Larotrectinib versus infigratinib for adult patients with both glioma and tyrosine kinase alterations after failure of initial therapies: Efficacy and safety analysis

Abstract Objectives To compare the efficacy and safety of larotrectinib with those of infigratinib in adult glioma patients with tyrosine kinase alterations. Methods Patients received oral infigratinib 125 mg (IN cohort, n = 125) or oral larotrectinib (LB cohort, n = 105) until unacceptable toxicity or disease progression. Results Duration of treatment was longer in the LB cohort than in the IN cohort (8 [9.5-6.25] months vs. 5.5 [6-5.25] months, p < 0.0001). Patients with partial responses (p = 0.0424) and overall survival (p = 0.03) were higher in the IN cohort than those in the LB cohort. The number of patients with disease progression was higher in the LB cohort (p = 0.0015). All the patients reported diarrhea, fatigue, vomiting, constipation, and decreased appetite. Patients in the IN cohort reported hyperphosphatemia, hyperlipasemia, stomatitis, dry skin, alopecia, dyspepsia, onycholysis, palmar-plantar erythrodysesthesia, nail disorders, and dry eyes. Patients in the LB cohort reported upper respiratory tract infections, pyrexia, cough, anemia, bacterial/viral infections, conjunctivitis, urinary tract infections, headaches, ataxia, dizziness, and muscle tremors. A total of 30 (24 %) and 40 (38 %) patients from the IN and the LB cohorts died at the follow-up of 18 months (p = 0.03). Patients who received bevacizumab initial therapy had higher overall survival (p = 0.048). Conclusions Infigratinib has higher efficacy and overall survival than larotrectinib but has higher adverse effects in the management of both glioma and tyrosine kinase alterations after failure of initial therapies. Initial bevacizumab therapy is associated with a higher overall survival.

Glioma of the optic nerve and chiasm: a case report / Glioma óptico-quiasmático: um relato de caso

ABSTRACT This article reports the case of an 11-year-old male patient with a history of proptosis and low progressive visual acuity in the left eye. He presented with a best corrected visual acuity of 20/25 in the right eye and light perception in the left eye. Exotropia and limitation in adduction were observed in the left eye. On automated perimetry, inferiortemporal quadrantopsia was observed in the right eye, while total scotoma was observed in the left eye. On magnetic resonance imaging, there was an expansive lesion in the left optic nerve, extending to the brainstem with chiasmatic involvement. This article aims to report a case of optic pathway glioma, as well as to discuss its clinical findings and their interconnection with the current literature.

RESUMO Este artigo relata o caso de um paciente do sexo masculino, 11 anos de idade, com história de proptose e baixa de acuidade visual progressiva. Ao exame oftalmológico apresentava melhor acuidade visual de 20/25 em olho direito e percepção de luz em olho esquerdo. Existia exotropia e limitação à adução no olho esquerdo. À campimetria automatizada, observou-se quadrantopsia temporal inferior em olho direito e escotoma total em olho esquerdo. À ressonância magnética, evidenciou-se lesão expansiva em trajeto do nervo óptico esquerdo estendendo-se até região do tronco encefálico, com acometimento quiasmático. O objetivo deste artigo é relatar o glioma de vias ópticas, bem como discutir os achados e sua interligação com a literatura atual.

Effects of anlotinib on the malignant phenotype of glioma cells by mediating NF-κB signaling pathway / 中国药房

OBJECTIVE To investigate the effects of anlotinib on the malignant phenotype of glioma cells by regulating the nuclear factor-κB （NF-κB） signaling pathway. METHODS Human glioma T98G cells were cultured in vitro， and 5-fluorouracil was used as positive control to investigate the effects of different concentrations of anlotinib （5， 10， 20 μmol/L） on the ability of proliferation， adhesion， migration and invasion， the expressions of epithelial-mesenchymal transition （EMT） related proteins [E-cadherin， N-cadherin， vimentin and fibronectin （FN）]. NF- κB signaling pathway inhibitor （BAY 11-7082） and activator （prostratin） were additionally used to verify the possible mechanism of the above effects of anlotinib. RESULTS Anlotinib with 5， 10， 20 μmol/L could significantly decrease the activity of cell proliferation （except for 5 μmol/L anlotinib group）， migration rate， and the number of adherent cells and invasive cells， could significantly up-regulate the expression of E-cadherin protein while down-regulate the expressions of N-cadherin， vimentin and FN protein （P＜0.05）； the effect of 20 μmol/L anlotinib was similar to that of positive control （P＞0.05）. Compared with 10 μmol/L anlotinib， pathway inhibitor could significantly decrease the ability of proliferation， adhesion， migration and invasion， and the expressions of N-cadherin， vimentin， FN and phosphorylated NF-κB p65 protein， while could significantly up-regulate the expression of E-cadherin protein （P＜0.05）； above indexes were reversed significantly by pathway activator （P＜0.05）. CONCLUSIONS Anlotinib may inhibit the proliferation， adhesion， migration and invasion of human glioma T98G cells， which may be associated with the inhibition of the NF-κB signaling pathway， thus inhibiting cell EMT-like processes.

