Mechanistically based blood proteomic markers in the TGF-ß pathway stratify risk of hepatocellular cancer in patients with cirrhosis.

Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer worldwide but is often diagnosed at an advanced incurable stage. Yet, despite the urgent need for blood-based biomarkers for early detection, few studies capture ongoing biology to identify risk-stratifying biomarkers. We address this gap using the TGF-ß pathway because of its biological role in liver disease and cancer, established through rigorous animal models and human studies. Using machine learning methods with blood levels of 108 proteomic markers in the TGF-ß family, we found a pattern that differentiates HCC from non-HCC in a cohort of 216 patients with cirrhosis, which we refer to as TGF-ß based Protein Markers for Early Detection of HCC (TPEARLE) comprising 31 markers. Notably, 20 of the patients with cirrhosis alone presented an HCC-like pattern, suggesting that they may be a group with as yet undetected HCC or at high risk for developing HCC. In addition, we found two other biologically relevant markers, Myostatin and Pyruvate Kinase M2 (PKM2), which were significantly associated with HCC. We tested these for risk stratification of HCC in multivariable models adjusted for demographic and clinical variables, as well as batch and site. These markers reflect ongoing biology in the liver. They potentially indicate the presence of HCC early in its evolution and before it is manifest as a detectable lesion, thereby providing a set of markers that may be able to stratify risk for HCC.

Racial Disparities in End-Stage Kidney Disease Outcomes among Asians and Native Hawaiians and Other Pacific Islanders across Geographic Residence.

INTRODUCTION: While Asian and Native Hawaiian and other Pacific Islander (NHOPI) patients have a high prevalence of kidney disease risk factors, there are sparse data examining their end-stage kidney disease (ESKD) outcomes. As Hawaii has high representation of Asian and NHOPI individuals, we compared their ESKD outcomes based on residence in the mainland USA versus Hawaii/Pacific Islands (PIs). MATERIALS AND METHODS: Using United States Renal Data System data, we examined the impact of geographic residence in the mainland versus Hawaii/PIs on race-mortality associations among incident ESKD patients transitioning to dialysis over January 1, 2000-December 31, 2016 using Cox regression. We examined likelihood of post-dialysis kidney transplantation using Cox models and cumulative incidence curves. RESULTS: Compared with White patients in the mainland, Asian and NHOPI patients in the mainland had lower mortality: adjusted HRs (95% CIs) 0.67 (0.66-0.67) and 0.72 (0.70-0.73), respectively. When examining Asian and NHOPI patients in Hawaii/PIs, survival benefit was attenuated in Asian and diminished to the null in NHOPI patients (ref: mainland White patients). Cumulative incidence curves comparing Asian, NHOPI, and White patients showed Asian and NHOPI patients in the mainland had the highest likelihood of transplantation, whereas NHOPI and Asian patients in Hawaii/PIs had the lowest likelihood. CONCLUSION: In the mainland, Asian and NHOPI patients had lower mortality versus White patients, whereas in Hawaii/PIs, this survival benefit was diminished in Asian and mitigated in NHOPI patients. NHOPI and Asian patients in Hawaii/PIs had less transplantation versus those in the mainland. Further research is needed to uncover factors contributing to differential ESKD outcomes among Asian and NHOPI patients across geographic residence.

Hepatocellular carcinoma in Pacific Islanders: comparison of Pacific Island-born vs. US-born.

Aim: To describe demographic, clinical, and outcome differences in Pacific Island-born (PI-born) compared to US-born hepatocellular carcinoma (HCC) patients of Pacific Island ancestry within a clinical cohort in Hawaii. Methods: A prospectively collected database of 1608 patients diagnosed with HCC over a 30-year period (1993-2022) identified 252 patients of Pacific Islander ethnicity. Data collected: demographics, medical history, laboratory data, tumor characteristics, treatment, and survival. Patients were divided into two groups: PI-born and US-born. Categorical variables were analyzed using ANOVA and chi-square analysis. Odds ratios with 95% confidence intervals were calculated using univariate and multivariate logistic regression. Overall survival was evaluated using Kaplan-Meier analysis. Results: PI-born patients were younger (57.3 vs. 61.8 years, P = 0.002) and more likely to have hepatitis B (OR 14.10, 7.50-26.50) and underlying cirrhosis (OR 2.28, 1.17-4.45). In comparison, US-born patients had a significantly higher likelihood of Hepatitis C, nonalcoholic steatohepatitis/nonalcoholic fatty liver disease, history of non-HCC cancer, and positive smoking history compared to PI-born patients. PI-born patients were more likely to forego treatment (OR 3.22, 1.77-5.87) and be lost to follow-up (OR 9.21, 1.97-43.03). Both groups were equally likely to have the opportunity for curative surgical treatment (liver resection or transplant). US-born status was associated with higher mortality risk, while transplantation was associated with lower mortality risk. The PI-born cohort demonstrated higher overall survival at 3 and 5 years compared to US-born. Conclusion: HBV remains the primary risk factor for HCC in PI-born patients, whereas HCC in US-born patients is more associated with the adoption of a Westernized lifestyle.

