BACKGROUND AND AIMS:Liver resection (LR) and orthotopic liver transplantation (OLT) are therapeutic options for locally advanced perihilar cholangiocarcinoma (pCCA) requiring hepatic artery reconstruction (HAR). This study aimed to compare short- and long-term outcomes of LR and OLT. Outcomes were major vascular complications, 90-day mortality, overall survival (OS) and recurrence-free survival (RFS). METHODS:A cohort of patients undergoing LR with HAR from 10 Western centres was compared with an OLT cohort comprising patients who received or did not receive neoadjuvant chemoradiotherapy (NACR). RESULTS:109 patients, 60 LR and 49 OLT (22 OLT no-NACR and 27 OLT NACR) were included. LR patients were older and had fewer Bismuth type 4 tumours (38.3% vs. 69.4%, p = 0.009). Positive margins (49.2% vs. 6.5%, p < 0.001) and lymph nodes (54.2% vs. 32.4%, p = 0.058) were found more frequently in LR patients. No differences were found between LR and OLT in major (40% vs. 46.9%, p = 0.56) and vascular complications (23.3% vs. 28.6%, p = 0.66); NACR was an independent prognostic factor for vascular complications (OR 2.63, 95% CI 1.03-6.70, p = 0.043). 90-day mortality (15% for LR vs. 10.2% for OLT, p = 0.57) and 5-year OS (HR 0.68, 95% CI 0.40-1.17, p = 0.17) were similar. Median OS after LR versus OLT was higher but not significant (24 vs. 40 months, p = 0.13). OLT had better 5-year RFS (HR 0.52, 95% CI 0.29-0.96, p = 0.035) than LR. R1 resection (HR 2.07, 95% CI 1.03-4.18, p = 0.041) and perineural invasion (HR 3.64, 95% CI 1.09-12.16, p = 0.035) were independent prognostic factors for RFS. CONCLUSIONS:LR and OLT for locally advanced pCCA had similar rates of major complications and post-operative mortality, but NACR was associated with increased vascular complications. Survival was difficult to compare in the groups due to their heterogeneity, but OLT, especially with NACR, seems to give better results than LR.

BACKGROUND:The Mayo protocol for liver transplantation in patients with unresectable perihilar cholangiocarcinoma is based on strict selection and neoadjuvant chemoradiotherapy. The role of neoadjuvant chemoradiotherapy in this scenario remains unclear. The aim of this study was to compare outcomes after transplantation for perihilar cholangiocarcinoma using strict selection criteria, either with or without neoadjuvant chemoradiotherapy.METHODS:This was an international, multicentre, retrospective cohort study of patients who underwent transplantation between 2011 and 2020 for unresectable perihilar cholangiocarcinoma using the Mayo selection criteria and receiving neoadjuvant chemoradiotherapy or not receiving neoadjuvant chemoradiotherapy. Endpoints were post-transplant survival, post-transplant morbidity rate, and time to recurrence.RESULTS:Of 49 patients who underwent liver transplantation for perihilar cholangiocarcinoma, 27 received neoadjuvant chemoradiotherapy and 22 did not. Overall 1-, 3-, and 5-year post-transplantation survival rates were 65 per cent, 51 per cent and 41 per cent respectively in the group receiving neoadjuvant chemoradiotherapy and 91 per cent, 68 per cent and 53 per cent respectively in the group not receiving neoadjuvant chemoradiotherapy (1-year hazards ratio (HR) 4.55 (95 per cent c.i. 0.98 to 21.13), P = 0.053; 3-year HR 2.07 (95 per cent c.i. 0.78 to 5.54), P = 0.146; 5-year HR 1.71 (95 per cent c.i. 0.71 to 4.09), P = 0.229). Hepatic vascular complications were more frequent in the group receiving neoadjuvant chemoradiotherapy compared with the group not receiving neoadjuvant chemoradiotherapy (nine of 27 versus two of 22, P = 0.045). In multivariable analysis, tumour recurrence occurred less frequently in the group receiving neoadjuvant chemoradiotherapy (HR 0.30 (95 per cent c.i. 0.09 to 0.97), P = 0.044).CONCLUSION:In selected patients undergoing liver transplantation for perihilar cholangiocarcinoma, neoadjuvant chemoradiotherapy resulted in a lower risk of tumour recurrence, but was associated with a higher rate of early hepatic vascular complications. Adjustments in neoadjuvant chemoradiotherapy reducing the risk of hepatic vascular complications, such as omitting radiotherapy, may further improve the outcome in patients undergoing liver transplantation for perihilar cholangiocarcinoma.

