Society: AASLD

Cholangiocarcinoma (CCA), a cancer of biliary epithelium is highly aggressive, and shows a high degree of lymphatic infiltration (lymphangiogenesis) in early stages of metastasis. Expansion of the lymphatic network associated with inflammation or infection often precedes metastatic progression and dissemination and contributes to aggressiveness of these CCA tumors. Yet the mechanisms remain unknown. The emergence of a global pandemic with COVID-19 also brought some of these mechanisms to the forefront. Several lines of evidence have implicated COVID-19 as an endothelial disease and the resultant cytokine storm, endothelial dysfunction, cause significant changes in the tissue microenvironment that in turn could be favorable for tumor progression and activate metabolic changes. We hypothesized that SARS-CoV-2 induced alterations in the lymphatic endothelial cells (LECs) contributes to tumor-LEC crosstalk by inducing an inflammatory milieu. LECs and CCA cells were treated with the spike protein (S1) and different pathway specific inhibitors to determine activation of lymphangiogenic and tumor promoting mechanisms. In addition, proliferation, migration, and metabolic assays were carried out. LECs express the angiotensin converting enzyme 2 (ACE2) the well-known receptor for SARS-CoV-2. Our data suggested that S1 protein, significantly increased the cellular proliferation and cellular lactate production with concomitant increase in the expression of the key metabolic genes PFKP, FASN. S1 protein also had a robust impact on lymphatic tube formation and invasion that was associated with alterations in VEGFR3 expression. Interestingly, S1 protein infected LEC produces high level of TGFβ, a well-known factor for liver fibrosis and cholangiocarcinoma. Our data suggested that high level of TGFβ induced the ROS production, endothelial to mesenchymal transition (EndMT), creates an inflammatory milieu and also increased production of CXCL5, that has been demonstrated to actively participate in the HLEC-CCA cross talk through the specific CCR2 receptor expressed by CCA cells. CCA cells treated with the conditioned media (CM) from S1 protein treated HLEC, showed increased migratory potential that was associated with an increase in transcription factors for epithelial to mesenchymal transition (EMT), e.g., Snail1, Snail2, Zeb1, Zeb2 and the EMT genes α-SMA, Vimentin, Fibronectin along with the increase in matrix metalloproteinases, MMP2, MMP21. Taken together, our data proposes a novel axis mediated by SARS-CoV-2 infection increasing CCA-HLEC cross talk via the TGFb-CXCL5-CCR2 axis and ROS production that accelerates the metastatic potential of CCA cells. Hence, targeting the TGFb-ROS axis through small molecule inhibitors can be potential therapeutic option for managing the post COVID susceptibility of CCA progression and expansion of the lymphatic vasculature.

Introduction:
Coronavirus disease 2019 (COVID-19) has become the greatest health threat of the last few years. It is well established that patients with metabolic syndrome have higher prevalence of COVID-19. In addition, metabolic syndrome is associated with increased severity of COVID-19. Non-alcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of metabolic syndrome. Data is limited regarding the COVID-19 related complications in patients with NAFLD. In our study, we aimed to investigate COVID-19 related outcomes in NAFLD.

Methods:
A retrospective cohort study was conducted using TriNetX, a multi-institutional database of more than 70 million patients from 49 healthcare organizations in the U.S between 1/2020 – 11/2022. We compared several COVID-19 related complications in patients with and without NAFLD. 1:1 propensity-score matching was performed for age, gender, race, ethnicity, and all major risk factors of COVID-19 among all cohorts. We assessed COVID-19 outcomes up to 3 months of index date (COVID-19 diagnosis). Adjusted odds ratios (aOR) with 95% confidence interval (CI) were calculated.

Results:
Of COVID-19 patients, we identified 17,937 patients with NAFLD (Cohort 1) and 3,077,926 patients with no NAFLD (Cohort 2). After propensity score matching, 17,936 patients were accounted for in each group (Table 1). Reviewing three-months outcomes of these patients after adjustment, cohort 1 had an increased risk of cardiac complications (aOR 1.64 [1.53-1.75]), VTE (aOR 3.01 [2.76-3.29]), cerebrovascular accident (1.82[1.62-2.03]), AKI (aOR 2.59 [2.37-2.83]) and PVD (aOR 1.48 [1.29-1.71]) compared to cohort 2. Moreover, Cohort 1 patients were at higher risk of acute respiratory distress syndrome (ARDS) (aOR 3.36 [3.12-3.62]), ICU-mechanical ventilation (aOR 3.22 [2.75-3.77]) and shock (aOR 4.35 [3.62-5.23]). In addition, cohort 1 had higher risk of hospitalization (aOR 1.20 [1.15-1.26]) and higher mortality (aOR 2.12 [1.89-2.38]) when compared with cohort 2 patients, table 2.

Discussion:
We found that NAFLD patients infected with COVID-19 have significantly worse COVID-19 related outcomes compared with COVID-19 patients without NAFLD. Targeting NAFLD and metabolic syndrome management could address modifiable risk factors to reduce COVID-19 related morbidity and morbidity.

Table 1: General Characteristics of cohorts before and after propensity score matching.

