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Background: In patients with localized pancreatic ductal adenocarcinoma (PDAC) undergoing neoadjuvant therapy (NAT) and resection, selection of adjuvant chemotherapy (AC) is typically guided by high-risk features on histopathologic examination. We evaluated the interaction between post-NAT lymph node metrics and AC receipt on survival., Methods: Patients who received NAT followed by pancreatectomy (2010-2020) at seven centers were reviewed. Overall survival (OS) in patients receiving AC or not was stratified by lymph node positivity (LNP) or lymph node ratio (LNR) dichotomized at 0.1. Cox models evaluated the independent association between these nodal metrics, AC receipt, and OS., Results: Of 464 patients undergoing NAT and resection, 264 (57%) received AC. Patients selected for AC were younger (median 63 vs. 67 years; p < 0.001), received shorter duration of NAT (2.8 vs. 3.2 months; p = 0.01), had fewer postoperative complications (Clavien-Dindo grade > 3: 1.2% vs. 11.7%; p < 0.001), and lower rates of pathologic complete response (4% vs. 11%; p = 0.01). The median number of nodes evaluated was similar between cohorts (n = 20 in both; p = 0.9). Post-NAT LNP rates were not different, and median LNR was 0.1, in AC and non-AC cohorts. Both LNP (hazard ratio [HR]: 2.1, p < 0.001) and LNR (0 < LNR ≤ 0.1: HR: 1.98, p = 0.002; LNR > 0.1: HR 2.46, p < 0.001) were independently associated with OS on Cox modeling, although receipt of AC was not associated with improved OS (median 30.6 vs. 29.4 months; p = 0.2). In patients with LNR > 0.1, receipt of AC was associated with significantly longer OS compared to non-AC (24 vs. 20 months, respectively; p = 0.04)., Conclusions: LNR following NAT, not simply nodal positivity, may be useful to refine selection of AC in resected PDAC., (© 2024 The Author(s). Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Background: Outcomes for pancreatic adenocarcinoma (PDAC) remain difficult to prognosticate. Multiple models attempt to predict survival following the resection of PDAC, but their utility in the neoadjuvant population is unknown. We aimed to assess their accuracy among patients that received neoadjuvant chemotherapy (NAC)., Methods: We performed a multi-institutional retrospective analysis of patients who received NAC and underwent resection of PDAC. Two prognostic systems were evaluated: the Memorial Sloan Kettering Cancer Center Pancreatic Adenocarcinoma Nomogram (MSKCCPAN) and the American Joint Committee on Cancer (AJCC) staging system. Discrimination between predicted and actual disease-specific survival was assessed using the Uno C-statistic and Kaplan-Meier method. Calibration of the MSKCCPAN was assessed using the Brier score., Results: A total of 448 patients were included. There were 232 (51.8%) females, and the mean age was 64.1 years (±9.5). Most had AJCC Stage I or II disease (77.7%). For the MSKCCPAN, the Uno C-statistic at 12-, 24-, and 36-month time points was 0.62, 0.63, and 0.62, respectively. The AJCC system demonstrated similarly mediocre discrimination. The Brier score for the MSKCCPAN was 0.15 at 12 months, 0.26 at 24 months, and 0.30 at 36 months, demonstrating modest calibration., Conclusions: Current survival prediction models and staging systems for patients with PDAC undergoing resection after NAC have limited accuracy., (© 2023 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Background: Major pathologic response (MPR) following neoadjuvant therapy (NAT) in pancreatic ductal adenocarcinoma (PDAC) patients undergoing resection is associated with improved survival. We sought to determine whether racial disparities exist in MPR rates following NAT in patients with PDAC undergoing resection., Methods: Patients with potentially operable PDAC receiving at least 2 cycles of neoadjuvant FOLFIRINOX or gemcitabine/nab-paclitaxel ± radiation followed by pancreatectomy (2010-2019) at 7 high-volume centers were reviewed. Self-reported race was dichotomized as Black and non-Black, and multivariable models evaluated the association between race and MPR (i.e., pathologic complete response [pCR] or near-pCR). Cox regression evaluated the association between race and disease-free (DFS) and overall survival (OS)., Results: Results of 486 patients who underwent resection following NAT (mFOLFIRINOX 56%, gemcitabine/nab-paclitaxel 25%, radiation 29%), 67 (13.8%) patients were Black. Black patients had lower CA19-9 at diagnosis (median 67 vs. 204 U/mL; P = 0.003) and were more likely to undergo mild/moderate chemotherapy dose modification (40 vs. 20%; P = 0.005) versus non-Black patients. Black patients had significantly lower rates of MPR compared with non-Black patients (13.4 vs. 25.8%; P = 0.039). Black race was independently associated with worse MPR (OR 0.26, 95% confidence interval [CI] 0.10-0.69) while controlling for NAT duration, CA19-9 dynamics, and chemotherapy modifications. There was no significant difference in DFS or OS between Black and non-Black cohorts., Conclusions: Black patients undergoing pancreatectomy appear less likely to experience MPR following NAT. The contribution of biologic and nonbiologic factors to reduced chemosensitivity in Black patients warrants further investigation., (© 2022. Society of Surgical Oncology.)

