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Background Pancreatic cancer often presents as locally advanced (LAPC) or borderline resectable (BRPC). Neoadjuvant systemic therapy is recommended as initial treatment. It is currently unclear what chemotherapy should be preferred for patients with BRPC or LAPC. Methods We performed a systematic review and multi-institutional meta-analysis of patient-level data regarding the use of initial systemic therapy for BRPC and LAPC. Outcomes were reported separately for tumor entity and by chemotherapy regimen including FOLFIRINOX (FIO) or gemcitabine-based. Results A total of 23 studies comprising 2930 patients were analyzed for overall survival (OS) calculated from the beginning of systemic treatment. OS for patients with BRPC was 22.0 months with FIO, 16.9 months with gemcitabine/nab-paclitaxel (Gem/nab), 21.6 months with gemcitabine/cisplatin or oxaliplatin or docetaxel or capecitabine (GemX), and 10 months with gemcitabine monotherapy (Gem-mono) (p < 0.0001). In patients with LAPC, OS also was higher with FIO (17.1 months) compared with Gem/nab (12.5 months), GemX (12.3 months), and Gem-mono (9.4 months; p < 0.0001). This difference was driven by the patients who did not undergo surgery, where FIO was superior to other regimens. The resection rates for patients with BRPC were 0.55 for gemcitabine-based chemotherapy and 0.53 with FIO. In patients with LAPC, resection rates were 0.19 with Gemcitabine and 0.28 with FIO. In resected patients, OS for patients with BRPC was 32.9 months with FIO and not different compared to Gem/nab, (28.6 months, p = 0.285), GemX (38.8 months, p = 0.1), or Gem-mono (23.1 months, p = 0.083). A similar trend was observed in resected patients converted from LAPC. Conclusions In patients with BRPC or LAPC, primary treatment with FOLFIRINOX compared with Gemcitabine-based chemotherapy appears to provide a survival benefit for patients that are ultimately unresectable. For patients that undergo surgical resection, outcomes are similar between GEM+ and FOLFIRINOX when delivered in the neoadjuvant setting.

Background Implementing a prospective lymphadenectomy protocol, we investigated the nodal yields and metastases per anatomical stations and nodal echelon following upfront pancreatoduodenectomy (PD) for cancer. Next, the relationship between the extension of nodal dissection, the number of examined and positive nodes (ELN/PLN), disease staging and prognosis was assessed. Methods Lymphadenectomy included stations 5, 6, 8a-p, 12a-b-p, 13, 14a-b, 17, and jejunal mesentery nodes. Data were stratified by N-status, anatomical stations, and nodal echelons. First echelon was defined as stations embedded in the main specimen and second echelon as stations sampled as separate specimens. Recurrence and survival analyses were performed by using standard statistics. Results Overall, 424 patients were enrolled from June 2013 through December 2018. The median number of ELN and PLN was 42 (interquartile range [IQR] 34-50) and 4 (IQR 2-8). Node-positive patients were 88.2%. The commonest metastatic sites were stations 13 (77.8%) and 14 (57.5%). The median number of ELN and PLN in the first echelon was 28 (IQR 23-34) and 4 (IQR 1-7). While first-echelon dissection provided enough ELN for optimal nodal staging, the aggregate rate of second-echelon metastases approached 30%. Nodal-related factors associated with recurrence and survival were N-status, multiple metastatic stations, metastases to station 14, and jejunal mesentery nodes. Conclusions First-echelon dissection provides adequate number of ELN for optimal staging. Nodal metastases occur mostly at stations 13/14, although second-echelon involvement is frequent. Only station 14 and jejunal mesentery nodes involvement was prognostically relevant. This latter station should be included in the standard nodal map and analyzed pathologically.

International audience; Background: Ampullary lesions are rare and can be locally treated either with endoscopic papillectomy or transduodenal surgical ampullectomy. Management of local recurrence after a first-line treatment has been poorly studied.Methods: Patients with a local recurrence of an ampullary lesion initially treated with endoscopic papillectomy or transduodenal surgical ampullectomy were retrospectively included from a multi-institutional database (58 centers) between 2005 and 2018.Results: A total of 103 patients were included, 21 (20.4%) treated with redo endoscopic papillectomy, 14 (13.6%) with transduodenal surgical ampullectomy, and 68 (66%) with pancreaticoduodenectomy. Redo endoscopic papillectomy had low morbidity with 4.8% (n = 1) severe to fatal complications and a R0 rate of 81% (n = 17). Transduodenal surgical ampullectomy and pancreaticoduodenectomy after a first procedure had a higher morbidity with Clavien III and more complications, respectively, 28.6% (n = 4) and 25% (n = 17); R0 resection rates were 85.7% (n = 12) and 92.6% (n = 63), both without statistically significant difference compared to endoscopic papillectomy (P = .1 and 0.2). Pancreaticoduodenectomy had 4.4% (n = 2) mortality. No deaths were registered after transduodenal surgical ampullectomy or endoscopic papillectomy. Recurrences treated with pancreaticoduodenectomy were more likely to be adenocarcinomas (79.4%, n = 54 vs 21.4%, n = 3 for transduodenal surgical ampullectomy and 4.8%, n = 1 for endoscopic papillectomy, P < .0001). Three-year overall survival and disease-free survival were comparable.Conclusion: Endoscopy is appropriate for noninvasive recurrences, with resection rate and survival outcomes comparable to surgery. Surgery applies more to invasive recurrences, with transduodenal surgical ampullectomy rather for carcinoma in situ and early cancers and pancreaticoduodenectomy for more advanced tumors.

