Successful treatment of severe passenger lymphocyte syndrome with efgartigimod synergy.

INTRODUCTION: This case describes passenger lymphocyte syndrome (PLS) generating human platelet antigen 1a (HPA-1a) alloantibodies against the recipient's platelets after liver transplant. Given the rarity of PLS, especially in liver transplant with HPA-1a alloantibodies, disease course and management options are poorly described. METHODS: The patient had cirrhosis secondary to nonalcoholic steatohepatitis complicated by hepatocellular carcinoma, encephalopathy, and severe ascites. The model for end-stage liver disease (MELD) score was 15 at presentation. The patient developed hepatic artery thrombosis after an orthotopic liver transplant and was relisted for transplant with a MELD score of 40. The patient received a hepatitis C virus antibody positive, hepatitis C virus nucleic amplification test positive donor liver on postoperative day (POD) 7 after first transplant. On POD 7 after the second transplant, the patient developed profound thrombocytopenia refractory to platelet infusion. They were found to have serum antibody to HPA-1a based upon serum platelet alloantibody testing. The donor was later found to be negative for HPA-1a by genetic testing. However, the patient's native platelets were HPA-1a positive. The patient was diagnosed with PLS. RESULTS: The patient's treatment course included 57 units of platelets transfused, emergency splenectomy, rituximab, plasma exchange, intravenous immunoglobulin (IVIG), eltrombopag, romiplostim, and efgartigimod. DISCUSSION: The synergistic effect of efgartigimod with eltrombopag and romiplostim most likely resolved the patient's thrombocytopenia. This case represents a novel use of efgartigimod in the treatment of passenger lymphocyte syndrome following liver transplant.

Bile Acid Profiles in Primary Sclerosing Cholangitis and Their Ability to Predict Hepatic Decompensation.

BACKGROUND AND AIMS: Altered bile acid (BA) homeostasis is an intrinsic facet of cholestatic liver diseases, but clinical usefulness of plasma BA assessment in primary sclerosing cholangitis (PSC) remains understudied. We performed BA profiling in a large retrospective cohort of patients with PSC and matched healthy controls, hypothesizing that plasma BA profiles vary among patients and have clinical utility. APPROACH AND RESULTS: Plasma BA profiling was performed in the Clinical Biochemical Genetics Laboratory at Mayo Clinic using a mass spectrometry based assay. Cox proportional hazard (univariate) and gradient boosting machines (multivariable) models were used to evaluate whether BA variables predict 5-year risk of hepatic decompensation (HD; defined as ascites, variceal hemorrhage, or encephalopathy). There were 400 patients with PSC and 302 controls in the derivation cohort (Mayo Clinic) and 108 patients with PSC in the validation cohort (Norwegian PSC Research Center). Patients with PSC had increased BA levels, conjugated fraction, and primary-to-secondary BA ratios relative to controls. Ursodeoxycholic acid (UDCA) increased total plasma BA level while lowering cholic acid and chenodeoxycholic acid concentrations. Patients without inflammatory bowel disease (IBD) had primary-to-secondary BA ratios between those of controls and patients with ulcerative colitis. HD risk was associated with increased concentration and conjugated fraction of many BA, whereas higher G:T conjugation ratios were protective. The machine-learning model, PSC-BA profile score (concordance statistic [C-statistic], 0.95), predicted HD better than individual measures, including alkaline phosphatase, and performed well in validation (C-statistic, 0.86). CONCLUSIONS: Patients with PSC demonstrated alterations of plasma BA consistent with known mechanisms of cholestasis, UDCA treatment, and IBD. Notably, BA profiles predicted future HD, establishing the clinical potential of BA profiling, which may be suited for use in clinical trials.

Early Cholangiocarcinoma Detection With Magnetic Resonance Imaging Versus Ultrasound in Primary Sclerosing Cholangitis.

