RESUMO
BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. METHODS: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. FINDINGS: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. INTERPRETATION: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. FUNDING: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.
Assuntos
Proteínas de Ligação a DNA , Síndromes Neoplásicas Hereditárias , Humanos , Masculino , Feminino , Criança , Pré-Escolar , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Estudos Transversais , Adolescente , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/epidemiologia , Reparo de Erro de Pareamento de DNA , Estudos Longitudinais , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/mortalidade , Incidência , Proteína 2 Homóloga a MutS/genética , Proteína 1 Homóloga a MutL/genética , Adulto , Adulto Jovem , MutaçãoRESUMO
Medulloblastoma is the most common malignant brain tumor in childhood. Initial treatment generally includes surgery, irradiation, and chemotherapy. Approximately 20-30% of patients will experience a recurrence, which portends a very poor prognosis. The current standard of care for evaluation for relapse includes radiographic surveillance with magnetic resonance imaging at regular intervals. The presence of circulating tumor DNA in the cerebrospinal fluid has been demonstrated to be a predictor of a higher risk of progression in a research setting for patients with medulloblastoma treated on a prospective single institution clinical trial. We have previously published and clinically validated a liquid-biopsy-based genetic assay utilizing low-pass whole genome sequencing to detect copy number alterations in circulating tumor DNA. Here, we present two teenage patients with posterior fossa medulloblastoma with recurrent disease who have been monitored with serial liquid biopsies showing tumor evolution over time, demonstrating the clinical utility of these approaches.
Assuntos
Neoplasias Cerebelares , Meduloblastoma , Recidiva Local de Neoplasia , Humanos , Meduloblastoma/líquido cefalorraquidiano , Meduloblastoma/genética , Meduloblastoma/diagnóstico , Meduloblastoma/patologia , Meduloblastoma/diagnóstico por imagem , Biópsia Líquida/métodos , Recidiva Local de Neoplasia/líquido cefalorraquidiano , Recidiva Local de Neoplasia/genética , Adolescente , Neoplasias Cerebelares/líquido cefalorraquidiano , Neoplasias Cerebelares/diagnóstico , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/genética , Masculino , DNA Tumoral Circulante/líquido cefalorraquidiano , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/sangue , Feminino , Progressão da Doença , Imageamento por Ressonância MagnéticaRESUMO
PURPOSE: To develop an MR multitasking-based dynamic imaging for cerebrovascular evaluation (MT-DICE) technique for simultaneous quantification of permeability and leakage-insensitive perfusion with a single-dose contrast injection. METHODS: MT-DICE builds on a saturation-recovery prepared multi-echo fast low-angle shot sequence. The k-space is randomly sampled for 7.6 min, with single-dose contrast agent injected 1.5 min into the scan. MR multitasking is used to model the data into six dimensions, including three spatial dimensions for whole-brain coverage, a saturation-recovery time dimension, and a TE dimension for dynamic T 1 $$ {\mathrm{T}}_1 $$ and T 2 * $$ {\mathrm{T}}_2^{\ast } $$ quantification, respectively, and a contrast dynamics dimension for capturing contrast kinetics. The derived pixel-wise T 1 / T 2 * $$ {\mathrm{T}}_1/{\mathrm{T}}_2^{\ast } $$ time series are converted into contrast concentration-time curves for calculation of kinetic metrics. The technique was assessed for its agreement with reference methods in T 1 $$ {\mathrm{T}}_1 $$ and T 2 * $$ {\mathrm{T}}_2^{\ast } $$ measurements in eight healthy subjects and, in three of them, inter-session repeatability of permeability and leakage-insensitive perfusion parameters. Its feasibility was also demonstrated in four patients with brain tumors. RESULTS: MT-DICE T 1 / T 2 * $$ {\mathrm{T}}_1/{\mathrm{T}}_2^{\ast } $$ values of normal gray matter and white matter were in excellent agreement with reference values (intraclass correlation coefficients = 0.860/0.962 for gray matter and 0.925/0.975 for white matter ). Both permeability and perfusion parameters demonstrated good to excellent intersession agreement with the lowest intraclass correlation coefficients at 0.694. Contrast kinetic parameters in all healthy subjects and patients were within the literature range. CONCLUSION: Based on dynamic T 1 / T 2 * $$ {\mathrm{T}}_1/{\mathrm{T}}_2^{\ast } $$ mapping, MT-DICE allows for simultaneous quantification of permeability and leakage-insensitive perfusion metrics with a single-dose contrast injection.
