Multiregional analysis of combined hepatocellular-cholangiocarcinoma reveals histologic diversity and molecular clonality.

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare type of liver tumour that exhibits both hepatocytic and biliary differentiation within the same tumour. The histology and genomic alterations of recurrent/metastatic cHCC-CC are poorly understood. We selected six patients with cHCC-CC whose recurrent or metastatic tumours were histologically confirmed. Four patients with classic cHCC-CCs and two with intermediate cell carcinomas (ICs) were included. The clinicopathological features were evaluated, and next-generation sequencing was performed in 17 multiregional and longitudinal tumour samples. The histology of recurrent/metastatic lesions of classic cHCC-CCs was variable: hepatocellular carcinoma (HCC) was observed in one (25.0%) patient, cHCC-CC in one (25.0%) patient, and cholangiocarcinoma (CC) in two (50.0%) patients. Among 13 samples from four classic cHCC-CC patients, the most frequent pathological variants were TP53 (46.2%), TERT promoter (38.5%), ARID1A mutations (23.1%), and MET amplification (30.8%). In the sequencing analysis of each HCC and CC component, three (75.0%) of the four classic cHCC-CCs shared pathogenic variants. A large proportion of mutations, both pathogenic and those of undetermined significance, were shared by each HCC and CC component. Regarding ICs, the ATM mutation was detected in one patient. In conclusion, the histology of recurrent/metastatic cHCC-CCs was heterogeneous. Genomic profiling of classic cHCC-CCs revealed similar genomic alterations to those of HCC. Considerable overlapping genomic alterations in each HCC and CC component were observed, suggesting a monoclonal origin. Genetic alterations in ICs were different from those in either HCC or CC, suggesting the distinct nature of this tumour.

Anemia Is a Risk Factor for the Development of Ischemic Stroke and Post-Stroke Mortality.

BACKGROUND: anemia is known to be a risk factor for developing ischemic stroke in long-term follow-up studies, and it is also known to increase the risk of death in ischemic stroke patients. We aimed to determine the association of anemia with the risk of ischemic stroke and the risk of death after ischemic stroke. METHODS: The study included patients from National Health Insurance Service cohort, from January 2005 to December 2015. Anemia patients were defined as those with confirmed diagnostic codes and related medications in the sample cohort, and patients under the age of 18 were excluded. To perform a comparative analysis with the control group, twice as many patients were extracted by propensity score matching. The effects of anemia on the development of ischemic stroke were analyzed. RESULTS: A total of 58,699 patients were newly diagnosed with anemia during the study period. In anemia group, the rate of ischemic stroke occurring within 1 year was 0.550%, and the rate was 0.272% in the control group. The odds ratio of anemia related to ischemic stroke was 1.602 (95% confidence intervals (CI) 1.363-1.883). During the follow-up period, 175 out of 309 (56.6%) died in anemia group, and 130 out of 314 (41.4%) died in control group. The anemia group showed a higher risk of death than the control group (Hazard ratio 1.509, 95% CI 1.197-1.902). CONCLUSION: Analysis of the nationwide health insurance data revealed that anemia is one of the risk factors for the development of ischemic stroke, and also an independent prognostic factor affecting post-stroke mortality.

Ferroportin and FBXL5 as Prognostic Markers in Advanced Stage Clear Cell Renal Cell Carcinoma.

PURPOSE: Advanced stage clear cell renal cell carcinoma (ccRCC) involves a poor prognosis. Several studies have reported that dysfunctions in iron metabolism‒related proteins may cause tumor progression and metastasis of this carcinoma. In this study, we investigated the impact of the expression of iron metabolism‒related proteins on patient prognoses in advanced stage ccRCCs. MATERIALS AND METHODS: All of 143 advanced stage ccRCC specimens were selected following validation with double blind reviews. Several clinicopathological parameters including nuclear grade, perirenal fat invasion, renal sinus fat invasion, vascular invasion, necrosis, and sarcomatoid/rhabdoid differentiation were compared with the expression of ferroportin (FPN), and F-Box and leucine rich repeat protein 5 (FBXL5), by immunohistochemistry. FPN and FBXL5 mRNA level of ccRCC from The Cancer Genome Atlas database were also analyzed for validation. RESULTS: FPN and FBXL5 immunohistochemistry showed membrane and cytoplasmic expression, respectively. Based on the H-score, cases were classified as low or high expression with a cutoff value of 20 for FPN and 15 for FBXL5, respectively. Low expression of FPN and FBXL5 were significantly associated with patient death (p=0.022 and p=0.005, respectively). In survival analyses, low expression of FPN and FBXL5 were significantly associated with shorter overall survival (p=0.003 and p=0.004, respectively). On multivariate analysis, low expression of FBXL5 (hazard ratio, 2.001; p=0.034) was significantly associated with shorter overall survival. CONCLUSION: FPN and FBXL5 can be used as potential prognostic markers and therapeutic targets for advanced stage ccRCC.