BACKGROUND AND AIMS: Early detection of perihilar cholangiocarcinoma (CCA) among patients with primary sclerosing cholangitis (PSC) is important to identify more people eligible for curative therapy. While many recommend CCA screening, there are divergent opinions and limited data regarding the use of ultrasound or magnetic resonance imaging (MRI) for early CCA detection, and it is unknown whether there is benefit in testing asymptomatic individuals. Our aims were to assess the diagnostic performances and prognostic implications of ultrasound and MRI-based CCA detection. APPROACH AND RESULTS: This is a multicenter review of 266 adults with PSC (CCA, n = 120) who underwent both an ultrasound and MRI within 3 months. Images were re-examined by radiologists who were blinded to the clinical information. Respectively, MRI had a higher area under the curve compared with ultrasound for CCA detection: 0.87 versus 0.70 for the entire cohort; 0.81 versus 0.59 for asymptomatic individuals; and 0.88 versus 0.71 for those listed for CCA transplant protocol. The absence of symptoms at CCA diagnosis was associated with improved 5-year outcomes including overall survival (82% vs. 46%, log-rank P < 0.01) and recurrence-free survival following liver transplant (89% vs. 65%, log-rank P = 0.04). Among those with asymptomatic CCA, MRI detection (compared with ultrasound) was associated with reduction in both mortality (hazard ratio, 0.10; 95% confidence interval, 0.01-0.96) and CCA progression after transplant listing (hazard ratio, 0.10; 95% confidence interval, 0.01-0.90). These benefits continued among patients who had annual monitoring and PSC for more than 1 year before CCA was diagnosed. CONCLUSIONS: MRI is superior to ultrasound for the detection of early-stage CCA in patients with PSC. Identification of CCA before the onset of symptoms with MRI is associated with improved outcomes.

Hepatocellular carcinoma radiation segmentectomy treatment intensification prior to liver transplantation increases rates of complete pathologic necrosis: an explant analysis of 75 tumors.

PURPOSE: To verify the correlation between yttrium-90 glass microsphere radiation segmentectomy treatment intensification of hepatocellular carcinoma (HCC) and complete pathologic necrosis (CPN) at liver transplantation. METHODS: A retrospective, single center, analysis of patients with HCC who received radiation segmentectomy prior to liver transplantation from 2016 to 2021 was performed. The tumor treatment intensification cohort (n = 38) was prescribed radiation segmentectomy as per response recommendations identified in a previously published baseline cohort study (n = 37). Treatment intensification and baseline cohort treatment parameters were compared for rates of CPN. Both cohorts were then combined for an overall analysis of treatment parameter correlation with CPN. RESULTS: Sixty-three patients with a combined 75 tumors were analyzed. Specific activity, dose, and treatment activity were significantly higher in the treatment intensification cohort (all p < 0.01), while particles per cubic centimeter of treated liver were not. CPN was achieved in 76% (n = 29) of tumors in the treatment intensification cohort compared to 49% (n = 18) in the baseline cohort (p = 0.013). The combined cohort CPN rate was 63% (n = 47). ROC analysis showed that specific activity ≥ 327 Bq (AUC 0.75, p < 0.001), dose ≥ 446 Gy (AUC 0.69, p = 0.005), and treatment activity ≥ 2.55 Gbq (AUC 0.71, p = 0.002) were predictive of CPN. Multivariate logistic regression demonstrated that a specific activity ≥ 327 Bq was the sole independent predictor of CPN (p = 0.013). CONCLUSION: Radiation segmentectomy treatment intensification for patients with HCC prior to liver transplantation increases rates of CPN. While dose strongly correlated with pathologic response, specific activity was the most significant independent radiation segmentectomy treatment parameter associated with CPN.

PNPLA3 Gene Polymorphism and Liver- and Extrahepatic Cancer-Related Mortality in the United States.

The palatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 G allele is associated with nonalcoholic fatty liver disease (NAFLD), hepatocellular carcinoma,1 and all-cause or cardiovascular mortality in the general population.2 One recent Italian study reported an association between PNPLA3 polymorphism and liver-related events and mortality in biopsy-confirmed NAFLD.3 Regarding extrahepatic cancer-related mortality, one study showed that only women carrying the G allele without hepatic steatosis had a 60% lower risk for cancer-related mortality.4 However, owing to insufficient follow-up and selected populations, the results from these studies cannot generalize about the association between PNPLA3 polymorphism and liver- and extrahepatic cancer-related mortality at a population level. Thus, we investigated the association between PNPLA3 polymorphism and liver- and extrahepatic cancer-related mortality based on the presence of NAFLD in the U.S. general population.

