Significant Reduction in Posttransplant Hepatocellular Carcinoma Recurrence in the Post 6-Mo Waiting Policy Era.

BACKGROUND: In 2015, the United Network for Organ Sharing implemented a policy introducing a 6-mo waiting period before granting model for end-stage liver disease exception points to liver transplant (LT) candidates with hepatocellular carcinoma (HCC). This study analyzes the policy impact on post-LT HCC recurrence. METHODS: This was a United Network for Organ Sharing retrospective cohort study of patients with HCC who underwent LT from January 1, 2010, to May 31, 2019. HCC-specific data included alpha-fetoprotein, tumor characteristics, locoregional therapy (LRT), and explant data used to calculate the Risk Estimation of Tumor Recurrence After Transplant score. The primary exposure was pre-/post-policy era, divided on October 8, 2015. Survival analysis techniques were used to evaluate the unadjusted and sequentially adjusted association between policy era and HCC recurrence, accounting for competing risks. RESULTS: A total of 7940 patients were included, 5879 (74.0%) pre-policy era and 2061 (26.0%) post-policy era. Post-policy patients were older, received more LRT, and had lower alpha-fetoprotein levels and smaller tumor sizes at transplant. Incidence rates of HCC recurrence were 19.8 and 13.7 events per 1000 person-years for pre- and post-policy eras, respectively. Post-policy era was associated with an unadjusted 35% reduction in the risk of HCC recurrence (P < 0.001). After adjusting for recipient, donor, and tumor characteristics at listing this association remained (subhazard ratio 0.69; 95% confidence interval, 0.55-0.86; P = 0.001); however, after additionally adjusting for LRT episodes and Risk Estimation of Tumor Recurrence After Transplant score, there was no longer a statistically significant association (subhazard ratio 0.77; 95% confidence interval, 0.59-1.00; P = 0.054). CONCLUSIONS: We observed a significant reduction in post-LT HCC recurrence after policy implementation. This may be due to waitlist selection of healthier patients, increased LRT utilization, and potential selection of favorable tumor biology.

Multigene Panel Testing in Individuals With Hepatocellular Carcinoma Identifies Pathogenic Germline Variants.

Hepatocellular carcinoma (HCC) has well-defined environmental risk factors. In addition, epidemiologic studies have suggested hereditary risk factors. The goals of this study were to determine the rate of pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes in patients with HCC, possible enrichment of P/LP variants in particular genes, and potential impact on clinical management. MATERIALS AND METHODS: A prospective study at a tertiary medical center enrolled 217 patients with a personal history of HCC. Multigene panel testing was performed for 134 cancer predisposition genes in all patients. The rate of P/LP variants was compared with population rates. A separate retrospective cohort included 219 patients with HCC who underwent testing at a commercial laboratory. RESULTS: In the prospective cohort, P/LP germline variants were identified in 25 of 217 patients with HCC (11.5%). Four patients (1.8%) had P/LP variants in the highly penetrant cancer genes BRCA2 (n = 2), MSH6 (n = 1), and PMS2 (n = 1). In addition, multiple patients had P/LP variants in FANCA (n = 5) and BRIP1 (n = 4), which were significantly enriched in HCC compared with the general population. Detection of P/LP variants led to changes in clinical management in regard to therapy selection, screening recommendations, and cascade testing of relatives. In a separate retrospective analysis of 219 patients with HCC, 30 (13.7%) were positive for P/LP variants including 13 (5.9%) with highly penetrant genes APC (n = 2), BRCA1 (n = 1), BRCA2 (n = 6), MSH2 (n = 2), or TP53 (n = 2). CONCLUSION: P/LP germline variants in cancer predisposition genes were detected in 11%-14% of patients with HCC. Inherited genetics should not be overlooked in HCC as there are important implications for precision treatment, future risk of cancers, and familial cancer risk.

Risk Factors and Center-Level Variation in Hepatocellular Carcinoma Under-Staging for Liver Transplantation.

