Mathur, Amit K.

Hepatocellular Carcinoma (HCC) is the most common liver malignancy and third leading cause of cancer death worldwide. For early- and intermediate-stage disease, liver-directed therapies for locoregional control, or down-staging prior to definitive surgical therapy with hepatic resection or liver transplantation, have been studied broadly, and are the mainstays of current treatment guidelines. As HCC incidence has continued to grow, and with more patients presenting with advanced disease, our current treatment modalities do not suffice, and better therapies are needed to improve disease-specific and overall survival. Until recently, sorafenib was the only systemic therapy utilized, and was associated with dismal results. The advent of immuno-oncology has been of significant interest, and has changed the paradigm of therapy for HCC. Lately, combination regimens including atezolizumab plus bevacizumab; durvalumab plus tremelimumab; and pembrolizumab plus Lenvatinib have shown impressive responses of between 25–35%; this is much higher than responses observed with single agents. Complete responses with checkpoint inhibitor therapy have been observed in advanced-stage HCC patients. These dramatic results have naturally led to several questions. Can or should checkpoint inhibitors, or other immunotherapy combinations, be used routinely before resection or transplant? Is there a synergistic effect of immunotherapy with locoregional therapy, and will pre-treatment increase disease-free survival after surgical intervention? Is it immunologically safe to use these therapies prior to transplantation? Much is still to be learned in terms of the dosing, timing, and overall utility of the use of immune checkpoint inhibitors for pre-transplant care and down-staging. More studies will be needed to understand the management of adverse events while maximizing the therapeutic window of these agents. In this review, we look at the current data on therapy with immune checkpoint inhibitors in advanced HCC, with a focus on pre-transplant treatment prior to liver transplant.

Abstract Donation after circulatory death (DCD) liver transplantation (LT) outcomes have been attributed to multiple variables, including procurement surgeon recovery techniques. Outcomes of 196 DCD LTs at Mayo Clinic Arizona were analyzed based on graft recovery by a surgeon from our center (transplant procurement team [TPT]) versus a local procurement surgeon (non‐TPT [NTPT]). A standard recovery technique was used for all TPT livers. The recovery technique used by the NTPT was left to the discretion of that surgeon. A total of 129 (65.8%) grafts were recovered by our TPT, 67 (34.2%) by the NTPT. Recipient age (p = 0.43), Model for End‐Stage Liver Disease score (median 17 vs. 18; p = 0.22), and donor warm ischemia time (median 21.0 vs. 21.5; p = 0.86) were similar between the TPT and NTPT groups. NTPT livers had longer cold ischemia times (6.5 vs. 5.0 median hours; p < 0.001). Early allograft dysfunction (80.6% vs. 76.1%; p = 0.42) and primary nonfunction (0.8% vs. 0.0%; p = 0.47) were similar. Ischemic cholangiopathy (IC) treated with endoscopy occurred in 18.6% and 11.9% of TPT and NTPT grafts (p = 0.23). At last follow‐up, approximately half of those requiring endoscopy were undergoing a stent‐free trial (58.3% TPT; 50.0% NTPT; p = 0.68). IC requiring re‐LT in the first year occurred in 0.8% (n = 1) of TPT and 3.0% (n = 2) of NTPT grafts (p = 0.23). There were no differences in patient (hazard ratio [HR], 1.95; 95% confidence interval [CI], 0.76–5.03; p = 0.23) or graft (HR, 1.99; 95% CI, 0.98–4.09; p = 0.10) survival rates. Graft survival at 1 year was 91.5% for TPT grafts and 95.5% for NTPT grafts. Excellent outcomes can be achieved using NTPT for the recovery of DCD livers. There may be an opportunity to expand the use of DCD livers in the United States by increasing the use of NTPT.

