Multitarget Stool RNA Test for Colorectal Cancer Screening.

Importance: Noninvasive tests for colorectal cancer screening must include sensitive detection of colorectal cancer and precancerous lesions. These tests must be validated for the intended-use population, which includes average-risk individuals 45 years or older. Objective: To evaluate the sensitivity and specificity of a noninvasive, multitarget stool RNA (mt-sRNA) test (ColoSense) test compared with results from a colonoscopy. Design, Setting, and Participants: This phase 3 clinical trial (CRC-PREVENT) was a blinded, prospective, cross-sectional study to support a premarket approval application for a class III medical device. A total of 8920 participants were identified online using social media platforms and enrolled from June 2021 to June 2022 using a decentralized nurse call center. All participants completed the mt-sRNA test, which incorporated a commercially available fecal immunochemical test (FIT), concentration of 8 RNA transcripts, and participant-reported smoking status. Stool samples were collected prior to participants completing a colonoscopy at their local endoscopy center. The mt-sRNA test results (positive or negative) were compared with index lesions observed on colonoscopy. Over the course of 12 months, individuals 45 years and older were enrolled in the clinical trial using the decentralized recruitment strategy. Participants were enrolled from 49 US states and obtained colonoscopies at more than 3800 different endoscopy centers. Main Outcomes and Measures: The primary outcomes included the sensitivity of the mt-sRNA test for detecting colorectal cancer and advanced adenomas and the specificity for no lesions on colonoscopy. Results: The mean (range) age of participants was 55 (45-90) years, with 4% self-identified as Asian, 11% as Black, and 7% as Hispanic. Of the 8920 eligible participants, 36 (0.40%) had colorectal cancer and 606 (6.8%) had advanced adenomas. The mt-sRNA test sensitivity for detecting colorectal cancer was 94%, sensitivity for detecting advanced adenomas was 46%, and specificity for no lesions on colonoscopy was 88%. The mt-sRNA test showed significant improvement in sensitivity for colorectal cancer (94% vs 78%; McNemar P = .01) and advanced adenomas (46% vs 29%; McNemar P < .001) compared with results of the FIT. Conclusions and Relevance: In individuals 45 years and older, the mt-sRNA test showed high sensitivity for colorectal neoplasia (colorectal cancer and advanced adenoma) with significant improvement in sensitivity relative to the FIT. Specificity for no lesions on colonoscopy was comparable to existing molecular diagnostic tests. Trial Registration: ClinicalTrials.gov Identifier: NCT04739722.

Prediction of 2-[18F]FDG PET-CT SUVmax for Adrenal Mass Characterization: A CT Radiomics Feasibility Study.

BACKGROUND: Indeterminate adrenal masses (AM) pose a diagnostic challenge, and 2-[18F]FDG PET-CT serves as a problem-solving tool. Aim of this study was to investigate whether CT radiomics features could be used to predict the 2-[18F]FDG SUVmax of AM. METHODS: Patients with AM on 2-[18F]FDG PET-CT scan were grouped based on iodine contrast injection as CT contrast-enhanced (CE) or CT unenhanced (NCE). Two-dimensional segmentations of AM were manually obtained by multiple operators on CT images. Image resampling and discretization (bin number = 16) were performed. 919 features were calculated using PyRadiomics. After scaling, unstable, redundant, and low variance features were discarded. Using linear regression and the Uniform Manifold Approximation and Projection technique, a CT radiomics synthetic value (RadSV) was obtained. The correlation between CT RadSV and 2-[18F]FDG SUVmax was assessed with Pearson test. RESULTS: A total of 725 patients underwent PET-CT from April 2020 to April 2021. In 150 (21%) patients, a total of 179 AM (29 bilateral) were detected. Group CE consisted of 84 patients with 108 AM (size = 18.1 ± 4.9 mm) and Group NCE of 66 patients with 71 AM (size = 18.5 ± 3.8 mm). In both groups, 39 features were selected. No statisticallyf significant correlation between CT RadSV and 2-[18F]FDG SUVmax was found (Group CE, r = 0.18 and p = 0.058; Group NCE, r = 0.13 and p = 0.27). CONCLUSIONS: It might not be feasible to predict 2-[18F]FDG SUVmax of AM using CT RadSV. Its role as a problem-solving tool for indeterminate AM remains fundamental.