Assuntos
Meios de Contraste , Imageamento por Ressonância Magnética , Humanos , Imageamento por Ressonância Magnética/métodos , Perfusão , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , PermeabilidadeRESUMO
PURPOSE: Primary germ cell tumors (GCTs) are the most common central nervous system (CNS) neoplasm in patients with Down syndrome (DS). However, a standard of care has not been established due to paucity of data. METHODS: A retrospective multi-institutional analysis was conducted, in addition to a comprehensive review of the literature. RESULTS: Ten patients from six institutions (five USA, one Brazil) were identified, in addition to 31 patients in the literature from 1975 to 2021. Of the 41 total patients (mean age 9.9 years; 61% male), 16 (39%) had non-germinomatous germ cell tumors (NGGCTs), 16 (39%) had pure germinomas, and eight (19.5%) had teratomas. Basal ganglia was the most common tumor location (n = 13; 31.7%), followed by posterior fossa (n = 7; 17%). Nine patients (22%) experienced disease relapse or progression, of which four died from tumor progression (one germinoma, three teratomas). Sixteen patients (39%) experienced treatment-related complications, of which eight (50%) died (five germinomas, three NGGCTs). Of the germinoma patients, two died from chemotherapy-related sepsis, one from postsurgery cardiopulmonary failure, one from pneumonia, and one from moyamoya following radiation therapy (RT). Of the NGGCT patients, one died from chemotherapy-related sepsis, one from postsurgical infection, and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival was 66% for all histological types: 62% germinomas, 79% for NGGCTs, and 53% for teratomas. CONCLUSION: Patients with DS treated for CNS GCTs are at an increased risk of treatment-related adverse events. A different therapeutic approach may need to be considered to mitigate treatment-related complications and long-term neurocognitive sequelae.
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Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Síndrome de Down , Germinoma , Neoplasias Embrionárias de Células Germinativas , Glândula Pineal , Sepse , Teratoma , Neoplasias Encefálicas/patologia , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/terapia , Criança , Síndrome de Down/complicações , Feminino , Germinoma/patologia , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/complicações , Neoplasias Embrionárias de Células Germinativas/terapia , Glândula Pineal/patologia , Estudos Retrospectivos , Neoplasias TesticularesRESUMO
BACKGROUND: Central nervous system (CNS) germinomas are treatment-sensitive tumors with excellent survival outcomes. Current treatment strategies combine chemotherapy with radiotherapy (RT) in order to reduce the field and dose of RT. Germinomas originating in the basal ganglia/thalamus (BGTGs) have proven challenging to treat given their rarity and poorly defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have all been utilized; however, the best treatment strategy remains unclear. METHODS: Retrospective multi-institutional analysis has been conducted across 18 institutions in four countries. RESULTS: For 43 cases of nonmetastatic BGTGs, the 5- and 10-year event-free survivals (EFS) were 85.8% and 81.0%, respectively, while the 5- and 10-year overall survivals (OS) were 100% and 95.5%, respectively (one patient fatality from unrelated cause). Median RT doses were as follows: CSI: 2250 cGy/cGy(RBE) (1980-2400); WBI: 2340 cGy/cGy(RBE) (1800-3000); WVI: 2340 cGy/cGy(RBE) (1800-2550); focal: 3600 cGy (3060-5400). Thirty-eight patients (90.5%) received chemotherapy. There was no statistically significant difference in the EFS based on initial field extent (p = .84). Nevertheless, no relapses were reported in patients who received CSI or WBI. Chemotherapy alone had significantly inferior EFS compared to combined therapy (p = .0092), but patients were salvageable with RT. CONCLUSION: Patients with BGTGs have excellent outcomes and RT proved to be an integral component of the treatment plan. This group of patients should be included in future prospective clinical trials and the best RT field should be investigated further.
