Importance of resection margin after resection of colorectal liver metastases in the era of modern chemotherapy: population-based cohort study.

BACKGROUND: Resection margin has been associated with overall survival following liver resection for colorectal liver metastasis. The aim of this study was to examine how resection margins of 0.0 mm, 0.1-0.9 mm and ≥1 mm influence overall survival in patients resected for colorectal liver metastasis in a time of modern perioperative chemotherapy and surgery. METHODS: Using data from the national registries Swedish Colorectal Cancer Registry and Swedish National Quality Registry for Liver, Bile Duct and Gallbladder Cancer, patients that had liver resections for colorectal liver metastasis between 2009 and 2013 were included. In patients with a narrow or unknown surgical margin the original pathological reports were re-reviewed. Factors influencing overall survival were analysed using a Cox proportional hazard model. RESULTS: A total of 754 patients had a known margin status, of which 133 (17.6%) patients had a resection margin <1 mm. The overall survival in patients with a margin of 0 mm or 0.1-0.9 mm was 42 (95% c.i. 31 to 53) and 48 (95% c.i. 35 to 62) months respectively, compared with 75 (95% c.i. 65 to 85) for patients with ≥1 mm margin, P < 0.001. Margins of 0 mm or 0.1-0.9 mm were associated with poor overall survival in the multivariable analysis, HR 1.413 (95% c.i. 1.030 to 1.939), P = 0.032, and 1.399 (95% c.i. 1.025 to 1.910), P = 0.034, respectively. CONCLUSIONS: Despite modern chemotherapy the resection margin is still an important factor for the survival of patients resected for colorectal liver metastasis, and a margin of ≥1 mm is needed to achieve the best possible outcome.

Minimally invasive robot-assisted and laparoscopic distal pancreatectomy in a pan-European registry a retrospective cohort study.

BACKGROUND: International guidelines recommend monitoring of the use and outcome of minimally invasive pancreatic surgery (MIPS). However, data from prospective international audits on minimally invasive distal pancreatectomy (MIDP) are lacking. This study examined the use and outcome of robot-assisted (RDP) and laparoscopic (LDP) distal pancreatectomy in the E-MIPS registry. MATERIALS AND METHODS: Post-hoc analysis in a prospective audit on MIPS, including consecutive patients undergoing MIDP in 83 centers from 19 European countries (01-01-2019/31-12-2021). Primary outcomes included intraoperative events (grade 1: excessive blood loss, grade 2: conversion/change in operation, grade 3: intraoperative death), major morbidity, and in-hospital/30-day mortality. Multivariable logistic regression analyses identified high-risk groups for intraoperative events. RDP and LDP were compared in the total cohort and in high-risk groups. RESULTS: Overall, 1672 patients undergoing MIDP were included; 606 (36.2%) RDP and 1066 (63.8%) LDP. The annual use of RDP increased from 30.5% to 42.6% (P<0.001). RDP was associated with fewer grade 2 intraoperative events compared to LDP (9.6% vs. 16.8%, P<0.001), with longer operating time (238 vs. 201 minutes,P<0.001). No significant differences were observed between RDP and LDP regarding major morbidity (23.4% vs. 25.9%, P=0.264) and in-hospital/30-day mortality (0.3% vs. 0.8%, P=0.344). Three high-risk groups were identified; BMI>25 kg/m2, previous abdominal surgery, and vascular involvement. In each group, RDP was associated with fewer conversions and longer operative times. CONCLUSION: This European registry-based study demonstrated favorable outcomes for MIDP, with mortality rates below 1%. LDP remains the predominant approach, whereas the use of RDP is increasing. RDP was associated with less conversions and longer operative time, including in high-risk subgroups. Future randomized trials should confirm these findings and assess cost differences.

Are enhanced recovery protocols after pancreatoduodenectomy still efficient when applied in elderly patients? A systematic review and individual patient data meta-analysis.

