US Liver Transplant Outcomes After Normothermic Regional Perfusion vs Standard Super Rapid Recovery.

Importance: Normothermic regional perfusion (NRP) is an emerging recovery modality for transplantable allografts from controlled donation after circulatory death (cDCD) donors. In the US, only 11.4% of liver recipients who are transplanted from a deceased donor receive a cDCD liver. NRP has the potential to safely expand the US donor pool with improved transplant outcomes as compared with standard super rapid recovery (SRR). Objective: To assess outcomes of US liver transplants using controlled donation after circulatory death livers recovered with normothermic regional perfusion vs standard super rapid recovery. Design, Setting, and Participants: This was a retrospective, observational cohort study comparing liver transplant outcomes from cDCD donors recovered by NRP vs SRR. Outcomes of cDCD liver transplant from January 2017 to May 2023 were collated from 17 US transplant centers and included livers recovered by SRR and NRP (thoracoabdominal NRP [TA-NRP] and abdominal NRP [A-NRP]). Seven transplant centers used NRP, allowing for liver allografts to be transplanted at 17 centers; 10 centers imported livers recovered via NRP from other centers. Exposures: cDCD livers were recovered by either NRP or SRR. Main Outcomes and Measures: The primary outcome was ischemic cholangiopathy (IC). Secondary end points included primary nonfunction (PNF), early allograft dysfunction (EAD), biliary anastomotic strictures, posttransplant length of stay (LOS), and patient and graft survival. Results: A total of 242 cDCD livers were included in this study: 136 recovered by SRR and 106 recovered by NRP (TA-NRP, 79 and A-NRP, 27). Median (IQR) NRP and SRR donor age was 30.5 (22-44) years and 36 (27-49) years, respectively. Median (IQR) posttransplant LOS was significantly shorter in the NRP cohort (7 [5-11] days vs 10 [7-16] days; P < .001). PNF occurred only in the SRR allografts group (n = 2). EAD was more common in the SRR cohort (123 of 136 [56.1%] vs 77 of 106 [36.4%]; P = .007). Biliary anastomotic strictures were increased 2.8-fold in SRR recipients (7 of 105 [6.7%] vs 30 of 134 [22.4%]; P = .001). Only SRR recipients had IC (0 vs 12 of 133 [9.0%]; P = .002); IC-free survival by Kaplan-Meier was significantly improved in NRP recipients. Patient and graft survival were comparable between cohorts. Conclusion and Relevance: There was comparable patient and graft survival in liver transplant recipients of cDCD donors recovered by NRP vs SRR, with reduced rates of IC, biliary complications, and EAD in NRP recipients. The feasibility of A-NRP and TA-NRP implementation across multiple US transplant centers supports increasing adoption of NRP to improve organ use, access to transplant, and risk of wait-list mortality.

Early United States experience with liver donation after circulatory determination of death using thoraco-abdominal normothermic regional perfusion: A multi-institutional observational study.

Mortality on the liver waitlist remains unacceptably high. Donation after circulatory determination of death (DCD) donors are considered marginal but are a potentially underutilized resource. Thoraco-abdominal normothermic perfusion (TA-NRP) in DCD donors might result in higher quality livers and offset waitlist mortality. We retrospectively reviewed outcomes of the first 13 livers transplanted from TA-NRP donors in the US. Nine centers transplanted livers from eight organ procurement organizations. Median donor age was 25 years; median agonal phase was 13 minutes. Median recipient age was 60 years; median lab MELD score was 21. Three patients (23%) met early allograft dysfunction (EAD) criteria. Three received simultaneous liver-kidney transplants; neither had EAD nor delayed renal allograft function. One recipient died 186 days post-transplant from sepsis but had normal presepsis liver function. One patient developed a biliary anastomotic stricture, managed endoscopically; no recipient developed clinical evidence of ischemic cholangiopathy (IC). Twelve of 13 (92%) patients are alive with good liver function at 439 days median follow-up; one patient has extrahepatic recurrent HCC. TA-NRP DCD livers in these recipients all functioned well, particularly with respect to IC, and provide a valuable option to decrease deaths on the waiting list.

