Role of cyclin D1 in glial tumors—A retrospective and observational study

Aim: High-grade glial tumors remain as one of the most lethal malignancies. Cyclin D1 is expressed in some human malignancies and is the potential target of intervention. The present study aims to determine the relationship of cyclin D1 expression with other clinicopathological parameters. Materials and Methods: A cross-sectional study was carried out in a tertiary care center. Biopsy proven 66 cases of glial tumor patients were included in the study. The patients with incomplete clinical details were excluded from the study. Immunohistochemistry using antibodies for IDH 1 and cyclin d1 was done in all the cases. Glial tumors were reclassified according to WHO 2016 classification. Data analysis was performed using SPSS 26.0 for the windows. Result: Among 66 patients, 49 (74.3%) were males and 17 (25.7%) were females. The age of the patients ranged from 20 years to 70 years. Overall, 6.02% were of grade I Glial tumors, 22.7% were of grade II Glial tumors, 19.6% patients were of grade III Glial tumors, and 51.6% patients were of grade IV Glial tumors. Of 66 samples tested cyclin D1 was positive in 25 (37.87%) as high expressers and 7 (10.60%) were low expressers. Our study showed a significant correlation between the expression of cyclin D1 with grade and IDH mutation status, No significant correlation of cyclin D1 was noted with age or sex of the patient. Conclusion: Cyclin D1 was associated with a higher grade of the glial tumor. It can be a potential marker both for prognosis and treatment of glial tumors.

Correlation Between Apparent Diffusion Coefficient and IDH-1/1p19q Genotype of Glioma / 肿瘤防治研究

Objective To investigate the correlation between ADC value and glioma IDH-1/1p19q genotype. Methods The MRI features and molecular pathological results of 69 patients with pathologically confirmed diagnosis of WHO grade Ⅱ/Ⅲ glioma between March 2013 and December 2020 were retrospectively analyzed. The diagnostic performance of ADC values on glioma genotypes (IDH-1, 1p19q) was evaluated using the ROC curve of the subjects' working characteristics. Results The ADCmean, ADCmin, rADCmean, and rADCmin in the IDH-1 mutation group were significantly higher than those in the IDH-1 wild group (P < 0.05, P < 0.01, P < 0.05, P < 0.01). The use of the rADCmin threshold (0.979×103mm2/s) had the highest efficacy (AUC=0.770) for diagnosis of IDH-1 mutant and IDH-1 wild-type gliomas as well as sensitivity and specificity of 84.61% and 59.09%, respectively. Conclusion ADC can be used as an imaging biomarker for noninvasive prediction of IDH-1 mutant and wild-type Ⅱ /Ⅲ gliomas.

The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer

Reprogramming of energy metabolism is one of the basic characteristics of cancer and has been proved to be an important cancer treatment strategy. Isocitrate dehydrogenases (IDHs) are a class of key proteins in energy metabolism, including IDH1, IDH2, and IDH3, which are involved in the oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG). Mutants of IDH1 or IDH2 can produce d-2-hydroxyglutarate (D-2HG) with α-KG as the substrate, and then mediate the occurrence and development of cancer. At present, no IDH3 mutation has been reported. The results of pan-cancer research showed that IDH1 has a higher mutation frequency and involves more cancer types than IDH2, implying IDH1 as a promising anti-cancer target. Therefore, in this review, we summarized the regulatory mechanisms of IDH1 on cancer from four aspects: metabolic reprogramming, epigenetics, immune microenvironment, and phenotypic changes, which will provide guidance for the understanding of IDH1 and exploring leading-edge targeted treatment strategies. In addition, we also reviewed available IDH1 inhibitors so far. The detailed clinical trial results and diverse structures of preclinical candidates illustrated here will provide a deep insight into the research for the treatment of IDH1-related cancers.

Direito Humano à Alimentação Adequada: um olhar para a pobreza extrema e a desnutrição infantil a partir da obra de Amartya Sen / Human Right to Adequate Food: an essay on extreme poverty and child malnutrition based on Amartya Sen

Resumo A promoção e garantia do Direito Humano à Alimentação Adequada (DHAA) é ponto central do combate à fome e à desnutrição infantil no Brasil, agravada pela situação da pobreza extrema, permitindo um aumento da expectativa de vida. O Índice de Desenvolvimento Humano (IDH) foi criado por Amartya Sen para transformar a ideia reducionista do desenvolvimento econômico, a fim de ampliar a concepção de progresso humano a partir da expansão das capacidades e das liberdades no capitalismo. O objetivo deste estudo foi relacionar as condições de pobreza, fome e desnutrição infantil à promoção da alimentação saudável, a partir do conceito de desenvolvimento como liberdade descrito na obra de Amartya Sen. A saúde e o desenvolvimento humano interligam-se e, quando analisados pela situação da extrema pobreza, intensificam os seus efeitos restritivos ao acesso à alimentação saudável. Urge a compreensão de que as políticas públicas precisam atuar em sinergia entre as áreas de saúde, alimentação, educação, renda, entre outros, considerando a intersetorialidade da segurança alimentar e nutricional.

