RESUMO
We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design.
Assuntos
Neoplasias/genética , Adulto , Criança , Análise por Conglomerados , DNA Polimerase II/genética , DNA Polimerase III/genética , Replicação do DNA , Humanos , Mutação , Neoplasias/classificação , Neoplasias/patologia , Neoplasias/terapia , Proteínas de Ligação a Poli-ADP-Ribose/genéticaRESUMO
An ongoing change in legislation means decision-makers in Aotearoa New Zealand need to incorporate 'matauranga' (Maori knowledge/knowledge system) in central and local government legislation and strategy. This paper develops a 'te ao Maori' (Maori worldview) disaster risk reduction (DRR) framework for non-Maori decision-makers to guide them through this process. This 'interface framework' will function as a Rosetta Stone between the 'two worlds'. It intends to help central and local officials trained in Western knowledge-based disciplines by translating standard DRR concepts into a te ao Maori DRR framework. It draws on previous work examining Maori DRR thinking to create a novel framework that can help these stakeholders when they are converting higher-level theoretical insights from matauranga Maori into more practical 'on the ground' applications. This type of interface is essential: while Indigenous knowledge's utility is increasingly recognised nationally and internationally, a gap remains between this acknowledgement and its practical and applied integration into emergency management legislation and strategy.
Assuntos
Planejamento em Desastres , Comportamento de Redução do Risco , Humanos , Tomada de Decisões , Planejamento em Desastres/organização & administração , Desastres , Povo Maori , Nova ZelândiaRESUMO
Tumors of the central nervous system (CNS) are a leading cause of morbidity and mortality in the pediatric population. Molecular characterization in the last decade has redefined CNS tumor diagnoses and risk stratification; confirmed the unique biology of pediatric tumors as distinct entities from tumors that occur in adulthood; and led to the first novel targeted therapies receiving Food and Drug Administration (FDA) approval for children with CNS tumors. There remain significant challenges to overcome: children with unresectable low-grade glioma may require multiple prolonged courses of therapy affecting quality of life; children with high-grade glioma have a dismal long-term prognosis; children with medulloblastoma may suffer significant short- and long-term morbidity from multimodal cytotoxic therapy, and approaches to improve survival in ependymoma remain elusive. The Children's Oncology Group (COG) is uniquely positioned to conduct the next generation of practice-changing clinical trials through rapid prospective molecular characterization and therapy evaluation in well-defined clinical and molecular groups.
Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Neoplasias Cerebelares , Glioma , Meduloblastoma , Criança , Humanos , Qualidade de Vida , Neoplasias do Sistema Nervoso Central/terapia , Glioma/patologia , Meduloblastoma/patologia , Neoplasias Encefálicas/patologiaRESUMO
INTRODUCTION: Brain tumors are the most common solid neoplasms and the second most common malignancy in the pediatric age group. Due to the complexity of their management, pediatric central nervous system (CNS) tumors are not a priority in low- and middle-income countries (LMICs). METHODS: In an attempt to improve the survival rate and overall care, we introduced a dedicated pediatric neuro-oncology service in our institute and evaluated its impact by dividing the pre- and post-era into two cohorts and comparing them: 1998-2013 (16 years: cohort A) and 2014-2019 (6 years: cohort B, after the start of dedicated neuro-oncology services). RESULTS: We observed that after the implementation of a proper neuro-oncology service, the proportion of patients treated with curative intent increased, and survival improved in cohort B. The patient volume also increased from 15.5 per year in cohort A to 44.8 per year in cohort B. The percentage of children given radiation therapy also increased significantly, while the proportion of children treated with chemotherapy remained stable. CONCLUSION: A dedicated multidisciplinary team trained and knowledgeable in the specialty of pediatric neuro-oncology can enhance and improve outcomes, and supportive care and help can provide good quality of life to children and their families with brain neoplasms.
Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Neoplasias Encefálicas/terapia , Neoplasias do Sistema Nervoso Central/terapia , Criança , Países em Desenvolvimento , Humanos , Paquistão , Qualidade de VidaRESUMO
BACKGROUND: Low- and middle-income countries sustain the majority of pediatric cancer burden, with significantly poorer survival rates compared to high-income countries. Collaboration between institutions in low- and middle-income countries and high-income countries is one of the ways to improve cancer outcomes. METHODS: Patient characteristics and effects of a pediatric neuro-oncology twinning program between the Hospital for Sick Children in Toronto, Canada and several hospitals in Karachi, Pakistan over 7 years are described in this article. RESULTS: A total of 460 patients were included in the study. The most common primary central nervous system tumors were low-grade gliomas (26.7%), followed by medulloblastomas (18%), high-grade gliomas (15%), ependymomas (11%), and craniopharyngiomas (11.7%). Changes to the proposed management plans were made in consultation with expert physicians from the Hospital for Sick Children in Toronto, Canada. On average, 24% of the discussed cases required a change in the original management plan over the course of the twinning program. However, a decreasing trend in change in management plans was observed, from 36% during the first 3.5 years to 16% in the last 3 years. This program also led to the launch of a national pediatric neuro-oncology telemedicine program in Pakistan. CONCLUSIONS: Multidisciplinary and collaborative efforts by experts from across the world have aided in the correct diagnosis and treatment of children with brain tumors and helped establish local treatment protocols. This experience may be a model for other low- and middle-income countries that are planning on creating similar programs.
Assuntos
Neoplasias Encefálicas , Neoplasias Cerebelares , Meduloblastoma , Neoplasias Encefálicas/terapia , Canadá , Criança , Países em Desenvolvimento , Ecossistema , Humanos , PaquistãoRESUMO
Embryonal tumor with multilayered rosettes is a rare and highly malignant early childhood brain tumor. We report a case of embryonal tumor with multilayered rosettes in the parietooccipital region of a 2-year-old girl. Histopathology of the tumor demonstrated amplification of the 19q13.42 locus and strong positivity for LIN28A. Treatment was multimodal and included 3 surgical resections, adjuvant chemotherapy with autologous stem cell rescue, and focal radiotherapy. The use of the agents vorinostat and isotretinoin, and the addition of focal radiation have not been extensively described in this patient population, but may attribute to our patient's sustained remission at 2.5-years follow-up.
Assuntos
Neoplasias Encefálicas , Cromossomos Humanos Par 19/genética , Loci Gênicos , Isotretinoína/administração & dosagem , Neoplasias Embrionárias de Células Germinativas , Transplante de Células-Tronco , Vorinostat/administração & dosagem , Autoenxertos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Quimiorradioterapia Adjuvante , Pré-Escolar , Feminino , Humanos , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Embrionárias de Células Germinativas/terapiaRESUMO
Galectin 3 is a multifunctional lectin implicated in cellular proliferation, differentiation, adhesion, and apoptosis. This lectin is broadly expressed in testicular somatic cells and germ cells, and is upregulated during testicular development. Since the role of galectin 3 in testicular function remains elusive, we aimed to characterize the role of galectin 3 in testicular physiology. We found that galectin 3 transgenic mice (Lgals3-/-) exhibited significantly decreased testicular weight in adulthood compared to controls. The transgenic mice also exhibited a delay to the first wave of spermatogenesis, a decrease in the number of germ cells at postnatal day 5 (P5) and P15, and defective Sertoli cell maturation. Mechanistically, we found that Insulin-like-3 (a Leydig cell marker) and enzymes involved in steroid biosynthesis were significantly upregulated in adult Lgals3-/- testes. These observations were accompanied by increased serum testosterone levels. To determine the underlying causes of the testicular atrophy, we monitored cellular apoptosis. Indeed, adult Lgals3-/- testicular cells exhibited an elevated apoptosis rate that is likely driven by downregulated Bcl-2 and upregulated Bax and Bak expression, molecules responsible for live/death cell balance. Moreover, the percentage of testicular macrophages within CD45+ cells was decreased in Lgals3-/- mice. These data suggest that galectin 3 regulates spermatogenesis initiation and Sertoli cell maturation in part, by preventing germ cells from undergoing apoptosis and regulating testosterone biosynthesis. Going forward, understanding the role of galectin 3 in testicular physiology will add important insights into the factors governing the development of germ cells and steroidogenesis and delineate novel biomarkers of testicular function.
