Fibrolamellar hepatocellular carcinoma, or fibrolamellar carcinoma, is a rare form of primary liver cancer that afflicts healthy young men and women without underlying liver disease. There are currently no effective treatments for fibrolamellar carcinoma other than resection or transplantation. In this study, we sought evidence of mechanistic target of rapamycin complex 1 (mTORC1) activation in fibrolamellar carcinoma, based on anecdotal reports of tumor response to rapamycin analogs. Using a tissue microarray of 89 primary liver tumors, including a subset of 10 fibrolamellar carcinomas, we assessed the expression of phosphorylated S6 ribosomal protein (P-S6), a downstream target of mTORC1, along with fibroblast growth factor receptor 1 (FGFR1). These results were extended and confirmed using an additional 13 fibrolamellar carcinomas, whose medical records were reviewed. In contrast to weak staining in normal livers, all fibrolamellar carcinomas on the tissue microarray showed strong immunostaining for FGFR1 and P-S6, whereas only 13% of non-fibrolamellar hepatocellular carcinomas had concurrent activation of FGFR1 and mTORC1 signaling (Po0.05). When individual samples were stratified according to staining intensity (scale 0-4), the average score in fibrolamellar carcinomas was 2.46 for FGFR1 and 3.77 for P-S6, compared with 0 and 0, respectively, in non-tumor liver. Immunoblot analyses of fibrolamellar carcinomas revealed high mTORC1 activities relative to AKT activities accompanied by reduced TSC2 expression, which was not observed in non-fibrolamellar hepatocellular carcinomas. Our findings provide evidence for mTORC1 activation and FGFR1 overexpression in human fibrolamellar carcinoma, and support the use of FGFR1 inhibitors and rapamycin analogs in the treatment of patients with unresectable fibrolamellar carcinoma.

This study replicates the results of previous natural history studies of eyes with DPED including the high rates of progression to late AMD and vision loss (regardless of progression to late AMD). The genetic associations are consistent with genes associated with AMD progression.

BACKGROUND AND OBJECTIVE: To assess the impact of the disorganization of retinal inner layers (DRIL) on visual acuity (VA) and its correlation with ischemic index (IsI) on ultra-widefield fluorescein angiography (UWFFA) in eyes with acute, treatment-naïve branch retinal vein occlusion (BRVO). PATIENTS AND METHODS: Retrospective, longitudinal study of BRVO eyes with 1 year of follow-up or more. Area of intraretinal cysts, DRIL length, extent of disruption of external limiting membrane (ELM), and ellipsoid zone (EZ) were graded on the central 1,000 μm of foveal optical coherence tomography (OCT) scan. Baseline IsI was calculated on UWFFA. RESULTS: Thirty eyes of 30 patients with a mean follow-up of 25.4 months ± 11.0 months were evaluated. At baseline, 50% had DRIL (mean 443.1 μm ± 460.4 μm). DRIL length at baseline was predictive of worse VA at 12 months ( P = .029), and DRIL length at 12 months was predictive of worse final VA( P = .011). In multivariate analyses, DRIL length was associated with final VA ( P = .008) after controlling for other OCT parameters. There was no association between baseline IsI on UWFFA and DRIL. CONCLUSIONS: DRIL served as an independent OCT biomarker predictive of worse VA during a period of 2 years in acute, treatment-naïve BRVO. Development of DRIL was influenced by presence of CME, intraretinal cyst area, and extent of ELM and EZ disruption, but not by severity of baseline IsI. [ Ophthalmic Surg Lasers Imaging Retina . 2019;50:354–364.]