Abstract Ensuring the Human Right to Adequate Food (HRAF) is a key point in the fight against hunger and child malnutrition in Brazil, aggravated by the context of extreme poverty, allowing an increase in life expectancy. The Human Development Index (HDI) was created by Amartya Sen to transform the reductionist idea of economic development to broaden the concept of human progress based on the expansion of capabilities and freedoms under capitalism. This study aims to relate the conditions of poverty, hunger, and child malnutrition to the healthy eating promotion, based on Amartya Sen's concept of development as freedom. Health and human development are interconnected and, when analyzed in contexts of extreme poverty, intensify their restrictive effects on access to healthy food. Public policies need to urgently act in synergy with the areas of health, food, education, income, among others, considering the intersectoriality of food and nutritional safety.

Berberine targets the electron transport chain complex I and reveals the landscape of OXPHOS dependency in acute myeloid leukemia with IDH1 mutation / 中国天然药物

Metabolic reprogramming, a newly recognized trait of tumor biology, is an intensively studied prospect for oncology medicines. For numerous tumors and cancer cell subpopulations, oxidative phosphorylation (OXPHOS) is essential for their biosynthetic and bioenergetic functions. Cancer cells with mutations in isocitrate dehydrogenase 1 (IDH1) exhibit differentiation arrest, epigenetic and transcriptional reprogramming, and sensitivity to mitochondrial OXPHOS inhibitors. In this study, we report that berberine, which is widely used in China to treat intestinal infections, acted solely at the mitochondrial electron transport chain (ETC) complex I, and that its association with IDH1 mutant inhibitor (IDH1mi) AG-120 decreased mitochondrial activity and enhanced antileukemic effect in vitro andin vivo. Our study gives a scientific rationale for the therapy of IDH1 mutant acute myeloid leukemia (AML) patients using combinatory mitochondrial targeted medicines, particularly those who are resistant to or relapsing from IDH1mi.

Algoritmo para el diagnóstico integrado de los gliomas 2021. Nuestra experiencia / Algorithm for the integrated diagnosis of gliomas 2021. Our experience

Resumen La aplicación de las diferentes técnicas moleculares para el diagnóstico de los gliomas según la clasificación de la OMS, sigue sin estar al alcance de todos en nuestro país. Nuestro objetivo fue describir el protocolo diagnóstico desarrollado en función de los recursos disponibles, conforme con la clasificación vigente (2021). También, describir el perfil epidemiológico de los gliomas diagnosticados entre 2018-2021 en el Instituto Roffo y contrastarlo con la literatura. Se evaluó la mutación en IDH1-R132H, ATRX, el estado del 1p19q, CDKN2A, EGFR y del p53. Se incluyeron 94 pacientes, 53.2% fueron masculinos, con una edad promedio de 50.9 años. El diagnóstico más frecuente fue el de GB IDH1-no mutado (63.8%). Considerando únicamente a los gliomas grado 2 y 3, el astrocitoma difuso IDH1-Mutado/ATRX-Mutado/p53-sobreexpresado, grado 2 (11.7%) fue el más frecuente. En cuanto a su localización, el 67% de los tumores se ubicaron en el telencéfalo neocortical: 24.5% del total en el lóbulo frontal. En el 95.7% de los casos se arribó a un diagnóstico integrado concluyente siguiendo el algoritmo propuesto. Las características epidemiológicas coinciden con lo publicado en la literatura. La biología molecular nos permitió diferenciar nítidamente enfermedades que suponíamos emparentadas desde un punto de vista histológico, pero que observando su historia natural, su genética y su respuesta a tratamientos instaurados eran tumores distintos, aunque todos fueran llamados "gliomas". Los estándares internacionales no conciben su diagnóstico sin la biología molecular. No es aceptable que se siga diagnosticando únicamente con estándares histológicos. El algoritmo propuesto podría ser una alternativa viable y confiable.

