Practice patterns in diagnostics, staging, and management strategies of gallbladder cancer among Nordic tertiary centers.

BACKGROUND AND OBJECTIVE: Gallbladder cancer (GBC) is a rare malignancy in the Nordic countries and no common Nordic treatment guidelines exist. This study aimed to characterize the current diagnostic and treatment strategies in the Nordic countries and disclose differences in these strategies. METHODS: This was a survey study with a cross-sectional questionnaire of all 19 university hospitals providing curative-intent surgery for GBC in Sweden, Norway, Denmark, and Finland. RESULTS: In all Nordic countries except Sweden, neoadjuvant/downstaging chemotherapy was used in GBC patients. In T1b and T2, majority of the centers (15-18/19) performed extended cholecystectomy. In T3, majority of the centers (13/19) performed cholecystectomy with resection of segments 4b and 5. In T4, majority of the centers (12-14/19) chose palliative/oncological care. The centers in Sweden extended lymphadenectomy beyond the hepatoduodenal ligament, whereas all other Nordic centers usually limited lymphadenectomy to the hepatoduodenal ligament. All Nordic centers except those in Norway used adjuvant chemotherapy routinely for GBC. There were no major differences between the Nordic centers in diagnostics and follow-up. CONCLUSIONS: The surgical and oncological treatment strategies of GBC vary considerably between the Nordic centers and countries.

A comparison of the simultaneous, liver-first, and colorectal-first strategies for surgical treatment of synchronous colorectal liver metastases at two major liver-surgery institutions in Sweden.

BACKGROUND: The optimal treatment strategy for patients with synchronous colorectal liver metastases (CRLM) is unclear. The aim of this study was to compare the outcome of the simultaneous, liver-first, and colorectal-first surgical approaches. METHODS: All consecutive patients who had been resected with curative intent for CRLM were included. A Cox regression model was constructed, and an intention-to-treat analysis was performed between the liver-first and the simultaneous approaches, after propensity score matching. RESULTS: 658 patients were included in the analysis. 92 patients had a simultaneous resection, 163 patients had liver-first, and 403 patients had a colorectal-first approach. Overall survival was 54.9 months (95% CI 39.2-70.4) in the liver-first group, 54.5 months (95% CI 46.8-62.3) in colorectal-first group, and 59.6 months (95% CI 42.2-77.0) in the simultaneous group (log-rank p =0.850). In the matched cohort there were no differences in Clavien-Dindo 3a (p = 0.992) or 3b and greater (p = 0.999). Median overall survival was for liver-first group 42.2 months (95% CI 26.3-58.2), and for the simultaneous group 56.2 months (95% CI 47.1-65.4) (stratified log-rank p = 0.455). CONCLUSION: A simultaneous approach was not associated with worse overall survival or morbidity compared to a liver-first approach.

Multimodal perioperative assessment of liver function and volume in patients undergoing hepatectomy for colorectal liver metastasis: a comparison of the indocyanine green retention test, 99mTc mebrofenin hepatobiliary scintigraphy and gadoxetic acid enhanced MRI.

OBJECTIVES: To compare the dynamic changes in future liver remnant (FLR) function and volume after hepatectomy and to evaluate the associations between three modalities in assessment of liver function. METHODS: Liver function and volume were quantified pre-operatively, at post-operative day (POD) 7 and POD 28 in 10 patients with colorectal liver metastases undergoing hemihepatectomy using the indocyanine green retention (ICG) test, hepatobiliary scintigraphy (HBS) and gadoxetic acid-enhanced MRI. The 99mTc mebrofenin uptake rate in the FLR was applied as a reference of liver function. MRI-derived parameters including liver-to-muscle ratio (LMR), liver-to-spleen ratio (LSR) and hepatocellular uptake index (HUI) were used for liver function assessment. Spearman's correlation analysis was used to evaluate the associations. RESULTS: Increase in liver function ranged from 13 to 152% (median 92%) and in volume from 37 to 134% (median 79%). There was no significant discrepancy in increase between FLR function and volume during the first month following hepatectomy. LMR showed a significant correlation to ICG test (r = -0.66, p < 0.05) while LSR had an association with standardized FLR function obtained by HBS (r = -0.71, p < 0.05). During the first week after hepatectomy, pre-operative HUI and LMR showed the strongest correlation to the FLR growth in function and volume respectively (p < 0.05). CONCLUSION: The observed growth in FLR volume is closely related to the functional increase within 1 month after hepatectomy. Gadoxetic acid-enhanced MRI might substitute HBS for regional liver function assessment and provide an imaging tool for liver growth prediction. ADVANCES IN KNOWLEDGE: Liver function growth was parallel with liver volume increase during the perioperative period. Liver function assessment with gadoxetic acid-enhanced MRI was comparable with that of HBS indicating that gadoxetic acid-enhanced MRI could substitute HBS for regional liver function evaluation.

