Liver Transplant for Management of Hepatic Complications of Dyskeratosis Congenita: A Case Report.

Dyskeratosis congenita, a rare genetic disorder typified by progressive bone marrow failure, is classically characterized by the triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia; however, it is a multisystem disease. Although hepatic involvement occurs in about 7% of patients with dyskeratosis congenita, end-stage liver disease is rare. Treatment of dyskeratosis congenita generally involves hematopoietic stem cell transplant. For patients with hepatic failure, liver transplant can be an option. Here, we describe a case of a patient with dyskeratosis congenita who presented with liver failure and pulmonary failure, precluding him from hematopoietic stem cell transplant. After liver transplant, the patient had significant improvements in pulmonary function and transfusion requirements, allowing the patient to qualify for hematopoietic stem cell transplant. Although hematopoietic stem cell transplant is typically the first step in the management of dyskeratosis congenita, for patients with severe hepatic manifestations of the disease, a liver transplant first approach may result in better disease management.

Neoadjuvant treatment strategies for intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignancy and is increasing in incidence. Long-term outcomes are optimized when patients undergo margin-negative resection followed by adjuvant chemotherapy. Unfortunately, a significant proportion of patients present with locally advanced, unresectable disease. Furthermore, recurrence rates are high even among patients who undergo surgical resection. The delivery of systemic and/or liver-directed therapies prior to surgery may increase the proportion of patients who are eligible for surgery and reduce recurrence rates by prioritizing early systemic therapy for this aggressive cancer. Nevertheless, the available evidence for neoadjuvant therapy in ICC is currently limited yet recent advances in liver directed therapies, chemotherapy regimens, and targeted therapies have generated increasing interest its role. In this article, we review the rationale for, current evidence for, and ongoing research efforts in the use of neoadjuvant therapy for ICC.

Defining a Liver Transplant Benefit Threshold for the Model for End-Stage Liver Disease-Sodium Score.

OBJECTIVES: The benefits of transplant are shown as the difference in survival posttransplant versus that shown if the patient had remained on the wait list. Serum sodium was added to improve prediction. We sought to revisit the question of which Model for End-Stage Liver Disease-Sodium score threshold corresponded to a predicted benefit of liver transplant. MATERIALS AND METHODS: Data on adult patients (≥ 18 years old) were obtained from the United Network for Organ Sharing registry (date range of June 18, 2013 to December 2016). Exclusion criteria were individuals listed for multiple organs or liver retransplant, patients who eventually underwent living-donor liver transplant, and patients with MELD score < 12. We used multivariable Cox proportional hazards regression to determine a time-dependent covariate for undergoing transplant with either MELD or MELD-sodium scores to describe the variability in estimated transplant benefit within 6 months of listing. RESULTS: Our study included 14 352 patients. There were 902 patients with MELD score of 39 to 40 (6.3%) and 931 patients with MELD-Na score of 39 to 40 (6.5%). Using the original MELD score, we found that 90% of the cohort could derive benefit from transplant compared with 83% when MELD-Na was used. We found that 13% of patients had a predicted transplant benefit when determined using either MELD or MELD-Na but not both. The threshold for transplant benefit was 16 and 17 using MELD and MELD-Na, respectively. CONCLUSIONS: Transition to MELD-Na did not define a more precise range at which patients benefited from transplant, and a similar percentage of patients was expected to derive benefit. Future revisions of donor liver allocation may allow better discrimination of expected transplant benefits among candidates currently assigned a high priority for donor livers.

County Rankings Have Limited Utility When Predicting Liver Transplant Outcomes.

