scholarly journals Diffuse Gliomas for Nonneuropathologists: The New Integrated Molecular Diagnostics

2018 ◽  
Vol 142 (7) ◽  
pp. 804-814 ◽  
Author(s):  
Sunhee C. Lee
Keyword(s):  
Krebs Cycle ◽  
Diagnostic Algorithm ◽  
World Health ◽  
Wild Type ◽  
Targeted Next Generation Sequencing ◽  
Idh Mutations ◽  
Diffuse Gliomas ◽  
Conventional Histology ◽  
Krebs Cycle Enzymes ◽  
Health Organization

Diffuse gliomas comprise the bulk of “brain cancer” in adults. The recent update to the 4th edition of the World Health Organization's classification of tumors of the central nervous system reflects an unprecedented change in the landscape of the diagnosis and management of diffuse gliomas that will affect all those involved in the management and care of patients. Of the recently discovered gene alterations, mutations in the Krebs cycle enzymes isocitrate dehydrogenases (IDHs) 1 and 2 have fundamentally changed the way the gliomas are understood and classified. Incorporating information on a few genetic parameters (IDH, ATRX and/or p53, and chromosome 1p19q codeletion), a relatively straightforward diagnostic algorithm has been generated with robust and reproducible results that correlate with patients' survival far better than relying on conventional histology alone. Evidence also supports the conclusion that the vast majority of diffuse gliomas without IDH mutations (IDH–wild-type astrocytomas) behave like IDH–wild-type glioblastomas (“molecular GBM”). Together, these changes reflect a big shift in the practice of diagnostic neuropathology in which tumor risk stratification aligns better with molecular information than histology/grading. The purpose of this review is to provide the readers with a brief synopsis of the changes in the 2016 World Health Organization update with an emphasis on diffuse gliomas and to summarize key gene abnormalities on which these classifications are based. Practical points involved in day-to-day diagnostic workup are also discussed, along with a comparison of the various diagnostic tests, including immunohistochemistry, with an emphasis on targeted next-generation sequencing panel technology as a future universal approach.

scholarly journals Estimation of the occurrence rates of IDH1 and IDH2 mutations in gliomas and the reconsideration of IDH-wildtype anaplastic astrocytomas: an institutional experience

2021 ◽  
Vol 49 (6) ◽  
pp. 030006052110192
Author(s):  
Uiju Cho ◽  
Seung Ho Yang ◽  
Changyoung Yoo
Keyword(s):  
Peptide Nucleic Acid ◽  
Treatment Strategies ◽  
World Health ◽  
Diffuse Astrocytoma ◽  
Idh Mutations ◽  
Institutional Experience ◽  
Diffuse Gliomas ◽  
Idh1 And Idh2 Mutations ◽  
Health Organization ◽  
Classification And Treatment

Objectives Most diffuse gliomas are reported to harbor isocitrate dehydrogenase ( IDH) mutations. However, when these mutations are tested in clinical practice, the results are often negative. Methods This study examined the frequency of IDH1 and IDH2 mutations in gliomas classified according to the revised 2016 World Health Organization classification, and investigated their prognostic relevance. We tested 87 gliomas for IDH1 and IDH2 mutations using the peptide nucleic acid clamp method. Results IDH1 mutations were observed in 42% of diffuse astrocytomas, 23% of anaplastic astrocytomas, all oligodendrogliomas and anaplastic oligodendrogliomas, and 17% of glioblastomas. An IDH2 mutation was identified in one case of diffuse astrocytoma. In the survival analysis of diffuse astrocytic tumors, patients with IDH1/2-wildtype anaplastic astrocytomas tended to have a poor prognosis, similar to that of glioblastomas. Conclusions IDH2 mutations were infrequent in gliomas. In anaplastic astrocytomas, the frequency of IDH1/2-wildtype was relatively high, and the prognosis of patients with this type of tumor was very similar to that of those with glioblastomas. It may therefore be necessary to reconsider the classification and treatment strategies for IDH1/2-wildtype anaplastic astrocytomas.

scholarly journals Prognostic irrelevance of ring sideroblast percentage in World Health Organization–defined myelodysplastic syndromes without excess blasts

Blood ◽  
2012 ◽  
Vol 119 (24) ◽  
pp. 5674-5677 ◽  
Author(s):  
Mrinal M. Patnaik ◽  
Curtis A. Hanson ◽  
Nanna H. Sulai ◽  
Janice M. Hodnefield ◽  
Ryan A. Knudson ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Multivariable Analysis ◽  
World Health ◽  
Refractory Anemia ◽  
Idh Mutations ◽  
Ring Sideroblasts ◽  
Transfusion Dependency ◽  
Health Organization ◽  
The Impact