Abstract The utilization of the different molecular techniques for the diagnosis of gliomas according to the WHO classification is still not available to everyone in our country. Our objective was to describe the diagnostic algorithm devel oped based on available resources, in accordance with the current classification (2021). Also, to describe the epidemiological profile of gliomas diagnosed between 2018-2021 at the Roffo Institute and compare it with the international literature. IDH1-R132H and ATRX mutation, as well as 1p19q status, CDKN2A, EGFR, and p53 were evaluated. 94 patients were included, 53.2% were male, with a mean age of 50.9 years. The most frequent diagnosis was GB IDH1-wild type (63.8%). Considering only grade 2 and 3 gliomas, diffuse astrocytoma IDH1- Mutated / ATRX-Mutated / p53-overexpressed, grade 2 (11.7%) was the most frequent diagnosis. Regarding their location, 67% of the tumors were located in the neocortical telencephalon: 24.5% of the total in the frontal lobe. In 95.7% of cases, a conclusive integrated diagnosis was reached following the proposed algorithm. The epidemiological characteristics coincide with what has been published in the literature. Molecular biology allowed us to clearly differentiate pathologies that we assumed were related from a histological point of view, but which, observing their natural history, their genetics and their response to established treatments were different tumors, although they were all called "gliomas". International standards do not conceive CNS tumor diagnosis without molecular biology. It is not acceptable to continue to diagnose only with histological standards. The proposed algorithm could be a viable and reliable alternative.

The relationship between IDH, P53 mutations, MGMT methylation with characteristics in high grade glioma patients / La relación entre IDH, mutaciones P53, metilación de MGMT con las características de pacientes con glioma de alto grado

ABSTRACT Introduction: Some gene mutations in high grade glioma patients have many implications in prognosis and treatment response. Objectives: To describe the characteristics and associations of IDH, TP53 gene mutations and MGMT methylation status with some characteristics and treatment response in patients with high grade glioma. Methods: A descriptive, prospective, uncontrolled study was conducted, in 52 patients with high-grade glioma. Research variables include age, sex, Karnofsky score, the rate of IDH, P53 mutation, MGMT methylation; the relationship between genes mutation with some characteristics and response to treatment according to the RECIST classification. Results: For IDH gene mutation, grade III patients (23.1%) have a higher positive rate than grade IV (11.5 %); for P53 gene mutation, grade III patients (55.6 %) have a higher positive rate than grade IV (44.1 %); the rate of MGMT promoter methylation occurred in the study group of patients with the rate of 42.3 %. There is a relationship between IDH gene mutation with pathological results and malignancy in studied patients. Patients with the mutant expression of the IDH gene, p53, MGMT methylation status had better RECIST responses than patients without these expressions. Conclusion: High-grade glioma mainly occurs in men, over 40 years old. The presence of mutations in IDH, P53 genes, and MGMT methylation status was a beneficial factor for treatment response as assessed by RECIST.

RESUMEN Introducción: Algunas mutaciones genéticas en pacientes con glioma de alto grado tienen implicaciones en el pronóstico y respuesta al tratamiento. Objetivos: Describir las características y asociaciones de IDH, mutaciones del gen TP53 y estado de metilación de MGMT con algunas características y respuesta al tratamiento en pacientes con glioma de alto grado. Métodos: Se realizó un estudio descriptivo, prospectivo no controlado, en 52 pacientes con glioma de alto grado. Las variables investigadas fueron: edad, sexo, puntuación de Karnofsky, tasa de IDH, mutación P53, estado de metilación de MGMT, relación entre la mutación de genes con algunas características y la respuesta al tratamiento según la clasificación RECIST. Resultados: Mutación del gen IDH: los pacientes grado III (23,1 %) tienen una tasa positiva más alta que los grado IV (11,5 %). Mutación del gen P53: los grado III (55,6 %) tienen una tasa positiva más alta que los grado IV (44,1 %). La tasa de metilación del promotor de MGMT se produjo con una tasa del 42,3 %. Existe relación entre la mutación del gen IDH con los resultados patológicos y la malignidad. Los pacientes con la expresión mutante del gen IDH, p53, estado de metilación de MGMT tuvieron mejores respuestas RECIST. Conclusión: El glioma de alto grado se presenta principalmente en hombres, mayores de 40 años. La presencia de mutaciones en los genes IDH, P53 y el estado de metilación de MGMT fue un factor beneficioso para la respuesta al tratamiento según lo evaluado por RECIST.