Background and aims: The DRAINAGE trial was a randomized controlled trial comparing preoperative endoscopic (EBD) and percutaneous biliary drainage (PTBD) in patients with potentially resectable, perihilar cholangiocarcinoma (pCCA). The aim of this study was to compare the long-term outcomes.Methods: Patients were randomized in four tertiary referral centers. Follow-up data were available for all included patients. Primary outcome was overall survival (OS). Secondary outcomes were readmissions, and re-interventions not including in-trial interventions.Results: A total of 54 patients were randomized; 27 in both groups. Median follow-up for both groups was 62 months (95% CI 54-70). The median OS was 13 months (95% CI 7.9-18.1) in the EBD and 7 months (95% CI 0.0-17.2) in the PTBD group (P = 0.28). Twenty (37%, n = 8 EBD vs n = 12 PTBD, P = 0.43) of 54 patients were readmitted at least once, mostly due to drainage-related complications (n = 13, 24%). Of note, 14 out of the 54 patients died within the trial. A total of 76 drainage procedures (32 EBD and 44 PTBD) were performed in 28 patients. The median number of stent or drain placements was 2 (2-4) for the EBD group and 2 (1-3) for the PTBD group (P = 0.77).Discussion: Although this follow-up study represented a small cohort, no long-term differences in survival, readmissions, and drainage procedures for EBD and PTBD were found, even when comparing the resected and unresected group. However, this study demonstrates the complexity of biliary drainage for patients with potentially resectable pCCA, even in tertiary referral centers.

Background: Currently, the potential benefits of additional resection after positive proximal intra-operative frozen sections (IFS) in perihilar cholangiocarcinoma (pCCA) on residual disease and onco-logical outcome remain uncertain. Therefore, the aim of this study is to investigate the number of R0 resections after additional resection of a positive proximal IFS and the influence of additional resections on overall survival (OS) in patients with pCCA. Materials and methods: A retrospective, multicenter, matched case-control study was performed, including patients undergoing resection for pCCA between 2000 and 2019 at three tertiary centers. Primary outcome was the number of achieved 'additional' R0 resections. Secondary outcomes were OS, recurrence, severe morbidity and mortality. Results: Forty-four out of 328 patients undergoing resection for pCCA had a positive proximal IFS. An additional resection was performed in 35 out of 44 (79.5%) patients, which was negative in 24 (68.6%) patients. Nevertheless, seven out of these 24 patients were eventually classified as R1 resection due to other positive resection margins. Therefore, 17 (48.6%) patients could be classified as "true" R0 resection after additional resection. Ninety-day mortality after R1 resections was high (25%) and strongly influ-enced OS. After correction for 90-day mortality, median OS after negative additional resection was 33 months (95%CI:29.5-36.5) compared to 30 months (95%CI:24.4-35.6) after initial R1 (P = 0.875) and 46 months (95%CI:32.7-59.3) after initial R0 (P = 0.348). Conclusion: There were only 17 patients (out of a total of 328 patients) that potentially benefitted from routine IFS. Additional resection for a positive IFS leading to R0 resection was not associated with improved long-term survival. (c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Introduction: The Mayo Clinic protocol for patients with unresectable perihilar cholangiocarcinoma (pCCA) is based on strict selection and neo-adjuvant chemo-radiation therapy (NAT) followed by liver transplantation (LT). With this protocol, 5-year survival up to 68% has been reported. It remains unclear whether these favorable results are attributable to NAT or strict selection only. Our aim was to compare outcomes after LT for unresectable pCCA after strict selection between patients with or without NAT. Method: International, multicenter, comparison of two cohorts of patients transplanted between 2011-2021, for unresectable pCCA using the Mayo Clinic selection criteria and receiving NAT (NAT+) or not (NAT-). Primary endpoint was overall survival. Secondary outcomes included post-transplant morbidity (including vascular complications) and tumor recurrence evaluated by inverse-probability-weighting and competing risk analysis. Results: A total of 49 patients underwent LT for unresectable pCCA (NAT+ n=27, NAT- n=22). Median age was 55 years. Median follow-up was 25 months. In the NAT+ group, the 1-, 3- and 5-year survival rates were 65%, 51% and 41%, respectively, compared to 91%, 68% and 53% for NAT- patients (p=0.20; Figure). Tumor 5-year recurrence rate was similar between groups: 32% in the NAT+ group versus 53% in the NAT- group (p=0.55). Major vascular complications (Clavien-Dindo grade ≥3A) post-LT were significantly higher in the NAT+ cohort with 11 patients (41%) versus 3 patients (14%) (p=0.04). Conclusions: Survival after LT for pCCA in strictly selected patients did not differ between patients with or without NAT. Post-transplant vascular complications were significantly higher in patients after NAT.