Background: The association between intraoperative estimated blood loss and outcomes after pancreatoduodenectomy has, thus far, been rarely explored. Methods: In total, 7,706 pancreatoduodenectomies performed at 18 international institutions composing the Pancreas Fistula Study Group were examined (2003-2020). High estimated blood loss (>700 mL) was defined as twice the median. Propensity score matching (1:1 exact-match) was employed to adjust for variables associated with high estimated blood loss and clinically relevant pancreatic fistula occurrence. The study was powered to detect a 33% clinically relevant pancreatic fistula increase in the high estimated blood loss group, with a = 0.05 and b = 0.2. Results: The propensity score model included 966 patients with high estimated blood loss and 966 patients with lower estimated blood loss; all covariate imbalantces were solved. Patients with high estimated blood loss patients experienced higher clinically relevant pancreatic fistula rates (19.4 vs 12.6%, odds ratio 1.66; P < .001), as well as higher severe complication rates (27.8 vs 15.6%), transfusions (50.1 vs 14.3%), reoperations (9.2 vs 4.0%), intensive care unit transfers (9.9 vs 4.8%) and 90-day mortality (4.7 vs 2.0%, all P < .001). High estimated blood loss was an independent predictor for clinically relevant pancreatic fistula (odds ratio 1.78, 95% confidence interval 1.37-2.32), as were prophylactic Octreotide administration (odds ratio 1.95, 95% confidence interval 1.46-2.61) and soft pancreatic texture (odds ratio 5.32, 95% confidence interval 3.74-5.57; all P < .001). Moreover, a second model including 1,126 pancreatoduodenectomies was derived including vascular resections as additional confounder (14.0% vascular resections performed in each group). On multivariable regression, high estimated blood loss was confirmed an independent predictor for clinically relevant pancreatic fistula reduction (odds ratio 1.80, 95% confidence interval 1.32-2.4 4; P < .001), whereas vascular resection was not (odds ratio 0.64, 95% confidence interval 0.34-1.88; P 1/4 .156). Conclusion: This study better establishes the relationship between estimated blood loss and outcomes after pancreatoduodenectomy. Despite inherent contributions to blood loss, its minimization is an actionable opportunity for clinically relevant pancreatic fistula reduction and performance optimization in pancreatoduodenectomy. Accordingly, practical insights are offered to achieve this goal. (c) 2021 Elsevier Inc. All rights reserved.

Survival outcomes after pancreatectomy for pancreatic ductal adenocarcinoma may be biased by right-censoring. We herein analyzed a large dataset with no censored events for up to 5 years and dynamically investigated the impact of known prognostic factors, accounting for unobserved tumor characteristics.Consecutive patients undergoing pancreatectomy from 2000 to July 2015 were included. The 1- to 5-year empirical survival rates were calculated, and factors associated with long-term survival (≥5 years) were analyzed using multivariable models. Dynamic analyses of survival and recurrence were conducted through landmarking, and the contribution of unobserved heterogeneity was estimated using frailty models.The study population included 1,048 patients. The median follow-up was 30.4 months in the whole cohort and 97.2 months in survivors. The median survival was 30.4 months, with empirical 1- to 5-year rates of 85.5%, 59.6%, 43.2%, 32.1%, and 27.5%. A favorable pathological profile was associated with 5-year survival, albeit 25.7% of long-survivors received an R1 resection, and 28.8% had N2 disease. The median recurrence-free survival was 17.2 months. At landmark analyses, baseline prognostic lost strength over time, with no independent predictors of survival being identified in the sets of patients alive at 4 and 5 years. There was a significant amount of unobserved heterogeneity in the early postoperative period.The 5-year post-pancreatectomy empirical survival was 27.5%. Dynamic analyses showed a time-varying structure of prognostic variables and a substantial impact of unobserved tumor characteristics that may drive the disease course under the selective pressure of surgical resection and adjuvant chemotherapy.

Background Data on recurrence after post-neoadjuvant pancreatectomy are scant. This study investigated the incidence and pattern of recurrence in patients with initially resectable and borderline resectable pancreatic ductal adenocarcinoma who received post-neoadjuvant pancreatectomy. Furthermore, preoperative predictors of recurrence-free survival (RFS) and their interactions were determined. Patients and Methods Patients undergoing post-neoadjuvant pancreatectomy at two academic facilities between 2013 and 2017 were analyzed using standard statistics. The possible interplay between preoperative parameters was scrutinized including interaction terms in multivariable Cox models. Results Among 315 included patients, 152 (48.3%) were anatomically resectable. The median RFS was 15.7 months, with 1- and 3-year recurrence rates of 41.9% and 74.2%, respectively. Distant recurrence occurred in 83.3% of patients, with lung-only patterns exhibiting the most favorable prognostic outlook. Normal posttreatment CA19.9, ΔCA19.9 (both in patients with normal and elevated baseline levels), and posttreatment tumor size were associated with RFS. Critical thresholds for ΔCA19.9 and tumor size were set at 50% and 20 mm, respectively. Interaction between ΔCA19.9 and posttreatment CA19.9 suggested a significant risk reduction in patients with elevated values when ΔCA19.9 exceeded 50%. Moreover, posttreatment tumor size interacted with posttreatment CA19.9 and ΔCA19.9, suggesting an increased risk in the instance of elevated posttreatment CA19.9 values and a protective effect associated with CA19.9 response in patients with tumor size >20 mm. Conclusion Recurrence following post-neoadjuvant pancreatectomy is common. Preoperative tumor size 50% were associated with longer RFS. These variables should not be taken in isolation, as their interaction significantly modulates the recurrence risk.

To investigate the role of intraoperative estimated blood loss (EBL) on development of clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreatoduodenectomy (PD).Minimizing EBL has been shown to decrease transfusions and provide better perioperative outcomes in PD. EBL is also felt to be influential on CR-POPF development.This study consists of 5534 PDs from a 17-institution collaborative (2003-2018). EBL was progressively categorized (≤150mL; 151-400mL; 401-1,000 mL;1,000 mL). Impact of additive EBL was assessed using 20 3- factor fistula risk score (FRS) scenarios reflective of endogenous CR-POPF risk.CR-POPF developed in 13.6% of patients (N = 753) and median EBL was 400 mL (interquartile range 250-600 mL). CR-POPF and Grade C POPF were associated with elevated EBL (median 350 vs 400 mL, P = 0.002; 372 vs 500 mL, P0.001, respectively). Progressive EBL cohorts displayed incremental CR-POPF rates (8.5%, 13.4%, 15.2%, 16.9%; P0.001). EBL400mL was associated with increased CR-POPF occurrence in 13/20 endogenous risk scenarios. Moreover, 8 of 10 scenarios predicated on a soft gland demonstrated increased CR-POPF incidence. Hypothetical projections demonstrate significant reductions in CR-POPF can be obtained with 1-, 2-, and 3-point decreases in FRS points attributed to EBL risk (12.2%, 17.4%, and 20.0%; P0.001). This is especially pronounced in high-risk (FRS7-10) patients, who demonstrate up to a 31% reduction (P0.001). Surgeons in the lowest-quartile of median EBL demonstrated CR-POPF rates less than half those in the upper-quartile (7.9% vs 18.8%; P0.001).EBL independently contributes significant biological risk to CR-POPF. Substantial reductions in CR-POPF occurrence are projected and obtainable by minimizing EBL. Decreased individual surgeon EBL is associated with improvements in CR-POPF.