Incidência, mortalidade e tendências do câncer de estômago no Brasil: um estudo de base populacional / Incidence, mortality and trends of stomach cancer in Brazil: a population-based study

INTRODUÇÃO: O câncer de estômago (CaE) ocupou o 5º lugar de todos os cânceres que ocorreram no mundo em 2020 e foi a 4ª principal causa de morte por câncer no Brasil, e a 4ª mais frequente entre os homens e o 6º nas mulheres. A incidência e mortalidade de CaE variam de acordo com o IDH (Índice de Desenvolvimento Humano). Essas variações são atribuídas a diferentes fatores de riscos associados ao estilo de vida, a prevalência de H. Pylori e detecção precoce do CaE. OBJETIVO: analisar o perfil epidemiológico de incidência, mortalidade e tendências do CaE no Brasil e verificar as suas associações com IDH. MÉTODOS: Os dados para a incidência foram extraídos dos Registros de Câncer de Base Populacional (RCBP), de 1988 à 2017, sob o código C-16 (neoplasias maligna do estômago) e os dados da mortalidade extraídos do Sistema de Informação de Mortalidade do Sistema Único de Saúde (DATASUS). Foram calculadas as taxas de incidência e mortalidade brutas e padronizadas. Para as análises de tendência foi utilizado a análise de regressão no programa Joinpoint Regression Program (SEER). Os dados do IDH foram extraídos do banco do Programa das Nações Unidas para o Desenvolvimento (PNUD). Para as análises de correlação de Pearson foi utilizada o programa Stata 15. Os efeitos de idade-período-coorte de nascimento foram estimados para a mortalidade pelo modelo de APC calculados pelo pacote Epi do software R. RESULTADOS: A incidência do CaE foi o dobro no sexo masculino. As maiores taxas incidência foram observadas na região Norte com tendência de estabilidade na maioria das capitais brasileiras. Foi observado correlação negativa do IDH e IDH-longevidade com as taxas padronizadas de incidência para homens e mulheres e IDH-educação para mulheres. A mortalidade foi maior para homens e as maiores taxas foram observadas no Amapá. A região Sul apresentou as maiores taxas de 2000-2009 e em 2010-2019 foi a região Norte para homens e mulheres. As regiões Sul, Sudeste e Centro-oeste apresentaram tendências de redução da mortalidade de CaE, enquanto as regiões Nordeste e Norte aumento nos últimos 20 anos. As taxas de mortalidade de CaE aumentam com a idade (> 60anos), com risco maior de óbito em homens e mulheres nascidos após a década de 1960 nas regiões Nordeste e Norte, o risco diminui nas regiões Sudeste, Sul e Centro-Oeste para ambos os sexos. Houve correlação positiva da taxa de CaE (2000-2010) com IDH (2000) para ambos os sexos e correlação negativa para a tendência. CONCLUSÃO: A incidência de CaE apresentou estabilidade para a maioria das capitais do Brasil e a mortalidade aumento para as regiões Norte e Nordeste. O risco de CaE é maior em pessoas acima de 60 anos e o IDH correlaciona-se inversamente com as taxas de incidência e tendências da mortalidade na primeira década e positivamente na taxa de mortalidade no mesmo período. A análise permite verificar que as melhorias no desenvolvimento socioeconômico ao longo do tempo podem contribuir para a redução na tendência da mortalidade do CaE.

INTRODUCTION: Stomach cancer (SC) ranked 5th among all cancers that occurred in the world in 2020 and was the 4th leading cause of cancer death in Brazil, and the 4th most frequent among men and the 6th among women. The incidence and mortality of SC varies according to the HDI (Human Development Index). These variations are attributed to different risk factors associated with lifestyle, H. pylori prevalence, and early detection of SC. OBJECTIVE: to analyze the epidemiological profile of incidence, mortality and trends of SC in Brazil and to verify its associations with HDI. METHODS: Data for incidence were extracted from the Population Based Cancer Registry (PBCR), 1993 to 2017, under code C-16 (malignant neoplasms of the stomach) and mortality data from the Information System of Mortality of the Unified Health System (DATASUS). Crude and standardized incidence and mortality rates were calculated. For trend analysis, linear regression analysis was used in the Joinpoint Regression Program (SEER). HDI data were extracted from the United Nations Development Program (UNDP) database. For Pearson's correlation analysis, the Stata 11.2 program was used. The age-period-birth cohort effects from 2000-2019 were estimated by the APC model calculated by Epi of the R software. RESULTS: The incidence of SC in Brazil were twice as high in males. The highest incidence rates were observed in the North region, with a trend towards stability in most Brazilian capitals. A negative correlation of IDH and HDI-longevity with the standardized incidence rates for men and women and HDI-education for women was observed. Mortality was higher for men and the highest rates were observed in Amapá. The South region had the highest rates from 2000-2000 and in 2010-2019 it was the North region for men and women. The South, Southeast and Central-West regions showed a tendency to reduce SC, while the Northeast and North regions increased in the last 20 years. SC mortality rates increase with age (> 60 years), with a higher risk of death in men and women born after the 1960s in the Northeast and North regions and the risk decreases in the Southeast, South and Midwest regions for both the sexes. There was a positive correlation between the SC rate (2000-2010) and the HDI (2000) for both sexes and a negative correlation for the trend. CONCLUSION: The incidence of SC remained stable for most capitals in Brazil and mortality increased in the North and Northeast regions. The risk of SC is higher in people over 60 years of age and the HDI is inversely correlated with incidence rates and mortality trends in the first decade and positively with the mortality rate in the same period. The analysis makes it possible to verify that improvements in socioeconomic development over time can contribute to a reduction in the mortality trend of SC