Tumor-associated fibrosis impairs immune surveillance and response to immune checkpoint blockade in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. Immune checkpoint blockade has improved survival for many patients with NSCLC, but most fail to obtain long-term benefit. Understanding the factors leading to reduced immune surveillance in NSCLC is critical in improving patient outcomes. Here, we show that human NSCLC harbors large amounts of fibrosis that correlates with reduced T cell infiltration. In murine NSCLC models, the induction of fibrosis led to increased lung cancer progression, impaired T cell immune surveillance, and failure of immune checkpoint blockade efficacy. Associated with these changes, we observed that fibrosis leads to numerically and functionally impaired dendritic cells and altered macrophage phenotypes that likely contribute to immunosuppression. Within cancer-associated fibroblasts, distinct changes within the Col13a1-expressing population suggest that these cells produce chemokines to recruit macrophages and regulatory T cells while limiting recruitment of dendritic cells and T cells. Targeting fibrosis through transforming growth factor-ß receptor signaling overcame the effects of fibrosis to enhance T cell responses and improved the efficacy of immune checkpoint blockade but only in the context of chemotherapy. Together, these data suggest that fibrosis in NSCLC leads to reduced immune surveillance and poor responsiveness to checkpoint blockade and highlight antifibrotic therapies as a candidate strategy to overcome immunotherapeutic resistance.

Comparison of gene fusion detection methods in salivary gland tumors.

Salivary gland neoplasms may pose diagnostic difficulties due to overlapping morphologic features. Recently, specific gene fusions have been discovered that correspond to particular tumor types, and can aid in accurate diagnosis. Gene rearrangements are commonly assessed by fluorescence in situ hybridization (FISH), although use of next-generation sequencing is increasing. However, there is no "gold standard" for fusion detection. We determined the concordance between FISH and a targeted RNA sequencing panel in gene fusion detection across twenty-two salivary gland tumors, including five mucoepidermoid carcinomas, four acinic cell carcinomas, four pleomorphic adenomas, two adenoid cystic carcinomas, two NUT carcinomas, and one each of basal cell adenoma, salivary duct carcinoma ex-pleomorphic adenoma, salivary duct carcinoma, clear cell carcinoma, and secretory carcinoma. Directed FISH testing based on the diagnosis was performed on cases that did not already have FISH conducted during clinical workup. Targeted RNA sequencing of 507 genes and their partners (using the Illumina TruSight Fusion Panel) was completed. Six of twenty-two (27.3%) cases had discordant results. In three cases, FISH results were negative while RNA sequencing results found fusion transcripts, which were all confirmed with RT-PCR and Sanger sequencing. In three cases, RNA sequencing results were negative while FISH results were positive for a gene rearrangement. Thus, if fusion analysis results are conflicting with the morphologic impression, a second mode of fusion detection may be warranted. Although both methods have advantages and drawbacks, RNA sequencing provides additional information about novel fusion partners and fusions that may not have been originally considered.

MRI Radiomics for the Prediction of Fuhrman Grade in Clear Cell Renal Cell Carcinoma: a Machine Learning Exploratory Study.

The Fuhrman nuclear grade is a recognized prognostic factor for patients with clear cell renal cell carcinoma (CCRCC) and its pre-treatment evaluation significantly affects decision-making in terms of management. In this study, we aimed to assess the feasibility of a combined approach of radiomics and machine learning based on MR images for a non-invasive prediction of Fuhrman grade, specifically differentiation of high- from low-grade tumor and grade assessment. Images acquired on a 3-Tesla scanner (T2-weighted and post-contrast) from 32 patients (20 with low-grade and 12 with high-grade tumor) were annotated to generate volumes of interest enclosing CCRCC lesions. After image resampling, normalization, and filtering, 2438 features were extracted. A two-step feature reduction process was used to between 1 and 7 features depending on the algorithm employed. A J48 decision tree alone and in combination with ensemble learning methods were used. In the differentiation between high- and low-grade tumors, all the ensemble methods achieved an accuracy greater than 90%. On the other end, the best results in terms of accuracy (84.4%) in the assessment of tumor grade were achieved by the random forest. These evidences support the hypothesis that a combined radiomic and machine learning approach based on MR images could represent a feasible tool for the prediction of Fuhrman grade in patients affected by CCRCC.

Blast flagging of the Sysmex XN-10 hematology analyzer with supervised cell image analysis: Impact on quality parameters.

