Is Repeat Resection for Recurrent Intrahepatic Cholangiocarcinoma Warranted? Outcomes of an International Analysis.

BACKGROUND: Recurrence of intrahepatic cholangiocarcinoma (ICC) after liver resection (LR) remains high, and optimal therapy for recurrent ICC is challenging. Herein, we assess the outcomes of patients undergoing repeat resection for recurrent ICC in a large, international multicenter cohort. PATIENTS AND METHODS: Outcomes of adults from six large hepatobiliary centers in North America, Europe, and Asia with recurrent ICC following primary LR between 2001 and 2015 were analyzed. Cox models determined predictors of post-recurrence survival. RESULTS: Of patients undergoing LR for ICC, 499 developed recurrence. The median time to recurrence was 10 months, and 47% were intrahepatic. Overall 3-year post-recurrence survival rate was 28.6%. In total, 121 patients (25%) underwent repeat resection, including 74 (61%) repeat LRs. Surgically treated patients were more likely to have solitary intrahepatic recurrences and significantly prolonged survival compared with those receiving locoregional or systemic therapy alone with a 3-year post-recurrence survival rate of 47%. Independent predictors of post-recurrence death included time to recurrence < 1 year [HR 1.66 (1.32-2.10), p < 0.001], site of recurrence [HR 1.74 (1.28-2.38), p < 0.001], macrovascular invasion [HR 1.43 (1.05-1.95), p = 0.024], and size of recurrence > 3 cm [HR 1.68 (1.24-2.29), p = 0.001]. Repeat resection was independently associated with decreased post-recurrence death [HR 0.58 0.43-0.78), p < 0.001]. CONCLUSIONS: Repeat resection for recurrent ICC in select patients can result in extended survival. Thus, challenging the paradigm of offering these patients locoregional or chemo/palliative therapy alone as the mainstay of treatment.

Liver transplantation and hepatocellular carcinoma 2023: a narrative review of management and outcomes.

BACKGROUND AND OBJECTIVE: Hepatocellular carcinoma (HCC) is a leading cause of morbidity and mortality in the United States. For certain patients, liver transplantation (LT) may be curative. The determination of which patients would benefit most from transplant and have the lowest risk of post-transplant recurrence has evolved as technology and treatments have expanded. We aim to review epidemiological changes in the HCC landscape, selection criteria for transplant, organ allocation, bridge therapies and post-transplant recurrence, and identify points for palliative care involvement. METHODS: Literature review was performed using PubMed MeSH searches in addition to reference list review. Additional information was retrieved from government regulatory and procurement organizations. KEY CONTENT AND FINDINGS: Metabolic and alcohol-associated liver diseases have surpassed hepatitis C as the leading causes of LT over the last decade, and have also risen as the underlying conditions seen in patients with HCC requiring LT. The United Network for Organ Sharing (UNOS) coordinates organ allocation, which includes disease severity, waitlist time, blood type, and distance from donor hospital. It has progressed to incorporate treatment response and alpha-fetoprotein into its listing criteria for patients with HCC, in addition to the well-established Milan Criteria (MC, one tumor <5 cm, ≤3 tumors ≤3 cm). Therapies to bridge patients until LT include locoregional therapies as well as immunotherapy. Dropout on the waitlist is seen up to 20% either due to decompensation or progression of disease. Recurrence of HCC post-transplant remains challenging. Given this, current guidelines recommend early palliative care involvement regardless of transplant listing status for both symptom management and advance care planning. CONCLUSIONS: For patients with HCC with favorable tumor biology, LT can be curative. However, given the symptom burden while awaiting LT and the notable number of patients who are unable to receive a transplant, early palliative care is critical in appropriate management of HCC.

Sustained in vivo perfusion of a re-endothelialized tissue engineered kidney graft in a human-scale animal model.

