Bridging and downstaging with TACE in early and intermediate stage hepatocellular carcinoma: Predictors of receiving a liver transplant.

Background and Aims: In patients with surgically unresectable early and intermediate stage hepatocellular carcinoma (HCC), only liver transplant (LT) offers a cure. Locoregional therapies, such as transarterial chemoembolization (TACE), are widely used to bridge patients waiting for an LT or downstage tumors beyond Milan Criteria (MC). However, there are no formal guidelines on the number of TACE procedures patients should receive. Our study explores the extent to which repeated TACE might offer diminishing gains toward LT. Approach: We retrospectively analyzed 324 patients with BCLC stage A and B HCC who had received TACE with the intention of disease downstaging or bridging to LT. In addition to baseline demographics, we collected data on LT status, survival, and the number of TACE procedures. Overall survival (OS) rates were estimated using the Kaplan-Meier method, and correlative studies were calculated using chi-square or Fisher's exact test. Results: Out of 324 patients, 126 (39%) received an LT, 32 (25%) of whom had responded favorably to TACE. LT significantly improved OS: HR 0.174 (0.094-0.322, P < .001). However, the LT rate significantly decreased if patients received ≥3 vs < 3 TACE procedures (21.6% vs 48.6%, P < .001). If their cancer was beyond MC after the third TACE, the LT rate was 3.7%. Conclusions: An increased number of TACE procedures may have diminishing returns in preparing patients for LT. Our study suggests that alternatives to LT, such as novel systemic therapies, should be considered for patients whose cancers are beyond MC after three TACE procedures.

Alcohol-associated liver disease predicts increased post-liver transplant opioid use.

BACKGROUND: Alcohol-associated liver disease (ALD) is a rising indication for liver transplantation (LT). Prolonged opioid use after LT leads to increased graft loss and mortality. The aim is to determine if patients transplanted with a primary diagnosis of ALD had higher risk of post-LT opioid use (p-LTOU) compared to non-ALD patients. METHODS: This is a retrospective study of patients who underwent LT between 2015 and 2018 at Medstar Georgetown Transplant Institute. Patients with prolonged hospitalization post-LT (>90 days), death within 90 days post-LT, and re-transplants were excluded. RESULTS: Two hundred and ninety seven patients were transplanted, among 29% for indications of ALD. ALD patients were younger (52 vs. 56 years), more likely to be male (76% vs. 61%), Caucasian (71% vs. 44%), have higher MELD (28.8±8.8 vs. 25±8.8), and psychiatric disease than non-ALD patients (P < .05). There was no difference in pre-LT use of opioids, tobacco, marijuana, or illicit drugs between ALD and non-ALD patients. Pre-LT opioid use (OR = 11.7, P < .001), ALD (OR = 2.5, P = .01), and MELD score (OR = .95, P = .02) independently predicted 90-day p-LTOU. CONCLUSIONS: ALD, pre-LT opioid use, and MELD score independently predict p-LTOU. Special attention should be paid to identify post-LT prolonged opioid use in ALD patients.

Postoperative Myocardial Injury and Outcomes in Liver and Kidney Transplant Patients.

BACKGROUND/PURPOSE: Myocardial injury after noncardiac surgery (MINS) is associated with major adverse cardiac events (MACE), but its significance post-liver and post-kidney transplantation is not well-defined. METHODS/MATERIALS: We retrospectively studied consecutive patients undergoing single-organ liver or kidney transplantation at a large tertiary transplant center. Liver and kidney transplant patients with troponins drawn within 30 days of transplantation were included. The primary exposure was MINS, defined as troponin elevation above the 99th percentile of the upper reference limit within 30 days of transplantation. The primary outcome was MACE, defined as death, myocardial infarction, revascularization, stroke, or heart failure hospitalization. RESULTS: Overall, 112 patients were included: 58 (51.7%) were liver transplant recipients, and 54 (48.3%) were kidney transplant recipients. Patients with MINS were significantly older (mean age 59 vs. 54 years, p = 0.01) and more likely to have diabetes (35% vs. 17%, p = 0.03). Other baseline characteristics were similar. Sixteen patients (14.2%) developed MACE, including 11 (9.8%) with 1-year MACE. MINS patients were significantly more likely to develop 1-year MACE (adjusted hazard ratio, 10.4; 95% confidence interval, 1.8-198). Kaplan-Meier cumulative MACE was significantly higher in the MINS group (p = 0.03). CONCLUSIONS: Liver and kidney transplant recipients with MINS are significantly more likely to develop 1-year MACE compared to those without MINS. Future prospective studies are needed to further delineate the cardiac risk and outcomes in transplanted patients.