Liver Stiffness Measured by Either Magnetic Resonance or Transient Elastography Is Associated With Liver Fibrosis and Is an Independent Predictor of Outcomes Among Patients With Primary Biliary Cholangitis.

GOALS: We aimed to describe the diagnostic and prognostic performance of transient elastography (TE) and magnetic resonance elastography (MRE) in patients with primary biliary cholangitis (PBC). BACKGROUND: The diagnostic performance of TE and MRE in detecting advanced fibrosis in PBC and in predicting outcomes independent of existing serologic prognostic markers is incompletely understood. MATERIALS AND METHODS: Five hundred thirty-eight consecutive patients with PBC at 3 centers with liver stiffness (LS) measurements by TE (n=286) or MRE (n=332) were reviewed. LS cutoffs for predicting fibrosis stages were determined by receiver operating characteristic curves among those with a liver biopsy (TE, n=63; MRE, n=98). Cox proportional hazard regression modeling was used to identify associations between covariates and hepatic decompensation. RESULTS: The optimal LS thresholds for predicting histologic stage F4 were 14.40 kPa (area under the curve=0.94) for TE and 4.60 kPa (area under the curve=0.82) for MRE. Both TE and MRE outperformed biochemical markers for the prediction of histologic advanced fibrosis. Optimal LS thresholds to predict hepatic decompensation were 10.20 kPa on TE and 4.30 kPa on MRE. LS by TE and MRE (respectively) remained predictors of hepatic decompensation after adjusting for ursodeoxycholic acid responsiveness [hazard ratio (HR), 1.14; 95% confidence interval (CI), 1.05-1.24 and HR, 1.68; 95% CI, 1.28-2.19] and the GLOBE score (HR, 1.13; 95% CI, 1.07-1.19 and HR, 2.09; 95% CI, 1.57-2.78). CONCLUSION: LS measurement with either TE or MRE can accurately detect advanced fibrosis and offers additional prognostic value beyond existing serologic predictive tools.

Smoking & risk of advanced liver fibrosis among patients with primary biliary cholangitis: A systematic review & meta-analysis.

Background & objectives: Studies have suggested that smoking may accelerate the progression of fibrosis among patients with primary biliary cholangitis (PBC), although the data are limited. The current review was undertaken with the aim to comprehensively analyze this possible association by identifying all relevant studies and summarizing their results. Methods: A comprehensive literature review on MEDLINE and EMBASE databases was performed from inception through February 2019 to identify all relevant studies. Eligible studies included cross-sectional studies that recruited patients with PBC and collected data on the smoking status and presence or absence of advanced liver fibrosis for each participant. Odds ratios (OR) with 95 per cent confidence intervals (CI) was desirable for inclusion or sufficient raw data to calculate the same for this association. Adjusted point estimates from each study were extracted and combined together using the generic inverse variance method of DerSimonian and Laird. I2 statistic, which quantifies the proportion of total variation across studies was used to determine the between-study heterogeneity. Results: Three cross-sectional studies with 544 participants were included. The pooled analysis found a significantly increased risk of advanced liver fibrosis among patients with PBC who were ever-smokers compared to those who were nonsmokers with the pooled OR of 3.00 (95% CI, 1.18-7.65). Statistical heterogeneity was high with I2 of 89 per cent. Interpretation & conclusions: This meta-analysis found that smoking is associated with a significantly higher risk of advanced liver fibrosis among patients with PBC. Further prospective studies are still required to determine whether this association is causal.

PNPLA3 gene polymorphism and overall and cardiovascular mortality in the United States.