Advances in diffuse glial tumors diagnosis / Avanços no diagnóstico dos gliomas difusos

Abstract In recent decades, there have been significant advances in the diagnosis of diffuse gliomas, driven by the integration of novel technologies. These advancements have deepened our understanding of tumor oncogenesis, enabling a more refined stratification of the biological behavior of these neoplasms. This progress culminated in the fifth edition of the WHO classification of central nervous system (CNS) tumors in 2021. This comprehensive review article aims to elucidate these advances within a multidisciplinary framework, contextualized within the backdrop of the new classification. This article will explore morphologic pathology and molecular/genetics techniques (immunohistochemistry, genetic sequencing, and methylation profiling), which are pivotal in diagnosis, besides the correlation of structural neuroimaging radiophenotypes to pathology and genetics. It briefly reviews the usefulness of tractography and functional neuroimaging in surgical planning. Additionally, the article addresses the value of other functional imaging techniques such as perfusion MRI, spectroscopy, and nuclear medicine in distinguishing tumor progression from treatment-related changes. Furthermore, it discusses the advantages of evolving diagnostic techniques in classifying these tumors, as well as their limitations in terms of availability and utilization. Moreover, the expanding domains of data processing, artificial intelligence, radiomics, and radiogenomics hold great promise and may soon exert a substantial influence on glioma diagnosis. These innovative technologies have the potential to revolutionize our approach to these tumors. Ultimately, this review underscores the fundamental importance of multidisciplinary collaboration in employing recent diagnostic advancements, thereby hoping to translate them into improved quality of life and extended survival for glioma patients.

Resumo Nas últimas décadas, houve avanços significativos no diagnóstico de gliomas difusos, impulsionados pela integração de novas tecnologias. Esses avanços aprofundaram nossa compreensão da oncogênese tumoral, permitindo uma estratificação mais refinada do comportamento biológico dessas neoplasias. Esse progresso culminou na quinta edição da classificação da OMS de tumores do sistema nervoso central (SNC) em 2021. Esta revisão abrangente tem como objetivo elucidar esses avanços de forma multidisciplinar, no contexto da nova classificação. Este artigo irá explorar a patologia morfológica e as técnicas moleculares/genéticas (imuno-histoquímica, sequenciamento genético e perfil de metilação), que são fundamentais no diagnóstico, além da correlação dos radiofenótipos da neuroimagem estrutural com a patologia e a genética. Aborda sucintamente a utilidade da tractografia e da neuroimagem funcional no planejamento cirúrgico. Destacaremos o valor de outras técnicas de imagem funcional, como ressonância magnética de perfusão, espectroscopia e medicina nuclear, na distinção entre a progressão do tumor e as alterações relacionadas ao tratamento. Discutiremos as vantagens das diferentes técnicas de diagnóstico na classificação desses tumores, bem como suas limitações em termos de disponibilidade e utilização. Além disso, os crescentes avanços no processamento de dados, inteligência artificial, radiômica e radiogenômica têm grande potencial e podem em breve exercer uma influência substancial no diagnóstico de gliomas. Essas tecnologias inovadoras têm o potencial de revolucionar nossa abordagem a esses tumores. Em última análise, esta revisão destaca a importância fundamental da colaboração multidisciplinar na utilização dos recentes avanços diagnósticos, com a esperança de traduzi-los em uma melhor qualidade de vida e uma maior sobrevida.

Biomarcadores genéticos en sangre, una nueva herramienta para el diagnóstico, pronóstico y supervivencia en pacientes con gliomas de alto grado / Genetic biomarkers in blood, a new tool for diagnosis, prognosis, and survival in patients with high-grade gliomas / Biomarcadores genéticos no sangue, uma nova ferramenta para diagnóstico, prognóstico e sobrevida em pacientes com gliomas de alto grau

Durante mucho tiempo, la clasificación de los tumores del sistema nervioso central (SNC) se ha basado en hallazgos histológicos respaldados por pruebas complementarias, como la inmunohistoquímica, establecidas en tejidos. La quinta edición de la clasificación de tumores del SNC de la Organización Mundial de la Salud (OMS), publicada en 2021 (SNC-5) incorpora numerosos marcadores moleculares con utilidad clínico-patológica que son importantes para una clasificación más precisa de las neoplasias del SNC. Ello permiten ayudar a definir los gliomas difusos del adulto, oligodendroglioma mutado para el gen de la IDH (isocitrato deshidrogenasa láctica), con codeleción 1p/19q grados 2 a 3, astrocitoma mutado para IDH sin codeleción 1p/19q, grados 2 a 4 y glioblastoma (GBM) silvestre para IDH. La mediana de sobrevida en los pacientes con GBM es de solo 14.6 meses, debido a la resistencia al protocolo de terapia más utilizado en el mundo, el cual involucra cirugía, radioterapia y quimioterapia con temozolamida (TMZ), un potente alquilante genotóxico. Los criterios de selección del tratamiento y la estimación del pronóstico en pacientes con esta enfermedad son clínico-patológicos. En los últimos años se reportaron numerosas alteraciones moleculares que amplían la comprensión de la biología de estos tumores, pero solo unas pocas influyen como biomarcadores en la toma de decisiones clínicas y del tratamiento. En este artículo se revisan las alteraciones moleculares reportadas para gliomas de alto grado en sangre periférica, también se resalta la importancia de estandarizar nuevos biomarcadores junto a los hallazgos histológicos para mejorar el conocimiento de estos tumores.

