Heimbach, Julie K.

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.

Objective: To establish comprehensive recommendations on the management of perihilar cholangiocarcinoma (pCCA) and to identify areas in need of future investigation. Summary Background Data: The lack of consensus in management of pCCA across institutions worldwide impairs optimal patient care and best-achievable oncological outcome. A holistic and critical assessment of the body of evidence and collaborative guidance are required. Methods: The Consensus4pCCA conference developed unbiased consensus using the Zurich-Danish model. An impartial and multidisciplinary jury adopted comprehensive recommendations grounded on the work of eight expert panels answering predefined clinical questions and considering the best-quality evidence through a systematic review. The development of recommendations complied with GRADE and SIGN50 methodologies. Results: Seventy-one international experts considered 570 studies. Ten jury members concluded 71 recommendations covering definition and diagnosis, preoperative assessment and optimization, surgical resection, liver transplantation, and outcome reporting for pCCA patients. The consensus underscored that making patients amenable to high-quality curative resection and reducing its associated morbidity must be of highest priority. As such, multidisciplinary expertise and centralized care at all stages of disease management are critical to ensure both safety and oncological adequacy. To overcome the evidence-gap for rare diseases like pCCA, the jury urged large-scale registries to address open questions across the disease continuum and highlighted priorities for future investigation. Conclusion: The Consensus4pCCA represents an unprecedented commitment to collectively harmonize global treatment strategies for pCCA. This collective effort bridges the gap between expert opinions and clinical evidence and holds great promise to improve patient outcomes in the future.

The prevalence of comorbid metabolic dysfunction–associated steatotic liver disease (MASLD) and obesity has increased exponentially over the last several years, with current estimates demonstrating that up to 40% of adults in the United States have MASLD. Metabolic dysfunction–associated steatohepatitis is now a leading indication for liver transplantation, and rates of obesity and MASLD pre-transplant and post-transplant are on the rise. Our understanding of the physiology of obesity and metabolic disease and the availability of effective obesity treatments have evolved over the same time frame. With the availability of new anti-obesity medications, there has been a debate over the role of pharmacotherapy versus interventional approaches in the treatment of obesity and MASLD in the liver transplantation population. In October 2024, the American Society of Transplantation (AST) Liver and Intestinal Community of Practice held a virtual Controversies Conference on obesity and liver transplantation. Experts in the field presented the available data, and smaller working groups had interactive breakout sessions that identified knowledge gaps and developed recommendations. This perspective prepared on behalf of the participants of the AST Controversies Conference on obesity and liver transplant aims to summarize the available evidence for surgical and pharmaceutical treatment in the liver transplantation population.

The epidemic of obesity in the United States has led to a significant increase in the prevalence of obesity in the liver transplant population, with metabolic dysfunction–associated steatotic liver disease becoming one of the most common indications for liver transplantation. Despite this rise in obesity, the optimal management strategies in the pretransplant, peritransplant, and posttransplant phases of care have not yet been determined. In the current review, we will present and discuss the available evidence for the surgical management of obesity, including the optimal timing, as well as a review of the novel medical therapies and how these strategies may best be utilized to provide ideal long-term outcomes for liver transplant patients with obesity.

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.

Portopulmonary hypertension (POPH), pulmonary arterial hypertension that develops in the setting of portal hypertension, has long been of significant interest to the pulmonary, cardiology, and hepatology communities. Optimal management of POPH has been challenging to define due to a lack of evidence from clinical trials regarding pulmonary arterial hypertension therapies and uncertainty regarding the role of liver transplantation (LT). Initially, the high risk of intraoperative and early post-transplant death in predominantly untreated patients with POPH tempered consideration of LT. More recently, the observation that POPH can improve, and sometimes even resolve, following LT, has led to reconsideration of the role of LT in selected patients. The first International Liver Transplantation Society (ILTS) POPH and hepatopulmonary syndrome practice guideline was a multidisciplinary consensus of expert opinions based on available evidence. Since that publication, hemodynamic definitions, management approaches, and POPH MELD exception criteria have evolved, and there have been new randomized controlled trials in POPH as well as studies regarding long-term outcomes. In order to ensure the guidelines remained current and reflected recent evidence, the original writing committee of the 2016 guidelines, leaders of the ILTS Cardiovascular Special Interest Group, and colleagues active in POPH research were invited to participate in the writing committee. In this document, approved for publication by the ILTS executive council, we provide an update to the prior guidelines with expert recommendations to guide and advance POPH management. Recommendations in these guidelines are based on expert opinion and available evidence and were agreed upon by consensus.