Progress of targeted therapy for acute myeloid leukemia / 白血病·淋巴瘤

The treatment of acute myeloid leukemia (AML) has made a great progress in recent years owing to the emergence of targeted drugs. While the problems such as drug resistance, the increasing incidence of adverse reactions of the combined therapies, the lack of the effective therapy targets became growing concerns with the further development of studies, which has posed a big challenge to the therapy strategies of AML. This article introduces the progress of the latest clinical trial outcomes in targeted therapy for AML at the 63rd American Society of Hematology (ASH) annual meeting which reported some hot issues like options for the treatment timing of targeted therapy, the selection for the drugs and the combined drugs.

Prognostic value of mutations in isocitrate dehydrogenase 1 (IDH1) and reverse telomerase transcriptase (TERT ) in Argentine patients` gliomas / Valor pronóstico de mutaciones en Isocitrato dehidrogenasa1 (IDH1) y Telomerasa transcriptasa reversa (TERT ) en gliomas de pacientes argentinos

Background and aim: Gliomas are the most common primary brain tumors, classified according to their histopathological and genetic features. Tumorigenesis depends on alterations in different genes. The aim of this study was the identification of mutations in IDH1 and TERT genes in gliomas of Argentine patients and to correlate them with clinical features and prognosis. Methods: DNA was isolated from 19 biopsies with different glioma grades matched with blood samples. IDH1 and TERT mutations were studied by PCR amplifica-tion and sequencing. Results: Six out of seven patients with low-grade glioma (grade II) harbor IDH1 mutations, mainly without tumor growth and overall survival of more than 12 months. Eleven out of twelve patients with high-grade gliomas (grade III/IV) showed wild type IDH1, mainly with tumor growth and shorter survival than low-grade gliomas. Mutated TERT promoter was present in 5 out of 11 high-grade gliomas, showing the prevalence of polymorphic C allele. In 1 out of 5 low-grade gliomas with a predominance of T allele. TERT and IDH1 mutations were mutually exclusive in most gliomas. Conclusions: Our results show that genetic tests provided a more accurate prognosis than histopathological analysis. The evolution of gliomas can be predicted primarily by the mutational status of IDH1 and secondarily by other markers, such as TERT mutational status

Antecedentes y objetivo: los gliomas son los tumores cerebrales primarios más comunes y se clasifican según sus características histopatológicas y genéticas. La tumorigénesis depende de alteraciones en diferentes genes. El objetivo de este estudio fue identificar mutaciones en los genes IDH1 y TERT en gliomas de pacientes argentinos y correlacionarlos con la evolución clínica. Métodos: se obtu-vieron 19 muestras pareadas de ADN de gliomas y de la sangre. Las mutaciones en IDH1 y TERT se analizaron por PCR y secuenciación. Resultados: la IDH1 mutada se encontró en 6 de los 7 gliomas de bajo grado (grado II), mayormente sin crecimiento tumoral y una sobrevida mayor de 12 meses. La IDH1 salvaje estaba presente en 11 de los 12 gliomas de alto grado (grado III y IV) mayormente con crecimiento tumoral y menor sobrevida que los tumores de bajo grado. Las mutaciones en el promotor del gen TERT se observaron en 5 de los 11 gliomas de alto grado, con la prevalencia de alelo polimórfico C, en cambio, en gliomas de bajo grado TERT mutado estaba presente en 1 de los 5 gliomas con predominio del alelo T. Las mutaciones en IDH1 y TERT fueron mutuamente excluyentes en la mayoría de los gliomas. Conclusiones: el análisis genético provee un pronóstico más certero que el análisis histopatológico. Nuestros resulta-dos muestran que la evolución de gliomas puede predecirse primariamente por el estado mutacional de IDH1 y secundariamente por mutaciones en otros marcadores tales como el TERT

