New-Onset Diabetes and Preexisting Diabetes Are Associated With Comparable Reduction in Long-Term Survival After Liver Transplant: A Machine Learning Approach.

OBJECTIVE: To identify key predictors and survival outcomes of new-onset diabetes after transplant (NODAT) in liver transplant (LT) recipients by using the Scientific Registry of Transplant Recipients. PATIENTS AND METHODS: Data of all adult LT recipients between October 1, 1987, and March 31, 2016, were analyzed using various machine learning methods. These data were divided into training (70%) and validation (30%) data sets to robustly determine predictors of NODAT. The long-term survival of patients with NODAT relative to transplant recipients with preexisting diabetes and those without diabetes was assessed. RESULTS: Increasing age (odds ratio [OR], 1.01; 95% CI, 1.00-1.02; P≤.001), male sex (OR, 1.09; 95% CI, 1.05-1.13; P=.03), and obesity (OR, 1.13; 95% CI, 1.08-1.18; P<.001) were significantly associated with NODAT. Sirolimus as a primary immunosuppressant carried a 33% higher risk of NODAT than did tacrolimus (OR, 1.33; 95% CI, 1.22-1.45; P<.001) at 1 year after LT. Patients with NODAT had significantly decreased 10-year survival than did those without diabetes (63.0% vs 74.9%; P<.001), similar to survival in patients with diabetes before LT (58.9%). CONCLUSION: Using a machine learning approach, we found that older, male, and obese recipients are at especially higher risk of NODAT. Donor features do not affect risk. In addition, sirolimus-based immunosuppression is associated with a significantly higher risk of NODAT than other immunosuppressants. Most importantly, NODAT adversely affects long-term survival after LT in a manner similar to preexisting diabetes, indicating the need for more aggressive care and closer follow-up.

Comparison of BQ123, Epoprostenol, and Verapamil as Vasodilators During Normothermic Ex Vivo Liver Machine Perfusion.

BACKGROUND: The optimal vasodilator to avoid hepatic artery vasospasm during normothermic ex vivo liver perfusion (NEVLP) is yet to be determined. We compared safety and efficacy of BQ123 (endothelin1 antagonist), epoprostenol (prostacyclin analogue), and verapamil (calcium channel antagonist). METHODS: Livers from porcine heart beating donors were perfused for 3 hours and transplanted into recipient pigs. Four groups were compared: group 1, livers perfused with a dose of 1.25 mg of BQ123 at baseline and at 2 hours of perfusion; group 2, epoprostenol at a continuous infusion of 4 mg/h; group 3, verapamil 2.5 mg at baseline and at 2 hours of perfusion; group 4, no vasodilator used during ex vivo perfusion. Liver injury and function were assessed during perfusion, and daily posttransplantation until postoperative day (POD) 3. All groups were compared with a cold storage group for postoperative graft function. RESULTS: Hepatic artery flow during NEVLP was significantly higher in BQ123 compared with verapamil, epoprostenol, and no vasodilator-treated livers. Aspartate aminotransferase levels were significantly lower with BQ123 and verapamil compared with epoprostenol and control group during perfusion. Peak aspartate aminotransferase levels were lower in pigs receiving BQ123 and verapamil perfused grafts compared with epoprostenol and control group. International Normalized Ratio, alkaline phosphatase, and total bilirubin levels were lower in the BQ123 and verapamil groups compared to epoprostenol group. Cold storage group had increased markers of ischemia reperfusion injury and slower graft function recovery compared to machine perfused grafts. CONCLUSION: The use of BQ123, epoprostenol, and verapamil during NEVLP is safe. Livers perfused with BQ123 and verapamil have higher hepatic artery flow and reduced hepatocyte injury during perfusion compared with epoprostenol. Hepatic artery flow is significantly reduced in the absence of vasodilators during NEVLP.

Use of Viral Load as a Surrogate Marker in Clinical Studies of Cytomegalovirus in Solid Organ Transplantation: A Systematic Review and Meta-analysis.

Symptomatic cytomegalovirus (CMV) disease has been the standard endpoint for clinical trials in organ transplant recipients. Viral load may be a more relevant endpoint due to low frequency of disease. We performed a meta-analysis and systematic review of the literature. We found several lines of evidence to support the validity of viral load as an appropriate surrogate end-point, including the following: (1) viral loads in CMV disease are significantly greater than in asymptomatic viremia (odds ratio, 9.3 95% confidence interval, 4.6-19.3); (2) kinetics of viral replication are strongly associated with progression to disease; (3) pooled incidence of CMV viremia and disease is significantly lower during prophylaxis compared with the full patient follow-up period (viremia incidence: 3.2% vs 34.3%; P < .001) (disease incidence: 1.1% vs 13.0%; P < .001); (4) treatment of viremia prevented disease; and (5) viral load decline correlated with symptom resolution. Based on the analysis, we conclude that CMV load is an appropriate surrogate endpoint for CMV trials in organ transplant recipients.

Performance of transient elastography and serum fibrosis biomarkers for non-invasive evaluation of recurrent fibrosis after liver transplantation: A meta-analysis.