Neoadjuvant chemotherapy has become a powerful tool to convert borderline resectable (BRPC) and locally advanced pancreatic cancers (LAPC) into a resectable scenario. However, data analyzing the optimal type of therapy are scarce. In the present multicenter retrospective study, we evaluated the influence of FOLFIRINOX (FFX) and gemcitabine (GEM)-based neoadjuvant therapy on patient prognosis.Data on 239 patients from 7 centers across Europe was gathered using an online database. Patients having received their first cycle of chemotherapy for BRPC/LAPC before 06/2017, with a minimum follow-up of 12 months, were included in the intention-to-treat analysis.Patients treated with neoadjuvant FFX (n = 135) or gemcitabine + nab-paclitaxel (GNP) (n = 38) had significantly improved radiological response according to RECIST criteria as compared to single-agent GEM (n = 16), with a partial/complete response of 59.3%, 55.3% and 6.25% respectively (p = 0.001). Treatment with FFX (n = 135) and GNP (n = 38) resulted in higher resection rates compared to GEM (73.3%, 81.6% and 43.8%; p = 0.01 and p = 0.005). Regardless of regimen, patients who were resected had significantly prolonged overall survival compared to non-resected patients (p 0.01). Complete pathological responses (ypT0 ypN0) were predominantly observed with FFX (p = 0.01). Adjuvant GNP in addition to successful neoadjuvant therapy and surgery resulted in a trend towards improved median survival as compared to postoperative observation (47.0 vs. 30.1 months, p = 0.06).Representing one of the largest studies published so far, our results reveal that patients with BRPC/LAPC should be offered either FFX or GNP to improve chances of resection and with this also survival.

Background The incidence and magnitude of indicators of radiographic response of pancreatic cancer to systemic chemotherapy and (chemo)radiation administered prior to anticipated pancreatectomy are unclear. Methods Sequential computed tomography scans of 226 patients with localized pancreatic cancer who received chemotherapy consisting of 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) or gemcitabine and nanoparticle albumin-bound paclitaxel (GA) with or without (chemo)radiation and who subsequently underwent surgery with curative intent from January 2010 to December 2018 at The University of Texas MD Anderson Cancer Center and Verona University Hospital were re-reviewed and compared. Results Overall, 141 patients (62%) received FOLFIRINOX, 70 (31%) received GA, and 15 (7%) received both; 164 patients (73%) received preoperative (chemo)radiation following chemotherapy and prior to surgery; and 151 (67%), 70 (31%), and 5 (2%) patients had Response Evaluation Criteria in Solid Tumors (RECIST) stable disease, partial response, and progressive disease, respectively. The tumors of 29% of patients with borderline resectable or locally advanced cancer were downstaged after preoperative therapy. Radiographic downstaging was more common with chemotherapy than with (chemo)radiation (24% vs. 6%; p = 0.04), and the median tumor volume loss after chemotherapy was significantly greater than that after (chemo)radiation (28% vs. 17%; p Conclusions Less than one-third of patients treated with FOLFIRINOX or GA with or without (chemo)radiation experienced either RECIST partial response or radiographic downstaging prior to surgery. The incidence of tumor downstaging was higher and the magnitude of tumor volume loss was greater following chemotherapy than after (chemo)radiation.

This study aims to present a full spectrum of individual patient presentations of pancreatic fistula risk, and to define the utility of mitigation strategies amongst some of the most prevalent, and vulnerable scenarios surgeons encounter.The FRS has been utilized to identify technical strategies associated with reduced CR-POPF incidence across various risk strata. However, risk-stratification using the FRS has never been investigated with greater granularity. By deriving all possible combinations of FRS elements, individualized risk assessment could be utilized for precision medicine purposes.FRS profiles and outcomes of 5533 PDs were accrued from 17 international institutions (2003-2019). The FRS was used to derive 80 unique combinations of patient "scenarios." Risk-matched analyses were conducted using a Bonferroni adjustment to identify scenarios with increased vulnerability for CR-POPF occurrence. Subsequently, these scenarios were analyzed using multivariable regression to explore optimal mitigation approaches.The overall CR-POPF rate was 13.6%. All 80 possible scenarios were encountered, with the most frequent being scenario #1 (8.1%) - the only negligible-risk scenario (CR-POPF rate = 0.7%). The moderate-risk zone had the most scenarios (50), patients (N = 3246), CR-POPFs (65.2%), and greatest non-zero discrepancy in CR-POPF rates between scenarios (18-fold). In the risk-matched analysis, 2 scenarios (#59 and 60) displayed increased vulnerability for CR-POPF relative to the moderate-risk zone (both P0.001). Multivariable analysis revealed factors associated with CR-POPF in these scenarios: pancreaticogastrostomy reconstruction [odds ratio (OR) 4.67], omission of drain placement (OR 5.51), and prophylactic octreotide (OR 3.09). When comparing the utilization of best practice strategies to patients who did not have these conjointly utilized, there was a significant decrease in CR-POPF (10.7% vs 35.5%, P0.001; OR 0.20, 95% confidence interval 0.12-0.33).Through this data, a comprehensive fistula risk catalog has been created and the most clinically-impactful scenarios have been discerned. Focusing on individual scenarios provides a practical way to approach precision medicine, allowing for more directed and efficient management of CR-POPF.