BACKGROUND:Radiological differentiation between benign and malignant gallbladder disease is important but remains challenging. Furthermore, the clinical value of diffusion-weighted imaging (DWI) remains unclear.PURPOSE:To determine the value of DWI in discriminating benign from malignant gallbladder disease by conducting a systematic review and meta-analysis.MATERIAL AND METHODS:The literature was systematically searched. Studies analyzing diagnostic value of DWI in gallbladder disease with histopathology or follow-up as reference standard were included. Study selection and data extraction were done by two reviewers independently. Methodological quality was assessed using the QUADAS-2 tool. Sensitivity and specificity were calculated and displayed in a forest plot. A sensitivity analysis was performed in case of outliers. Pooled sensitivity and specificity of DWI were plotted on a hierarchical summary receiver operating characteristic curve. If available, the added value of DWI to conventional magnetic resonance imaging (MRI) sequences was analyzed.RESULTS:Out of 2456 articles, eight studies fulfilled the inclusion criteria; 592 patients with 221 malignant lesions were included. Pooled sensitivity and specificity rates were 0.87 and 0.84, respectively. In two studies, diagnostic accuracy rates improved after adding DWI to conventional MRI (64% and 75% for conventional MRI vs. 89% and 94% after combining conventional MRI with DWI). In another study, the area under the curve increased from 0.92 to 0.95.CONCLUSION:DWI appears to be an accurate imaging technique in discriminating benign from malignant gallbladder disease. To achieve optimal patient care, it should be part of multiparametric MRI and should be combined with other imaging modalities.

PURPOSE:To determine diagnostic performance of preoperative CT in differentiating between benign and malignant suspicious gallbladder lesions and to develop a preoperative risk score.METHOD:All patients referred between January 2007 and September 2018 for suspicion of gallbladder cancer (GBC) or incidentally found GBC were retrospectively analyzed. Patients were excluded when preoperative CT or histopathologic examination was lacking. Two radiologists, blinded to histopathology results, independently reviewed CT images to differentiate benign disease from GBC. Multivariable analysis and internal validation were used to develop a risk score for GBC. Model discrimination, calibration, and diagnostic performance were assessed.RESULTS:In total, 118 patients with 39 malignant (33 %) and 79 benign (67 %) lesions were included. Sensitivity of CT for diagnosing GBC was 90 % (95 % confidence interval [CI]: 76-97). Specificity rates were 61 % (95 % CI: 49-72) and 59 % (95 % CI: 48-70). Three predictors of GBC (irregular lesion aspect, absence of fat stranding, and locoregional lymphadenopathy) were included in the risk score ranging from -1 to 4. Adequate performance was found (AUC: 0.79, calibration slope: 0.89). In patients allocated >0 points, the model showed higher performance in excluding GBC than the radiologists (sensitivity 92 % [95 % CI: 79-98]). Moreover, when allocated >3 points, the risk score was superior in diagnosing GBC (specificity 99 % [95 % CI: 93-100]).CONCLUSIONS:Sensitivity rates of CT for differentiation between benign and malignant gallbladder lesions are high, however specificity rates are relatively low. The proposed risk score may facilitate differentiation between benign and malignant suspicious gallbladder lesions.

