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Objective: This nationwide multicenter study aimed to define clinically relevant thresholds of relative serum CA19-9 response after 2 months of induction chemotherapy in patients with locally advanced pancreatic cancer (LAPC). Background: CA19-9 is seen as leading biomarker for response evaluation in patients with LAPC, but early clinically useful cut-offs are lacking. Methods: All consecutive patients with LAPC after 4 cycles (m)FOLFIRINOX or 2 cycles gemcitabine-nab-paclitaxel induction chemotherapy ( ± radiotherapy) with CA19-9 ≥5 U/mL at baseline were analyzed (2015–2019). The association of CA19-9 response with median OS (mOS) was evaluated for different CA19-9 cut-off points. Minimum and optimal CA19-9 response were established via log-rank test. Predictors for OS were analyzed using COX regression analysis. Results: Overall, 212 patients were included, of whom 42 (19.8%) underwent resection. Minimum CA19-9 response demonstrating a clinically significant median OS difference (12.7 vs. 19.6 months) was seen at ≥ 40% CA19-9 decrease. The optimal cutoff for CA19-9 response was ≥ 60% decrease (21.7 vs. 14.0 mo, P = 0.021). Only for patients with elevated CA19-9 levels at baseline (n = 184), CA19-9 decrease ≥ 60% [hazard ratio (HR) = 0.59, 95% CI, 0.36–0.98, P = 0.042] was independently associated with prolonged OS, as were SBRT (HR = 0.42, 95% CI, 0.25–0.70; P = 0.001), and resection (HR = 0.25, 95% CI, 0.14–0.46, P < 0.001), and duration of chemotherapy (HR = 0.75, 95% CI, 0.69–0.82, P < 0.001). Conclusions: CA19-9 decrease of ≥60% following induction chemotherapy as optimal response cut-off in patients with LAPC is an independent predictor for OS when CA19-9 is increased at baseline. Furthermore, ≥40% is the minimum cut-off demonstrating survival benefit. These cut-offs may be used when discussing treatment strategies during early response evaluation. [ABSTRACT FROM AUTHOR]

Objective: To assess the nationwide long-term uptake and outcomes of minimally invasive distal pancreatectomy (MIDP) after a nationwide training program and randomized trial. Background: Two randomized trials demonstrated the superiority of MIDP over open distal pancreatectomy (ODP) in terms of functional recovery and hospital stay. Data on implementation of MIDP on a nationwide level are lacking. Methods: Nationwide audit-based study including consecutive patients after MIDP and ODP in 16 centers in the Dutch Pancreatic Cancer Audit (2014 to 2021). The cohort was divided into three periods: early implementation, during the LEOPARD randomized trial, and late implementation. Primary endpoints were MIDP implementation rate and textbook outcome. Results: Overall, 1496 patients were included with 848 MIDP (56.5%) and 648 ODP (43.5%). From the early to the late implementation period, the use of MIDP increased from 48.6% to 63.0% and of robotic MIDP from 5.5% to 29.7% ( P <0.001). The overall use of MIDP (45% to 75%) and robotic MIDP (1% to 84%) varied widely between centers ( P <0.001). In the late implementation period, 5/16 centers performed >75% of procedures as MIDP. After MIDP, in-hospital mortality and textbook outcome remained stable over time. In the late implementation period, ODP was more often performed in ASA score III-IV (24.9% vs. 35.7%, P =0.001), pancreatic cancer (24.2% vs. 45.9%, P <0.001), vascular involvement (4.6% vs. 21.9%, P <0.001), and multivisceral involvement (10.5% vs. 25.3%, P <0.001). After MIDP, shorter hospital stay (median 7 vs. 8 d, P <0.001) and less blood loss (median 150 vs. 500 mL, P <0.001), but more grade B/C postoperative pancreatic fistula (24.4% vs. 17.2%, P =0.008) occurred as compared to ODP. Conclusion: A sustained nationwide implementation of MIDP after a successful training program and randomized trial was obtained with satisfactory outcomes. Future studies should assess the considerable variation in the use of MIDP between centers and, especially, robotic MIDP. [ABSTRACT FROM AUTHOR]

Objective: To develop a prediction model for long-term (≥5 years) disease-free survival (DFS) after the resection of pancreatic ductal adenocarcinoma (PDAC). Background: Despite high recurrence rates, ~10% of patients have longterm DFS after PDAC resection. A model to predict long-term DFS may aid individualized prognostication and shared decision-making. Methods: This nationwide cohort study included all consecutive patients who underwent PDAC resection in the Netherlands (2014-2016). The best-performing prognostic model was selected by Cox-proportional hazard analysis and Akaike's Information Criterion, presented by hazard ratios (HRs) with 95% confidence intervals (CIs). Internal validation was performed, and discrimination and calibration indices were assessed. Results: In all, 836 patients with a median follow-up of 67 months (interquartile range 51-79) were analyzed. Long-term DFS was seen in 118 patients (14%). Factors predictive of long-term DFS were low preoperative carbohydrate antigen 19-9 (logarithmic; HR 1.21; 95% CI 1.10-1.32), no vascular resection (HR 1.33; 95% CI 1.12-1.58), T1 or T2 tumor stage (HR 1.52; 95% CI 1.14-2.04, and HR 1.17; 95% CI 0.98-1.39, respectively), well/moderate tumor differentiation (HR 1.44; 95% CI 1.22-1.68), absence of perineural and lymphovascular invasion (HR 1.42; 95% CI 1.11-1.81 and HR 1.14; 95% CI 0.96-1.36, respectively), N0 or N1 nodal status (HR 1.92; 95% CI 1.54-2.40, and HR 1.33; 95% CI 1.11-1.60, respectively), R0 resection margin status (HR 1.25; 95% CI 1.07-1.46), no major complications (HR 1.14; 95% CI 0.97-1.35) and adjuvant chemotherapy (HR 1.74; 95% CI 1.47-2.06). Moderate performance (concordance index 0.68) with adequate calibration (slope 0.99) was achieved. Conclusions: The developed prediction model, readily available at www. pancreascalculator.com, can be used to estimate the probability of longterm DFS after resection of pancreatic ductal adenocarcinoma. