Molecular Profile of Tumours with an Oligodendroglial Morphology: Clinical Relevance

AIM OF THE STUDY: Characterization of the molecular profile of oligodendroglial tumors with relation to 1p/19q status and IDH mutation. OBJECTIVES: 1. To determine the frequency of IDH1 and IDH2 mutations by polymerase chain reaction (PCR) sequencing and IDH1 mutations by immunohistochemistry among 50 cases of oligodendroglial tumours. 2. To calculate the performance indicators of IDH1 immunohistochemistry as a diagnostic marker. 3. To correlate 1p/19q status and IDH1/2 mutations with clinico-pathological variables and measures of outcome. METHODS: 50 oligodendroglial tumours diagnosed from January 2009 to January 2012 were included in the study. These included, 11 WHO grade II Oligodendroglioma, 15 WHO grade III Oliodendroglioma, 7 WHO grade II Oligoastrocytoma, 10 WHO grade III Oligoastrocytoma and 7 Glioblastoma with an oligodendroglial component. 1p/19q status was determined for all cases by Fluorescence in situ hybridization (FISH). Immunohistochemistry was performed for IDH1 mutations. Molecular analysis for IDH1 and IDH2 mutations was done by PCR. Association between combined 1p/19q deletion, polysomy of chromosome 1/19 and IDH mutation with the various clinical, radiological and histopathological parameters was calculated using Pearson’s Chi square test/Fishers exact test. Sensitivity and specificity of IDH1 immunohistochemistry was calculated taking PCR as the gold standard. Odds ratio and risk ratio was calculated for individual risk factors. Logistic regression model was used for multivariate analysis. A p value of ≤ 0.05 was considered significant. RESULTS: 1p/19q co-deletion and polysomy of chromosome 1/19 was seen in 46% (23/50) and 36% (18/50) of the cases respectively. 1p/19q co-deletion was significantly associated with pure oligodendroglial tumours (p = 0.0001), frontal lobe location and classical histology. Polysomy 1/19 was associated with mixed oligoastrocytic tumours (p=<0.00001). IDH1 and IDH2 mutations were seen in 86% and 6% of the cases respectively. The most common type of IDH1 mutation was of IDH1R132H (42 cases) type, followed by IDH1R132C (1 case). All 3 IDH2 mutations were of the IDH2R172H type.IDH1 immunohistochemistry was positive in 42 (84%) cases with IDH1R132H mutation and negative in the remaining cases. The sensitivity and specificity of IDH1 immunohistochemistry was 91.3% and 100% respectively. 23 of the 46 cases with IDH mutation showed 1p/19q co-deletion and all 4 cases negative for IDH mutation were also negative for 1p/19q co-deletion. On univariate analysis, necrosis, WHO grade and IDH mutation were found to have increased risk of recurrence and death. On multivariate analysis, utilizing the following variables, WHO grade (Grade IV vs. Grade II and III combined), classic histology, 1p/19q co-deletion and 1/19 polysomy, only WHO grade was found to be significantly associated with a poor PFS (p = 0.022). CONCLUSION: IDH1/2 mutations were seen with a high frequency in this cohort of oligodendroglial neoplasms. IDH1 immunohistochemistry is a sensitive and specific marker for determining mutational status. There is a role for PCR for detecting IDH mutations in cases that are immunonegative for IDH1

The 20-minute whole blood clotting test (20WBCT) for snakebite coagulopathy—A systematic review and meta-analysis of diagnostic test accuracy

Background The 20-minute whole blood clotting test (20WBCT) has been used to detect coagulopathy following snakebite for almost 50 years. A systematic review and meta-analysis of the 20WBCT was conducted to evaluate the accuracy of the 20WBCT to detect coagulopathy, indicative of systemic envenoming. Methods and findings Databases were searched from inception up to 09/12/2020 to identify studies that compared the 20WBCT and INR/fibrinogen on five or more subjects. Data was extracted from full-text articles by two reviewers using a predetermined form. Authors of 29 studies that lacked sufficient details in the manuscript were contacted and included if data meeting the inclusion criteria were provided. Included studies were evaluated for bias using a tailored QUADAS-2 checklist. The study protocol was prospectively registered on PROSPERO database (CRD42020168953). The searches identified 3,599 studies, 15 met the inclusion criteria and 12 were included in the meta-analysis. Data was reported from 6 countries and included a total of 2,270 patients. The aggregate weighted sensitivity of the 20WBCT at detecting INR >1.4 was 0.84 (CI 0.61 to 0.94), the specificity was 0.91 (0.76 to 0.97) and the SROC AUC was 0.94 (CI 0.91 to 0.96). The aggregate weighted sensitivity of the 20WBCT at detecting fibrinogen <100 mg/dL was 0.72 (CI 0.58 to 0.83), the specificity was 0.94 (CI 0.88 to 0.98) and the SROC AUC was 0.93 (0.91 to 0.95). Both analyses that used INR and fibrinogen as the reference test displayed considerable heterogeneity. Conclusions In the absence of laboratory clotting assays, the 20WBCT remains a highly specific and fairly sensitive bedside test at detecting coagulopathy following snakebite. However, clinicians should be aware of the importance of operator training, standardized equipment and the lower sensitivity of the 20WBCT at detecting mild coagulopathy and resolution of coagulopathy following antivenom