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Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Germinoma , Gânglios da Base/patologia , Neoplasias Encefálicas/radioterapia , Germinoma/radioterapia , Humanos , Recidiva Local de Neoplasia , Dosagem Radioterapêutica , Estudos Retrospectivos , Tálamo/diagnóstico por imagemRESUMO
Intradural extramedullary peripheral primitive neuroectodermal tumor (pPNET) with t(11;22) is a rare clinical finding in the pediatric population with few published cases in the literature. The authors report 3 cases of intradural primary pPNET and discuss the clinical presentation, treatment, and survival of the patients. Clinicians should be vigilant in considering pPNET in the differential diagnosis of extradural masses. The authors also compare the clinical course and outcome of therapy with primary PNET of the central nervous system and Ewing sarcoma family of tumors. In addition, this report highlights the risk for leptomeningeal dissemination at recurrence and discusses the importance of central nervous system-targeted therapy for durable disease control.
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Neoplasias Ósseas/diagnóstico , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 22/genética , Tumores Neuroectodérmicos Primitivos/diagnóstico , Sarcoma de Ewing/diagnóstico , Neoplasias da Coluna Vertebral/diagnóstico , Translocação Genética , Adolescente , Adulto , Neoplasias Ósseas/genética , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Tumores Neuroectodérmicos Primitivos/genética , Prognóstico , Sarcoma de Ewing/genética , Neoplasias da Coluna Vertebral/genéticaRESUMO
INTRODUCTION: Medulloblastoma is a malignant embryonal tumor of the cerebellum that occurs predominantly in children. To find germline genetic variants associated with medulloblastoma risk, we conducted a genome-wide association study (GWAS) including 244 medulloblastoma cases and 247 control subjects from Sweden and Denmark. METHODS: Genotyping was performed using Illumina BeadChips, and untyped variants were imputed using IMPUTE2. RESULTS: Fifty-nine variants in 11 loci were associated with increased medulloblastoma risk (p < 1 × 10-5), but none were statistically significant after adjusting for multiple testing (p < 5 × 10-8). Thirteen of these variants were genotyped, whereas 46 were imputed. Genotyped variants were further investigated in a validation study comprising 249 medulloblastoma cases and 629 control subjects. In the validation study, rs78021424 (18p11.23, PTPRM) was associated with medulloblastoma risk with OR in the same direction as in the discovery cohort (ORT = 1.59, pvalidation = 0.02). We also selected seven medulloblastoma predisposition genes for investigation using a candidate gene approach: APC, BRCA2, PALB2, PTCH1, SUFU, TP53, and GPR161. The strongest evidence for association was found for rs201458864 (PALB2, ORT = 3.76, p = 3.2 × 10-4) and rs79036813 (PTCH1, ORA = 0.42, p = 2.6 × 10-3). CONCLUSION: The results of this study, including a novel potential medulloblastoma risk loci at 18p11.23, are suggestive but need further validation in independent cohorts.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Cerebelares/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Meduloblastoma/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Neoplasias Cerebelares/patologia , Estudos de Coortes , Genótipo , Humanos , Meduloblastoma/patologia , PrognósticoRESUMO
Primary diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare tumors, recently recognized as a unique entity based on their unique pathologic and clinical characteristics. We report three cases of DLGNT and compare their clinical characteristics and presentation with other reported cases, and with primary leptomeningeal gliomatosis. Because their prognosis is better than that of diffuse leptomeningeal gliomatosis, and pathologic diagnosis may be difficult, clinicians should consider this diagnosis in patients who present with new neurological symptoms, hydrocephalus and diffuse leptomeningeal enhancement on MRI. Further studies are required to better understand the unique biological characteristics of these tumors and to improve therapy.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Imageamento por Ressonância Magnética , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Neoplasias Meníngeas/terapiaRESUMO