Introduction: Staging laparoscopy (SL) is recommended before attempting resection in patients with gallbladder cancer (GBC). The aim of this study was to assess the yield of SL in terms of reducing unnecessary surgical exploration and to delineate factors associated with disseminated disease (DD). Material and methods: Data were collected from all GBC patients undergoing SL and/or surgical exploration in eight Dutch academic hospitals from 2000-2019. Outcomes after laparotomy with or without SL were assessed and factors predictive for DD were identified. Results: A total of 210 patients was included; SL was performed in 43 (20%). SL was more frequently performed in patients with tumor invasion in the liver on pre-operative imaging (53% vs 30%, p=0.014). DD was detected by SL in 8/43 patients (19%). Of the 35 patients with SL that underwent surgical exploration, 25(72%) were resected and in 10 patients (28%) DD was diagnosed during laparotomy. Accuracy of SL for detecting DD was 44%(8/18). Of 167 patients without SL, resection was performed in 125(75%) and in 44(25%) DD was found. DD was most frequently detected at the hepatic hilum (16/44, 36%) and the peritoneum (10/44, 23%). In total, 62 (30%) patients had DD. Liver invasion on imaging was associated with high rates of DD (50/76, 66%) and predictive for DD in multivariate analysis (OR 12.5,P=0.021). Conclusion: SL in GBC is infrequently used despite a 30% chance of occult metastatic disease. In patients with liver invasion on imaging risk of DD is 66% and SL be recommended.Tabled 1Baseline characteristics of patients with and without SLCharacteristicSL (N=43)No SL (N=167)P-valueAge (mean/range)64 (45-86)66 (33-81)0.391ASA >29 (21%)41 (25%)0.690Cholecystitis0 (0%)10 (6%)0.220Primary Sclerosing Cholangitis3 (7%)6 (4%)0.394Gallbladder polyp3 (7%)8 (5%)0.700N1 disease (imaging)8 (35%)28 (36%)0.906Liver invasion (imaging)21 (53%)45 (30%)0.014Pre-operative jaundice18 (42%)54 (32%)0.160Pre-operative biliairy drainage21 (49%)56 (34%)0.063 Open table in a new tab

Due to the fast progression in molecular technologies such as next-generation sequencing, knowledge of genetic alterations in gallbladder cancer (GBC) increases. This systematic review provides an overview of frequently occurring genetic alterations occurring in GBC and their possible therapeutic implications. A literature search was performed utilizing PubMed, EMBASE, Cochrane Library, and Web of Science. Only studies reporting genetic alterations in human GBC were included. In total, data were extracted from 62 articles, describing a total of 3893 GBC samples. Frequently detected genetic alterations (>5% in >5 samples across all studies) in GBC for which targeted therapies are available in other cancer types included mutations in ATM, ERBB2, and PIK3CA, and ERBB2 amplifications. High tumor mutational burden (TMB-H) and microsatellite instability (MSI-H) were infrequently observed in GBC (1.7% and 3.5%, respectively). For solid cancers with TMB-H or MSI-H pembrolizumab is FDA-approved and shows an objective response rates of 50% for TMB-H GBC and 41% for MSI-H biliary tract cancer. Only nine clinical trials evaluated targeted therapies in GBC directed at frequently altered genes (ERBB2, ARID1A, ATM, and KRAS). This underlines the challenges to perform such clinical trials in this rare, heterogeneous cancer type and emphasizes the need for multicenter clinical trials.

Background Extended resections (i.e., major hepatectomy and/or pancreatoduodenectomy) are rarely performed for gallbladder cancer (GBC) because outcomes remain inconclusive. Data regarding extended resections from Western centers are sparse. This Dutch, multicenter cohort study analyzed the outcomes of patients who underwent extended resections for locally advanced GBC. Methods Patients with GBC who underwent extended resection with curative intent between January 2000 and September 2018 were identified from the Netherlands Cancer Registry. Extended resection was defined as a major hepatectomy (resection of ≥ 3 liver segments), a pancreatoduodenectomy, or both. Treatment and survival data were obtained. Postoperative morbidity, mortality, survival, and characteristics of short- and long-term survivors were assessed. Results The study included 33 patients. For 16 of the patients, R0 resection margins were achieved. Major postoperative complications (Clavien Dindo ≥ 3A) occurred for 19 patients, and 4 patients experienced postoperative mortality within 90 days. Recurrence occurred for 24 patients. The median overall survival (OS) was 12.8 months (95% confidence interval, 6.5–19.0 months). A 2-year survival period was achieved for 10 patients (30%) and a 5-year survival period for 5 patients (15%). Common bile duct, liver, perineural and perivascular invasion and jaundice were associated with reduced survival. All three recurrence-free patients had R0 resection margins and no liver invasion. Conclusion The median OS after extended resections for advanced GBC was 12.8 months in this cohort. Although postoperative morbidity and mortality were significant, long-term survival (≥ 2 years) was achieved in a subset of patients. Therefore, GBC requiring major surgery does not preclude long-term survival, and a subgroup of patients benefit from surgery.