A Dual Genetic Alteration (Mitochondrial and Nuclear DNA): First Case in Malaysia Detected in Glioblastoma Multiforme

@#Although the precise etiology of Glioblastoma multiforme (GBM, WHO grade IV) remains unknown, its progression is believed to be driven by the accumulation of multiple genetic alterations. Here, we report a case of a patient who developed GBM, and associated with dual alterations, particularly 4977-bp deletion in mtDNA (mtDNA4977) and p.Arg132His (R132H) mutation in IDH1. A 35-year old Malaysian woman patient who primary diagnosed with astrocytoma WHO grade I and subsequently after four years developed a GBM, was detected with a mtDNA4977. This deletion appears to be a sporadic mutation. Additionally, analysis of patient’s tumor tissue also found to harbor a heterozygous IDH1 R132H mutation. This represents the first case report of coexisting mtDNA4977 together with IDH1 R132H mutation in a Malaysian patient of GBM. The findings of dual alterations could be of therapeutic benefit if these alterations were justified to be contributing to GBM growth and aggressiveness.

Study of Isocitrate Dehydrogenase 1and 2 Mutations in Adult Egyptian Patients with Denovo Acute Myeloblastic Leukemia, Their Relation to Clinical Characteristics, FLT3/ITD and Nucleophosmin 1 Mutations and Impact on Treatment Outcome

Background: Acute myeloid leukaemia (AML) is a malignancy that is heterogeneous in nature characterized by genetic abnormalities some of which are established in the diagnosis and prognosis of the disease. An additional role for alterations in epigenetic mechanisms has been also highlighted in the pathogenesis of the disease. This may have a role in determining the disease outcome, impact the treatment decision and provide options for targeted therapies especially in patients who lack genetic aberrations. One of the modes of epigenetic dysregulation is mutation in genes encoding isocitrate dehydrogenase 1 and 2 that has been observed in AML with a higher incidence in patients with normal karyotype (NK). Aim of the work: The aim of this work was to study the frequency of IDH1 (R132) and IDH2 (R140Q, R172K) mutations in adult Egyptian patients with de novo acute myeloblastic leukemia (AML), their relation with clinical characteristics, other molecular markers (the internal tandem duplication (ITD)) mutation of FLT3 gene and NPM1 gene mutation) and impact on treatment outcome. Methods: Peripheral blood samples from 50 adult patients with denovo acute myeloid leukemia, admitted to the haematology unit at Alexandria Main University Hospital from February 2015 to February 2017, were used. The polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP) was used for detection of IDH1 codon R132 and IDH2 codons (R140, R172) mutations on genomic DNA. PCR was used for detection of FLT3-ITD mutation on genomic DNA. PCR was used for detection of NPM1 mutation on RNA. Results: IDH 1and 2 mutations occurred in 30% of newly diagnosed AML patients and 47.6% of NK patients. Both mutations did not co-occur except in one case. IDH positive patients were significantly older than IDH negative patients (p=0.003). There was no statistically significant correlation between any of the clinical parameters and the IDH mutations. FAB-M2 was the most common FAB subtype among IDH positive patients. No correlation between IDH mutations and NPM1 or FLT3 could be demonstrated. IDH positive patients had significantly lower CR rates after induction chemotherapy than IDH negative patients (p=0.021). Conclusion: IDH1, 2 mutations are recurring genetic alterations in AML with a higher incidence in patients with normal karyotype and they may have an unfavorable impact on clinical outcome in adult AML patients.

Previsão do Índice de Desenvolvimento Humano e da expectativa de vida nos países da América Latina por meio de técnicas de mineração de dados / Forecasting the human development index and life expectancy in Latin American countries using data mining techniques

Resumo A previsibilidade de indicadores epidemiológicos pode contribuir na projeção de variáveis dependentes, auxiliar em tomadas de decisões para sustentar ou não políticas públicas e justificar o cenário vivido pelos países e o mundo. O artigo tem por objetivo predizer o Índice de Desenvolvimento Humano e a expectativa de vida nos países latino-americanos no período de 2015 a 2020, utilizando técnicas de mineração de dados. Foram percorridas as etapas do processo Descoberta de Conhecimento em Base Dados. Adotaram-se para previsões modelos desenvolvidos com séries multivariadas através do algoritmo de mineração de dados SMOReg, que apresentaram melhor desempenho em testes desenvolvidos durante o experimento. As médias do Índice de Desenvolvimento Humano e da expectativa de vida nos países latino-americanos tendem a aumentar no período analisado, respectivamente, 4,99 ± 3,90 % e 2,65 ± 0,06 anos. Experiências multivariadas possibilitam maior aprendizagem dos algoritmos, aumentando sua precisão. As técnicas de mineração de dados apresentaram melhor qualidade nas previsões em relação à técnica mais popular, ARIMA. As previsões sugerem média de crescimento do IDH e EV dos países latino-americanos maiores que a mundial.