Liver Transplantation vs Partial Hepatectomy for Stage T2 Multifocal Hepatocellular Carcinoma <3 cm Without Vascular Invasion: A Propensity Score-Matched Survival Analysis.

BACKGROUND: Multifocal hepatocellular carcinoma (HCC) differs biologically and immunologically from single-nodule HCC. Asian and European guidelines consider liver transplantation (LT) and partial hepatectomy (PH) as effective for T2 multifocal HCC, with preference toward LT, but few US studies compare these treatments directly. This propensity score-based observational study uses an established national cancer outcomes registry to compare overall survival in patients undergoing PH and LT for multifocal HCC. STUDY DESIGN: Data from the 2020 National Cancer Database were obtained on patients who underwent LT or PH for multifocal stage 2 HCC within Milan criteria and without vascular invasion. Propensity score matching and Cox regression analysis was applied to evaluate overall survival in an observational cohort balanced by age, sex, treatment facility type, treatment year, prothrombin time, α-fetoprotein, comorbidity burden, liver fibrosis severity, and pretreatment creatinine and bilirubin levels. RESULTS: Of 21,248 T2 HCC patients identified, 6,744 had multifocal tumors with largest tumor diameter <3 cm without major vascular invasion, with 1,267 and 181 having undergone LT and PH, respectively. Propensity score-matched Cox regression analysis associated LT with a hazard ratio of 0.39 (95% CI 0.30 to 0.50) relative to PH. Landmark analyses to account for a longer interval to LT demonstrated survival benefits of similar magnitude. CONCLUSIONS: Although early-stage HCC can be effectively treated with either LT or PH, propensity score-matched analysis comparatively shows a survival benefit for LT in patients with multifocal HCC who are within the Milan criteria.

Disparities in Hepatocellular Carcinoma Outcomes Among Subgroups of Asians and Pacific Islanders: A SEER Database Study.

Hepatocellular carcinoma (HCC) is highly prevalent in Asians and Pacific Islanders (API) but this heterogenous group is often aggregated into a single category, despite vast differences in culture, socioeconomic status, education, and access to care among subgroups. There remains a significant knowledge gap in HCC outcomes among different subgroups of API. The Surveillance, Epidemiology, and End Results (SEER) database was accessed, and site/ICD codes were used to identify HCC patients during 2010-2019 who were API ethnicity. Data collected: demographics, socioeconomic status, tumor characteristics, treatment, and survival. Subgroup analyses were performed among different Asian ethnicities in a secondary analysis. 8,249 patients were identified/subdivided into subgroups of Asian ethnicities and Other Pacific Islanders (NHOPI) groups. The median age was 65 years for Asians and 62 years for NHOPI (p < 0.01), and significant differences were found in income (p < 0.01). A higher proportion of NHOPI lived in rural areas compared to Asians (8.1 vs. 1.1%, p < 0.01). There were no statistically significant differences in tumor size, stage, pre-treatment AFP level, or surgical treatments between the two groups. However, Asians had higher overall median survival than NHOPI (20 months v 12 months, p < 0.01). Secondary analyses among different subgroups of Asian ethnicities revealed significant differences in tumor size and staging, surgical resection, transplant rates, and median survival. While API had similar tumor characteristics and treatment, Asians had much higher survival than NHOPI. Socioeconomic differences and access to care may contribute to these differences. This study also found significant survival disparities within API ethnicities.

Cyanotoxin exposure and hepatocellular carcinoma.