Background: Data regarding the survival impact of converting frozen-section (FS):R1 pancreatic neck margins to permanent section (PS):R0 by additional resection (i.e., converted-R0) during upfront pancreaticoduodenectomy for pancreatic ductal adenocarcinoma (PDAC) are conflicting. The impact of neoadjuvant therapy on this practice and its relationship with overall survival (OS) is incompletely understood., Methods: We reviewed PDAC patients (80% borderline resectable/locally advanced [BR/LA]) undergoing pancreaticoduodenectomy after neoadjuvant therapy at seven, academic, high-volume centers (2010-2018). Multivariable models examined the association of PS:R0, PS:R1, and converted-R0 margins with OS., Results: Of 272 patients receiving at least 2 (median 4) cycles of neoadjuvant chemotherapy (71% mFOLFIRINOX or gemcitabine/nab-paclitaxel) and undergoing pancreaticoduodenectomy with intraoperative frozen-section assessment of the transected pancreatic neck margin, PS:R0 (n = 220, 80.9%) was observed in a majority of patients; 18 patients (6.6%) had converted-R0 margins following additional resection, whereas 34 patients (12.5%) had persistently positive PS:R1 margins. At a median follow-up of 42 months, PS:R0 resection was associated with improved OS compared with either converted-R0 or PS:R1 resection (median 25 vs. 14 vs. 16 months, respectively; p = 0.023), with no survival difference between the converted-R0 and PS:R1 groups (p = 0.9). On Cox regression, SMA margin positivity (hazard ratio 2.2, p = 0.012), but not neck margin positivity (hazard ratio 1.2, p = 0.65), was associated with worse OS., Conclusions: In this multi-institutional cohort of predominantly BR/LA PDAC patients undergoing pancreaticoduodenectomy following modern neoadjuvant therapy, pursuing a negative neck margin intraoperatively if the initial margin is positive does not appear to be associated with improved survival., (© 2022. Society of Surgical Oncology.)

An important goal of cancer surgery is to achieve negative surgical margins and remove all disease completely. For pancreatic neoplasms, microscopic margins may remain positive despite gross removal of the palpable mass, and surgeons must then consider extending resection, even to the point of completion pancreatectomy, an option that renders the patient with significant adverse effects related to exocrine and endocrine insufficiency. Counterintuitively, extending resection to ensure clear margins may not improve patient outcome. Furthermore, the goal of improving survival by extending the resection may not be achieved, as an initial positive margin may indicate more aggressive underlying tumor biology. There is a growing body of literature on this topic, and this landmark series review will examine the key publications that guide our management for resection of pancreatic ductal adenocarcinoma, intraductal papillary mucinous neoplasms, and pancreatic neuroendocrine tumors., (© 2021. Society of Surgical Oncology.)

Background: Recently, the first randomized trials comparing minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) for non-malignant and malignant disease showed a 2-day reduction in time to functional recovery after MIDP. However, for pancreatic ductal adenocarcinoma (PDAC), concerns have been raised regarding the oncologic safety (i.e., radical resection, lymph node retrieval, and survival) of MIDP, as compared to ODP. Therefore, a randomized controlled trial comparing MIDP and ODP in PDAC regarding oncological safety is warranted. We hypothesize that the microscopically radical resection (R0) rate is non-inferior for MIDP, as compared to ODP., Methods/design: DIPLOMA is an international randomized controlled, patient- and pathologist-blinded, non-inferiority trial performed in 38 pancreatic centers in Europe and the USA. A total of 258 patients with an indication for elective distal pancreatectomy with splenectomy because of proven or highly suspected PDAC of the pancreatic body or tail will be randomly allocated to MIDP (laparoscopic or robot-assisted) or ODP in a 1:1 ratio. The primary outcome is the microscopically radical resection margin (R0, distance tumor to pancreatic transection and posterior margin ≥ 1 mm), which is assessed using a standardized histopathology assessment protocol. The sample size is calculated with the following assumptions: 5% one-sided significance level (α), 80% power (1-β), expected R0 rate in the open group of 58%, expected R0 resection rate in the minimally invasive group of 67%, and a non-inferiority margin of 7%. Secondary outcomes include time to functional recovery, operative outcomes (e.g., blood loss, operative time, and conversion to open surgery), other histopathology findings (e.g., lymph node retrieval, perineural- and lymphovascular invasion), postoperative outcomes (e.g., clinically relevant complications, hospital stay, and administration of adjuvant treatment), time and site of disease recurrence, survival, quality of life, and costs. Follow-up will be performed at the outpatient clinic after 6, 12, 18, 24, and 36 months postoperatively., Discussion: The DIPLOMA trial is designed to investigate the non-inferiority of MIDP versus ODP regarding the microscopically radical resection rate of PDAC in an international setting., Trial Registration: ISRCTN registry ISRCTN44897265 . Prospectively registered on 16 April 2018., (© 2021. The Author(s).)

Importance: Although margin-negative (R0) resection is the gold standard for surgical management of localized pancreatic ductal adenocarcinoma (PDAC), the question of how to manage the patient with a microscopically positive intraoperative neck margin (IONM) during pancreaticoduodenectomy remains controversial., Observations: In the absence of randomized clinical trials, we critically evaluated high-quality retrospective studies examining the oncologic utility of re-resecting positive IONMs during pancreaticoduodenectomy for PDAC (2000-2019). Several studies have concluded that additional pancreatic resection to achieve an R0 margin in IONM-positive cases does not influence survival. The largest is a multi-institutional study of 1399 patients undergoing pancreaticoduodenectomy, which demonstrated that in comparison with patients undergoing R0 resection (n = 1196; median survival, 21 months), those with either final R1 resections (n = 131) or undergoing margin conversion from IONM-positive to R0 resection on permanent section (n = 72) demonstrated similar median survival times (13.7 and 11.9 months, respectively). Conversely, recent reports suggest that the conversion of IONM to R0 resection with additional resection or even total pancreatectomy may be associated with improved survival. The discordance between these conflicting studies could be explained in part by the influence of biologic and physiologic selection on the association of IONM re-resection and survival. Since most studies did not include patients receiving modern combination chemotherapy regimens, the intersection between margin status, tumor biology, and chemoresponsiveness remains unclear. Furthermore, there are no dedicated data to guide surgical management in IONM-positive pancreaticoduodenectomy for patients receiving neoadjuvant chemotherapy., Conclusions and Relevance: Although data regarding the oncologic utility of additional resection to achieve a tumor-free margin following initial IONM positivity during pancreaticoduodenectomy for PDAC are conflicting, they suggest that IONM positivity may be a surrogate for biologic aggressiveness that is unlikely to be mitigated by the extent of surgical resection. The complex relationship between margin status and chemoresponsiveness warrants exploration in studies including patients receiving increasingly effective neoadjuvant chemotherapy.