BACKGROUND AND AIM: The association between palatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) polymorphism and mortality is not well understood. We investigated the impact of PNPLA3 I148M (rs738409) polymorphism on overall and cardiovascular mortality based on the presence of nonalcoholic fatty liver disease (NAFLD). METHODS: The third National Health and Nutrition Examination Survey (NHANES) from 1991 to 1994 and National Health and Nutrition Examination Survey III-linked mortality data through 31 December 2015 were utilized in this study. RESULTS: Of 4814 participants, 50.7% were homozygous for the C-allele and 12.6% were homozygous for the G-allele. During a follow up of 20 years, there were a total of 1255 deaths, 422 attributed to cardiovascular disease. There was a significant association with overall mortality among those with the PNPLA3 I148M (rs738409) GG genotype (hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.02-1.77) or G-allele (HR 1.22, 95% CI 1.09-1.36) in the general population. NAFLD with homozygous PNPLA3 I148M (rs738409) GG genotype had higher overall mortality after adjusting for multiple metabolic risk factors (HR 1.45, 95% CI 1.01-2.08). The PNPLA3 I148M (rs738409) G-allele had a tendency of increased cardiovascular mortality in the total population. This association was not noted in those with NAFLD. CONCLUSIONS: The homozygous PNPLA3 I148M (rs738409) GG genotype showed an increase in overall mortality in the general population and NAFLD independent of multiple metabolic risk factors.

Nutritional Assessment and Malnutrition in Patients With Cirrhosis.

We sought to determine the incidence and outcomes of malnutrition in patients with cirrhosis. We performed a retrospective chart review of 134 patients listed for liver transplant (LT) to assess the presence and degree of malnutrition identified by the Subjective Global Assessment score at the time of initial transplant evaluation, follow-up nutrition visits, and at the time of transplant. Number of admissions/readmissions to the hospital, reason for hospitalization(s), and length of stay were determined. Malnutrition was prevalent at initial nutrition visit (51.9%) and underdiagnosed. By the time of transplant, 61% of the patients were identified as malnourished. Most patients (52%) were awaiting LT for more than 180 days. The change in Subjective Global Assessment score after the initial nutrition assessment was statistically significant (p ≤ .007), with worsening malnutrition severity. Seventy-one patients (53%) required hospitalization while awaiting transplant, with a median hospital stay of 9 days. Nutrition expertise is required for prompt and accurate diagnosis of malnutrition in patients with cirrhosis. Nurses caring for patients with advanced liver disease are in a prime position to provide guidance to optimize patient outcomes.

Cystic Fibrosis-Associated Liver Disease in Lung Transplant Recipients.

Cystic fibrosis (CF) is an autosomal recessive disease characterized by mutations in the gene that encodes for the cystic fibrosis transmembrane conductance regulator protein (CFTR). CFTR gene mutations manifest as epithelial cell dysfunction in the airways, biliary tract, pancreas, gut, sweat glands, paranasal sinuses, and genitourinary tract. The clinical manifestations of this dysfunction include respiratory tract infections, bronchiectasis, pancreatic insufficiency, malabsorption, intestinal obstruction, liver disease, and male infertility. The liver disease manifestations of CF can include biliary disease, multilobular cirrhosis, and portal hypertension with and without cirrhosis. Pulmonary disease is the main cause for morbidity and mortality in individuals with CF, and according to the International Society for Heart and Lung Transplantation, CF is the third most common indication for lung transplantation in adults, accounting for 16% of procedures performed. The survival after lung transplantation in individuals with CF continues to improve and is now the highest among end-stage lung diseases requiring transplant. The survival rate at 10 years is close to 50%. Given the potential presence of liver disease in CF patients undergoing an evaluation for lung transplantation and in lung transplant recipients, it is important to understand the manifestations of liver disease in CF patients and the recommended workup and follow-up. This review aims to discuss the current literature and provide guidance in the management of these patients.

The mRECIST Classification Provides Insight into Tumor Biology for Patients With Hepatocellular Carcinoma Awaiting Liver Transplantation.