Assuntos
Apoptose , Galectina 3/fisiologia , Células Intersticiais do Testículo/patologia , Células de Sertoli/patologia , Espermatogênese , Espermatozoides/patologia , Animais , Hormônio Foliculoestimulante/metabolismo , Células Intersticiais do Testículo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células de Sertoli/metabolismo , Espermatozoides/metabolismo , Testosterona/metabolismoRESUMO
Bucket chlorination, where chlorine is dosed directly into water collection containers, is a point-of-source water treatment intervention commonly implemented in cholera outbreaks. There is little previous data on chlorine efficacy against Vibrio cholerae in different waters and appropriate dosage regimes. We evaluated V. cholerae reduction and free chlorine residual (FCR) in waters with four turbidities (1/5/10/50 NTU), two total organic carbon (TOC) concentrations (0.4, 1 mg/L), and two dosing schemes (fixed-dose of 2 or 4 mg/L, variable-dose based on jar testing) treated with three chlorine types (HTH, NaOCl, NaDCC). We found that chlorine was efficacious at reducing V. cholerae by ≥2.75 to ≥3.63 log reduction value (LRV); variably dosed reactors were dosed higher, met ≥0.5 mg/L FCR at 30 min, and had higher LRVs (p=0.024) than fixed doses; and low TOC reactors had more samples ≥0.2 mg/L FRC at 4 h (p=0.007). Our results are conservative, as internationally recommended additives to create test water increased chlorine demand, highlighting the challenge of replicating field conditions in laboratory testing. Overall, we found that chlorine can efficaciously reduce V. cholerae; we recommend further research on appropriate chlorine demand for test waters; and we recommend establishing appropriate chlorine doses based on source water and taste/odor acceptability in bucket chlorination programs.
Assuntos
Cólera , Vibrio cholerae , Purificação da Água , Cloro/farmacologia , Cólera/prevenção & controle , Halogenação , Humanos , Purificação da Água/métodosRESUMO
Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system. The underlying genetic cause are inactivating bi-allelic mutations in SMARCB1 or (rarely) in SMARCA4. ATRT-SMARCA4 have been associated with a higher frequency of germline mutations, younger age, and an inferior prognosis in comparison to SMARCB1 mutated cases. Based on their DNA methylation profiles and transcriptomics, SMARCB1 mutated ATRTs have been divided into three distinct molecular subgroups: ATRT-TYR, ATRT-SHH, and ATRT-MYC. These subgroups differ in terms of age at diagnosis, tumor location, type of SMARCB1 alterations, and overall survival. ATRT-SMARCA4 are, however, less well understood, and it remains unknown, whether they belong to one of the described ATRT subgroups. Here, we examined 14 ATRT-SMARCA4 by global DNA methylation analyses. We show that they form a separate group segregating from SMARCB1 mutated ATRTs and from other SMARCA4-deficient tumors like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) or SMARCA4 mutated extra-cranial malignant rhabdoid tumors. In contrast, medulloblastoma (MB) samples with heterozygous SMARCA4 mutations do not group separately, but with established MB subgroups. RNA sequencing of ATRT-SMARCA4 confirmed the clustering results based on DNA methylation profiling and displayed an absence of typical signature genes upregulated in SMARCB1 deleted ATRT. In summary, our results suggest that, in line with previous clinical observations, ATRT-SMARCA4 should be regarded as a distinct molecular subgroup.