Cyanobacteria are ubiquitous in aquatic and terrestrial environments worldwide and include a number of species producing tumor-promoting hepatotoxins. Human exposure to cyanobacteria and cyanotoxins primarily occurs though ingestion of contaminated drinking water and food sources. In a Northeast U.S. population, we recently reported an independent association of oral cyanobacteria with risk of hepatocellular carcinoma (HCC). In a cross-sectional study of 55 HCC patients in Hawaii, U.S.A., serum microcystin/nodularin (MC/NOD), cylindrospermopsin (CYN), and anabaenopeptin (AB) were measured by ELISA. In a subset of 16 patients, cyanotoxin levels were compared by tumor expression of over 700 genes analyzed via the Nanostring nCounter Fibrosis panel. MC/NOD, CYN, and AB were detected in all HCC patients. MC/NOD and CYN levels significantly varied by etiology with the highest levels in cases attributed to metabolic risk factors, specifically, hyperlipidemia, type 2 diabetes, and non-alcoholic fatty liver disease/non-alcoholic steatohepatitis. Cyanotoxin levels were significantly positively correlated with tumor expression of genes functioning in PPAR signaling and lipid metabolism. Our study provides novel albeit limited evidence that cyanotoxins may a role in the pathogenesis of HCC through the dysregulation of lipid metabolism and progression of hepatic steatosis.

Target Trial Emulation: A Design Tool for Cancer Clinical Trials.

PURPOSE: To apply target trial emulation to explore the potential impact of eligibility criteria on the primary outcome of a randomized controlled trial. METHODS: Simulations of a real-world explanatory trial of transarterial radioembolization for advanced unresectable hepatocellular carcinoma with portal vein invasion were performed to examine the effects of cohort specification on survival outcomes and patient sample size. Simulations comprised 24 different permutations of the trial varied on three disease nonspecific eligibility parameters. Treatment and control arms for these emulated trials were drawn from the National Cancer Database and matched by treatment propensity. Target trial emulation served as the causal framework for this analysis, allowing the architecture of a true controlled experiment to address forms of bias routinely encountered in comparative effectiveness studies involving real-world observational data. RESULTS: Twenty-four propensity score-matched cohorts comprising a wider clinical spectrum of patients than specified by the original target trial were successfully generated using the National Cancer Database. The arms for each of the emulated trials demonstrated exchangeability across all eligibility criteria and other clinical covariates. Significant treatment benefits were associated with only a narrow range of eligibility criteria, indicating that the original target trial was well specified. CONCLUSION: The impact of patient selection on treatment outcomes can be studied using target trial emulation. This analytical framework can furthermore serve to leverage existing real-world data to inform the task of cohort specification for a randomized controlled trial, facilitating a more data-driven approach for this important step in clinical trial design.

Racial and Ethnic Differences in Chronic Kidney Disease and Its Risk Factors among Asian-Americans and Pacific Islanders in Hawaii.

BACKGROUND: Several studies suggest that Asian-American and Native Hawaiian and Other Pacific Islander (NHOPI) racial/ethnic groups have a heightened risk of chronic kidney disease (CKD), but provide limited inference due to the aggregation of these groups into a single racial/ethnic category. We thus examined the association of granularly defined racial/ethnic groups with specific CKD indicators among a diverse group of participants from the National Kidney Foundation of Hawaii's Kidney Early Detection Screening (KEDS) Program. METHODS: Among 1,243 participants enrolled in 19 KEDS screening events over 2006-2009, we examined the association between Asian-American and NHOPI groups and specific CKD indicators, defined as self-reported CKD, microalbuminuria, and macroalbuminuria, using multivariable logistic regression. We then examined associations of race/ethnicity with various CKD risk factors. RESULTS: The most predominant racial/ethnic groups were White (22.0%), Multiracial (18.9%), Japanese (19.2%), Filipino (13.4%), NHOPI (8.4%), and Chinese (4.5%) participants. NHOPI and Chinese participants had a higher risk of microalbuminuria (adjusted ORs [aORs] [95% CIs] 2.48 [1.25-4.91] and 2.37 [1.07-5.27], respectively), while point estimates for all other minority groups suggested higher risk (reference: Whites). NHOPI participants also had a higher risk of macroalbuminuria and self-reported CKD. While most minorities had a higher risk of diabetes and hypertension, NHOPI and Multiracial participants had a higher risk of obesity, whereas the East Asian groups had a lower risk. CONCLUSIONS: In this community-based cohort, compared with Whites, Asian-Americans had a higher risk of early CKD indicators, whereas NHOPIs had a higher risk of more severe CKD indicators. Further studies are needed to elucidate the distinct pathways leading to CKD across diverse racial/ethnic groups in Hawaii.