PURPOSE: Irradiation-avoiding strategies have been used with relative success in the treatment of infants and young children with medulloblastoma. While advances in cancer genomics have significantly improved our understanding of the tumor biology of medulloblastoma allowing for improved prognostication and risk-stratification, the molecular subgroup-specific outcomes of infants and young children with medulloblastoma treated with irradiation-avoiding strategies remains unknown. METHODS: Molecular and clinical features of children with medulloblastoma treated with irradiation-avoiding strategies at Children's Hospital Los Angeles were analyzed. Molecular subgrouping of these patients was determined using a 31-gene TaqMan Low Density Array signature. Survival analyses were conducted based on 3 molecular subgroups (SHH, Group 3, and Group 4). RESULTS: Twenty-eight patients with medulloblastoma received irradiation-sparing regimens and were included in this analysis. Patients were divided into SHH (n = 16), Group 3 (n = 3) and Group 4 subgroups (n = 9). Subgroup specific 5-year progression-free and overall survival was 81.2% (95% CI 52.5-93.5) and 93.7% (95% CI 63.2-99.1) for SHH, 0% and 0% for Group 3 and 0% and 44.4% (95% CI 13.6-71.9) for Group 4. CONCLUSION: The majority of young children with SHH-subgroup medulloblastoma can be treated effectively with irradiation-sparing regimens. Our results support the use of chemotherapy-only strategies for upfront treatment of young children with SHH medulloblastoma, while demonstrating the urgent need for intensification/augmentation of treatment for patients with group 3/4 medulloblastoma.
Assuntos
Neoplasias Cerebelares/diagnóstico , Neoplasias Cerebelares/radioterapia , Meduloblastoma/diagnóstico , Meduloblastoma/cirurgia , Neoplasias Cerebelares/genética , Criança , Pré-Escolar , Humanos , Lactente , Meduloblastoma/genética , Patologia Molecular , Prognóstico , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: Germ cell tumors (GCT) arising from non-midline structures (basal ganglia, thalamus, and posterior fossa) are rare. Although patients with midline (pineal and suprasellar) germinoma have excellent survival with chemotherapy and whole ventricular irradiation (WVI), germinoma in non-midline locations have traditionally been treated with craniospinal irradiation (CSI) or whole brain irradiation (WBI) to achieve similar outcomes. However, CSI and WBI are associated with significant long-term neuropsychological sequelae. METHODS: We describe the clinical and neuropsychological outcomes of patients with non-midline germinoma treated at the Children's Hospital Los Angeles between 1990 and 2015. RESULTS: Nine patients had basal ganglia/thalamic germinoma and one patient had a cerebellar primary. Eight patients received chemotherapy followed by reduced dose/volume irradiation, whereas two patients received chemotherapy alone as upfront therapy. One patient in the chemotherapy alone group relapsed after 4.3 years and was salvaged with CSI plus boost. The overall survival for the entire cohort was 100% at a median follow-up of 8.5 years. Neuropsychological data were available for six patients at a median of five months (baseline) and 4.2 years (follow-up) post-diagnosis. At four-year follow-up, data available revealed intact overall cognitive ability, verbal memory, and executive functioning, but persistent deficits in fine motor function. Comparison of baseline to follow-up suggests a downward trend in working memory, planning/problem-solving, verbal memory, and visuospatial integration. CONCLUSION: Chemotherapy followed by reduced dose/volume of irradiation is an effective strategy resulting in long-term survival in patients with non-midline germinoma. Neuropsychological data suggest relatively minimal morbidity over time.