Introduction: Despite progress in whole-organ decellularization and recellularization, maintaining long-term perfusion in vivo remains a hurdle to realizing clinical translation of bioengineered kidney grafts. The objectives for the present study were to define a threshold glucose consumption rate (GCR) that could be used to predict in vivo graft hemocompatibility and utilize this threshold to assess the in vivo performance of clinically relevant decellularized porcine kidney grafts recellularized with human umbilical vein endothelial cells (HUVECs). Materials and methods: Twenty-two porcine kidneys were decellularized and 19 were re-endothelialized using HUVECs. Functional revascularization of control decellularized (n = 3) and re-endothelialized porcine kidneys (n = 16) was tested using an ex vivo porcine blood flow model to define an appropriate metabolic glucose consumption rate (GCR) threshold above which would sustain patent blood flow. Re-endothelialized grafts (n = 9) were then transplanted into immunosuppressed pigs with perfusion measured using angiography post-implant and on days 3 and 7 with 3 native kidneys used as controls. Patent recellularized kidney grafts underwent histological analysis following explant. Results: The glucose consumption rate of recellularized kidney grafts reached a peak of 39.9 ± 9.7 mg/h at 21 ± 5 days, at which point the grafts were determined to have sufficient histological vascular coverage with endothelial cells. Based on these results, a minimum glucose consumption rate threshold of 20 mg/h was set. The revascularized kidneys had a mean perfusion percentage of 87.7% ± 10.3%, 80.9% ± 33.1%, and 68.5% ± 38.6% post-reperfusion on Days 0, 3 and 7, respectively. The 3 native kidneys had a mean post-perfusion percentage of 98.4% ± 1.6%. These results were not statistically significant. Conclusion: This study is the first to demonstrate that human-scale bioengineered porcine kidney grafts developed via perfusion decellularization and subsequent re-endothelialization using HUVEC can maintain patency with consistent blood flow for up to 7 days in vivo. These results lay the foundation for future research to produce human-scale recellularized kidney grafts for transplantation.

Ten-Year Outcomes of Liver Transplant and Downstaging for Hepatocellular Carcinoma.

Importance: National guidelines on transplant selection have adopted successful downstaging to within Milan criteria (MC) as a viable option for the treatment of hepatocellular carcinoma (HCC) before liver transplant (LT). Recurrence of HCC after LT carries a poor prognosis, and treatment modalities remain challenging. Objective: To establish the 10-year outcomes of patients with HCC after LT in a large, multicenter US study based on individual data; provide robust data on the long-term role of downstaging; and evaluate the association of treatment modalities with postrecurrence survival. Design, Setting, and Participants: In this cohort study, a retrospective, multicenter analysis of prospectively collected data was conducted for 2645 adults who had undergone LT for HCC at 5 US academic centers between January 2001 and December 2015. The analysis was performed from May 2019 through June 2021. Outcomes of 341 patients whose disease was downstaged to within MC were compared with those in 2122 patients whose disease was always within MC and 182 patients whose disease was not downstaged. The associations of tumor and treatment factors on postrecurrence survival were analyzed using Cox proportional hazards regression and multivariable logistic regression models. Main Outcomes and Measures: The primary outcome was overall survival for the whole cohort and according to downstaging status. Secondary outcomes were time to recurrence, recurrence-free survival, and recurrence after specific post-LT therapies. Results: Of the 2645 patients studied, the median age was 59.9 years (IQR, 54.7-64.7 years). The majority of the patients were men (2028 [76.7%] vs 617 [23.3%] women). The 10-year post-LT survival and recurrence rates were, respectively, 52.1% and 20.6% among those whose disease was downstaged; 61.5% and 13.3% in those always within MC; and 43.3% and 41.1% in those whose disease was not downstaged. Independent variables associated with downstaging failure were tumor size greater than 7 cm at diagnosis (OR, 2.62; 95% CI, 1.20-5.75; P = .02), more than 3 tumors at diagnosis (OR, 2.34; 95% CI, 1.22-4.50; P = .01), and α-fetoprotein response of at least 20 ng/mL with less than 50% improvement from maximum α-fetoprotein before LT (OR, 1.99; 95% CI, 1.14-3.46; P = .02). Surgically treated patients with recurrent HCC differed in clinicopathologic characteristics and had improved 5-year postrecurrence survival rates (31.6% vs 7.3%; P < .001). Conclusions and Relevance: In a large, multicenter cohort of patients with HCC successfully downstaged to within MC, 10-year post-LT outcomes were excellent, validating national downstaging policies and showing a clear utility benefit for LT prioritization decision making. Surgical management of HCC recurrence after LT was associated with improved survival in well-selected patients and should be pursued, if feasible.

Outcomes of transplantation for HBV- vs. HCV-related HCC: impact of DAA HCV therapy in a national analysis of >20,000 patients.