Abstract The predictability of epidemiological indicators can help estimate dependent variables, assist in decision-making to support public policies, and explain the scenarios experienced by different countries worldwide. This study aimed to forecast the Human Development Index (HDI) and life expectancy (LE) for Latin American countries for the period of 2015-2020 using data mining techniques. All stages of the process of knowledge discovery in databases were covered. The SMOReg data mining algorithm was used in the models with multivariate time series to make predictions; this algorithm performed the best in the tests developed during the evaluation period. The average HDI and LE for Latin American countries showed an increasing trend in the period evaluated, corresponding to 4.99 ± 3.90% and 2.65 ± 0.06 years, respectively. Multivariate models allow for a greater evaluation of algorithms, thus increasing their accuracy. Data mining techniques have a better predictive quality relative to the most popular technique, Autoregressive Integrated Moving Average (ARIMA). In addition, the predictions suggest that there will be a higher increase in the mean HDI and LE for Latin American countries compared to the mean values for the rest of the world.

The progress of pathogenesis and treatment in angioimmunoblastic T-cell lymphoma / 中国肿瘤临床

Angioimmunoblastic T-cell lymphoma (AITL) is one of the most common subtypes of peripheral T-cell lymphomas. It is a fol-licular T-helper-derived neoplasm, and characterized by the presence of some genetic alterations, such as mutations in TET2, DN-MT3A, IDH2, and RHOA. Anthracycline-containing regimens represent the most widely adopted first-line option; however, new biolog-ic agents should be designed and incorporated to improve treatment response. The elucidation of the specific roles of these genetic al-terations in AITL will facilitate the development of molecularly targeted therapies to treat this disease.

Oncometabolite 2-HG in glioma evolution and recent progress of detection method / 中国药理学通报

IDH mutation is prevalent in lower-grade glioma and secondary glioblastoma. Patients bearing IDH mutation are char-acterized by overproduction of 2-HG. 2-HG plays a role in regu-lation of DNA and histone hypermethylation in glioma, thus re-sulting in impaired cell differentiation and tumor formation. As a surrogate marker of mutant IDH, there is increasing interest in development of detection methods for 2-HG. LC-MS is widely used in detecting 2-HG in vitro, and reliable measurement of 2-HG by the non-invasive MRS has been tested in vivo and ex vivo previously. However, whether 2-HG could represent an inde-pendent predictor of patient survival or other clinical features for glioma still needs further study. In this review, we summarize the mechanism adopted by 2-HG in glioma initiation and pro-gression, as well as the detection method tested in clinic. We try to provide guidance to the future combination therapy using mu-tant IDH inhibitors.

Effect of systemic inflammation response index on clinical prognosis of patients with glioma and its relationship with IDH1 mutation / 实用肿瘤学杂志

Objective The objective of this study was to investigate the effect of systemic inflammation response index(SI-RI)on clinical prognosis of patients with glioma and its relationship with dehydrogenase 1(IDH1)mutation.Methods Eighty patients with glioma who underwent surgery in the department of Neurosurgery were collected from August 2006 to November 2015.The best clinical cutoff value for SIRI was determined using operating characteristic curve(ROC)and grouped accordingly.The Kaplan-Meier and log-rank methods were used to analyze the postoperative survival of the two groups of patients.The independent clinical prognos-tic factors were evaluated by Cox′s proportional hazards regression model.The IDH1 mutation was detected by immunohistochemistry and DNA sequencing.Results SIRI was an independent prognostic factor of glioma,and the best clinical cutoff value was 0.67 × 109/L.The median progress free survival(PFS)and overall survival(OS)of patients with low SIRI group were 46.90 months and 57.90 months,and the median PFS and OS of patients with high SIRI group were 31.78 months and 47.22 months,respectively.There was significant difference between the two groups in the median survival time of PFS and OS by log-rank method(P<0.05).Univa-riate and multivariate analysis showed that age,gender,type of surgery,WHO stage,SIRI and IDH1 mutation were the independent prognostic factors in neurostein stromal tumors.Patients with low-grade SIRI and glioma with IDH1 mutation have a better prognosis than other conditions.Conclusion SIRI is an independent prognostic factor of glioma.It is simple,convenient and reproducible,and may be used to predict the prognosis of patients with glioma.