Current status of disparity in liver disease.

Disparities have emerged as an important issue in many aspects of healthcare in developed countries and may be based on race, ethnicity, sex, geographical location, and socioeconomic status. For liver disease specifically, these potential disparities can affect access to care and outcome in viral hepatitis, chronic liver disease, and hepatocellular carcinoma. Shortages in hepatologists and medical providers versed in liver disease may amplify these disparities by compromising early detection of liver disease, surveillance for hepatocellular carcinoma, and prompt referral to subspecialists and transplant centers. In the United States, continued efforts have been made to address some of these disparities with better education of healthcare providers, use of telehealth to enhance access to specialists, reminders in electronic medical records, and modifying organ allocation systems for liver transplantation. This review will detail the current status of disparities in liver disease and describe current efforts to minimize these disparities.

Pathogenesis to management of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer whose incidence continues to rise in many parts of the world due to a concomitant rise in many associated risk factors, such as alcohol use and obesity. Although early-stage HCC can be potentially curable through liver resection, liver-directed therapies, or transplantation, patients usually present with intermediate to advanced disease, which continues to be associated with a poor prognosis. This is because HCC is a cancer with significant complexities, including substantial clinical, histopathologic, and genomic heterogeneity. However, the scientific community has made a major effort to better characterize HCC in those aspects via utilizing tissue sampling and histological classification, whole genome sequencing, and developing viable animal models. These efforts ultimately aim to develop clinically relevant biomarkers and discover molecular targets for new therapies. For example, until recently, there was only one approved systemic therapy for advanced or metastatic HCC in the form of sorafenib. Through these efforts, several additional targeted therapies have gained approval in the United States, although much progress remains to be desired. This review will focus on the link between characterizing the pathogenesis of HCC with current and future HCC management.

Vasoactive Intestinal Peptide-Secreting Pheochromocytoma: A Case Report and Review of Literature.

Objective: To describe a case of composite vasoactive intestinal peptide (VIP)-secreting pheochromocytoma and review literature to provide insight into the various presentations and potential management of these rare tumors. Case Report: A 64-year-old male patient presented with hypertensive emergency and coronary demand ischemia with development of watery diarrhea, hypokalemia, and achlorhydria syndrome. Serum and urine studies demonstrated elevated metanephrine and VIP levels. Definitive surgical resection resolved symptoms and normalized laboratory values. Pathologic examination of the specimen revealed pheochromocytoma with a Pheochromocytoma of the Adrenal gland Scaled Score of 4 and patchy expression of VIP. Discussion: Given the different actions of hormones that can be secreted by these composite tumors, we suggest that pheochromocytomas with diversified secretory capabilities may be an underrecognized clinical entity. Localized disease is often amenable to surgical resection, although management of metastatic disease is not well established due to the rarity of these tumors and lack of randomized trials. Conclusion: In patients presenting with diarrhea of unclear etiology or the suggestion of secondary hypertension, assessment for a possible neuroendocrine tumor may be prudent. If an adrenal mass is discovered but the patient exhibits atypical symptoms of catecholamine excess, a diagnosis of composite pheochromocytoma with multisecretory properties should be considered.

Management of hepatocellular carcinoma in patients who are 70 years or older.