Background: Existing research suggests patients with blood group O are less likely to develop pancreatic ductal adenocarcinoma (PDAC) compared to those with non-O blood groups, and that survival from PDAC may be affected by ABO blood type. This study assessed survival outcomes in PDAC patients who underwent pancreatoduodenectomy (PD) in one health system., Methods: From 2010 to 2017, demographic, operative, chemotherapy and survival data for patients undergoing PD at Emory Healthcare were reviewed. Patients with blood type AB were excluded due to small sample size. The relationship between ABO blood group and survival was analyzed using Kaplan-Meier survival curves and multivariate cox proportional regression analysis., Results: Of 449 PDAC patients assessed, 204 (45.4%), 60 (13.4%) and 185 (41.2%) were blood groups A, B and O, respectively. Patients were well matched in clinicopathologic characteristics. Median survival did not differ by blood group (p = 0.82), and this relationship remained insignificant on cox regression analysis (p = 0.15). On multivariate analysis, lymph node positivity (p < 0.001) and increasing age (p = 0.001) were associated with reduced survival., Conclusion: In contrast to recent reports, this larger study found that blood group did not impact overall survival among patients undergoing PD for PDAC., (Copyright © 2020. Published by Elsevier Ltd.)

Background: For pancreatic adenocarcinoma (PDAC), no studies have established any association between earlier treatment initiation and long-term outcomes. In addition, an optimal type of initial treatment for the localized disease remains ill-defined., Methods: Patients in the National Cancer Database (2004-2015) with clinical stage I (CS-I) and II (CS-II) PDAC who underwent curative-intent resection were included. Optimal time from diagnosis-to-treatment including neoadjuvant chemotherapy, neoadjuvant chemoradiation, or upfront surgery was assessed. An optimal type of treatment was evaluated. The primary outcome was overall survival (OS)., Results: Among 29 167 patients, starting any treatment within 0 to 6 weeks was associated with improved median OS compared with 7 to 12 weeks (21.0 vs 20.1 months; P = .004). This persisted when accounting for sex, race, and Charlson-Deyo score (hazard ratio [HR], 0.94; P = 0.02) and on subset analysis for CS-I (23.5 vs 21.8 months; P = .04) and CS-II (19.4 vs 18.3 months; P = .03). Neoadjuvant chemotherapy was associated with improved OS compared with neoadjuvant chemoradiation (25.6 vs 22.7 months; P < .0001) or US (25.6 vs 20.1 months; P < .0001) even when accounting for sex, race, and Charlson-Deyo score (neoadjuvant chemoradiation: HR, 0.86; P < .001; US: HR, 0.79; P < .001). This improvement persisted in subset analysis with NC compared with neoadjuvant chemoradiation (CS-I: 28.6 vs 25.0 months; CS-II: 25.0 vs 22.9 months; both P < .0001) and to US (CS-I: 28.6 vs 22.9 months; CS-II: 24.7 vs 18.4 months; both P < .0001). On multivariable analysis for each CS-I/CS-II, NC remained associated with 20% improved survival compared with neoadjuvant chemoradiation or upfront surgery., Conclusions: For PDAC, initiation of therapy within 6 weeks from diagnosis is associated with improved survival, with neoadjuvant chemotherapy associated with the best survival compared with neoadjuvant chemoradiation or upfront surgery., (© 2020 Wiley Periodicals LLC.)

