Efficacy and Safety of a Botanical Formula Fuzheng Huayu for Hepatic Fibrosis in Patients with CHC: Results of a Phase 2 Clinical Trial.

Background: Hepatitis C virus (HCV) is a common cause of progressive hepatic fibrosis, cirrhosis, and hepatocellular carcinoma worldwide. Despite the availability of effective direct-acting antivirals, patients often have significant hepatic fibrosis at the time of diagnosis due to delay in diagnosis and comorbidities which promote fibrogenesis. Thus, antifibrotic agents represent an attractive adjunctive therapy.

Biospecimen Collection During the COVID-19 Pandemic.

Objectives: Millions of biospecimens will be collected during the coronavirus disease 2019 (COVID-19) pandemic. As learned from severe acute respiratory syndrome (SARS), proper biospecimen handling is necessary to prevent laboratory-related infections.

Methods: Centers for Disease Control and Prevention and World Health Organization severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interim biosafety guidelines continue to be updated.

NADPH oxidase 1 is highly expressed in human large and small bowel cancers.

To facilitate functional investigation of the role of NADPH oxidase 1 (NOX1) and associated reactive oxygen species in cancer cell signaling, we report herein the development and characterization of a novel mouse monoclonal antibody that specifically recognizes the C-terminal region of the NOX1 protein. The antibody was validated in stable NOX1 overexpression and knockout systems, and demonstrates wide applicability for Western blot analysis, confocal microscopy, flow cytometry, and immunohistochemistry. We employed our NOX1 antibody to characterize NOX1 expression in a panel of 30 human colorectal cancer cell lines, and correlated protein expression with NOX1 mRNA expression and superoxide production in a subset of these cells.

State of the Art: Toward Improving Outcomes of Lung and Liver Tumor Biopsies in Clinical Trials-A Multidisciplinary Approach.

Purpose: National Cancer Institute (NCI)-sponsored clinical trial network studies frequently require biopsy specimens for pharmacodynamic and molecular biomarker analyses, including paired pre- and post-treatment samples. The purpose of this meeting of NCI-sponsored investigators was to identify local institutional standard procedures found to ensure quantitative and qualitative specimen adequacy.

Methods: NCI convened a conference on best biopsy practices, focusing on the clinical research community.

Clinical Evolution of Epithelial-Mesenchymal Transition in Human Carcinomas.

The significance of the phenotypic plasticity afforded by epithelial-mesenchymal transition (EMT) for cancer progression and drug resistance remains to be fully elucidated in the clinic. We evaluated epithelial-mesenchymal phenotypic characteristics across a range of tumor histologies using a validated, high-resolution digital microscopic immunofluorescence assay (IFA) that incorporates β-catenin detection and cellular morphology to delineate carcinoma cells from stromal fibroblasts and that quantitates the individual and colocalized expression of the epithelial marker E-cadherin (E) and the mesenchymal marker vimentin (V) at subcellular resolution ("EMT-IFA"). We report the discovery of β-catenin cancer cells that coexpress E-cadherin and vimentin in core-needle biopsies from patients with various advanced metastatic carcinomas, wherein these cells are transitioning between strongly epithelial and strongly mesenchymal-like phenotypes.

Toward Improving Practices for Submission of Diagnostic Tissue Blocks for National Cancer Institute Clinical Trials.

Objectives: The National Cancer Institute (NCI) National Clinical Trials Network performs phase II and III clinical trials, which increasingly rely on the submission of diagnostic formalin-fixed, paraffin-embedded tissue blocks for biomarker assessment. Simultaneously, advances in precision oncology require that clinical centers maintain diagnostic specimens for ancillary, standard-of-care diagnostics. This has caused tissue blocks to become a limited resource for advancing the NCI clinical trial enterprise and the practice of modern molecular pathology.

IL-4 and IL-17A Cooperatively Promote Hydrogen Peroxide Production, Oxidative DNA Damage, and Upregulation of Dual Oxidase 2 in Human Colon and Pancreatic Cancer Cells.