Molecular adsorbent recirculating system treatment in patients with post-hepatectomy liver failure: Long-term results of a pilot study.

BACKGROUND: Post-hepatectomy liver failure (PHLF) is the leading cause of postoperative mortality following major liver resection. Between December 2012 and May 2015, 10 consecutive patients with PHLF (according to the Balzan criteria) following major/extended hepatectomy were included in a prospective treatment study with the molecular adsorbent recirculating system (MARS). Sixty- and 90-day mortality rates were 0% and 10%, respectively. Of the nine survivors, four still had liver dysfunction at 90 days postoperatively. One-year overall survival (OS) of the MARS-PHLF cohort was 50%. The present study aims to assess long-term outcome of this cohort compared to a historical control cohort. METHODS: To compare long-term outcome of the MARS-PHLF treatment cohort with PHLF patients not treated with MARS, the present study includes all 655 patients who underwent major hepatectomy at Karolinska University Hospital between 2010 and 2018. Patients with PHLF were identified according to the Balzan criteria. RESULTS: The cohort was split into three time periods: pre-MARS period (n = 192), MARS study period (n = 207), and post-MARS period (n = 256). The 90-day mortality of patients with PHLF was 55% (6/11) in the pre-MARS period, 14% during the MARS study period (2/14), and 50% (3/6) in the post-MARS period (p = 0.084). Median OS (95% confidence interval (CI)) was 37.8 months (29.3-51.7) in the pre-MARS cohort, 57 months (40.7-75.6) in the MARS cohort, and 38.8 months (31.4-51.2) in the post-MARS cohort. The 5-year OS of 10 patients included in the MARS study was 40% and the median survival 11.6 months (95% CI: 3 to not releasable). In contrast, for the remaining 21 patients fulfilling the Balzan criteria during the study period but not treated with MARS, the 5-year OS and median survival were 9.5% and 7.3 months (95% CI, 0.5-25.9), respectively (p = 0.138)). CONCLUSIONS: MARS treatment may contribute to improved outcome of patients with PHLF. Further studies are needed.The initial pilot study was registered at ClinicalTrials.gov (NCT03011424).

Outcome of ERCP related to case-volume.

BACKGROUND AND AIMS: In some studies, high endoscopic retrograde cholangiopancreatography (ERCP) case-volume has been shown to correlate to high success rate in terms of successful cannulation and fewer adverse events. The aim of this study was to analyze the association between ERCP success and complications, and endoscopist and centre case-volumes. METHODS: Data were obtained from the Swedish National Register for Gallstone Surgery and ERCP (GallRiks) on all ERCPs performed for Common Bile Duct Stone (CBDS) (n = 17,873) and suspected or confirmed malignancy (n = 6152) between 2009 and 2018. Successful cannulation rate, procedure time, intra- and postoperative complication rates and post-ERCP pancreatitis (PEP) rate, were compared with endoscopist and centre ERCP case-volumes during the year preceding the procedure as predictor. RESULTS: In multivariable analyses of the CBDS group adjusting for age, gender and year, a high endoscopist case-volume was associated with higher successful cannulation rate, lower complication and PEP rates, and shorter procedure time (p < 0.05). Centres with a high annual case-volume were associated with high successful cannulation rate and shorter procedure time (p < 0.05), but not lower complication and PEP rates. When indication for ERCP was malignancy, a high endoscopist case-volume was associated with high successful cannulation rate and low PEP rates (p < 0.05), but not shorter procedure time or low complication rate. Centres with high case-volume were associated with high successful cannulation rate and low complication and PEP rates (p < 0.05), but not shorter procedure time. CONCLUSIONS: The results suggest that higher endoscopist and centre case-volumes are associated with safer ERCP and successful outcome.

Composite Score: prognostic tool to predict survival in patients undergoing surgery for colorectal liver metastases.