Assuntos
Neoplasias do Sistema Nervoso Central/genética , DNA Helicases/genética , Proteínas Nucleares/genética , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Teratoma/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Idade de Início , Neoplasias do Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Biologia Computacional , Metilação de DNA , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Mutação/genética , Tumor Rabdoide/patologia , Análise de Sobrevida , Teratoma/patologia , Adulto JovemRESUMO
Recent genomic studies have shed light on the biology and inter-tumoral heterogeneity underlying pineal parenchymal tumors, in particular pineoblastomas (PBs) and pineal parenchymal tumors of intermediate differentiation (PPTIDs). Previous reports, however, had modest sample sizes and lacked the power to integrate molecular and clinical findings. The different proposed molecular group structures also highlighted a need to reach consensus on a robust and relevant classification system. We performed a meta-analysis on 221 patients with molecularly characterized PBs and PPTIDs. DNA methylation profiles were analyzed through complementary bioinformatic approaches and molecular subgrouping was harmonized. Demographic, clinical, and genomic features of patients and samples from these pineal tumor groups were annotated. Four clinically and biologically relevant consensus PB groups were defined: PB-miRNA1 (n = 96), PB-miRNA2 (n = 23), PB-MYC/FOXR2 (n = 34), and PB-RB1 (n = 25). A final molecularly distinct group, designated PPTID (n = 43), comprised histological PPTID and PBs. Genomic and transcriptomic profiling allowed the characterization of oncogenic drivers for individual tumor groups, specifically, alterations in the microRNA processing pathway in PB-miRNA1/2, MYC amplification and FOXR2 overexpression in PB-MYC/FOXR2, RB1 alteration in PB-RB1, and KBTBD4 insertion in PPTID. Age at diagnosis, sex predilection, and metastatic status varied significantly among tumor groups. While patients with PB-miRNA2 and PPTID had superior outcome, survival was intermediate for patients with PB-miRNA1, and dismal for those with PB-MYC/FOXR2 or PB-RB1. Reduced-dose CSI was adequate for patients with average-risk, PB-miRNA1/2 disease. We systematically interrogated the clinical and molecular heterogeneity within pineal parenchymal tumors and proposed a consensus nomenclature for disease groups, laying the groundwork for future studies as well as routine use in tumor diagnostic classification and clinical trial stratification.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glândula Pineal/patologia , Pinealoma/genética , Pinealoma/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Metilação de DNA , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Transcriptoma , Adulto JovemRESUMO
INTRODUCTION: Choroid Plexus Tumours (CPTs) account for 1-4% of all brain tumours in children. Atypical choroid plexus papillomas (aCPPs) are a subset of these tumours, defined over a decade ago, yet no consensus exists on the optimal approach to their management. METHODS: We conducted a retrospective analysis of all patients treated for CPTs at the Hospital for Sick Children between January 1, 2000, and December 31, 2018, and focused on patients with aCPP. Data extracted from the patient records for analysis included: demographic and clinical features, radiological imaging, surgical and adjuvant therapies, key pathological features, immunohistochemical staining for TP53 and tumour karyotype. Six of seven aCPP samples were profiled using Illumina HumanMethylationEPIC arrays and the top 10,000 most variably methylated probes were visualized using tSNE. Copy number inferencing was also performed. RESULTS: Twenty-nine patients were diagnosed with CPT, seven of whom had a diagnosis of aCPP as confirmed by histological review. Methylation profiling demonstrated that aCPPs clustered with both choroid plexus papillomas (CPPs) and choroid plexus carcinomas (CPCs). Complete resection of the tumour was pursued in all cases of aCPP and no patient received adjuvant therapy. All aCPP patients were alive at last follow up. CONCLUSIONS: This limited case series suggests that paediatric aCPP can be successfully managed with surgical resection alone, followed by a 'watch and wait' approach thus avoiding adjuvant therapies. A deeper understanding of the biology of aCPP is required to identify objective markers which can help provide robust risk stratification and inform treatment strategies.
