Exposição a agrotóxicos e o risco de tumores do Sistema Nervoso Central em crianças: revisão sistemática com metanálise / Pesticide exposure and risk of Central Nervous System tumors in children: a systematic review with meta-analysis

Resumo Os tumores do Sistema Nervoso Central (SNC) representam mais da metade das neoplasias infantis malignas que acometem crianças. Objetivou-se analisar o risco de exposição a agrotóxicos relacionado com o desenvolvimento de tumores do SNC em crianças. Realizou-se uma revisão sistemática da literatura nas bases de dados PubMed/MEDILINE, Embase, Web of Science, Scopus e CINAHL. Foram incluídos estudos de coorte e caso-controle sobre o desenvolvimento de tumores do SNC (todos os tipos histológicos do grupo III Classificação de Câncer Infantil) decorrentes da exposição a agrotóxicos em crianças de 0-14 anos. Na metanálise utilizou-se o modelo de efeito aleatório e o método estatístico de Mantel-Haenszel. A Razão de Chances (RC) ou Odds Ratio (OR) foi a medida de associação aplicada. A revisão foi registrada no International Prospective Register of Systematic Reviews (PROSPERO) sob o número CRD42021209354. A busca identificou 1.158 estudos, dos quais 14 compuseram a revisão. Verificou-se evidência de associação entre o desenvolvimento de astrocitomas e a exposição a todas as classes de pesticidas (OR 1,50; IC95% 1,15-1,96; p=0,03). A síntese dos resultados apontou para uma relação da exposição aos agrotóxicos com o desfecho de alguns tipos histológicos de tumores do SNC na infância.

Abstract Central Nervous System (CNS) tumors represent more than half of all childhood malignant neoplasms. The aim of this study was to determine the relationship between environmental exposure to pesticides and the development of CNS tumors in children. We conducted a systematic review of the literature in the PubMed/MEDILINE, Embase, Web of Science, Scopus, and CINAHL databases. The inclusion criteria were cohort and case-control studies investigating the association between exposure to pesticides and CNS tumors (all histological types included in group III of the WHO Classification of Childhood Cancer) in children aged 0-14 years. The meta-analysis was performed using a random effects model and the Mantel-Haenszel method. Strength of association was measured using odds ratios (OR). The review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under identification number CRD42021209354. The search identified 1,158 studies, 14 of which were included in the review. There was evidence of an association between the development of astrocytomas and exposure to all classes of pesticides (OR 1.50; 95%CI 1.15-1.96; p=0.03). The synthesis of the evidence pointed to a relationship between exposure to pesticides and some histological types of CNS tumors in childhood.

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.

Clinical characteristics and prognosis of newly-treated patients with primary central nervous system lymphoma: a multicenter retrospective study / 白血病·淋巴瘤

Objective:To investigate the clinical characteristics, treatment and prognosis of newly-treated patients with primary central nervous system lymphoma (PCNSL).Methods:Clinical data of 117 newly-treated PCNSL patients who were admitted to the First Hospital of Jilin University, the Fifth Medical Center of Chinese PLA General Hospital, Harbin Medical University Cancer Hospital, and Cancer Hospital of Chinese Academy of Medical Sciences & Peking Union Medical College from August 2009 to February 2018 were retrospectively analyzed. The patients' age, sex, Eastern Cooperative Oncology Group (ECOG) physical status (PS) score, pathological type, involvement of deep brain tissue, number of lesions, cerebrospinal fluid protein concentration, International Extranodal Lymphoma Study Group (IELSG) score, Memorial Sloan Kettering Cancer Center (MSKCC) score, treatment strategy, and response after the first-line therapy were analyzed using univariate and multivariate Cox proportional hazards models to identify the independent influencing factors for progression-free survival (PFS) and overall survival (OS) of PCNSL patients. Kaplan-Meier method was used for survival analysis.Results:In 117 newly-treated PCNSL patients, 59 cases (50.4%) presented with increased intracranial pressure or focal neurological symptoms at diagnosis; there were 65 cases (55.6%) with single lesions and 52 cases (44.4%) with multiple lesions; 1 patient (0.9%) had lymphoma of T-cell origin, and 116 cases (99.1%) had diffuse large B-cell lymphoma (DLBCL). Among 95 evaluable patients, 41 patients (43.2%) achieved complete remission (CR), 20 patients (21.1%) achieved partial remission (PR), 16 patients (16.8%) achieved stable disease (SD), and 18 patients (18.9%) had progressive disease (PD). In 117 patients with median follow-up of 66.0 months (95% CI 57.9-74.1 months), the median PFS and OS were 17.4 months (95% CI 11.5-23.3 months) and 45.6 months (95% CI 20.1-71.1 months), respectively. The 2-, 3- and 5-year PFS rates were 41.2%, 28.6% and 19.3%, and OS rates were 63.7%, 52.4% and 46.3%, respectively. Univariate Cox regression analysis showed that baseline high-risk MSKCC score group was an adverse prognostic factor for PFS ( P = 0.037), and the first-line chemotherapy with ≥4 cycles of high-dose methotrexate (HDMTX), HDMTX in combination with rituximab, ≥4 cycles of rituximab in combination with HDMTX, and achieving CR or ≥PR after the first-line treatment reduced the risk of disease progression and prolonged the PFS time (all P <0.01); age >60 years old, ECOG-PS score of 2-4 points, elevated cerebrospinal fluid protein concentration, high-risk IELSG score, and high-risk MSKCC score were adverse prognostic factors for OS, and ≥4 cycles of HDMTX and achieving CR or ≥PR after the first-line treatment were favorable factors for OS. Multivariate Cox regression analysis verified that rituximab in combination with HDMTX (yes vs. no: HR = 0.349, 95% CI 0.133-0.912, P = 0.032) and achieving ≥PR after the first-line chemotherapy (yes vs. no: HR = 0.028, 95% CI 0.004-0.195, P < 0.001) were independent favorable factors for PFS; age >60 years old (>60 years old vs. ≤60 years old: HR = 10.878, 95% CI 1.807-65.488, P = 0.009) was independent unfavorable factor for OS, while ≥4 cycles of HDMTX treatment (≥4 cycles vs. <4 cycles: HR = 0.225, 95% CI 0.053-0.947, P = 0.042) was independent favorable factor for OS. Conclusions:The older the PCNSL patients at initial treatment, the worse the prognosis. Intensive and continuous treatment for achieving deeper remission may be the key for improving the outcome of PCNSL patients.