Background: Although liver transplantation has been done successfully in elderly patients with hepatocellular carcinoma, these are likely well-selected patients. This study uses a large database of patients with hepatocellular carcinoma to explore treatment and potential candidacy for liver transplantation in the elderly. Methods: Retrospective review of 1,533 hepatocellular carcinoma cases identified 2 groups: 475 patients 70 years or older (70 +) and 1,058 patients < 70 years. Demographics, risk factors, tumor characteristics, treatments, and survival were compared. Three- and 5-year survival rates were determined, and logistic regression was used to identify factors predictive of 3-year survival. Results: Patients 70 + were more likely to have metabolic factors and less likely to have viral hepatitis, cirrhosis, hepatocellular carcinoma found with surveillance (21.7% vs 28.4%, P = .005), and hepatocellular carcinoma within Milan criteria (37.3% vs 43.8%, P = .019). Model for End-stage Liver Disease score was similar, but patients 70 + had higher mean creatinine and lower mean bilirubin. Patients 70 + were equally likely to undergo liver resection but less likely to undergo liver transplantation (0.4% vs 10.2%, P < .001). Three- and 5-year survival rates were significantly worse in 70 +, and predictors of 3-year survival included hepatocellular carcinoma found with surveillance, meeting Milan criteria, and normal alpha fetoprotein. Discussion: Elderly patients with hepatocellular carcinoma were less likely to undergo liver transplantation potentially due to metabolic factors and advanced disease. Although there is no age cutoff for liver transplantation, elderly patients should be given realistic expectations of liver transplantation candidacy. Continued surveillance for hepatocellular carcinoma in elderly patients may allow for earlier diagnosis and improved liver transplantation candidacy. Key Message: Hepatocellular carcinoma in patients who are 70 years or older can be managed with liver transplantation in select cases, but more patients will be managed with liver resection and nonoperative therapies.

Using quantitative immunohistochemistry in patients at high risk for hepatocellular cancer.

Hepatocellular carcinoma (HCC) is the primary form of liver cancer and a major cause of cancer death worldwide. Early detection is key to effective treatment. Yet, early diagnosis is challenging, especially in patients with cirrhosis, who are at high risk of developing HCC. Dysfunction or loss of function of the transforming growth factor ß (TGF-ß) pathway is associated with HCC. Here, using quantitative immunohistochemistry analysis of samples from a multi-institutional repository, we evaluated if differences in TGF-ß receptor abundance were present in tissue from patients with only cirrhosis compared with those with HCC in the context of cirrhosis. We determined that TGFBR2, not TGFBR1, was significantly reduced in HCC tissue compared with cirrhotic tissue. We developed an artificial intelligence (AI)-based process that correctly identified cirrhotic and HCC tissue and confirmed the significant reduction in TGFBR2 in HCC tissue compared with cirrhotic tissue. Thus, we propose that a reduction in TGFBR2 abundance represents a useful biomarker for detecting HCC in the context of cirrhosis and that incorporating this biomarker into an AI-based automated imaging pipeline could reduce variability in diagnosing HCC from biopsy tissue.

Survival characteristics of fibrolamellar hepatocellular carcinoma: A Surveillance, Epidemiology, and End Results database study.

BACKGROUND: Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare and distinct type of hepatocellular carcinoma that frequently presents in an advanced stage in younger patients with no underlying liver disease. Currently, there is a limited understanding of factors that impact outcomes in FL-HCC. AIM: To characterize the survival of FL-HCC by age, race, and surgical intervention. METHODS: This is a retrospective study of The Surveillance, Epidemiology, and End Results database. We identified patients with FL-HCC between 2000-2018 by using an ICD-O-3 site code C22.0 and a histology code 8171/3: Hepatocellular carcinoma, fibrolamellar. In addition, demographics, tumor characteristics, types of surgical procedure, stages, and survival data were obtained. We conducted three separate survival analyses by age groups; ≤ 19, 20-59, and ≥ 60-year-old, and race; White, Black, Hispanic, Asian and Pacific islanders (API), and surgical types; Wedge resection or segmental resection, lobectomy, extended lobectomy (lobectomy + locoregional therapy or resection of the other lobe), and transplant. The Chi-Square test analyzed categorical variables, and continuous variables were examined using the Mann-Whitney U test. The Kaplan-Meier survival curve was used to compare survival. Multivariate analysis was done with Cox regression analysis. RESULTS: We identified 225 FL-HCC patients with a mean age of 36.9. Overall median survival was 34 (95%CI: 27-41) mo. Patients ≤ 19-years-old had more advanced disease with positive lymph nodes status. However, they received more surgical interventions such as a wedge, segmental resection, lobectomy, extended lobectomy, and transplant. Survival for ≤ 19 was 85 (95%CI: 37-137) mo, age 20-59 was 29 (95%CI: 18-41) mo, and age ≥ 60 years was 12 (95%CI: 7-31) mo (P < 0.001). There were no differences in stage, lymph node status, metastasis status, and surgical treatment among races. The median survival were; Whites had 39 (95%CI: 29-63), Blacks 26 (95%CI: 5-92), Hispanics 31 (95%CI: 11-54), and APIs 28 (95%CI: 5-39) mo (P = 0.28). Of 225 patients, 111 FL-HCC patients had surgical procedures. Median survivals for a wedge or segmental resection was 112 (95%CI: 78-NA), lobectomy was 92 (95%CI: 57-NA), extended lobectomy was 54 (95%CI: 23-NA), and a transplant was 63 (95%CI: 20-NA) mo (P < 0.001). The median survival was better in patients who had surgical treatments regardless of lymph nodes or metastasis status (P < 0.001). CONCLUSION: FL-HCC occurs in a primarily younger population, but survival can be prolonged despite the aggressive disease. There were no racial differences in the survival of FL-HCC; however, Asians with FL-HCC tended to be older than in other races. Surgical treatment provided better survival even in those patients with nodal disease or metastases. Although future studies are needed to explore other therapies for FL-HCC, surgical options should be considered in all cases of FL-HCC unless contraindicated.

