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1.
J Environ Radioact ; 238-239: 106734, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34521026

RESUMO

BACKGROUND: Exposure to high doses of ionizing radiation is known to cause cancer. Exposure during childhood is associated with a greater excess relative risk for leukemia and tumors of the central nervous system (CNS) than exposure in later life. Cancer risks associated with low-dose exposure (<100 mSv) are uncertain. We previously investigated the association between the incidence of childhood cancer and levels of exposure to external background radiation from terrestrial gamma and cosmic rays in Switzerland using data from a nationwide census-based cohort study. Here, we provide an update of that study using an extended follow-up period and an improved exposure model. METHODS: We included all children 0-15 years of age registered in the Swiss national censuses 1990, 2000, and 2010-2015. We identified incident cancer cases during 1990-2016 using probabilistic record linkage with the Swiss Childhood Cancer Registry. Exposure to terrestrial and cosmic radiation at children's place of residence was estimated using geographic exposure models based on aerial spectrometric gamma-ray measurements. We estimated and included the contribution from 137Cs deposition after the Chernobyl accident. We created a nested case-control sample and fitted conditional logistic regression models adjusting for sex, year of birth, neighborhood socioeconomic position, and modelled outdoor NO2 concentration. We also estimated the population attributable fraction for childhood cancer due to external background radiation. RESULTS: We included 3,401,113 children and identified 3,137 incident cases of cancer, including 951 leukemia, 495 lymphoma, and 701 CNS tumor cases. Median follow-up in the cohort was 6.0 years (interquartile range: 4.3-10.1) and median cumulative exposure since birth was 8.2 mSv (range: 0-31.2). Hazard ratios per 1 mSv increase in cumulative dose of external background radiation were 1.04 (95% CI: 1.01-1.06) for all cancers combined, 1.06 (1.01-1.10) for leukemia, 1.03 (0.98-1.08) for lymphoma, and 1.06 (1.01-1.11) for CNS tumors. Adjustment for potential confounders had little effect on the results. Based on these results, the estimated population attributable fraction for leukemia and CNS tumors due to external background radiation was 32% (7-49%) and 34% (5-51%), respectively. CONCLUSIONS: Our results suggest that background ionizing radiation contributes to the risk of leukemia and CNS tumors in children.


Assuntos
Neoplasias do Sistema Nervoso Central , Monitoramento de Radiação , Criança , Estudos de Coortes , Humanos , Incidência , Radiação Ionizante
2.
Lancet Haematol ; 8(10): e711-e722, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34560014