BACKGROUND: This meta-analysis investigated the effects of enhanced recovery after surgery (ERAS) protocols compared to conventional care on postoperative outcomes in patients aged 70 years or older undergoing pancreatoduodenectomy (PD). METHODS: Five databases were systematically searched. Comparative studies with available individual patient data (IPD) were included. The main outcomes were postoperative morbidity, length of stay, readmission and postoperative functional recovery elements. To assess an age-dependent effect, the group was divided in septuagenarians (70-79 years) and older patients (≥80 years). RESULTS: IPD were obtained from 15 of 31 eligible studies comprising 1109 patients. The overall complication and major complication rates were comparable in both groups (OR 0.92 [95% CI: 0.65-1.29], p = .596 and OR 1.22 [95% CI: 0.61-2.46], p = .508). Length of hospital stay tended to be shorter in the ERAS group compared to the conventional care group (-0.14 days [95% CI: -0.29 to 0.01], p = .071) while readmission rates were comparable and the total length of stay including days in hospital after readmission tended to be shorter in the ERAS group (-0.28 days [95% CI: -0.62 to 0.05], p = .069). In the subgroups, the length of stay was shorter in octogenarians treated with ERAS (-0.36 days [95% CI: -0.71 to -0.004], p = .048). The readmission rate increased slightly but not significantly while the total length of stay was not longer in the ERAS group. CONCLUSION: ERAS in the elderly is safe and its benefits are preserved in the care of even in patients older than 80 years. Standardized care protocol should be encouraged in all pancreatic centers.

Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): a multicentre, randomised, phase 2 trial.

BACKGROUND: In patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma. METHODS: NORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing. FINDINGS: Between Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49-71) in the neoadjuvant FOLFIRINOX group versus 73% (62-84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2-34·9) versus 38·5 months (27·6-not reached; hazard ratio [HR] 1·52 [95% CI 1·00-2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46-67) in the neoadjuvant FOLFIRINOX group versus 70% (55-83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2-34·9) versus 34·4 months (19·4-not reached; HR 1·46 [95% CI 0·99-2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event. INTERPRETATION: This phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven. FUNDING: Norwegian Cancer Society, South Eastern Norwegian Health Authority, The Sjöberg Foundation, and Helsinki University Hospital Research Grants.

Impact of Neoadjuvant Therapy for Pancreatic Cancer: Transatlantic Trend and Postoperative Outcomes Analysis.

BACKGROUND: The introduction of modern chemotherapy a decade ago has led to increased use of neoadjuvant therapy (NAT) in patients with pancreatic ductal adenocarcinoma (PDAC). A recent North American study demonstrated increased use of NAT and improved operative outcomes in patients with PDAC. The aims of this study were to compare the use of NAT and short-term outcomes in patients with PDAC undergoing pancreatoduodenectomy (PD) among registries from the US and Canada, Germany, the Netherlands, and Sweden. STUDY DESIGN: Databases from 2 multicenter (voluntary) and 2 nationwide (mandatory) registries were queried from 2018 to 2020. Patients undergoing PD for PDAC were compared based on the use of upfront surgery vs NAT. Adoption of NAT was measured in each country over time. Thirty-day outcomes, including the composite measure (ideal outcomes), were compared by multivariable analyses. Sensitivity analyses of patients undergoing vascular resection were performed. RESULTS: Overall, 11,402 patients underwent PD for PDAC with 33.7% of patients receiving NAT. The use of NAT increased steadily from 28.3% in 2018 to 38.5% in 2020 (p < 0.0001). However, use of NAT varied widely by country: the US (46.8%), the Netherlands (44.9%), Sweden (11.0%), and Germany (7.8%). On multivariable analysis, NAT was significantly (p < 0.01) associated with reduced rates of serious morbidity, clinically relevant pancreatic fistulae, reoperations, and increased ideal outcomes. These associations remained on sensitivity analysis of patients undergoing vascular resection. CONCLUSIONS: NAT before PD for pancreatic cancer varied widely among 4 Western audits yet increased by 26% during 3 years. NAT was associated with improved short-term outcomes.

Tailoring the Use of Central Pancreatectomy Through Prediction Models for Major Morbidity and Postoperative Diabetes: International Retrospective Multicenter Study.