Risk factors for bleeding hepatocellular adenoma in a United States cohort.

BACKGROUND & AIMS: Known risk factors for hepatocellular adenoma (HCA) bleeding are size >5 cm, growth rate, visible vascularity, exophytic lesions, ß-catenin and Sonic Hedgehog activated HCAs. Most studies are based on European cohorts. The objective of this study is to identify additional risk factors for HCA bleeding in a US cohort. METHODS: Retrospective chart review was performed on patients diagnosed with HCA on magnetic resonance imaging (n = 184) at an academic tertiary institution. Clinical, pathological, and imaging data were collected. Primary outcomes measured were HCA bleeding and malignancy. Statistical analysis was performed with SAS 9.4 using Chi-Square, Fisher's exact test, sample t test, non-parametric Wilcoxon test, and logistic regression. RESULTS: After excluding patients whose pathology showed focal nodular hyperplasia and non-adenoma lesions, follow-up data were available for 167 patients. 16% experienced microscopic or macroscopic bleeding and 1.2% had malignancy. HCA size predicted bleeding (P < .0001) and no patients with lesion size <1.8 cm bled. In unadjusted analysis, hepatic adenomatosis (≥10 lesions) trended towards 2.8-fold increased risk of bleeding. Of patients with a single lesion that bled, 77% bled from a lesion >5 cm. In patients with multiple HCAs that bled, 50% bled from lesions <5 cm. In patients with multiple adenomas, size (P = .001) independently predicted bleeding and hepatic steatosis trended towards increased risk of bleeding (P = .05). CONCLUSIONS: In a large US cohort, size predicted increased risk of HCA bleeding while hepatic adenomatosis trended towards increased risk of bleeding. In patients with multiple HCAs, size predicted bleeding and hepatic steatosis trended toward increased risk of bleeding.

Extracorporeal cellular therapy (ELAD) in severe alcoholic hepatitis: A multinational, prospective, controlled, randomized trial.

Severe alcoholic hepatitis (sAH) is associated with a poor prognosis. There is no proven effective treatment for sAH, which is why early transplantation has been increasingly discussed. Hepatoblastoma-derived C3A cells express anti-inflammatory proteins and growth factors and were tested in an extracorporeal cellular therapy (ELAD) study to establish their effect on survival for subjects with sAH. Adults with sAH, bilirubin ≥8 mg/dL, Maddrey's discriminant function ≥ 32, and Model for End-Stage Liver Disease (MELD) score ≤ 35 were randomized to receive standard of care (SOC) only or 3-5 days of continuous ELAD treatment plus SOC. After a minimum follow-up of 91 days, overall survival (OS) was assessed by using a Kaplan-Meier survival analysis. A total of 203 subjects were enrolled (96 ELAD and 107 SOC) at 40 sites worldwide. Comparison of baseline characteristics showed no significant differences between groups and within subgroups. There was no significant difference in serious adverse events between the 2 groups. In an analysis of the intent-to-treat population, there was no difference in OS (51.0% versus 49.5%). The study failed its primary and secondary end point in a population with sAH and with a MELD ranging from 18 to 35 and no upper age limit. In the prespecified analysis of subjects with MELD < 28 (n = 120), ELAD was associated with a trend toward higher OS at 91 days (68.6% versus 53.6%; P = .08). Regression analysis identified high creatinine and international normalized ratio, but not bilirubin, as the MELD components predicting negative outcomes with ELAD. A new trial investigating a potential benefit of ELAD in younger subjects with sufficient renal function and less severe coagulopathy has been initiated. Liver Transplantation 24 380-393 2018 AASLD.