Abstract The presence of ≥ 15% bone marrow (BM) ring sideroblasts (RS) and < 5% blasts is required for a diagnosis of refractory anemia with ring sideroblasts. We examined the phenotypic and prognostic relevance of this “15%” RS threshold in 200 patients with myelodysplastic syndromes (MDS) without excess blasts and with ≥ 1% RS. The impact of RS% was assessed both as a continuous and categorical variable: < 5% (n = 56), 5%-14% (n = 32), 15%-50% (n = 79), and > 50% (n = 33). RS% correlated (P < .05) directly with age, platelet count, transfusion dependency, BM cellularity, and mutant SF3B1 and inversely with hemoglobin level, multilineage dysplasia, and high-risk karyotype; but did not correlate with IDH mutations. At a median follow-up of 33 months, 156 (73%) deaths and 24 (12%) leukemic transformations were documented. Neither univariate nor multivariable analysis showed significant effect for RS% on overall or leukemia-free survival, suggesting the limited prognostic value of quantifying BM RS in MDS.

scholarly journals Self-Limiting OX513A Aedes aegypti Demonstrate Full Susceptibility to Currently Used Insecticidal Chemistries as Compared to Indian Wild-Type Aedes aegypti

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Prabhakargouda B. Patil ◽  
Kevin J. Gorman ◽  
Shaibal K. Dasgupta ◽  
K. V. Seshu Reddy ◽  
Shirish R. Barwale ◽  
...  
Keyword(s):  
Aedes Aegypti ◽  
Mortality Rates ◽  
Standard Test ◽  
Genetically Engineered ◽  
World Health ◽  
Wild Type ◽  
Test Procedures ◽  
Male And Female ◽  
Health Organization ◽  
Type Strains

OX513A Aedes aegypti is a genetically engineered strain carrying a self-limiting gene. Studies in several countries have shown the effectiveness of the strain at reducing pest Aedes aegypti populations. As a component of biosafety assessments relevant to Indian environments, OX513A and two Indian wild-type Ae. aegypti strains (from Aurangabad and Delhi) were tested for susceptibility to a range of commonly used insecticides in India, such as dichlorodiphenyltrichloroethane (DDT), malathion, deltamethrin, and permethrin using World Health Organization (WHO) testing kits and following WHO standard test procedures. Knockdown times (KDT) for all compounds were determined separately for male and female adults of the three mosquito strains. Results indicated that adults of OX513A, Aurangabad, and Delhi strains were resistant to DDT, yielding mortality rates of 90.9, 87.4, and 44.4% and 70.1, 3.0, and 6.0% for male and female adults, respectively. In contrast, adults of all three strains were found to be susceptible to malathion, deltamethrin, and permethrin, exhibiting mortalities between 98 and 100%. The magnitudes of susceptibility, based on the KDT50 values, were greater in the OX513A strain, as compared to wild-type strains of Ae. aegypti for all insecticides tested. The results confirm that, aside from historical resistance to DDT, OX513A has retained full sensitivity to these commonly used compounds and exhibits responses akin to those of susceptible Indian wild-type strains.

scholarly journals Molecular surveillance for polymorphisms associated with artemisinin-based combination therapy resistance in Plasmodium falciparum isolates collected in Mozambique, 2018

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Arlindo Chidimatembue ◽  
Samaly S. Svigel ◽  
Alfredo Mayor ◽  
Pedro Aíde ◽  
Abel Nhama ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Artemisinin Resistance ◽  
Therapy Resistance ◽  
Malaria Treatment ◽  
World Health ◽  
Wild Type ◽  
Pcr Assay ◽  
Molecular Surveillance ◽  
Study Sites ◽  
Health Organization

Abstract Background Due to the threat of emerging anti-malarial resistance, the World Health Organization recommends incorporating surveillance for molecular markers of anti-malarial resistance into routine therapeutic efficacy studies (TESs). In 2018, a TES of artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) was conducted in Mozambique, and the prevalence of polymorphisms in the pfk13, pfcrt, and pfmdr1 genes associated with drug resistance was investigated. Methods Children aged 6–59 months were enrolled in four study sites. Blood was collected and dried on filter paper from participants who developed fever within 28 days of initial malaria treatment. All samples were first screened for Plasmodium falciparum using a multiplex real-time PCR assay, and polymorphisms in the pfk13, pfcrt, and pfmdr1 genes were investigated by Sanger sequencing. Results No pfk13 mutations, associated with artemisinin partial resistance, were observed. The only pfcrt haplotype observed was the wild type CVMNK (codons 72–76), associated with chloroquine sensitivity. Polymorphisms in pfmdr1 were only observed at codon 184, with the mutant 184F in 43/109 (39.4%) of the samples, wild type Y184 in 42/109 (38.5%), and mixed 184F/Y in 24/109 (22.0%). All samples possessed N86 and D1246 at these two codons. Conclusion In 2018, no markers of artemisinin resistance were documented. Molecular surveillance should continue to monitor the prevalence of these markers to inform decisions on malaria treatment in Mozambique.