OBJECTIVE: To develop a prediction model for major morbidity and endocrine dysfunction after CP which could help in tailoring the use of this procedure. SUMMARY BACKGROUND DATA: Central pancreatectomy (CP) is a parenchyma-sparing alternative to distal pancreatectomy for symptomatic benign and pre-malignant tumors in body and neck of the pancreas CP lowers the risk of new-onset diabetes and exocrine pancreatic insufficiency compared to distal pancreatectomy but it is thought to increase the risk of short-term complications including postoperative pancreatic fistula (POPF). METHODS: International multicenter retrospective cohort study including patients from 51 centers in 19 countries (2010-2021). Primary endpoint was major morbidity. Secondary endpoints included POPF grade B/C, endocrine dysfunction, and the use of pancreatic enzymes. Two risk model were designed for major morbidity and endocrine dysfunction utilizing multivariable logistic regression and internal and external validation. RESULTS: 838 patients after CP were included (301 (36%) minimally invasive) and major morbidity occurred in 248 (30%) patients, POPF B/C in 365 (44%), and 30-day mortality in 4 (1%). Endocrine dysfunction in 91 patients (11%) and use of pancreatic enzymes in 108 (12%). The risk model for major morbidity included male sex, age, BMI, and ASA score≥3. The model performed acceptable with an area under curve (AUC) of 0.72(CI:0.68-0.76). The risk model for endocrine dysfunction included higher BMI and male sex and performed well (AUC:0.83 (CI:0.77-0.89)). CONCLUSIONS: The proposed risk models help in tailoring the use of CP in patients with symptomatic benign and premalignant lesions in the body and neck of the pancreas and are readily available via www.pancreascalculator.com.

Antibiotic prophylaxis and post-procedure infectious complications in endoscopic retrograde cholangiopancreatography with peroral cholangioscopy.

Background and study aims Single-operator peroral cholangioscopy (SOC) has gained increasing attention in modern biliary and pancreatic therapy and diagnosis. This procedure has shown higher rates of infectious complications than conventional endoscopic retrograde cholangiopancreatography (ERCP); therefore, many guidelines recommend antibiotic prophylaxis (AP). However, whether AP administration decreases infectious or overall adverse events (AEs) has been little studied. We aimed to study whether AP affects post-procedure infectious or overall AEs in ERCP with SOC. Patients and methods We collected data from the Swedish Registry for Gallstone Surgery and ERCP (GallRiks). Of the 124,921 extracted ERCP procedures performed between 2008 and 2021, 1,605 included SOC and represented the study population. Exclusion criteria were incomplete 30-day follow-up, ongoing antibiotic use, and procedures with unspecified indication. Type and dose of antibiotics were not reported. Post-procedure infectious complications and AEs at 30-day follow-up were the main outcomes. Results AP was administered to 1,307 patients (81.4%). In this group, 3.4% of the patients had infectious complications compared with 3.7% in the non-AP group. The overall AE rates in the AP and non-AP groups were 14.6% and 15.2%, respectively. The incidence of cholangitis was 3.1% in the AP group and 3.4% in the non-AP group. Using multivariable analysis, both infectious complications (odds ratio [OR] 0.92, 95% confidence interval [CI] 0.54-1.57) and AEs (OR 0.87, 95% CI 0.65-1.16) remained unaffected by AP administration. Conclusions No reduction in infectious complication rates and AEs was seen with AP administration for SOC. The continued need for AP in SOC remains uncertain.

Hyperglycemia and insulin infusion in pancreatoduodenectomy: a prospective cohort study on feasibility and impact on complications.