AbstractBackgroundCenters discard high kidney donor profile index (KDPI) allografts, potentially related to delayed graft function and prolonged hospital use by kidney transplant recipients (KTR). We sought to determine whether high KDPI KTRs have excess health care utilization.MethodsWe conducted a retrospective cohort study from a high‐volume center analyzing KTRs from January 3, 2011 to April 12, 2015 (n = 652). We measured differences in hospital use, emergency visits, and outpatient visits within the first 90 days between low (≤85%) versus high KDPI (>85%) KTRs, as well as long‐term graft function and patient survival.ResultsHigh (n = 107) and low KDPI (n = 545) KTRs had similar length of stay (median = 3 days, P = .66), and readmission rates at 7, 30, and 90 days after surgery (all, P > .05). High KDPI kidneys were not associated with excess utilization of the hospital, emergency services, outpatient transplant clinics, or ambulatory infusion visits on univariate or multivariate analysis (all, P > .05). Low KDPI KTRs had significantly better eGFR at 2 years (Low vs. High KDPI: 60.35 vs. 41.54 ml/min, P < .001), but similar 3‐year patient and graft survival (both, P > .09).ConclusionsHigh and low KDPI KTRs demonstrated similar 90‐day risk‐adjusted health care utilization, which should encourage use of high KDPI kidneys.

AbstractBackground and objectivesWe aimed to determine outcomes with transplanting kidneys from deceased donors with severe acute kidney injury requiring acute renal replacement therapy (RRT).Materials and methodsA total of 172 recipients received a kidney from donors with acute kidney injury stage 3 (AKIN3) requiring RRT. We compared the study group to 528 recipients who received a kidney from donors with AKIN stage 3 not on RRT and 463 recipients who received < 85% Kidney Donor Profile Index (KDPI) AKIN stage 0 kidney.ResultsThe study group donors were younger compared to the 2 control groups. Despite higher DGF in the study group, the length of hospital stay and acute rejection were similar. Death censored graft survival (96% AKIN3‐RRT vs. 97%AKIN3 no RRT vs. 96% KDPI < 85% AKIN0,P = 0.26) and patient survival with functioning graft at 1 year (95% across all groups,P = 0.402) were similar. The estimated glomerular filtration rate were similar across the 3 groups after first month. Interstitial fibrosis and tubular atrophy score ≥ 2 on protocol biopsy at time 0, 4 and 12 months were similar. Primary nonfunction was rare and associated with high KDPI.ConclusionsTransplanting selected kidneys from deceased donors with AKIN3 requiring RRT is safe and has good outcomes.

During 2001–2015, numbers of donation after circulatory death (DCD) liver transplantations (LTs) remained surprisingly low. Post-transplant outcomes improved overall over time, regardless of centre volume. High-volume centres that promoted DCD LT significantly shortened their waiting list time, therefore limiting waiting list mortality and drop-outs.

Background. As the number of donation after circulatory death (DCD) liver transplants (LTs) performed in the United States continues to increase annually, there has been interest by policy makers to develop a more robust exception point safety net for patients who develop ischemic cholangiopathy (IC) following DCD LT. As such, there is a need for better understanding of the clinical course and long-term outcomes in patients who develop IC, as well as determining if IC can be classified into distinct categories with distinctly different clinical outcomes. Methods. All DCD LT performed at Mayo Clinic Florida, Mayo Clinic Arizona, and Mayo Clinic Rochester from January 1999 to March 2020 were included (N = 770). Outcomes were compared between 4 distinct radiologic patterns of IC: diffuse necrosis, multifocal progressive, confluence dominant, and minor form. Results. In total, 88 (11.4%) patients developed IC, of which 42 (5.5%) were listed for retransplantation of liver (ReLT). Patients with diffuse necrosis and multifocal progressive patterns suffered from frequent hospital admissions for cholangitis in the first year following DCD LT (median 3 and 2), were largely stent dependent (100% and 85.7%), and almost universally required ReLT. Patients with confluence dominant disease were managed with multiple stents and frequently recovered, ultimately becoming stent free without need for ReLT. Patients with the minor form IC did well with limited need for stent placement or repeat procedures and did not require ReLT. Graft survival was different between the 4 distinct IC patterns ( P < 0.001). Conclusions. The present analysis provides a detailed analysis on the natural history and clinical course of IC. Patients developing IC can be classified into 4 distinct patterns with distinct clinical courses.