OBJECTIVE To reappraise the optimal number of examined lymph nodes (ELN) in pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). SUMMARY BACKGROUND DATA The well-established threshold of 15 ELN in PD for PDAC is optimized for detecting one positive node (PLN) per the previous 7 edition of the AJCC staging manual. In the framework of the 8 edition, where at least four PLN are needed for an N2 diagnosis, this threshold may be inadequate for accurate staging. METHODS Patients who underwent upfront PD at two academic institutions between 2000 and 2016 were analyzed. The optimal ELN threshold was defined as the cut-point associated with a 95% probability of identifying at least 4 PLN in N2 patients. The results were validated addressing the N-status distribution and stage migration. RESULTS Overall, 1218 patients were included. The median number of ELN was 26 (IQR 17-37). ELN was independently associated with N2-status (OR 1.27, p < 0.001). The estimated optimal threshold of ELN was 28. This cut-point enabled improved detection of N2 patients and stage III disease (58% versus 37%, p = 0.001). The median survival was 28.6 months. There was an improved survival in N0/N1 patients when ELN exceeded 28, suggesting a stage migration effect (47 versus 29 months, adjusted HR 0.649, p < 0.001). In N2 patients, this threshold was not associated with survival on multivariable analysis. CONCLUSION Examining at least 28 LN in PD for PDAC ensures optimal staging through improved detection of N2/stage III disease. This may have relevant implications for benchmarking processes and quality implementation.

Pancreatic intraductal papillary mucinous neoplasms (IPMNs) have gained substantial attention because they represent one of the only radiographically identifiable precursors of invasive pancreatic ductal adenocarcinoma. Although most of these neoplasms have low-grade dysplasia and will remain indolent, a subset of IPMNs will progress to invasive cancer. The role of the immune system in the progression of IPMNs is unclear, but understanding its role could reveal the mechanism of neoplastic progression and targets for immunotherapy to inhibit progression or treat invasive disease. The available evidence supports a shift in the immune composition of IPMNs during neoplastic progression. Although low-grade lesions contain a high proportion of effector T cells, high-grade IPMNs, and IPMNs with an associated invasive carcinoma lose the T-cell infiltrate and are characterised by a predominance of immunosuppressive elements. Several possible therapeutic strategies emerge from this analysis that are unique to IPMNs and its microbiome.

Background The association between higher surgical volume and better perioperative outcomes after pancreatectomy has been extensively demonstrated. However, how different notions of experience impact outcomes of surgeons operating within high-quality scenarios remains unclear. Methods Self-reported experience parameters from ACS-NSQIP HPB-Collaborative surgeons were merged with 2014–2016 ACS-NSQIP clinical data. The association of various experience parameters with outcomes was investigated through uni- and multivariable analyses. Hierarchical regression assessed surgeon performance. Results 111/151 HPB-Collaborative surgeons provided responses (73.5%). Compared to the other 532 ACS-NSQIP surgeons performing pancreatectomy, HPB-Collaborative surgeons performed 7692/16,239 of the overall pancreatectomies (47.3%), with improved outcomes of serious morbidity, pancreatic fistula, reoperation, duration of stay and readmissions. Median age of respondents was 49 years and 92.8% were fellowship-trained. Median career and annual pancreatectomy volume were 400 and 35, respectively; median annual institutional volume was 100 resections. On unadjusted analyses, several aspects of experience were associated with the outcomes studied, especially for pancreatoduodenectomy; however, none remained significant after multivariable adjustment. Surgeons’ profiling showed substantial homogeneity in performance for both pancreatoduodenectomy and distal pancreatectomy. Conclusions Contemporary data shows that for surgeons operating in high quality settings clinical outcomes are largely independent of indicators of greater experience.

Hyperbilirubinemia is commonly observed in patients requiring pancreatoduodenectomy (PD). Thus far, literature regarding the danger of operating in the setting of hyperbilirubinemia is equivocal. What remains undefined is at what specific level of bilirubin there is an adverse safety profile for undergoing PD. The aim of this study is to identify the optimal safety profile of patients with hyperbilirubinemia undergoing PD. The present work analyzed 803 PDs from 2004 to 2018. A generalized additive model was used to determine cutoff values of total serum bilirubin (TB) that were associated with increases in adverse outcomes, including 90-day mortality. Subgroup comparisons and biliary stent-specific analyses were performed for patients with TB below and above the cutoff. TB of 13 mg/dL was associated with an increase in 90-day mortality (P = 0.043) and was the dominant risk factor on multivariate logistic regression [odds ratio (OR) 8.193, P = 0.001]. Increased TB levels were also associated with reoperations, number of complications per patient, and length of stay. Patients with TB greater than or equal to 13 mg/dL (TB ≥ 13) who received successful biliary decompression through stenting had less combined death and serious morbidity (P = 0.048). Preoperative TB ≥ 13 mg/dL was associated with increased 90-day mortality after PD. Reducing a TB ≥ 13 is generally recommended before proceeding to surgery.

MINI: The characteristics of cystic pancreatic neuroendocrine neoplasms (cPanNENs) are largely unknown, and their clinical management remains unclear; specifically, an observational strategy for asymptomatic cPanNENs ≤2 cm has been proposed by recent guidelines, but evidence is scarce and limited to single institutional series. In this international cohort study of 263 resected cPanNENs from 16 institutions worldwide, a preoperative size >2 cm was independently associated with aggressive behavior both in the whole cohort and in the subset of asymptomatic patients; notably, only 1 of 61 asymptomatic cPanNENs ≤2 cm was aggressive. Based on these results, a watch-and-wait policy for sporadic asymptomatic cPanNENs ≤2 cm seems justified and safe. Objective The aim of this study was to characterize an international cohort of resected cystic pancreatic neuroendocrine neoplasms (cPanNENs) and identify preoperative predictors of aggressive behavior. Background The characteristics of cPanNENs are unknown and their clinical management remains unclear. An observational strategy for asymptomatic cPanNENs ≤2 cm has been proposed by recent guidelines, but evidence is scarce and limited to single-institutional series. Methods Resected cPanNENs (1995-2017) from 16 institutions worldwide were included. Solid lesions (>50% solid component), functional tumors, and MEN-1 patients were excluded. Aggressiveness was defined as lymph node (LN) involvement, G3 grading, distant metastases, and/or recurrence. Results Overall, 263 resected cPanNENs were included, among which 177 (63.5%) were >2 cm preoperatively. A preoperative diagnosis of cPanNEN was established in 162 cases (61.6%) and was more frequent when patients underwent endoscopic ultrasound [EUS, odds ratio (OR) 2.69, 95% confidence interval (CI) 1.52-4.77] and somatostatin-receptor imaging (OR 3.681, 95% CI 1.809-7.490), and for those managed in specialized institutions (OR 3.12, 95% CI 1.57-6.21). Forty-one cPanNENs (15.6%) were considered aggressive. In the whole cohort, LN involvement on imaging, age >65 years, preoperative size >2 cm, and pancreatic duct dilation were independently associated with aggressive behavior. In asymptomatic patients, older age and a preoperative size >2 cm remained independently associated with aggressiveness. Only 1 of 61 asymptomatic cPanNENs ≤2 cm displayed an aggressive behavior. Conclusions The diagnostic accuracy of cPanNENs is increased by the use of EUS and somatostatin-receptor imaging and is higher in specialized institutions. Preoperative size >2 cm is independently associated with aggressive behavior. Consequently, a watch-and-wait policy for sporadic asymptomatic cPanNENs ≤2 cm seems justified and safe for most patients.