BACKGROUND: Several existing scoring systems predict survival of patients with colorectal liver metastases. Many lack validation, rely on old clinical data, and have been found to be less accurate since the introduction of chemotherapy. This study aimed to construct and validate a clinically relevant preoperative prognostic model for patients with colorectal liver metastases. METHODS: A predictive model with data available before surgery was developed. Survival was analysed by Cox regression analysis, and the quality of the model was assessed using discrimination and calibration. The model was validated using multifold cross-validation. RESULTS: The model included 1212 consecutive patients who underwent liver resection for colorectal liver metastases between 2005 and 2015. Prognostic factors for survival included advanced age, raised C-reactive protein level, hypoalbuminaemia, extended liver resection, larger number of metastases, and midgut origin of the primary tumour. A Composite Score was developed based on the prognostic variables. Patients were classified into those at low, medium, and high risk. Survival differences between the groups were significant; median overall survival was 87.4 months in the low-risk group, 50.1 months in the medium-risk group, and 22.6 months in the high-risk group. The discriminative performance, assessed by the concordance index, was 0.71, 0.67, and 0.67 respectively at 1, 3, and 5 years. Calibration, assessed graphically, was close to perfect. A multifold cross-validation of the model confirmed its internal validity (C-index 0.63 versus 0.62). CONCLUSION: The Composite Score categorizes patients into risk strata, and may help identify patients who have a poor prognosis, for whom surgery is questionable.

Aspirin as secondary prevention in colorectal cancer liver metastasis (ASAC trial): study protocol for a multicentre randomized placebo-controlled trial.

BACKGROUND: Colorectal cancer is one the most common cancers in the western world with increasing incidence. Approximately 50% of the patients develop liver metastases. Resection of liver metastases is the treatment of choice although almost half of the resected patients get recurrence in the liver. METHODS: The ASAC trial is a Scandinavian, multicentre, double-blinded, randomized, placebo-controlled study to determine whether adjuvant treatment with low-dose aspirin (acetylsalicylic acid (ASA)) can improve disease-free survival in patients treated for colorectal cancer liver metastases (CRCLM). Up to 800 patients operated for CRCLM will be randomized to Arm#1 ASA 160 mg once daily or Arm#2 Placebo, for a period of 3 years or until disease recurrence. The patients will be recruited at all major hepatobiliary surgical units in Norway, Sweden and Denmark and have follow-up according to standard of care and the National Guidelines. DISCUSSION: The ASAC trial will be the first clinical interventional trial to assess the potential beneficial role of ASA in recurrence of CRCLM and survival. ASA is an inexpensive, well-tolerated and easily accessible drug that will be highly potential as adjuvant drug in secondary prevention of CRCLM if the study shows a beneficial effect. We will also determine the effect of ASA as adjuvant treatment on Health-Related Quality of Life and the cost-effectiveness. TRIAL REGISTRATION: ClinicalTrials.gov NCT03326791 . Registered on 31 October 2017.

The effect of glucose control in liver surgery on glucose kinetics and insulin resistance.

BACKGROUND & AIMS: Clinical outcome is negatively correlated to postoperative insulin resistance and hyperglycemia. The magnitude of insulin resistance can be modulated by glucose control, preoperative nutrition, adequate pain management and minimal invasive surgery. Effects of glucose control on perioperative glucose kinetics in liver surgery is less studied. METHODS: 18 patients scheduled for open hepatectomy were studied per protocol in this prospective, randomized study. In the treatment group (n = 9), insulin was administered intravenously to keep arterial blood glucose between 6 and 8 mmol/l during surgery. The control group (n = 9) received insulin if blood glucose >11.5 mmol/l. Insulin sensitivity was measured by an insulin clamp on the day before surgery and immediately postoperatively. Glucose kinetics were assessed during the clamp and surgery. RESULTS: Mean intraoperative glucose was 7.0 mM (SD 0.7) vs 9.1 mM (SD 1.9) in the insulin and control group respectively (p < 0.001; ANOVA). Insulin sensitivity decreased in both groups but significantly (p = 0.03, ANOVA) more in the control group (M value: 4.6 (4.4-6.8) to 2.1 (1.2-2.6) and 4.6 (4.1-5.0) to 0.6 (0.1-1.8) mg/kg/min in the treatment and control group respectively). Endogenous glucose production (EGP) increased and glucose disposal (WGD) decreased significantly between the pre- and post-operative clamps in both groups, with no significant difference between the groups. Intraoperative kinetics demonstrated that glucose control decreased EGP (p = 0.02) while WGD remained unchanged (p = 0.67). CONCLUSION: Glucose control reduces postoperative insulin resistance in liver surgery. EGP increases and WGD is diminished immediately postoperatively. Insulin seems to modulate both reactions, but mostly the WGD is affected. Intraoperative EGP decreased while WGD remained unaltered. REGISTRATION NUMBER OF CLINICAL TRIAL: ANZCTR 12614000278639.