Recurrent fibrosis after liver transplantation (LT) impacts on long-term graft and patient survival. We performed a meta-analysis to compare the accuracy of non-invasive methods to diagnose significant recurrent fibrosis (stage F2-F4) following LT. Studies comparing serum fibrosis biomarkers, namely AST-to-platelet ratio index (APRI), fibrosis score 4 (FIB-4), or transient elastography (TE) with liver biopsy in LT recipients were systematically identified through electronic databases. In the meta-analysis, we calculated the weighted pooled odds ratio and used a fixed effect model, as there was no significant heterogeneity between studies. Eight studies were included for APRI, four for FIB-4, and twelve for TE. The mean prevalence of significant liver fibrosis was 37.4%. The summary odds ratio was significantly higher for TE (21.17, 95% CI confidence interval 14.10-31.77, p = 1X10-30) as compared to APRI (9.02, 95% CI 5.79-14.07; p = 1X10-30) and FIB-4 (7.08, 95% CI 4.00-12.55; p = 1.93X10-11). In conclusion, TE performs best to diagnose recurrent fibrosis in LT recipients. APRI and FIB-4 can be used as an estimate of significant fibrosis at centres where TE is not available. Longitudinal assessment of fibrosis by means of these non-invasive tests may reduce the need for liver biopsy.

Characteristics of liver transplant candidates delisted following recompensation and predictors of such delisting in alcohol-related liver disease: a case-control study.

Whether and when recovery beyond the need for transplant may occur in patients listed for decompensation remains unclear. This study aimed to investigate the characteristics of patients delisted following recompensation. Seventy-seven patients who were listed between 2005 and 2015 for decompensation, but later delisted following recompensation were included. Alcohol-related liver disease (ALD) was the underlying etiology in the majority (n = 47, 61%). Listing characteristics of these patients were compared with those of decompensated ALD patients who either underwent deceased donor liver transplantation or died on the waiting list. The model for end-stage liver disease (MELD) score <20 and serum albumin ≥32 g/l at listing were the only independent predictors of recompensation/delisting in ALD. The probability of recompensation was 70% when both factors were present at listing. Interestingly, about a tenth of decompensated ALD patients who died on the waiting list (median duration on waiting list 11 months) and a quarter of decompensated ALD patients who underwent living donor liver transplantation (median duration on waiting list 2 months) also had both factors at listing. In conclusion, ALD seems to be the most favorable etiology for recompensation beyond the need for transplantation. Both MELD and serum albumin at listing independently predict recompensation/delisting in ALD. It seems advisable to implement a period of observation for ALD patients with both favorable factors, before embarking on living donor liver transplantation.

Proposal of a novel MELD exception point system for hepatocellular carcinoma based on tumor characteristics and dynamics.

BACKGROUND & AIMS: Patients listed with exception points for hepatocellular carcinoma (HCC) have been more likely to be transplanted than those listed for chronic liver failure (LF) based on the model for end-stage liver disease (MELD) score. The aim of this study was to determine outcomes in the 5-year experience of a scoring system designed to reflect heterogeneity of tumor load of patients listed for HCC. METHODS: A novel MELD exception point system based on size and number of HCC was implemented in July 2009. This system allows stratification of patients based on risk of dropping out from the waiting list according to Milan criteria. LF patients were listed according to biological MELD sodium score; HCC patients were reassigned points every three months upon repeat imaging. RESULTS: Among 624 patients listed for liver transplant (LT), 505 were eligible. 94 (18.6%) were assigned MELD HCC points. Only 24.7% required changes in allocated points over time. Transplantation rates (HCC 83% vs. LF 73%, p=0.04) and waiting time in days (HCC 258 vs. LF 325; p=0.07) were similar. The method of competing risk analysis revealed that HCC patients were more likely to be transplanted than LF during the 5-year period preceding implementation, whereas transplant rates became equivalent for HCC and non-HCC in 2009-2014. One- and two-year survivals were similar between the two groups. CONCLUSIONS: Our study demonstrates that a novel MELD point system for HCC, taking into account dynamics in tumor size and number, allows for equitable liver allocation without compromising graft and patient survival. LAY SUMMARY: It has historically been difficult to achieve equitable liver allocation for liver cancer and chronic liver failure with the allocation systems currently in place in many countries worldwide. We designed a new system to help improve access to organs for liver failure patients in Québec, Canada. Our 5-year experience demonstrates that this unique system renders access to transplant similar for both liver cancer and liver failure indications.

Systematic meta-analyses and field synopsis of genetic association studies in colorectal cancer.

BACKGROUND: Colorectal cancer is a major global public health problem, with approximately 950,000 patients newly diagnosed each year. We report the first comprehensive field synopsis and creation of a parallel publicly available and regularly updated database (CRCgene) that catalogs all genetic association studies on colorectal cancer (http://www.chs.med.ed.ac.uk/CRCgene/). METHODS: We performed two independent systematic reviews, reviewing 10 145 titles, then collated and extracted data from 635 publications reporting on 445 polymorphisms in 110 different genes. We carried out meta-analyses to derive summary effect estimates for 92 polymorphisms in 64 different genes. For assessing the credibility of associations, we applied the Venice criteria and the Bayesian False Discovery Probability (BFDP) test. RESULTS: We consider 16 independent variants at 13 loci (MUTYH, MTHFR, SMAD7, and common variants tagging the loci 8q24, 8q23.3, 11q23.1, 14q22.2, 1q41, 20p12.3, 20q13.33, 3q26.2, 16q22.1, and 19q13.1) to have the most highly credible associations with colorectal cancer, with all variants except those in MUTYH and 19q13.1 reaching genome-wide statistical significance in at least one meta-analysis model. We identified less-credible (higher heterogeneity, lower statistical power, BFDP >0.2) associations with 23 more variants at 22 loci. The meta-analyses of a further 20 variants for which associations have previously been reported found no evidence to support these as true associations. CONCLUSION: The CRCgene database provides the context for genetic association data to be interpreted appropriately and helps inform future research direction.