With recent changes in United Network for Organ Sharing policy, patients in the United States with hepatocellular carcinoma (HCC) are likely to spend more time on the liver transplantation (LT) waiting list. The increasing wait time will allow for an opportunity to assess tumor biology prior to LT. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) paradigm provides such a framework for this assessment, and yet little is understood of its utility as it would apply for patients listed for LT in the United States. Through a collaboration between the University of California, San Francisco, and the Mayo Clinic, Jacksonville, Florida, the experience of 772 patients listed for LT were retrospectively reviewed to study the impact of immediate mRECIST classification following locoregional therapy (LRT) on pre- and post-LT outcomes. Patients who had progression of disease (PD; n = 72), failed to respond to LRT (n = 89) at any time point, or did not achieve radiologic complete response (CR; n = 224) were all at significant risk for wait-list dropout (odds ratio [OR] = 12.11, 4.81, and 2.48; respectively). CR identified a cohort of patients who were at a reduced risk for wait-list dropout. However, 24.9% eventually required further intervention while waiting for transplant, and as many as 82.4% were found to have residual HCC on explant pathology. Failure to respond to LRT was associated with increased risk for recurrence (OR = 3.00) more so than PD (OR = 1.36), suggesting that despite PD, patients who eventually can respond to LRT may represent favorable candidates for LT. In conclusion, for patients awaiting LT, the mRECIST assessment provides critical guidance for patient management. Although PD portends a poor prognosis, our findings suggest that further aggressive LRT should be pursued because a response to LRT may yield acceptable results for patients awaiting LT as well as after LT.

Evolving Role of Liver Transplantation in Elderly Recipients.

The need for liver transplantation (LT) among older patients is increasing, but the role of LT in the elderly (≥70 years) is not well defined. We retrospectively reviewed all primary LTs from 1998 through 2016 at our center. Survival and associated risk factors were analyzed with Cox regression and Kaplan-Meier methods for LT recipients in 3 age groups: <60, 60-69, and ≥70 years. Among 2281 LT recipients, the median age was 56 years (range, 15-80 years), and 162 were aged ≥70 years. The estimated 5- and 10-year patient survival probabilities for elderly LT recipients were lower (70.8% and 43.6%) than for recipients aged 60-69 years (77.2% and 64.6%) and <60 years (80.7% and 67.6%). Patient and graft survival rates associated with LT improved over time from the pre-Model for End-Stage Liver Disease era to Share 15, pre-Share 35, and Share 35 for the cohort overall (P < 0.001), but rates remained relatively stable in septuagenarians throughout the study periods (all P > 0.45). There was no incremental negative effect of age at LT among elderly patients aged 70-75 years (log-rank P = 0.32). Among elderly LT recipients, greater requirement for packed red blood cells and longer warm ischemia times were significantly associated with decreased survival (P < 0.05). Survival of LT recipients, regardless of age, markedly surpassed that of patients who were denied LT, but it was persistently 20%-30% lower than the expected survival of the general US population (P < 0.001). With the aging of the population, select older patients with end-stage liver diseases can benefit from LT, which largely restores their expected life spans.

Sexual dimorphism in the incidence of human cancers.

BACKGROUND: Sex differences in the incidences of cancers become a critical issue in both cancer research and the development of precision medicine. However, details in these differences have not been well reported. We provide a comprehensive analysis of sexual dimorphism in human cancers. METHODS: We analyzed four sets of cancer incidence data from the SEER (USA, 1975-2015), from the Cancer Registry at Mayo Clinic (1970-2015), from Sweden (1970-2015), and from the World Cancer Report in 2012. RESULTS: We found that all human cancers had statistically significant sexual dimorphism with male dominance in the United States and mostly significant in the Mayo Clinic, Sweden, and the world data, except for thyroid cancer, which is female-dominant. CONCLUSIONS: Sexual dimorphism is a clear but mostly neglected phenotype for most human cancers regarding the clinical practice of cancer. We expect that our study will facilitate the mechanistic studies of sexual dimorphism in human cancers. We believe that fully addressing the mechanisms of sexual dimorphism in human cancers will greatly benefit current development of individualized precision medicine beginning from the sex-specific diagnosis, prognosis, and treatment.

Liver transplantation for intrahepatic cholangiocarcinoma.