BACKGROUND: Hyperglycemia is a risk factor for postoperative complications but its impact on outcome after pancreatoduodenectomy (PD) is scarcely studied. This prospective cohort study aimed to assess the effect of continuous insulin infusion on postoperative complications and blood glucose, as well as to evaluate the impact of hyperglycemia on complications, after PD. MATERIALS AND METHODS: One hundred patients planned for PD at Skåne University Hospital, Sweden were prospectively included for perioperative continuous insulin infusion and a historic cohort of 100 patients was included retrospectively. Median blood glucose levels were calculated and data on complications were analyzed and compared between the historic cohort and the intervention group as well as between normo- and hyperglycemic patients. RESULTS: Median glucose levels were significantly lower in the intervention group compared to the historic cohort up to 30 days postoperatively (median glucose 8.5 mmol/l (interquartile range 6.4-11) vs. 9.1 mmol/l (interquartile range 6.8-17) ( P =0.007)). No significant differences in complication rates were recorded between these two groups. The incidence of complications classified as Clavien ≥3 was higher in hyperglycemic patients (100 vs. 27%, P =0.024). Among hyperglycemic patients the prevalence of preoperative diabetes was higher compared to normoglycemic patients (52 vs.12%, P <0.001). In patients with a known diagnosis of diabetes, a trend, although not statistically significant, towards a lower incidence of postoperative pancreatic fistula grade B and C, as well as postpancreatectomy hemorrhage grade B and C, was seen compared to those without preoperative diabetes (6.8 vs. 14%, P =0.231 and 2.3 vs. 7.0%, P =0.238, respectively). CONCLUSION: Insulin infusion in the early postoperative phase after PD is feasible in a non-ICU setting and significantly decreased blood glucose levels. The influence on complications was limited. Preoperative diabetes was a significant predictor of postoperative hyperglycemia and was associated with a lower incidence of clinically significant postoperative pancreatic fistula.

Intermittent scanning continuous glucose monitoring is safe and useful in postsurgical glucose monitoring after pancreatoduodenectomy.

AIMS: Intermittently scanned continuous glucose monitoring (isCGM) systems have not been thoroughly evaluated during in-hospital stay, and there are concerns about accuracy during various conditions. Patients undergoing pancreatoduodenectomy have an increased risk of hyperglycaemia after surgery which is aggravated by parenteral nutrition therapy. This study aims to evaluate glycaemic control and safety during insulin infusion in a surgical non-ICU ward, using a hybrid glucose monitoring approach with isCMG and periodic point-of-care (POC) testing. METHODS: We prospectively included 100 patients with a resectable pancreatic tumour. After surgery, continuous insulin infusion was initiated when POC glucose was > 7 mmol/l and titrated to maintain glucose between 7 and 10 mmol/l. Glucose was monitored with isCGM together with intermittent POC, every 3-6 h. Median absolute relative difference (MARD) and hypoglycaemic events were evaluated. Mean glucose was compared with a historic control (n = 100) treated with multiple subcutaneously insulin injections, monitored with POC only. RESULTS: The intervention group (isCGM/POC) had significantly lower POC glucose compared with the historic control group (8.8 ± 2.2 vs. 10.4 ± 3.4 mmol/l, p < 0.001). MARD was 17.8% (IQR 10.2-26.7). isCGM readings were higher than POC measurements in 91% of the paired cases, and isCGM did not miss any hypoglycaemic event. About 4.5% of all isCGM readings were < 3.9 mmol/l, but only six events were confirmed with POC, and none was < 3.0 mmol/l. CONCLUSIONS: A hybrid approach with isCGM/POC is a safe and effective treatment option in a non-ICU setting after pancreatoduodenectomy.

Ideal Outcome After Pancreatoduodenectomy: A Transatlantic Evaluation of a Harmonized Composite Outcome Measure.

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 whom 11,194 (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 ALD of 2% length of stay, 4% for in-hospital mortality, 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.

Antibiotic prophylaxis and its effect on postprocedural adverse events in endoscopic retrograde cholangiopancreatography for primary sclerosing cholangitis.