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the performance of published fistula risk models by external validation, and to identify independent risk factors for postoperative pancreatic fistula (POPF). Background: Multiple risk models have been developed to predict POPF after pancreatoduodenectomy. External validation in high-quality prospective cohorts is, however, lacking or only performed for individual models. Methods: A post hoc analysis of data from the stepped-wedge cluster cluster-randomized Care After Pancreatic Resection According to an Algorithm for Early Detection and Minimally Invasive Management of Pancreatic Fistula versus Current Practice (PORSCH) trial was performed. Included were all patients undergoing pancreatoduodenectomy in the Netherlands (January 2018--November 2019). Risk models on POPF were identified by a systematic literature search. Model performance was evaluated by calculating the area under the receiver operating curves (AUC) and calibration plots. Multivariable logistic regression was performed to identify independent risk factors associated with clinically relevant POPF. Results: Overall, 1358 patients undergoing pancreatoduodenectomy were included, of whom 341 patients (25%) developed clinically relevant POPF. Fourteen risk models for POPF were evaluated, with AUCs ranging from 0.62 to 0.70. The updated alternative fistula risk score had an AUC of 0.70 (95% confidence intervals [CI]: 0.69--0.72). The alternative fistula risk score demonstrated an AUC of 0.70 (95% CI: 0.689--0.71), whilst an AUC of 0.70 (95% CI: 0.699--0.71) was also found for the model by Petrova and colleagues. Soft pancreatic texture, pathology other than pancreatic ductal adenocarcinoma or chronic pancreatitis, small pancreatic duct diameter, higher body mass index, minimally invasive resection and male sex were identified as independent predictors of POPF. Conclusion: Published risk models predicting clinically relevant POPF after pancreatoduodenectomy have a moderate predictive accuracy. Their clinical applicability to identify high-risk patients and guide treatment strategies is therefore questionable. [ABSTRACT FROM AUTHOR]

Objective: To assess the learning curve of pancreaticojejunostomy during robotic pancreatoduodenectomy (RPD) and to predict the risk of postoperative pancreatic fistula (POPF) by using the objective structured assessment of technical skills (OSATS), taking the fistula risk into account. Background: RPD is a challenging procedure that requires extensive training and confirmation of adequate surgical performance. Video grading, modified for RPD, of the pancreatic anastomosis could assess the learning curve of RPD and predict the risk of POPF. Methods: Post hoc assessment of patients prospectively included in 4 Dutch centers in a nationwide LAELAPS-3 training program for RPD. Video grading of the pancreaticojejunostomy was performed by 2 graders using OSATS (attainable score: 12--60). The main outcomes were the combined OSATS of the 2 graders and POPF (grade B/C). Cumulative sum analyzed a turning point in the learning curve for surgical skill. Logistic regression determined the cutoff for OSATS. Patients were categorized for POPF risk (ie, low, intermediate, and high) based on the updated alternative fistula risk scores. Results: Videos from 153 pancreatic anastomoses were included. Median OSATS score was 48 (interquartile range: 41--52) points and with a turning point at 33 procedures. POPF occurred in 39 patients (25.5%). An OSATS score below 49, present in 77 patients (50.3%), was associated with an increased risk of POPF (odds ratio: 4.01, P=0.004). The POPF rate was 43.6% with OSATS < 49 versus 15.8% with OSATS ≥ 49. The updated alternative fistula risk scores category "soft pancreatic texture" was the second strongest prognostic factor of POPF (odds ratio: 3.37, P= 0.040). Median cumulative surgical experience was 17 years (interquartile range: 8--21). Conclusions: Video grading of the pancreatic anastomosis in RPD using OSATS identified a learning curve and a reduced risk of POPF in case of better surgical performance. Video grading may provide a valid method to surgical training, quality control, and improvement. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study is to define and assess Ideal Outcome in the national or multicenter registries of North America, Germany, the Netherlands, and Sweden. Background: Assessing outcomes after pancreatoduodenectomy among centers and countries requires a broad evaluation that cannot be captured by a single parameter. Previously, 2 composite outcome measures (textbook outcome and optimal pancreatic surgery) for pancreatoduodenectomy have been described from Europe and the United States. These composites were harmonized into ideal outcome (IO). Methods: This analysis is a transatlantic retrospective study (2018--2020) of patients after pancreatoduodenectomy within the registries from North America, Germany, The Netherlands, and Sweden. After 3 consensus meetings, IO for pancreatoduodenectomy was defined as the absence of all 6 parameters: (1) in-hospital mortality, (2) severe complications--Clavien-Dindo ≥3, (3) postoperative pancreatic fistula --International Study Group of Pancreatic Surgery (ISGPS) grade B/C, (4) reoperation, (5) hospital stay >75th percentile, and (6) readmission. Outcomes were evaluated using relative largest difference (RLD) and absolute largest difference (ALD), and multivariate regression models. Results: Overall, 21,036 patients after pancreatoduodenectomy were included, of whom11,194 (54%) reached IO. The rate of IO varied between 55% in North America, 53% in Germany, 52% in The Netherlands, and 54% in Sweden (RLD: 1.1, ALD: 3%, P<0.001). Individual components varied with an ALDof 2%length of stay, 4% for in-hospitalmortality, 12% severe complications, 10% postoperative pancreatic fistula, 11% reoperation, and 9% readmission. Age, sex, absence of chronic obstructive pulmonary disease, body mass index, performance status, American Society of Anesthesiologists (ASA) score, biliary drainage, absence of vascular resection, and histologic diagnosis were associated with IO. In the subgroup of patients with pancreatic adenocarcinoma, country, and neoadjuvant chemotherapy also was associated with improved IO. Conclusions: The newly developed composite outcome measure "Ideal Outcome" can be used for auditing and comparing outcomes after pancreatoduodenectomy. The observed differences can be used to guide collaborative initiatives to further improve the outcomes of pancreatic surgery. [ABSTRACT FROM AUTHOR]

Objective: To develop a fistula risk score for auditing, to be able to compare postoperative pancreatic fistula (POPF) after pancreatoduodenectomy among hospitals. Background: For proper comparisons of outcomes in surgical audits, case-mix variation should be accounted for. Methods: This study included consecutive patients after pancreatoduodenectomy from the mandatory nationwide Dutch Pancreatic Cancer Audit. Derivation of the score was performed with the data from 2014 to 2018 and validation with 2019 to 2020 data. The primary endpoint of the study was POPF (grade B or C). Multivariable logistic regression analysis was performed for case-mix adjustment of known risk factors. Results: In the derivation cohort, 3271 patients were included, of whom 479 (14.6%) developed POPF. Male sex [odds ratio (OR)=1.34; 95% confidence interval (CI): 1.09–1.66], higher body mass index (OR=1.07; 95% CI: 1.05–1.10), a final diagnosis other than pancreatic ductal adenocarcinoma/pancreatitis (OR=2.41; 95% CI: 1.90–3.06), and a smaller duct diameter (OR=1.43/mm decrease; 95% CI: 1.32–1.55) were independently associated with POPF. Diabetes mellitus (OR=0.73; 95% CI: 0.55–0.98) was independently associated with a decreased risk of POPF. Model discrimination was good with a C -statistic of 0.73 in the derivation cohort and 0.75 in the validation cohort (n=913). Hospitals differed in particular in the proportion of pancreatic ductal adenocarcinoma/pancreatitis patients, ranging from 36.0% to 58.1%. The observed POPF risk per center ranged from 2.9% to 25.4%. The expected POPF rate based on the 5 risk factors ranged from 11.6% to 18.0% among hospitals. Conclusions: The auditing fistula risk score was successful in case-mix adjustment and enables fair comparisons of POPF rates among hospitals. [ABSTRACT FROM AUTHOR]

Objective: To describe outcome after pancreatic surgery in the first 6 years of a mandatory nationwide audit. Background: Within the Dutch Pancreatic Cancer Group, efforts have been made to improve outcome after pancreatic surgery. These include collaborative projects, clinical auditing, and implementation of an algorithm for early recognition and management of postoperative complications. However, nationwide changes in outcome over time have not yet been described. Methods: This nationwide cohort study included consecutive patients after pancreatoduodenectomy (PD) and distal pancreatectomy from the mandatory Dutch Pancreatic Cancer Audit (January 2014–December 2019). Patient, tumor, and treatment characteristics were compared between 3 time periods (2014–2015, 2016–2017, and 2018–2019). Short-term surgical outcome was investigated using multilevel multivariable logistic regression analyses. Primary endpoints were failure to rescue (FTR) and in-hospital mortality. Results: Overall, 5345 patients were included, of whom 4227 after PD and 1118 after distal pancreatectomy. After PD, FTR improved from 13% to 7.4% [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.50–0.80, P <0.001] and in-hospital mortality decreased from 4.1% to 2.4% (OR 0.68, 95% CI 0.54–0.86, P =0.001), despite operating on more patients with age >75 years (18%–22%, P =0.006), American Society of Anesthesiologists score ≥3 (19%–31%, P <0.001) and Charlson comorbidity score ≥2 (24%–34%, P <0.001). The rates of textbook outcome (57%–55%, P =0.283) and major complications remained stable (31%–33%, P =0.207), whereas complication-related intensive care admission decreased (13%–9%, P =0.002). After distal pancreatectomy, improvements in FTR from 8.8% to 5.9% (OR 0.65, 95% CI 0.30–1.37, P =0.253) and in-hospital mortality from 1.6% to 1.3% (OR 0.88, 95% CI 0.45–1.72, P =0.711) were not statistically significant. Conclusions: During the first 6 years of a nationwide audit, in-hospital mortality and FTR after PD improved despite operating on more high-risk patients. Several collaborative efforts may have contributed to these improvements. [ABSTRACT FROM AUTHOR]

Objective: To establish an evidence-based cutoff and predictors for early recurrence in patients with resected locally advanced pancreatic cancer (LAPC). Background: It is unclear how many and which patients develop early recurrence after LAPC resection. Surgery in these patients is probably of little benefit. Methods: We analyzed all consecutive patients undergoing resection of LAPC after induction chemotherapy who were included in prospective databases in The Netherlands (2015–2019) and the Johns Hopkins Hospital (2016–2018). The optimal definition for "early recurrence" was determined by the post-recurrence survival (PRS). Patients were compared for overall survival (OS). Predictors for early recurrence were evaluated using logistic regression analysis. Results: Overall, 168 patients were included. After a median follow-up of 28 months, recurrence was observed in 118 patients (70.2%). The optimal cutoff for recurrence-free survival to differentiate between early (n=52) and late recurrence (n=66) was 6 months (P <0.001). OS was 8.4 months [95% confidence interval (CI): 7.3–9.6] in the early recurrence group (n=52) versus 31.1 months (95% CI: 25.7–36.4) in the late/no recurrence group (n=116) (P <0.001). A preoperative predictor for early recurrence was postinduction therapy carbohydrate antigen (CA) 19-9≥100 U/mL [odds ratio (OR)=4.15, 95% CI: 1.75–9.84, P =0.001]. Postoperative predictors were poor tumor differentiation (OR=4.67, 95% CI: 1.83–11.90, P =0.001) and no adjuvant chemotherapy (OR=6.04, 95% CI: 2.43–16.55, P <0.001). Conclusions: Early recurrence was observed in one third of patients after LAPC resection and was associated with poor survival. Patients with post-induction therapy CA 19-9 ≥100 U/mL, poor tumor differentiation and no adjuvant therapy were especially at risk. This information is valuable for patient counseling before and after resection of LAPC. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to assess the clinical impact and risk factors of chyle leak (CL). Background: In 2017, the International Study Group for Pancreatic Surgery (ISGPS) published the consensus definition of CL. Multicenter series validating this definition are lacking and previous studies investigating risk factors have used different definitions and showed heterogeneous results. Methods: This observational cohort study included all consecutive patients after pancreatoduodenectomy in all 19 centers in the mandatory nationwide Dutch Pancreatic Cancer Audit (2017–2019). The primary endpoint was CL (ISGPS grade B/C). Multivariable logistic regression analyses were performed. Results: Overall, 2159 patients after pancreatoduodenectomy were included. The rate of CL was 7.0% (n=152), including 6.9% (n=150) grade B and 0.1% (n=2) grade C. CL was independently associated with a prolonged hospital stay [odds ratio (OR)=2.84, 95% confidence interval (CI): 1.85–4.36, P <0.001] but not with mortality (OR=0.3, 95% CI: 0.0–2.3, P =0.244). In multivariable analyses, independent predictors for CL were vascular resection (OR=2.1, 95% CI: 1.4–3.2, P <0.001) and open surgery (OR=3.5, 95% CI: 1.7–7.2, P =0.001). The number of resected lymph nodes and aortocaval lymph node sampling were not identified as predictors in multivariable analysis. Conclusions: In this nationwide analysis, the rate of ISGPS grade B/C CL after pancreatoduodenectomy was 7.0%. Although CL is associated with a prolonged hospital stay, the clinical impact is relatively minor in the vast majority (>98%) of patients. Vascular resection and open surgery are predictors of CL. [ABSTRACT FROM AUTHOR]

Objective: To develop 2 distinct preoperative and intraoperative risk scores to predict postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP) to improve preventive and mitigation strategies, respectively. Background: POPF remains the most common complication after DP. Despite several known risk factors, an adequate risk model has not been developed yet. Methods: Two prediction risk scores were designed using data of patients undergoing DP in 2 Italian centers (2014–2016) utilizing multivariable logistic regression. The preoperative score (calculated before surgery) aims to facilitate preventive strategies and the intraoperative score (calculated at the end of surgery) aims to facilitate mitigation strategies. Internal validation was achieved using bootstrapping. These data were pooled with data from 5 centers from the United States and the Netherlands (2007–2016) to assess discrimination and calibration in an internal-external validation procedure. Results: Overall, 1336 patients after DP were included, of whom 291 (22%) developed POPF. The preoperative distal fistula risk score (preoperative D-FRS) included 2 variables: pancreatic neck thickness [odds ratio: 1.14; 95% confidence interval (CI): 1.11–1.17 per mm increase] and pancreatic duct diameter (OR: 1.46; 95% CI: 1.32–1.65 per mm increase). The model performed well with an area under the receiver operating characteristic curve of 0.83 (95% CI: 0.78–0.88) and 0.73 (95% CI: 0.70–0.76) upon internal-external validation. Three risk groups were identified: low risk (<10%), intermediate risk (10%–25%), and high risk (>25%) for POPF with 238 (18%), 684 (51%), and 414 (31%) patients, respectively. The intraoperative risk score (intraoperative D-FRS) added body mass index, pancreatic texture, and operative time as variables with an area under the receiver operating characteristic curve of 0.80 (95% CI: 0.74–0.85). Conclusions: The preoperative and the intraoperative D-FRS are the first validated risk scores for POPF after DP and are readily available at: http://www.pancreascalculator.com. The 3 distinct risk groups allow for personalized treatment and benchmarking. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the effect of preoperative chemoradiotherapy on surgical complications in patients after pancreatic resection for (borderline-)resectable pancreatic cancer. Summary of Background Data: Preoperative chemoradiotherapy is increasingly used in patients with (borderline-)resectable pancreatic cancer. concerns have been raised about the potential harmful effect of any preoperative therapy on the surgical complication rate after pancreatic resection. Methods: An observational analysis was performed within the multicenter randomized controlled PREOPANC trial (April 2013–July 2017). The trial randomly assigned (1:1) patients to preoperative chemoradiotherapy followed by surgery and the remaining adjuvant chemotherapy or to immediate surgery, followed by adjuvant chemotherapy. The main analysis consisted of a per-protocol approach. The endpoints of the present analyses were the rate of postoperative complications. Results: This study included 246 patients from 16 centers, of whom 66 patients underwent resection after preoperative therapy and 98 patients after immediate surgery. No differences were found regarding major complications (37.9% vs 30.6%, P =0.400), postpancreatectomy hemorrhage (9.1% vs 5.1%, P =0.352), delayed gastric emptying (21.2% vs 22.4%, P =0.930), bile leakage (4.5% vs 3.1%, P =0.686), intra-abdominal infections (12.1% vs 10.2%, P =0.800), and mortality (3.0% vs 4.1%, P =1.000). There was a significant lower incidence of postoperative pancreatic fistula in patients who received preoperative chemoradiotherapy (0% vs 9.2%, P =0.011). Conclusions: Preoperative chemoradiotherapy did not increase the incidence of surgical complications or mortality and reduced the rate of postoperative pancreatic fistula after resection in patients with (borderline-)resectable pancreatic cancer. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the accrual proportion and patients' reasons for not participating in the PREOPANC trial on neoadjuvant chemoradiotherapy versus immediate surgery in resectable and borderline resectable pancreatic cancer, and to compare these patients' outcomes with those of patients who had been randomized in the trial. Summary of Background Data: The external validity of multicenter randomized trials in cancer treatment has been criticized for suboptimal non-representative inclusion. In trials, it is unclear how outcomes compare between randomized and nonrandomized patients. Methods: At 8 of 16 participant centers, this multicenter observational study identified validation patients, who had been eligible but not randomized during recruitment for the PREOPANC trial. We assessed the accrual proportion, investigated their most common reasons for not participating in the trial, and compared resection rates, radical (R0) resection rates, and overall survival between the validation patients and PREOPANC patients, who had been randomized in the trial to immediate surgery. Results: In total, 455 patients had been eligible during the recruitment period, 151 of whom (33%) had been randomized. Fifty-five percent of the 304 validation patients had refused to participate. Median overall survival in the validation group was 15.2 months, against 15.5 months in the PREOPANC group (P = 1.00). The respective resection rates (76% vs 73%) and R0 resection rates (51% vs 46%) did not differ between the groups. Conclusions: The PREOPANC trial included a reasonable percentage of 33% of eligible patients. In terms of the outcomes survival, resection rate, and R0 resection rate, this appeared to be a representative group. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether detection of recurrent pancreatic ductal adenocarcinoma (PDAC) in an early, asymptomatic stage increases the number of patients receiving additional treatment, subsequently improving survival. Summary of Background data: International guidelines disagree on the value of standardized postoperative surveillance for early detection and treatment of PDAC recurrence. Methods: A nationwide, observational cohort study was performed including all patients who underwent PDAC resection (2014-2016). Prospective baseline and perioperative data were retrieved from the Dutch Pancreatic Cancer Audit. Data on follow-up, treatment, and survival were collected retrospectively. Overall survival (OS) was evaluated using multivariable Cox regression analysis, before and after propensity-score matching, stratified for patients with symptomatic and asymptomatic recurrence. Results: Eight hundred thirty-six patients with a median follow-up of 37 months (interquartile range 30-48) were analyzed. Of those, 670 patients (80%) developed PDAC recurrence after a median follow-up of 10 months (interquartile range 5-17). Additional treatment was performed in 159/511 patients (31%) with symptomatic recurrence versus 77/159 (48%) asymptomatic patients (P < 0.001). After propensity-score matching on lymph node ratio, adjuvant therapy, disease-free survival, and recurrence site, additional treatment was independently associated with improved OS for both symptomatic patients [hazard ratio 0.53 (95% confidence interval 0.42-0.67); P < 0.001] and asymptomatic patients [hazard ratio 0.45 (95% confidence interval 0.29-0.70); P < 0.001]. Conclusions: Additional treatment of PDAC recurrence was independently associated with improved OS, with asymptomatic patients having a higher probability to receive recurrence treatment. Therefore, standardized postoperative surveillance aiming to detect PDAC recurrence before the onset of symptoms has the potential to improve survival. This provides a rationale for prospective studies on standardized surveillance after PDAC resection. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text Objective: To quantify the impact of individual complications on mortality, organ failure, hospital stay, and readmission after pancreatoduodenectomy. Summary of Background Data: An initial complication may provoke a sequence of adverse events potentially leading to mortality after pancreatoduodenectomy. This study was conducted to aid prioritization of quality improvement initiatives. Methods: Data from consecutive patients undergoing pancreatoduodenectomy (2014–2017) were extracted from the Dutch Pancreatic Cancer Audit. Population attributable fractions (PAF) were calculated for the association of each complication (ie, postoperative pancreatic fistula, postpancreatectomy hemorrhage, bile leakage, delayed gastric emptying, wound infection, and pneumonia) with each unfavorable outcome [ie, in-hospital mortality, organ failure, prolonged hospital stay (>75th percentile), and unplanned readmission), whereas adjusting for confounders and other complications. The PAF represents the proportion of an outcome that could be prevented if a complication would be eliminated completely. Results: Overall, 2620 patients were analyzed. In-hospital mortality occurred in 95 patients (3.6%), organ failure in 198 patients (7.6%), and readmission in 427 patients (16.2%). Postoperative pancreatic fistula and postpancreatectomy hemorrhage had the greatest independent impact on mortality [PAF 25.7% (95% CI 13.4–37.9) and 32.8% (21.9–43.8), respectively] and organ failure [PAF 21.8% (95% CI 12.9–30.6) and 22.1% (15.0–29.1), respectively]. Delayed gastric emptying had the greatest independent impact on prolonged hospital stay [PAF 27.6% (95% CI 23.5–31.8)]. The impact of individual complications on unplanned readmission was smaller than 11%. Conclusion: Interventions focusing on postoperative pancreatic fistula and postpancreatectomy hemorrhage may have the greatest impact on in-hospital mortality and organ failure. To prevent prolonged hospital stay, initiatives should in addition focus on delayed gastric emptying. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text Objective: This study compared median OS after resection of LAPC after upfront FOLFIRINOX versus a propensity-score matched cohort of LAPC patients treated with FOLFIRINOX-only (ie, without resection). Background: Because the introduction of FOLFIRINOX chemotherapy, increased resection rates in LAPC patients have been reported, with improved OS. Some studies have also reported promising OS with FOLFIRINOX-only treatment in LAPC. Multicenter studies assessing the survival benefit associated with resection of LAPC versus patients treated with FOLFIRINOX-only are lacking. Methods: Patients with non-progressive LAPC after 4 cycles of FOLFIRINOX treatment, both with and without resection, were included from a prospective multicenter cohort in 16 centers (April 2015–December 2019). Cox regression analysis identified predictors for OS. One-to-one propensity score matching (PSM) was used to obtain a matched cohort of patients with and without resection. These patients were compared for OS. Results: Overall, 293 patients with LAPC were included, of whom 89 underwent a resection. Resection was associated with improved OS (24 vs 15 months, P < 0.01), as compared to patients without resection. Before PSM, resection, Charlson Comorbidity Index, and Response Evaluation Criteria in Solid Tumors (RECIST) response were predictors for OS. After PSM, resection remained associated with improved OS [Hazard Ratio (HR) 0.344, 95% confidence interval (0.222–0.534), P < 0.01], with an OS of 24 versus 15 months, as compared to patients without resection. Resection of LAPC was associated with improved 3-year OS (31% vs 11%, P < 0.01). Conclusions: Resection of LAPC after FOLFIRINOX was associated with increased OS and 3-year survival, as compared to propensity-score matched patients treated with FOLFIRINOX-only. [ABSTRACT FROM AUTHOR]