OBJECTIVE: To establish an international core set of patient-reported outcomes (PROs) selected by both patients and healthcare providers (HCPs) from the United States (US), Europe, and Asia. SUMMARY BACKGROUND DATA: PROs are increasingly recognized in pancreatic cancer studies. There is no consensus on which of the many available PROs are most important. METHODS: A multicenter Delphi study among patients with pancreatic cancer (curative- and palliative-setting) and HCPs in 6 pancreatic centers in the US (Baltimore, Boston), Europe (Amsterdam, Verona), and Asia (Mumbai, Seoul) was performed. In round 1, participants rated the importance of 56 PROs on a 1 to 9 Likert scale. PROs rated as very important (scores 7-9) by the majority (≥80%) of curative- and/or palliative-patients as well as HCPs were included in the core set. PROs not fulfilling these criteria were presented again in round 2, together with feedback on individual and group ratings. Remaining PROs were ranked based on the importance ratings. RESULTS: In total 731 patients and HCPs were invited, 501 completed round 1, and 420 completed both rounds. This included 204 patients in curative-setting, 74 patients in palliative-setting, and 142 HCPs. After 2 rounds, 8 PROs were included in the core set: general quality of life, general health, physical ability, ability to work/do usual activities, fear of recurrence, satisfaction with services/care organization, abdominal complaints, and relationship with partner/family. CONCLUSIONS: This international Delphi study among patients and HCPs established a core set of PROs in pancreatic cancer, which should facilitate the design of future pancreatic cancer trials and outcomes research.

Soft tissue sarcomas (STS) represent a rare and heterogeneous group of tumors. We sought to characterize national trends in referral patterns, treatment strategies, and overall survival (OS) over the course of a decade.Adult patients with extra-abdominal STS were identified using the National Cancer Database and categorized by diagnosis year (2005-2009 and 2010-2014). High-volume hospitals (HVH) were defined as those90Of 55,212 patients, 25,469 (46.1%) were diagnosed in 2005-2009 and 29,743 (53.9%) in 2010-2014. Despite increased utilization of neoadjuvant radiation therapy (26.6% vs. 34.8%, P 0.001), the rate of R0 resections did not change (75.0% vs. 74.8%, P = 0.067). Furthermore, at a national level, OS did not improve over time (HR 0.99, 95% CI 0.96-1.01). When outcomes were stratified by volume, treatment at HVH compared to LVH was associated with improved rates of R0 resection (OR 1.27, 95% CI 1.20-1.35) and OS (HR 0.92, 95% CI 0.89-0.95). Moreover, there was a modest improvement in OS at HVH (HR 0.95, 95% CI 0.91-1.00), but not at LVH (HR 1.01, 95% CI 0.97-1.04). However, referral to HVH did not change over time (40.7% vs. 40.7%, P = 0.91).OS for STS did not change at a national level over the course of a decade, although it improved at HVH. Further outcome improvements will likely require more effective systemic therapies.

Introduction: Natural history of cystic pancreatic neuroendocrine neoplasms (cPanNENs) is unknown, and their clinical management remains unclear. An observational strategy for asymptomatic cPanNENs ...

The aim of this study was to develop and validate a pretreatment prognostic score in pancreatic cancer (PDAC).Pretreatment prognostication in PDAC is important for treatment decisions but remains challenging. Available prognostic tools are derived from selected cohorts of patients who underwent resection, excluding up to 20% of patients with exploration only, and do not adequately reflect the pretreatment scenario.Patients undergoing surgery for PDAC in Heidelberg from July 2006 to June 2014 were identified from a prospective database. Pretreatment parameters were extracted from the database and the laboratory information system. Parameters independently associated with overall survival by uni- and multivariable analyses were used to build a prognostic score. A contemporary cohort from Verona was used for external validation.In 1197 patients, multiple pretreatment parameters were associated with overall survival by univariable analyses. American Society of Anesthesiology classification, carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen, C-reactive protein, albumin, and platelet count were independently associated with survival and were used to create the Heidelberg Prognostic Pancreatic Cancer (HELPP)-score. The HELPP-score was closely associated with overall survival (median survival between 31.3 and 4.8 months; 5-year survival rates between 35% and 0%) and was able to stratify survival in subgroups with or without resection as well as in CA19-9 nonsecretors. In the resected subgroup the HELPP-score stratified survival independently of pathological prognostic factors. The HELPP-score was externally validated and was superior to CA19-9 in both the development and validation cohorts.The HELPP-score is a readily available prognostic tool based on pretreatment routine parameters to stratify survival in PDAC independently of resection status and pathological tumor stage.

Objective To test the hypothesis that complete, tumor-free resection at the pancreatic neck, achieved either en-bloc or non-en-bloc (ie, revision based on intraoperative frozen section [FS] analysis), is associated with improved survival as compared with incomplete resection (IR) in pancreatic ductal adenocarcinoma. Summary background data Given the likely systemic nature of pancreatic ductal adenocarcinoma, the oncologic benefit of achieving a histologically complete local resection, particularly through revision of a positive intraoperative FS at the pancreatic neck, remains controversial. Methods Clinicopathologic and treatment data were reviewed for 986 consecutive patients with ductal adenocarcinoma at the head, neck, or uncinate process of the pancreas who underwent open pancreatectomy as well as intraoperative FS analysis between 1998 and 2012 at Massachusetts General Hospital and between 1998 and 2013 at the University of Verona. Overall survival (OS) and perioperative morbidity and mortality were compared across 3 groups: complete resection achieved en-bloc (CR-EB), complete resection achieved non-en-bloc (CR-NEB), and IR. Results The CR-EB cohort comprised 749 (76%) patients, CR-NEB 159 patients (16%), and IR 78 patients (8%). Other than a higher incidence of vascular resection among CR-NEB and IR patients, no demographic, pathologic (eg, tumor grade, lymph node positivity, superior mesenteric artery involvement), or treatment factors (eg, neoadjuvant and adjuvant therapy use) differed between the groups. Median OS was significantly higher in patients with CR-EB (28 mo, P = 0.01) and CR-NEB resections (24 mo, P = 0.02) as compared with patients with IR resections (19 mo). After adjusting for clinicopathologic and treatment characteristics, CR-EB and CR-NEB margin status were found to be independent predictors of improved OS (relative to IR, CR-EB hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.49-0.86; CR-NEB HR 0.69, 95% CI 0.50-0.96). There were no intergroup differences in perioperative morbidity and mortality, including rates of pancreatic fistula. Conclusions For patients with ductal adenocarcinoma at the head, neck, or uncinate process of the pancreas undergoing pancreatectomy, complete tumor extirpation via either en-bloc or non-en-bloc complete resection based on FS analysis is associated with improved OS, without an associated increased perioperative morbidity or mortality.