Background and Aim: Primary sclerosing cholangitis (PSC) is characterized by multiple strictures of the biliary tree. Patients with PSC frequently require repeated endoscopic retrograde cholangiopancreatography (ERCP) procedures. These procedures are encumbered by an increased incidence of infectious adverse events such as cholangitis. Evidence regarding whether antibiotic prophylaxis (AP) should be administered is sparse; however, prophylaxis is recommended. We aimed to determine whether AP affects the rate of postprocedural infectious and overall adverse events. Methods: We conducted a retrospective cohort study and extracted all ERCP procedures with indicated PSC performed between 1 January 2006 and 31 December 2019, which were registered in the Swedish Registry for Gallstone Surgery and ERCP (GallRiks). The exclusion criteria were incomplete 30-day follow-up, non-index procedures, or ongoing antibiotics. The main outcomes were postprocedural infectious adverse events and overall adverse events at the 30-day follow-up. Results: A total of 2144 procedures with indication of PSC were eligible for inclusion. AP was administered in 1407 (66%) of these procedures. Patients receiving AP were slightly younger (44 vs 46 years, P = 0.005) and had more comorbidities (ASA ≥3, 19.8% vs 13.6%; P  < 0.001). Procedures with AP demonstrated an infectious adverse event rate of 3.3% compared to 4.5% for non-AP procedures (P = 0.19). Postprocedural infectious adverse events (odds ratio [OR] 0.76, 95% confidence interval [CI] 0.48-1.21) and overall adverse events (OR 0.79, 95% CI 0.60-1.04) did not differ between AP and non-AP. Conclusion: Patients with PSC who undergo ERCP have the same frequency of adverse events regardless of whether AP was used.

Bile leakage and the number of metal clips on the cystic duct during laparoscopic cholecystectomy.

BACKGROUND AND OBJECTIVE: The most common way of closing the cystic duct in laparoscopic cholecystectomy is by using metal clips (>80%). Nevertheless, bile leakage occurs in 0.4%-2.0% of cases, and thus causes significant morbidity. However, the optimal number of clips needed to avoid bile leakage has not been determined. The primary aim of this study was to evaluate bile leakage and post-procedural adverse events after laparoscopic cholecystectomy concerning whether two or three clips were used to seal the cystic duct. METHODS: Using a retrospective observational design, we gathered data from the Swedish Registry for Gallstone Surgery and Endoscopic Retrograde Cholangiopancreatography (ERCP) (GallRiks). From 2006 until 2019, 124,818 patients were eligible for inclusion. These were nested to cohorts of 75,322 (60.3%) for uncomplicated gallstone disease and 49,496 (39.7%) with complicated gallstone disease. The cohorts were grouped by the number (i.e. two or three) of metal clips applied to the proximal cystic duct. The main outcome was 30-day bile leakage and post-procedural adverse events. RESULTS: No significant differences surfaced in the rate of bile leakage (0.8% vs 0.8%; P = .87) or post-procedural adverse events (three clips, 5.7% vs two clips, 5.4%; P = .16) for uncomplicated gallstone disease. However, for complicated disease, bile leakage (1.4% vs 1.0%; P < .001) and post-procedural adverse events (10.2% vs 8.6%; P < .001) significantly increased when the cystic duct was sealed with three clips compared with two. CONCLUSIONS: Because no differences in the rates of bile leakage or adverse events emerged in uncomplicated gallstone disease when a third clip was applied, a third clip for additional safety is not recommended in such cases. On the contrary, bile leakage and adverse events increased when a third clip was used in patients with complicated gallstone disease. This finding probably indicates a more difficult cholecystectomy rather than being caused by the third clip itself.

Perioperative interventions to reduce pancreatic fistula following pancreatoduodenectomy: meta-analysis.