RESUMO

BACKGROUND: CNS relapse of acute lymphocytic leukaemia is difficult to treat. Durable remissions of relapsed or refractory B-cell acute lymphocytic leukaemia have been observed following treatment with CD19-directed chimeric antigen receptor (CAR) T cells; however, most trials have excluded patients with active CNS disease. We aimed to assess the safety and activity of CAR T-cell therapy in patients with a history of CNS relapsed or refractory B-cell acute lymphocytic leukaemia. METHODS: In this post-hoc analysis, we included 195 patients (aged 1-29 years; 110 [56%] male and 85 [44%] female) with relapsed or refractory CD19-positive acute lymphocytic leukaemia or lymphocytic lymphoma from five clinical trials (Pedi CART19, 13BT022, ENSIGN, ELIANA, and 16CT022) done at the Children's Hospital of Philadelphia (Philadelphia, PA, USA), in which participants received CD19-directed CAR T-cell therapy between April 17, 2012, and April 16, 2019. The trials required control of CNS disease at enrolment and infusion and excluded treatment in the setting of acute neurological toxic effects (>grade 1 in severity) or parenchymal lesions deemed to increase the risk of neurotoxicity. 154 patients from Pedi CART19, ELIANA, ENSIGN, and 16CT022 received tisagenlecleucel and 41 patients from the 13BT022 trial received the humanised CD19-directed CAR, huCART19. We categorised patients into two strata on the basis of CNS status at relapse or within the 12 months preceding CAR T-cell infusion-either CNS-positive or CNS-negative disease. Patients with CNS-positive disease were further divided on the basis of morphological bone marrow involvement-either combined bone marrow and CNS involvement, or isolated CNS involvement. Endpoints were the proportion of patients with complete response at 28 days after infusion, Kaplan-Meier analysis of relapse-free survival and overall survival, and the incidence of cytokine release syndrome and neurotoxicity. FINDINGS: Of all 195 patients, 66 (34%) were categorised as having CNS-positive disease and 129 (66%) as having CNS-negative disease, and 43 (22%) were categorised as having isolated CNS involvement. The median length of follow-up was 39 months (IQR 25-49) in the CNS-positive stratum and 36 months (18-49) in the CNS-negative stratum. The proportion of patients in the CNS-positive stratum with a complete response at 28 days after infusion was similar to that in the CNS-negative stratum (64 [97%] of 66 vs 121 [94%] of 129; p=0·74), with no significant difference in relapse-free survival (60% [95% CI 49-74] vs 60% [51-71]; p=0·50) or overall survival (83% [75-93] vs 71% [64-79]; p=0·39) at 2 years between the two groups. Overall survival at 2 years was significantly higher in patients with isolated CNS involvement compared with those with bone marrow involvement (91% [82-100] vs 71% [64-78]; p=0·046). The incidence and severity of neurotoxicity (any grade, 53 [41%] vs 38 [58%]; grade 1, 24 [19%] vs 20 [30%]; grade 2, 14 [11%] vs 10 [15%]; grade 3, 12 [9%] vs 6 [9%], and grade 4, 3 [2%] vs 2 [3%]; p=0·20) and cytokine release syndrome (any grade, 110 [85%] vs 53 [80%]; grade 1, 12 [9%] vs 2 [3%]; grade 2, 61 [47%] vs 38 [58%]; grade 3, 18 [14%] vs 7 [11%] and grade 4, 19 [15%] vs 6 [9%]; p=0·26) did not differ between the CNS-negative and the CNS-positive disease strata. INTERPRETATION: Tisagenlecleucel and huCART19 are active at clearing CNS disease and maintaining durable remissions in children and young adults with CNS relapsed or refractory B-cell acute lymphocytic leukaemia or lymphocytic lymphoma, without increasing the risk of severe neurotoxicity; although care should be taken in the timing of therapy and disease control to mitigate this risk. These preliminary findings support the use of these CAR T-cell therapies for patients with CNS relapsed or refractory B-cell acute lymphocytic leukaemia. FUNDING: Children's Hospital of Philadelphia Frontier Program.


Assuntos
Antígenos CD19/imunologia , Neoplasias do Sistema Nervoso Central/terapia , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Neoplasias do Sistema Nervoso Central/imunologia , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Receptores de Antígenos Quiméricos/imunologia , Recidiva , Adulto Jovem
3.
J Biomed Nanotechnol ; 17(8): 1459-1485, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34544527

RESUMO

Primary central nervous system lymphoma (PCNSL) is a rare but highly aggressive subtype of extra nodal non-Hodgkin lymphoma (NHL), which is confined in the central nervous system (CNS). Despite recent advancements in treatment options, the overall prognosis of PCNSL remains poor. Among many unfavorable factors affecting efficacy, inadequate drug delivery into the CNS is still the thorniest challenge. Blood-brain barrier (BBB) constitutes a significant impediment, restricting entry of most therapeutics to the brain. Nanotechnology has offered great promise for brain diseases, as various nano-based drug delivery systems (NDDSs) have been developed for delivery of theranostic agents in to the CNS. These drug delivery systems possess significant advantages, including good feasibility, reliable safety profile, excellent BBB penetration and potent antitumor effects. As for treatment of PCNSL, numerous well-developed BBB-crossing nano-based strategies can be applied with proper modifications and improvements. Some exquisitely designed NDDSs specific for PCNSL have shown great potential. In this review, we provide a summary on current status of diagnosis and treatment of PCNSL, followed by an overview of BBB-crossing strategies applied in management of PCNSL, both novel and wellestablished. Finally, challenges and future perspectives in this field are also discussed.


Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma não Hodgkin , Barreira Hematoencefálica , Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Humanos , Nanomedicina
4.
BMJ Case Rep ; 14(9)2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34518180

RESUMO

Primary central nervous system lymphoma (PCNSL) is infrequent and often poses diagnostic conundrums due to its protean manifestations. We present the case of a South Asian young man presenting with raised intracranial pressure and a lymphocytic cerebrospinal fluid (CSF) with pronounced hypoglycorrhachia. Progression of the neuro-ophthalmic signs while on early stages of antitubercular treatment led to additional investigations that produced a final diagnosis of primary leptomeningeal lymphoma. Treatment with chemoimmunotherapy (methotrexate, cytarabine, thiotepa and rituximab (MATRix)) achieved full radiological remission followed by successful autologous transplant. This case highlights the difficulties and diagnostic dilemmas when PCNSL presents as a chronic meningeal infiltrative process. While contextually this CSF is most often indicative of central nervous system tuberculosis and justifies empirical treatment initiation alone, it is essential to include differential diagnoses in the investigation work-up, which also carry poor prognosis without timely treatment. High suspicion, multidisciplinary collaboration and appropriate CSF analysis were the key for a correct diagnosis.


Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma não Hodgkin , Tuberculose Meníngea , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Masculino , Tiotepa/uso terapêutico , Tuberculose Meníngea/diagnóstico
9.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(4): 1175-1180, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34362499

RESUMO

OBJECTIVE: To investigate the clinical efficacy of high dose methotrexate (HD-MTX), temozolomide (TMZ), and rituximab (R) in the treatment of patients with primary central nervous system lymphoma (PCNSL). METHODS: Clinical data of patients with PCNSL diagnosed and treated in Guangdong Provincial People's Hospital from February 2010 to May 2017 were collected. First, patients were given 6-8 cycles of MTX (3.5 g/m2) for induction treatment, and then 12 cycles of TMZ (150 mg/m2) for maintenance treatment. The day before induction treatment, patients were given rituximab 375 mg/m2 according to their economic status. A retrospective cohort study was performed on patients receiving HD-MTX+TMZ or HD-MTX+TMZ+R to analyze the efficacy and survival. RESULTS: There were 42 patients enrolled in the study, 17 cases in HD-MTX+TMZ group and 25 cases in HD-MTX+TMZ+R group. The median PFS and OS times in HD-MTX+TMZ+R group were 56.7 months and N/A, respectively, while, 7.3 months and 34.7 months in HD-MTX+TMZ group, respectively. In addition, there was no significant difference in median survival between patients who received TMZ maintenance therapy and those who were only actively monitored. During the induction period, all the patients had grade 1-2 nausea and vomiting, while in the consolidation treatment period, no grade 3/4 toxicity was observed. CONCLUSION: The combination of HD-MTX+TMZ+R in the treatment of PCNSL patients shows a definite short-term effect, which can increase the survival rate of the patients. The side effects are mild, and the patients can generally tolerate.


Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma não Hodgkin , Protocolos de Quimioterapia Combinada Antineoplásica , Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Metotrexato/uso terapêutico , Estudos Retrospectivos , Rituximab/uso terapêutico , Temozolomida/uso terapêutico , Resultado do Tratamento
10.
Zhonghua Bing Li Xue Za Zhi ; 50(8): 876-881, 2021 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-34344070