For a long time, the classification of central nervous system (CNS) tumors has been based on histological findings supported by complementary tests, such as immunohistochemistry, established in tissues. The fifth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System, published in 2021 (CNS-5), incorporates numerous molecular markers with clinical-pathological utility that are important for a more accurate classification of CNS neoplasms. These markers help to define adult diffuse gliomas, including IDH-mutant oligodendroglioma with 1p/19q codeletion (grades 2-3), IDH-mutant astrocytoma without 1p/19q codeletion (grades 2-4), and wild-type IDH glioblastoma (GBM). The median survival in patients with GBM is only 14.6 months, primarily due to resistance to the most widely used treatment protocol worldwide, which involves surgery, radiotherapy, and chemotherapy with temozolomide (TMZ), a potent genotoxic alkylating agent. The selection criteria for treatment and the estimation of prognosis in patients with this disease are predominantly based on clinical and pathological factors. In recent years, numerous molecular alterations have been reported, expanding our understanding on the biology of these tumors. However, only a few of these molecular alterations serve as biomarkers that influence clinical decision-making and treatment strategies. This article reviews the molecular alterations reported in peripheral blood for high-grade gliomas and emphasizes the importance of standardizing new biomarkers alongside histological findings to enhance our knowledge of these tumors.

Por muito tempo, a classificação dos tumores do sistema nervoso central (SNC) baseou-se em achados histológicos respaldados por exames complementares, como a imuno-histoquímica, estabelecidos nos tecidos. A quinta edição da classificação de tumores do SNC da Organização Mundial da Saúde (OMS), publicada em 2021 (CNS-5), incorpora inúmeros marcadores moleculares com utilidade clinicopatológica importantes para uma classificação mais precisa das neoplasias do SNC. Isso permite definir gliomas difusos adultos, oligodendroglioma mutado para o gene IDH (lactic isocitrato desidrogenase), com codeleção 1p/19q graus 2 a 3, astrocitoma mutado para IDH sem codeleção 1p/19q, graus 2 a 4 e wild- tipo glioblastoma (GBM) para IDH. A sobrevida mediana em pacientes com GBM é de apenas 14,6 meses, devido à resistência ao protocolo terapêutico mais utilizado no mundo, que envolve cirurgia, radioterapia e quimioterapia com temozolamida (TMZ), um potente alquilador genotóxico . Os critérios de seleção para o tratamento e estimativa do prognóstico em pacientes com essa doença são clínico-patológicos. Nos últimos anos, foram relatadas inúmeras alterações moleculares que ampliam o entendimento da biologia desses tumores, mas apenas algumas influenciam na decisão clínica e terapêutica como biomarcadores. Este artigo revisa as alterações moleculares relatadas para gliomas de alto grau no sangue periférico, destacando também a importância da padronização de novos biomarcadores juntamente com os achados histológicos para melhorar o conhecimento desses tumores

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.

The 2021 World Health Organization classification of gliomas: an imaging approach / Nova classificação das neoplasias gliais segundo a Organização Mundial da Saúde 2021, com enfoque radiológico

Abstract The purpose of this pictorial essay is to describe the recommendations of the 2021 World Health Organization classification for adult-type and pediatric-type gliomas and to discuss the main modifications in relation to the previous (2016) classification, exemplified by imaging, histological, and molecular findings in nine patients followed at our institutions. In recent years, molecular biomarkers have gained importance in the diagnosis and classification of gliomas, mainly because they have been shown to correlate with the biological behavior and prognosis of such tumors. It is important for neuroradiologists to familiarize themselves with this new classification of central nervous system tumors, so that they can use this knowledge in evaluating and reporting the imaging examinations of patients with glioma.

Resumo O propósito deste ensaio iconográfico é descrever e discutir as novas recomendações da Organização Mundial da Saúde de 2021, referente aos gliomas dos tipos adulto e infantil, e suas principais diferenças com a classificação anterior (2016), exemplificadas com imagens de nove casos de pacientes atendidos nas nossas instituições. Recentemente, há uma crescente significância dos marcadores moleculares no diagnóstico e classificação dos gliomas e tumores do sistema nervoso central, principalmente pela correlação com o comportamento biológico e o prognóstico. É importante que os neurorradiologistas estejam familiarizados com a nova classificação dos tumores do sistema nervoso central para a prática clínica, na avaliação e emissão de laudos e opiniões nas imagens dos pacientes com gliomas.

Ventajas de la secuenciación de próxima generación sobre la hibridación fluorescente in situ para detectar la codeleción 1p/19q en oligodendrogliomas / Advantages of next generation sequencing over fluorescent in situ hybridization to detect 1p/19q codeletion in oligodendroglioma / Vantagens do sequenciamento de próxima geração sobre a hibridização fluorescente in situ para detectar codeleção 1p/19q em oligodendrogliomas