BACKGROUND: The development of direct-acting antiviral (DAA) therapy has revolutionized HCV management. We present a large national study comparing post-LT outcomes for HBV-HCC vs. HCV-HCC according to DAA era. METHODS: Data were collected from OPTN/UNOS Registry. Groups included pre-DAA (January 2003-October 2013) and post-DAA (November2013-January2019) eras. Outcomes for patients with HBV(n = 2000) vs. HCV(n = 18,964) were compared in each era. RESULTS: In the pre-DAA era, there were significant differences between HBV-versus HCV, including the percentage of Caucasian race, pre-LT and maximum AFP levels <20 ng/mL, MELD-score, complete tumor necrosis, and vascular invasion. In the post-DAA-era, differences were noted in wait time>9 months, the percentage of Caucasian race, pre-LT and AFP(max) levels<20 ng/mL, and MELD-score. In the pre-DAA-era, the 5-and-10 year survival rates were 80.5% and 71% for HBV-HCC, and 69% and 54.4% for HCV-HCC (p < 0.001); in the post-DAA-era, 5-year survival was 83.4% for HBV-HCC and 78.5% for HCV-HCC(p = 0.08). Independent pre-LT predictors of lower survival included recipient and donor age>50yrs, wait-time>9months, higher MELD-score (p < 0.001), AFP level>20 ng/mL, and MC at diagnosis. HCV status did not predict outcome in the post-DAA-era after adjusting for tumor characteristics. CONCLUSION: After the introduction of effective DAA-HCV therapy, results of LT for HCV-HCC are significantly improved and are no longer statistically different from results in patients with HBV-HCC.

Outcomes of liver transplantation for nonalcoholic steatohepatitis-associated hepatocellular carcinoma.

BACKGROUND: Nonalcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) is the second-leading cause of liver transplantation (LT) performed for HCC. Despite this, little is known about the clinical characteristics and outcomes of NASH-HCC. METHODS: Patients undergoing LT for HCC from 2001 to 2017 at a single center were reviewed. Outcomes of NASH-HCC (n = 51) were compared to other etiologies of HCC including hepatitis C (HCV) hepatitis B (HBV), and alcoholic liver disease (ALD). Outcomes of NASH-HCC were also compared to HCV in the direct-acting antiviral (DAA) era (2014-2017). RESULTS: The frequency of NASH-HCC as the primary indication for LT in patients with HCC increased significantly during the study period from 4.4% (2001-2008) to 15.6% in 2017. NASH-HCC patients were significantly older (median age 65 vs. 60; P < 0.001) with significantly lower alpha-fetoprotein levels (7.5 vs. 26.5, P < 0.001) compared to other etiologies. The 1-, 3-, and 5-year overall survival of NASH-HCC was 92%, 86%, and 80%. Overall survival of NASH-HCC was not significantly different compared to HCV, HBV, or ALD. Compared to HCV-HCC in the DAA era (n = 99), NASH-HCC had comparable post-LT survival (3-year survival 87% vs. 86%, P = 0.870). CONCLUSION: In this large single-center experience of NASH-HCC, we demonstrate favorable outcomes of NASH-HCC following LT comparable to other common etiologies of HCC.

Left lateral segment pediatric liver transplantation: a 25 year experience at Mount Sinai.

BACKGROUND: Outcomes of left lateral segment (LLS) grafts in pediatric recipients were compared between living (LD-LLS) and deceased donor (DD-LLS) grafts. METHODS: 195 LLS grafts (99DD-LLS-96LD-LLS) were analyzed with a median follow-up of 9.1years. The primary endpoints were overall patient/graft survival. RESULTS: LD-LLS grafts were younger (0.9vs.1.4years, p = 0.039), more likely to have a fulminant liver failure (17.9%vs.5.3%,p = 0.002), less likely to have a metabolic disorder (6.3%vs.25.5%,p = 0.002), and less likely to be undergoing retransplantation (5.3% vs.16.2%,p = 0.015). There was a trend toward decreased hepatic artery thrombosis in LD-LLS grafts (6.6% vs. 15.5%,p = 0.054). No differences in the overall biliary complications occurred. The LD-LLS group had prolonged survival compared to the DD-LLS group with 10-year survival rates of 81%, and 74% (p = 0.005), respectively. LD-LLS grafts had longer graft survival compared to DD-LLS grafts (10-year graft survival 85%vs.67%,p = 0.005). Recipient age >1year (HR 2.39,p = 0.026), aortic reconstruction (HR 2.12,p = 0.046) and vascular complication (HR 3.12,p < 0.001) were independent predictors of poor patient survival. Non-biliary liver disease (HR 2.17,p = 0.015), DD-LLS (HR 2.06,p = 0.034) and vascular complication (HR 4.61,p < 0.001) were independent predictors of poor graft survival. CONCLUSION: The use of SLT remains a viable option with excellent long-term outcomes. We show improved graft and patient survival with living donor grafts.