Diagnosis and treatment progress of primary central nervous system lymphoma / 白血病·淋巴瘤

Primary central nervous system lymphoma (PCNSL) is a rare lymphoma type. The prognosis of PCNSL patients after treated by traditional therapy regimen is very poor. The way to evaluate the prognosis of PCNSL and to increase therapeutic efficacy have become the clinical problem. The 64th American Society of Hematology (ASH) annual meeting reported the latest research progress of diagnosis and treatment of PCNSL, including image examination, genetic sequencing, targeted therapy, chimeric antigen receptor T-cell (CAR-T) therapy and autologous hematopoietic stem cell transplantation (ASCT). This paper reviews the latest progress of PCNSL in the 64th ASH annual meeting.

Pancytopenia caused by intrathecal injections of chemotherapeutic agents in central nervous system leukemia: report of 1 case and review of literature / 白血病·淋巴瘤

Methods:The clinical data of a CNSL patient with pancytopenia caused by intrathecal injections of chemotherapeutic agents in the First Affiliated Hospital of Zhengzhou University in January 2017 were retrospectively analyzed, and the related literature was reviewed.Results:The patient was a 71-year-old man who was diagnosed with acute myeloid leukemia. During regular chemotherapy, he suffered from extramedullary relapse, and leukemic cells invaded the superior sagittal sinus of brain. Lumbar puncture and intrathecal injections of chemotherapeutic agents were given intermittently. During this period, the complete blood count of patient progressively declined, and oral mucositis appeared. After calcium folinate rescue and intermittent blood transfusion, the complete blood count recovered. Eventually, the patient developed bone marrow relapse and died of infection.Conclusions:On the one hand, the invasion of leukemia cells into the central nervous system leads to increased intracranial pressure and accelerated absorption of cerebrospinal fluid; on the other hand, it induces the structural damage of the superior sagittal sinus or increased permeability, and therefore chemotherapy agents continue to enter the blood with cerebrospinal fluid, which may be the cause of pancytopenia.

Zanubrutinib combined regimens for treatment of elderly patients with central nervous system lymphoma: report of 3 cases and review of literature / 白血病·淋巴瘤

Objective:To investigate the efficacy and safety of zanubrutinib combined regimens for treatment of elderly patients with central nervous system lymphoma (CNSL).Methods:The clinical data of 3 elderly patients with CNSL who received zanubrutinib combined regimens from July 2020 to March 2022 in the Affiliated Suzhou Hospital of Nanjing Medical University were retrospectively analyzed. Two of them were primary central nervous system lymphoma (PCNSL) and one was secondary central nervous system lymphoma (SCNSL). Relevant literature was reviewed at the same time.Results:The two patients with PCNSL were treated with zanubrutinib in combination with rituximab and lenalidomide (Z-R 2) regimen. One of them achieved complete remission (CR) after 6 cycles, and the other patient achieved partial remission (PR) after 1 cycle of Z-R 2 regimen. The patient with SCNSL was diagnosed with diffuse large B-cell lymphoma (DLBCL) previously and suffered from central nervous system relapse after achieving CR. The patient achieved PR after 2 cycles of Z-R 2 regimen, and then achieved CR followed by 4 cycles of zanubrutinib in combination with rituximab and high-dose methotrexate (Z-R-HD-MTX) regimen. Two of the three patients were still in CR until April 2022, and the longest disease-free survival time was 15 months. There were no severe adverse reactions during the treatment. Conclusions:Zanubrutinib combined regimens for 3 elderly patients with CNSL have shown promising effect and well tolerance, which may be considered as novel treatment for CNSL patients who are unable to tolerate severe chemotherapies or autologous hematopoietic stem cell transplantations.