BACKGROUND: Evidence of geographical differences in liver transplantation (LT) outcomes has been proposed as a reason to include community characteristics in risk adjustment of transplant quality metrics. However, consistency and utility of rankings in LT outcomes for counties have not been demonstrated. AIMS: We sought to evaluate the utility of county rankings (county socioeconomic status (SES) or county health scores (CHS)) on outcomes after LT. METHODS: Using the United Network for Organ Sharing Registry, adults ≥ 18 years of age undergoing LT between 2002 and 2014 were identified. County-specific 1-year survival was calculated using the Kaplan-Meier method for counties with ≥ 5 LT performed during this period. Agreement between high-risk designation by 1-year mortality rate and county ranking was calculated using the Spearman correlation coefficient. RESULTS: The analysis included 47,769 LT recipients in 1092 counties. County 1-year mortality rates were not correlated with county CHS (Spearman ρ = 0.01, p = 0.694) or county SES (Spearman ρ = - 0.01, p = 0.734). After controlling for individual-level covariates, a statistically significant variability in mortality hazards across counties (p < 0.001) persisted. Although both CHS and SES measures improved the model fit (p = 0.004 and p = 0.048, respectively), an unexplained residual variation in mortality hazard across counties continued. CONCLUSIONS: There is poor agreement between county rankings on various socioeconomic indicators and LT outcomes. Although there is variability in outcomes across counties, this appears not to be due to county-level socioeconomic indices.

Neoadjuvant and adjuvant treatment strategies for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common liver malignancy worldwide and a major cause of cancer-related mortality for which liver resection is an important curative-intent treatment option. However, many patients present with advanced disease and with underlying chronic liver disease and/or cirrhosis, limiting the proportion of patients who are surgical candidates. In addition, the development of recurrent or de novo cancers following surgical resection is common. These issues have led investigators to evaluate the benefit of neoadjuvant and adjuvant treatment strategies aimed at improving resectability rates and decreasing recurrence rates. While high-level evidence to guide treatment decision making is lacking, recent advances in locoregional and systemic therapies, including antiviral treatment and immunotherapy, raise the prospect of novel approaches that may improve the outcomes of patients with HCC. In this review, we evaluate the evidence for various neoadjuvant and adjuvant therapies and discuss opportunities for future clinical and translational research.

[D-Ala2, D-Leu5] Enkephalin Improves Liver Preservation During Normothermic Ex Vivo Perfusion.

BACKGROUND: Meeting the metabolic demands of donor livers using normothermic ex vivo liver perfusion (NEVLP) preservation technology is challenging. The delta opioid agonist [D-Ala2, D-Leu5] enkephalin (DADLE) has been reported to decrease the metabolic demand in models of ischemia and cold preservation. We evaluated the therapeutic potential of DADLE by investigating its ability to protect against oxidative stress and hepatic injury during normothermic perfusion. MATERIALS AND METHODS: Primary rat hepatocytes were used in an in vitro model of oxidative stress to determine the minimum dose of DADLE needed to induce protection and the mechanisms associated with protection. NEVLP was then used to induce injury in rat livers and determine the effectiveness of DADLE in preventing liver injury. RESULTS: In hepatocytes, DADLE was protective against oxidative stress and led to a decrease in phosphorylation of JNK and p38. Naltrindole, a δ-opioid receptor antagonist, blocked this effect. DADLE also activated the PI3K/Akt signaling pathway, and PI3K/Akt inhibition decreased the protective effects of DADLE treatment. In addition, DADLE treatment during NEVLP resulted in lower perfusate alanine aminotransferase and tissue malondialdehyde and better tissue adenosine triphosphate and glutathione. Furthermore, perfusion with DADLE compared with perfusate alone preserved tissue architecture. CONCLUSIONS: DADLE confers protection against oxidative stress in hepatocytes and during NEVLP. These data suggest that the mechanism of protection involved the prevention of mitochondrial dysfunction by opioid receptor signaling and subsequent increased expression of prosurvival/antiapoptotic signaling pathways. Altogether, data suggest that opioid receptor agonism may serve as therapeutic target for improved liver protection during NEVLP.

Intrahepatic Delivery of Pegylated Catalase Is Protective in a Rat Ischemia/Reperfusion Injury Model.