El perfil molecular de los gliomas permite garantizar la precisión del diagnóstico, informar el pronóstico e identificar opciones de tratamiento. Esta revisión tiene como objetivo exponer que con la secuenciación de próxima generación (NSG) el diagnóstico de los pacientes con oligodendrogliomas puede ser más exacto. Además, con un dispositivo de diagnóstico in vitro, basado en la NSG (F1CDx), en el que se utilizan los bloques de parafina de gliomas para analizar hasta 395 genes relacionados con cáncer (incluido IDH 1 y 2), se puede también informar la pérdida de la totalidad del brazo corto del cromosoma 1 y del brazo largo del cromosoma 19 (codeleción 1p/19q), a diferencia de la hibridación fluorescente in situ (FISH) que detecta desde la más mínima deleción, lo cual los hace sensibles pero no específicos ya que el FISH es incapaz de distinguir entre la pérdida de la totalidad del brazo del cromosoma y una deleción focal. Esta distinción es importante ya que la sobrevida es inferior en tumores con deleción parcial en rela­ción con los oligodendrogliomas, que tienen por definición la pérdida total de ambos cromosomas. Se hace también alusión a otras plataformas genómicas como GlioSeq y GLIO-DNA panel, que pueden cumplir la misma función. En conclusión, la F1CDx puede determinar con precisión 1p/19q con una concordancia del 96.7% frente a FISH. Los casos en que el FISH dio positivo y no concordaban con F1CDx, era porque no se trataba de oligodendrogliomas. F1CDx también analiza todos los genes que permiten la aproximación más exacta al diagnóstico de oligodendroglioma.

Molecular profiling of gliomas helps ensure diagnostic accuracy, inform prognosis, and identify treatment options. This review aims to show that with next generation sequencing (NGS) the diagnosis of patients with oligodendrogliomas can be more accurate. In addition, with an in vitro diagnostic device, based on NSG (F1CDx), in which glioma paraffin blocks are used to analyze up to 395 cancer-related genes (including IDH 1 and 2), it is also possible to report the loss of the entire short arm of chromosome 1 and the long arm of chromosome 19 (1p/19q codeletion), unlike fluorescence in situ hybridization (FISH) that detects even the slightest deletion, making them sensitive but not specific, as FISH is unable to distinguish between the loss of the entire arm of the chromosome and a focal deletion. This distinction is important since survival is lower in tumors with partial deletion compared to oligodendrogliomas, which by definition have the total loss of both chromosomes. Reference is also made to other genomic platforms such as GlioSeq and GLIO-DNA panel, which can fulfill the same function. In conclusion, the F1CDx can accurately determine 1p/19q with a concordance of 96.7% against FISH. The cases in which the FISH was positive and did not agree with F1CDx, it was because they were not oligodendrogliomas. F1CDx also analyzes all the genes that allow the most accurate approach to the diagnosis of oligodendroglioma.

O perfil molecular de gliomas ajuda a garantir a precisão do diagnóstico, informar o prognóstico e identificar as opções de tratamento. Esta revisão tem como objetivo mostrar que com o sequenciamento de próxima geração (NSG) o diagnóstico de pacientes com oligodendrogliomas pode ser mais preciso. Além disso, com um dispositivo de diagnóstico in vitro baseado em NSG (F1CDx), no qual blocos de parafina de glioma são usados para analisar até 395 genes relacionados ao câncer (incluindo IDH 1 e 2), também é possível relatar a perda do todo o braço curto do cromossomo 1 e o braço longo do cromossomo 19 (codeleção 1p/19q), ao contrário da hibridização fluorescente in situ(FISH) que detecta desde a menor deleção, o que os torna sensíveis, mas não específicos, pois o FISH é incapaz de distinguir entre a perda de todo o braço do cromossomo e uma deleção focal. Essa distinção é importante, pois a sobrevida é menor nos tumores com deleção parcial em relação aos oligodendrogliomas, que por definição apresentam a perda total de ambos os cromossomos. Também é feita referência a outras plataformas genômicas, como GlioSeq e painel GLIO-DNA, que podem cumprir a mesma função. Em conclusão, o F1CDx pode determinar com precisão 1p/19q com uma concordância de 96,7% versus FISH. Os casos em que FISH foi positivo e não concordaram com F1CDx, foi porque não eram oligodendrogliomas. O F1CDx também analisa todos os genes que permitem a abordagem mais precisa para o diagnóstico de oligodendroglioma.

Impacto pronóstico de la utilización intensiva de tecnologías complementarias intraoperatorias en gliomas cerebrales. Revisión de la literatura y presentación de 1 caso

Introducción: El manejo de los gliomas cerebrales durante las últimas cuatro décadas ha sufrido cambios relevantes en su estudio y tratamiento. Dentro de estos cambios se encuentra el desarrollo de técnicas imagenológicas, neurofisiológicas e histopatológicas. El presente trabajo intenta estimar el impacto que la utilización de dichas tecnologías ha tenido sobre el pronóstico de los pacientes. Material y método: Revisión exhaustiva de la literatura en medios digitales e impresos abarcando mayormente publicaciones y comunicaciones desde la década de 1980 hasta el presente. Se expone 1 caso sometido recientemente a cirugía por los autores en el que se utilizaron varias de estas herramientas, presentando el análisis que se llevó a cabo en la planificación quirúrgica. Resultados: La literatura muestra mejorías consistentes pero discretas en el pronóstico asociado al uso de tecnologías complementarias intraoperatorias en gliomas cerebrales, relacionadas a la ayuda que prestarían en la extensión de la resección tumoral y en la preservación funcional. Conclusiones: La utilización intensiva de las tecnologías complementarias descritas parece recomendable si la planificación quirúrgica anticipa beneficios fundados en cuanto a morbi-mortalidad para un paciente en particular. Se debe ser cauto en anticipar y generalizar el impacto pronóstico global que puedan tener, beneficio que es consistente en la literatura pero que en estos momentos parece modesto en términos generales en especial para gliomas de alto grado.