Efficacy observation of lenalidomide in treatment of relapsed/refractory diffuse large B-cell lymphoma / 白血病·淋巴瘤

Objective:To explore the clinical efficacy of lenalidomide combined with second-line immunochemotherapy as a salvage regimen in the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL).Methods:The clinical data of 37 relapsed/refractory DLBCL patients receiving lenalidomide combined with second-line immunochemotherapy as a salvage regimen who had recurrence after autologous hematopoietic stem cell transplantation or who were not eligible for transplantation or had no intention to transplant between January 2016 and December 2020 in the First Affiliated Hospital of University of Science and Technology of China were retrospectively analyzed. Among 37 patients, 6 cases with primary central nervous system (CNS) lymphoma and 3 cases with secondary CNS lymphoma. The short-term efficacy after treatment was evaluated. Kaplan-Meier method was used to analyze the overall survival (OS) and progression-free survival (PFS), and log-rank test was used for subgroup comparison.Results:The median follow-up time of 37 patients was 20.4 months (2.7-37.0 months). At the end of treatment, the overall response rate (ORR) of all patients was 64.9% (24/37), the complete response (CR) rate was 45.9% (17/37), and the median duration of response (DOR) of 24 patients who responded to treatment was 17.7 months (3.6-33.6 months). The median PFS time of all patients was 11.2 months, and the 1-year PFS rate was 48.6% (95% CI 32.5%-64.7%). The median OS time of all patients was not reached, and the 1-year OS was 67.6% (95% CI 52.5%-82.7%). Among 24 responding patients, 17 cases who received lenalidomide maintenance therapy after remission tended to have a better response compared with 7 cases who did not receive lenalidomide maintenance therapy after remission, although there was no significant difference in OS and PFS between both groups (both P > 0.05). Additionally, neutropenia was the most common adverse reaction with an incidence of 81.1% (30/37). Conclusions:Lenalidomide combined with the second-line immunochemotherapy may be an effective salvage therapy for patients with relapsed/refractory DLBCL, especially for patients with CNS involvement. The patients achieving remission after salvage therapy continue to receive lenalidomide maintenance therapy and could have a better prognosis.

The diagnosis and treatment of primary vitreoretinal lymphoma: 10 years of experience / 中华眼底病杂志

Objective:To investigate the clinical characteristics, treatment and prognosis of primary vitreoretinal lymphoma (PVRL) diagnosed and treated in our hospital during the past 10 years.Methods:A retrospective clinical study. From 2011 to 2021, 126 eyes of 67 patients with PVRL who were diagnosed and treated in Department of Ophthalmology, Eye-ENT Hospital, Fudan University were included in the study. Among them, there were 23 males (34.3%, 23/67) and 44 females (65.7%, 44/67); the average age was 57.1 years. There were 59 cases with both eyes (88.1%, 59/67) and 8 cases with one eye (11.9%, 8/67). At the initial eye diagnosis, 22 cases had a clear history of primary central nervous system lymphoma (PCNSL); 5 cases were found to have intracranial lesions by head imaging examination; 40 cases had no central nervous system involvement. Twenty cases were treated with glucocorticoids due to misdiagnosed uveitis. All patients received intravitreal injection of methotrexate (IVM) treatment. The treatment regimen was twice a week in the induction period for 2 weeks, once a week in the consolidation period for 1 month, and once a month in the maintenance period. Patients with PCNSL or both eyes received concurrent systemic chemotherapy (chemotherapy), and some in combination with radiation therapy to the brain (radiotherapy). The mean follow-up time was 39.3 months. The clinical manifestations, treatment and prognosis of the patients were retrospectively analyzed. The visual acuity before and after treatment was compared by t test. Results:Among the 22 cases with a clear history of PCNSL at the initial eye diagnosis, the average time from intracranial diagnosis to eye diagnosis was 22.9 months. Among the 40 cases without central nervous system involvement at first, 14 cases (20.9%, 14/67) developed central nervous system lesions during follow-up period. The mean time from ocular diagnosis to intracranial diagnosis was 9.9 months. Among the 126 eyes, 42 eyes (33.3%, 42/126) had anterior segment inflammation. vitreous inflammation type, retinal type, and vitreous retinal type were 58 (46.0%, 58/126), 7 (5.6%, 7/126), and 61 (48.4%, 61/126) eyes, and 9 of them (7.1%, 9/126) had optic nerve involvement at the same time. Patients received an average of 12 IVM treatments. IVM combined with systemic chemotherapy in 59 cases (88.1%, 59/67), of which 16 cases were combined with brain radiotherapy. All patients achieved complete remission after completing the treatment cycle (100.0%, 67/67). After treatment, 21 eyes (16.7%, 21/126) had ocular recurrence; 22 (32.8%, 22/67) had intracranial recurrence; 8 cases (11.9%, 8/67) died. The mean progression-free survival of patients was 23.7 months; the mean survival time was 43.6 months; the 5-year overall survival rate was 72.5%.Conclusions:The manifestations of PVRL are complex and diverse, and most of them are accompanied by involvement of the central nervous system. It can be divided into vitreitis type, retinal type and vitreoretinal type, and the optic nerve can be involved at the same time; IVM combined with systemic treatment can completely relieve the disease.