Impact of Sarcopenia, BMI, and Inflammatory Biomarkers on Survival in Advanced Hepatocellular Carcinoma Treated With Anti-PD-1 Antibody.

BACKGROUND: Sarcopenia and inflammation are independently associated with worse survival in cancer patients. This study aims to determine the impact of sarcopenia, body mass index (BMI), and inflammatory biomarkers on survival in advanced hepatocellular carcinoma (HCC) patients treated with anti-PD-1 antibody-based immunotherapy. METHODS: A retrospective review of advanced HCC patients treated with immunotherapy at Winship Cancer Institute between 2015 and 2019 was performed. Baseline computed tomography and magnetic resonance images were collected at mid-L3 level, assessed for skeletal muscle density using SliceOmatic (TomoVision, version 5.0) and converted to skeletal muscle index (SMI) by dividing it by height (m2). Sex-specific sarcopenia was defined by the median value of SMI. The optimal cut for continuous inflammation biomarker was determined by bias-adjusted log-rank test. Overall survival (OS) was set as primary outcome and Cox proportional hazard model was used for association with survival. RESULTS: A total of 57 patients were included; 77.2% male, 52.6% Caucasian, 58.5% Eastern Cooperative Oncology Group performance status 0-1, 80.7% Child Pugh A. Treatment was second line and beyond in 71.9% of patients. The median follow-up time was 6 months. Sarcopenia cut-off for males and females was SMI of 43 and 39, respectively. 49.1% of patients had sarcopenia. Median OS was 5 versus 14.3 months in sarcopenic versus nonsarcopenic patients (Log-rank P=0.054). Median OS was 5 and 17.5 months in patients with BMI <25 and BMI ≥25, respectively (Log-rank P=0.034). Median OS was 3.6 and 14.3 months for patients with neutrophil-to-lymphocyte ratio (NLR) ≥5.15 versus NLR <5.15 (Log-rank P<0.001). In multivariable Cox regression model, higher baseline NLR was associated with worse OS (hazard ratio [HR]: 4.17, 95% confidence interval [CI]: 1.52-11.39, P=0.005). Sex-specific sarcopenia showed a trend of worse OS (HR: 1.71, 95% CI: 0.73-4.00, P=0.215) but was not statistically significant. BMI<25 was associated with worse OS (HR: 2.28, 95% CI: 0.92-5.65, P=0.076). In the association with progression free survival, neither baseline BMI nor sex-specific sarcopenia showed statistical significance. CONCLUSION: After controlling for baseline Child Pugh score and NLR, sex-specific sarcopenia does not predict OS. Baseline BMI and NLR together may predict OS in advanced HCC patients treated with anti-PD-1 antibody.

Evaluation of Medium-Term Efficacy of Y90 Radiation Segmentectomy vs Percutaneous Microwave Ablation in Patients with Solitary Surgically Unresectable < 4 cm Hepatocellular Carcinoma: A Propensity Score Matched Study.

OBJECTIVE: To evaluate the efficacy and safety of Y90 radiation segmentectomy (RS) vs. percutaneous microwave ablation (MWA) in patients with solitary HCC ≤ 4 cm. METHODS: From 2014 to 2017, 68 consecutive treatment naïve patients were included (34 per treatment arm). Chi-square and t-test were used to evaluate differences in baseline demographics between groups. Objective response was evaluated using mRECIST and toxicity using CTCAE. Overall survival (OS) and progression free survival (PFS) in the targeted tumor and the remainder of liver from initial treatment was calculated using Kaplan-Meier estimation. Propensity score matching was then performed with n = 24 patients matched in each group. Similar outcome analysis was then pre-formed. RESULTS: In the overall study population, both groups had similar baseline characteristics with the exception of larger lesions in the RS group. There was no difference in toxicity, objective tumor response, OS and non-target liver PFS between the MWA and RS group (p's > 0.05). In the matched cohort, the objective tumor response was 82.6% in MWA vs. 90.9%% in RS (p = 0.548). The mean OS in the MWA group (44.3 months) vs RS (59.0 months; p = 0.203). The targeted tumor mean PFS for the MWA groups was 38.6 months vs. 57.8 months in RS group (p = 0.005). There was no difference overall PFS and toxicity between the 2 matched groups. CONCLUSIONS: Our data suggest Y90 RS achieves similar tumor response and OS with a similar safety compared to MWA in the management of HCC lesions ≤ 4 cm. Additionally, targeted tumor PFS appears to be prolonged in the RS group with similar non-target liver PFS between RS and MWA group.