Dual oxidase 2 (DUOX2) generates HO that plays a critical role in both host defense and chronic inflammation. Previously, we demonstrated that the proinflammatory mediators IFN-γ and LPS enhance expression of DUOX2 and its maturation factor DUOXA2 through STAT1- and NF-κB‒mediated signaling in human pancreatic cancer cells. Using a panel of colon and pancreatic cancer cell lines, we now report the induction of DUOX2/DUOXA2 mRNA and protein expression by the T2 cytokine IL-4.

What Can Be Done to Improve Research Biopsy Quality in Oncology Clinical Trials?

Purpose:: Research biopsy specimens collected in clinical trials often present requirements beyond those of tumor biopsy specimens collected for diagnostic purposes. Research biopsies underpin hypothesis-driven drug development, pharmacodynamic assessment of molecularly targeted anticancer agents, and, increasingly, genomic assessment for precision medicine; insufficient biopsy specimen quality or quantity therefore compromises the scientific value of a study and the resources devoted to it, as well as each patient's contribution to and potential benefit from a clinical trial.

Methods:: To improve research biopsy specimen quality, we consulted with other translational oncology teams and reviewed current best practices.

Residual tissue repositories as a resource for population-based cancer proteomic studies.

Background: Mass spectrometry-based proteomics has become a powerful tool for the identification and quantification of proteins from a wide variety of biological specimens. To date, the majority of studies utilizing tissue samples have been carried out on prospectively collected fresh frozen or optimal cutting temperature (OCT) embedded specimens. However, such specimens are often difficult to obtain, in limited in supply, and clinical information and outcomes on patients are inherently delayed as compared to banked samples.

Nonalcoholic steatofibrosis independently predicts mortality in nonalcoholic fatty liver disease.

Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD). The minimal pathologic criteria for NASH include hepatic steatosis, ballooning degeneration, and lobular inflammation. The resolution of NASH, which relies on the loss of ballooning degeneration, is subject to sampling and observer variability in pathologic interpretation.

NADPH oxidase 5 (NOX5)-induced reactive oxygen signaling modulates normoxic HIF-1α and p27 expression in malignant melanoma and other human tumors.

NADPH oxidase 5 (NOX5) generated reactive oxygen species (ROS) have been implicated in signaling cascades that regulate cancer cell proliferation. To evaluate and validate NOX5 expression in human tumors, we screened a broad range of tissue microarrays (TMAs), and report substantial overexpression of NOX5 in malignant melanoma and cancers of the prostate, breast, and ovary. In human UACC-257 melanoma cells that possesses high levels of functional endogenous NOX5, overexpression of NOX5 resulted in enhanced cell growth, increased numbers of BrdU positive cells, and increased γ-H2AX levels.

Decoding NADPH oxidase 4 expression in human tumors.

NADPH oxidase 4 (NOX4) is a redox active, membrane-associated protein that contributes to genomic instability, redox signaling, and radiation sensitivity in human cancers based on its capacity to generate HO constitutively. Most studies of NOX4 in malignancy have focused on the evaluation of a small number of tumor cell lines and not on human tumor specimens themselves; furthermore, these studies have often employed immunological tools that have not been well characterized. To determine the prevalence of NOX4 expression across a broad range of solid tumors, we developed a novel monoclonal antibody that recognizes a specific extracellular region of the human NOX4 protein, and that does not cross-react with any of the other six members of the NOX gene family.

Biliary Adenofibroma of Liver: Morphology, Tumor Genetics, and Outcomes in 6 Cases.

Biliary adenofibroma is a rare primary hepatic neoplasm, recognized in the World Health Organization classification, although only 14 cases have been reported to date. This series includes extended follow-up from 2 of the early case reports and 4 novel cases. Clinical history and histology were reviewed in all 6 cases.

The root causes of pharmacodynamic assay failure.

Robust pharmacodynamic assay results are valuable for informing go/no-go decisions about continued development of new anti-cancer agents and for identifying combinations of targeted agents, but often pharmacodynamic results are too incomplete or variable to fulfill this role. Our experience suggests that variable reagent and specimen quality are two major contributors to this problem. Minimizing all potential sources of variability in procedures for specimen collection, processing, and assay measurements is essential for meaningful comparison of pharmacodynamic biomarkers across sample time points.