Background: Postoperative pancreatic fistula (POPF) is a potentially debilitating complication following pancreatoduodenectomy (PD). There are limited data correlating pancreatic parenchymal histopathologic features specifically fat and fibrosis content with development of POPF after PD., Methods: Patients who underwent PD (January 2010-May 2015) with archived pathologic slides were included. Each pancreatic neck transection margin was histologically graded for fat and fibrosis, scored from 0 to 4, and grader was blinded to clinical outcomes. Main pancreatic duct diameter and duct wall thickness were microscopically measured. Patients were dichotomized into high and low categories with respect to pancreatic fat and fibrosis and primary outcome of POPF., Results: Of 301 patients, 24 developed POPF (8.0%). One hundred ten patients (36.5%) had low fat (score <2), and 149 (49.5%) had low fibrosis (score <2), and average duct diameter was 3.9 ± 1.3 mm. Patients with low fibrosis had a higher rate of POPF (12.8% versus 3.3%, P = 0.005). Low fibrosis (odds ratio [OR] 4.29, 95% confidence interval [CI] 1.56-11.7, P = 0.005), nonpancreatic adenocarcinoma pathology (OR 3.25, 95% CI 1.25-8.43, P = 0.02), and increased body mass index (BMI) (OR 1.11, 95% CI 1.03-1.12, P = 0.007) were associated with POPF development on univariate analysis. Low fibrosis and increased BMI remained independently associated on multivariate analysis. High fat content was frequently concurrently identified in specimens with high fibrosis (67.8%). Surgeon-described gland consistency did not correlate with histopathologic findings (Spearman's rank correlation coefficients of -0.144 and 0.304, respectively) or to incidence of POPF. No patient who underwent preoperative chemotherapy developed POPF (n = 30, 10%)., Conclusions: Low pancreatic neck fibrosis content and increased patient BMI are associated with increased rates of POPF following PD, while pancreatic fat content does not appear to influence this outcome. Pancreatic neck fat and fibrosis often coexist in the same specimen. The association between preoperative chemotherapy and low POPF rates needs further examination. Frozen section analysis of pancreatic neck margin for fibrosis content may be more accurate than surgeon assessment in identifying patients at risk for POPF. These assessments can potentially guide therapeutic interventions, including selective prophylactic drain placement and use of postoperative somatostatin analog therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To compare the survival outcomes associated with clinical and pathological response in pancreatic ductal adenocarcinoma (PDAC) patients receiving neoadjuvant chemotherapy (NAC) with FOLFIRINOX (FLX) or gemcitabine/nab-paclitaxel (GNP) followed by curative-intent pancreatectomy., Background: Newer multiagent NAC regimens have resulted in improved clinical and pathological responses in PDAC; however, the effects of these responses on survival outcomes remain unknown., Methods: Clinicopathological and survival data of PDAC patients treated at 7 academic medical centers were analyzed. Primary outcomes were overall survival (OS), local recurrence-free survival (L-RFS), and metastasis-free survival (MFS) associated with biochemical (CA 19-9 decrease ≥50% vs <50%) and pathological response (complete, pCR; partial, pPR or limited, pLR) following NAC., Results: Of 274 included patients, 46.4% were borderline resectable, 25.5% locally advanced, and 83.2% had pancreatic head/neck tumors. Vein resection was performed in 34.7% and 30-day mortality was 2.2%. R0 and pCR rates were 82.5% and 6%, respectively. Median, 3-year, and 5-year OS were 32 months, 46.3%, and 30.3%, respectively. OS, L-RFS, and MFS were superior in patients with marked biochemical response (CA 19-9 decrease ≥50% vs <50%; OS: 42.3 vs 24.3 months, P < 0.001; L-RFS-27.3 vs 14.1 months, P = 0.042; MFS-29.3 vs 13 months, P = 0.047) and pathological response [pCR vs pPR vs pLR: OS- not reached (NR) vs 40.3 vs 26.1 months, P < 0.001; L-RFS-NR vs 24.5 vs 21.4 months, P = 0.044; MFS-NR vs 23.7 vs 20.2 months, P = 0.017]. There was no difference in L-RFS, MFS, or OS between patients who received FLX or GNP., Conclusion: This large, multicenter study shows that improved biochemical, pathological, and clinical responses associated with NAC FLX or GNP result in improved OS, L-RFS, and MFS in PDAC. NAC with FLX or GNP has similar survival outcomes.

In the absence of randomized trials, uncertainty regarding the oncologic efficacy of minimally invasive distal pancreatectomy (MIDP) remains. This systematic review aimed to compare oncologic outcomes after MIDP (laparoscopic or robot-assisted) and open distal pancreatectomy (ODP) in patients with pancreatic ductal adenocarcinoma (PDAC). Matched and non-matched studies were included. Pooled analyses were performed for pathology (e.g., microscopically radical (R0) resection and lymph node retrieval) and oncologic outcomes (e.g., overall survival). After screening 1760 studies, 21 studies with 11,246 patients were included. Overall survival (hazard ratio 0.86; 95% confidence interval (CI) 0.73 to 1.01; p = 0.06), R0 resection rate (odds ratio (OR) 1.24; 95%CI 0.97 to 1.58; p = 0.09) and use of adjuvant chemotherapy (OR 1.07; 95%CI 0.89 to 1.30; p = 0.46) were comparable for MIDP and ODP. The lymph node yield (weighted mean difference (WMD) -1.3 lymph nodes; 95%CI -2.46 to -0.15; p = 0.03) was lower after MIDP. Patients undergoing MIDP were more likely to have smaller tumors (WMD -0.46 cm; 95%CI -0.67 to -0.24; p < 0.001), less perineural (OR 0.48; 95%CI 0.33 to 0.70; p < 0.001) and less lymphovascular invasion (OR 0.53; 95%CI 0.38 to 0.74; p < 0.001) reflecting earlier staged disease as a result of treatment allocation bias. Based on these results we can conclude that in patients with PDAC, MIDP is associated with comparable survival, R0 resection, and use of adjuvant chemotherapy, but a lower lymph node yield, as compared to ODP. Due to treatment allocation bias and lower lymph node yield the oncologic efficacy of MIDP remains uncertain., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objective: The relevance of margin positivity on recurrence after resection of intraductal papillary mucinous neoplasms (IPMNs) is poorly defined and represents one reason controversy remains regarding optimal surveillance recommendations., Methods: Patients undergoing surgery for noninvasive IPMN at 8 academic medical centers from the Central Pancreas Consortium were analyzed. A positive margin was defined as presence of IPMN or pancreatic intraepithelial neoplasia., Results: Five hundred two patients underwent surgery for IPMN; 330 (66%) did not have invasive cancer on final pathology and form the study cohort. Of these, 20% harbored high grade dysplasia. A positive margin was found in 20% of cases and was associated with multifocal disease (P = 0.02). The majority of positive margins were associated with low grade dysplasia. At a median follow-up of 36 months, 34 (10.3%) patients recurred, with 6.7% developing recurrent cystic disease and 3.6% developing invasive cancer. On multivariate analysis, margin positivity was not associated with recurrence of either IPMN or invasive cancer (P > 0.05). No association between margin status and development of recurrence at the margin was found. Only 6% of recurrences developed at the resection margin and median time to recurrence was 22 months. Of note, 18% of recurrences occurred > 5 years following surgery., Conclusion: Margin positivity after resection for noninvasive IPMNs is primarily due to low grade dysplasia and is not associated with developing recurrence in the remnant pancreas or at the resection margin. Long-term surveillance is required for all patients, as a significant number of recurrences developed over 5 years after the index operation.