Liver transplantation (LT) is curative for most patients with hepatocellular carcinoma (HCC). However, 10%-15% of patients experience HCC recurrence. Patients who are reported as within Milan criteria by imaging are frequently found to be outside the criteria on explant. This under-staging of HCC worsens post-LT outcomes. However, risk factors for under-staging have not been elucidated. Furthermore, it is not known if there is regional or center-level variation in under-staging. We conducted a retrospective analysis of adult patients transplanted for HCC in the United Network for Organ Sharing (UNOS) database between 2012 and 2016. Under-staging was determined on the basis of comparing pre-LT imaging to explant findings. Kaplan-Meier methods and Cox regression were used to evaluate the impact of under-staging on HCC recurrence and post-LT survival. Mixed effects logistic regression was used to identify risk factors for under-staging and to study regional and center-level variation in adjusted analyses. A total of 5424 patients were included in the cohort, of whom 24.9% (n = 1353) were under-staged. Post-LT HCC recurrence and death were significantly associated with under-staging (each P < 0.001). In adjusted analyses, independent predictors of under-staging included age (odds ratio [OR], 1.13 per 10 years; 95% confidence interval [CI], 1.03-1.25), male sex (OR, 1.61; 95% CI, 1.36-1.89), down-staging (OR, 4.03; 95% CI, 2.65-6.11), and pre-LT alpha-fetoprotein (P < 0.001). There was also significant variation in under-staging between UNOS regions and among transplant centers, ranging from 14.8% to 38.1%. We report novel risk factors for HCC under-staging, which worsens post-LT outcomes. Significant center-level and regional variation in under-staging highlights the need for standards that achieve greater uniformity in staging.

Patterns of Discordance Between Pretransplant Imaging Stage of Hepatocellular Carcinoma and Posttransplant Pathologic Stage: A Contemporary Appraisal of the Milan Criteria.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) exceeding Milan criteria on explant pathology are at increased risk of recurrence and death. Discordance between contemporary magnetic resonance imaging (MRI) and explant pathology, and preoperative characteristics predictive of discordance are not well understood. METHODS: Patients who underwent orthotopic liver transplantation for HCC after preoperative MRI were identified in a prospectively collected institutional database (January 2003 to December 2013). Patients were dichotomized to "within" or "outside" Milan criteria by both imaging and explant pathologic evaluation. Binary logistic regression and Kaplan-Meier methodology were used to identify independent predictors of imaging/pathologic discordance and its impact on posttransplant survival. RESULTS: Of 318 patients with HCC meeting Milan criteria by MRI at the time of orthotopic liver transplantation, 248 (78.0%) remained within a pathological correlate of Milan criteria on explant examination. Understaging was associated with worse median recurrence-free survival (64.0 months vs 140.0 months, P = 0.002) and overall survival (96.0 months vs 143.0 months, P = 0.005), and did not vary between patients exceeding criteria due to tumor explant greater than 5 cm, more than 3 tumor foci, or a tumor greater than 3 cm in the setting of multifocality. Discordance was independently associated with an increasing serum alpha fetal protein level (odds ratio, 2.82; 95% confidence interval, 1.37-5.79; P = 0.005). CONCLUSIONS: Underestimating HCC burden before liver transplant remains frequent despite contemporary imaging technologies. Patients with an increasing alpha fetal protein before transplantation may benefit from more frequent testing or novel neoadjuvant therapies.

Trajectory analysis of winds and vesicular stomatitis in North America, 1982-5.

Outbreaks of vesicular stomatitis, serotype New Jersey, during epidemics in the United States and northern Mexico, 1982-5, were examined by backward trajectories of winds to investigate spread and possible sources. The outbreaks selected for analysis did not involve introduction of disease by infected animals. The findings indicate that wind could have been responsible for carrying infection from northern Mexico to Arizona and New Mexico and thence to Colorado and Utah and on to Wyoming, Idaho and Montana. The results of these analyses are consistent with the findings from T1 RNAse fingerprinting of virus isolates from outbreaks during the epidemics. The arrival of the trajectories was associated with the passage of a front and rain or passage of a front alone or rain alone. At the time of the trajectories temperatures of 10 degrees C and higher were recorded at heights up to 2500-3500 m. Introduction by airborne particles would appear unlikely as it would have required a source of at least 10(5) infectious units per minute per animal. Vesicular stomatitis virus had been isolated from Simulium and Culicoides during the epidemic with amounts of virus from Simulium sufficient to suggest biological transmission. The possibility of Simulium infected with vesicular stomatitis virus being carried downwind to introduce disease is discussed in relation to the behaviour of Simulium and the pathogenesis of vesicular stomatitis in large animals.

Trajectory analysis and bluetongue virus serotype 2 in Florida 1982.

Examination of Northern Hemisphere synoptic charts and computation of backward trajectories indicated that Culicoides infected with bluetongue virus serotype 2 could have been carried on the wind and brought the virus to Florida on the afternoon of August 19, 1982 after leaving northern Cuba the previous evening. Flight would have occurred at a height of 1-1.5 km at temperatures of 15-17 degrees C. The distance of 500 km from northern Cuba to Ona would have been covered in 20 h at an average speed of 25 km h-1. Computation of trajectories indicated that a second electropherotype, Ona B, was unlikely to have been introduced by infected Culicoides.