BACKGROUND: Although most transplant centers preferentially offer minimally invasive approaches to donor nephrectomies, there remains less standardization specific to the kidney extraction site. This study aimed to evaluate incisional hernia occurrence in living kidney donors based on kidney extraction site location. STUDY DESIGN: This was a retrospective study of all donors who underwent minimally invasive living donor nephrectomies at the Mayo Clinic Arizona between 2011 and 2023 with a 2-year external validation cohort from Mayo Clinic Florida and Mayo Clinic Minnesota. The cohort was divided into 2 groups based on the kidney extraction site type: midline infraumbilical and Pfannenstiel. RESULTS: In the primary cohort, incisional hernia occurrence was observed in 1.2% of donors with an infraumbilical midline kidney extraction site compared with 0.1% with a Pfannenstiel extraction site (p = 0.04). Donors with an infraumbilical midline kidney extraction site were more likely to be men (50.8% vs 23.3%, p < 0.0001), have a higher BMI (mean 27.2 vs 26 kg/m2, p < 0.0001), and have current or former tobacco use (p = 0.002). There were no differences in incisional hernia occurrence when comparing minimally invasive surgical techniques (p = 0.52). In the external validation cohort, hernia occurrence was observed in 4.5% of donors with a midline incision compared with 0.0% with a Pfannenstiel incision (p = 0.09). Using combined data from the 3 sites, the use of a Pfannenstiel incision as the extraction site was associated with significantly lower odds of developing a hernia compared with the infraumbilical midline incision (odds ratio 0.06, 95% CI 0.008 to 0.456). CONCLUSIONS: Although the risk of hernia in living kidney donors is generally low, the use of a Pfannenstiel incision for kidney extraction appears to offer an additional incremental reduction in risk.

Background. The current model for end-stage liver disease (MELD) exception policies for portopulmonary hypertension (POPH) require serial right heart catheterizations (RHCs) every 3 mo to maintain exception points. RHC is necessary for the initial diagnosis of POPH, but the utility of serial catheterizations has not been studied. In patients with POPH MELD exceptions, we sought to compare noninvasive and invasive hemodynamics and determine the sensitivity of echocardiography for the detection of hemodynamically severe POPH that would preclude liver transplant. Methods. We performed a single-center retrospective cohort study of patients with POPH MELD exceptions who underwent liver transplant from December 2008 to January 2024. Results were validated at an external center. Echocardiograms and RHCs performed within 1 mo were compared. Pearson correlation coefficient and Bland-Altman plots assessed the association between echocardiogram and RHC variables. We examined varied echocardiographic parameters to optimize sensitivity for the detection of hemodynamically severe POPH. Results. Twenty-two individuals underwent 60 follow-up RHCs with paired echocardiograms. Right ventricular systolic pressure (RVSP) and cardiac index estimated with echocardiogram were not strongly correlated with RHC measurements at follow-up (RVSP and RHC pulmonary artery systolic pressure: R = 0.30, P = 0.02; cardiac index: R = 0.17, P = 0.21). However, echocardiograms with RVSP ≥48 mm Hg had 100% sensitivity for detecting hemodynamically severe POPH, with 100% negative predictive value. In external validation of 13 paired echocardiograms and RHCs, our algorithm had 64% specificity and 100% negative predictive value. Conclusions. Although echocardiogram and RHC hemodynamic estimates were not strongly correlated, these results could potentially negate the current requirement for repeat RHC every 3 mo to maintain POPH MELD exception.