Background: Despite randomized trials addressing adjuvant therapy (AT) for pancreas cancer, the ideal time to initiate therapy remains undefined. Retrospective analyses of the ESPAC-3 trial demonstrated that time to initiation of AT did not impact overall survival (OS). Given the absence of confirmatory data outside of a clinical trial, we sought to determine if AT timing in routine clinical practice is associated with OS differences., Methods: Perioperative data of pancreatectomies for ductal adenocarcinoma from five institutions (2005-2015) were assessed. Delay in AT was defined as initiation >12 weeks after surgery. Multivariate analysis was performed to identify predictors of mortality., Results: Of 867 patients, 172 (19.8%) experienced omission of AT. Improved OS was observed in patients who received AT compared with patients who did not (24.8 vs. 19.1 months, p < 0.01). Information on time to initiation of AT was available in 488 patients, of whom 407 (83.4%) and 81 (16.6%) received chemotherapy ≤12 and >12 weeks after surgery, respectively. There were no differences in recurrence-free survival or OS (all p > 0.05) between the timely and delayed AT groups. After controlling for perioperative characteristics and tumor pathology, patients who initiated AT ≤ 12 or > 12 weeks after surgery had a 50% lower odds of mortality than patients who only underwent resection (p < 0.01)., Conclusions: In a multi-institutional experience of resected pancreas cancer, delayed initiation of AT was not associated with poorer survival. Patients who do not receive AT within 12 weeks after surgery are still appropriate candidates for multimodal therapy and its associated survival benefit.

Background: Distal cholangiocarcinoma (DC) and pancreatic ductal adenocarcinoma (PDAC) are often managed as 1 entity, yet direct comparisons are lacking. Our aim was to use 2 large multi-institutional databases to assess treatment, pathologic, and survival differences between these diseases., Study Design: This study included patients with DC and PDAC who underwent curative-intent pancreaticoduodenectomy from 2000 to 2015 at 13 institutions comprising the US Extrahepatic Biliary Malignancy and Central Pancreas Consortiums. Primary endpoint was disease-specific survival (DSS)., Results: Of 1,463 patients, 224 (15%) had DC and 1,239 (85%) had PDAC. Compared with PDAC, DC patients were less likely to be margin-positive (19% vs 25%; p = 0.005), lymph node (LN)-positive (55% vs 69%; p < 0.001), and receive adjuvant therapy (57% vs 71%; p < 0.001). Of DC patients treated with adjuvant therapy, 62% got gemcitabine alone and 16% got gemcitabine/cisplatin. Distal cholangiocarcinoma was associated with improved median DSS (40 months) compared with PDAC (22 months; p < 0.001), which persisted on multivariable analysis (hazard ratio 0.65; 95% CI 0.50 to 0.84; p = 0.001). Lymph node involvement was the only factor independently associated with decreased DSS for both DC and PDAC. The DC/LN-positive patients had similar DSS as PDAC/LN-negative patients (p = 0.74). Adjuvant therapy (chemotherapy ± radiation) was associated with improved median DSS for PDAC/LN-positive patients (21 vs 13 months; p = 0.001), but not for DC patients (38 vs 40 months; p = 0.62), regardless of LN status., Conclusions: Distal cholangiocarcinoma and pancreatic ductal adenocarcinoma are distinct entities. Distal cholangiocarcinoma has a favorable prognosis compared with PDAC, yet current adjuvant therapy regimens are only associated with improved survival in PDAC, not DC. Therefore, treatment paradigms used for PDAC should not be extrapolated to DC, despite similar operative approaches, and novel therapies for DC should be explored., (Copyright © 2016 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Histologic classification of ampullary carcinomas as intestinal versus pancreatobiliary is rapidly becoming a part of management algorithms, with immunohistochemical classification schemes also being devised using this classification scheme as their basis. However, data on the reproducibility and prognostic relevance of this classification system are limited. In this study, five observers independently evaluated 232 resected ampullary carcinomas with invasive component >3 mm. Overall interobserver agreement was 'fair' (κ 0.39; P<0.001) with complete agreement in 23%. Using agreement by 3/5 observers as 'consensus' 40% of cases were classified as 'mixed' pancreatobiliary and intestinal. When observers were asked to provide a final diagnosis based on the predominant pattern in cases initially classified as mixed, there was 'moderate' agreement (κ 0.44; P<0.0001) with 5/5 agreeing in 35%. Cases classified as pancreatobiliary by consensus (including those with pure-pancreatobiliary or mixed-predominantly pancreatobiliary features) had shorter overall (median 41 months) and 5-year survival (38%) than those classified as pure-intestinal/mixed-predominantly intestinal (80 months and 57%, respectively; P=0.026); however, on multivariate analysis this was not independent of established prognostic parameters. Interestingly, when compared with 476 cases of pancreatic ductal adenocarcinomas, the pancreatobiliary-type ampullary carcinomas had better survival (16 versus 41 months, P<0.001), even when matched by size and node status. In conclusion, presumably because of the various cell types comprising the region, ampullary carcinomas frequently show mixed phenotypes and intratumoral heterogeneity, which should be considered when devising management protocols. Caution is especially warranted when applying this histologic classification to biopsies and tissue microarrays. While ampullary carcinomas with more pancreatobiliary morphology have a worse prognosis than intestinal ones this does not appear to be an independent prognostic factor. However, pancreatobiliary-type ampullary carcinomas have a much better prognosis than their pancreatic counterparts.

