Hepatocellular carcinoma (HCC) is the third most common cause of cancer related death worldwide. Prognosis and treatment options largely depend on tumor stage at diagnosis, with curative treatments only available if detected at an early stage. However, two thirds of patients with HCC are diagnosed at a late stage and not eligible for cure. Therefore several liver professional societies recommend HCC surveillance using abdominal ultrasound with or without alpha fetoprotein in at-risk populations, including patients with cirrhosis and subsets of those with chronic hepatitis B. Available data suggest HCC surveillance can significantly improve early tumor detection, curative treatment eligibility, and overall survival. However, the potential benefits of HCC surveillance must be considered in light a shifting HCC demographic from a viral-mediated cancer to an increasing proportion of patients having non-alcoholic steatohepatitis, which has been shown to limit ultrasound sensitivity and may mitigate observed benefits. Further, benefits of HCC surveillance must be weighed against potential physical, financial and psychological harms. Continued data for both benefits and harms of HCC surveillance in contemporary populations are necessary. In the interim, providers should continue to strive for high quality HCC surveillance in at-risk patients.
alpha-Fetoproteins ; Carcinoma, Hepatocellular ; Diagnosis ; Fatty Liver ; Fibrosis ; Hepatitis B, Chronic ; Humans ; Liver ; Liver Neoplasms ; Mass Screening ; Prognosis ; Ultrasonography

Non-alcoholic fatty liver disease (NAFLD), one of the most common causes of liver disease, is an increasingly common cause of hepatocellular carcinoma (HCC). Several demographic, clinical, and genetic factors contribute to HCC risk in NAFLD patients, which may inform risk stratification scores. Proven efficacious approaches to primary prevention approach in patients with non-viral liver disease remain an area of need. Semi-annual surveillance is associated with improved early tumor detection and reduced HCC-related mortality; however, patients with NAFLD have several challenges to effective surveillance, including under-recognition of at-risk patients, low surveillance utilization in clinical practice, and lower sensitivity of current tools for early-stage HCC detection. Treatment decisions are best made in a multidisciplinary fashion and are informed by several factors including tumor burden, liver dysfunction, performance status, and patient preferences. Although patients with NAFLD often have larger tumor burden and increased comorbidities compared to counterparts, they can achieve similar post-treatment survival with careful patient selection. Therefore, surgical therapies continue to provide a curative treatment option for patients diagnosed at an early stage. Although there has been debate about the efficacy of immune checkpoint inhibitors in patients with NAFLD, current data are insufficient to change treatment selection based on liver disease etiology.

Non-alcoholic fatty liver disease (NAFLD) may progress to cirrhotic or non-cirrhotic hepatocellular carcinoma (HCC), and is currently recognized as the fastest growing cause of HCC worldwide. Accordingly, professional society guidelines recommend HCC surveillance in patients with cirrhosis from any etiology, and some may consider it beneficial in subgroups with non-cirrhotic NAFLD at higher risk for HCC. Notably, patients with NAFLD-related HCC are more likely to have HCC diagnosed at more advanced stages and have poorer outcomes when compared to other etiologies, and suboptimal effectiveness of HCC surveillance programs is a major culprit. In this review, we summarize the current guidelines for HCC surveillance and discuss its benefits versus potential harms for NAFLD patients. We also address the unique challenges of HCC surveillance in NAFLD, including higher proportion of NAFLD-related HCC without cirrhosis, poor recognition of at-risk patients, lack of consensus regarding the value of surveillance in non-cirrhotic NAFLD, subpar effectiveness of surveillance tools related to NAFLD phenotype, and preponderant surveillance underuse among NAFLD patients. Finally, we examine the effectiveness of currently used surveillance tools (i.e., ultrasound and alpha fetoprotein) and outline future perspectives including emerging risk stratification tools, imaging surveillance strategies (e.g., abbreviated magnetic resonance imaging protocols), blood-based biomarkers (e.g., GALAD and circulating tumor DNA panels), and interventions to improve surveillance adherence.