Portal vein embolization with n-butyl-cyanoacrylate before hepatectomy: a single-center retrospective analysis of 46 consecutive patients.

BACKGROUND: Preoperative portal vein embolization (PVE) is performed to induce hypertrophy of the future liver remnant enabling major liver resection in patients with various types of liver tumors. PURPOSE: To evaluate safety and effectiveness of PVE with n-butyl-cyanoacrylate (NBCA). MATERIAL AND METHODS: All consecutive patients referred to our hospital for PVE between July 2006 and July 2017 were retrospectively reviewed. Volumetry was performed on computed tomography images before and after PVE, segmenting the total liver volume and the future liver remnant (FLR), i.e. liver segments I-III. RESULTS: PVE was performed in 46 patients (18 women, 28 men; mean age = 61 years) using local anesthesia. The ipsilateral technique was used in 45 patients. Adverse events were rare. The mean FLR volume increase was 56%, the degree of hypertrophy was 9.7%, and the kinetic growth rate was 2.1%/week. The median ± SD period between PVE and liver surgery was 7 ± 3 weeks. Forty-two patients (91%) had surgery; liver resection was performed in 37 (80%) patients. Three patients (7%) developed transient liver failure after surgery. There was no 90-day post-PVE or postoperative mortality. CONCLUSION: PVE using NBCA through the ipsilateral approach in local anesthesia is safe and effective in inducing hypertrophy of the future liver remnant enabling surgery, and thereby increasing survival in patients with liver tumors.

ALPPS Improves Survival Compared With TSH in Patients Affected of CRLM: Survival Analysis From the Randomized Controlled Trial LIGRO.

OBJECTIVE: To evaluate the oncological outcome for patients with colorectal liver metastases (CRLM) randomized to associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) or 2-stage hepatectomy (TSH). BACKGROUND: TSH with portal vein occlusion is an established method for patients with CRLM and a low volume of the future liver remnant (FLR). ALPPS is a less established method. The oncological outcome of these methods has not been previously compared in a randomized controlled trial. METHODS: One hundred patients with CRLM and standardized FLR (sFLR) <30% were included and randomized to resection by ALPPS or TSH, with the option of rescue ALPPS in the TSH group, if the criteria for volume increase was not met. The first radiological follow-up was performed approximately 4 weeks postoperatively and then after 4, 8, 12, 18, and 24 months. At all the follow-ups, the remaining/recurrent tumor was noted. After the first follow-up, chemotherapy was administered, if indicated. RESULTS: The resection rate, according to the intention-to-treat principle, was 92% (44 patients) for patients randomized to ALPPS compared with 80% (39 patients) for patients randomized to TSH (P = 0.091), including rescue ALPPS. At the first postoperative follow-up, 37 patients randomized to ALPPS were assessed as tumor free in the liver, and also 28 patients randomized to TSH (P = 0.028). The estimated median survival for patients randomized to ALPPS was 46 months compared with 26 months for patients randomized to TSH (P = 0.028). CONCLUSIONS: ALPPS seems to improve survival in patients with CRLM and sFLR <30% compared with TSH.

The prognostic value of C-reactive protein and albumin in patients undergoing resection of colorectal liver metastases. A retrospective cohort study.

BACKGROUND: The systemic inflammation-based Glasgow Prognostic Score (GPS) and modified GPS (mGPS), as measured by preoperative C-reactive protein (CRP) and albumin, correlate with poor survival in several cancers. This study evaluates the prognostic value of these scores in patients with colorectal liver metastases (CRLM). METHODS: This retrospective study assessed the prognostic role of preoperatively measured GPS and mGPS in patients undergoing liver resection because of CRLM. Clinicopathological data were retrieved from local databases. The prognostic value of GPS and mGPS were compared and a Cox regression model was used to find independent predictors of overall survival. RESULTS: In total, 849 consecutive patients between January 2005 and December 2015 were included. Patients with GPS 0 had a median survival of 70 months compared to 49 months in patients with GPS 1, and 27 months in patients with GPS 2. Multivariable analyses showed that GPS 1 (HR = 1.51, 95%CI [1.14-2.01]) and GPS 2 (HR = 2.78, 95%CI [1.79-4.31]), after correction for age >70 years (HR = 1.75 [1.36-2.26]), and extended resection (HR = 2.53, 95%CI[1.79-3.58]), were associated with poor overall survival. CONCLUSION: A preoperative GPS is an independent prognostic factor in patients with CRLM, and appears to be a better prognostic tool than mGPS.