Primary central nervous system T-cell lymphoma: a case report / 中华神经科杂志

Primary central nervous system T-cell lymphomas (PCNSTL) are rare, the clinical symptoms and radiographic imaging of which are unspecific, and the pathological morphology is antypical, leading to misdiagnosis and delays in treatment. A 45-year-old male patient with diplopia accompanied by numbness and dysarthria was reported in this paper, which was considered as "lymphoma or lymphoproliferative lesions" on magnetic resonance imaging (MRI) while no typical tumor cells in brain biopsy. The clinical symptoms worsened one month later and the reexamined MRI showed that the scope of the lesion was enlarged and the enhancement was more obvious than before, which was still considered as lymphoma or lymphoproliferative lesion. The second biopsy was performed and still no typical tumor lymphocytes were seen. Finally, gene rearrangement was carried out and showed the β and γ chains both present positive mutations in T cell receptor (TCR) gene rearrangement. Combined with cell morphology, immunophenotype and TCR gene rearrangement results, the patient was finally diagnosed as PCNSTL. This article reviewed the clinical symptoms, imaging features, laboratory examinations, pathological characteristics, diagnosis and differential diagnosis of PCNSTL, so as to improve the understanding of this rare disease.

Clinicopathological features and myeloid differentiation factor 88 L265P gene mutation in patients with diffuse large B-cell lymphoma of central nervous system / 中华神经科杂志

Objective:To analyze the clinical features and mutation of myeloid differentiation factor 88 (MYD88) L265P in patients with diffuse large B-cell lymphoma (DLBCL) of central nervous system (CNS).Methods:The clinicopathological materials of 45 cases of DLBCL of CNS were retrospectively collected in Xuanwu Hospital, Capital Medical University from September 2014 to February 2017. The clinicopathological data were retrospectively analyzed, combined with immunohistochemistry, EB virus in situ hybridization, imaging and medical history. The mutation of MYD88 L265P gene was detected by pyrosequencing and its clinical significance was analyzed. Results:The age of the patients ranged from 42 to 82 years [(57.6±8.8) years], including 24 males and 21 females. Totally 93.3% (42/45) of the patients had supratentorial tumours, which were single or multiple. The cerebral hemisphere (31/45, 68.9%) was the most common involved site, and 21 cases (21/45, 46.7%) had multiple lesions. Histologically, DLBCL in the CNS showed diffuse infiltration of tumor tissue, some of which grew around blood vessels in a "sleeve" arrangement. CD 20 and CD 79a were diffusely and strongly positive. Thirty-nine cases (39/45, 86.7%) were non-germinal center B cell (non-GCB) subtype and 6 cases (6/45, 13.3%) were germinal center B cell (GCB) subtype. MYD88 L265P mutation was found in 64.4% (29/45) patients. There was statistically significant difference between non-GCB type (71.8%, 28/39) and GCB type DLBCL (1/6, P=0.017). Compared with the operation/biopsy group without chemotherapy, operation+chemotherapy, biopsy+chemotherapy, operation/biopsy+chemotherapy+stem cell transplantation can improve the survival and prognosis ( HR=0.05, 95% CI 0.01-0.33 , P=0.002; HR=0.04, 95% CI 0.01-0.36 , P=0.004; HR=0.01, 95% CI 0.00-0.17 , P=0.001; respectively). Conclusions:DLBCL of the CNS is aggressive tumor with poor prognosis, the clinical manifestations are complex and diverse, and the diagnosis is challenging. MYD88 L265P is a common and specific gene mutation in primary CNS lymphoma(PCNSL), which is of great significance in the diagnosis and treatment of lymphoma. The MYD88 L265P mutation was more frequently detected in non-GCB than GCB subtype. Chemotherapy can improve the survival rate of PCNSL patients. If chemotherapy achieves complete remission and autologous hematopoietic stem cell transplantation is performed, there may be a chance of long-term survival.