BACKGROUND: Data on interventions to reduce postoperative pancreatic fistula (POPF) following pancreatoduodenectomy (PD) are conflicting. The aim of this study was to assimilate data from RCTs. METHODS: MEDLINE and Embase databases were searched systematically for RCTs evaluating interventions to reduce all grades of POPF or clinically relevant (CR) POPF after PD. Meta-analysis was undertaken for interventions investigated in multiple studies. A post hoc analysis of negative RCTs assessed whether these had appropriate statistical power. RESULTS: Among 22 interventions (7512 patients, 55 studies), 12 were assessed by multiple studies, and subjected to meta-analysis. Of these, external pancreatic duct drainage was the only intervention associated with reduced rates of both CR-POPF (odds ratio (OR) 0.40, 95 per cent c.i. 0.20 to 0.80) and all-POPF (OR 0.42, 0.25 to 0.70). Ulinastatin was associated with reduced rates of CR-POPF (OR 0.24, 0.06 to 0.93). Invagination (versus duct-to-mucosa) pancreatojejunostomy was associated with reduced rates of all-POPF (OR 0.60, 0.40 to 0.90). Most negative RCTs were found to be underpowered, with post hoc power calculations indicating that interventions would need to reduce the POPF rate to 1 per cent or less in order to achieve 80 per cent power in 16 of 34 (all-POPF) and 19 of 25 (CR-POPF) studies respectively. CONCLUSION: This meta-analysis supports a role for several interventions to reduce POPF after PD. RCTs in this field were often relatively small and underpowered, especially those evaluating CR-POPF.

Risk factors and outcomes for patients with pancreatic cancer undergoing surgical exploration without resection due to metastatic disease: A national cohort study.

BACKGROUND: Unresectable disease is sometimes diagnosed during surgery in patients with pancreatic ductal adenocarcinoma (PDAC). This study aimed to identify preoperative risk factors for metastatic disease diagnosed at surgical exploration and to investigate and compare survival in resected and non-resected patients. METHODS: Patients were identified from the Swedish National Pancreatic and Periampullary Cancer Registry 2010-2018. Predictors of metastatic disease were evaluated with a multivariable logistic regression model, and survival was evaluated with Kaplan-Meier estimates and log-rank tests. RESULTS: In total, 1938 patients with PDAC were scheduled for surgery. An unresectable situation was diagnosed intraoperatively in 399 patients (20.6%), including 234 (12.1%) with metastasized disease. Independent risk factors for metastasis were involuntary weight loss (OR = 1.72; 95% CI: 1.27-2.33) and elevated carbohydrate antigen 19-9 (CA19-9) (35-599 U/mL, OR = 1.79, 95% CI: 1.11-2.89; ≥ 600 U/mL, OR = 3.24, 95% CI: 2.04-5.17). Overall survival was lower among patients with metastasized disease than that among patients with a resectable tumor (P < 0.001). CONCLUSIONS: Involuntary weight loss and an elevation of CA19-9 are preoperative risk factors for diagnosing metastasized disease during surgical exploration.

Can trainees safely perform pancreatoenteric anastomosis? A systematic review, meta-analysis, and risk-adjusted analysis of postoperative pancreatic fistula.

BACKGROUND: The complexity of pancreaticoduodenectomy and fear of morbidity, particularly postoperative pancreatic fistula, can be a barrier to surgical trainees gaining operative experience. This meta-analysis sought to compare the postoperative pancreatic fistula rate after pancreatoenteric anastomosis by trainees or established surgeons. METHODS: A systematic review of the literature was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, with differences in postoperative pancreatic fistula rates after pancreatoenteric anastomosis between trainee-led versus consultant/attending surgeons pooled using meta-analysis. Variation in rates of postoperative pancreatic fistula was further explored using risk-adjusted outcomes using published risk scores and cumulative sum control chart analysis in a retrospective cohort. RESULTS: Across 14 cohorts included in the meta-analysis, trainees tended toward a lower but nonsignificant rate of all postoperative pancreatic fistula (odds ratio: 0.77, P = .45) and clinically relevant postoperative pancreatic fistula (odds ratio: 0.69, P = .37). However, there was evidence of case selection, with trainees being less likely to operate on patients with a pancreatic duct width <3 mm (odds ratio: 0.45, P = .05). Similarly, analysis of a retrospective cohort (N = 756 cases) found patients operated by trainees to have significantly lower predicted all postoperative pancreatic fistula (median: 20 vs 26%, P < .001) and clinically relevant postoperative pancreatic fistula (7 vs 9%, P = .020) rates than consultant/attending surgeons, based on preoperative risk scores. After adjusting for this on multivariable analysis, the risks of all postoperative pancreatic fistula (odds ratio: 1.18, P = .604) and clinically relevant postoperative pancreatic fistula (odds ratio: 0.85, P = .693) remained similar after pancreatoenteric anastomosis by trainees or consultant/attending surgeons. CONCLUSION: Pancreatoenteric anastomosis, when performed by trainees, is associated with acceptable outcomes. There is evidence of case selection among patients undergoing surgery by trainees; hence, risk adjustment provides a critical tool for the objective evaluation of performance.