AbstractBiliary strictures can be a challenging clinical problem to manage and often have unclear etiologies, including benign and malignant causes. Left untreated, these problems can lead to significant morbidity and mortality linked to their underlying diagnosis. The approach to adult patients with biliary strictures requires a multidisciplinary team involving surgeons, interventional endoscopists, and interventional radiologists for diagnosis, symptom relief, palliation, as well as potential curative management. From a surgeon's perspective, there are many ways to classify and approach these strictures. It is of paramount importance to start with an excellent understanding of the patient's prior surgical history. In approaching a patient with a new diagnosis of biliary stricture, it is also critical to understand its etiology relatively quickly, as 70% are malignant in the adult population. Concurrently, one must clearly define the location and extent of the stricture: intrahepatic, hilar, or distal extrahepatic bile duct, as well as whether it is a singular lesion or multifocal phenotypes. This information provides a path forward in clinical decision-making regarding durability and efficacy of therapy, which is typically aimed at decompression and/or surgical resection to prevent cholangitis, sepsis, and progressive hepatic insufficiency.

AbstractBackgroundOpioids are associated with negative transplant outcomes. We sought to identify patient and center effects on over‐prescribing of opioids (> 200 OME (oral morphine equivalents)).Study designClinical and opioid prescription data (2014–2017) were collected from three academic transplant centers for kidney (KT), liver (LT), and simultaneous liver‐kidney transplant (SLK) patients. Multivariable models were used to identify predictors of opioid over‐prescribing at discharge and the occurrence of refill prescriptions at 90 days.ResultsThree‐thousand seven‐hundred and two patients underwent transplant in the cohort (KT: n = 2358, LT: n = 1221, SLK: n = 123). More than 80% of recipients were over‐prescribed opioids at discharge (Median OME (mOME) = 300 (IQR 225–375). LT and SLK had the largest prescription size (LT mOME 338 (IQR 300–450); SLK mOME 338 (IQR 225–450) and refill rate (LT: 64%, SLK 59%) (all, P < .001). Multivariable analysis indicated that transplant center was a significant predictor of opioid over‐prescription after KT and LT (all, P < .001); older age (in KT) and length of stay (LOS) (in LT) were protective factors (both, P < .05). Refill occurrence was associated with initial prescription size and was reduced by older age and initial LOS (all, P < .05).ConclusionsThe wide variation in opioid prescribing patterns has implications for transplant practice innovation, guideline development, and further study.

Statin therapy may reduce the risk of venous thromboembolism (VTE), which may impact solid organ transplant outcomes. We evaluated the incidence of VTE and other complications after liver transplantation stratified by hyperlipidemia status and statin use using a retrospective cohort study approach. We reviewed all primary orthotopic liver transplantation (OLT) records from January 2014 to December 2019 from our center. Intraoperative deaths were excluded. Recipient, donor clinical and demographic data were collected. We developed risk‐adjusted models to assess the effect of statin use on the occurrence of VTE, hepatic artery complications (HACs), graft failure, and death, accounting for clinical covariates and competing risks. A total of 672 OLT recipients were included in the analysis. Of this cohort, 11.9% (n = 80) received statin therapy. A total of 47 patients (7.0%) had VTE events. HACs occurred in 40 patients (6.0%). A total of 42 (6.1%) patients experienced graft loss, whereas 9.1% (n = 61) of the cohort died during the study interval. Eighty OLT recipients (29.8%) were treated with statins. In the statin treated group, 0% of patients had VTE versus 7.9% of those not on statins (P = 0.02). HACs were identified in 1.2% of the statin group and 6.8% of the nonstatin group. Untreated hyperlipidemia was associated with a 2.1‐fold higher risk of HACs versus patients with no hyperlipidemia status (P = 0.05). Statin therapy was associated with significantly better risk‐adjusted thromboembolic event‐free survival (absence of VTE, cerebrovascular accident, myocardial infarction, HACs, and death); hazard ratio, 2.7; P = 0.01. These data indicate that statin therapy is correlated with a lower rate of VTE and HACs after liver transplantation.