Cardiovascular complications after common bile duct stone extractions.

BACKGROUND: Common bile duct stone (CBDS) is a common condition the rate of which increases with age. Decision to treat in particular elderly and frail patients with CBDS is often complex and requires careful assessment of the risk for treatment-related cardiovascular complications. The aim of this study was to compare the rate of postoperative cardiovascular events in CBDS patients treated with the following: ERCP only; cholecystectomy only; cholecystectomy followed by delayed ERCP; cholecystectomy together with ERCP; or ERCP followed by delayed cholecystectomy. METHODS: The study was based on data from procedures for gallstone disease registered in the Swedish National Quality Register for Cholecystectomy and Endoscopic Retrograde Cholangiopancreatography (GallRiks) 2006-2014. ERCP and cholecystectomy procedures performed for confirmed or suspected CBDS were included. Postoperative events were registered by cross-matching GallRiks with the National Patient Register (NPR). A postoperative cardiovascular event was defined as an ICD-code in the discharge notes indicating myocardial infarct, pulmonary embolism or cerebrovascular disease within 30 days after surgery. In cases where a patient had undergone ERCP and cholecystectomy on separate occasions, the 30-day interval was timed from the first intervention. RESULTS: A total of 23,591 underwent ERCP or cholecystectomy for CBDS during the study period. A postoperative cardiovascular event was registered in 164 patients and death within 30 days in 225 patients. In univariable analysis, adverse cardiovascular event and death within 30 days were more frequent in patients who underwent primary ERCP (p < 0.05). In multivariable analysis, adjusting for history of cardiovascular disease or events, neither risk for cardiovascular complication nor death within 30 days remained statistically significant in the ERCP group. CONCLUSIONS: Primary ERCP as well as cholecystectomy may be performed for CBDS with acceptable safety. More studies are required to provide reliable guidelines for the management of CBDS.

Survival and prognostic factors after transplantation, resection and ablation in a national cohort of early hepatocellular carcinoma.

BACKGROUND: In patients with early hepatocellular cancer (HCC) and preserved liver function, the choice between transplantation, resection and ablation and which factors to consider is not obvious and guidelines differ. In this national cohort study, we aimed to compare posttreatment survival in patients fulfilling predefined criteria, and to analyse preoperative risk factors that could influence decision. METHODS: We used data from HCC-patients registered with primary transplantation, resection or ablation 2008-2016 in the SweLiv-registry. In Child A-subgroups, 18-75 years, we compared survival after transplantation or resection, with different tumour criteria; either corresponding to our transplantation criteria (N = 257) or stricter with single tumours ≤50 mm (N = 159). A subgroup with single tumours ≤30 mm, compared all three treatments (N = 193). RESULTS: We included 1022 HCC-patients; transplantation n = 223, resection n = 438, ablation n = 361. In the transplant criteria subgroup, differences in five-year survival, adjusted for age and gender, were not significant, with 71.2% (CI 62.3-81.3) after transplantation (n = 109) and 63.5% (CI 54.9-73.5) after resection (n = 148). Good liver function (Child 5 vs. 6, Albumin ≥36), increased the risk after transplantation, but decreased the risk after resection and ablation. CONCLUSION: Even within Child A, detailed liver function assessment is important before treatment decision, and for stratifying survival comparisons.

Outcomes of Simultaneous Resections and Classical Strategy for Synchronous Colorectal Liver Metastases in Sweden: A Nationwide Study with Special Reference to Major Liver Resections.