Downstaging Outcomes for Hepatocellular Carcinoma: Results From the Multicenter Evaluation of Reduction in Tumor Size before Liver Transplantation (MERITS-LT) Consortium.

BACKGROUND & AIMS: United Network of Organ Sharing (UNOS) has adopted uniform criteria for downstaging (UNOS-DS) of hepatocellular carcinoma (HCC) before liver transplantation (LT), but the downstaging success rate and intention-to-treat outcomes across broad geographic regions are unknown. METHODS: In this first multiregional study (7 centers, 4 UNOS regions), 209 consecutive patients with HCC undergoing downstaging based on UNOS-DS criteria were prospectively evaluated from 2016 to 2019. RESULTS: Probability of successful downstaging to Milan criteria and dropout at 2 years from the initial downstaging procedure was 87.7% and 37.3%, respectively. Pretreatment with lectin-reactive α-fetoprotein ≥10% (hazard ratio, 3.7; P = .02) was associated with increased dropout risk. When chemoembolization (n = 132) and yttrium-90 radioembolization (n = 62) were compared as the initial downstaging treatment, there were no differences in Modified Response Evaluation Criteria In Solid Tumors response, probability of or time to successful downstaging, waiting list dropout, or LT. Probability of LT at 3 years was 46.6% after a median of 17.2 months. In the explant, 17.5% had vascular invasion, and 42.8% exceeded Milan criteria (understaging). The only factor associated with understaging was the sum of the number of lesions plus largest tumor diameter on the last pre-LT imaging, and the odds of understaging increased by 35% per 1-unit increase in this sum. Post-LT survival at 2 years was 95%, and HCC recurrence occurred in 7.9%. CONCLUSION: In this first prospective multiregional study based on UNOS-DS criteria, we observed a successful downstaging rate of >80% and similar efficacy of chemoembolization and yttrium-90 radioembolization as the initial downstaging treatment. A high rate of tumor understaging was observed despite excellent 2-year post-LT survival of 95%. Additional LRT to reduce viable tumor burden may reduce tumor understaging.

Multi-Center Analysis of Liver Transplantation for Combined Hepatocellular Carcinoma-Cholangiocarcinoma Liver Tumors.

BACKGROUND: Combined hepatocellular-cholangiocarcinoma liver tumors (cHCC-CCA) with pathologic differentiation of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma within the same tumor are not traditionally considered for liver transplantation due to perceived poor outcomes. Published results are from small cohorts and single centers. Through a multicenter collaboration, we performed the largest analysis to date of the utility of liver transplantation for cHCC-CCA. STUDY DESIGN: Liver transplant and resection outcomes for HCC (n = 2,998) and cHCC-CCA (n = 208) were compared in a 12-center retrospective review (2009 to 2017). Pathology defined tumor type. Tumor burden was based on radiologic Milan criteria at time of diagnosis and applied to cHCC-CCA for uniform analysis. Kaplan-Meier survival curves and log-rank test were used to determine overall survival and disease-free survival. Cox regression was used for multivariate survival analysis. RESULTS: Liver transplantation for cHCC-CCA (n = 67) and HCC (n = 1,814) within Milan had no significant difference in overall survival (5-year cHCC-CCA 70.1%, HCC 73.4%, p = 0.806), despite higher cHCC-CCA recurrence rates (23.1% vs 11.5% 5 years, p < 0.001). Irrespective of tumor burden, cHCC-CCA tumor patient undergoing liver transplant had significantly superior overall survival (p = 0.047) and disease-free survival (p < 0.001) than those having resection. For cHCC-CCA within Milan, liver transplant was associated with improved disease-free survival over resection (70.3% vs 33.6% 5 years, p < 0.001). CONCLUSIONS: Regardless of tumor burden, outcomes after liver transplantation are superior to resection for patients with cHCC-CCA. Within Milan criteria, liver transplant for cHCC-CCA and HCC result in similar overall survival, justifying consideration of transplantation due to the higher chance of cure with liver transplantation in this traditionally excluded population.

Resection of Mixed Hepatocellular-Cholangiocarcinoma, Hepatocellular Carcinoma, and Intrahepatic Cholangiocarcinoma.