RESUMO

Objective: To investigate the clinicopathological features, diagnosis and prognosis of diffuse leptomeningeal glioneuronal tumor (DLGNT). Methods: Five cases of DLGNT diagnosed from January 2016 to January 2020 were collected from Xuanwu Hospital, Capital Medical University. The clinical features, histopathologic characteristics, immunohistochemical and molecular genetic findings and prognosis were analyzed and the relevant literature was reviewed. Results: The five patients (two males and three females) were aged 2 to 52 years (median 11 years), and had history of increased intracranial pressure (headache and vomiting) or limb weakness. Three of them were younger than 16 years of age. The imaging studies showed diffuse intracranial and intraspinal nodular leptomeningeal thickening and enhancement, with or without parenchymal involvement. At times there were associated small cyst-like lesions. Imaging interpretations were inflammatory lesions in three cases and space occupying lesions in two. Microscopically, in three cases the tumors showed low to moderate cellularity, consisting of relatively monomorphous oligodendrocyte-like cells arranged in small nests or diffusely distribution. No mitosis and necrosis were observed. In two cases there were increased cellularity with a diffuse honeycomb pattern. The tumor showed mild to moderate polymorphism with hyperchromatic nuclei. Mitosis, endothelial vascular proliferation and glomeruloid vessels were seen. Necrosis was absent. The tumor cells in all five cases were positive for synaptophysin,Olig2 and negative for IDH1 and H3 K27M. GFAP was focally positive in four cases and only one case expressed NeuN partly. The Ki-67 labeling index was 1%-35%. BRAF fusion was detected in four cases. Genetic analysis showed solitary 1p deletion in two cases (2/5), while all cases were negative for 1p/19q co-deletion (0/5). The five patients were followed up for 13 to 28 months (median 15 month). One patient died after 27 months. There was no evidence of tumor progression in the remaining four patients. Conclusions: DLGNT is rare and easily confused with other central nervous system tumors and inflammatory lesions. Therefore, the diagnosis of DLGNT should be made based on comprehensive information including imaging, morphologic and corresponding immunohistochemical examinations and molecular genetics to avoid misdiagnosis and delay in management.


Assuntos
Neoplasias do Sistema Nervoso Central , Neoplasias Meníngeas , Oligodendroglioma , Neoplasias do Sistema Nervoso Central/genética , Feminino , Testes Genéticos , Humanos , Masculino , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/genética , Meninges , Oligodendroglioma/genética
12.
Cell Mol Life Sci ; 78(17-18): 6161-6200, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34333711

RESUMO

Despite advances in the understanding of the molecular mechanisms underlying the basic biology and pathogenesis of pediatric central nervous system (CNS) malignancies, patients still have an extremely unfavorable prognosis. Over the years, a plethora of natural and synthetic compounds has emerged for the pharmacologic intervention of the NF-kB pathway, one of the most frequently dysregulated signaling cascades in human cancer with key roles in cell growth, survival, and therapy resistance. Here, we provide a review about the state-of-the-art concerning the dysregulation of this hub transcription factor in the most prevalent pediatric CNS tumors: glioma, medulloblastoma, and ependymoma. Moreover, we compile the available literature on the anti-proliferative effects of varied NF-kB inhibitors acting alone or in combination with other therapies in vitro, in vivo, and clinical trials. As the wealth of basic research data continues to accumulate, recognizing NF-kB as a therapeutic target may provide important insights to treat these diseases, hopefully contributing to increase cure rates and lower side effects related to therapy.


Assuntos
Neoplasias do Sistema Nervoso Central/patologia , NF-kappa B/metabolismo , 2-Metoxiestradiol/química , 2-Metoxiestradiol/metabolismo , 2-Metoxiestradiol/uso terapêutico , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/metabolismo , Criança , Glioma/metabolismo , Glioma/patologia , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Humanos , Meduloblastoma/metabolismo , Meduloblastoma/patologia , NF-kappa B/antagonistas & inibidores , Proteínas Wnt/antagonistas & inibidores , Proteínas Wnt/metabolismo
14.
J Int Med Res ; 49(8): 3000605211035197, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34461767