Spontaneous Rupture of Hepatocellular Carcinoma: New Insights.

Background: Spontaneous rupture of hepatocellular carcinoma (HCC) is a potentially fatal complication and the third leading cause of death in patients with HCC after tumor progression and liver failure. Previous studies suggested that improved HCC surveillance has decreased the incidence of rupture. This study aims to characterize patients with ruptured HCC over time and identify predictors of rupture. Methods: We retrospectively reviewed a prospectively collected database of 1451 HCC patients to identify cases with rupture and predictors of rupture. Data were divided into three 9-year eras to compare and trend patient/tumor characteristics and rupture. Results: Fifty-seven patients (3.9%) presented with spontaneous HCC rupture and the following characteristics: mean age 62.6 years, 73.7% males, 41% cirrhosis, and mean tumor size of 8.0 cm. On multivariate analyses, predictors of rupture included obesity, tumor >5 cm, and single tumors, whereas the presence of cirrhosis was a negative predictor for rupture.Across three eras, there were changes in disease etiology and decreases in tumor size, and more HCCs were found with surveillance. However, more patients were noncirrhotic, and the incidence of spontaneous rupture was unchanged over time. Conclusion: Despite improved early detection of HCC over time, the incidence of rupture has been unchanged. The persistent incidence of rupture may possibly be attributed to increasing proportion of fatty liver-related HCC patients who lack traditional risk factors for surveillance and may not have cirrhosis. Better identification of fatty liver disease and determining which patients need HCC surveillance may be needed in the future to prevent spontaneous rupture.

Disaggregating Asian Race Reveals COVID-19 Disparities Among Asian American Patients at New York City's Public Hospital System.

OBJECTIVES: Data on the health burden of COVID-19 among Asian American people of various ethnic subgroups remain limited. We examined COVID-19 outcomes of people of various Asian ethnic subgroups and other racial and ethnic groups in an urban safety net hospital system. METHODS: We conducted a retrospective analysis of 85 328 adults aged ≥18 tested for COVID-19 at New York City's public hospital system from March 1 through May 31, 2020. We examined COVID-19 positivity, hospitalization, and mortality, as well as demographic characteristics and comorbidities known to worsen COVID-19 outcomes. We conducted adjusted multivariable regression analyses examining racial and ethnic disparities in mortality. RESULTS: Of 9971 Asian patients (11.7% of patients overall), 48.2% were South Asian, 22.2% were Chinese, and 29.6% were in other Asian ethnic groups. South Asian patients had the highest rates of COVID-19 positivity (30.8%) and hospitalization (51.6%) among Asian patients, second overall only to Hispanic (32.1% and 45.8%, respectively) and non-Hispanic Black (27.5% and 57.5%, respectively) patients. Chinese patients had a mortality rate of 35.7%, highest of all racial and ethnic groups. After adjusting for demographic characteristics and comorbidities, only Chinese patients had significantly higher odds of mortality than non-Hispanic White patients (odds ratio = 1.44; 95% CI, 1.04-2.01). CONCLUSIONS: Asian American people, particularly those of South Asian and Chinese descent, bear a substantial and disproportionate health burden of COVID-19. These findings underscore the need for improved data collection and reporting and public health efforts to mitigate disparities in COVID-19 morbidity and mortality among these groups.

Oral Cyanobacteria and Hepatocellular Carcinoma.