Stability and utility of flow cytometric platelet activation tests: A modality to bridge the gap between diagnostic demand and supply

Light transmission aggregometry (LTA) is the gold standard for the diagnosis of platelet function disorders (PFDs). The requirement of customized aggregometer, large blood volume, normal platelet count and processing within 4 hours of venipuncture for LTA makes platelet function testing inaccessible to wider population. Flow cytometric platelet activation test (PACT) may overcome these limitations. This study compares the performance of PACT with LTA, characterizes diagnostic patterns of PFDs on PACT and assesses the stability of PACT beyond 4 hours of venipuncture in controls (n = 5) at different temperature conditions. LTA and PACT were performed in 121 healthy controls and 66 patients with suspected PFD. PACT had excellent agreement (kappa = 0.93) with LTA and 94.1% sensitivity, 98.5% specificity. PACT had distinct patterns in Bernard Soulier Syndrome (n = 10), Glanzmann Thrombasthenia (n = 24), δ-granule disorder (n = 7), and other PFDs (n = 12). PACT could assess platelet function in patients (14%) with thrombocytopenia/lipemia wherein LTA was inconclusive. PACT was stable up to 24 hours in samples stored/transported at 2–8◦C. The results of utility and stability are only valid for the specific markers, agonist concentrations, and conditions investigated in this paper. PACT is a useful modality for the diagnosis of PFD, especially in children, thrombocytopenia cases or in the setup where an aggregometer is not readily available

Rotational Thromboelastometry Reduces Fresh Frozen Plasma Requirement in Patients without Liver Disease Undergoing Therapeutic Endoscopic Procedures with Deranged Screening Coagulation Tests—A Pilot Study

Background/Aims Rotational thromboelastometry (ROTEM) is a viscoelastic test that is used in patients with liver disease for guiding blood component use. This study is aimed at comparing the amount of blood products transfused and bleeding rates in patients without liver disease, who underwent therapeutic endoscopic procedures with deranged screening coagulation tests (prothrombin time [PT]; activated partial thromboplastin time [aPTT]), with and without hypocoagulable ROTEM

Correction: The 20-minute whole blood clotting test (20WBCT) for snakebite coagulopathy-A systematic review and meta-analysis of diagnostic test accuracy.

[This corrects the article DOI: 10.1371/journal.pntd.0009657.]

Biomarkers of coagulation, endothelial, platelet function, and fibrinolysis in patients with COVID-19: a prospective study

Abstract Prospective and sequential evaluation of homeostatic changes leading to thrombosis across COVID 19 disease severity spectrum are limited. In this prospective observational study, haemostasis was evaluated in patients with mild, moderate-severe, and critical COVID-19 infection. Markers of endothelial activation [Soluble thrombomodulin (sTM), von Willebrand Factor (VWF)], platelet activation [Soluble P-selectin, beta-thromboglobulin (BTG)] and global haemostasis [Rotational thromboelastometry (ROTEM)] were evaluated on days 1 and 5 after admission. The study cohort comprised of 100 adult patients (mild = 20, moderate-severe = 22, critical = 58). Sixty-five patients received anticoagulation for 10 (7–14) days. Thrombotic events were seen in 9 patients. In-hospital mortality was 21%. Endothelial activation markers were elevated at baseline in all subgroups, with levels in moderate-severe (sTM = 4.92 ng/ml, VWF = 295 U/dl) [reference-ranges: sTM = 2.26–4.55 ng/ml; Soluble P-selectin = 13.5–31.5 ng/ml; BTG = 0.034–1.99 ng/ml] and critical patients (sTM = 6.07 ng/ml, VWF = 294 U/dl) being significantly higher than in the mild group (sTM = 4.18 ng/ml, VWF = 206 U/dl). In contrast, platelet activation markers were elevated only in critically ill patients at baseline (Soluble P-selectin = 37.3 ng/ml, BTG = 2.51 ng/ml). The critical group had significantly lower fibrinolysis on days 1 and 5 when compared with the moderate-severe arm. COVID-19 infection was associated with graded endothelial activation and lower fibrinolysis that correlated with illness severity