Background: It is controversial whether patients with gallbladder cancer (GBC) presenting with jaundice benefit from resection. This study re-evaluates the impact of jaundice on resectability and survival. Methods: Data was collected on surgically explored GBC patients in all Dutch academic hospitals from 2000 to 2018. Survival and prognostic factors were assessed. Results: In total 202 patients underwent exploration and 148 were resected; 124 non-jaundiced patients (104 resected) and 75 jaundiced patients (44 resected). Jaundiced patients had significantly (P 0.05) more pT3/T4 tumors, extended ( 3 segments) liverand organ resections, major postoperative complications and margin-positive resection. 90-day mortality was higher in jaundiced patients (14% vs. 0%, P < 0.001). Median overall survival (OS) was 7.7 months in jaundiced patients (2-year survival 17%) vs. 26.1 months in non-jaundiced patients (2-year survival 39%, P < 0.001). In multivariate analysis, jaundice (HR1.89) was a poor prognostic factor for OS in surgically explored but not in resected patients. Six jaundiced patients did not develop a recurrence; none had liveror common bile duct (CBD) invasion on imaging. Conclusion: Jaundice is associated with poor survival. However, jaundice is not an independent adverse prognostic factor in resected patients. Surgery should be considered in patients with limited disease and no CBD invasion on imaging.

Background: Gallbladder cancer (GBC) is an aggressive tumor with a poor prognosis. Early detection is essential for best treatment results. To evaluate gallbladder lesions, CT and MRI have been increasingly used. However, differentiating benign from malignant lesions remains challenging and their diagnostic value remains to be clarified. The aim of this study was to determine the diagnostic performance of CT and MRI in the characterization of suspicious gallbladder lesions in a large single center population.

Background: The peritoneal cancer index (PCI) calculated during exploratory laparotomy is a strong prognostic factor for overall survival (OS) in patients with colorectal peritoneal metastases (PM) who undergo cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). Progression of the PCI between diagnostic laparoscopy (DLS) and potential CRS + HIPEC (Delta PCI) might be a more dynamic prognostic factor for OS after CRS + HIPEC. Materials and methods: Between 2012 and 2018, all colorectal PM patients who underwent an exploratory laparotomy for potential CRS + HIPEC after DLS were retrospectively identified from a prospectively maintained database. Patients were divided into stable disease (Delta PCI 0-3), mild progression (Delta PCI 4-9), or severe progression (Delta PCI >= 10). Kaplan-Meier analysis and a multivariate Cox regression were performed. Results: Eighty-four patients (Delta PCI 0-3, n = 35; Delta PCI 4-9, n = 34; and Delta PCI >= 10, n = 15) were analysed. Median OS after CRS + HIPEC was significantly decreased in patients with a Delta PCI of 4-9 (35.1 [95% CI 25.5-44.6]) or Delta PCI >= 10 (24.1 [95% CI 11.7-36.5]) compared to patients with a Delta PCI of 0-3 (47.9 [95% CI 40.0-55.7], p = 0.004). In multivariate regression analysis, Delta PCI remained an independent risk factor for OS: Delta PCI 4-9 HR 3.1 (95% CI 1.4-7.2, p = 0.007) and Delta PCI >= 10 HR 4.4 (95% CI 1.5-13.1, p = 0.007). Conclusion: A high Delta PCI is an independent dynamic prognostic factor for OS and might reflect a more aggressive tumour biology in patients with colorectal PM. HIPEC surgeons should be aware of a high-Delta PCI-associated diminished prognosis and should reconsider CRS + HIPEC when confronted with a Delta PCI >= 10. (C) 2019 Elsevier Ltd, BASO - The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has significantly improved overall survival of patients with peritonitis carcinomatosa (PC) of colorectal origin. Whether development of synchronous PC (sPC) or metachronous PC (mPC) - early or late onset - has a different impact on survival is often subject of debate in multidisciplinary meetings. Therefore, we aimed to identify the impact of synchronous versus early or late metachronous PC on overall survival (OS) and disease-free survival (DFS).

Careful selection of patients with colorectal peritoneal metastases (PM) for cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is crucial. It remains unknown whether the time of onset of colorectal PM (synchronous vs metachronous) influences surgical morbidity and survival outcomes after CRS with HIPEC.