Clinical outcomes of rare hepatocellular carcinoma variants compared to pure hepatocellular carcinoma.

BACKGROUND: HCC variants are rare primary hepatic tumors. The aim of this study is to compare clinical characteristics and outcomes of HCC variants with pure HCC. METHODS: Patients diagnosed between 2004 and 2013 with ICD-O-3 8180/3 and 8170/3-8175/3 were identified from the National Cancer Database. Univariate and multivariate survival analyses were conducted to analyze the association between histology and overall survival (OS). RESULTS: 80,280 patients were identified; pure HCC 78,461 (97.7%), fibrolamellar (FLHCC) 310 (0.4%), scirrhous 161 (0.2%), spindle cell 72 (0.1%), clear cell 487 (0.6%), pleomorphic 23 (0.0%), and combined HCC and cholangiocarcinoma (mixed HCC) 766 (1.0%). 76.7% were male and 72% Caucasian. Liver transplant was performed in 10.1% of pure HCC, 14.5% of mixed HCC, 16.2% of scirrhous, 6.9% of spindle cell, 8.8% of clear cell, 8.7% of pleomorphic, and 3.2% of FLHCC (p<0.001). Pure HCC (10.6%) underwent surgical resection without transplant less often than variants except for scirrhous (9.9%) (p<0.001). More than a third of patients in each histological type received chemotherapy. FLHCC had the best 5-year OS (38.7%), spindle cell and pleomorphic had the worst (9.6% and 13.0%). In multivariate analysis stratified by histology variants, chemotherapy was associated with improved OS in all histologies except for scirrhous and pleomorphic HCC. CONCLUSION: HCC variants underwent surgical resection more often than pure HCC. FLHCC had the best 5-year OS. Liver transplant was commonly performed in HCC variants.

Building the multidisciplinary team for management of patients with hepatocellular carcinoma.

Optimal care of the patient with hepatocellular carcinoma (HCC) necessitates the involvement of multiple providers. Because the patient with HCC often carries 2 conditions with competing mortality risks (cancer and underlying cirrhosis), no single provider is equipped to deal with all of these patients' needs adequately. Multidisciplinary teams (MDTs) have evolved to facilitate care coordination, reassessments of clinical course, and nimble changes in treatment plans required for this complex group of patients. Providers or sites that elect to manage patients with HCC thus are increasingly aware of the need to build their own MDT or communicate with an established one. The availability of new communication technologies, such as teleconferencing or teleconsultation, offers the possibility of MDT expansion into underserved or rural areas, as well as areas such as correctional facilities. Although the availability of resources for HCC patient care varies from site to site, construction of an MDT is possible in a wide spectrum of clinical practices, and this article suggests a blueprint for assembly of such collaboration. Research strategies are needed to explain how MDTs improve clinical outcomes so that MDTs themselves can be improved.

Multivariate analysis of prognostic factors for survival following doxorubicin-eluting bead transarterial chemoembolization for hepatocellular carcinoma.