BACKGROUND: About 20% of patients with colorectal cancer have liver metastases at the time of diagnosis, and surgical resection offers a chance for cure. The aim of the present study was to compare outcomes for patients that underwent simultaneous resection to those that underwent a staged procedure with the bowel-first (classical) strategy by using information from two national registries in Sweden. METHODS: In this prospectively registered cohort study, we analyzed clinical, pathological, and survival outcomes for patients operated in the period 2008-2015 and compared the two strategies. RESULTS: In total, 537 patients constituted the study cohort, where 160 were treated with the simultaneous strategy and 377 with the classical strategy. Patients managed with the simultaneous strategy had less often rectal primary tumors (22% vs. 31%, p = 0.046) and underwent to a lesser extent a major liver resection (16% vs. 41%, p < 0.001), but had a shorter total length of stay (11 vs. 15 days, p < 0.001) and more complications (52% vs. 36%, p < 0.001). No significant 5-year overall survival (p = 0.110) difference was detected. Twenty-five patients had a major liver resection in the simultaneous strategy group and 155 in the classical strategy group without difference in 5-year overall survival (p = 0.198). CONCLUSION: Simultaneous resection of the colorectal primary cancer and liver metastases can possibly have more complications, with no difference in overall survival compared to the classical strategy.

Liver resection is beneficial for patients with colorectal liver metastases and extrahepatic disease.

BACKGROUND: Liver metastases are the most common cause of death for patients with colorectal cancer and affect up to half of the patients. Liver resection is an established method that can potentially be curative. For patients with extrahepatic disease (EHD), the role of liver surgery is less established. METHODS: This is a retrospective study based on data from the national quality registry SweLiv. Data were obtained between 2009 and 2015. SweLiv is a validated registry and has been in use since 2009, with coverage above 95%. Patients with liver metastases and EHD were analyzed and cross-checked against the national death cause registry for survival analysis. RESULTS: During the study period, 2,174 patients underwent surgery for colorectal liver metastases (CRLM), and 277 patients with EHD were treated with resection or ablation. The estimated median survival time for the entire cohort from liver resection/ablation was 40 months (95% CI, 32-47). The survival time for patients treated with liver resection was 45 months compared to 26 months for patients treated with ablation (95% CI 38-53, 18-33, P=0.001). A subgroup analysis of resected patients revealed that the group with pulmonary metastases had a significantly longer estimated median survival (50 months; 95% CI, 39-60) than the group with lymph node metastases (32 months; 95% CI, 7-58) or peritoneal carcinomatosis (28 months; 95% CI, 14-41) (P=0.022 and 0.012, respectively). Other negative prognostic factors were major liver resection and nonradical liver resection. CONCLUSIONS: For patients with liver metastases and limited EHD, liver resection results in prolonged survival compared to what can be expected from chemotherapy alone.

ERCP-related perforations: a population-based study of incidence, mortality, and risk factors.

BACKGROUND: Perforations related to endoscopic retrograde cholangiopancreatography (ERCP) are rare but feared adverse events with highly reported morbidity and mortality rates. The aim was to evaluate the incidence and outcome of ERCP-related perforations and to identify risk factors for death due to perforations in a population-based study. METHODS: Between May 2005 and December 2013, a total of 52,140 ERCPs were registered in GallRiks, a Swedish nationwide, population-based registry. A total of 376 (0.72%) were registered as perforations or extravasation of contrast during ERCP or as perforation in the 30-day follow-up. The patients with perforation were divided into fatal and non-fatal groups and analyzed for mortality risk factors. The case volume of centers and endoscopists were divided into the upper quartile (Q4) and the lower three quartile (Q1-3) groups. Furthermore, fatal group patients' records were reviewed. RESULTS: Death within 90 days after ERCP-related perforations or at the index hospitalization occurred in 20% (75 out of 376) for all perforations and 0.1% (75 out of 52,140) for all ERCPs. The independent risk factors for death after perforation were malignancy (OR 11.2, 95% CI 5.8-21.6), age over 80 years (OR 3.8, 95% CI 2.0-7.4), and sphincterotomy in the pancreatic duct (OR 2.8, 95% CI 1.1-7.5). In Q4 centers, the mortality was similar with or without pancreatic duct sphincterotomy (14% vs. 13%, p = 1.0), but in Q1-3 centers mortality was higher (45% vs. 21%, p = 0.024). CONCLUSIONS: ERCP-related perforations are severe adverse events with low incidence (0.7%) and high mortality rate up to 20%. Malignancy, age over 80 years, and sphincterotomy in the pancreatic duct increase the risk to die after a perforation. The risk of a fatal outcome in perforations after pancreatic duct sphincterotomy was reduced when occurred at a Q4-center. In the case of a complicated perforation a transfer to a Q4-center may be considered.