BACKGROUND: Ischemia/reperfusion injury (IRI) can occur during liver surgery. Endogenous catalase is important to cellular antioxidant defenses and is critical to IRI prevention. Pegylation of catalase (PEG-CAT) improves its therapeutic potential by extending plasma half-life, but systemic administration of exogenous PEG-CAT has been only mildly therapeutic for hepatic IRI. Here, we investigated the protective effects of direct intrahepatic delivery of PEG-CAT during IRI using a rat hilar clamp model. MATERIALS AND METHODS: PEG-CAT was tested in vitro and in vivo. In vitro, enriched rat liver cell populations were subjected to oxidative stress injury (H2O2), and measures of cell health and viability were assessed. In vivo, rats underwent segmental (70%) hepatic warm ischemia for 1 h, followed by 6 h of reperfusion, and plasma alanine aminotransferase and aspartate aminotransferase, tissue malondialdehyde, adenosine triphosphate, and GSH, and histology were assessed. RESULTS: In vitro, PEG-CAT pretreatment of liver cells showed substantial uptake and protection against oxidative stress injury. In vivo, direct intrahepatic, but not systemic, delivery of PEG-CAT during IRI significantly reduced alanine aminotransferase and aspartate aminotransferase in a time-dependent manner (P < 0.01, P < 0.0001, respectively, for all time points) compared to control. Similarly, tissue malondialdehyde (P = 0.0048), adenosine triphosphate (P = 0.019), and GSH (P = 0.0015), and the degree of centrilobular necrosis, were improved by intrahepatic compared to systemic PEG-CAT delivery. CONCLUSIONS: Direct intrahepatic administration of PEG-CAT achieved significant protection against IRI by reducing the volume distribution and taking advantage of the substantial hepatic first-pass uptake of this molecule. The mode of delivery was an important factor for protection against hepatic IRI by PEG-CAT.

Enterovesical Fistula After Enteric Conversion of a Bladder-Drained Pancreatic Allograft: A Case Report.

Since the inception of pancreas transplant as a treatment for type 1 diabetes mellitus, there has been considerable debate about the best way to manage exocrine secretions and monitor patients for graft rejection. For patients who undergo bladder exocrine drainage of a pancreatic allograft, a bladder-to-enteric drainage conversion can serve as a rescue procedure in case of anastomotic leaks or other complications. However, this procedure is associated with its own complications, including a rarely described enterovesical fistula. Here we report on a 45-year-old man who underwent a simultaneous kidney and pancreas transplant with bladder drainage to the latter. He developed a pancreatic allograft duodenal leak (duodenal-vesical anastomosis) requiring a bladder-to-enteric drainage conversion. The patient returned 2 weeks after discharge with an enterovesical fistula. He was treated nonsurgically with intravenous antibiotics, bowel rest, and parenteral nutrition, and the fistula successfully closed in approximately 2 weeks. Overall, enterovesical fistula formation is a rare but treatable complication that can occur after a bladder-to-enteric drainage conversion of a pancreatic transplant allograft. It can be managed nonsurgically, which is preferable in these immunocompromised patients.

Normothermic Ex-vivo Liver Perfusion and the Clinical Implications for Liver Transplantation.

Despite significant improvements in outcomes after liver transplantation, many patients continue to die on the waiting list, while awaiting an available organ for transplantation. Organ shortage is not only due to an inadequate number of available organs, but also the inability to adequately assess and evaluate these organs prior to transplantation. Over the last few decades, ex-vivo perfusion of the liver has emerged as a useful technique for both improved organ preservation and assessment of organs prior to transplantation. Large animal studies have shown the superiority of ex-vivo perfusion over cold static storage. However, these studies have not, necessarily, been translatable to human livers. Small animal studies have been essential in understanding and improving this technology. Similarly, these results have yet to be translated into clinical use. A few Phase 1 clinical trials have shown promise and confirmed the viability of this technology. However, more robust studies are needed before ex-vivo liver perfusion can be widely accepted as the new clinical standard of organ preservation. Here, we aimed to review all relevant large and small animal research, as well as human liver studies on normothermic ex-vivo perfusion, and to identify areas of deficiency and opportunities for future research endeavors.