Table 1: General Characteristics of cohorts before and after propensity score matching.

Table 2: COVID-19 outcomes in NAFLD patients compared with control after propensity matching score.

Table 2: COVID-19 outcomes in NAFLD patients compared with control after propensity matching score.

Background:
Coronavirus Disease-19 (COVID-19) unmasked significant racial disparities in rates of infection and mortality in the United States. A large multicenter observational study of over 900 patients reported Black and Hispanic patients to have higher rates of COVID-19, be uninsured/underinsured, but no difference in adjusted mortality. We studied healthcare utilization and outcomes in patients with cirrhosis who developed COVID-19 in 2020 by ethnicity.

Methods:
The United States Healthcare Cost and Utilization Project’s National Inpatient Sample (HCUP-NIS) 2020 was queried to identify patients with cirrhosis and COVID-19 using ICD-10 codes and divided in 3 groups – White (WH), African American (AA), and Hispanic (HISP). We studied patient and hospital demographics, comorbidities, cirrhosis etiologies, complications, mean length of stay (LOS), mean Total Hospital Charges (THC), and adjusted odds ratio (aOR) for all-cause mortality. Statistical analysis utilized the chi-square test, univariate and multinomial logistic regression.

Results:
We identified 13,465 WH, 3405 AA, and 7375 HISP admissions. Hispanics were significantly younger (59.5 years vs. 64.5 in WH and 62.8 in AA, p<0.001) and fewer women (35.7% vs. 51.9% WH and 46.6% AA, p=0.002). Compared to WH, HISP and AA were more likely to come from the lowest quartile income zip codes and on Medicaid or uninsured (p<0.001). HISP had the highest rates of Diabetes while the lowest rates of dyslipidemia, COPD, CAD, CHF, CKD, smoking (all p<0.001). AA had the highest comorbidities of CAD, CHF, and CKD, while WH had highest comorbid COPD, smoking, and obesity rates (all p<0.01). Chronic viral hepatitis was highest in AA, while alcoholic cirrhosis was highest in HISP, and NASH was highest in WH (all p<0.001). Cirrhosis complications portal hypertension, varices, variceal and non-variceal bleed, and ascites were significantly higher in HISP and lowest in AA (all p<0.05). LOS was similar between all 3 groups (p=NS), while mean THC were highest in HISP ($134,021), AA ($110,894), WH ($95,098), p=0.001. Overall cohort mortality was 6.6% but in cirrhosis with COVID-19 was 19.4% (p<0.001). By ethnicity, mortality (adjusted for patient demographics, hospital demographics, medical comorbidities, cirrhosis etiology) was significantly higher in AA and HISP, aOR 1.12, p=0.01.

Conclusion:
There were significant racial disparities in patients with cirrhosis and COVID-19. HISP and AA had higher mortality than WH. HISP also had the highest THC despite similar LOS, younger age, and low co-morbidity burden. Higher charges in AA and HISP amounted to over $340 million in 2020 alone. The THC difference may be explained by higher rates of cirrhosis complications in HISP, but unclear for AA group. Further studies would be needed to explore this finding.

Background: The Coronavirus Disease 2019 (COVID-19) pandemic has had a considerable impact on healthcare systems. Due to fear of exposure, medical resource allocation, delay or cancelation of appointment, and the stay-at-home mandate, a dramatic drop in hepatocellular carcinoma (HCC) surveillance was reported in small retrospective studies. Little is known about the change in magnitude of HCC diagnosis during the pandemic period in the United States (U.S.). Herein, we sought to determine the impact of the pandemic on incident HCC cases and the characteristics in the U.S.
Methods: This is a retrospective study of the US National Cancer Database (NCDB) analyzing the number of incident HCC in the U.S. from 2010 to 2020. The diagnosis of HCC was based on the International Classification of Diseases–Oncology 3^rd Edition. The number of reported HCC cases was assessed and the rate was calculated using the total population for each year from the census bureau. Trend analysis was performed using joinpoint regression analysis and a polynomial regression model was used to calculate estimated number of HCC cases in 2020 according to the trend of rates from 2010-2019. Additionally, cancer stage, and treatment modality were calculated.
Results: The number of HCC cases reported during the pandemic year was significantly reduced from the prior year (19,597 cases in 2019 to 16,188 in 2020). Prior to the COVID-19 pandemic, the number of HCC cases was increasing from 2010 to 2017 (13,032 to 19,666 cases, respectively), and stabilized (19,673 in 2018, 19,597 in 2019). Extrapolating from this trend, the predicted number of HCC cases in 2020 was 19,011. However, 14.8% less than the estimated number of HCC cases were diagnosed in 2020. While less than estimated HCC cases were diagnosed in 2020, there was minimal impact on tumor stage and receipt of curative treatment in 2020. The average tumor size of HCC was minimally increased from 4.2 cm in 2019 to 4.3 cm in 2020 (p <0.001).
Conclusions: There was a clinically significant reduction in reported cases of HCC in 2020 versus pre-COVID years. Despite the implementation of COVID-19-associated healthcare restrictions, tumor stage and proportion of patients receiving curative treatment remain largely stable during the first year of COVID-19 pandemic.

Hirsh Trivedi

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