BACKGROUND: Gut microbial alterations have been linked to chronic liver disease and hepatocellular carcinoma (HCC). The role of the oral microbiome in liver cancer development has not been widely investigated. METHODS: Bacterial 16S rRNA sequences were evaluated in oral samples from 90 HCC cases and 90 controls who were a part of a larger U.S. case-control study of HCC among patients diagnosed from 2011 to 2016. RESULTS: The oral microbiome of HCC cases showed significantly reduced alpha diversity compared with controls (Shannon P = 0.002; Simpson P = 0.049), and beta diversity significantly differed (weighted Unifrac P = 0.004). The relative abundance of 30 taxa significantly varied including Cyanobacteria, which was enriched in cases compared with controls (P = 0.018). Cyanobacteria was positively associated with HCC [OR, 8.71; 95% confidence interval (CI), 1.22-62.00; P = 0.031] after adjustment for age, race, birthplace, education, smoking, alcohol, obesity, type 2 diabetes, Hepatitis C virus (HCV), Hepatitis B virus (HBV), fatty liver disease, aspirin use, other NSAID use, laboratory batch, and other significant taxa. When stratified by HCC risk factors, significant associations of Cyanobacteria with HCC were exclusively observed among individuals with negative histories of established risk factors as well as females and college graduates. Cyanobacterial genes positively associated with HCC were specific to taxa producing microcystin, the hepatotoxic tumor promotor, and other genes known to be upregulated with microcystin exposure. CONCLUSIONS: Our study provides novel evidence that oral Cyanobacteria may be an independent risk factor for HCC. IMPACT: These findings support future studies to further examine the causal relationship between oral Cyanobacteria and HCC risk.

ß2-spectrin (SPTBN1) as a therapeutic target for diet-induced liver disease and preventing cancer development.

The prevalence of nonalcoholic steatohepatitis (NASH) and liver cancer is increasing. De novo lipogenesis and fibrosis contribute to disease progression and cancerous transformation. Here, we found that ß2-spectrin (SPTBN1) promotes sterol regulatory element (SRE)­binding protein (SREBP)­stimulated lipogenesis and development of liver cancer in mice fed a high-fat diet (HFD) or a western diet (WD). Either hepatocyte-specific knockout of SPTBN1 or siRNA-mediated therapy protected mice from HFD/WD-induced obesity and fibrosis, lipid accumulation, and tissue damage in the liver. Biochemical analysis suggested that HFD/WD induces SPTBN1 and SREBP1 cleavage by CASPASE-3 and that the cleaved products interact to promote expression of genes with sterol response elements. Analysis of human NASH tissue revealed increased SPTBN1 and CASPASE-3 expression. Thus, our data indicate that SPTBN1 represents a potential target for therapeutic intervention in NASH and liver cancer.

Genetic susceptibility to hepatocellular carcinoma in chromosome 22q13.31, findings of a genome-wide association study.

BACKGROUND AND AIM: Chronic hepatitis C virus (HCV) infection, long-term alcohol use, cigarette smoking, and obesity are the major risk factors for hepatocellular carcinoma (HCC) in the United States, but the disease risk varies substantially among individuals with these factors, suggesting host susceptibility to and gene-environment interactions in HCC. To address genetic susceptibility to HCC, we conducted a genome-wide association study (GWAS). METHODS: Two case-control studies on HCC were conducted in the United States. DNA samples were genotyped using the Illumian microarray chip with over 710 000 single nucleotide polymorphisms (SNPs). We compared these SNPs between 705 HCC cases and 1455 population controls for their associations with HCC and verified our findings in additional studies. RESULTS: In this GWAS, we found that two SNPs were associated with HCC at P < 5E-8 and six SNPs at P < 5E-6 after adjusting for age, sex, and the top three principal components (PCs). Five of the SNPs in chromosome 22q13.31, three in PNPLA3 (rs2281135, rs2896019, and rs4823173) and two in SAMM50 (rs3761472, rs3827385), were replicated in a small US case-control study and a cohort study in Singapore. The associations remained significant after adjusting for body mass index and HCV infection. Meta-analysis of multiple datasets indicated that these SNPs were significantly associated with HCC. CONCLUSIONS: SNPs in PNPLA3 and SAMM50 are known risk loci for nonalcoholic fatty liver disease (NAFLD) and are suspected to be associated with HCC. Our GWAS demonstrated the associations of these SNPs with HCC in a US population. Biological mechanisms underlying the relationship remain to be elucidated.