Objectives: Limited data exist comparing robotic and open approaches to pancreaticoduodenectomy (PD). We performed a multicenter comparison of perioperative outcomes of robotic PD (RPD) and open PD (OPD)., Methods: Perioperative data for patients who underwent postlearning curve PD at 8 centers (8/2011-1/2015) were assessed. Univariate analyses of clinicopathologic and treatment factors were performed, and multivariable models were constructed to determine associations of operative approach (RPD or OPD) with perioperative outcomes., Results: Of the 1028 patients, 211 (20.5%) underwent RPD (4.7% conversions) and 817 (79.5%) underwent OPD. As compared with OPD, RPD patients had higher body mass index, rates of prior abdominal surgery, and softer pancreatic remnants, whereas OPD patients had a higher percentage of pancreatic ductal adenocarcinoma cases, and greater proportion of nondilated (<3 mm) pancreatic ducts. On multivariable analysis, as compared with OPD, RPD was associated with longer operative times [mean difference = 75.4 minutes, 95% confidence interval (CI) 17.5-133.3, P = 0.01], reduced blood loss (mean difference = -181 mL, 95% CI -355-(-7.7), P = 0.04) and reductions in major complications (odds ratio = 0.64, 95% CI 0.47-0.85, P = 0.003). No associations were demonstrated between operative approach and 90-day mortality, clinically relevant postoperative pancreatic fistula and wound infection, length of stay, or 90-day readmission. In the subset of 522 (51%) pancreatic ductal adenocarcinomas, operative approach was not a significant independent predictor of margin status or suboptimal lymphadenectomy (<12 lymph nodes harvested)., Conclusions: Postlearning curve RPD can be performed with similar perioperative outcomes achieved with OPD. Further studies of cost, quality of life, and long-term oncologic outcomes are needed.

Laparoscopic distal pancreatectomy for pancreatic cancer can be a challenging procedure that requires adherence to surgical principles respecting tissue planes and critical vascular structures to obtain the optimal surgical margins and peripancreatic node harvest, while minimizing damage to surrounding structures. This report provides a basic approach with some tips and tricks based on my experience with this procedure., (© 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: Level 1 data demonstrate that adjuvant chemotherapy (ACT) improves survival after surgical resection of pancreatic ductal adenocarcinoma (PDAC), (adjuvant gemcitabine, CONKO-001 study; adjuvant 5-FU, ESPAC3 study). The role of adjuvant chemoradiation therapy (ACRT) remains controversial. What is less clear is whether adjuvant therapy influences patterns of recurrence. The purpose of this study was to perform the first multicenter study analyzing patterns of recurrence after adjuvant therapy for PDAC., Study Design: Patients undergoing resection for PDAC from 8 medical centers over a 10-year period were analyzed. Demographics, tumor characteristics, operative treatment, type of adjuvant therapy, recurrence pattern, and survival were reviewed. Using Cox-proportional hazards multivariate (MV) regression, the impact of ACT and ACRT on overall survival (OS), local recurrence (LR), and distant recurrence (DR) was investigated., Results: There were 1,130 patients who were divided into those having surgery alone (n = 392), ACT (n = 291), or ACRT (n = 447). Median follow-up was 18 months. Compared with patients undergoing surgery alone, ACT, but not ACRT, demonstrated a significant OS advantage on MV analysis. Patients receiving ACT had significantly fewer recurrences (LR and DR); those receiving ACRT had significantly less LR but not DR. On subset MV analysis, ACT and ACRT resulted in less LR in patients with lymph node (LN) positive and margin negative disease. No improvements in LR, DR, or OS were seen in margin positive patients with either ACT or ACRT., Conclusions: This is the first analysis demonstrating differences in recurrence patterns in PDAC patients based on type of adjuvant therapy. Adjuvant chemotherapy provided an OS advantage likely related to its effect on reducing both LR and DR. Adjuvant chemoradiation therapy appears to decrease LR, but not DR, and therefore has less impact on OS. Future investigations and treatment protocols should consider additional ACT rather than ACRT in the treatment of PDAC., (Copyright © 2016. Published by Elsevier Inc.)

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with a grim prognosis. Surgical resection offers the best chance for long-term survival, yet recurrence rates are high and outcomes are poor. The influence of margin status in PDAC is controversial, as conflicting data have been plagued by a lack of standardization in margin definitions, pathologic analysis, and reporting. Despite recent efforts, international consensus is still needed for this disease., (© 2015 Wiley Periodicals, Inc.)

Background: Residual disease after pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PDAC) adversely impacts survival. The value of taking additional neck margin after a positive frozen section (FS) to achieve a negative margin remains uncertain., Methods: All patients who underwent PD for PDAC from January 2000 August 2012 were identified and classified as negative (R0) or positive (R1) based on final neck margin. We examined factors for association with a positive FS neck margin and overall survival (OS). We assessed the value of converting an R1 neck margin to R0 via additional parenchymal resection., Results: A total of 382 patients had FS neck margin analysis, of which 53 (14 %) were positive. Positive FS neck margin was associated with decreased OS (11.1 vs. 17.3 months, p = 0.01) on univariate analysis. On multivariate analysis poor histologic grade (p = 0.007), increased tumor size (p = 0.003), and a positive retroperitoneal margin (p = 0.009) were independently associated with decreased OS, but positive FS neck margin was not. Of the 53 patients with positive FS, 41 underwent additional neck resection and 23 were converted to R0. On permanent section, R0 neck margin was achieved in 322 patients (84 %), R1 in 37 patients (10 %), and R1 converted to R0 in 23 patients (6 %). Both the converted and the R1 groups had significantly poorer OS than the R0 group (11.3 vs. 11.1 vs. 17.3 months respectively; p = 0.04)., Conclusions: Positive FS margin at the pancreatic neck during PD for PDAC is associated with poor survival. Extending the neck resection after a positive FS to achieve R0 margin status does not appear to improve OS.