Mixed hepatocellular-cholangiocarcinoma (HCC-CC) is a biphenotypic liver cancer thought to have unfavorable tumor biology and a poor prognosis. Surgical outcomes of HCC-CC remain unclear. We aimed to evaluate the clinical characteristics and surgical outcomes of HCC-CC. We analyzed a series of patients undergoing resection for HCC-CC (n = 47), hepatocellular carcinoma (HCC; n = 468), and intrahepatic cholangiocarcinoma (ICC; n = 108) at a single Western center between 2001 and 2015. Patients with HCC-CC were matched to patients with HCC and ICC on important clinical factors including tumor characteristics (size, vascular invasion, and differentiation) and underlying cirrhosis. Patients with HCC-CC had rates of viral hepatitis comparable to patients with HCC (78.7% versus 80.0%), and 42.5% had underlying cirrhosis. When matched on tumor size, HCC-CC was more poorly differentiated than HCC (68.3% versus 27.3%; P < 0.001) and ICC (68.3% versus 34.8%; P = 0.01) but had similar postresection survival (5-year survival: HCC-CC 49.7%, HCC 54.8%, ICC 68.7%; P = 0.61) and recurrence (3-year recurrence: HCC-CC 57.9%, HCC 61.5%, and ICC 56%; P = 0.58). Outcomes were similar between HCC-CC and HCC when matched on underlying cirrhosis and tumor size. Cancer type was not predictive of survival or tumor recurrence. Survival after resection of HCC-CC is similar to HCC when matched for tumor size, despite HCC-CC tumors being more poorly differentiated. Exclusion of HCC-CC from management strategies recommended for HCC, including consideration for liver transplantation, may not be warranted.

Renal Safety of Intravenous Ketorolac Use After Donor Nephrectomy.

INTRODUCTION: The benefit and short-term safety of ketorolac have been established in previous studies however, the risk of bleeding and long-term renal impairment in patients undergoing donor nephrectomy remain unclear. We report our experience at a high-volume transplant center. METHOD: Between January 1996 and January 2014, 862 consecutive patients underwent laparoscopic donor nephrectomy. Exclusion criteria included nonsteroidal anti-inflammatory drug allergy, asthma, bleeding disorders, long-term opioid use, intraoperative blood loss >700 mL, peptic ulcer disease, bleeding diathesis, and baseline creatinine greater than 1.9 mg/dL. Intravenous ketorolac was administered within 30 minutes following the surgical procedure at a dose of 15 to 30 mg every 6 hours. Patients were categorized into 2 groups according to the administration of ketorolac after surgery. Differences between the groups were analyzed. Primary outcomes were changes in serum creatinine and hemoglobin levels. Poor outcome was defined as postsurgical complications. RESULTS: During this time, 469 (55.3%) received ketorolac. The mean donor age was 39 years, and 360 (42.5%) were male. Left kidneys were procured in 82%. Operative time averaged 210 minutes and warm ischemia time117 seconds. Baseline demographic and operative outcomes were comparable in both groups. No statistically significant differences were found between the ketorolac group and the nonketorolac group in preoperative and postoperative hemoglobin levels and serum creatinine at 1 week, 1 year, and 5 years (P = .6). Ketorolac use was not associated with increased perioperative morbidity (P = NS). CONCLUSION: The use of intravenous ketorolac in patients undergoing donor nephrectomy was not associated with an increased risk of bleeding or renal impairment.

Reconstruction of a Pancreatic Allograft With Variant Arterial Anatomy for Transplantation.

Donor pancreas utilization rates remain low and aberrant donor anatomy can lead to organ discard by transplant centers. We report on a case of successful pancreas transplantation using a graft with variant arterial anatomy demonstrating that arterial reconstruction is a viable option if aberrant anatomy is encountered at the donor operation. Efforts must be made to use all pancreas grafts that are felt to be of appropriate quality.

Video-assisted thoracoscopic surgery for complex mediastinal mass resections.

Minimally invasive surgery has changed the way operative procedures are performed in many specialties. As surgeons have become progressively facile with these techniques, the opportunities to use them have expanded. In thoracic surgery, many surgeons now use minimally invasive techniques to resect small, uncomplicated pathologies of the mediastinum as well as to perform thymectomy for myasthenia gravis. Experience with these techniques has allowed new knowledge to be gained and expansion of the use of these techniques for more complicated mediastinal pathology. This keynote address will outline the instrumentation and techniques that we have adopted over a decade of using these techniques for more complicated mediastinal pathology.