Correlations of mutations of IDH1,IDH2,p53 gene and Ki-67 protein expression in gliomas with the clini cal features of pathological grading / 实用医学杂志

Objective To investigate the mutations of IDH1,IDH2,p53 gene,and Ki-67 protein expression in different grade of gliomas and identify the association with its clinical relevance. Methods The mutations of IDH1,IDH2 and p53 gene were detected by direct DNA sequencing,and protein expression of Ki-67 was analyzed by immunohistochemistry. The correlations between gender,age,tumor site,differentiation degree and pathological type of patients were analyzed. Results R132H mutation of IDH1 gene was detected in 32.6% samples (14/46 cases),of which the proportion of WHO classification grade Ⅱ was 40.0%,and grade Ⅲ was 58.3%. IDH1 mutations were shown correlated with age,pathology level Ⅱ-Ⅲ,and Ki-67 low expression. p53 mutations were detected in 4 glioblastomas,with mutations located at exon 7,8. IDH1 gene mutation was negatively correlated with Ki-67 expression. Conclusions The proportion of IDH1 gene mutation in different pathological types of gliomas is different,which is the highest in gradeⅡ~Ⅲ. It is suggested that the subtypes should be listed independently by routine tests. Mutations in p53 gene are more common in primary glioblastomas and may be associated with adverse outcomes. The combined detection of DH1,p53 and Ki-67 is conducive to the diagnosis and prognosis of glioma.

Effect of IDH gene mutation on acute myeloid leukemia / 上海交通大学学报（医学版）

Isocitrate dehydrogenase (IDH) is an important metabolic enzyme involved in the tricarboxylic acid cycle. In recent years, IDH has become the most frequent tumor metabolic mutation gene in acute myeloid leukemia (AML). Unlike other mutations, it gains new functions which can catalyze α-ketoglutarate (α-KG) to produce the tumor metabolite D-2-hydroxyglutarate (D-2-HG). The increased D-2-HG in the cells can affect bone marrow cell differentiation and proliferation and induce myeloid tumors by the genetic controls, cell signaling, bone marrow microenvironment changes and other ways. Currently, the new IDH2 inhibitors AG-221 and IDH1 inhibitors become the first-line drugs targeted therapy in patients with IDH mutations in AML. This paper focused on the mutation of IDH and its mutation characteristics, the formation mechanism of AML by the metabolites produced by mutation, the metabolic pathway of tumor metabolites and the research progress of IDH inhibitors.

The clinicopathological significances of LDHA and mutant p53 co-expression in gliomas / 实用医学杂志

Objective To investigate the clinicopathological significances of LDHA/mutant p53 co-expres-sion in gliomas. Methods According to the 2016 WHO CNS,archived 68 gliomas were collected and analyzed retrospectively. The co-expression of LDHA/mutant p53 was detected by immunohistochemical staining. Results High expression of LDHA alone was always found in high grade gliomas(48.5%). Mutant p53 high expression was usually observed in glioblastomas (26.5%). There was a close relationship between co-expression of LDHA/mutant p53 in glioblastoma(27.9%,P = 0.005),or gliomas with high histological grading(27.9%,P = 0.002). Conclusions Co-expression of LDHA/mutant p53 in tumor cells might be a specific immunohistochemical pheno-type of gliomas,and may help for distinguishing glioblastoma and other high grade gliomas from low grade gliomas.

Research progress on integrated molecular pathological classification of diffuse lower-grade gliomas / 中国肿瘤临床

Diffuse lower-grade glioma is a diversified group of infiltrative brain tumors comprising WHO grades II and III astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas. These tumors exhibit a wide range of clinical heterogeneity;thus, histopathological classification does not adequately predict clinical outcomes. In recent years, a number of molecular markers closely related to the clini-cal features and prognosis of gliomas have been discovered. These molecular markers include isocitrate dehydrogenase (IDH) muta-tion, chromosome 1p/19q codeletion, ATRX mutation, TERT promoter mutation, and MGMT promoter methylation. Furthermore, nu-merous studies focusing on the integrated molecular classification of diffuse lower-grade gliomas combined with these molecular markers have been conducted. Results indicate that integrated molecular pathological classification can improve the diagnostic and prognostic accuracy and facilitate therapeutic formulation. This paper reviews the research progress on integrated molecular classifica-tion of diffuse lower-grade gliomas.