Facilitating Safe Discharge Through Predicting Disease Progression in Moderate Coronavirus Disease 2019 (COVID-19): A Prospective Cohort Study to Develop and Validate a Clinical Prediction Model in Resource-Limited Settings

BACKGROUND: In locations where few people have received coronavirus disease 2019 (COVID-19) vaccines, health systems remain vulnerable to surges in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Tools to identify patients suitable for community-based management are urgently needed. METHODS: We prospectively recruited adults presenting to 2 hospitals in India with moderate symptoms of laboratory-confirmed COVID-19 to develop and validate a clinical prediction model to rule out progression to supplemental oxygen requirement. The primary outcome was defined as any of the following: SpO2  30 BPM; SpO2/FiO2 < 400; or death. We specified a priori that each model would contain three clinical parameters (age, sex, and SpO2) and 1 of 7 shortlisted biochemical biomarkers measurable using commercially available rapid tests (C-reactive protein [CRP], D-dimer, interleukin 6 [IL-6], neutrophil-to-lymphocyte ratio [NLR], procalcitonin [PCT], soluble triggering receptor expressed on myeloid cell-1 [sTREM-1], or soluble urokinase plasminogen activator receptor [suPAR]), to ensure the models would be suitable for resource-limited settings. We evaluated discrimination, calibration, and clinical utility of the models in a held-out temporal external validation cohort. RESULTS: In total, 426 participants were recruited, of whom 89 (21.0%) met the primary outcome; 257 participants comprised the development cohort, and 166 comprised the validation cohort. The 3 models containing NLR, suPAR, or IL-6 demonstrated promising discrimination (c-statistics: 0.72-0.74) and calibration (calibration slopes: 1.01-1.05) in the validation cohort and provided greater utility than a model containing the clinical parameters alone. CONCLUSIONS: We present 3 clinical prediction models that could help clinicians identify patients with moderate COVID-19 suitable for community-based management. The models are readily implementable and of particular relevance for locations with limited resources

Facilitating Safe Discharge Through Predicting Disease Progression in Moderate Coronavirus Disease 2019 (COVID-19): A Prospective Cohort Study to Develop and Validate a Clinical Prediction Model in Resource-Limited Settings.

Background: In locations where few people have received coronavirus disease 2019 (COVID-19) vaccines, health systems remain vulnerable to surges in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Tools to identify patients suitable for community-based management are urgently needed. Methods: We prospectively recruited adults presenting to 2 hospitals in India with moderate symptoms of laboratory-confirmed COVID-19 to develop and validate a clinical prediction model to rule out progression to supplemental oxygen requirement. The primary outcome was defined as any of the following: SpO2  30 BPM; SpO2/FiO2 < 400; or death. We specified a priori that each model would contain three clinical parameters (age, sex, and SpO2) and 1 of 7 shortlisted biochemical biomarkers measurable using commercially available rapid tests (C-reactive protein [CRP], D-dimer, interleukin 6 [IL-6], neutrophil-to-lymphocyte ratio [NLR], procalcitonin [PCT], soluble triggering receptor expressed on myeloid cell-1 [sTREM-1], or soluble urokinase plasminogen activator receptor [suPAR]), to ensure the models would be suitable for resource-limited settings. We evaluated discrimination, calibration, and clinical utility of the models in a held-out temporal external validation cohort. Results: In total, 426 participants were recruited, of whom 89 (21.0%) met the primary outcome; 257 participants comprised the development cohort, and 166 comprised the validation cohort. The 3 models containing NLR, suPAR, or IL-6 demonstrated promising discrimination (c-statistics: 0.72-0.74) and calibration (calibration slopes: 1.01-1.05) in the validation cohort and provided greater utility than a model containing the clinical parameters alone. Conclusions: We present 3 clinical prediction models that could help clinicians identify patients with moderate COVID-19 suitable for community-based management. The models are readily implementable and of particular relevance for locations with limited resources