Background: The effect of diabetes on survival after resection pancreatic ductal carcinoma (PDAC) is unclear. The present study was undertaken to determine whether pre-operative diabetes has any predictive value for survival., Methods: A retrospective review from seven centres was performed. Metabolic factors, tumour characteristics and outcomes of patients undergoing resection for PDAC were collected. Univariate and multivariable analyses were performed to determine factors associated with disease-free (DFS) and overall survival (OS)., Results: Of the 509 patients in the present study, 31.2% had diabetes. Scoring systems were devised to predict OS and DFS based on a training set (n= 245) and were subsequently tested on an independent set (n= 264). Pre-operative diabetes (P < 0.001), tumour size >2 cm (P= 0.001), metastatic nodal ratio >0.1 (P < 0.001) and R1 margin (P < 0.001) all correlated with DFS and OS on univariate analysis. Scoring systems were devised based on multivariable analysis of the above factors. Diabetes and the metastatic nodal ratio were the most important factors in each system, earning two points for OS and four points for DFS. These scoring systems significantly correlated with both DFS (P < 0.001) and OS (P < 0.001)., Conclusion: Pre-operative diabetes status provides useful information that can help to stratify patients in terms of predicted post-operative OS and DFS., (© 2012 International Hepato-Pancreato-Biliary Association.)

Background: The premise that allogeneic red blood cell transfusion (RBCT) contributes to adverse oncologic outcomes after surgery remains controversial. We examined the effects of RBCT during and after pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) on disease recurrence and survival., Methods: A prospective database of 220 patients undergoing PD for PDAC from 2000 to 2008 was reviewed and transfusion data collected. Univariate and multivariate analyses were performed for factors influencing RBCT, recurrence-free survival (RFS), and overall survival (OS). The effect of amount and timing (intraoperative vs. postoperative) of RBCT was analyzed., Results: One hundred forty-seven patients (67%) received RBCT: 70 (32%) received 1 to 2 units, and 77 (35%) received >2 units. Median RFS and OS for the entire cohort was 12 and 16 months, respectively. RBCT of >2 units was associated with reduced RFS (9 vs. 15 months; P = 0.033) and OS (14 vs. 20 months; P = 0.003). Stratified by timing of transfusion, postoperative RBCT was associated with shortened RFS and OS. Controlling for age, body mass index, comorbidities, tumor factors, and major complications, each incremental unit of postoperative RBCT was associated with reduced RFS (hazard ratio 1.10, 95% confidence interval 1.02-1.18) and OS (hazard ratio 1.08, 95% confidence interval 1.03-1.12). Low hemoglobin and presence of comorbidities were the only preoperative factors independently associated with RBCT., Conclusions: Allogeneic red blood cell transfusion after PD for PDAC is independently associated with earlier cancer recurrence and reduced survival, in particular when administered postoperatively and in larger quantities. Blood-conservation methods are especially indicated for patients with preoperative anemia and medical comorbidities.

The aim of this study was to examine differences in presentation and outcome in pancreaticoduodenectomy for benign and malignant processes. Pancreaticoduodenectomies performed for pancreatic adenocarcinoma or chronic pancreatitis from 2000 to 2008 were identified from a prospectively maintained database and compared. Pancreaticoduodenectomy revealed adenocarcinoma in 220 patients and benign chronic pancreatitis in 40 patients. Patients with adenocarcinoma were older (64 +/- 10.6 years and 47.6 +/- 10.8 years, respectively, P < 0.001) and more likely to demonstrate jaundice (92 and 13%, respectively, P < 0.001), weight loss (76 and 58%, respectively, P = 0.01), and discrete masses (72 and 55%, respectively, P = 0.03). By contrast, chronic pancreatitis presented with increased pain (98 and 49%, respectively, P < 0.001) and nausea (68 and 32%, respectively, P < 0.001). Patients with pancreatitis experienced reduced blood loss (227 +/- 156 and 571 +/- 626 mL, respectively, P = 0.05) and transfusion (10 and 42%, respectively, P < 0.001). Postoperatively, the groups were similar in risk of fistula, gastroparesis, overall morbidity, and mortality. Infection rates were higher in adenocarcinoma (42 and 20%, respectively, P = 0.01). Forty-nine patients underwent pancreaticoduodenectomy for presumptive chronic pancreatitis, of which nine had adenocarcinoma; logistic regression identified increasing age and jaundice as predictors of malignancy. Compared with patients with adenocarcinoma, those who undergo pancreaticoduodenectomy for chronic pancreatitis are less likely to require preoperative biliary drainage and perioperative transfusion. Infectious complication risk is higher in patients with adenocarcinoma. Increased age and jaundice should raise suspicion of cancer in patients with chronic pancreatitis undergoing evaluation for surgical treatment.