Hepatic small vessel neoplasm, a rare infiltrative vascular neoplasm of uncertain malignant potential.

Characteristic but rare vascular neoplasms in the adult liver composed of small vessels with an infiltrative border were collected from an international group of collaborators over a 5-year period (N=17). These tumors were termed hepatic small vessel neoplasm (HSVN), and the histologic differential diagnosis was angiosarcoma (AS). The average age of patients was 54years (range, 24-83years).

Histology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis in Adults and Children.

Nonalcoholic fatty liver disease (NAFLD) is the liver disease associated with obesity, diabetes, and the metabolic syndrome. Although steatosis is a key histologic feature, liver biopsies of patients with NAFLD can show a wide range of findings. Nonalcoholic steatohepatitis (NASH) is a progressive subtype of NAFLD first defined by analogy to alcoholic hepatitis.

Robustness of Next Generation Sequencing on Older Formalin-Fixed Paraffin-Embedded Tissue.

Next Generation Sequencing (NGS) technologies are used to detect somatic mutations in tumors and study germ line variation. Most NGS studies use DNA isolated from whole blood or fresh frozen tissue. However, formalin-fixed paraffin-embedded (FFPE) tissues are one of the most widely available clinical specimens.

Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD).

Aim: Non-alcoholic steatohepatitis (NASH) patients are at increased risk for progression to cirrhosis. The aim of this study was to assess all-cause and liver-specific mortality in a cohort of non-alcoholic fatty liver disease (NAFLD) patients.

Methods: Biopsy-proven NAFLD patients with and without NASH from two historic databases were included.

Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality.

Unlabelled: Since the initial description of nonalcoholic steatohepatitis (NASH), several sets of pathologic criteria for its diagnosis have been proposed. However, their interprotocol agreement and ability to predict long-term liver-related mortality (LRM) have not been demonstrated. In this study, we examined patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) for whom liver biopsy slides and clinical and mortality data were available.

Fibrolamellar carcinomas are positive for CD68.

Fibrolamellar carcinomas are a unique type of liver carcinoma that arise in non-cirrhotic livers of young individuals. Despite their distinctive appearance, recent studies have demonstrated a lack of consistency in how fibrolamellar carcinomas are diagnosed by pathologists. As a potential aide in diagnosis, we investigated the staining properties of CD68.

Tumors of the liver and intrahepatic bile ducts: radiologic-pathologic correlation.

Primary tumors of the liver can be classified pathologically based on their cell of origin into epithelial tumors, arising from hepatocytes or biliary epithelium, and nonepithelial tumors, including mesenchymal tumors and lymphoma. Characteristic findings on MR imaging can be seen in many cases. This article reviews the MR imaging appearance of these tumors with pathologic correlation.

Fibrolamellar hepatocellular carcinoma: an immunohistochemical comparison with conventional hepatocellular carcinoma.

The fibrolamellar variant of hepatocellular carcinoma (FLC) differs from conventional hepatocellular carcinoma (HCC) in some clinical and pathological features. The authors investigated possible differences in reactivity between FLCs and HCCs using glypican-3 (GPC3), an oncofetal protein, and survivin, an antiapoptotic protein. They also compared staining of FLC and HCC with antibodies to cytokeratins 7 (CK7) and 19 (CK19) and CD34.

Farglitazar lacks antifibrotic activity in patients with chronic hepatitis C infection.

Background & Aims: Farglitazar (GI262570), an insulin-sensitizing agent, selectively binds and activates peroxisome proliferator-activated receptor gamma (PPARgamma) and inhibits stellate cell activation. We evaluated its antifibrotic effect in patients with chronic hepatitis C that did not respond to standard-of-care therapy.

Methods: Patients with fibrosis of Ishak stages 2-4 (n = 265), based on analysis of liver biopsy samples, were randomly assigned to groups given once-daily doses of 0.

Plexiform fibromyxoma: a distinctive benign gastric antral neoplasm not to be confused with a myxoid GIST.

A great majority of gastric mesenchymal tumors are gastrointestinal stromal tumor (GIST). A rare group of non-GISTs include myxoid mesenchymal neoplasms. In this report, we describe 12 cases of a distinctive gastric tumor, named here as plexiform fibromyxoma.