PURPOSE: To identify prognostic factors for survival in patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization with doxorubicin-eluting beads (DEBs). MATERIALS AND METHODS: In a retrospective, single-center analysis, tumor- and patient-related factors were recorded for univariate and multivariate analyses via Kaplan-Meier and Cox regression. Infiltrative HCC phenotype and portal vein invasion (PVI) were correlated, and patients with either or both were classified as having radiographically advanced (RAdv) HCC. The primary endpoint was overall survival, which was calculated from the time of first DEB chemoembolization procedure. RESULTS: A total of 168 patients underwent 248 procedures, of which 215 (86.7%) were outpatient procedures. Mean length of stay was 0.33 days, and 25 patients (10.1%) were readmitted within 30 days. A total of 33 patients underwent liver transplantation and were excluded from survival analyses. A total of 130 had cirrhosis; 62, 50, and 18 had Child class A, B, and C disease, respectively. Forty-one patients had infiltrative HCC phenotype, 28 of whom also had PVI. Multivariate analysis of survival in all patients showed α-fetoprotein (AFP), performance status (PS), RAdv HCC, Child classification, albumin level, and ascites to predict survival. In patients without RAdv HCC, AFP, PS, Child classification, albumin level, and International Normalized Ratio were independent predictors. Increased bilirubin level was not an independent risk factor for death. CONCLUSIONS: Independent prognostic factors in patients with HCC undergoing DEB chemoembolization have been identified. Increased bilirubin level was not an independent risk factor. These data can be used in HCC patient selection and counseling for DEB chemoembolization.

Embolization of hepatocellular carcinoma with drug-eluting beads: doxorubicin tissue concentration and distribution in patient liver explants.

BACKGROUND & AIMS: To follow the local tissue delivery of doxorubicin in HCC explants from patients embolized with drug-eluting beads and to compare it with histologic modifications. METHODS: Six patients with HCC underwent chemoembolization with doxorubicin-eluting beads (caliber 100-300 µm, dose 75-150 mg) followed by liver transplantation at different time points (8 h to 36 days). On sections of the explanted liver, the tissue concentration of doxorubicin was determined radially around bead-occluded vessels with microspectrofluorimetry. The intra/peritumoral location of the beads and the modifications of the surrounding tissue were determined on an adjacent hematein-eosin-saffron-stained section and compared to drug measurements. RESULTS: Doxorubicin was detected in the tissue surrounding the beads at all times of explantation. The drug impregnates an area of at least 1.2 mm in diameter around the occluded vessel. The tissue concentration of drug ranges from 5 µM at 8 h to 0.65 µM at 1 month. In patient transplanted at 8 h, no major tissue modification was observed and we found 42% of the beads occluding intratumoral vessels. Drug concentration was not different around intratumoral and peritumoral occluded vessels. After 9-14 days, necrosis was present around 37% of vessels and at 32-36 days, around 40% of vessels. Necrotic tissue was associated with a deeper penetration and a higher concentration of the drug than non necrotized areas, though statistically significant only at 32-36 days. CONCLUSIONS: Doxorubicin-eluting beads provide a sustained delivery of drug for a period of 1 month and local tissue concentrations above cytotoxic threshold in HCC-bearing livers.

Chromophobe renal cell carcinoma in a pediatric living-related kidney transplant recipient.

Renal cell carcinoma can occur in children who have received renal allografts from adults. Chromophobe renal cell carcinoma is a rare variant of renal carcinoma with distinct histochemical, ultrastructural, and genetic characteristics. We describe the incidental finding of a chromophobe renal cell carcinoma in a 13 1/2-year-old boy 5 years after receiving a living-related renal transplant. This tumor was found by serendipity during the evaluation of fever and inguinal lymphadenopathy, with the presumptive diagnosis of posttransplantation lymphoproliferative disorder. The patient was found to have cat-scratch disease. A renal cell carcinoma should be considered in the differential diagnosis of a pediatric recipient of an adult kidney with an incidental finding of a tumor in the graft.

Expanded-criteria donor kidneys: a single-center clinical and short-term financial analysis--cause for concern in retransplantation.