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Nervoso Central/terapia , Quimiorradioterapia/efeitos adversos , Irradiação Craniana/efeitos adversos , Germinoma/terapia , Doenças do Sistema Nervoso/patologia , Adolescente , Adulto , Neoplasias do Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Feminino , Seguimentos , Germinoma/patologia , Humanos , Masculino , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/psicologia , Testes Neuropsicológicos , Prognóstico , Dosagem Radioterapêutica , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: For several types of cancer, biological differences and outcome disparities have been documented in adolescents/young adults (AYAs, 15-39 years old) versus children. This study compared clinicopathological features and survival between younger AYAs and children with low-grade glioma (LGG), a common brain tumor among AYAs. METHODS: This was a secondary analysis of Children's Oncology Group legacy study CCG-9891/POG-9130, which enrolled participants 0-21 years of age with newly-diagnosed LGG treated with surgery alone. For analysis, participants were categorized as children (0-14 years old) or early AYAs (eAYAs, 15-21 years old) and compared on demographics, clinical presentation, tumor characteristics, surgical outcomes, progression-free survival (PFS) and overall survival (OS). RESULTS: Among 468 children and 50 eAYAs, more eAYAs presented with seizures (34.0% vs. 19.2%; p = 0.015), without other significant differences in clinicopathological features. 5-year PFS rates for children and eAYA were 80.2% (95% confidence interval [95% CI], 76.1-83.7) and 83.0% (95% CI 68.8-91.1), respectively; 5-year OS rates were 97.3% (95% CI 95.2-98.5) and 95.4% (95% CI 82.7-98.8), respectively. Multivariable analysis including all participants showed presence of residual tumor to be an independent predictor of PFS (< 1.5 cm3, hazard ratio [HR] 5.93 [95% CI 3.45-10.18]) and (≥ 1.5 cm3, HR 8.38 [95% CI 4.75-14.79]) (p < 0.001), while midline-chiasmatic location (HR 9.69 [95% CI 3.05-30.75], p < 0.001) and non-pilocytic astrocytoma histology (HR 6.77 [95% CI 2.35-19.49], p < 0.001) were independent predictors of OS. CONCLUSION: Unlike several other cancers, LGG has similar presenting features and survival for both eAYAs and children. This support continuing a unified treatment approach and enrollment of eAYAs in pediatric clinical trials for LGGs.
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Neoplasias Encefálicas/epidemiologia , Glioma/epidemiologia , Adolescente , Adulto , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Criança , Pré-Escolar , Feminino , Glioma/patologia , Glioma/cirurgia , Humanos , Lactente , Recém-Nascido , Masculino , Gradação de Tumores , Intervalo Livre de Progressão , Adulto JovemRESUMO
Single agent studies targeting the tumor microenvironment in central nervous system (CNS) tumors have largely been disappointing. Combination therapies targeting various pathways and cell types may be a more effective strategy. In this phase I study, we evaluated the combination of dasatinib, lenalidomide, and temozolomide in children with relapsed or refractory primary CNS tumors. Patients 1-21 years old with relapsed or refractory CNS tumors were eligible. Starting doses of dasatinib and lenalidomide were 65 mg/m2/dose twice daily and 55 mg/m2 once daily, respectively, while temozolomide was constant at 75 mg/m2 daily. The study followed a 3 + 3 phase I design, with a 4-week dose-limiting toxicity (DLT) evaluation period. Serial peripheral blood lymphocyte subsets were evaluated in consenting patients. Fifteen patients were enrolled and thirteen were DLT-evaluable. DLTs occurred in 5 patients, including somnolence and confusion (1 patient), hypokalemia (1 patient) and thrombocytopenia (3 patients). The maximum tolerated dose for the combination was dasatinib 65 mg/m2 twice daily, lenalidomide 40 mg/m2 daily, and temozolomide 75 mg/m2 daily, for 21 days followed by 7 days rest in repeating 28-day cycles. Transient increases in natural killer effector cells and cytotoxic T-cells were seen after 1 week of treatment. One out of six response-evaluable patients showed a partial response. The combination was feasible and relatively well tolerated in this heavily pre-treated population. The most common toxicities were hematologic. Preliminary evidence of clinical benefit was seen.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adolescente , Antígenos CD/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Terapia Combinada , Dasatinibe/uso terapêutico , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Lenalidomida/uso terapêutico , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Masculino , Temozolomida/uso terapêutico , Adulto JovemRESUMO
