Watt, Kymberly D.

AbstractGraft‐versus‐hostdisease (GVHD) following liver transplantation (LT) is rare but can lead tosignificant mortality. The leading cause of death following GVHD diagnosis isinfectious complications. However, there is a lack of clear descriptions concerning infection and antimicrobial management patterns. Our study aims toprovide the focused details of all infectious complications of acute GVHDfollowing LT. We retrospectively reviewed all adult LT recipients with acute GVHD at Mayo Clinic's Transplant Centers from January 1, 2010, to December 31, 2021. Detailed characteristics of infection in each case were described. Among 4,585 LTs performed during this period, 12 (0.3%) patients developed acuteGVHD. The median time from transplantation to GVHD diagnosis was 49.0 days [IQR 31.5–99.0]. Ten (83.3%) patients developed severe infections leading tomortality. The most common cause of infection was nosocomial bacteremia fromenteric bacteria such as vancomycin‐resistant enterococci and gram‐negative bacilli. Other infections included breakthrough invasive fungal infections,cytomegalovirus (CMV) reactivation, and Clostridioides difficile colitis. Antimicrobial prophylaxis strategies in most cases were based on the degree of neutropenia—these include levofloxacin for bacterial prophylaxis, nebulized pentamidine for Pneumocystis jiroveci pneumonia prophylaxis, posaconazole for invasive fungal prophylaxis, and valganciclovir based on CMVstatus. All GVHD patients with severe infections succumbed to thesecomplications. Ourstudy reiterates that despite prophylaxis, infectious complications in GVHDfollowing LT are common and lead to exceptionally high mortality. Individualizedantimicrobial treatment, prophylaxis and monitoring strategies remain a criticalcomponent of GVHD management. Further study to optimize these practices isrequired. image

AbstractBackground and aimsNonalcoholic steatohepatitis (NASH) is associated with metabolic conditions that increase the risk of de novo malignancy following transplant. Patients often have more than one underlying liver disease, which could change the risk of de novo malignancy. This study assessed the incidence of NASH overlap and its effect on de novo malignancy in liver transplant recipients.MethodsData was analyzed from the United Network for Organ Sharing database for all liver transplant recipients from 1997 to 2017 for NASH alone or in combination with another liver disease.ResultsThere is an increasing prevalence of NASH overlap. Of the 98,679 patients included in the analysis, 1238 had a de novo malignancy identified (7.4% by 5 years post‐transplant). The cumulative incidence of de novo malignancy increases in primary sclerosing cholangitis (PSC)/NASH overlap after 5 years and was increased in alcohol‐related liver disease (ALD)/NASH through 10 years compared to ether disease alone. NASH overlaps with “other” diseases experience a cumulative incidence similar to NASH and not the “other” disease. An increased risk of de novo solid organ malignancy was associated with older age, male gender, previous malignancy, and multiorgan transplant.ConclusionThe prevalence of liver transplant recipients with NASH overlap is increasing. These patients may experience different long‐term outcomes than patients with either diagnosis alone. De novo malignancy risk can be influenced by multiple factors and metabolic comorbidities. Further study of patients with overlap diagnoses is important moving forward to guide individualized care and cancer screening programs.

Abstract Liver transplantation (LT) is the definitive treatment for end‐stage liver disease. Unfortunately, women are disadvantaged at every stage of the LT process. We conducted a literature review to increase the understanding of this disparity. Hormonal differences, psychological factors, and Model for End‐Stage Liver Disease (MELD) score inequalities are some pretransplantation factors that contribute to this disparity. In the posttransplantation setting, women have differing risk than men in most major outcomes (perioperative complications, rejection, long‐term renal dysfunction, and malignancy) and assessing the two groups together is disadvantageous. Herein, we propose interventions including standardized criteria for LT referral, using an alternate MELD, education for support of women, and motivating women to seek living donors. Understanding sex‐based differences will allow us to improve access, tailor management, and improve overall outcomes for all patients, particularly women.

Post‐transplant diabetes mellitus (PTDM) is a significant contributor to morbidity and mortality in liver transplant recipients (LTRs). With concurrent comorbidities and use of various immunosuppression medications, identifying a safe and personalized regimen for management of PTDM is needed. There are many comorbidities associated with the post‐transplant course including chronic kidney disease, cardiovascular disease, allograft steatosis, obesity, and de novo malignancy. Emerging data suggest that available diabetes medications may carry beneficial or, in some cases, harmful effects in the setting of these co‐existing conditions. Sodium‐glucose co‐transporter 2 inhibitors and glucagon‐like peptide 1 receptor agonists have shown the most promising beneficial results. Although there is a deficiency of LTR‐specific data, they appear to be generally safe. Effects of other medications are varied. Metformin may reduce the risk of malignancy. Pioglitazone may be harmful in patients combatting obesity or heart failure. Insulin may exacerbate obesity and increase the risk of developing malignancy. This review thoroughly discusses the roles of these extra‐glycemic effects and safety considerations in LTRs. Through weighing the risks and benefits, we conclude that alternatives to insulin should be strongly considered, when feasible, for personalized long‐term management based on risk factors and co‐morbidities.