Background: Pancreatoduodenectomies at high risk for clinically relevant pancreatic fistula are uncommon, yet intimidating, situations. In such scenarios, the impact of individual surgeon experience on outcomes is poorly understood.Methods: The fistula risk score was applied to identify high-risk patients (fistula risk score 7-10) from 7,706 pancreatoduodenectomies performed at 18 international institutions (2003-2020). For each case, surgeon pancreatoduodenectomy career volume and years of practice were linked to intraoperative fistula mitigation strategy adoption and outcomes. Consequently, best operative approaches for clinically relevant pancreatic fistula prevention and best performer profiles were identified through multivariable analysis models.Results: Eight hundred and thirty high-risk pancreatoduodenectomies, performed by 64 surgeons, displayed an overall clinically relevant pancreatic fistula rate of 33.7%. Clinically relevant pancreatic fistula rates decreased with escalating surgeon career pancreatoduodenectomy (-49.7%) and career length (-41.2%; both P < .001), as did transfusion and reoperation rates, postoperative morbidity index, and duration of stay. Great experience (>400 pancreatoduodenectomies performed or >21-year-long career) was a significant predictor of clinically relevant pancreatic fistula prevention (odds ratio 0.52, 95% confidence interval 0.35-0.76) and was more often associated with pancreatojejunostomy reconstruc-tion and prophylactic octreotide omission, which were both independently associated with clinically relevant pancreatic fistula reduction. A risk-adjusted performance analysis also correlated with experi-ence. Moreover, minimizing blood loss (

Background Pancreatic metastases (PM) from renal cell carcinoma (RCC) are uncommon. We herein describe the long-term outcomes associated with pancreatectomy at two academic institutions, with a specific focus on 10-year survival. Methods This investigation was limited to patients undergoing pancreatectomy for PM between 2000 and 2008 at the University of Verona and Memorial Sloan Kettering Cancer Center, allowing a potential for 10 years of surveillance. The probabilities of further RCC recurrence and RCC-related death were estimated using a competing risk analysis (method of Fine and Gray) to account for patients who died of other causes during follow-up. Results The study population consisted of 69 patients, mostly with isolated metachronous PM (77%). The median interval from nephrectomy to pancreatic metastasectomy was 109 months, whereas the median post-pancreatectomy follow-up was 141 months. The 10-year cumulative incidence of new RCC recurrence was 62.7%. In the adjusted analysis, the relative risk of repeated recurrence was significantly higher in PM synchronous to the primary RCC (sHR = 1.27) and in patients receiving extended pancreatectomy (sHR = 3.05). The 10-year cumulative incidence of disease-specific death was 25.5%. The only variable with an influence on disease-specific death was the recurrence-free interval following metastasectomy (sHR = 0.98). In patients with repeated recurrence, the 10-year cumulative incidence of RCC-related death was 35.4%. Conclusion In a selected group of patients followed for a median of 141 months and mostly with isolated metachronous PM, resection was associated with a high possibility of long-term disease control in surgically fit patients with metastases confined to the pancreas.

Background Health care expenditure is increasing around the world and surgery is a major cause of financial hardship to patients and their families. Using pancreatoduodenectomy (PD), one of the most complex, morbid and costly operation as an example, this study aimed to identify the cost drivers of surgery, estimate relative contribution of these drivers, and derive and validate a cohort-specific cost forecasting tool. Methods Data on the costs of 1406 patients undergoing PD in three tertiary hospitals in India, Italy and the United States were analysed. Cost drivers were identified and cost models developed using a 4-stage process. Results There was a significant difference in overall cost of PD between the 3 cohorts. The cost drivers common to the 3 cohorts included duration of hospital stay and the outcome of death (Clavien-Dindo 5). Significant cohort-specific cost drivers included co-morbidities, operating theatre utilisation times and operative blood loss, development of pancreatectomy-specific complications (POPF, DGE, PPH), and need for interventional radiology to manage complications. Based on this, a cost forecasting tool was developed. Conclusions Drivers of costs for a surgical procedure (e.g. PD) are different between hospitals. Developing cost models/nomograms to predict the expected cost of surgery and perioperative care will not be applicable between hospitals. However, the approach could be used to develop context-specific data that will provide patients (at the time of the informed financial consent) and funding agencies with a more realistic cost estimate for a given operation. The developed cost forecasting tool warrants future validation.

Background Weight change offers the simplest indication of a patient’s recovery after an operation. There have been no studies that have thoroughly investigated postoperative weight dynamics after pancreatectomy. The aim of this study was to define postoperative weight change after a pancreatectomy and determine factors associated with optimal and poor weight trajectories. Methods From 2004 to 2019, 1,090 proximal (65%) and distal (35%) pancreatectomies were performed in patients with adequate data in the medical records. Patient weights were acquired preoperatively and at postoperative months 1, 3, and 12. Optimal (top quartile, weight restoration) and poor (bottom quartile, persistent weight loss) postoperative weight cohorts were identified at 1 year postoperatively. Results The median percentage weight change 1 year postpancreatectomy was –6.6% (interquartile range: –1.4% to –12.5%), –7.8% for proximal pancreatectomy, and –4.2% for distal pancreatectomy. For most patients (interquartile range cohort), the median percentage weight change at 1, 3, and 12 months was –6.2%, –7.2%, and –6.6%. The independent factors associated with weight restoration were age 10%, distal pancreatectomy, not undergoing vascular resection, and no readmission within 30 days. Conversely, persistent weight loss was associated with American Society of Anesthesiologists classes III to IV, obesity, malignancy, proximal pancreatectomy, blood loss ≥350mL, and experiencing readmission within 30 days. Focusing on pancreatic ductal adenocarcinoma (n = 372) patients, the factors associated with persistent weight loss were obesity, proximal pancreatectomy, and experiencing recurrence within 1 year; however, weight cohorts were not associated with overall survival for pancreatic ductal adenocarcinoma patients. Conclusion These data define weight kinetics after pancreatectomy. Ultimately, postoperative weight trajectories appear to be largely predetermined but may be mitigated by limiting readmissions and complications. Clinicians should use these data to identify patients who continue to lose weight between the first and third month postoperatively with a high suspicion for the requirement of nutritional monitoring or other interventions.

Introduction The number of people aged 60 and above will rise from 46 million in 2015 to 157 in 2050 million, exceeding 30% of the population in many western countries. Consequently, the demand for oncological therapy for elderly patients will increase within the next decades. Currently, sufficient data on neoadjuvant therapy (NTx) of pancreatic cancer in elderly patients are lacking. Methods Data of a multinational, retrospective database were screened for patients having received preoperative FOLFIRINOX (FFx) or Gemcitabine/nab-paclitaxel (GNP) for locally advanced and borderline resectable pancreatic cancer (LAPC/BRPC) before June 2017. Data were included in an intention-to-treat-analysis and outcomes were compared between non-aged and elderly patients using a cut-off age of 63 (comparison 1) and 70 years (comparison 2). Results Of 165 patients receiving NTx, 76 and 33 were older than 63 and 70 years. Baseline characteristics revealed that elderly patients preferably undergo GNP (comparison 1: p = 0.063; comparison2: p = 0.005), with less cycles of NTx (comparison 1: p = 0.057). Whereas reductions of NTx dosage was more common in elderly patients in comparison 1 (p = 0.003), resection rates (p = 0.575; p = 1.000) and median survival (p = 0.406; p = 0.499) were not different. Whereas resected patients showed no differences in survival (p = 0.328; p = 0.132), patients aged >70 years showed a decreased progression-free survival (p = 0.019). Conclusion Elderly patients treated with NTx show encouragingly high resection rates. If comorbidities allow for FFx or GNP, elderly patients with LAPC/BRPC can offered NTx with the prospect of survival comparable to younger patients.

The authors hypothesized that in resected pancreatic adenocarcinoma (PDAC), pathologic characteristics, oncologic outcomes, prognostic factors, and the accuracy of the American Joint Committee on Cancer (AJCC) staging system might differ based on tumor location. Patients undergoing pancreatectomy for PDAC at two academic institutions from 2000 to 2015 were retrieved. A comparative analysis between head (H-PDAC) and body–tail (BT-PDAC) tumors was performed using uni- and multivariable models. The accuracy of the eighth AJCC staging system was analyzed using C-statistics. Among 1466 patients, 264 (18%) had BT-PDAC, which displayed greater tumor size but significantly lower rates of perineural invasion and G3/4 grading. Furthermore, BT-PDAC was associated with a lower frequency of nodal involvement and a greater representation of earlier stages. The recurrence-free survival and disease-specific survival times were longer for BT-PDAC (16 vs 14 months [p = 0.020] and 33 vs 26 months [p = 0.026], respectively), but tumor location was not an independent predictor of recurrence or survival in the multivariable analyses. The recurrence patterns did not differ. Certain prognostic factors (i.e., CA 19.9, grading, R-status, and adjuvant treatment) were common, whereas others were site-specific (i.e., preoperative pain, diabetes, and multivisceral resection). The performances of the AJCC staging system were similar (C-statistics of 0.573 for H-PDAC and 0.597 for BT-PDAC, respectively). Despite differences in pathologic profile found to be in favor of BT-PDAC, tumor location was not an independent predictor of recurrence or survival after pancreatectomy. An array of site-specific prognostic factors was identified, but the AJCC staging system displayed similar prognostic power regardless of primary tumor location.

Objective To reappraise the concept of conditional survival (CS) following pancreatectomy for pancreatic ductal adenocarcinoma (PDAC), accounting for the patient's present disease status relative to recurrence. Background CS, defined as the probability of surviving an additional time frame based on accrued lifespan, offers dynamic survival projections as compared with baseline overall survival. Methods Patients undergoing pancreatectomy for PDAC at 2 institutions from 2000 to 2013 were retrospectively analyzed. The 12-month CS was estimated separately for patients who were disease-free or with recurrence at the given time points. Next, the conditional probability of reaching 60-months of survival was examined in each conditioning set across strata of prognostic covariates, including American Joint Committee on Cancer stage, tumor grade, R-status, and adjuvant treatment. Results The study population consisted of 1005 patients. In disease-free patients, the 12-month CS increased as a function of time already survived, showing an opposite trend compared with overall survival. In patients who recurred, the 12-month CS was lower than the disease-free counterpart, especially within 24 months postoperatively. When stratifying by the levels of prognostic covariates, the 60-months CS estimates for disease-free patients tended to level off progressively, indicating that factors independently associated with survival at the time of pancreatectomy lost power over time. This concept did not apply to the conditioning set of patients with recurrence, where CS estimates across variables strata diverged with accrued lifespan. Conclusion This paper provides new information on how prognosis following pancreatectomy for PDAC evolves over time, adjusting for the time the patient already survived, and for the patient's present disease status relative to recurrence.

