HBV DNA Integration into Telomerase or MLL4 Genes and TERT Promoter Point Mutation as Three Independent Signatures in Subgrouping HBV-Related HCC with Distinct Features.

Introduction: A set of genetic mutations to classify hepatocellular carcinoma (HCC) useful to clinical studies is an unmet need. Hepatitis B virus-related HCC (HBV-HCC) harbors a unique genetic mutation, namely, the HBV integration, among other somatic endogenous gene mutations. We explored a combination of HBV DNA integrations and common somatic mutations to classify HBV-HCC by using a capture-sequencing platform. Methods: A total of 153 HBV-HCCs after surgical resection were subjected to capture sequencing to identify HBV integrations and three common somatic mutations in genomes. Three mutually exclusive mutations, HBV DNA integration into the TERT promoter, HBV DNA integration into MLL4, or TERT promoter point mutation, were identified in HBV-HCC. Results: They were used to classify HBV-HCCs into four groups: G1 with HBV-TERT integration (25.5%); G2 with HBV-MLL4 integration (10.5%); G3 with TERT promoter mutation (30.1%); and G4 without these three mutations (34.0%). Clinically, G3 has the highest male-to-female ratio, cirrhosis rate, and associated with higher early recurrence and mortality after resection, but G4 has the best outcome. Transcriptomic analysis revealed a grouping different from the published ones and G2 with an active immune profile related to immune checkpoint inhibitor response. Analysis of integrated HBV DNA provided clues for HBV genotype and variants in carcinogenesis of different HCC subgroup. This new classification was also validated in another independent cohort. Conclusion: A simple and robust genetic classification was developed to aid in understanding HBV-HCC and in harmonizing clinical studies.

Mitral Annular Disjunction: Review of an Increasingly Recognized Mitral Valve Entity.

Mitral annular disjunction (MAD) refers to atrial displacement of the hinge point of the mitral valve annulus from the ventricular myocardium. MAD leads to paradoxical expansion of the annulus in systole and may often be associated with mitral valve prolapse (MVP), leaflet degeneration, myocardial and papillary muscle fibrosis, and, potentially, malignant cardiac arrhythmias. Patients with MAD and MVP may present similarly, and MAD is potentially the missing link in explaining why some patients with MVP experience adverse outcomes. Patients with a 5 mm or longer MAD distance have an elevated risk of malignant cardiac arrhythmia compared with those with a shorter MAD distance. Evaluation for MAD is an important component of cardiac imaging, especially in patients with MVP and unexplained cardiac arrhythmias. Cardiac MRI is an important diagnostic tool that aids in recognizing and quantifying MAD, MVP, and fibrosis in the papillary muscle and myocardium, which may predict and help improve outcomes following electrophysiology procedures and mitral valve surgery. This article reviews the history, pathophysiology, controversy, prevalence, clinical implications, and imaging considerations of MAD, focusing on cardiac MRI. Keywords: MR-Dynamic Contrast Enhanced, Cardiac, Mitral Valve, Mitral Annular Disjunction, Mitral Valve Prolapse, Floppy Mitral Valve, Cardiac MRI, Arrhythmia, Sudden Cardiac Death, Barlow Valve © RSNA, 2023.

Cardio-Oncology: Understanding the Intersections Between Cardiac Metabolism and Cancer Biology.

An important priority in the cardiovascular care of oncology patients is to reduce morbidity and mortality, and improve the quality of life in cancer survivors through cross-disciplinary efforts. The rate of survival in cancer patients has improved dramatically over the past decades. Nonetheless, survivors may be more likely to die from cardiovascular disease in the long term, secondary, not only to the potential toxicity of cancer therapeutics, but also to the biology of cancer. In this context, efforts from basic and translational studies are crucial to understanding the molecular mechanisms causal to cardiovascular disease in cancer patients and survivors, and identifying new therapeutic targets that may prevent and treat both diseases. This review aims to highlight our current understanding of the metabolic interaction between cancer and the heart, including potential therapeutic targets. An overview of imaging techniques that can support both research studies and clinical management is also provided. Finally, this review highlights opportunities and challenges that are necessary to advance our understanding of metabolism in the context of cardio-oncology.

Reliability of a single-region sample to evaluate tumor immune microenvironment in hepatocellular carcinoma.

BACKGROUND & AIMS: Intratumor heterogeneity has frequently been reported in patients with hepatocellular carcinoma (HCC). Thus, the reliability of single-region tumor samples for evaluation of the tumor immune microenvironment is also debatable. We conducted a prospective study to analyze the similarity in tumor immune microenvironments among different regions of a single tumor. METHODS: Multi-region sampling was performed on newly resected tumors. The tumor immune microenvironment was evaluated by immunohistochemical staining of PD-L1, CD4, CD8, CD20, FoxP3, DC-LAMP (or LAMP3), CD68, MPO, and tertiary lymphoid structures (TLSs). PD-L1 expression was manually quantified according to the percentage of PD-L1-stained tumor or stromal cells. The densities (number/mm2) of immune cells and the number of TLSs per sample were determined by whole-section counting. RNA-sequencing was applied in selected samples. Similarities in tumor immune microenvironments within each tumor were evaluated by multivariate Mahalanobis distance analyses. RESULTS: Thirteen tumors were collected from 12 patients. The median diameter of tumors was 9 cm (range 3-16 cm). A median of 6 samples (range 3-12) were obtained from each tumor. Nine (69.2%) tumors exhibited uniform expression of PD-L1 in all regions of the tumor. Out of 13 tumors analyzed by immunohistochemical staining, 8 (61.5%) tumors displayed a narrow Mahalanobis distance for all regions within the tumor; while 8 (66.7%) of the 12 tumors analyzed by RNA-sequencing displayed a narrow Mahalanobis distance. Immunohistochemistry and RNA-sequencing had a high concordance rate (83.3%; 10 of 12 tumors) for the evaluation of similarities between tumor immune microenvironments within a tumor. CONCLUSIONS: A single-region tumor sample might be reliable for the evaluation of tumor immune microenvironments in approximately 60-70% of patients with HCC. LAY SUMMARY: Heterogeneity in the regional immune microenvironments of tumors has been reported in patients with hepatocellular carcinoma. This heterogeneity could be an obstacle when trying to reliably evaluate the immune microenvironment of an entire tumor using only a single-region tumor sample, which may be the only option in patients with more advanced disease. Our study utilized both immunohistochemical and transcriptomic analyses to demonstrate that a single-region sample is reliable for evaluation of tumor immune microenvironments in 60-70% of patients with hepatocellular carcinoma.