De novo malignancies (DNMs) following liver transplantation (LT) have been reported as 1 of the major causes of late mortality, being the most common cause of death in the second decade after LT. The overall incidence of DNMs is reported to be in the range of 3.1% to 14.4%, and the incidence is 2- to 3-fold higher in transplant recipients than in age- and sex-matched healthy controls. Long-term immunosuppressive therapy, which is the key in maintaining host tolerance and achieving good long-term outcomes, is known to contribute to a higher risk of DNMs. However, the incidence and type of DNM also depends on different risk factors, including patient demographics, cause of the underlying chronic liver disease, behavior (smoking and alcohol abuse), and pre-existing premalignant conditions. The estimated standardized incidence ratio for different DNMs is also variable. The International Liver Transplantation Society–Spanish Society of Liver Transplantation Consensus Conference working group on DNM has summarized and discussed the current available literature on epidemiology, risk factors, management, and survival after DNMs. Recommendations for screening and surveillance for specific tumors, as well as immunosuppression and cancer-specific management in patients with DNM, are summarized.

The International Liver Transplantation Society and the Spanish Society of Liver Transplantation consensus conference on extrahepatic cancer and liver transplantation (LT) was held on January 28–30, 2021. Working groups were organized to focus on one topic and develop evidence-based recommendations specifically addressing (a) nonhepatic cancer in LT candidates, (b) de novo malignancies after LT, (c) prevention and management of donor-derived malignancies after LT, and (d) nonhepatic cancer in the pediatric population. All consensus conference attendees voted on the recommendations proposed as well as the quality of evidence according to the Grading of Recommendations, Assessment, Development and Evaluation system.

AbstractBackgroundHypertrophic cardiomyopathy (HCM) presents with a hypertrophied left ventricle (LV). It is often associated with LV outflow tract obstruction (LVOTO) and a risk for sudden death. This study aimed to describe outcomes of patients with HCM who underwent liver transplant (LT).MethodsA retrospective review was conducted for patients diagnosed with HCM undergoing LT. Patient characteristics, preoperative echocardiography results, HCM risk of sudden cardiac death prediction model score, and 5‐year mortality were examined. A univariable Cox proportional hazards model was used to evaluate the association between risk factors and 5‐year mortality. All tests were two‐sided with the alpha level set at .05.ResultsTwenty‐nine patients were included in the analysis. Six patients (21%) had a perioperative cardiopulmonary complication. The 5‐year survival rate was 61% (95% CI, 45–82). The analyzed risk factors showed that 5‐year post‐LT survival was significantly predicted by maximal LV outflow tract gradient at rest > 60 mmHg (hazard ratio, 1.04 [95% CI, 1.01‐1.06]).ConclusionsPreoperative LV outflow tract resting gradient > 60 mmHg was associated with 5‐year post‐LT mortality. The results suggest the severity of LVOTO identified by echocardiography is a prognostic tool for patients with HCM after LT.

Prostate‐specific membrane antigen (PSMA) is a validated target for molecular diagnostics and targeted radionuclide therapy. Our purpose was to evaluate PSMA expression in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatic adenoma (HCA); investigate the genetic pathways in HCC associated with PSMA expression; and evaluate HCC detection rate with 68Ga‐PSMA‐11 positron emission tomography (PET). In phase 1, PSMA immunohistochemistry (IHC) on HCC (n = 148), CCA (n = 111), and HCA (n = 78) was scored. In a subset (n = 30), messenger RNA (mRNA) data from the Cancer Genome Atlas HCC RNA sequencing were correlated with PSMA expression. In phase 2, 68Ga‐PSMA‐11 PET was prospectively performed in patients with treatment‐naïve HCC on a digital PET scanner using cyclotron‐produced 68Ga. Uptake was graded qualitatively and semi‐quantitatively using standard metrics. On IHC, PSMA expression was significantly higher in HCC compared with CCA and HCA (P < 0.0001); 91% of HCCs (n = 134) expressed PSMA, which principally localized to tumor‐associated neovasculature. Higher tumor grade was associated with PSMA expression (P = 0.012) but there was no association with tumor size (P = 0.14), fibrosis (P = 0.35), cirrhosis (P = 0.74), hepatitis B virus (P = 0.31), or hepatitis C virus (P = 0.15). Overall survival tended to be longer in patients without versus with PSMA expression (median overall survival: 4.2 vs. 1.9 years; P = 0.273). FGF14 (fibroblast growth factor 14) mRNA expression correlated positively (rho = 0.70; P = 1.70 × 10‐5) and MAD1L1 (Mitotic spindle assembly checkpoint protein MAD1) correlated negatively with PSMA expression (rho = −0.753; P = 1.58 × 10‐6). Of the 190 patients who met the eligibility criteria, 31 patients with 39 HCC lesions completed PET; 64% (n = 25) lesions had pronounced 68Ga‐PSMA‐11 standardized uptake value: SUVmax (median [range] 9.2 [4.9‐28.4]), SUVmean 4.7 (2.4‐12.7), and tumor‐to‐liver background ratio 2 (1.1‐11). Conclusion: Ex vivo expression of PSMA in neovasculature of HCC translates to marked tumor avidity on 68Ga‐PSMA‐11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC.