In the United States, there are significant geographic disparities in the time to transplantation for patients with hepatocellular carcinoma (HCC); it is possible that rapid transplantation contributes to higher rates of posttransplant HCC recurrence because there is insufficient time for the tumor biology to manifest. In this study, we compared HCC recurrence in rapid transplant patients and their slower transplant counterparts. We identified adult liver transplantation (LT) candidates in the Organ Procurement and Transplantation Network/United Network for Organ Sharing (UNOS) data set who were granted an initial exception for an HCC diagnosis between January 1, 2006 and September 30, 2010 and underwent transplantation in the same time window. Patients were followed until HCC recurrence, non-HCC-related death, or last follow-up. The cumulative incidence of HCC recurrence was compared for patients waiting ≤ 120 days and patients waiting >120 days from an HCC exception to LT. The association between the risk of posttransplant recurrence and the wait time was further evaluated via competing risks regression with the Fine and Gray model. For 5002 LT recipients with HCC, the median wait time from an exception to LT was 77 days, and it varied from 30 to 169 days by UNOS region. The cumulative incidence of posttransplant HCC recurrence was 3.3% [95% confidence interval (CI) = 2.8%-3.8%] and 5.6% (95% CI = 5.0%-6.3%) within 1 and 2 years, respectively. The rate of observed recurrence within 1 year of transplantation was significantly lower for patients waiting >120 days versus patients waiting ≤ 120 days (2.2% versus 3.9%, P = 0.002); however, the difference did not persist at 2 years (5.0% versus 5.9%, P = 0.09). After we accounted for clinical factors, the HCC recurrence risk was reduced by 40% for patients waiting >120 days (subhazard ratio = 0.6, P = 0.005). In conclusion, the risk of HCC recurrence within the first year after transplantation may be lessened by the institution of a mandatory waiting time after an exception is granted.

We investigated the possibility that patients with hepatocellular carcinoma (HCC) listed for liver transplant with tumors just outside stage T2 size criteria may be inaccurately reported as just meeting the tumor size criteria for transplant. The United Network for Organ Sharing/Standard Transplant Analysis and Research database identified 12,958 patients listed for liver transplants with HCC exception points from 2006 to 2013, 9,168 of whom were listed with one tumor. A logistic power peak function was fitted to the single-tumor size histogram, with the fitted values representing unbiased expected values. The difference between the observed and expected tumor counts for 2.0 cm and 5.0 cm was 238 (22%) and 66 (57%), respectively. This suggests that up to 304 (3.0%) patients with tumors outside of transplant criteria had their measurements recorded at the margins of eligibility. A risk-adjusted Poisson model evaluated the ratio of observed to expected HCC recurrence by tumor size. There were 435 HCC recurrences among 6,049 transplants. Only 2.0-cm tumors had observed to expected recurrence differing from 1 (ratio 0.73, 95% confidence interval 0.57-0.94), indicating a 27% lower than expected rate of recurrence.

Conclusion

Higher than expected observed tumor counts at the lower transplant criteria margin were corroborated by lower than expected HCC recurrence, suggesting that tumor sizes at the margins of HCC transplant criteria may be subject to inaccurate reporting. (Hepatology 2017;66:1144-1150).

Liver transplant allocation policy does not give model for end-stage liver disease (MELD) exception points for patients with a single hepatocellular carcinoma (HCC) <2 cm in size, but does give points to patients with multiple small nodules. Because standard-of-care imaging for HCC struggles to differentiate HCC from other nodules, it is possible that a subset of patients receiving liver transplant for multiple nodules <2 cm in size does not have HCC. We evaluate risk of post-transplant HCC recurrence and wait-list dropout for patients with multiple small nodules using competing risks regression based on the Fine and Gray model. We identified 5002 adult HCC patients in the OPTN/UNOS dataset diagnosed and transplanted between January 2006 and September 2010. Compared to patients with >1 tumor <2 cm, risk of developing recurrence was significantly higher in patients with one or more tumors with only one tumor ≥2 cm (SHR 1.63, p = 0.009), as well as in patients with 2-3 tumors ≥2 cm (SHR 1.84, p = 0.02). Dropout risk was not significantly different among size categories. HCC recurrence risk was significantly lower in patients with multiple nodules <2 cm in size than in those with larger tumors, supporting the possibility that some patients received unnecessary transplants. The priority given to these patients must be re-examined.