Assuntos
Papiloma do Plexo Corióideo , Carcinoma , Criança , Plexo Corióideo , Neoplasias do Plexo Corióideo/diagnóstico por imagem , Neoplasias do Plexo Corióideo/terapia , Glioma , Humanos , Papiloma do Plexo Corióideo/diagnóstico por imagem , Papiloma do Plexo Corióideo/terapia , Estudos Retrospectivos , Neoplasias SupratentoriaisRESUMO
Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (DICER1, DROSHA, and DGCR8) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic MYC-miR-17/92-RB1 pathway were observed in the RB and MYC sub-group, respectively, characterized by RB1 loss with gain of miR-17/92, and recurrent gain or amplification of MYC. PB sub-groups exhibited distinct clinical features: group 1-3 arose in older children (median ages 5.2-14.0 years) and had intermediate to excellent survival (5-year OS of 68.0-100%), while Group RB and MYC PB patients were much younger (median age 1.3-1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glândula Pineal , Pinealoma/genética , Pinealoma/patologia , Adolescente , Adulto , Fatores Etários , Neoplasias Encefálicas/mortalidade , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , MicroRNAs/metabolismo , Mutação/genética , Pinealoma/mortalidade , Sistema de Registros , Taxa de Sobrevida , Adulto JovemRESUMO
INTRODUCTION: ETMRs are highly lethal, pediatric embryonal brain tumors, previously classified as various histologic diagnoses including supratentorial primitive neuroectodermal tumors (sPNET) and CNS PNET. With recognition that these tumors harbor recurrent amplification of a novel oncogenic miRNA cluster on chr19, C19MC, ETMRs were designated as a distinct biological and molecular entity with a spectrum of histologic and clinical manifestations. METHODS: We reviewed published literature describing clinical presentation, the genetic and epigenetic drivers of oncogenesis, and recent therapeutic strategies adopted to combat these aggressive tumors. RESULTS: As a consequence of C19MC amplification, ETMRs upregulate several oncogenic and pluripotency proteins, including LIN28A, DNMT3B and MYCN, that confer a unique epigenetic signature reminiscent of nascent embryonic stem cells. In this review, we focus on the dysregulation of miRNAs in ETMR, the major pathogenic mechanism identified in this disease. CONCLUSION: Despite the use of multi-modal therapeutic regimens, ETMR patients have dismal survival. Understanding the unique biology of these tumors has provided new insights towards novel therapeutic targets.
Assuntos
Neoplasias Encefálicas , MicroRNAs , Neoplasias Embrionárias de Células Germinativas , Tumores Neuroectodérmicos Primitivos , Neoplasias Encefálicas/genética , Criança , Humanos , MicroRNAs/genética , Recidiva Local de Neoplasia , Neoplasias Embrionárias de Células Germinativas/genética , Tumores Neuroectodérmicos Primitivos/genéticaRESUMO
INTRODUCTION: Atypical teratoid rhabdoid tumor (ATRT) is a rare, often lethal brain tumor of childhood characterized by a complex epigenetic landscape amongst a simple genetic background. Recent molecular studies have defined key biologic events that contribute to tumorigenesis and molecular subtypes of ATRT. METHODS: Seminal studies on ATRT are reviewed with an emphasis on molecular pathogenesis and its relevance to novel therapeutics. RESULTS: In this review, we summarize the key clinicopathologic and molecular features of ATRT, completed and ongoing clinical trials and outline the translational potential of novel insights into the molecular pathogenesis of this tumor. CONCLUSIONS: SMARCB1 loss is the key genetic event in ATRT pathogenesis that leads to widespread epigenetic dysregulation and loss of lineage-specific enhancers. Current work is defining subtype-specific treatments that target underlying molecular derangements that drive tumorigenesis.