Introduction: The management of cerebral gliomas during the last four decades has undergone relevant changes in terms of its study and treatment. Among these changes is the development of imaging, neurophysiological and histopathological techniques. The present study attempts to estimate the impact that the use of these technologies has had on the prognosis of patients. Material and Method: Comprehensive review of the literature in digital and print media covering mostly publications and communications from the 1980s to the present. 1 case recently submitted to surgery by the authors in which several of these tools were used is exposed, presenting the analysis that was carried out in the surgical planning. Results: The literature shows consistent but discrete improvements in the prognosis associated with the use of intraoperative complementary technologies in cerebral gliomas, related to the help they would provide in the extension of tumor resection and functional preservation. Conclusions: The intensive use of the complementary technologies described seems advisable if surgical planning anticipates well-founded benefits in terms of morbidity and mortality for a particular patient. Caution should be exercised in anticipating and generalizing the global prognostic impact they may have, a benefit that is consistent in the literature but currently seems modest in general terms especially for high grade gliomas.

RGS16 regulated by let-7c-5p promotes glioma progression by activating PI3K-AKT pathway / 医学前沿

Gliomas are the most common central nervous system tumours; they are highly aggressive and have a poor prognosis. RGS16 belongs to the regulator of G-protein signalling (RGS) protein family, which plays an important role in promoting various cancers, such as breast cancer, pancreatic cancer, and colorectal cancer. Moreover, previous studies confirmed that let-7c-5p, a well-known microRNA, can act as a tumour suppressor to regulate the progression of various tumours by inhibiting the expression of its target genes. However, whether RGS16 can promote the progression of glioma and whether it is regulated by miR let-7c-5p are still unknown. Here, we confirmed that RGS16 is upregulated in glioma tissues and that high expression of RGS16 is associated with poor survival. Ectopic deletion of RGS16 significantly suppressed glioma cell proliferation and migration both in vitro and in vivo. Moreover, RGS16 was validated as a direct target gene of miR let-7c-5p. The overexpression of miR let-7c-5p obviously downregulated the expression of RGS16, and knocking down miR let-7c-5p had the opposite effect. Thus, we suggest that the suppression of RGS16 by miR let-7c-5p can promote glioma progression and may serve as a potential prognostic biomarker and therapeutic target in glioma.

The Oncogenesis of Glial Cells in Diffuse Gliomas and Clinical Opportunities / 神经科学通报·英文版

Glioma is the most common and lethal intrinsic primary tumor of the brain. Its controversial origins may contribute to its heterogeneity, creating challenges and difficulties in the development of therapies. Among the components constituting tumors, glioma stem cells are highly plastic subpopulations that are thought to be the site of tumor initiation. Neural stem cells/progenitor cells and oligodendrocyte progenitor cells are possible lineage groups populating the bulk of the tumor, in which gene mutations related to cell-cycle or metabolic enzymes dramatically affect this transformation. Novel approaches have revealed the tumor-promoting properties of distinct tumor cell states, glial, neural, and immune cell populations in the tumor microenvironment. Communication between tumor cells and other normal cells manipulate tumor progression and influence sensitivity to therapy. Here, we discuss the heterogeneity and relevant functions of tumor cell state, microglia, monocyte-derived macrophages, and neurons in glioma, highlighting their bilateral effects on tumors. Finally, we describe potential therapeutic approaches and targets beyond standard treatments.

MAGED4B Promotes Glioma Progression via Inactivation of the TNF-α-induced Apoptotic Pathway by Down-regulating TRIM27 Expression / 神经科学通报·英文版

MAGED4B belongs to the melanoma-associated antigen family; originally found in melanoma, it is expressed in various types of cancer, and is especially enriched in glioblastoma. However, the functional role and molecular mechanisms of MAGED4B in glioma are still unclear. In this study, we found that the MAGED4B level was higher in glioma tissue than that in non-cancer tissue, and the level was positively correlated with glioma grade, tumor diameter, Ki-67 level, and patient age. The patients with higher levels had a worse prognosis than those with lower MAGED4B levels. In glioma cells, MAGED4B overexpression promoted proliferation, invasion, and migration, as well as decreasing apoptosis and the chemosensitivity to cisplatin and temozolomide. On the contrary, MAGED4B knockdown in glioma cells inhibited proliferation, invasion, and migration, as well as increasing apoptosis and the chemosensitivity to cisplatin and temozolomide. MAGED4B knockdown also inhibited the growth of gliomas implanted into the rat brain. The interaction between MAGED4B and tripartite motif-containing 27 (TRIM27) in glioma cells was detected by co-immunoprecipitation assay, which showed that MAGED4B was co-localized with TRIM27. In addition, MAGED4B overexpression down-regulated the TRIM27 protein level, and this was blocked by carbobenzoxyl-L-leucyl-L-leucyl-L-leucine (MG132), an inhibitor of the proteasome. On the contrary, MAGED4B knockdown up-regulated the TRIM27 level. Furthermore, MAGED4B overexpression increased TRIM27 ubiquitination in the presence of MG132. Accordingly, MAGED4B down-regulated the protein levels of genes downstream of ubiquitin-specific protease 7 (USP7) involved in the tumor necrosis factor-alpha (TNF-α)-induced apoptotic pathway. These findings indicate that MAGED4B promotes glioma growth via a TRIM27/USP7/receptor-interacting serine/threonine-protein kinase 1 (RIP1)-dependent TNF-α-induced apoptotic pathway, which suggests that MAGED4B is a potential target for glioma diagnosis and treatment.