Cirrhosis leads to sarcopenia and functional decline that can severely impact one's ability to function at home and in society. Self-reported disability scales to quantify disability-Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL)-are validated to predict mortality in older adults. To evaluate disability in liver transplantation (LT) candidates and quantify its impact on outcomes, consecutive outpatients ≥18 years listed for LT with laboratory Model for End-Stage Liver Disease scores of ≥12 at a single high-volume US LT center were assessed for ADLs and IADLs during clinic visits. Multivariate competing risk models explored the effect of disabilities on wait-list mortality (death or delisting for illness). Of 458 patients, 36% were women, median (interquartile range [IQR]) age was 60 years (IQR, 54-64 years), and initial Model for End-Stage Liver Disease-Sodium (MELD-Na) was 17 (IQR 14-20). At first visit, 31% had lost ≥ 1 ADL, and 40% had lost ≥ 1 IADL. The most prevalent ADL deficits lost were continence (22%), dressing (12%), and transferring (11%); the most prevalent IADLs lost were shopping (28%), food preparation (23%), and medication management (22%). After adjustment for age, MELD-Na, and encephalopathy, dressing (subdistribution hazard ratio [SHR], 1.7; 95% confidence interval [CI], 1.0-2.8; P = 0.04), toileting (SHR, 1.9; 95% CI, 1.1-3.5; P = 0.03), transferring (SHR, 1.9; 95% CI, 1.1-3.0; P = 0.009), housekeeping (SHR, 1.8; 95% CI, 1.2-3.0; P = 0.009), and laundry (SHR, 2.2; 95% CI, 1.3-3.5; P = 0.002) remained independent predictors of wait-list mortality. In conclusion, ADL/IADL deficits are common in LT candidates. LT candidates would benefit from chronic disease management programs developed to address the impact of cirrhosis on their daily lives. Liver Transplantation 23 292-298 2017 AASLD.

The Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) database is the most comprehensive collection of liver transplantation data, but the quality of these data with respect to hepatocellular carcinoma (HCC) recurrence has not been well assessed. In this study, we compared observed HCC recurrence rates in the UNOS database to expected rates calculated with a hierarchical model for recurrence adjusted for recipient and tumor characteristics. We used the UNOS Standard Transplant Analysis and Research data set for adult transplant patients with an initial exception for an HCC diagnosis granted between January 1, 2006 and September 30, 2010 who underwent transplantation within the same time window. We developed a risk-adjusted Poisson model with patients as the unit of analysis, random effects for transplant centers, and years of follow-up as an offset to predict expected recurrences for each center. To further investigate the possibility of underreporting, we imputed expected recurrences for non-HCC deaths. In all, 5034 HCC liver transplant recipients were identified, and 6.8% experienced recurrence at a median of 1 year after transplantation. The covariate-adjusted shrinkage estimates of the observed/expected HCC recurrence ratios by transplant center ranged from 0.6 to 1.76 (median = 0.97). The 95% confidence intervals for the shrinkage ratios included unity for every center, and this indicated that none could be unambiguously identified as having lower or higher than expected HCC recurrence rates. Imputing outcomes for patients potentially experiencing unreported recurrence changed the center-specific shrinkage ratios to 0.72 to 1.39 (median = 0.98), with no centers having a shrinkage ratio significantly different from 1. The observed HCC recurrence rate was not significantly lower than the expected rate at any center, and this suggests that no systematic underreporting has occurred. This study validates the OPTN HCC recurrence data and supports their potential for further analysis.

Production of haploid gametes from diploid progenitor cells is mediated by a specialized cell division, meiosis, where two divisions, meiosis I and II, follow a single S phase. Errors in progression from meiosis I to meiosis II lead to aneuploid and polyploid gametes, but the regulatory mechanisms controlling this transition are poorly understood. Here, we demonstrate that the conserved kinase Ime2 regulates the timing and order of the meiotic divisions by controlling translation. Ime2 coordinates translational activation of a cluster of genes at the meiosis I-meiosis II transition, including the critical determinant of the meiotic chromosome segregation pattern CLB3. We further show that Ime2 mediates translational control through the meiosis-specific RNA-binding protein Rim4. Rim4 inhibits translation of CLB3 during meiosis I by interacting with the 5' untranslated region (UTR) of CLB3. At the onset of meiosis II, Ime2 kinase activity rises and triggers a decrease in Rim4 protein levels, thereby alleviating translational repression. Our results elucidate a novel developmentally regulated translational control pathway that establishes the meiotic chromosome segregation pattern.