BACKGROUND: Expanded-criteria donor (ECD) kidneys are associated with a higher risk of posttransplant failure, but they remain a favorable alternative to dialysis. Now that a uniform definition of "expanded criteria" exists, it is more appropriate than ever to evaluate their utility compared with that seen with non-ECD kidneys. METHODS: The authors analyzed 202 cadaveric kidney-only recipients that underwent transplantation from January 1999 to September 2001, including 45 (22%) recipients whose donors met current ECD criteria. RESULTS: ECD and non-ECD kidney recipients had similar pretransplant characteristics except for older age and increased duration of renal failure in the ECD group. Patient, graft, and death-censored graft survival in both groups were similar in primary recipients but significantly worse in retransplant recipients of ECD kidneys. The relative risk of death-censored graft loss was 1.58 in the ECD group (P = 0.45). Overall inpatient charges (minus organ acquisition charge) for 1 year posttransplant were 76,962 US dollars (ECD) versus 71,026 US dollars (non-ECD) (P = 0.53); the same charges in retransplant recipients were 136,596 US dollars (ECD) versus 91,296 US dollars (non-ECD) (P = 0.25). ECD recipients, especially retransplant recipients, had consistently higher creatinine concentrations, although the average current value of all functioning ECD grafts remains less than 2 mg/dL. ECD recipients had a higher incidence of ureteral stricture (4.4% vs. 0%), but this never resulted in graft loss. CONCLUSIONS: Considering the widening disparity between renal allograft availability and need and the fact that ECD kidneys provide superior outcomes compared with dialysis, the authors' data encourage the continued use of ECD kidneys in primary recipients but justify caution in the retransplant setting.

Brain death significantly reduces isolated pancreatic islet yields and functionality in vitro and in vivo after transplantation in rats.

Although approximately 1 million islets exist in the adult human pancreas, current pancreas preservation and islet isolation techniques recover <50%. Presently, cadaveric donors remain the sole source of pancreatic tissue for transplantation. Brain death is characterized by activation of proinflammatory cytokines and organ injury during preservation and reperfusion. In this study, we assessed the effects of brain death on islet isolation yields and functionality. Brain death was induced in male 250- to 350-g Lewis rats by inflation of a Fogarty catheter placed intracranially. The rats were mechanically ventilated for 2, 4, and 6 h before removal of the pancreas (n = 6). In controls, the catheter was not inflated (n = 6). Shortly after brain death induction, a significant increase in serum tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 was demonstrated in a time-dependent manner. Upregulation of TNF-alpha, IL-1beta, and IL-6 mRNA was noted in the pancreas. Brain death donors presented lower insulin release after glucose stimulation assessed by in situ perfusion of the pancreas. Islet recovery was reduced in brain death donors compared with controls (at 6 h 602.3 +/- 233.4 vs. 1,792.5 +/- 325.4 islet equivalents, respectively; P < 0.05). Islet viability assessed in dissociated islet cells and in intact cultured islets was reduced in islets recovered from brain death donors, an effect associated with higher nuclear activities of NF-kappaB p50, c-Jun, and ATF-2. Islet functionality evaluated in vitro by static incubation and in vivo after intraportal transplantation in syngeneic streptozotocin-induced diabetic rats was significantly reduced in preparations obtained from brain death donors. In conclusion, brain death significantly reduced islet yields and functionality. These observations may lead to strategies to reduce the effects of brain death on pancreatic islets and improve the results in clinical transplantation.

Quercetin inhibits human vascular smooth muscle cell proliferation and migration.

BACKGROUND: The French paradox has been associated with regular intake of red wine, which is enriched with flavonoids. Quercetin, a flavonoid present in the human diet, exerts cardiovascular protection through its antioxidant properties. We hypothesized that the beneficial effect of quercetin also could be related to the inhibition of vascular smooth muscle cell proliferation and migration. METHODS: Human aortic smooth muscle cells (AoSMC) were grown in culture in the presence of serum. Quercetin inhibited the serum-induced proliferation of AoSMC. This inhibition was dose-dependent and not attributed to toxicity. Cell cycle analysis revealed that quercetin arrested AoSMC in the G(0)/G(1) phase. The effect of quercetin on AoSMC migration was examined using explant migration and Transwell migration assays. Quercetin significantly decreased migration in both assays in a consistent manner. Finally, Western blot analysis of AoSMC exposed to quercetin demonstrated a significant reduction in the activation of mitogen-activated protein kinase, a signaling pathway associated with the migration of vascular smooth muscle cells. CONCLUSIONS: Quercetin inhibits the proliferation and migration of AoSMC, concomitant with inhibition of mitogen-activated protein kinase phosphorylation. These findings provide new insights and a rationale for the potential use of quercetin in the prophylaxis of cardiovascular diseases.