Background: As compared with open distal pancreatectomy (ODP), laparoscopic distal pancreatectomy (LDP) affords improved perioperative outcomes. The role of LDP for patients with pancreatic ductal adenocarcinoma (PDAC) is not defined., Study Design: Records from patients undergoing distal pancreatectomy (DP) for PDAC from 2000 to 2008 from 9 academic medical centers were reviewed. Short-term (node harvest and margin status) and long-term (survival) cancer outcomes were assessed. A 3:1 matched analysis was performed for ODP and LDP cases using age, American Society of Anesthesiologists (ASA) class, and tumor size., Results: There were 212 patients who underwent DP for PDAC; 23 (11%) of these were approached laparoscopically. For all 212 patients, 56 (26%) had positive margins. The mean number of nodes (+/- SD) examined was 12.6 +/-8.4 and 114 patients (54%) had at least 1 positive node. Median overall survival was 16 months. In the matched analysis there were no significant differences in positive margin rates, number of nodes examined, number of patients with at least 1 positive node, or overall survival. Logistic regression for all 212 patients demonstrated that advanced age, larger tumors, positive margins, and node positive disease were independently associated with worse survival; however, method of resection (ODP vs. LDP) was not. Hospital stay was 2 days shorter in the matched comparison, which approached significance (LDP, 7.4 days vs. ODP, 9.4 days, p = 0.06)., Conclusions: LDP provides similar short- and long-term oncologic outcomes as compared with OD, with potentially shorter hospital stay. These results suggest that LDP is an acceptable approach for resection of PDAC of the left pancreas in selected patients., (Copyright 2010 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Associations between diabetes mellitus (DM) and pancreatic ductal adenocarcinoma (PDAC) are well established; however, the impact of DM on perioperative morbidity and mortality after PDAC resection is unclear., Study Design: A prospectively maintained database review identified all patients undergoing PDAC resection between January 1, 2000, and December 31, 2008. Diagnosis of DM was established by history and biochemical profile. Records were reviewed for comorbidities, operative variables, and histologic parameters. Postoperative morbidity and mortality were assessed for diabetic and nondiabetic patients using standardized definitions., Results: Of 251 PDAC cases, 116 (46%) patients had preoperative DM. Pancreaticoduodenectomy was performed in 220 (87.6%), left pancreatectomy in 29 (11.6%), and total pancreatectomy in 2 (0.8%). The major complication rate was 25.5%, with 60-day mortality of 3.6%. Delayed gastric emptying (DGE) occurred in 40.1% of patients. Pancreatic fistulas developed in 17 (6.8%) patients; 11 of them were clinically significant (grades B/C). DM patients had a higher likelihood of developing fistulas (DM 10.3%, non-DM 3.7%, p = 0.04). When controlled for age, comorbidities, body mass index, preoperative albumin level, operation type, operative time, and pancreatic quality, DM maintained an independent association with fistula formation (odds ratio 4.3, 95% CI 1.18 to 15.8, p = 0.027). Acute kidney injury was more frequent in the DM group (DM 23.3%, non-DM 12.6%, p = 0.03). DM and non-DM patients had similar frequency of DGE, wound infections, intra-abdominal abscesses, and cardiovascular and pulmonary complications, as well as length of stay and mortality., Conclusions: Comorbid DM does not influence perioperative outcomes dramatically after pancreatectomy for ductal adenocarcinoma. The role of PDAC-associated DM as a risk factor for postresection pancreatic fistula should be further explored. Evaluation of glycemic control and outcomes after PDAC resection may be useful., (Copyright (c) 2010 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess clinicopathologic features and postresection survival of diabetes mellitus (DM)-associated pancreatic ductal adenocarcinoma (PDAC)., Methods: Records of resected PDAC patients from 2000 to 2007 were reviewed. DM was classified as new-onset (<24 months before PDAC) or longstanding (> or =24 months). Clinicopathologic features were compared by univariate and multivariate analyses. Survival was assessed by Kaplan-Meier method and Cox regression., Results: Of 209 patients, 93 (45%) met criteria for DM (35 longstanding DM, 55 new-onset DM, 3 duration unknown). DM patients were older (DM 66 +/- 9 years, non-DM 63 +/- 12 years, P = 0.06); a majority had additional preoperative comorbidities (DM 64.5%, non-DM 25.9%, P < 0.001). Tumor size was larger in patients with DM (DM 3.8 +/- 1.7 cm, non-DM 3.2 +/- 1.5 cm, P = 0.003). Groups were similar in terms of tumor location, perineural/lymphovascular invasion, and node and margin status. On logistic regression, tumor size >/=3.0 cm was independently associated with both overall DM (odds ratio [OR] 3.60; 95% confidence interval [1.79-7.26]) and new-onset DM (OR 3.69, [1.65-8.24]). Median survival was reduced in patients with DM compared with non-DM (15 versus 17 months, P = 0.015). Multivariate analysis controlling for prognostic variables including age, comorbidities, and tumor size demonstrated that DM was independently associated with reduced survival (hazard ratio [HR] 1.55, [1.02-2.35]). This association was more pronounced for patients with new-onset DM (HR 1.75 [1.10-2.78]) than those with longstanding DM (HR 1.30 [0.75-2.25])., Conclusions: Preexisting DM is associated with reduced survival in patients undergoing resection for PDAC. PDAC with new-onset DM may exhibit increased tumor size and decreased postresection survival. Additional investigation is needed to clarify etiology and impact of PDAC-associated DM.

Lymph node status is one of the most important predictors of survival in resectable pancreatic ductal adenocarcinoma; therefore, thorough lymph node evaluation is a critical assessment in pancreatoduodenectomy specimens. There is considerable variability in pancreatoduodenectomy specimens processed histologically. This study compares two approaches of lymph node dissection and evaluation (standard vs orange peeling) of pancreatoduodenectomy specimens. A different approach to dissection of pancreatoduodenectomy specimens was designed to optimize lymph node harvesting: All peripancreatic soft tissues were removed in an orange-peeling manner before further dissection of the pancreatic head. This approach was applied to 52 consecutive pancreatoduodenectomy specimens performed for ductal adenocarcinoma at two institutions. Specimen dissection was otherwise performed routinely. Overall number of lymph nodes harvested, number of positive lymph nodes, and their anatomic distribution were analyzed and compared with cases that had been dissected by the conventional approach. The mean number of lymph nodes identified by the orange-peeling approach was 14.1 (by institution, 13.8 and 14.4), as opposed to 6.1 (by institution, 7 and 5.3) in cases processed by conventional approach (P=0.0001). The number of lymph node-positive cases also increased substantially from 50% (by institution, 54 and 46%) in the conventional method to 73% (by institution, 88 and 58%) in the orange-peeling method (P=0.02). The orange-peeling method of lymph node harvest in pancreatoduodenectomy specimens for ductal adenocarcinoma enhances overall and positive lymph node yield and optimizes ductal adenocarcinoma staging. Therefore, lymph node harvest by the orange-peeling method should be performed routinely before specimen sectioning in assessment of pancreatoduodenectomy for ductal adenocarcinoma.