Application and research progress on PET-CT in radiotherapy and follow-up for glioma / 中华放射肿瘤学杂志

Glioma is the most common primary intracranial central nervous system tumor, and postoperative radiotherapy is an important treatment for glioma. At present, computed tomography (CT) and magnetic resonance imaging (MRI) are widely applied in the delineation of radiotherapy targets for glioma. However, there are still some deficiencies in evaluating tumor scope, recurrence, radiation necrosis and prognosis, etc. Positron emission tomography (PET) / computed tomography (PET-CT) combines the molecular images of PET with the anatomical images of CT, which plays an important role in the diagnosis and differential diagnosis of glioma. With the popularization and application of multimodal imaging technology in radiotherapy, PET-CT molecular imaging, as an important supplement, contributes to the delineation of glioma target volume and the development of accurate radiotherapy, and brings benefits to the prognosis and follow-up of glioma patients. In this article, the application and research progress on PET-CT in the diagnosis, treatment and follow-up for glioma were reviewed.

Apoptosis-promoting effect of temozolomide loaded nanoparticles combined with low intensity focused ultrasound on human glioma cells / 中华超声影像学杂志

Objective:To prepare liquid-gas phase modified nanoparticles (TMZ/PFP/PLGA NPs) of perfluoropentane (PFP) and temozolomide (TMZ) encapsulated by polylactic-glycolic acid copolymer (PLGA), combined with low intensity focused ultrasound (LIFU) irradiation, and to investigate its ultrasound imaging ability and intervention effect on human glioma cells in vitro.Methods:TMZ/PFP/PLGA NPs were prepared by compound emulsion method. The basic physical and chemical properties and drug loading ability of TMZ/PFP/PLGA NPs were detected. CCK-8 assay was used to detect the cytotoxicity of nanoparticles in vitro and the effect of synergistic intervention with LIFU on the survival rate of glioma cells. The expression levels of apoptosis related proteins Bcl-2, Bax and caspase-3 were detected by Western blot.Results:Under transmission electron microscope, TMZ/PFP/PLGA NPs showed a circular core-shell structure with regular morphology, particle size was (137.9±63.31)nm, encapsulation efficiency of TMZ was (83.01±5.57)%, drug loading was (3.19±0.22)%. The survival rate of U251 cells was still above 70% after 24 hours of co-incubation with nanoparticles. Under the synergistic effect of LIFU irradiation, the apoptosis of U251 cells was accelerated and the survival rate of U251 cells was significantly decreased. The results of Western blot showed that the synergic intervention could significantly down-regulate the expression of apoptosis related protein Bcl-2, and significantly up-regulate the expression of Bax protein and caspase-3 protein (all P<0.05). Conclusions:TMZ/PFP/PLGA NPs have good basic physical and chemical properties. TMZ/PFP/PLGA NPs have low cytotoxicity in vitro while efficiently loading chemotherapeutic drug timozolomide. Synergistic intervention under LIFU irradiation can significantly accelerate the apoptosis of U251 glioma cells, which has a good application prospect.

Effects of over-expression of E2F transcription factor 1 on radiosensitivity glioma U251 cells / 中华行为医学与脑科学杂志