Assuntos
Neoplasias Neuroepiteliomatosas , Tumor Rabdoide , Teratoma , Transformação Celular Neoplásica , Humanos , Tumor Rabdoide/tratamento farmacológico , Tumor Rabdoide/genética , Teratoma/tratamento farmacológico , Teratoma/genéticaRESUMO
PURPOSE: Primary benign and malignant central nervous system (CNS) tumors are the most frequent solid tumors in the pediatric age and represent the leading cause of death by cancer in children in high income countries. However, information regarding specific causes of death in this population is still limited. The objective of this work was to investigate mortality in a large cohort of children diagnosed at our institution. METHODS: We identified patients consecutively diagnosed with CNS tumor and treated at a Tertiary Care Canadian Children's Hospital between January 2000 and December 2017. Patient charts were reviewed and different variables such as tumor diagnosis, location, gender, age at diagnosis, age at death and cause of death collected. RESULTS: Of 1274 patients, 306 (24%) succumbed to their disease. Mortality rate varied significantly according to tumor subtype, ranging from 3.1% in low grade glioma (LGG) to 97.8% in diffuse intrinsic pontine glioma (DIPG). While high grade gliomas (HGG) and DIPG represented only 6.3 and 7.1% of total diagnoses respectively, together they accounted for 49.3% of total deaths (n = 151). Median time from diagnosis to death was 15 months (4 days to 15 years) and shortest for DIPG (11 months). Two hundred and ninety patients (94.8%) died as a result of the primary disease, 4 of treatment-related toxicity, two patients' deaths were unrelated to the primary disease (idiopathic encephalopathy and domestic fire) whereas 10 patients succumbed to a secondary malignancy. Of note, four of these ten patients had a confirmed underlying cancer predisposition syndrome. CONCLUSION: Disease progression is the main cause of death in children with brain tumor, while treatment related mortality is low in this series. Research should continue to focus on improving treatment strategies for patients whose prognosis remains dismal.
Assuntos
Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Causas de Morte/tendências , Adolescente , Neoplasias Encefálicas/classificação , Criança , Pré-Escolar , Progressão da Doença , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de TempoRESUMO
Medulloepithelioma is a rare early childhood tumor typically presenting in the intraocular region and neuroaxis. We report a rare case of a 2-year-old girl that presented with a peripheral medulloepithelioma in the presacral region. Examination of the tumor revealed that it lacked amplification of the 19q13.42 locus yet was positive for LIN28A. The patient was treated with intensive and high-dose chemotherapy as per 99703 protocol followed by complete surgical resection of the tumor and rapamycin maintenance and remains disease-free 5 years postinitial diagnosis. Ten previous cases were reported, including 5 patients who were alive disease free at the time of the publication. Optimal management of this rare condition is still controversial, particularly with regard to the respective role of chemotherapy and radiation.
Assuntos
Tumores Neuroectodérmicos Primitivos/patologia , Neoplasias de Tecidos Moles/patologia , Pré-Escolar , Feminino , HumanosRESUMO
PURPOSE: Children with recurrent medulloblastoma have a poor prognosis. Re-irradiation is an option for some patients, but has not been well-studied in the era of molecular characterization for pediatric medulloblastoma. METHODS: This was a retrospective cohort study of 14 children age 18 years and younger at initial diagnosis with recurrent medulloblastoma, who received two or more courses of radiation therapy (RT). Molecular subgrouping was performed using nanoString and was available for nine patients. The primary study endpoint was overall survival. RESULTS: Re-irradiation (RT2) was directed at the supratentorial brain in six patients, infratentorial brain in one patient, and spine in seven patients. In addition, six patients received stem cell transplant as part of salvage therapy. Median OS for all patients was 12.4 months. One patient with recurrent Wnt-activated medulloblastoma remains alive with 154 months' survival; median survival was not reached for four patients with Group 4 disease, while three with Shh-activated disease had median survival of 2.2 months. A single patient with Group 3 disease died 4.3 months after RT2. Patients treated with RT2 to the spine for diffuse disease had poorer OS (p = 0.02), as compared to focal RT2 for intracranial recurrence. Distant failure, outside RT2 volumes, was the predominant pattern of recurrence after RT2. CONCLUSIONS: Re-irradiation for recurrent pediatric medulloblastoma can offer some patients disease control, particularly those with focally recurrent disease in the brain. Prospective studies are needed to confirm subgroups of patients who may benefit most from RT2.