Atypical magnetic resonance imaging findings, misdiagnosis analysis and functional imaging value of primary central nervous system lymphoma / 中国医师杂志

Objective:To observe and analyze the atypical magnetic resonance imaging (MRI) findings and misdiagnosis reasons of primary central nervous system lymphoma (PCNSL), and to explore the value of conventional MRI signs combined with minimum apparent diffusion coefficient value (ADCmin) and imaging features of magnetic resonance spectroscopy (MRS) in the diagnosis and differentiation of atypical PCNSL.Methods:The clinical and imaging data of 15 patients with atypical PCNSL confirmed by clinical and pathological findings from Lianyungang Second People′s Hospital and the Affiliated Hospital of Xuzhou Medical University from January 2015 to December 2020 was collected. All cases were examined by plain MRI, enhanced and diffusion weighted imaging (DWI), and 3 cases were examined by MRS. The conventional MRI features, DWI signal features and MRS imaging features of 15 cases of atypical PCNSL were observed and analyzed, and the MRI findings of atypical PCNSL and the causes of misdiagnosis were summarized and analyzed. The ADCmin of tumor parenchyma, the mean ADC values of proximal peritumor, distal peritumor and contralateral white matter were detected and compared to explore the variation rules of ADC values in different regions.Results:Of the 15 cases of PCNSL, 14 cases were single and 1 case was multiple, with a total of 21 lesions. (1) Single lesions in rare sites: 4 cases in the superficial part of the brain, 1 case in the bridge arm, 1 case in the cerebellar hemisphere, 1 case in the suprasellar saddle, and 1 case in the third ventricle. (2) Atypical MRI findings: cystic degeneration or necrosis in 5 lesions (5/21), accompanied by hemorrhage in 1 lesion (1/21); There were 3 isosensitive lesions on DWI, and isosensitive lesions on ADC false color images. There were 5 ring enhancement lesions and 3 sheet enhancement lesions. (3) Multi-center growth pattern: 1 case with a total of 7 lesions, located in the right thalamus, basal ganglia and corona radiata, showing multiple nodules and ring enhancement. 1H-MRS examination showed that choline (Cho) peak increased, creatine (Cr) peak decreased, N-acetyl aspartate (NAA) peak decreased, and obvious Lip peak appeared in all the 3 cases with single lesions. 2 cases showed high Lip peak as the first peak. The ADCmin values of tumor parenchyma, proximal peritumor, distal peritumor and contralateral white matter showed a parabola pattern of first rise and then decline, as follows: (0.54±0.06)×10 -3 mm 2/s, (1.55±0.10)×10 -3 mm 2/s, (1.45±0.09)×10 -3 mm 2/s, (0.85±0.03)×10 -3 mm 2/s, overall difference was statistically significant ( F=630.570, P<0.001). The pairwise comparison was statistically significant (all P<0.05). Conclusions:Atypical PCNSL is easy to be misdiagnosed. Conventional MRI feature analysis combined with DWI and MRS imaging features and comparison of ADC values in different tumor areas are helpful for the diagnosis and differentiation of PCNSL and are expected to improve diagnostic accuracy.

Progress of targeted therapy for primary central nervous system lymphoma / 白血病·淋巴瘤

Primary central nervous system lymphoma (PCNSL) is a rare invasive non-Hodgkin lymphoma. Although high dose methotrexate-based induced chemotherapy regimen has significantly improved prognosis of patients, 30 percent -40 percent of patients still relapse with poor prognosis. With the development of molecular biology, new targeted drugs like cell signaling pathway kinase inhibitors have become new treatment options for PCNSL.

Refractory primary central nervous system lymphoma treated with programmed death-1 monoclonal antibody and Bruton tyrosine kinase inhibitor combined with rituximab: report of 1 case and review of literature / 白血病·淋巴瘤

Objective:To investigate the effect and safety of rituximab, programmed death 1 (PD-1) monoclonal antibody, and Bruton tyrosine kinase (BTK) inhibitor on elderly refractory primary central nervous system lymphoma (PCNSL).Methods:The clinical data of an elderly patient with refractory PCNSL treated with the combination of rituximab, PD-1 monoclonal antibody and BTK inhibitor in the First Hospital of Jilin University in February 2020 were retrospectively analyzed. The relevant literature was reviewed.Results:The patient had primary central nervous system diffuse large B-cell lymphoma (high-risk group), and the Memorial Sloan Kettering Cancer Center (MSKCC) score was 2 (estimated overall survival time was 7 months). Disease progressed after 1 course of treatment. Complete remission was achieved after the therapy of rituximab, PD-1 monoclonal antibody combined with BTK inhibitor. PD-1 monoclonal antibody maintenance therapy was performed and patient was followed up until November 17, 2021. The patient's condition was stable. The second progression-free survival (PFS) time was 20 months, and the overall survival time was 21 months. The patient well tolerated the new drug treatment, and no adverse reactions of grade 3 or above occurred.Conclusions:The new targeted combination therapy can be used as a treatment option for elderly PCNSL patients, which can further improve the curative effect and significantly improve the prognosis.

