Eaton, John E.

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.

Background and Aims: This systematic review and meta-analysis aims to compare the performance of UroVysion® FISH based on the different definitions of a positive result used in published literature with the goal of determining the optimal FISH definition for detecting pancreaticobiliary malignancy. Methods: A systematic literature search identified studies from database inception to Sept 2024 that evaluated the diagnostic performance of FISH in determining malignancy among patients with biliary strictures. All thresholds for positive FISH, as defined by the individual study, were included in this review. Subgroup analysis was performed based on the definitions of positive FISH as follows: (1) polysomy only; (2) polysomy, tetrasomy, or trisomy; and (3) polysomy or 9p deletion. Results: Eighteen studies comprising 2516 FISH specimens were analyzed, including 1133 (45.0%) with malignancy. Using a threshold for positivity as defined in individual studies, the overall sensitivity of FISH was 57.6% (95% confidence interval [CI], 49.4–65.4%), and the overall specificity was 87.8% (95% CI, 79.2–93.2%). Subgroup analysis showed that polysomy as the threshold for positive FISH yielded a sensitivity of 49.4% (95% CI, 43.2–55.5%), with an increased specificity of 96.2% (95% CI, 92.7–98.1%), while polysomy + tetrasomy/trisomy as positive FISH resulted in an increased sensitivity of 64.3% (95% CI 55.4–72.2%) but a decreased specificity of 78.9% (95% CI 64.4–88.5%). The addition of 9p deletion to polysomy as the criteria for a positive test resulted in a non-significant increase in sensitivity (54.7% (95% CI 42.4–66.5%) while maintaining specificity (95.1% (95% CI 84.0–98.6%). Conclusions: Based on these findings, polysomy only or polysomy/9p deletion should be considered as the criterion for defining a positive FISH test to improve diagnostic sensitivity while maintaining high specificity.