segment of vein resected (≤2 cm) compared to the end-to-end (83% vs. 43%; P = 0.004) with no difference in R0 rate. Short-term morbidity was similar. The median and 5-year survival was 30.0 months and 18% respectively for patients undergoing transverse closure and 28.6 months and 7% respectively for patients undergoing end-to-end reconstruction (P = 0.766). CONCLUSION: Without compromising the R0 rate, transverse closure to reconstruct the mesenteric-portal vein is shown to be feasible and safe in the setting when a short segment of vein resection is required during pancreatoduodenectomy. Synopsis - We describe a vein closure technique, transverse closure, which avoids the need for a graft, or re-implantation of the splenic vein when resection of the mesenteric-portal vein confluence is required during pancreatoduodenectomy.

8 Article Somatostatin Receptor SSTR-2a Expression Is a Stronger Predictor for Survival Than Ki-67 in Pancreatic Neuroendocrine Tumors. 2015

Mehta, Shreya / de Reuver, Philip R / Gill, Preetjote / Andrici, Juliana / D'Urso, Lisa / Mittal, Anubhav / Pavlakis, Nick / Clarke, Stephen / Samra, Jaswinder S / Gill, Anthony J. ·From Department of Gastrointestinal Surgery, Royal North Shore Hospital and North Shore Private Hospital, University of Sydney, New South Wales, Australia (SM, PDR, PG, AM, JSS) · Department of Medical Oncology, Royal North Shore Hospital and North Shore Private Hospital, University of Sydney, New South Wales, Australia (NP, SC) · Macquarie University Hospital, Macquarie University, New South Wales, Australia (JSS) · and Department of Anatomical Pathology Royal North Shore Hospital, Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, University of Sydney, New South Wales, Australia (JA, LDU, AJG). ·Medicine (Baltimore) · Pubmed #26447992.

ABSTRACT: Somatostatin receptors (SSTR) are commonly expressed by neuroendocrine tumors. Expression of SSTR-2a and SSTR-5 may impact symptomatic management; however, the impact on survival is unclear. The aim of this study is to correlate SSTR-2a and SSTR-5 expression in pancreatic neuroendocrine tumors (PNETs) with survival. This study is designed to determine the prognostic significance of somatostatin receptors SSTR-2a and SSTR-5 in PNETs. This retrospective cohort study included cases of resected PNETs between 1992 and 2014. Clinical data, histopathology, expression of SSTR and Ki-67 by immunohistochemistry, and long-term survival were analyzed. A total of 99 cases were included in this study. The mean age was 57.8 years (18-87 years) and median tumor size was 25 mm (range 8-160 mm). SSTR-2a and SSTR-5 expression was scored as negative (n = 19, 19.2%; n = 75, 75.8%, respectively) and positive (n = 80, 80.1%; n = 24, 24.2%). The median follow-up was 49 months. SSTR-2a expression was associated with improved overall survival, with cumulative survival rates at 1, 3, and 5 years being 97.5%, 91.5%, and 82.9%, respectively. Univariate analysis demonstrated better survival in SSTR-2a positive patients (log rank P = 0.04). SSTR-5 expression was not associated with survival outcomes (log rank P = 0.94). Multivariate analysis showed that positive SSTR-2a expression is a stronger prognostic indicator for overall survival [Hazard Ratio (HR): 0.2, 95% Confidence interval (CI): 0.1-0.8] compared to high Ki-67 (HR: 0.8, 95% CI: 0.1-5.7). Expression of SSTR-2a is an independent positive prognostic factor for survival in PNETs.

9 Article Extended pancreatoduodenectomy as defined by the International Study Group for Pancreatic Surgery is associated with worse survival but not with increased morbidity. 2015

De Reuver, Philip R / Mittal, Anubhav / Neale, Michael / Gill, Anthony J / Samra, Jaswinder S. ·Department of Gastrointestinal Surgery, Royal North Shore Hospital and North Shore Private Hospital, University of Sydney, Sydney, New South Wales, Australia. Electronic address: philipdereuver@gmail.com. · Department of Gastrointestinal Surgery, Royal North Shore Hospital and North Shore Private Hospital, University of Sydney, Sydney, New South Wales, Australia. · Department of Vascular Surgery, Royal North Shore Hospital and North Shore Private Hospital, University of Sydney, Sydney, New South Wales, Australia. · Department of Anatomical Pathology, Royal North Shore Hospital and North Shore Private Hospital, University of Sydney, Sydney, New South Wales, Australia. · Department of Gastrointestinal Surgery, Royal North Shore Hospital and North Shore Private Hospital, University of Sydney, Sydney, New South Wales, Australia; Macquarie University Hospital, Macquarie University, Sydney, New South Wales, Australia. ·Surgery · Pubmed #25920909.

ABSTRACT: BACKGROUND: Recently, the International Study Group for Pancreatic Surgery presented a consensus statement on the definition of an extended pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). Because extended resections are associated with increased morbidity and mortality, prognostic factors for outcome are mandatory to optimize patient selection. The aim of this study was to apply the new definition of an extended PD and to assess prognostic factors for short-term complications and survival in patients with PDAC. METHODS: A retrospective analysis was performed on a prospectively collected database running from 2004 to 2014. Inclusion criteria were all PD resections with histopathology-proven PDAC. Clinical data, operative results, and short- and long-term outcomes were analyzed. RESULTS: We included 177 patients who underwent PD for PDAC in this study. Sixty-six patients (37%) underwent a standard PD and 111 (63%) underwent an extended PD. No differences were found in duration of postoperative stay (median, 13 days) or overall complication rate of 35% (n = 61). Severe complications occurred in 24 patients (13%). Male sex (odds ratio, 2.4; 95% CI, 0.9-6.6) was a prognostic factor for severe complications. There was no in-hospital or 90-day mortality in either group. Multivariate survival analysis showed that poor tumor differentiation (hazard ratio [HR], 2.0; 95% CI, 1.3-3.1), lymph node metastasis (HR, 2.3; 95% CI, 1.4-3.9), neural invasion (HR, 1.9; 95% CI, 1.2-3.1), were independent prognostic factors for worse survival. An extended resection was associated with worse survival, but was not an independent prognostic factor (HR, 1.5; 95% CI, 1.0-2.3). CONCLUSION: Extended PD is associated with worse survival but not with increased morbidity.