Intratumoral CD3 and CD8 T-cell Densities Associated with Relapse-Free Survival in HCC.

Immune cells that infiltrate a tumor may be a prognostic factor for patients who have had surgically resected hepatocellular carcinoma (HCC). The density of intratumoral total (CD3(+)) and cytotoxic (CD8(+)) T lymphocytes was measured in the tumor interior and in the invasive margin of 65 stage I to IV HCC tissue specimens from a single cohort. Immune cell density in the interior and margin was converted to a binary score (0, low; 1, high), which was correlated with tumor recurrence and relapse-free survival (RFS). In addition, the expression of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) was correlated with the density of CD3(+) and CD8(+) cells and clinical outcome. High densities of both CD3(+) and CD8(+) T cells in both the interior and margin, along with corresponding Immunoscores, were significantly associated with a low rate of recurrence (P = 0.007) and a prolonged RFS (P = 0.002). In multivariate logistic regression models adjusted for vascular invasion and cellular differentiation, both CD3(+) and CD8(+) cell densities predicted recurrence, with odds ratios of 5.8 [95% confidence interval (CI), 1.6-21.8] for CD3(+) and 3.9 (95% CI, 1.1-14.1) for CD8(+) Positive PD-L1 staining was correlated with high CD3 and CD8 density (P = 0.024 and 0.005, respectively) and predicted a lower rate of recurrence (P = 0.034), as well as prolonged RFS (P = 0.029). Immunoscore and PD-L1 expression, therefore, are useful prognostic markers in patients with HCC who have undergone primary tumor resection. Cancer Immunol Res; 4(5); 419-30. ©2016 AACR.

Polypharmacy and comorbidity are associated with a lower early virologic response in hepatitis C patients treated with first generation protease inhibitor triple therapy: a preliminary analysis.

BACKGROUND AND AIMS: The protease inhibitors (PIs) boceprevir and telaprevir are currently standard treatment as part of triple therapy regimens (TTx) for chronic HCV genotype 1 (GT1) patients. In this preliminary analysis, we have compared demographic variables, polypharmacy, and Charlson's comorbid index (CCI) with Rapid Virological Response (RVR) and extended RVR (eRVR) rates in HCV GT1 patients receiving PI containing TTx. METHODS: Retrospective descriptive cohort study. RESULTS: Among 74 HCV patients (46 M, 28 F; age: 54.43 ± 9.52 years; African Americans: 59.5 %) in this initial analysis, 44 % achieved RVR. All these RVR patients also achieved eRVR. Patients achieving RVR and eRVR were 50 ± 11.7 (mean ± SD) years old, compared to 58 ± 5.2 years without an RVR (p < 0.005). The average number of medications taken by patients achieving RVR and eRVR was 5 ± 2.7 compared to 9.24 ± 3.4 in patients not achieving RVR and eRVR (p < 0.005). Twenty-five percent of patients who were not on CYP3A4 inhibitors had an RVR and eRVR compared to 63.2 % who were taking CYP3A4 inhibitors (p = 0.001). Patients achieving RVR and eRVR had a lower CCI (1.61 ± 1.37) compared to those not achieving RVR and eRVR (2.8 ± 2.7; p = 0.02). Multivariate analysis also revealed a significant correlation between increased polypharmacy and CCI with lower RVR and eRVR rates. CONCLUSIONS: These preliminary treatment data demonstrate that increased polypharmacy and higher degrees of comorbidity decrease RVR and eRVR rates among patients receiving first generation PI-containing TTx regimens.