Posterior fossa ependymomas (EPN_PF) in children comprise two morphologically identical, but biologically distinct tumor entities. Group-A (EPN_PFA) tumors have a poor prognosis and require intensive therapy. In contrast, group-B tumors (EPN_PFB) exhibit excellent prognosis and the current consensus opinion recommends future clinical trials to test the possibility of treatment de-escalation in these patients. Therefore, distinguishing these two tumor subtypes is critical. EPN_PFA and EPN_PFB can be distinguished based on DNA methylation signatures, but these assays are not routinely available. We have previously shown that a subset of poorly prognostic childhood EPN_PF exhibits global reduction in H3K27me3. Therefore, we set out to determine whether a simple immunohistochemical assay for H3K27me3 could be used to segregate EPN_PFA from EPN_PFB tumors. We assembled a cohort of 230 childhood ependymomas and H3K27me3 immunohistochemistry was assessed as positive or negative in a blinded manner. H3K27me3 staining results were compared with DNA methylation-based subgroup information available in 112 samples [EPN_PFA (n = 72) and EPN_PFB tumors (n = 40)]. H3K27me3 staining was globally reduced in EPN_PFA tumors and immunohistochemistry showed 99% sensitivity and 100% specificity in segregating EPN_PFA from EPN_PFB tumors. Moreover, H3K27me3 immunostaining was sufficient to delineate patients with worse prognosis in two independent, non-overlapping cohorts (n = 133 and n = 97). In conclusion, immunohistochemical evaluation of H3K27me3 global reduction is an economic, easily available and readily adaptable method for defining high-risk EPN_PFA from low-risk posterior fossa EPN_PFB tumors to inform prognosis and to enable the design of future clinical trials.
Assuntos
Ependimoma/metabolismo , Neoplasias Infratentoriais/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Criança , Pré-Escolar , Intervalo Livre de Doença , Ependimoma/mortalidade , Ependimoma/patologia , Feminino , Humanos , Lactente , Neoplasias Infratentoriais/mortalidade , Neoplasias Infratentoriais/patologia , Masculino , Prognóstico , Sistema de Registros , Taxa de SobrevidaRESUMO
High-dose chemotherapy (HDC) strategies were developed in brain tumor protocols for young children to prevent neuropsychological (NP) impairments associated with radiotherapy. However, comprehensive NP evaluations of these children treated with such strategies remain limited. We examined the long-term neurocognitive outcomes of young children (<6 years) with medulloblastoma, treated similarly, with a HDC strategy "according to" the chemotherapy regimen of the protocol CCG 99703. This retrospective study included young children less than 6 years of age at diagnosis of medulloblastoma treated from 1998 to 2011 at 7 North American institutions. Twenty-four patients who had at least one NP assessment post-treatment are the focus of the current study. Of 24 patients in this review, 15 (63%) were male and the mean age at diagnosis was 29.4 months (SD = 13.5). Posterior fossa syndrome (PFs) was reported in five patients (21%). Nine (37.5%) received radiotherapy (5 focal, 4 craniospinal). On average, children were assessed 3.5 years (SD = 1.8) post-diagnosis, and full-scale intellectual quotient (FSIQ) scores ranged from 56 to 119 ([Formula: see text]= 92; SD = 16.8). The majority of children (74%) had low-average to average NP functioning. Very young children treated with radiotherapy, who needed hearing support or with PFs had worse neurocognitive outcomes. Clinically significant deficits (<10th percentile) in at least one area of NP functioning were found in 25% of the children. NP data obtained from this sample of survivors of medulloblastoma in early childhood, all treated with sequential HDC and 1/3 with radiotherapy, describe NP functioning within average normal limits overall. However, almost 25% of children had significant deficits in specific domains.