A Small Animal Model of Ex Vivo Normothermic Liver Perfusion.

There is a significant shortage of liver allografts available for transplantation, and in response the donor criteria have been expanded. As a result, normothermic ex vivo liver perfusion (NEVLP) has been introduced as a method to evaluate and modify organ function. NEVLP has many advantages in comparison to hypothermic and subnormothermic perfusion including reduced preservation injury, restoration of normal organ function under physiologic conditions, assessment of organ performance, and as a platform for organ repair, remodeling, and modification. Both murine and porcine NEVLP models have been described. We demonstrate a rat model of NEVLP and use this model to show one of its important applications - the use of a therapeutic molecule added to liver perfusate. Catalase is an endogenous reactive oxygen species (ROS) scavenger and has been demonstrated to decrease ischemia-reperfusion in the eye, brain, and lung. Pegylation has been shown to target catalase to the endothelium. Here, we added pegylated-catalase (PEG-CAT) to the base perfusate and demonstrated its ability to mitigate liver preservation injury. An advantage of our rodent NEVLP model is that it is inexpensive in comparison to larger animal models. A limitation of this study is that it does not currently include post-perfusion liver transplantation. Therefore, prediction of the function of the organ post-transplantation cannot be made with certainty. However, the rat liver transplant model is well established and certainly could be used in conjunction with this model. In conclusion, we have demonstrated an inexpensive, simple, easily replicable NEVLP model using rats. Applications of this model can include testing novel perfusates and perfusate additives, testing software designed for organ evaluation, and experiments designed to repair organs.

Cystoisospora belli Gallbladder Infection in a Liver Transplant Donor.

INTRODUCTION: Cystoisospora belli (previously Isospora belli) is a parasitic protozoan of the human gastrointestinal system. It rarely causes symptoms in immunocompetent hosts but can cause severe diarrhea in immunocompromised patients, with a rate of recurrence and risk of dissemination. Gallbladder infections are however rare. The treatment of choice for symptomatic patients is a 7-10-day course of trimethoprim-sulfamethoxazole. CASE: In this case, we report on an incidental finding of Cystoisospora belli organisms in the donor gallbladder following a transplant cholecystectomy. There was no report of symptoms in the donor. The recipient was treated with a course of trimethoprim-sulfamethoxazole, without evidence of cystoisosporiasis. Given the risk of recurrence in immunocompromised hosts, the patient will continue to be monitored for reactivation in the future. CONCLUSION: Despite advances in transplant protocols and screening, disease transmission from the donor to recipient still occurs in about 0.2% of all organ transplants. With the increased use of organs from drug overdose victims and other high-risk donors, practitioners (including pathologists, hepatologists, and surgeons) must maintain a high index of suspicion for such potentially harmful organisms.

Change in Health Insurance Coverage After Liver Transplantation Can Be Associated with Worse Outcomes.

BACKGROUND: Health insurance coverage changes for many patients after liver transplantation, but the implications of this change on long-term outcomes are unclear. AIMS: To assess post-transplant patient and graft survival according to change in insurance coverage within 1 year of transplantation. METHODS: We queried the United Network for Organ Sharing for patients between ages 18-64 years undergoing liver transplantation in 2002-2016. Patients surviving > 1 year were categorized by insurance coverage at transplantation and the 1-year transplant anniversary. Multivariable Cox regression characterized the association between coverage pattern and long-term patient or graft survival. RESULTS: Among 34,487 patients in the analysis, insurance coverage patterns included continuous private coverage (58%), continuous public coverage (29%), private to public transition (8%) and public to private transition (4%). In multivariable analysis of patient survival, continuous public insurance (HR 1.29, CI 1.22, 1.37, p < 0.001), private to public transition (HR 1.17, CI 1.07, 1.28, p < 0.001), and public to private transition (HR 1.14, CI 1.00, 1.29, p = 0.044), were associated with greater mortality hazard, compared to continuous private coverage. After disaggregating public coverage by source, mortality hazard was highest for patients transitioning from private insurance to Medicaid (HR vs. continuous private coverage = 1.32; 95% CI 1.14, 1.52; p < 0.001). Similar differences by insurance category were found for death-censored graft failure. CONCLUSION: Post-transplant transition to public insurance coverage is associated with higher risk of adverse outcomes when compared to retaining private coverage.