RESUMO

Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma, but its diagnosis is challenging in some cases. A brain biopsy is the gold standard for diagnosing PCNSL, but its invasiveness can be problematic. Thus, noninvasive imaging examinations have been developed for the pre-surgical diagnosis of PCNSL, including gadolinium-enhanced magnetic resonance imaging (MRI), 123I-N-isopropyl-p-iodoamphetamine single-photon emission computed tomography (123I-IMP SPECT), and positron emission tomography with 18F-fluorodeoxyglucose (18F-FDG PET). Here, we report the case of a 71-year-old woman with negative imaging findings for PCNSL, but who was diagnosed with PCNSL by a brain biopsy and histological analysis. Her imaging results were negative for gadolinium-enhanced cranial MRI, with low uptake in 123I-IMP SPECT and hypometabolism in 18F-FDG PET. However, a stereotactic brain biopsy from an abnormal lesion revealed that many round cells had infiltrated into the brain. Moreover, many infiltrating cells were positive for cluster of differentiation (CD)20 and CD79a, and proliferation marker protein Ki-67-positive cells accounted for nearly 80% of all cells. Based on these results, our final pathological diagnosis was PCNSL. The present case highlights the possibility of a PCNSL diagnosis even when all imaging-related examinations display negative results.


Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma não Hodgkin , Linfoma , Idoso , Biópsia , Encéfalo/diagnóstico por imagem , Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Feminino , Fluordesoxiglucose F18 , Humanos , Linfoma não Hodgkin/diagnóstico por imagem , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X
15.
Int J Clin Oncol ; 26(10): 1805-1811, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34236556

RESUMO

BACKGROUND: Addition of cytarabine to high-dose methotrexate (HD-MTX) chemotherapy improves outcome of primary CNS lymphoma (PCNSL); however, the combination therapy increases toxicity. Sequential chemotherapy and cranial radiation may decrease toxicity without altering efficacy. METHODS: This was a single-center, retrospective cohort study of consecutive newly diagnosed immunocompetent PCNSL patients treated with HD-MTX (5 cycles of 3 g/m2 every 2 weeks) followed by consolidation whole-brain radiotherapy (WBRT) and cytarabine (2 cycles of 3 g/m2/d for 2 days every 3 weeks) from January 2013 to December 2020. Initial WBRT before HD-MTX was allowed in patients with significant disability or brain edema at presentation. Primary outcome was progression-free survival (PFS). Key secondary outcomes were response rate, treatment-related toxicity, and overall survival (OS). RESULTS: Of 41 patients, 25 patients had a complete response (CR) and ten patients had a partial response, inferring an overall response rate (ORR) of 85.4% and a CR rate of 60.9%. More than 90% of patients were able to tolerate and complete the HD-MTX. The incidence of ≥ grade 3 hematologic and non-hematologic toxicities were 4.8% and 17.1%, respectively. Treatment-related mortality rate was 2.4%. There was no difference in toxicity between patients with age < 60 and ≥ 60 years. At the median follow-up duration of 39.8 months, the median PFS was 35.2 months (95% CI 12.4-69.3) and median OS was 46.5 months (95% CI 21.8-NR). CONCLUSION: High-dose methotrexate followed by consolidation whole-brain radiotherapy and cytarabine has acceptable efficacy, great tolerability, and low toxicity in newly diagnosed PCNSL patients.


Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Encéfalo , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/radioterapia , Estudos de Coortes , Citarabina/efeitos adversos , Humanos , Linfoma/tratamento farmacológico , Linfoma/radioterapia , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
16.
Cancer Sci ; 112(10): 3953-3961, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34327781

RESUMO

Intravascular large B-cell lymphoma is a rare disease of the large B cells characterized by selective growth in the lumina of small vessels in systemic organs. Since first reported in 1959, the difficulty of obtaining sufficient tumor cells from biopsy specimens has hampered the elucidation of its underlying biology. Recent progress using xenograft models and plasma cell-free DNA has uncovered genetic features that are similar to those of activated B-cell type diffuse large B-cell lymphoma, including MYD88 and CD79B mutations and frequent alterations in immune check point-related genes such as PD-L1 and PD-L2. Given the improvement in clinical outcomes and a higher risk of secondary central nervous system (CNS) involvement in the rituximab era, a phase 2 trial of R-CHOP combined with high-dose methotrexate and intrathecal chemotherapy as a CNS-oriented therapy has been conducted. This trial, the PRIMEUR-IVL study, has displayed good progression-free survival and a low cumulative incidence of secondary CNS involvement. Long-term follow-up within this trial is still ongoing. Further understanding of the pathophysiology of the disease and improvements in clinical outcomes are still needed.