INTRODUCTION: The Sysmex XN-10 automated hematology analyzer (Sysmex Corporation) is routinely used in hematology laboratories to perform complete blood cell count with differential (CBC w/ diff). The sensitivity of this system for blast detection is unclear, since many prior studies evaluating the blast flagging capabilities of Sysmex XN series used the white precursor cell (WPC) channel, which is not cleared for use in the United States. METHODS: We assessed the blast flagging capabilities of the Sysmex XN-10 compared with CellaVision (a cell image analyzer)-assisted visual hematology results. We evaluated the following flags: "blasts?/abnormal lymph?" and "immature granulocytes present" and compared differences in turnaround time between methods. RESULTS: We collected data on 2239 CBC w/ diff Sysmex automated analyzer differential and CellaVision-assisted visual differential from the inpatient hematology-oncology population of a tertiary care medical center. Solely analyzing the first CBC/diff from each unique patient, both flags had a combined sensitivity of 100%, specificity of 50.2%, PPV of 21.7%, and NPV of 100%. The mean turnaround time for the automated differential was 19.5 minutes (SD 35.9 minutes) compared with 66.4 minutes for the CellaVision-assisted visual differential (SD 68.5 minutes; P < 0.001; Figure 1). CONCLUSION: The Sysmex XN-10 abnormal lymphocyte/blast and immature granulocytes flags had excellent sensitivity and acceptable specificity in detecting circulating blasts with shorter turnaround time than the CellaVision-assisted visual differential. Our study suggests that automated differentials performed on Sysmex XN-10 can replace visual differentials as a first-line screening method for blast detection with improved turnaround time in hematology-oncology populations.

Racial differences in beliefs of physician prescribing practices for low-cost pharmacy options.

BACKGROUND: Previous studies have reported that certain populations are sensitive to high out-of-pocket drug costs, and drug noncompliance leads to poorer health outcomes. OBJECTIVE: Our aim was to measure patient awareness of discount pharmacy options, cost barriers to medication access, and beliefs about health care provider's use of low-cost medications. METHODS: This cross-sectional 17-item survey was administered to patients in the emergency department of an urban trauma center in February 2011. Differences in responses by sex and race groups were assessed. A logistic regression model was created to estimate the association of sociodemographic factors and medication use with awareness of discount pharmacy options. RESULTS: Five hundred and fifty-two surveys were analyzed. Among respondents who were prescribed medications within the past year, three fourths of patients felt comfortable asking physicians for cheaper medicines. Slightly more than half were aware of low-cost pharmacy options, and 78% of these respondents correctly listed at least one of these pharmacies. Caucasian patients were more comfortable than African American patients asking for cheaper medicines (82.5% vs. 72.2%; p < 0.05) and were more aware of low-cost prescription programs (63.9% vs. 43.5%; p < 0.001). When adjusted for insurance status and current medication use, Caucasian patients were 2.7 times more likely to name a valid discount pharmacy option compared to African Americans (95% confidence interval 1.85-4.07). CONCLUSIONS: This study suggests populations may be more uncomfortable initiating a discussion about medication costs and selection of lower-cost alternatives. Health care providers may need to develop communication strategies in which medication cost is addressed with sensitivity and consistency.

Up-regulation of circulating miR-20a is correlated with hepatitis C virus-mediated liver disease progression.

UNLABELLED: Chronic hepatitis C virus (HCV) infection is one of the major causes of liver fibrosis and liver transplantation in the United States. Circulating microRNAs (miRNAs) in the blood are emerging as biomarkers for pathological conditions. In the present study we performed a systematic screening approach to identify up-regulated miRNAs in the plasma/serum of HCV-infected patients with different stages of hepatic histological disease severity. We initially screened serum samples of HCV-infected patients with fibrosis and compared them with sera of healthy volunteers using serum miRNA array profiling and identified a group of modulated miRNAs. Subsequent study demonstrated that miR-20a and miR-92a in HCV-infected fibrosis patients sera were significantly up-regulated when compared with that of healthy volunteers or non-HCV-associated liver disease. We have also observed an increase of plasma miR-20a and miR-92a in acute and chronic HCV-infected patients as compared to that of healthy volunteers. However, there was no correlation between the plasma/serum levels of any of these miRNAs with HCV viral loads. We next investigated longitudinal plasma samples from HCV-infected patients. Our results suggested that miR-20a and miR-92a remained unaltered in HCV-infected patients who progressed from acute to chronic infection. On the other hand, miR-92a expression was reduced in acute to resolved individuals. These data provide evidence that plasma/serum levels of miR-20a and miR-92a have potential as sensitive and cost-effective biomarkers for early detection of HCV infection. CONCLUSION: Circulating miR-20a may serve as a potential for predictive biomarker in HCV-mediated fibrosis.