Objective:To investigate the effects of over-expression of E2F transcription factor 1 (E2F1) on proliferation, invasion, apoptosis and radiosensitivity of glioma cell U251.Methods:Real-time quantitative PCR (qRT-PCR) were used to detect the differential expression of E2F1 mRNA in glioma cells LN18, SW1088, U251 and normal brain glial cells. The stable over-expression of E2F1 plasmid was constructed and transfected into U251 cells. qRT-PCR and Western blot test were used to detect the expression of E2F1, pituitary tumor transforming gene 1(PTTG1), C-Myc, B-cell lymphoma-2 (Bcl-2), Bcl2-associated X (Bax) mRNA and protein expression in the control group and E2F1 over-expression group.U251 cells were divided into control group(no X-ray irradiation), irradiation group(6 Gy dose of X-ray), and irradiation + E2F1 over-expression group(transfected with E2F1 first, then irradiated by 6 Gy of X-ray). Cell proliferation ability was detected by cell counting Kit-8(CCK-8) cell viability detection reagent, and cell invasion and migration ability were detected by Transwell chamber. Apoptosis and cell cycle were detected by flow cytometry.GraphPad Prism 8.0 was used for data analysis.The statistical methods were one-way ANOVA and independent sample t-test. Results:qRT-PCR showed that there was statistical difference in the mRNA levels of E2F1( F=201.92, P<0.05) in different cell lines.The expression levels of E2F1 mRNA in LN18(4.04±0.29), SW1088(3.19±0.16)and U251(4.66±0.20) cells were higher than those in HEB(1.02±0.07)cells ( q=27.00, 19.40, 32.52, all P<0.05). After successfully constructing U251 cells with stable over-expression of E2F1 plasmid, qRT-PCR and Western blot detection results showed that: the mRNA and protein levels of E2F1, PTTG1, C-Myc and Bcl-2 in E2F1 over-expression group were higher than those in control group ( t=77.16, 57.88, 4.63, 51.13, 7.50, 70.85, 8.38, 48.81, all P<0.05). Bax mRNA(0.20±0.01) and protein(0.66±0.01) levels were lower than those in control group((1.00±0.02), (0.94±0.01)), and the differences were statistically significant ( t=1.74, 54.65, both P<0.05). After X-ray irradiation (6 Gy), CCK8 detection results showed: the proliferation ability of the three groups at 24, 48, 72 and 96 h were significantly different ( F=95.41, 187.53, 1 158.49, 7 883.78, all P<0.05). The proliferation capacity of the irradiation group were lower than those of the control group at 24, 48, 72 and 96 h ( q=19.51, 27.20, 66.60, 174.9, all P<0.05). The proliferation capacity of irradiation + E2F1 over-expression group at 24, 48, 72 and 96 h were higher than those of irradiation group ( q=10.63, 10.81, 21.11, 60.90, all P<0.05). Transwell assay results showed that there were significant differences in cell invasion and migration ability among the three groups ( F=315.38, 681.10, both P<0.05). The invasion and migration ability of cells in the irradiation group were lower than those in the control group ( q=35.09, 12.76, both P<0.05), and the invasion and migration ability of cells in the irradiation + E2F1 over-expression group were higher than those in the irradiation group ( q=52.06, 22.81, both P<0.05). Flow cytometry showed that there were significant differences in apoptosis rate and percentage of cells in each cycle among the three groups ( F=667.63, 3 213.30, 3 011.26, 861.98, all P<0.05). The percentage of the apoptosis rate, S phase and G2 phase cells in the irradiation group were higher than those in the control group ( q=51.10, 89.39, 51.82, all P<0.05), while the percentage of G1 phase cells in the irradiation group was lower than that in the control group ( q=141.2, P<0.05). The apoptosis rate and percentage of S phase and G2 phase cells in the irradiation + E2F1 over-expression group were lower than those in the irradiation group ( q=18.87, 41.42, 29.31, all P<0.05), while the number of G1 phase cells in the irradiation + E2F1 over-expression group was lower than that in the irradiation group ( q=70.73, P<0.05). Conclusion:Over-expression of E2F1 can reduce the radiosensitivity of glioma U251 cells by regulating the expression of mRNA and protein of genes related to cell cycle and apoptosis, and E2F1 may be involved in the radioresistance of glioma cells.

Efficacy of intensity modulated radiotherapy with sequential chemotherapy in the treatment of high-grade glioma and analysis of influential factors / 中国基层医药

Objective:To investigate the efficacy of intensity-modulated radiotherapy with sequential chemotherapy in the treatment of high-grade glioma and analyze the influential factors.Methods:A total of 56 patients with high-grade glioma who received treatment in Yantai Municipal Laiyang Central Hospital from January 2014 to January 2016 were retrospectively analyzed. All patients underwent three-dimensional conformal radiotherapy or enhanced radiotherapy. The use of bevacizumab, pathological grade, and preoperative and postoperative Karnofsky Performance Status scores in all patients were recorded. Cox and other proportional risk regression models were used to analyze the predictors of patient mortality and receiver operating characteristic (ROC) curve analysis was performed.Results:All patients were followed up to April 2022. Follow-up results showed that the median survival time of patients receiving concurrent chemotherapy with temozolomide and adjuvant chemotherapy with temozolomide was 11.6 months. Univariate analysis showed that pathological grade, Karnofsky Performance Status scores, and the degree of tumor resection were correlated with the prognosis of patients ( P = 0.022, 0.049, 0.022). Multivariate analysis showed that the degree of tumor resection and pathological grade were the independent influential factors of prognosis ( P = 0.010, 0.010). Survival curve analysis revealed that the median survival time of patients subjected to total tumor resection was 12.6 months and that of patients subjected to partial tumor resection was 4.8 months. The median survival time of patients subjected to total tumor resection was longer than that of patients subjected to partial tumor resection. The median survival time of patients with WHO grade Ⅲ tumors was 25.2 months, and it was 6.3 months for patients with WHO grade Ⅳ tumors. The median survival time of patients with WHO grade Ⅲ tumors was longer than that of patients with WHO grade Ⅳ tumors. The receiver operating characteristic curve analysis results showed that the area under the receiver operating characteristic curve plotted for using WHO classification of tumors in the neurological system and surgical methods to predict the death of patients with high-grade glioma was 0.783 and 0.814, respectively. WHO tumor grade and surgical methods for prediction of prognosis of high-grade glioma had high accuracy. Conclusion:Low pathological grade and total resection are independent protective factors for the prognosis of patients with high-grade glioma.

Practice and reflection of glioma subspecialist training in Neurosurgery / 中华医学教育探索杂志

The standardized training system for physicians has been implemented for many years in China. Based on the current situation of neurosurgery specialist training and the sub-professional development, the study discusses the specific plan and direction of glioma sub-professional physicians training from the aspects of glioma sub-professional physicians training outline, training content, requirements of glioma sub-professional training base, training assessment methods and training management. It provided reference for the training of neurosurgical glioma professionals in China, so as to make glioma receive comprehensive and standardized treatment.

Construction of glioma prognosis model with n7-methylguanosine related long non-coding RNA based on transcriptome / 中国医师进修杂志

Objective:To investigate the relationship between n7-methylguanosine (m7G) related long non-coding RNA (lncRNA) expression and glioma prognosis, and to construct a prognosis model with m7G-related lncRNA in patients with glioma.Methods:Data related to the test set and validation set were downloaded from the Cancer and Tumor Genome Atlas (TCGA) database and the China Glioma Genome Atlas (CGGA) database. LASSO regression and random forest algorithm were used to establish the glioma prognosis model with m7G related lncRNA. Individualized risk scores were calculated using the weighted expression levels of the 12 extracted lncRNA coefficients, and test set and validation set glioma patients were categorized into high and low risk groups based on median risk score. Kaplan-Meier survival curve was drawn, the comparison method used log rank test. The efficacy of risk score in predicting the 1-, 2- and 5-year survival rate in patients with glioma was evaluated using the receiver operating characteristics (ROC) curve.Results:A total of 12 lncRNA associated with m7G were obtained, with a risk score = 1.026 × AC002454.1 + 1.086 × AC131097.4 + 1.039 × AC147651.3 + 1.01 × AGAP2-AS1 + 1.036 × CRNDE + 0.733 × GDNF-AS1 + 1.321 × HOXD-AS2 + 0.934 × LINC00641 + 1.183 × PAXIP1-AS2 + 1.258 × PVT1 + 0.909 × SOX21-AS1 + 0.754 × TTC28-AS1, with a median risk score of - 0.45 scores. Kaplan-Meier survival curve analysis result showed that the median survival time in high risk group was significantly shorter than that in low risk group (1.98 years vs. 9.51 years, log-rank χ2 = 131.78, P<0.01). ROC curve analysis result showed that the area under the curve (AUC) of risk score in predicting the 1-, 2- and 5-year survival rate in patients with glioma was 0.891, 0.923 and 0.912. In the validation set of glioma patients, Kaplan-Meier survival curve analysis result showed that the median survival time in high risk group was significantly shorter than that in low risk group (1.29 years vs. 6.88 years, log-rank χ2 = 103.27, P<0.01); ROC curve analysis result showed that the AUC of risk score in predicting the 1-, 2- and 5-year survival rate in patients with glioma was 0.724, 0.795 and 0.762. In the test set and validation set, multivariate Cox regression analysis result showed that the risk score was the independent risk factors of prognosis in patients with glioma ( HR = 1.992 and 1.247, P<0.01 or <0.05). Conclusions:A risk score model with m7G related lncRNA based on transcriptome is a novel approach to predict the prognosis of glioma patients.

Effects and mechanism of ginsenoside Rh2 on the proliferation and apoptosis of human glioma cells / 中国药房

ABSTRACT OBJECTIVE To investigate the effects and mechanism of ginsenoside Rh2 on the proliferation and apoptosis in human glioma U87 and U251 cells. METHODS Using human glioma U87 and U251 cells as subjects， the proliferation and apoptosis， as well as the expression of histone deacetylase 1（HDAC1） protein and apoptosis-related proteins [B cell lymphoma-2（Bcl-2）， Bcl-2-associated X protein （Bax） and cleaved caspase-3] were detected after being treated with different concentrations of ginsenoside Rh2. RESULTS The concentrations of 10，20，30，40，50，60，70，80 μmol/L ginsenoside Rh2 could generally significantly increase the proliferation inhibition rate of U87 and U251 cells （P＜0.05 or P＜0.01）， and the half inhibitory concentrations of this component after 48 hours of action were 51.34 and 55.84 μmol/L， respectively；30，50 μmol/L ginsenoside Rh2 could increase the total apoptotic rate of both types of cells， reduced the protein expressions of HDAC1 and Bcl-2， and increased the protein expressions of Bax and cleaved caspase-3 significantly （P＜0.05 or P＜0.01）. CONCLUSIONS Ginsenoside Rh2 has a significant inhibitory effect on the proliferation of glioma cells and promotes the apoptosis of cells， which may be through reducing the expression of HDAC1 protein and activating the Bcl-2 family protein-mediated apoptosis pathway.

Construction of albumin nanoparticles loading PROTAC and its inhibition effect on NAD+ in glioma cells / 药学实践杂志

Objective To prepare and optimize the formulation of Albumin nanoparticles loading PROTAC molecule and observe the inhibition effect of nanoparticles on the proliferation and NAD+ metabolism of glioma cells. Methods Albumin nanoparticles loading NPT-B2 were prepared and characterized with a thermal driving method, and the prescription was optimized. An HPLC method was established to determine the content of NPT-B2. The proliferation inhibition of NPT-B2 and B2-BSA-NPs on U251 cells were investigated by the CCK8 method, and the degradation effects of NPT-B2 and B2-BSA-NPs on NAMPT in glioma cells were investigated by western blotting. Results The HPLC method was stable, with good linearity, precision, and recovery rate. The nanoparticles had a particle size of about 55.48 nm, a potential of about −12.9 mV, an encapsulation rate of about 94.74%, and a drug loading amount of about 8.61%. The IC50 of NPT-B2 on glioma cells was 61.16 nmol/L, which had a degradation effect on NAMPT. The IC50 of B2-BSA-NPs on glioma was 41.21 nmol/L, which had a very significant degradation effect on NAMPT. Conclusion Albumin nanoparticles loading PROTAC molecules were constructed. The prescription was optimized to improve the drug encapsulation rate, and the low water solubility of PROTAC molecule was improved, which had a significant inhibitory effect on the proliferation and NAD+ energy metabolism of glioma cells.