County socioeconomic characteristics and pediatric renal transplantation outcomes.

BACKGROUND: Existing risk adjustment models for solid organ transplantation omit socioeconomic status (SES). With limited data available on transplant candidates' SES, linkage of transplant outcomes data to geographic SES measures has been proposed. We investigate the utility of county SES for understanding differences in pediatric kidney transplantation (KTx) outcomes. METHODS: We identified patients < 18 years of age receiving first-time KTx using United Network for Organ Sharing registry data in two eras: 2006-2010 and 2011-2015, corresponding to periods of county SES data collection. In each era, counties were ranked by 1-year rates of survival with intact graft, and by county SES score. We used Spearman correlation (ρ) to evaluate the association between county rankings on SES and transplant outcomes in each era and consistency between these measures across eras. We also evaluated the utility of county SES for improving prediction of individual KTx outcomes. RESULTS: The analysis included 2972 children and 108 counties. County SES and transplant outcomes were not correlated in either 2006-2010 (ρ = 0.06; p = 0.525) or 2011-2015 (ρ = 0.162, p = 0.093). County SES rankings were strongly correlated between eras (ρ = 0.99, p < 0.001), whereas county rankings of transplant outcomes were not correlated between eras (ρ = 0.16, p = 0.097). Including county SES quintile in individual-level models of transplant outcomes did not improve model predictive utility. CONCLUSIONS: Pediatric kidney transplant outcomes are unstable from period to period at the county level and are not correlated with county-level SES. Appropriate adjustment for SES disparities in transplant outcomes could require further collection of detailed individual SES data.

Racial disparities in esophageal cancer outcomes.

BACKGROUND: Racial disparities in outcomes have been documented among patients with esophageal cancer. The purpose of this study is to identify mechanisms for ethnicity/race-related differences in the use of cancer-directed surgery and mortality. METHODS: Data from the Surveillance, Epidemiology and End Results (SEER) program were used to evaluate non-Hispanic black, non-Hispanic white and Hispanic patients diagnosed with non-metastatic esophageal cancer (squamous cell carcinoma or adenocarcinoma) from 2003-2008. Age, marital status, stage, histology and location were examined as predictors of receipt of surgery and mortality in multivariate analyses. RESULTS: A total of 6,737 patient files (84 % white, 10 % black, 6 % Hispanic) were analyzed. Black and Hispanic patients were more likely than whites to have squamous cell carcinoma (86 vs. 41 vs. 26 %, respectively; p < 0.001) and lesions in the midesophagus (58 vs. 38 vs. 26 %, respectively; p < 0.001). Blacks and Hispanics were less likely to undergo esophagectomy (adjusted odds ratio 0.48, 95 % confidence interval (CI) 0.39-0.60 and 0.71, 95 % CI 0.56-0.90]. We noted significant variations in esophagectomy rates among patients with midesophageal cancers; 15 % of blacks underwent esophagectomy compared to 22 % of Hispanics and 29 % of whites (p < 0.001). Black and Hispanic patients had a higher unadjusted risk of mortality (hazard ratio 1.38, 95 % CI 1.25-1.52 and 1.20, 95 % CI 1.05-1.37). However, differences in mortality were no longer significant after adjusting for receipt of surgery. CONCLUSIONS: Disparities in esophageal cancer outcomes are associated with the lower use of cancer-directed surgery. To decrease disparities in mortality it will be necessary to understand and target underlying causes of lower surgery rates in nonwhite patients and develop interventions, especially for midesophageal cancers.