Objective: This analysis aimed to compare failure to rescue (FTR) after pancreatoduodenectomy across the Atlantic. Summary Background Data: FTR, or mortality after development of a major complication, is a quality metric originally created to compare hospital results. FTR has been studied in North American and Northern European patients undergoing pancreatoduodenectomy (PD). However, a direct comparison of FTR after PD between North America and Northern Europe has not been performed. Methods: Patients who underwent PD in North America, the Netherlands, Sweden and Germany (GAPASURG dataset) were identified from their respective registries (2014–17). Patients who developed a major complication defined as Clavien-Dindo ≥3 or developed a grade B/C postoperative pancreatic fistula (POPF) were included. Preoperative, intraoperative, and postoperative variables were compared between patients with and without FTR. Variables significant on univariable analysis were entered into a logistic regression for FTR. Results: Major complications occurred in 6188 of 22,983 patients (26.9%) after PD, and 504 (8.1%) patients had FTR. North American and Northern European patients with complications differed, and rates of FTR were lower in North America (5.4% vs 12%, P < 0.001). Fourteen factors from univariable analysis contributing to differences in patients who developed FTR were included in a logistic regression. On multivariable analysis, factors independently associated with FTR were age, American Society of Anesthesiology ≥3, Northern Europe, POPF, organ failure, life-threatening complication, nonradiologic intervention, and reoperation. Conclusions: Older patients with severe systemic diseases are more difficult to rescue. Failure to rescue is more common in Northern Europe than North America. In stable patients, management of complications by interventional radiology is preferred over reoperation. [ABSTRACT FROM AUTHOR]

Objective: To assess short-term outcomes after minimally invasive (laparoscopic, robot-assisted, and hybrid) pancreatoduodenectomy (MIPD) versus open pancreatoduodenectomy (OPD) among European centers. Background: Current evidence on MIPD is based on national registries or single expert centers. International, matched studies comparing outcomes for MIPD and OPD are lacking. Methods: Retrospective propensity score matched study comparing MIPD in 14 centers (7 countries) performing ≥10 MIPDs annually (2012-2017) versus OPD in 53 German/Dutch surgical registry centers performing ≥10 OPDs annually (2014-2017). Primary outcome was 30-day major morbidity (Clavien-Dindo ≥3). Results: Of 4220 patients, 729/730 MIPDs (412 laparoscopic, 184 robot-assisted, and 130 hybrid) were matched to 729 OPDs. Median annual case-volume was 19 MIPDs (interquartile range, IQR 13-22), including the first MIPDs performed in 10/14 centers, and 31 OPDs (IQR 21-38). Major morbidity (28% vs 30%, P = 0.526), mortality (4.0% vs 3.3%, P = 0.576), percutaneous drainage (12% vs 12%, P = 0.809), reoperation (11% vs 13%, P = 0.329), and hospital stay (mean 17 vs 17 days, P > 0.99) were comparable between MIPD and OPD. Grade-B/C postoperative pancreatic fistula (POPF) (23% vs 13%, P < 0.001) occurred more frequently after MIPD. Single-row pancreatojejunostomy was associated with POPF in MIPD (odds ratio, OR 2.95, P < 0.001), but not in OPD. Laparoscopic, robot-assisted, and hybrid MIPD had comparable major morbidity (27% vs 27% vs 35%), POPF (24% vs 19% vs 25%), and mortality (2.9% vs 5.2% vs 5.4%), with a fewer conversions in robot-assisted- versus laparoscopic MIPD (5% vs 26%, P < 0.001). Conclusions: In the early experience of 14 European centers performing ≥10 MIPDs annually, no differences were found in major morbidity, mortality, and hospital stay between MIPD and OPD. The high rates of POPF and conversion, and the lack of superior outcomes (ie, hospital stay, morbidity) could indicate that more experience and higher annual MIPD volumes are needed. [ABSTRACT FROM AUTHOR]

Background: Textbook outcome (TO) is a multidimensional measure for quality assurance, reflecting the "ideal"surgical outcome. Methods: Post-hoc analysis of patients who underwent pancreatoduodenectomy (PD) or distal pancreatectomy (DP) for all indications between 2014 and 2017, queried from the nationwide prospective Dutch Pancreatic Cancer Audit. An international survey was conducted among 24 experts from 10 countries to reach consensus on the requirements for TO in pancreatic surgery. Univariable and multivariable logistic regression was performed to identify TO predictors. Between-hospital variation in TO rates was compared using observed-versus-expected rates. Results: Based on the survey (92% response rate), TO was defined by the absence of postoperative pancreatic fistula, bile leak, postpancreatectomy hemorrhage (all ISGPS grade B/C), severe complications (Clavien-Dindo _III), readmission, and in-hospital mortality. Overall, 3341 patients were included (2633 (79%) PD and 708 (21%) DP) of whom 60.3% achieved TO; 58.3% for PD and 67.4% for DP. On multivariable analysis, ASA class 3 predicted a worse TO rate after PD (ASA 3 OR 0.59 [0.44-0.80]), whereas a dilated pancreatic duct (>3 mm) and pancreatic ductal adenocarcinoma (PDAC) were associated with a better TO rate (OR 2.22 [2.05-3.57] and OR 1.36 [1.14-1.63], respectively). For DP, female sex and the absence of neoadjuvant therapy predicted better TO rates (OR 1.38 [1.01-1.90] and OR 2.53 [1.20-5.31], respectively). When comparing institutions, the observedversus- expected rate for achieving TO varied from 0.71 to 1.46 per hospital after casemix-adjustment. Conclusions: TO is a novel quality measure in pancreatic surgery. TO varies considerably between pancreatic centers, demonstrating the potential benefit of quality assurance programs. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text Objective: To use the concept of benchmarking to establish robust and standardized outcome references after pancreatico-duodenectomy (PD). Background: Best achievable results after PD are unknown. Consequently, outcome comparisons among different cohorts, centers or with novel surgical techniques remain speculative. Methods: This multicenter study analyzes consecutive patients (2012–2015) undergoing PD in 23 international expert centers in pancreas surgery. Outcomes in patients without significant comorbidities and major vascular resection (benchmark cases) were analyzed to establish 20 outcome benchmarks for PD. These benchmarks were tested in a cohort with a poorer preoperative physical status (ASA class ≥3) and a cohort treated by minimally invasive approaches. Results: Two thousand three hundred seventy-five (38%) low-risk cases out of a total of 6186 PDs were analyzed, disclosing low in-hospital mortality (≤1.6%) but high morbidity, with a 73% benchmark morbidity rate cumulated within 6 months following surgery. Benchmark cutoffs for pancreatic fistulas (B-C), severe complications (≥ grade 3), and failure-to-rescue rate were 19%, 30%, and 9%, respectively. The ASA ≥3 cohort showed comparable morbidity but a higher in hospital-mortality (3% vs 1.6%) and failure-to-rescue rate (16% vs 9%) than the benchmarks. The proportion of benchmark cases performed varied greatly across centers and continents for both open (9%–93%) and minimally invasive (11%–62%) PD. Centers operating mostly on complex PD cases disclosed better results than those with a majority of low-risk cases. Conclusion: The proposed outcome benchmarks for PD, established in a large-scale international patient cohort and tested in 2 different cohorts, may allow for meaningful comparisons between different patient cohorts, centers, countries, and surgical techniques. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text 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. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to develop an alternative fistula risk score (a-FRS) for postoperative pancreatic fistula (POPF) after pancreatoduodenectomy, without blood loss as a predictor. Background: Blood loss, one of the predictors of the original-FRS, was not a significant factor during 2 recent external validations. Methods: The a-FRS was developed in 2 databases: the Dutch Pancreatic Cancer Audit (18 centers) and the University Hospital Southampton NHS. Primary outcome was grade B/C POPF according to the 2005 International Study Group on Pancreatic Surgery (ISGPS) definition. The score was externally validated in 2 independent databases (University Hospital of Verona and University Hospital of Pennsylvania), using both 2005 and 2016 ISGPS definitions. The a-FRS was also compared with the original-FRS. Results: For model design, 1924 patients were included of whom 12% developed POPF. Three predictors were strongly associated with POPF: soft pancreatic texture [odds ratio (OR) 2.58, 95% confidence interval (95% CI) 1.80–3.69], small pancreatic duct diameter (per mm increase, OR: 0.68, 95% CI: 0.61–0.76), and high body mass index (BMI) (per kg/m2 increase, OR: 1.07, 95% CI: 1.04–1.11). Discrimination was adequate with an area under curve (AUC) of 0.75 (95% CI: 0.71–0.78) after internal validation, and 0.78 (0.74–0.82) after external validation. The predictive capacity of a-FRS was comparable with the original-FRS, both for the 2005 definition (AUC 0.78 vs 0.75, P = 0.03), and 2016 definition (AUC 0.72 vs 0.70, P = 0.05). Conclusion: The a-FRS predicts POPF after pancreatoduodenectomy based on 3 easily available variables (pancreatic texture, duct diameter, BMI) without blood loss and pathology, and was successfully validated for both the 2005 and 2016 POPF definition. The online calculator is available at www.pancreascalculator.com. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to assess feasibility and outcomes of a multicenter training program in laparoscopic pancreatoduodenectomy (LPD). Background: Whereas expert centers have reported promising outcomes of LPD, nationwide analyses have raised concerns on its safety, especially during the learning curve. Multicenter, structured LPD training programs reporting outcomes including the first procedures are lacking. No LPD had been performed in the Netherlands before this study. Methods: During 2014–2016, 8 surgeons from 4 high-volume centers completed the Longitudinal Assessment and Realization of Laparoscopic Pancreatic Surgery (LAELAPS-2) training program in LPD, including detailed technique description, video training, and proctoring. In all centers, LPD was performed by 2 surgeons with extensive experience in pancreatic and laparoscopic surgery. Outcomes of all LPDs were prospectively collected. Results: In total, 114 patients underwent LPD. Median pancreatic duct diameter was 3 mm [interquartile range (IQR = 2–4)] and pancreatic texture was soft in 74% of patients. The conversion rate was 11% (n = 12), median blood loss 350 mL (IQR = 200–700), and operative time 375 minutes (IQR = 320–431). Grade B/C postoperative pancreatic fistula occurred in 34% of patients, requiring catheter drainage in 22% and re-operation in 2%. A Clavien-Dindo grade ≥ III complication occurred in 43% of patients. Median length of hospital stay was 15 days (IQR = 9–25). Overall, 30-day and 90-day mortality were both 3.5%. Outcomes were similar for the first and second part of procedures. Conclusions: This LPD training program was feasible and ensured acceptable outcomes during the learning curve in all centers. Future studies should determine whether such a training program is applicable in other settings and assess the added value of LPD. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text Objective: To assess whether the location of wound catheters (ie, preperitoneal vs. subcutaneous) impacts outcomes, when compared with alternatives such as epidural analgesia. Background: Continuous wound infiltration is an alternative for epidural analgesia in abdominal surgery but studies have shown conflicting results. This difference could be explained by different efficacy of preperitoneal versus subcutaneous placement of the infiltrative catheters. Methods: A systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines until April 3, 2017. Primary endpoints were pain scores in rest and when moving at 24 hours postoperatively. Secondary endpoints included postoperative pain scores at 12 and 48 hours, functional recovery, pain treatment-related complications, and patient satisfaction. Results: After screening 2283 studies, 29 randomized controlled trials (RCTs) with 2059 patients were included. Methodological quality of these RCTs ranged from moderate to high. In the one direct comparison (60 patients), preperitoneal catheters led to better pain control than subcutaneous catheters. Superiority of preperitoneal compared with subcutaneous placement was confirmed indirectly in placebo-controlled RCTs. Preperitoneal wound catheters provided comparable pain control compared with active controls, such as epidural analgesia. Recovery parameters, opioid consumption, incidence of hypotension, and patient satisfaction seemed to be in favor of preperitoneal wound catheters compared with active alternatives, as well as placebo. Conclusion: Continuous wound infiltration with preperitoneal wound catheters is an effective pain modality in abdominal surgery. Pain control is as effective as epidural analgesia, but could be favored based upon recovery parameters and patient satisfaction. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text Objective: The aim of this study was to compare oncological outcomes after minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) in patients with pancreatic ductal adenocarcinoma (PDAC). Background: Cohort studies have suggested superior short-term outcomes of MIDP vs. ODP. Recent international surveys, however, revealed that surgeons have concerns about the oncological outcomes of MIDP for PDAC. Methods: This is a pan-European propensity score matched study including patients who underwent MIDP (laparoscopic or robot-assisted) or ODP for PDAC between January 1, 2007 and July 1, 2015. MIDP patients were matched to ODP patients in a 1:1 ratio. Main outcomes were radical (R0) resection, lymph node retrieval, and survival. Results: In total, 1212 patients were included from 34 centers in 11 countries. Of 356 (29%) MIDP patients, 340 could be matched. After matching, the MIDP conversion rate was 19% (n = 62). Median blood loss [200 mL (60–400) vs 300 mL (150–500), P = 0.001] and hospital stay [8 (6–12) vs 9 (7–14) days, P < 0.001] were lower after MIDP. Clavien-Dindo grade ≥3 complications (18% vs 21%, P = 0.431) and 90-day mortality (2% vs 3%, P > 0.99) were comparable for MIDP and ODP, respectively. R0 resection rate was higher (67% vs 58%, P = 0.019), whereas Gerota's fascia resection (31% vs 60%, P < 0.001) and lymph node retrieval [14 (8–22) vs 22 (14–31), P < 0.001] were lower after MIDP. Median overall survival was 28 [95% confidence interval (CI), 22–34] versus 31 (95% CI, 26–36) months (P = 0.929). Conclusions: Comparable survival was seen after MIDP and ODP for PDAC, but the opposing differences in R0 resection rate, resection of Gerota's fascia, and lymph node retrieval strengthen the need for a randomized trial to confirm the oncological safety of MIDP. [ABSTRACT FROM AUTHOR]

Objective: Assessment of long-term comprehensive outcome of multimodality treatment of bile duct injury (BDI) in terms of morbidity, mortality, quality of life (QoL), survival, and work related limitations. Background: The impact of BDI on work ability is scarcely investigated. Methods: BDI patients referred to a tertiary center after BDI were included (n = 800). QoL and work related limitations (HLQ) were compared with 175 control patients after uncomplicated laparoscopic cholecystectomy. Results: The mean survival after BDI was 17.6 years (95% confidence interval, CI, 17.2-18.0 years). BDI related mortality was 3.5% (28/800). Corrected for sex, ASA classification, treatment and type of injury, survival is worse in male patients (hazard ratio, HR 1.50, 95% CI 1.01-2.33) and progressively worse with higher ASA classification (ASA2: 5.25 (2.94-9.37), ASA3: 18.1 (9.79-33.3). Patients treated surgically had a significantly better survival (HR: 0.45 (95% CI: 0.25-0.80). BDI patients reported a significantly worse physical QoL compared with the control group and worse disease specific QoL. Loss of productivity of work was significantly higher among BDI patients. There also was a significant hindrance in unpaid work. A higher number of bile duct injury patients were receiving disability benefits after long-term follow-up (34.9% vs 19.6%, P = 0.004). Conclusions: Reconstructive surgery in BDI patients is associated with improved survival. Although the clinical outcome of multidisciplinary treatment of bile duct injury is good, it is associated with a significant decrease in QoL, loss of productivity in both paid and unpaid work and high rates of disability benefits use. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to appraise and to evaluate the current evidence on minimally invasive pancreatoduodenectomy (MIPD) versus open pancreatoduodenectomy only in comparative cohort and registry studies. Background: Outcomes after MIPD seem promising, but most data come from single-center, noncomparative series. Methods: Comparative cohort and registry studies on MIPD versus open pancreatoduodenectomy published before August 23, 2015 were identified systematically and meta-analyses were performed. Primary endpoints were mortality and International Study Group on Pancreatic Fistula grade B/C postoperative pancreatic fistula (POPF). Results: After screening 2293 studies, 19 comparative cohort studies (1833 patients) with moderate methodological quality and 2 original registry studies (19,996 patients) were included. For cohort studies, the median annual hospital MIPD volume was 14. Selection bias was present for cancer diagnosis. No differences were found in mortality [odds ratio (OR) = 1.1, 95% confidence interval (CI) = 0.6-1.9] or POPF [(OR) = 1.0, 95% CI = 0.8 to 1.3]. Publication bias was present for POPF. MIPD was associated with prolonged operative times [weighted mean difference (WMD) = 74 minutes, 95% CI = 29-118], but lower intraoperative blood loss (WMD = -385mL, 95% CI = -616 to -154), less delayed gastric emptying (OR = 0.6, 95% = CI 0.5-0.8), and shorter hospital stay (WMD = -3 days, 95% CI = -5 to -2). For registry studies, the median annual hospital MIPD volume was 2.5. Mortality after MIPD was increased in low-volume hospitals (7.5% vs 3.4%; P = 0.003). Conclusions: Outcomes after MIPD seem promising in comparative cohort studies, despite the presence of bias, whereas registry studies report higher mortality in low-volume centers. The introduction of MIPD should be closely monitored and probably done only within structured training programs in high-volume centers. [ABSTRACT FROM AUTHOR]