Biomarker Development Using Liquid Biopsy in Hepatocellular Carcinoma.

Liver cancer incidence rate continues to increase and currently ranks third in the total number of annual deaths, behind only lung and colorectal cancer. Most patients with hepatocellular carcinoma (HCC) are diagnosed at advanced stages, and they live for less than 2 years after diagnosis on average. This contrasts with those diagnosed at an early stage, who can be cured with surgery. However, even after curative resection, there remains a risk of up to 70% of postoperative HCC recurrence. There have been major changes in the management of HCC in the past 5 years, particularly for patients at advanced stages. Despite this multitude of new therapies, there is a lack of clear biomarkers to guide providers on the best approach to sequence therapies, which would maximize efficacy while minimizing toxicity. There are several areas in clinical management of HCC that are particularly challenging, and would benefit from development and implementation of new biomarkers to improve patient overall survival. Here, we review the major advances in liquid biopsy biomarkers for early detection of HCC, minimum residual disease, and predicting response to treatment.

Impact of COVID-19 pandemic on gastrointestinal cancer diagnosis and resection: An observational study.

BACKGROUND: The COVID-19 pandemic disrupted routine screening for and treatment of gastrointestinal (GI) cancers. We analyzed changes in GI cancer pathology specimens resulting from diagnostic and therapeutic procedures at a single academic center in an epicenter of the COVID-19 pandemic. Our aim was to determine which cancer types, procedures, and patients were impacted by the pandemic. METHODS: This was a retrospective, cohort study of patients identified based on carcinoma containing pathologic specimens reviewed in our institution resulting from diagnostic or resection procedures. Pathology and medical records of patients with GI and liver carcinoma and high-grade dysplasia were reviewed from February 1 to April 30 in 2018, 2019 and 2020. We used March 16, 2020 to delineate the pre-COVID-19 and COVID-19 period in 2020. Chi-squared or t-tests, as appropriate, were used to compare these time periods in each year. Mann Kendall test was used to test for trend in volume. ANCOVA was used to compare differences across years. RESULTS: A total of 1028 pathology samples from 949 unique patients were identified during the study period. There was a 57% drop in samples within 2020 (p = 0.01) that was not present in either 2018 or 2019 (p<0.01). In 2020, there were significantly fewer resections compared to biopsies overall in the COVID-19 period (p = 0.01). There were fewer colorectal cancer specimens (p = 0.04) which were procured from older patients (p<0.01) in the 2020 COVID-19 period compared to pre-COVID-19. CONCLUSIONS: In our institution, there was a significant drop in diagnostic and resection specimens of GI cancers during the COVID-19 pandemic, disproportionately affecting older colorectal cancer patients.

Limited intestinal inflammation despite diarrhea, fecal viral RNA and SARS-CoV-2-specific IgA in patients with acute COVID-19.

Gastrointestinal symptoms are common in COVID-19 patients but the nature of the gut immune response to SARS-CoV-2 remains poorly characterized, partly due to the difficulty of obtaining biopsy specimens from infected individuals. In lieu of tissue samples, we measured cytokines, inflammatory markers, viral RNA, microbiome composition, and antibody responses in stool samples from a cohort of 44 hospitalized COVID-19 patients. SARS-CoV-2 RNA was detected in stool of 41% of patients and more frequently in patients with diarrhea. Patients who survived had lower fecal viral RNA than those who died. Strains isolated from stool and nasopharynx of an individual were the same. Compared to uninfected controls, COVID-19 patients had higher fecal levels of IL-8 and lower levels of fecal IL-10. Stool IL-23 was higher in patients with more severe COVID-19 disease, and we found evidence of intestinal virus-specific IgA responses associated with more severe disease. We provide evidence for an ongoing humeral immune response to SARS-CoV-2 in the gastrointestinal tract, but little evidence of overt inflammation.

Cooperation Between Distinct Cancer Driver Genes Underlies Intertumor Heterogeneity in Hepatocellular Carcinoma.

BACKGROUND AND AIMS: The pattern of genetic alterations in cancer driver genes in patients with hepatocellular carcinoma (HCC) is highly diverse, which partially explains the low efficacy of available therapies. In spite of this, the existing mouse models only recapitulate a small portion of HCC inter-tumor heterogeneity, limiting the understanding of the disease and the nomination of personalized therapies. Here, we aimed at establishing a novel collection of HCC mouse models that captured human HCC diversity. METHODS: By performing hydrodynamic tail-vein injections, we tested the impact of altering a well-established HCC oncogene (either MYC or ß-catenin) in combination with an additional alteration in one of eleven other genes frequently mutated in HCC. Of the 23 unique pairs of genetic alterations that we interrogated, 9 were able to induce HCC. The established HCC mouse models were characterized at histopathological, immune, and transcriptomic level to identify the unique features of each model. Murine HCC cell lines were generated from each tumor model, characterized transcriptionally, and used to identify specific therapies that were validated in vivo. RESULTS: Cooperation between pairs of driver genes produced HCCs with diverse histopathology, immune microenvironments, transcriptomes, and drug responses. Interestingly, MYC expression levels strongly influenced ß-catenin activity, indicating that inter-tumor heterogeneity emerges not only from specific combinations of genetic alterations but also from the acquisition of expression-dependent phenotypes. CONCLUSIONS: This novel collection of murine HCC models and corresponding cell lines establishes the role of driver genes in diverse contexts and enables mechanistic and translational studies.