Dataset Information

Molecular diagnostic testing of diffuse gliomas in the real-life setting: A practical approach.

ABSTRACT: Typing of diffuse gliomas according to the WHO 2016 Classification of Tumors of the Central Nervous System is based on the integration of histology with molecular biomarkers. However, the choice of appropriate methods for molecular analysis and criteria for interpretation of test results is left to each diagnostic laboratory. In the present study, we tested the applicability of combined immunohistochemistry, direct sequencing, and multiplex ligation-dependent probe amplification (MLPA) for diagnostic assessment of IDH1/2 mutation status, chromosome 1p/19q status, and TERT promoter mutations. To this end, we analyzed a consecutive series of 165 patients with diffuse low- and high-grade gliomas (WHO grade II and III) from three Austrian centers in which tissue specimens were routinely processed. We could reliably detect IDH1/2 mutations by combining immunohistochemistry, direct sequencing, and MLPA analysis. MLPA analysis also allowed reliable detection of combined whole chromosomal arm 1p/19q codeletion when using carefully selected criteria providing an optimal balance between sensitivity and specificity. Direct sequencing proved to be suitable for identification of TERT promoter mutations, although its analytical performance remains to be assessed. To conclude, we propose a practicable combination of methods and criteria which allow reliable molecular diagnostic testing of diffuse gliomas in the real-life setting.?.

SUBMITTER: Bienkowski M

PROVIDER: S-EPMC6102559 | biostudies-literature | 2018 Jul/Aug

REPOSITORIES: biostudies-literature

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Molecular diagnostic testing of diffuse gliomas in the real-life setting: A practical approach.

Bieńkowski Michał M Wöhrer Adelheid A Moser Patrizia P Kitzwögerer Melitta M Ricken Gerda G Ströbel Thomas T Hainfellner Johannes A JA

Clinical neuropathology 20180701 4

Typing of diffuse gliomas according to the WHO 2016 Classification of Tumors of the Central Nervous System is based on the integration of histology with molecular biomarkers. However, the choice of appropriate methods for molecular analysis and criteria for interpretation of test results is left to each diagnostic laboratory. In the present study, we tested the applicability of combined immunohistochemistry, direct sequencing, and multiplex ligation-dependent probe amplification (MLPA) for diagn ...[more]

PMID: 29923492

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Project description:BackgroundA newly developed brain molecular marker (BMM) data item was implemented by US cancer registries for individuals diagnosed with brain tumors in 2018-including IDH and 1p/19q-co-deletion statuses for adult-type diffuse gliomas. We thus investigated the testing/reporting completeness of BMM in the United States.MethodsCases of histopathologically confirmed glioblastoma, astrocytoma, and oligodendroglioma diagnosed in 2018 were identified in the National Cancer Database. Adjusted odds ratios (ORadj) and 95% confidence intervals (CI) of BMM testing/reporting were evaluated for association with the selected patient, treatment, and facility-level characteristics using multivariable logistic regression. As a secondary analysis, predictors of MGMT promoter methylation testing/reporting among IDH-wildtype glioblastoma individuals were assessed. Key limitations of the BMM data item were that it did not include any details regarding testing technique or assay type and could not distinguish between a lack of testing and a lack of cancer registry reporting of testing results.ResultsAmong 8306 histopathologically diagnosed adult-type diffuse gliomas nationally, overall BMM testing/reporting completeness was 81.1%. Compared to biopsy-only cases, odds of testing/reporting increased for subtotal (ORadj= 1.38 [95% CI: 1.20-1.59], P < .001) and gross total resection (ORadj=1.50 [95% CI: 1.31-1.72], P < .001). Furthermore, the odds were lowest at community centers (hospitals (67.3%; ORadj=0.35 [95% CI: 0.26-0.46], P < .001) and highest at academic/NCI-designated comprehensive cancer centers (85.4%; referent). By geographical location, BMM testing/reporting completeness ranged from a high of 86.8% at New England (referent) to a low of 76.0 % in the West South Central region (ORadj=0.57 [95% CI: 0.42-0.78]; P < .001). Extent of resection, Commission-on-Cancer facility type, and facility location were additionally significant predictors of MGMT testing/reporting among IDH-wildtype glioblastoma cases.ConclusionsInitial BMM testing/reporting completeness for individuals with adult-type diffuse gliomas in the United States was promising, although patterns varied by hospital attributes and extent of resection.

Project description:Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions. Frequent mutations in chromatin-modifier genes were identified including, noticeably, a truncating mutation in SETD2 (n = 4), which resulted in loss of H3K36 trimethylation and was mutually exclusive with H3F3A K27M mutation (n = 3), suggesting that epigenetic dysregulation may lead to DCG tumorigenesis. Alterations that cause loss of p53 function including TP53 mutation (n = 9), PPM1D mutation (n = 2), and a novel type of PPM1D fusion (n = 1), were also frequent. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. DNA methylation profile analysis demonstrated that all DCGs except for those with H3F3A mutations were categorized in the "RTK I (PDGFRA)" group, and those DCGs had a gene expression signature that was highly associated with PDGFRA. Furthermore, compared with the data of 315 gliomas derived from different brain regions, promoter methylation of transcription factors genes associated with glial development showed a characteristic pattern presumably reflecting their tumor origin. Notably, SOX10, a key transcription factor associated with oligodendroglial differentiation and PDGFRA regulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline glioma, suggesting their developmental and biological commonality. In contrast, SOX10 was silenced by promoter methylation in most cerebral gliomas. These findings may suggest potential tailored targeted therapy for gliomas according to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs.

Project description:After stool culture was replaced by an enteric bacterial panel (EBP) at the Johns Hopkins Hospital (JHH), many EBPs were ordered >3 days after admission (EBP >3 days) with low yield. To reduce unnecessary testing, a hard stop for ordering EBP >3 days was established with the option to override the restriction. The present study retrospectively evaluates the usefulness of overriding that restriction. A retrospective chart review was performed on all patients with an EBP >3 days at the JHH from November 2021 to October 2022. The override provided only one new diagnosis of Salmonella infection in a patient who developed diarrhea within 3 days of admission but was not tested by EBP until day 5. There were no positive EBPs >3 days in patients without diarrhea or who developed diarrhea >3 days after admission (diarrhea >3 days). Most patients with requests to override the restriction were also tested for Clostridioides difficile. All patients positive for C. difficile received treatment and their C. difficile positive test resulted >1 day before the EBP was run. There were no differences in yield in patients >65 years of age with significant comorbidities or associated with neutropenia, leukocytosis, human immunodeficiency virus status, or lactoferrin positivity. There were no positive tests in patients receiving stool softeners within the previous 48 hours of testing. Overriding the hard stop should not be approved in patients without diarrhea or with diarrhea >3 days, who received stool softeners within the previous 48 hours or have not been tested for more common causes of hospital-acquired diarrhea.IMPORTANCETesting for enteric bacterial pathogens in patients hospitalized for more than 3 days is almost always inappropriate. Our study validates the utility of the 3-day rule and the use of clinical decision support tools to decrease unnecessary testing of enteropathogenic bacteria other than C. difficile. Overriding the restriction was very low yield. Our study highlights the importance of diagnostic stewardship and further refines the criteria for allowing providers to override the restriction while monitoring the impact of the interventions.

Dataset Information

Molecular diagnostic testing of diffuse gliomas in the real-life setting: A practical approach.

Publications

Molecular diagnostic testing of diffuse gliomas in the real-life setting: A practical approach.

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