Assuntos
Neoplasias Encefálicas/psicologia , Neoplasias Encefálicas/terapia , Meduloblastoma/psicologia , Meduloblastoma/terapia , Adolescente , Quimiorradioterapia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Testes Neuropsicológicos , Estudos RetrospectivosRESUMO
BACKGROUND: High-dose chemotherapy (HDC) strategies were developed to avoid unacceptable neurotoxicity associated with craniospinal irradiation in infants with embryonal brain tumors. However, the impact of molecular and pathological characterizations in such approaches and long-term outcome have not been widely described in young children. METHODS: We retrospectively collected information from seven North American institutions, on young children with medulloblastoma (MB) treated with sequential HDC, as per the CCG 99703 protocol. Data collection included clinical presentation, histology, molecular subgroup, irradiation, ototoxicity, and neurocognitive evaluations. RESULTS: The cohort included 53 patients diagnosed at a median age of 24 months (2.9-63.2). Seventeen patients (32.1%) had nodular desmoplatic MB, all belonging to the sonic Hedgehog (SHH) subgroup, as did 30% of classic MB. The 5-year progression-free survival (PFS) and overall survival (OS) was 69.6% (±6·9%) and 76.1% (±6.5%), respectively. Seventeen (32.1%) patients received irradiation (nine adjuvant radiotherapy [RT]). Patients with SHH and group 3 MB had a 5-year PFS of 86·2% (±7.4%) and 49·1% (±14%), respectively (P = 0.03). The 5-year PFS radiation free for group 3 MB was 46.4%. Patients with macroscopic metastasis (M2 and M3) had a worst survival. Fifteen (45.5%) patients had significant ototoxicity. Mean Full Scale Intellectual Quotient (FSIQ) for 24 survivors was 91.6 (range 52-119). CONCLUSIONS: This HDC strategy led to an encouraging OS while only 20% of the patients received adjuvant RT. SHH MB, irrespective of histological subgroup, had an excellent outcome. Such intensive therapy may not be needed for this subgroup. Patients with classic histology or group 3 had an encouraging PFS of 58% and 46.4%, respectively, in the absence of adjuvant RT. The neurocognitive profile of the survivors appears to be within the normal range.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Cerebelares/tratamento farmacológico , Meduloblastoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Cerebelares/mortalidade , Neoplasias Cerebelares/patologia , Pré-Escolar , Cognição/efeitos dos fármacos , Feminino , Audição/efeitos dos fármacos , Humanos , Lactente , Masculino , Meduloblastoma/mortalidade , Meduloblastoma/patologia , Prognóstico , Estudos RetrospectivosRESUMO
Pediatric brain tumors as a group, including medulloblastomas, gliomas, and atypical teratoid rhabdoid tumors (ATRT) are the most common solid tumors in children and the leading cause of death from childhood cancer. Brain tumor-derived cell lines are critical for studying the biology of pediatric brain tumors and can be useful for initial screening of new therapies. Use of appropriate brain tumor cell lines for experiments is important, as results may differ depending on tumor properties, and can thus affect the conclusions and applicability of the model. Despite reports in the literature of over 60 pediatric brain tumor cell lines, the majority of published papers utilize only a small number of these cell lines. Here we list the approximately 60 currently-published pediatric brain tumor cell lines and summarize some of their central features as a resource for scientists seeking pediatric brain tumor cell lines for their research.