Impact of enhanced recovery protocols after pancreatoduodenectomy: meta-analysis.

BACKGROUND: This individual-patient data meta-analysis investigated the effects of enhanced recovery after surgery (ERAS) protocols compared with conventional care on postoperative outcomes in patients undergoing pancreatoduodenectomy. METHODS: The Cochrane Library, MEDLINE, Embase, Scopus, and Web of Science were searched systematically for articles reporting outcomes of ERAS after pancreatoduodenectomy published up to August 2020. Comparative studies were included. Main outcomes were postoperative functional recovery elements, postoperative morbidity, duration of hospital stay, and readmission. RESULTS: Individual-patient data were obtained from 17 of 31 eligible studies comprising 3108 patients. Time to liquid (mean difference (MD) -3.23 (95 per cent c.i. -4.62 to -1.85) days; P < 0.001) and solid (-3.84 (-5.09 to -2.60) days; P < 0.001) intake, time to passage of first stool (MD -1.38 (-1.82 to -0.94) days; P < 0.001) and time to removal of the nasogastric tube (3.03 (-4.87 to -1.18) days; P = 0.001) were reduced with ERAS. ERAS was associated with lower overall morbidity (risk difference (RD) -0.04, 95 per cent c.i. -0.08 to -0.01; P = 0.015), less delayed gastric emptying (RD -0.11, -0.22 to -0.01; P = 0.039) and a shorter duration of hospital stay (MD -2.33 (-2.98 to -1.69) days; P < 0.001) without a higher readmission rate. CONCLUSION: ERAS improved postoperative outcome after pancreatoduodenectomy. Implementation should be encouraged.

Enhanced recovery protocols consist of interdisciplinary interventions aimed at standardizing care and reducing the impact of surgical stress. They often include a short period of preoperative fasting during the night before surgery, early removal of lines and surgical drains, early food intake and mobilization out of bed on the day of surgery. This study gives a summary of reports assessing such care protocols in patients undergoing pancreatic head surgery, and assesses the impact of these protocols on functional recovery in an analysis of individual-patient data. The study revealed the true benefits of enhanced recovery protocols, including shorter time to food intake, earlier bowel activity, fewer complications after surgery, and a shorter hospital stay compared with conventional care.

External validation of postoperative pancreatic fistula prediction scores in pancreatoduodenectomy: a systematic review and meta-analysis.

BACKGROUND: Multiple risk scores claim to predict the probability of postoperative pancreatic fistula (POPF) after pancreatoduodenectomy. It is unclear which scores have undergone external validation and are the most accurate. The aim of this study was to identify risk scores for POPF, and assess the clinical validity of these scores. METHODS: Areas under receiving operator characteristic curve (AUROCs) were extracted from studies that performed external validation of POPF risk scores. These were pooled for each risk score, using intercept-only random-effects meta-regression models. RESULTS: Systematic review identified 34 risk scores, of which six had been subjected to external validation, and so included in the meta-analysis, (Tokyo (N=2 validation studies), Birmingham (N=5), FRS (N=19), a-FRS (N=12), m-FRS (N=3) and ua-FRS (N=3) scores). Overall predictive accuracies were similar for all six scores, with pooled AUROCs of 0.61, 0.70, 0.71, 0.70, 0.70 and 0.72, respectively. Considerably heterogeneity was observed, with I2 statistics ranging from 52.1-88.6%. CONCLUSION: Most risk scores lack external validation; where this was performed, risk scores were found to have limited predictive accuracy. . Consensus is needed for which score to use in clinical practice. Due to the limited predictive accuracy, future studies to derive a more accurate risk score are warranted.

Failure to Rescue After Pancreatoduodenectomy: A Transatlantic Analysis.

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.