Assuntos
Neoplasias Cerebelares/radioterapia , Meduloblastoma/radioterapia , Reirradiação/métodos , Terapia de Salvação , Adolescente , Adulto , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Meduloblastoma/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: There are very few studies about the role of repeat irradiation (RT2) for children with recurrent supratentorial high-grade glioma (HGG). It was the aim of this study to assess the effectiveness and safety of RT2 in this population. PROCEDURE: This was a retrospective cohort study of 40 children age 18 years and under with recurrent supratentorial HGG who had received at least one course of RT. In-field reirradiation volumes included focal or whole brain RT, with doses ranging from 30 to 54 Gy. The primary endpoint was overall survival (OS) from the first day of RT2. RESULTS: Fourteen patients underwent RT2. The median survival of these patients was 6.5 months. Patients with ≥12 months elapsed time between RT1 and RT2 experienced longer OS than patients who had < 12 months (P = 0.009). There was no difference in OS between patients with or without germline mutations (e.g., Lynch, Li-Fraumeni, or constitutional mismatch-repair deficiency, P = 0.20). Ten patients received RT2 that overlapped with RT1 volumes for locally recurrent disease. Of this group, 80% experienced clinical benefit from in-field RT2, defined as clinical/radiologic response or stable disease. Ninety-three percent completed the prescribed course of RT2, with one patient developing grade 3 radiation necrosis four months after RT2. When compared with 26 patients who were not offered reirradiation, those selected for RT2 had improved median survival from the time of first disease progression (9.4 vs 3.8 months, P = 0.005). CONCLUSIONS: Reirradiation for children with recurrent supratentorial HGG is a safe, effective treatment that provides short-term disease control.
Assuntos
Neoplasias do Tronco Encefálico/mortalidade , Neoplasias do Tronco Encefálico/radioterapia , Glioma/mortalidade , Glioma/radioterapia , Reirradiação , Adolescente , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/patologia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Glioma/genética , Glioma/patologia , Humanos , Masculino , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Intratumoral heterogeneity greatly hinders efficiency of target therapy in glioblastoma (GBM). To decipher the underlying mechanisms of heterogeneity, patient-derived adult GBM cells were separately isolated from margins of T1 gadolinium enhancing tumor lesions (PNCs) and T1 gadolinium enhancing core lesions (ECs). Single clone culture was conducted in ECs and U87MG cell line to screen clones with distinct biological phenotypes. Single cell clones with diverse phenotypes were simultaneously separated from ECs and U87 cell line. PNCs, GCs(H) and U87(H) exhibited longer cellular protrusion than ECs, GCs(L) and U87(L), respectively. Cell strains with longer protrusion exhibited higher invasive ability and lower sensitivity to temozolomide (TMZ) and radiation. Subsequently, TPD52L2 was verified as the functional protein to regulate the cellular heterogeneity by the proteomics analysis. Downregulation of TPD52L2 enhanced cell invasion whereas inhibited cell proliferation rate and sensitivity to chemotherapy in vivo and in vitro, this condition was reversed when TPD52L2 was overexpressed. The invasiveness was facilitated by up-regulating CTNNB1/ß-catenin and SNAI1/Snail mediated EMT process. In addition, the clinical data of 88 GBM cases in our neurosurgery center was analyzed to reveal the influence of TPD52L2 in the prognosis of GBM. Low expression of TPD52L2 exacerbated prognosis of GBM patients received standard radiotherapy plus concomitant and adjuvant TMZ (Stupp strategy). Taken together, TPD52L2 is an important biomarker influencing GBM prognosis.