Terapias dirigidas con inhibidores del braf en gliomas pediátricos de alto y bajo grado con la mutación brafv600e. Experiencia del hospital Prof. Dr. Juan P. Garrahan / Targeted therapies with BRAF inhibitors for pediatric low- and high-grade gliomas with BRAF v600e mutation. Prof. Dr. Juan P. Garrahan Hospital experience

Resumen La mutación puntual V600E del gen BRAF juega un papel fundamental en la tumorigénesis de muchos gliomas. La inhibición de su producto forma parte de terapias innovadoras emergentes en los últimos años. Conocer el rol de estos tratamientos resulta imprescindible. El objetivo del trabajo fue describir la respuesta clínico-radiológica en niños con gliomas BRAF V600E mutado tratados con inhibidores BRAF. Para ello se realizó un estudio descriptivo y retrospectivo en pacientes menores de 16 años con gliomas BRAF V600E mu tado que recibieron vemurafenib o dabrafenib en el Hospital Garrahan. Trece pacientes tratados en los últimos 7 años fueron incluidos: 9 gliomas de bajo grado y 4 de alto grado. La mediana de edad al diagnóstico fue 8.6 años (0.89-14.04) y del comienzo del inhibidor 11.62 años (3.64-15.42). Inicialmente, todos habían realizado tratamiento quirúrgico, y 12/13 recibieron previamente otra terapia: 11 quimioterapia (eventualmente hasta 4 líneas distintas) y 4 radioterapia. Con la terapia dirigida, 10 pacientes tuvieron una disminución tumoral mayor o igual al 25%, quedando evidenciada en 7 niños la mejor respuesta dentro de los 6 meses del inicio. Hubo 4 progresados intratratamiento (todos alto grado), y 2 progresados prontamente luego de suspender el inhibidor (ambos bajo grado). Cinco presentaron efectos adversos grado 3-4, con recuperación ad-integrum. Se describe una buena y sostenida respuesta clínico-radiológica, con tolerancia aceptable, en pacientes con gliomas de bajo grado BRAF V600E mutado tratados con inhibidores BRAF V600E . En contraste, la respuesta en pacientes con gliomas de alto grado fue intermedia y de poca duración, con progresión tumoral precoz.

Abstract The BRAF V600E point mutation plays a key role in the tumorigenesis of many gliomas. Inhibiting its product is part of the innovative therapies emerging in recent years. Knowing the role of these treatments is essential. The aim of this experience was to describe the clinical-radiological response of pediatric BRAF V600E mutated gliomas treated with BRAF inhibitors. To this end, a descriptive and retrospective study was performed in patients under 16 years of age with BRAF V600E gliomas, who received vemurafenib or dabrafenib at Hospital Garrahan. Thirteen patients treated in the last 7 years were included: 9 were low-grade and 4 high-grade gliomas. The median age at diagnosis was 8.6 years (0.89-14.04) and at start of targeted therapy was 11.62 years (3.64-15.42). All patients had previously a surgical procedure, and 12/13 had received another therapy prior BRAF inhibition: 11 chemotherapy (in one case, up to 4 different protocols) and 4 radiotherapy. Under targeted therapy, tumour response was obtained in 10 patients (size reduction equal to or greater than 25%), and best response was observed in the first 6 months of treatment in 7 children. Four patients progressed under treatment (all high-grade gliomas) and 2 progressed shortly after stopping the inhibitor (both low-grade gliomas). Five patients had grade 3-4 toxicity, with subsequent full recovery. A good and sustained clinical-radiological response, with acceptable tolerance, is described in patients with BRAF V600E mutated low-grade gliomas treated with BRAF V600E inhibitors. In contrast, the response in patients with high-grade gliomas was intermediate and of short duration, with early tumour progression.

The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) plus radiotherapy in the treatment of lung adenocarcinoma patients with central nervous system metastases: a meta-analysiss / 中国医师杂志

Objective:To systematically evaluate the efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) combined with radiotherapy in the treatment of lung adenocarcinoma with central nervous system (CNS) metastasis.Methods:PubMed, EMBASE, Medline, Cochrane Library, clinical trials and other databases were searched to collect the clinical control studies of EGFR-TKI combined with radiotherapy versus EGFR-TKI or radiotherapy alone in the treatment of lung adenocarcinoma with CNS metastasis published at home and abroad from January 2012 to April 2019. After evaluating the data, Revman 5.3 software was used for meta-analysis.Results:10 studies involving 1 379 participants were included. The results indicated that compared with EGFR-TKI or radiotherapy alone, EGFR-TKI plus radiotherapy had a significant benefit on overall response rate (ORR) [ OR: 3.81, 95% CI(1.73, 8.39); P<0.01], overall survival (OS) [ HR: 0.60, 95% CI(0.41, 0.89); P=0.01], neurological progression free survival (nPFS) [ HR: 0.65, 95% CI(0.46, 0.91); P=0.01] compared with EGFR-TKI or radiotherapy alone. Conclusions:EGFR-TKI plus radiotherapy had better ORR, OS, nPFS compared with TKI or radiotherapy alone.