Solid pseudopapillary neoplasms (SPN) of the pancreas are rare, low-grade malignant neoplasms that metastasise to the liver or peritoneum in 10-15% of cases. They almost invariably present somatic activating mutations of CTNNB1. No comprehensive molecular characterisation of metastatic disease has been conducted to date. We performed whole-exome sequencing and copy-number variation (CNV) analysis of 10 primary SPN and comparative sequencing of five matched primary/metastatic tumour specimens by high-coverage targeted sequencing of 409 genes. In addition to CTNNB1-activating mutations, we found inactivating mutations of epigenetic regulators (KDM6A, TET1, BAP1) associated with metastatic disease. Most of these alterations were shared between primary and metastatic lesions, suggesting that they occurred before dissemination. Differently from mutations, the majority of CNVs were not shared among lesions from the same patients and affected genes involved in metabolic and pro-proliferative pathways. Immunostaining of 27 SPNs showed that loss or reduction of KDM6A and BAP1 expression was significantly enriched in metastatic SPNs. Consistent with an increased transcriptional response to hypoxia in pancreatic adenocarcinomas bearing KDM6A inactivation, we showed that mutation or reduced KDM6A expression in SPNs is associated with increased expression of the HIF1α-regulated protein GLUT1 at both primary and metastatic sites. Our results suggest that BAP1 and KDM6A function is a barrier to the development of metastasis in a subset of SPNs, which might open novel avenues for the treatment of this disease. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Recent data illustrates improved outcomes when adhering to early drain removal following pancreatoduodenectomy (PD). This study aims to explore the potential benefits of expanding the timeframe for early drain removal. Six hundred forty PDs were originally managed by selective drain placement and early removal. Outcomes were reappraised in the framework of a novel proposal; intraoperative drains were omitted based on a low-risk profile (Fistula Risk Score 0–2), followed by drain removal at PODs 1, 3, and 5 if drain fluid amylase (DFA) fell below specific cutoffs based on optimized negative predictive values (NPV) for clinically relevant postoperative pancreatic fistula (CR-POPF). Characteristics of the remaining cohort with drains in situ on POD5 were examined using multivariable analysis (MVA). Intraoperative FRS would preclude drains from 230 (35.9%) negligible/low-risk cases with a cohort CR-POPF rate of 1.7%. Of the remaining patients, 30.5% would have drains removed on POD1 based on a DFA threshold of 300 IU/L (NPV = 98.4%), demonstrating a 1.6% CR-POPF rate. On POD3, drains could be removed in the residual cohort from 21.1% of patients with DFA ≤ 150 IU/L (NPV = 96.6%), reflecting a 3.4% CR-POPF rate. On POD5, a DFA threshold of 50 IU/L (NPV = 84%) identified 16.3% more patients whose drains could be removed. The remaining cohort (POD5 DFA > 50 IU/L), “enriched” for fistula development and reflecting just 18.4% of the original patients, displays a 61% CR-POPF rate. Among these patients on POD5, a DFA threshold > 2000 IU/L best predicted subsequent CR-POPF (PPV = 89.5%), and MVA revealed a positive association between pancreatic cancer/pancreatitis (OR = 4.37, p = 0.022) and longer operations (OR = 3.74, p = 0.014) with CR-POPF development. Early drain removal is a dynamic concept and can be employed throughout the postoperative time course using conditional thresholds to better identify patients at risk for CR-POPF.

Background/Objectives Screening/surveillance programs for pancreatic cancer (PC) in familial high-risk individuals (FPC-HRI) have been widely reported, but their merits remain unclear. The data reported so far are heterogeneous—especially in terms of screening yield. We performed a systematic review and meta-analysis of currently available data coming from screening/surveillance programs to evaluate the proportion of screening goal achievement (SGA), overall surgery and unnecessary surgery. Methods We searched MEDLINE, Embase, PubMed and the Cochrane Library database from January 2000 to December 2016to identify studies reporting results of screening/surveillance programs including cohorts of FPC-HRI. The main outcome measures were weighted proportion of SGA, overall surgery, and unnecessary surgery among the FPC-HRI cohort, using a random effects model. SGA was defined as any diagnosis of resectable PC, PanIN3, or high-grade dysplasia intraductal papillary mucinous neoplasm (HGD-IPMN). Unnecessary surgery was defined as any other final pathology. Results In a meta-analysis of 16 studies reporting on 1551 FPC-HRI cases, 30 subjects (1.82%), received a diagnosis of PC, PanIN3 or HGD-IPMNs. The pooled proportion of SGA was 1.4%(95% CI 0.8–2, p Conclusions The weighted proportion of SGA of screening/surveillance programs published thus far is excellent. However, the probability of receiving surgery during the screening/surveillance program is non-negligible, and unnecessary surgery is a potential negative outcome.

High-volume centers have to deal with long surgical waiting-lists leading to a potential delay in treatment. This study assessed whether a longer time from diagnosis to surgery worsened pathological and survival outcomes in resectable pancreatic ductal adenocarcinoma (PDAC).A retrospective analysis of patients treated for resectable PDAC. Difference in size between preoperative CT-scan and specimen, pathological features, the rate of vascular and R1 resections as well as recurrence and survival were analyzed depending on the waiting time using a 30-day cut-off.Waiting more than 30 days for surgery was associated with an increase in tumor size on specimen when compared with CT-scan (+3 vs. +1 mm, p = 0.04). T and N status, rate of vascular resection, grading, perineural and lymphovascular infiltration, and R1 rates did not differ between groups, as well as tumor recurrence (48.8% vs. 48.9%, p = 0.5) and survival (31 vs. 29 months, p = 0.7). For PDAC20 mm, waiting less than 30 days improved overall survival (p = 0.02).The duration of the surgical waiting-list did not affect pathological features and survival. Delayed surgery was associated with increased cancer size on the specimen. However, surgery should not be delayed for PDACs20 mm as this may negatively affect the prognosis.

Pancreatic cancer surgery is a continuously evolving field. Despite tremendous advances in perioperative outcomes, pancreatic resection is still associated with substantial morbidity, and mortality is not nil. Institutional caseload is a well-established determinant of patient outcomes, and centralization to experienced centers is essential to the safety and oncological appropriateness of the resection. Minimally invasive approaches are increasingly applied for pancreatic resection, even in cancer patients. Nevertheless, the level of evidence in this field remains low. Minimally invasive distal pancreatectomy appears potentially beneficial towards some perioperative outcomes, although its oncological results remain incompletely studied. Data regarding perioperative and oncologic outcomes for minimally invasive pancreaticoduodenectomy (Whipple's resection) is even less mature, but suggest that similar results as the open approach can be achieved in selected, high-volume centers. Conversely, its indiscriminate adoption by inexperienced surgeons and institutions has potential deleterious effects given its steep learning curve. Newer neoadjuvant treatment protocols display enhanced ability to downstage advanced tumors, increasing candidates for potentially curative surgery. Conversely, putative benefits of neoadjuvant treatment in patients with technically resectable tumors have not been reliably demonstrated and its optimal indications remain highly controversial.