Citations

Introduction: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease without approved medical therapies. We examined the efficacy and safety of oral vancomycin (OV) in those with PSC. Methods: In this phase 3, 18-month, double-blind, placebo-controlled trial, we randomly assigned adults with PSC and a serum alkaline phosphatase (SAP) greater than 1.5 times the upper limit of normal to placebo or oral vancomycin (OV) with dosages ranging from 125-375 mg four times daily pending biochemical response. The primary endpoint was normalization of SAP. Results: Of the 82 patients who underwent randomization, 73 individuals had at least one outcome assessment. Individuals who withdrew early were less likely to rate their baseline health as excellent or very good (23.4% vs 54.5%, p<0.01) despite having similar PSC prognostic features to those who completed the study. SAP normalization rates were similar (5% placebo, 6.7% OV, p=1.00) after 18 months. Those who received OV had greater reduction in SAP (+1.2% placebo, -21.9% OV, p=0.03). There were no differences in the changes in either the Mayo PSC risk score (-0.1 placebo, -0.1 OV, p=0.88) or liver stiffness values (+0.1 kPa placebo, -4.0 kPa OV, p=0.15). Discoloration of the teeth and tongue was the most common side effect of OV (17.5%). Conclusions: OV was not associated with clinically significant reductions in markers of PSC disease severity. Impairments in quality of life may influence patient retention in clinical trials.

Background: Patients with primary sclerosing cholangitis (PSC) are at risk for developing gallbladder neoplasia (GBN) and biliary neoplasia, including cholangiocarcinoma (CCA), because of chronic inflammation and an underlying field effect. However, the risk of CCA after GBN detection in those with PSC remains poorly understood. We aimed to determine if the incidence of CCA is higher in those with GBN. Methods: We conducted a retrospective review of adult patients with large-duct PSC seen at Mayo Clinic between January 1, 1995, and December 31, 2019. Incidence rates for CCA development were calculated. Cox regression analyses were performed to determine features associated with CCA development beginning at the time of PSC diagnosis. Results: Our study included 1,829 patients with PSC. CCA and GBN developed in 334 (18.26%) and 71 individuals (3.88%), respectively. Among those with GBN, 14 (19.72%) developed CCA. The annual incidence of CCA was nearly twofold higher in patients with GBN (4.34% versus 2.21%). GBN was associated with CCA in an unadjusted analysis (hazard ratio 2.14 [95% CI 1.16–3.94]). When adjusting for other predictors of CCA, an association between GBN and CCA may remain. Conclusions: While few patients with PSC develop GBN, this subgroup is more likely to develop CCA. Consequently, once GBN is detected, clinicians should consider more intensive screening for CCA.

ABSTRACT Background Obeticholic acid (OCA) was conditionally approved in 2016 as a second‐line therapy for patients with primary biliary cholangitis (PBC) and incomplete response to ursodeoxycholic acid (UDCA) monotherapy. We aimed to evaluate the impact of OCA add‐on therapy on biochemical outcomes and safety in those patients. Methods We systematically searched MEDLINE, Embase, and Cochrane CENTRAL for papers published up to October 29, 2024, evaluating OCA in patients with PBC at the 12‐month timepoint. Pooled analyses of liver enzymes were performed using the standard mean difference (SMD) and 95% confidence interval (CI) from the OCA baseline. Side effects and the achievement of criteria for adequate response are presented in percentages (95% CI). Results We included 1285 patients from 10 studies, two of which were RCTs. The addition of OCA significantly reduced alkaline phosphatase (ALP) (SMD −0.86; −1.15 to −0.56; p < 0.001) and total bilirubin (SMD −0.29; −0.43 to −0.15; p < 0.001). Overall, 37.23% of the patients (95% CI 31.47–43.39) responded to OCA (POISE criteria). The response rate was greater in the POISE trial results compared with real‐world data (46.15% vs. 30.54%, respectively; p = 0.0089). Pruritus was the most common adverse event (40.23%; 24.65–58.07). Approximately one‐fifth of the patients stopped OCA (18.05%; 12.72–24.99), with pruritus being the main reason for discontinuation (47.70%; 34.15–61.60). Conclusion Adding OCA improves ALP, bilirubin, and biochemical remission rates in patients with PBC who did not respond well to UDCA monotherapy. Real‐world data show an attenuated response. Pruritus is the most common side effect and the leading cause of drug discontinuation.

Background: Fluorescence in situ hybridization (FISH) is recommended as part of multimodality sampling in the evaluation of biliary strictures, but can be false negative in 40%–50% cases. The aim of this study was to comprehensively assess predictors of false-negative FISH in patients with biliary strictures. Methods: Patients undergoing tissue sampling for biliary strictures from October 20 to February 22 were prospectively enrolled (NCT04572711). Procedural factors such as sampling techniques, order, and utilization of combination sampling were recorded. Results of an optimized pancreatobiliary FISH panel with locus-specific probes for 1q21, 7p12, 8q24, and 9p21 were reported per guidelines. Statistical analyses were performed using BlueSky Statistics v.10.3.1, R package v8.81. Results: Of 327 patients, 93 (28.5%) were diagnosed with malignancy. A false-negative pancreatobiliary fluorescence in situ hybridization (PB-FISH) was reported in 40 (43.1%) patients. A history of primary sclerosing cholangitis was associated with lower odds of having a false-negative PB-FISH (aOR=0.38, 95% CI=0.16–0.82, p=0.02), whereas a hilar stricture was associated with a significantly higher false-negative PB-FISH in those with cholangiocarcinoma (aOR=3.2 [1.4–7.9], p=0.009). Dilation of biliary strictures prior to brushing was not associated with a lower rate of false-negative PB-FISH. Conclusions: In this prospective study, hilar strictures were more likely to have false-negative PB-FISH. Dilation of strictures did not affect PB-FISH performance. These results can help guide PB-FISH interpretation.