Assuntos
Neoplasias Encefálicas/patologia , Ependimoma/patologia , Glioblastoma/patologia , Meduloblastoma/patologia , Adolescente , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Criança , Pré-Escolar , Ependimoma/genética , Feminino , Amplificação de Genes , Glioblastoma/genética , Humanos , Lactente , Masculino , Meduloblastoma/genética , Mutação , Fatores de Transcrição Otx/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
Despite the documented benefit of voriconazole therapeutic drug monitoring, nonlinear pharmacokinetics make the timing of steady-state trough sampling and appropriate dose adjustments unpredictable by conventional methods. We developed a nonparametric population model with data from 141 previously richly sampled children and adults. We then used it in our multiple-model Bayesian adaptive control algorithm to predict measured concentrations and doses in a separate cohort of 33 pediatric patients aged 8 months to 17 years who were receiving voriconazole and enrolled in a pharmacokinetic study. Using all available samples to estimate the individual Bayesian posterior parameter values, the median percent prediction bias relative to a measured target trough concentration in the patients was 1.1% (interquartile range, -17.1 to 10%). Compared to the actual dose that resulted in the target concentration, the percent bias of the predicted dose was -0.7% (interquartile range, -7 to 20%). Using only trough concentrations to generate the Bayesian posterior parameter values, the target bias was 6.4% (interquartile range, -1.4 to 14.7%; P = 0.16 versus the full posterior parameter value) and the dose bias was -6.7% (interquartile range, -18.7 to 2.4%; P = 0.15). Use of a sample collected at an optimal time of 4 h after a dose, in addition to the trough concentration, resulted in a nonsignificantly improved target bias of 3.8% (interquartile range, -13.1 to 18%; P = 0.32) and a dose bias of -3.5% (interquartile range, -18 to 14%; P = 0.33). With the nonparametric population model and trough concentrations, our control algorithm can accurately manage voriconazole therapy in children independently of steady-state conditions, and it is generalizable to any drug with a nonparametric pharmacokinetic model. (This study has been registered at ClinicalTrials.gov under registration no. NCT01976078.).
Assuntos
Voriconazol/farmacocinética , Adolescente , Adulto , Algoritmos , Criança , Pré-Escolar , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto JovemAssuntos
Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Diabetes Insípido Neurogênico/patologia , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Doenças Raras/patologia , Temozolomida/efeitos adversos , Neoplasias Encefálicas/patologia , Criança , Diabetes Insípido Neurogênico/induzido quimicamente , Humanos , Masculino , Neoplasias Neuroepiteliomatosas/patologia , Prognóstico , Doenças Raras/induzido quimicamenteRESUMO
"Just Accepted" papers have undergone full peer review and have been accepted for publication in Radiology: Artificial Intelligence. This article will undergo copyediting, layout, and proof review before it is published in its final version. Please note that during production of the final copyedited article, errors may be discovered which could affect the content. Purpose To evaluate nn-Unet-based segmentation models for automated delineation of medulloblastoma (MB) tumors on multi-institutional MRI scans. Materials and Methods This retrospective study included 78 pediatric patients (52 male, 26 female), with ages ranging from 2-18 years, with MB tumors from three different sites (28 from Hospital A, 18 from Hospital B, 32 from Hospital C), who had data from three clinical MRI protocols (gadolinium-enhanced T1-weighted, T2-weighted, FLAIR) available. The scans were retrospectively collected from the year 2000 until May 2019. Reference standard annotations of the tumor habitat, including enhancing tumor, edema, and cystic core + nonenhancing tumor subcompartments, were performed by two experienced neuroradiologists. Preprocessing included registration to age-appropriate atlases, skull stripping, bias correction, and intensity matching. The two models were trained as follows: (1) transfer learning nn-Unet model was pretrained on an adult glioma cohort (n = 484) and fine-tuned on MB studies using Models Genesis, and (2) direct deep learning nn-Unet model was trained directly on the MB datasets, across five-fold cross-validation. Model robustness was evaluated on the three datasets when using different combinations of training and test sets, with data from 2 sites at a time used for training and data from the third site used for testing. Results Analysis on the 3 test sites yielded Dice scores of 0.81, 0.86, 0.86 and 0.80, 0.86, 0.85 for tumor habitat; 0.68, 0.84, 0.77 and 0.67, 0.83, 0.76 for enhancing tumor; 0.56, 0.71, 0.69 and 0.56, 0.71, 0.70 for edema; and 0.32, 0.48, 0.43 and 0.29, 0.44, 0.41 for cystic core + nonenhancing tumor for the transfer learning-and direct-nn-Unet models, respectively. The models were largely robust to site-specific variations. Conclusion nn-Unet segmentation models hold promise for accurate, robust automated delineation of MB tumor subcompartments, potentially leading to more effective radiation therapy planning in pediatric MB. ©RSNA, 2024.
RESUMO
Why, when, and how to consider external control cohorts in pediatric brain tumor clinical trials.