Assuntos
Linfoma Difuso de Grandes Células B , Neoplasias Vasculares , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/genética , Pontos de Checagem do Ciclo Celular/genética , Neoplasias do Sistema Nervoso Central/prevenção & controle , Ensaios Clínicos Fase II como Assunto , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Previsões , Xenoenxertos , Humanos , Injeções Espinhais , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Transplante de Neoplasias , Prednisona/uso terapêutico , Proteína 2 Ligante de Morte Celular Programada 1/genética , Intervalo Livre de Progressão , Rituximab/uso terapêutico , Neoplasias Vasculares/diagnóstico por imagem , Neoplasias Vasculares/tratamento farmacológico , Neoplasias Vasculares/genética , Neoplasias Vasculares/patologia , Vincristina/uso terapêutico
17.
Pediatr Clin North Am ; 68(4): 811-824, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34247711

RESUMO

This article provides general principles of managing children with central nervous system tumors. The distribution, diagnostic work-up, and key principles of treatment are reviewed, and special circumstances that may be encountered by pediatricians in the community are discussed.


Assuntos
Neoplasias Encefálicas/terapia , Neoplasias do Sistema Nervoso Central/terapia , Oncologia/normas , Atenção Primária à Saúde/normas , Neoplasias da Medula Espinal/terapia , Criança , Humanos , Pediatria/normas
18.
Neurol Clin ; 39(3): 829-845, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34215389

RESUMO

Central nervous system (CNS) tumors are the most common solid tumor in pediatrics and represent the largest cause of childhood cancer-related mortality. With advances in molecular characterization of tumors, considerable developments have occurred impacting diagnosis and management, and refined prognostication. Advances in management have led to better survival, but mortality remains high and significant morbidity persists. Novel therapeutic approaches targeting the biology of these tumors are being investigated to improve overall survival and decrease treatment-related morbidity. Further molecular understanding of pediatric CNS tumors will lead to continued refinement of tumor classification, management, and prognostication.


Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Pediatria , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/terapia , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias do Sistema Nervoso Central/terapia , Criança , Humanos
20.
Oncoimmunology ; 10(1): 1932365, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34235002

RESUMO

The interaction of CNS tumors with infiltrating lymphocytes plays an important role in their initiation and progression and might be related to therapeutic responses. Gene expression-based methods have been successfully used to characterize the tumor microenvironment. However, methylation data are now increasingly used for molecular diagnostics and there are currently only few methods to infer information about the microenvironment from this data type. Using an approach based on differential methylation and principal component analysis, we developed DIMEimmune (Differential Methylation Analysis for Immune Cell Estimation) to estimate CD4+ and CD8+ T cell abundance as well as tumor-infiltrating lymphocytes (TILs) scores from bulk methylation data. Well-established approaches based on gene expression data and immunohistochemistry-based lymphocyte counts were used as benchmarks. The comparison of DIMEimmune to the previously published MethylCIBERSORT and MeTIL algorithms showed an improved correlation with both gene expression-based and immunohistological results across different brain tumor types. Further, we applied our method to large datasets of glioma, medulloblastoma, atypical teratoid/rhabdoid tumors (ATRTs) and ependymoma. High-grade gliomas showed higher scores of tumor-infiltrating lymphocytes than lower-grade gliomas. There were overall only few tumor-infiltrating lymphocytes in medulloblastoma subgroups. ATRTs were highly infiltrated by lymphocytes, most prominently in the MYC subgroup. DIMEimmune-based estimates of TILs were a significant prognostic factor in the overall cohort of gliomas and medulloblastomas, but not within methylation-based diagnostic subgroups. To conclude, DIMEimmune allows for robust estimates of TIL abundance and might contribute to establishing them as a prognostic or predictive factor in future studies of CNS tumors.


Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Glioma , Neoplasias Encefálicas/genética , Neoplasias do Sistema Nervoso Central/genética , Metilação de DNA/genética , Glioma/genética , Humanos , Linfócitos do Interstício Tumoral , Microambiente Tumoral/genética
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