scholarly journals Clinical, Morphological, and Molecular Study of Diffuse WHO Grade II and III Astrocytomas: A Retrospective Analysis from a Single Tertiary Care Institute

2021 ◽  
Vol 42 (06) ◽  
pp. 569-576
Author(s):  
Ramya Lakshmi Veduruvada ◽  
Megha S. Uppin ◽  
Meher Lakshmi Konatam ◽  
Rajesh Alugolu ◽  
Vamsi Krishna Yeramneni ◽  
...  
Keyword(s):  
World Health ◽  
Survival Duration ◽  
Diffuse Astrocytoma ◽  
Wild Type ◽  
Immunohistochemical Expression ◽  
Who Grade ◽  
Genetic Characteristics ◽  
Integrated Diagnosis ◽  
Idh Mutations ◽  
Grade Ii

Abstract Introduction Astrocytomas are the most common gliomas, classified on the basis of grade and IDH mutation status according to the World Health Organization (WHO) 2016 update. IDH mutations are seen in 70 to 80% of diffuse grade II and III astrocytomas and are associated with better outcome. They serve as predictive biomarker in IDH-targeted therapies such as small-molecule inhibitors or vaccines. Objective The aim of this study was to analyze the clinical, morphological, immunohistochemical, and molecular genetic characteristics of diffuse astrocytoma (DA: grades II and III). The IDH mutant and wild-type tumors are compared and contrasted with survival analysis on follow-up. Materials and Methods This was a retrospective study conducted on surgically resected tumor specimens. The hematoxylin and eosin-stained slides were examined for histologic features. Immunohistochemistry (IHC) was performed using IDH1R132H, ATRX, p53, and Ki67. All cases of negative immunohistochemical expression of IDH1R132H were subjected to IDH1 mutation analysis by Sanger sequencing. Overall survival was estimated by the Kaplan-Meier method using the log-rank (Mantel–Cox) test. Results The study included 51 cases of DA in the age of 17 to 66 years, mean ± standard deviation was 35.5 ± 9.7 years, and male:female ratio was 2:1.The IDH1R132H cytoplasmic immunopositivity was seen in 36 cases (70.5%), of which 63.6% were of grade II and 72.5% were of grade III. ATRX showed loss of expression in 50 cases (98%), and p53 showed diffuse strong immunohistochemical expression in all the cases of IDH mutant tumors. The difference in the age at presentation for IDH mutant (32.5 years) and wild type tumors (38 years) was statistically significant. Median survival was 55.3 months and 22.2 months in of IDH mutant and wild type cases, respectively. Conclusion IHC and sequencing for IDH mutations is helpful in making an integrated diagnosis and classifying definite molecular subgroups of astrocytic tumors. Mutations in IDH core-elate with survival. IDH mutant tumors showed longer survival duration and are good prognostic indicators.

Proteomic characterization of a second-generation version of the BCGΔBCG1419c vaccine candidate by means of Electrospray-ionization quadrupole time-of-flight mass spectrometry

2020 ◽  
Author(s):  
Jesús Bernardino Velázquez-Fernández ◽  
Gustavo Henrique Martins Ferreira Souza ◽  
Jacobo Rodríguez-Campos ◽  
Michel de Jesús Aceves-Sánchez ◽  
Jorge Bravo-Madrigal ◽  
...  
Keyword(s):  
Second Generation ◽  
Vaccine Candidate ◽  
World Health ◽  
Label Free ◽  
Wild Type ◽  
Flight Mass Spectrometry ◽  
Proteomic Approach ◽  
Antigenic Proteins ◽  
Health Organization

Abstract Tuberculosis (TB) is the most important infectious disease worldwide, based on the number of new cases and deaths reported by the World Health Organization. Several vaccine candidates against TB have been characterized at the preclinical and clinical levels. The BCGΔBCG1419c vaccine candidate, which lacks the BCG1419c gene that encodes for a c-di-GMP phosphodiesterase, provides improved efficacy against chronic TB, reactivation from latent-like infection, and against TB in the presence of type 2 diabetes in murine models. We previously reported that compared to wild type BCG, BCGΔBCG1419c changed several proteins. Here, using a label-free proteomic approach, we confirmed that a novel, second-generation version of BCGΔBCG1419c maintains changes in antigenic proteins already reported, including differences in secreted proteins, and also found that it modifies its production of proteins involved in redox and nitrogen/protein metabolism, compared with wild type BCG. This work contributes to the proteomic characterization of a novel vaccine candidate that is effective against chronic TB.

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