PURPOSE: Estrogens control the development and cell proliferation of various tissues including the normal mammary epithelial cells, where they induce the expression of the immediate and delayed hormone-responsive genes. The proliferative effects of estrogen have been attributed to its ability to increase the expression of the key cell cycle regulatory genes responsible for cell cycle progression. However, the regulation of cell proliferation is only one aspect of estrogen function. It has also been well documented that estrogen plays a critical role in the etiology and progression of human breast and gynecological cancers. This tumorigenic effect of estrogen might be associated with its anti- apoptotic activities such as of Bcl-2 induction. The aim of this study was to clarify the role of E2IG5, which is an estrogen-induced downstream effector molecule, in breast cancer cell lines. RESULTS: This study shows that E2IG5 is a pro-apoptotic protein that is localized to the mitochondrial membrane via two distinct transmembrane domains. When over-expressed, it induces a mitochondrial permeability transition with the resultant of release cytochrome c and caspase activation. However, three out of four breast cancer cell lines lost their estrogen dependence of E2IG5 expression, which suggests the possible involvement of E2IG5 in the development of breast cancer. CONCLUSION: These results suggest that breast cancer cells may loose their pro-apoptotic signals and selectively use the proliferative mechanism of estrogen, which drives the normal mammary epithelial cells to transform into cancer cells. Further studies using breast cancer tissues will be needed.
Breast Neoplasms* ; Breast* ; Cell Cycle ; Cell Line* ; Cell Proliferation ; Cytochromes c ; Epithelial Cells ; Estradiol ; Estrogens ; Genes, Regulator ; Humans ; Mitochondrial Membranes ; Permeability

PURPOSE: The prognosis of patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE) is often uncertain. We aimed to utilize analytic morphomics, a high-throughput imaging analysis, to assess if body composition is predictive of post-TACE survival. MATERIALS AND METHODS: We included patients from a single center (Ann Arbor VA)who had TACE as the primary treatment forHCC and had a pre-treatment computed tomography scans. Univariate analysis and multivariate conditional inference tree analysis were utilized to identify the morphomic characteristics predictive of 1-year survival. Results were validated in an external cohort (University of Michigan Health System) of HCC patients who underwent TACE as their primary treatment. RESULTS: In the 75 patients in the derivation cohort, median survival was 439 (interquartile range, 377 to 685) days from receipt of TACE, with 1-year survival of 61%. Visceral fat density (VFD) was the only morphomic factor predictive of overall and 1-year survival (p < 0.001). Patients with VFD above the 56th percentile had a 1-year survival of 39% versus 78% for those below the 56th percentile. VFD also correlated with 1-year survival in the external validation cohort (44% vs. 72%, p < 0.001). In a secondary analysis, patients with higher VFD were significantly more likely to experience hepatic decompensation after TACE (p < 0.001). CONCLUSION: VFD served as an objective predictor of mortality in patients undergoing TACE, possibly through its ability to predict hepatic decompensation. VFD may serve as a radiographic biomarker in predicting TACE outcomes.
Body Composition* ; Carcinoma, Hepatocellular* ; Cohort Studies ; Humans ; Intra-Abdominal Fat ; Michigan ; Mortality ; Prognosis ; Trees

Background/Aims: Cirrhosis is the most important risk factor of hepatocellular carcinoma (HCC), and patients with cirrhosis are recommended to receive semiannual surveillance for early HCC detection. However, early cirrhosis is often asymptomatic and can go undiagnosed for years, leading to underuse of HCC surveillance in clinical practice. We characterized the frequency and associated factors of unrecognized cirrhosis in a national sample of patients with HCC from the United States. Methods: HCC patients aged 68 years and older, diagnosed during 2011 to 2015 were included from the SEERMedicare Linked Database. If cirrhosis was diagnosed within 6 months immediately preceding HCC diagnosis or after HCC diagnosis, cases were categorized as unrecognized cirrhosis. Factors associated with unrecognized cirrhosis were identified using logistic regression analyses. Factors associated with overall survival were evaluated using Cox regression analyses. Results: Among 5,098 HCC patients, 74.8% patients had cirrhosis. Among those with cirrhosis, 57.4% had unrecognized cirrhosis, with the highest proportion (76.3%) among those with NAFLD-related HCC. Male sex (aOR: 2.12, 95% CI: 1.83–2.46), non-Hispanic Black race (aOR: 1.93, 95% CI: 1.45–2.57), and NAFLD etiology (aOR: 4.46, 95% CI: 3.68–5.41) were associated with having unrecognized cirrhosis. Among NAFLD-related HCC patients, male sex (aOR: 2.32, 95% CI: 1.71–3.14) was associated with unrecognized cirrhosis. Unrecognized cirrhosis was independently associated with worse overall survival (aHR: 1.17, 95% CI: 1.08–1.27) compared to recognized cirrhosis. Conclusions Unrecognized cirrhosis is common in NAFLD-related HCC, particularly among male and Black patients, highlighting these groups as important intervention targets to improve HCC surveillance uptake and outcomes.