Background and Aims: The optimal treatment strategy for de novo perihilar cholangiocarcinoma (pCCA) remains debated. This study compares outcomes between liver transplantation following neoadjuvant chemoradiation (RT+LT) and liver resection (LR), with (LR+VR) and without vascular resection (LR w/o VR). Approach and Results: This single-center, retrospective study included patients with de novo perihilar cholangiocarcinoma treated at the Mayo Clinic Rochester (1993–2023) with curative-intent surgery. Patients underwent either (1) LR, classified as LR+VR or LR w/o VR, or (2) RT+LT following the transplant protocol. Overall survival (OS) and recurrence-free survival were analyzed using as-treated and intention-to-treat approaches, incorporating competing risk analysis and direct matching. In the as-treated analysis, RT+LT showed superior median OS compared with LR w/o VR (78.0 vs. 58.2 mo, p =0.03) and LR+VR (25.8 mo, p <0.001). Considering dropout rates (RT+LT: 41%, LR: 28%), intention-to-treat analysis showed no significant OS difference between LR and RT + LT (31.7 vs. 38.5 mo, p =0.19). In matched as-treated analysis, RT + LT had no significant survival benefit over LR w/o VR (50.6 vs. 140.6 mo, p =0.08) or LR+VR (25.8 mo, p =0.11). Perioperative mortality was 4% (RT+LT), 7% (LR w/o VR), and 8% (LR + VR). Conclusions: Both LR and RT+LT achieve excellent oncological outcomes in selected patients with de novo perihilar cholangiocarcinoma. Key challenges remain dropouts during neoadjuvant therapy in patients planned for LT and high perioperative mortality for patients undergoing LR. OS doubles in patients undergoing LR+VR compared with dropouts, supporting LR+VR as a viable option for patients who are ineligible for LT. Appropriate patient selection is crucial, as those not undergoing surgery suffer from a dismal prognosis.

Objective: To develop and validate a risk score for predicting post-transplant recurrence in perihilar cholangiocarcinoma (pCCA) patients. Background: pCCA is an aggressive malignancy with a poor prognosis. Although neoadjuvant chemoradiation (CRT) followed by liver transplantation (LT) offers a potential cure for patients with unresectable, early-stage de novo or primary sclerosing cholangitis (PSC)-associated pCCA, post-transplant recurrence negatively impacts survival. Currently, no risk stratification tools exist. Methods: This retrospective study included consecutive patients with unresectable de novo or PSC-associated pCCA who underwent neoadjuvant CRT followed by LT at Mayo Clinic (1993–2024). Predictors of post-transplant recurrence were identified using multivariable Cox regression with LASSO variable selection. The Perihilar Cholangiocarcinoma Risk Estimation of Tumor Recurrence after Transplant (PRETREAT) risk score was created by assigning points from model coefficients. Score performance was evaluated by discrimination (c-statistic), internally validated with 10-fold cross-validation, and externally validated in a separate cohort. Survival outcomes were compared across 3 PRETREAT risk groups and between 2 time periods. Results: This study included 399 patients (development: 301; validation: 98). The 5-year cumulative incidence of post-transplant recurrence was 29.7% in the development cohort and 27.6% in the validation cohort. Multivariable analysis identified 4 independent predictors: macroscopic residual tumor on explant [hazard ratio (HR): 12.4], vascular encasement (HR: 2.18), lymphovascular invasion (HR: 2.04), and radial tumor diameter (HR: 1.02/mm). The PRETREAT score (0–22), based on these factors, demonstrated excellent performance in both internal and external validation (C-index 0.83 and 0.85, respectively). Patients were stratified into low-risk (0–7), moderate-risk (8–15), and high-risk (16–22) groups. The 5-year recurrence-free survival rates significantly differed across low-risk, moderate-risk, and high-risk groups (89.0%, 38.3%, and 15.4%, respectively; P<0.001). Over the last decade, overall survival improved significantly only in moderate-risk patients (70.4% vs 46.9%, P=0.024), without significant improvement in recurrence-free survival. Conclusions: The PRETREAT score provides a valuable tool for guiding post-transplant management of pCCA, enabling risk-stratified surveillance, and laying the foundation for future clinical trials.

Background and Aims: Among those with primary sclerosing cholangitis (PSC), perihilar cholangiocarcinoma (pCCA) is often diagnosed at a late stage and is a leading source of mortality. Detection of pCCA in PSC when curative action can be taken is challenging. Our aim was to create a deep learning model that analyzed MRI to detect early-stage pCCA and compare its diagnostic performance with expert radiologists. Approach and Results: We conducted a multicenter, international, retrospective cohort study involving adults with large duct PSC who underwent contrast-enhanced MRI. Senior abdominal radiologists reviewed the images. All patients with pCCA had early-stage cancer and were registered for liver transplantation. We trained a 3D DenseNet-121 model, a form of deep learning, using MRI images and assessed its performance in a separate test cohort. The study included 398 patients (training cohort n=150; test cohort n=248). pCCA was present in 230 individuals (training cohort n=64; test cohort n=166). In the test cohort, the respective performances of the model compared to the radiologists were: sensitivity 87.9% versus 50.0%, p <0.001; specificity 84.1% versus 100.0%, p <0.001; area under receiving operating curve 86.0% versus 75.0%, p <0.001. Even when a mass was absent, the model had a higher sensitivity for pCCA than radiologists (91.6% vs. 50.6%, p <0.001) and maintained good specificity (84.1%). Conclusions: The 3D DenseNet-121 MRI model effectively detects early-stage pCCA in PSC patients. Compared to expert radiologists, the model missed fewer cases of cancer.