Potential consequences of healthcare recommendations: a focus on the U.S. Preventive Services Task Force.

UNLABELLED: Healthcare guidelines and recommendations have broad-reaching impact. They serve as the evidence to enforce medical testing by establishing a bar for standard of care through their intrinsic credibility but also by affecting reimbursement. In this article, we discuss the various organizations in the United States that develop healthcare policy and guidelines. We focus on the recent recommendations for hepatitis C virus (HCV) screening put forward by these agencies and the potential effect of these documents. Additional discussion is provided on the recent draft HCV screening recommendations provided by the United States Preventive Services Task Force (USPSTF), comparison of these to the Centers for Disease Control and Prevention (CDC) guidelines, and professional societies' response to these. CONCLUSION: As written, the USPSTF recommendations may reduce physician adoption of HCV screening in the 1945-1965 birth cohort as advocated by the CDC. Conflicting guidelines may further confuse providers and the public. This will ultimately hinder recognition of chronic HCV in an otherwise easily identifiable, high prevalence group, allowing progression of disease at a time when therapeutic advances make cure a realistic opportunity for many.

Use of immune function test in monitoring immunosuppression in liver transplant recipients.

Immune function test (Immuknow™) is a measure of cell-mediated immunity based on peripheral CD4+ T cell adenosine triphosphate activity (desired range, 225-525 ng/mL). We evaluated the role of immune function test (IFT) in monitoring and adjustment of immunosuppression in orthotopic liver transplant (OLT) recipients. A total of 289 IFTs were obtained from 171 patients from March 2007 to June 2008. Graft/patient status was classified as stable, serious infection, or malignancy. IFT levels were analyzed with duration of follow-up after OLT, graft/patient status, and the presence of hepatitis C (HCV) infection. The mean age was 54±14 yr, with 62% men. The median follow-up was 65 (2-249) months. Mean IFT levels were significantly lower in patients who were <24 months than in those≥24 months post-OLT (220±19.5 vs. 257±11.3 ng/mL, p=0.03). Clinically stable patients had higher IFT levels than those with serious infection or malignancy (254±11.1 vs. 162.5±23.9, p<0.001). HCV-infected patients had lower IFT levels than uninfected patients (206.7±15.7 vs. 273±12.0 ng/mL, p<0.001). Immunosuppression was reduced in 58 patients with IFT levels<225 ng/mL, and 90% maintained stable graft function after a median follow-up of 22 (1-39) months. IFT may be a useful tool in monitoring and lowering of immunosuppression in long-term OLT recipients.

Successful nonoperative management of gastrointestinal mucormycosis: novel therapy for invasive disease.

BACKGROUND: Invasive opportunistic fungal infections caused by agents of Mucorales that involve the gastrointestinal tract are uncommon but aggressive. These ubiquitous fungal spores typically are inhaled and can germinate in immunocompromised hosts. Standard therapy for invasive mucormycosis includes parenteral amphotericin B (AMB) in combination with radical debridement of infected tissues. Early diagnosis and treatment are of paramount importance. Unfortunately, long-term survival is poor owing to the prohibitive morbidity and mortality rates associated with the medical and surgical therapies. Posaconazole is a novel, extended-spectrum triazole oral antifungal agent with documented success in the treatment of patients with invasive mucormycosis. METHODS: Case report and literature review. RESULTS: A 50-year-old man presented with invasive mucormycosis of the lower esophagus, stomach, and liver, resulting in gastrointestinal hemorrhage. The infection did not respond to AMB but was treated successfully with a combination of posaconazole and liposomal AMB (LAMB) without surgical debridement. CONCLUSIONS: To our knowledge, this is the first reported case of extensive gastric and intrahepatic mucormycosis that responded to combination posaconazole and LAMB without surgical debridement. This approach may be an alternative to surgery in patients who are precluded from extensive surgical intervention.