Clinical, demographic, anatomopathological, and molecular findings in patients with medulloblastoma treated in a single health facility / Achados clínicos, demográficos, anatomopatológicos e moleculares de portadores de meduloblastoma tratados em uma única instituição

ABSTRACT Objective: To describe the clinical, demographic, anatomopathological, molecular, and survival characteristics of patients with medulloblastoma. Methods: Retrospective study based on patient information obtained from the review of medical records. Overall and event-free survival were analyzed using the Kaplan-Meier estimator, and the curves were compared by the log-rank test. Results: Among the patients investigated, 70 were male (66%), and age at diagnosis ranged from 2 months to 22 years. The most frequent signs and symptoms were headache (80.8%) and vomiting (75.8%). Regarding treatment, most patients (63.2%) underwent complete surgical resection, with a predominance of classic histology (63.2%). The 5-year overall survival rate was 67.9%, and the 10-year rate was 64.2%. Patients with molecular profile characteristic of the wingless (WNT) subgroup had a better prognosis, with 5-year overall survival of 75%. Conclusions: The clinical, demographic, anatomopathological, and molecular characteristics of patients with medulloblastoma described in the present study were mostly similar to those reported in the literature. Patients submitted to complete tumor resection had better clinical outcomes than those who underwent incomplete resection/biopsy. Patients classified as high-risk showed worse overall and event-free survival than those in the standard-risk group, and the presence of metastasis at diagnosis was associated with recurrence.

RESUMO Objetivo: Descrever as características clínicas, demográficas, anatomopatológicas, moleculares e de sobrevida de pacientes portadores de meduloblastoma. Métodos: Estudo retrospectivo, no qual as informações dos pacientes foram obtidas pela revisão dos prontuários médicos. Análises de sobrevida global e de sobrevida livre de eventos foram realizadas por meio da construção de curvas de Kaplan-Meier e a comparação entre as curvas foi feita pelo teste log-rank. Resultados: Entre os pacientes analisados, 70 pertenciam ao sexo masculino (66%) e a idade ao diagnóstico variou de dois meses a 22 anos. Os sinais e sintomas de maior frequência foram cefaleia (80,8%) e vômitos (75,8%). Em relação ao tratamento, a maioria (63,2%) dos pacientes foi submetida à ressecção cirúrgica total e apresentava como histologia predominante a forma clássica (63,2%). A taxa de sobrevida global em cinco anos foi de 67,9% e, em 10 anos, de 64,2%. Os pacientes com perfil molecular característico do subgrupo wingless (WNT) apresentaram melhor prognóstico, com sobrevida global em cinco anos de 75%. Conclusões: As características clínicas, demográficas, anatomopatológicas e moleculares dos pacientes com meduloblastoma descritas no presente estudo foram majoritariamente semelhantes às descritas na literatura. Pacientes submetidos à ressecção completa do tumor tiveram melhor evolução clínica do que aqueles com ressecção incompleta/biópsia. Pacientes estratificados como de alto risco apresentaram pior sobrevida global e livre de eventos do que o grupo standard e a presença de metástases ao diagnóstico se mostrou associada à ocorrência de recidiva da doença.

Epidemiología descriptiva y cambios en la frecuencia de tumores astrocíticos en el Instituto Nacional de Neurología y Neurocirugía de México / Descriptive epidemiology and frequency variations of astrocytic tumors in the National Institute of Neurology and Neurosurgery of Mexico

Resumen: Objetivo: Determinar distribución, localización y cambios de la frecuencia de tumores astrocíticos (TA) en un instituto mexicano de neurología. Material y métodos: Se revisaron los registros institucionales de TA de cinco décadas. Se compararon las relaciones TA/egresos quirúrgicos (EQ) y TA/total de tumores del sistema nervioso central (TSNC) de 1995 a 2014. Resultados: Se analizaron 2 287 TA (1 356 en hombres y 931 en mujeres). El glioma más común fue el glioblastoma multiforme (GBM), que estuvo presente en adultos jóvenes con una frecuencia mayor a la reportada en otros estudios. La relación TA/EQ y TA/TNSC fue similar entre 1995 y 2014. Conclusiones: En general, la frecuencia de TA atendidos en el Instituto es similar a la reportada internacionalmente. No obstante, los casos de TA en el subgrupo de adultos jóvenes con GBM son más frecuentes (40%) que las incidencias reportadas en otros estudios (menores al 5%). No se encontró variación significativa en la frecuencia de TA durante las últimas dos décadas.