Although hepatocellular carcinoma (HCC) has become a common indication for liver transplantation (LT), intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) are historically contraindicated due to their aggressive behavior. On the basis of recent experiences, some groups have proposed a clinical trial investigating the role of LT for patients with early cholangiocarcinoma (CCA), defined as a single lesion ≤ 2 cm. The purpose of this study is to assess the clinicopathologic features and outcomes following LT for patients who were initially diagnosed with HCC and subsequently found to have either ICC or cHCC-CCA on explant. Patients with the diagnosis of primary liver cancer (PLC) after LT from a single center were retrospectively reviewed. Outcomes for patients with early CCA were compared with patients with HCC within Milan criteria (MC). Out of 618 patients transplanted with PLC, 44 patients were found to have CCA on explant. On the basis of preoperative imaging, 12 patients met criteria for early CCA and were compared with 319 patients who had HCC within MC. The 1- and 5-year overall survival for early CCA versus HCC was 63.6% versus 90.0% and 63.6% versus 70.3% (log-rank, P = 0.25), respectively. Overall recurrence was 33.3% for early CCA versus 11% for HCC. On explant the patients with CCA were more likely understaged with higher tumor grade and vascular invasion. In conclusion, patients with CCA present a diagnostic challenge, which often leads to the finding of more aggressive lesions on explant after LT, higher recurrence rates, and worse post-LT survival. Careful consideration of this diagnostic conundrum needs to be made before a clinical trial is undertaken. Liver Transplantation 24 634-644 2018 AASLD.

Volumetric laser endomicroscopy in the biliary and pancreatic ducts: a feasibility study with histological correlation.

BACKGROUND: Volumetric laser endomicroscopy (VLE) provides circumferential images 3 mm into the biliary and pancreatic ducts. We aimed to correlate VLE images with the normal and abnormal microstructure of these ducts. METHODS: Samples from patients undergoing hepatic or pancreatic resection were evaluated. VLE images were collected using a low-profile VLE catheter inserted manually into the biliary and pancreatic ducts ex vivo. Histological correlation was assessed by two unblinded investigators. RESULTS: 25 patients (20 liver and 5 pancreatic samples) and 111 images were analyzed. VLE revealed three histological layers: epithelium, connective tissue, and parenchyma. It identified distinctive patterns for primary sclerosing cholangitis (PSC), pancreatic cysts, neuroendocrine tumor, and adenocarcinoma adjacent to the pancreatic duct or ampulla. VLE failed to identify dysplasia in a dominant stricture and inflammatory infiltrates in PSC. Reflectivity measurements of the liver parenchyma diagnosed liver cirrhosis with high sensitivity. CONCLUSIONS: VLE can identify histological changes in the biliary and pancreatic ducts allowing real-time diagnosis. Further studies are needed to measure the accuracy of VLE in a larger sample and to validate our findings in vivo.

Liver Transplantation for Hepatocellular Carcinoma: Impact of Wait Time at a Single Center.

INTRODUCTION AND AIM: Liver transplantation (LT) provides durable survival for hepatocellular carcinoma (HCC). However, there is continuing debate concerning the impact of wait time and acceptable tumor burden on outcomes after LT. We sought to review outcomes of LT for HCC at a single, large U.S. center, examining the influence of wait time on post-LT outcomes. MATERIAL AND METHODS: We reviewed LT for HCC at Mayo Clinic in Florida from 1/1/2003 until 6/30/2014. Follow up was updated through 8/1/ 2015. RESULTS: From 2003-2014, 978 patients were referred for management of HCC. 376 patients were transplanted for presumed HCC within Milan criteria, and the results of these 376 cases were analyzed. The median diagnosis to LT time was 183 days (8 - 4,337), and median transplant list wait time was 62 days (0 - 1815). There was no statistical difference in recurrence-free or overall survival for those with wait time of less than or greater than 180 days from diagnosis of HCC to LT. The most important predictor of long term survival after LT was HCC recurrence (HR: 18.61, p < 0.001). Recurrences of HCC as well as survival were predicted by factors related to tumor biology, including histopathological grade, vascular invasion, and pre-LT serum alpha-fetoprotein levels. Disease recurrence occurred in 13%. The overall 5-year patient survival was 65.8%, while the probability of 5-year recurrence-free survival was 62.2%. CONCLUSIONS: In this large, single-center experience with long-term data, factors of tumor biology, but not a longer wait time, were associated with recurrence-free and overall survival.