Abstract: Objective: To determine distribution, localization and frequency variations of astrocytic tumors (AT) in a Mexican Institute of neurology. Materials and methods: Institutional registries of AT from five decades were analyzed. AT/Surgical discharges (SD) and AT/Central Nervous System Tumors (CNST) from 1995 to 2014 were compared. Results: Two thousand two hundred and eighty-seven AT (1 356 men and 931 women) were analyzed. The most common glioma was glioblastoma multiforme (GBM), found in young adults with a higher frequency to that reported in other studies. Relation of AT/SD, as well as, relation of AT/CNST was similar between 1995 and 2014. Conclusions: In general, the frequency of AT attended at the Institute is similar to that found worldwide, being only higher the number of GBM in younger adults. There was not significant variation in the frequency of AT during the time studied.

Central Nervous System Failure in Korean Breast Cancer Patients with HER2-Enriched Subtype: Korean Radiation Oncology Group 16-15 Multicenter Retrospective Study / 한국유방암학회지

PURPOSE: The purpose of this study was to evaluate the risk of central nervous system (CNS) failure in Korean patients with human epidermal growth factor receptor 2 (HER2)-enriched breast cancer treated with surgery followed by postoperative radiotherapy (RT). METHODS: A total of 749 patients from eight institutions were enrolled in this study. All of them underwent surgery followed by postoperative RT from 2003 to 2011; 246 (32.8%) received neoadjuvant chemotherapy and 649 (81.7%) received adjuvant chemotherapy. Adjuvant trastuzumab was administered to 386 patients (48.6%). RESULTS: The median follow-up duration was 84 (range, 8–171) months. The 7-year disease-free and overall survival rates were 79.0% and 84.2%, respectively. On multivariate analysis, mastectomy, nodal involvement, and presence of lymphatic invasion were correlated with poor overall survival (p = 0.004, 0.022, and 0.011, respectively), whereas T stage and lymphatic invasion were associated with disease-free survival (p = 0.018 and 0.005, respectively). Regarding CNS failures, 30 brain metastases, 2 leptomeningeal metastases, and 8 brain and leptomeningeal metastases were noted. The 7-year CNS relapse-free survival rates in patients receiving and not receiving trastuzumab were 91.2% and 96.9%, respectively (p = 0.005). On multivariate analysis, the administration of adjuvant trastuzumab was the only prognostic factor in predicting a higher CNS failure rate (hazard ratio, 2.260; 95% confidence interval, 1.076–4.746; p = 0.031). CONCLUSION: Adjuvant trastuzumab was associated with higher CNS failure rate in Korean patients with HER2-enriched breast cancer. Close monitoring and reasonable approaches such as CNS penetrating HER2 blockades combined with the current standard therapy could contribute to improving intracranial tumor control and quality of life in patients with CNS metastasis from HER2-enriched breast cancer.

Progress of cerebrospinal fluid biomarkers in primary central nervous system lymphoma / 白血病·淋巴瘤

Primary central nervous system lymphoma (PCNSL) is one of the subtypes of non-Hodgkin lymphoma, its most pathological type is diffuse large B-cell lymphoma. At present, the gold standard of PCNSL diagnosis is biopsy and pathological examination, but many patients cannot be diagnosed early due to high risk of puncture, patient compliance problems and lack of specific symptoms. PCNSL is sensitive to chemotherapy, but many patients cannot tolerate high-dose chemotherapy or develop drug resistance, leading to disease progression or recurrence. Therefore, the search and identification of biomarkers in cerebrospinal fluid for early diagnosis, efficacy judgment and prognosis monitoring are particularly important for improving the diagnosis and treatment of PCNSL.

Progress of cerebrospinal fluid biomarkers in primary central nervous system lymphoma / 白血病·淋巴瘤

Primary central nervous system lymphoma (PCNSL) is one of the subtypes of non-Hodgkin lymphoma, its most pathological type is diffuse large B-cell lymphoma. At present, the gold standard of PCNSL diagnosis is biopsy and pathological examination, but many patients cannot be diagnosed early due to high risk of puncture, patient compliance problems and lack of specific symptoms. PCNSL is sensitive to chemotherapy, but many patients cannot tolerate high-dose chemotherapy or develop drug resistance, leading to disease progression or recurrence. Therefore, the search and identification of biomarkers in cerebrospinal fluid for early diagnosis, efficacy judgment and prognosis monitoring are particularly important for improving the diagnosis and treatment of PCNSL.