RESUMO
Chemical probing experiments have transformed RNA structure analysis, enabling high-throughput measurement of base-pairing in living cells. Dimethyl sulfate (DMS) is one of the most widely used structure probing reagents and has played a pivotal role in enabling next-generation single-molecule probing analyses. However, DMS has traditionally only been able to probe adenine and cytosine nucleobases. We previously showed that, using appropriate conditions, DMS can also be used to interrogate base-pairing of uracil and guanines in vitro at reduced accuracy. However, DMS remained unable to informatively probe guanines in cells. Here, we develop an improved DMS mutational profiling (MaP) strategy that leverages the unique mutational signature of N1-methylguanine DMS modifications to enable high-fidelity structure probing at all four nucleotides, including in cells. Using information theory, we show that four-base DMS reactivities convey greater structural information than current two-base DMS and SHAPE probing strategies. Four-base DMS experiments further enable improved direct base-pair detection by single-molecule PAIR analysis, and ultimately support RNA structure modeling at superior accuracy. Four-base DMS probing experiments are straightforward to perform and will broadly facilitate improved RNA structural analysis in living cells.
Assuntos
Guanina , Mutagênicos , RNA , Ésteres do Ácido Sulfúrico , Pareamento de Bases , Mutação , Conformação de Ácido Nucleico , RNA/genética , RNA/química , Mutagênicos/farmacologia , Ésteres do Ácido Sulfúrico/farmacologiaRESUMO
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
Hyaline protoplasmic astrocytopathy (HPA) describes a rare histologic finding of eosinophilic, hyaline cytoplasmic inclusions in astrocytes, predominantly in the cerebral cortex. It has mainly been observed in children and adults with a history of developmental delay and epilepsy, frequently with focal cortical dysplasia (FCD), but the nature and significance of these inclusions are unclear. In this study, we review the clinical and pathologic features of HPA and characterize the inclusions and brain tissue in which they are seen in surgical resection specimens from five patients with intractable epilepsy and HPA compared to five patients with intractable epilepsy without HPA using immunohistochemistry for filamin A, previously shown to label these inclusions, and a variety of astrocytic markers including aldehyde dehydrogenase 1 family member L1 (ALDH1L1), SRY-Box Transcription Factor 9 (SOX9), and glutamate transporter 1/excitatory amino acid transporter 2 (GLT-1/EAAT2) proteins. The inclusions were positive for ALDH1L1 with increased ALDH1L1 expression in areas of gliosis. SOX9 was also positive in the inclusions, although to a lesser intensity than the astrocyte nuclei. Filamin A labeled the inclusions but also labeled reactive astrocytes in a subset of patients. The immunoreactivity of the inclusions for various astrocytic markers and filamin A as well as the positivity of filamin A in reactive astrocytes raise the possibility that these astrocytic inclusions may be the result of an uncommon reactive or degenerative phenomenon.
Assuntos
Epilepsia Resistente a Medicamentos , Epilepsia , Criança , Adulto , Humanos , Filaminas/metabolismo , Hialina , Encéfalo/patologia , Astrócitos/patologiaRESUMO
In 2016, medulloblastoma classification was restructured to allow for incorporation of updated data about medulloblastoma biology, genomics, and clinical behavior. For the first time, medulloblastomas were classified according to molecular characteristics ("genetically defined" categories) as well as histologic characteristics ("histologically defined" categories). Current genetically-defined categories include WNT-activated, SHH-activated TP53 wildtype, SHH-activated TP53-mutant, and non-WNT/non-SHH. In this article, we review the most recent update to the classification of medulloblastomas, provide a practical approach to immunohistochemical and molecular testing for these tumors, and demonstrate how to use key molecular genetic findings to develop an integrated diagnosis.
Assuntos
Neoplasias Cerebelares , Meduloblastoma , Neoplasias Cerebelares/diagnóstico , Neoplasias Cerebelares/genética , Humanos , Meduloblastoma/diagnóstico , Meduloblastoma/genética , Organização Mundial da SaúdeRESUMO
Since the 1990s, the sheer number of defined central nervous system (CNS) embryonal tumor entities has continuously increased, with the trend accelerating in the most recent editions of the World Health Organization (WHO) Classification of Tumours of the CNS. The introduction of increasingly specific tumor groups is an effort to create more internally homogeneous categories, to allow more precise prognostication, and potentially to develop targeted therapies. However, these ever-smaller categories within an already rare group of tumors pose a challenge for pediatric pathologists. In this article we review the current categorization of non-medulloblastoma CNS embryonal tumors (including atypical teratoid/rhabdoid tumor, cribriform neuroepithelial tumor, embryonal tumor with multilayered rosettes, CNS neuroblastoma, FOXR2-activated, and CNS tumor with BCOR internal tandem duplication) and provide an overview of available ancillary techniques to characterize these tumors. We provide a practical approach to workup and development of an integrated diagnosis for CNS embryonal tumors.
Assuntos
Neoplasias do Sistema Nervoso Central , Neoplasias Cerebelares , Meduloblastoma , Neoplasias Embrionárias de Células Germinativas , Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central/diagnóstico , Criança , Fatores de Transcrição Forkhead , Humanos , Meduloblastoma/diagnóstico , Meduloblastoma/terapia , Neoplasias Embrionárias de Células Germinativas/diagnósticoRESUMO
Tumor classification in neuropathology is a dynamic and complex topic, with many changes emerging in the past 5 years, up to and including the 2021 publication of the 5th edition of the World Health Organization Classification of Tumours of the Central Nervous System (CNS). For pediatric pathologists who will encounter brain tumors with varying frequency, it is important to understand the principles of these classification updates, particularly the inclusion of molecular genetic features and development of a layered, or integrated, diagnosis. This issue of Perspectives in Pediatric Pathology is dedicated to the examination of pediatric brain tumors, and features articles on intraoperative diagnosis and updated information on molecular-based classification for pediatric glial, glioneuronal, ependymal, and embryonal tumors of the CNS.
Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Neoplasias Embrionárias de Células Germinativas , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central/diagnóstico , Criança , Humanos , Organização Mundial da SaúdeRESUMO
Central nervous system (CNS) tumors are now the most common type of solid tumor in individuals aged 0-19 years, with an incidence rate in the United States around 5 per 100,000, accounting for about 1 out of 4 childhood cancers. Pediatric pathologists encounter brain tumor cases with varying frequency, but many of these encounters begin in the context of intraoperative consultation or "frozen section." This review provides an overview of the technical aspects of intraoperative consultation specific to, or more helpful in, CNS tumors, emphasizing helpful cytologic and histologic features of the more commonly encountered pediatric CNS tumors, and illustrating some common diagnostic pitfalls and how these may be avoided.
Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Adolescente , Adulto , Neoplasias Encefálicas/diagnóstico , Neoplasias do Sistema Nervoso Central/diagnóstico , Criança , Pré-Escolar , Secções Congeladas , Humanos , Lactente , Recém-Nascido , Encaminhamento e Consulta , Adulto JovemRESUMO
Paired-like homeobox 2b (PHOX2B) is an established immunomarker for peripheral neuroblastoma and autonomic nervous system cells. We aimed to evaluate the utility of PHOX2B immunostaining in central nervous system (CNS) tumors with embryonal morphology. Fifty-one tumors were stained with PHOX2B and submitted for whole slide image analysis: 35 CNS tumors with embryonal morphology (31 CNS embryonal tumors and four gliomas); and 16 peripheral neuroblastomas were included for comparison. Diffuse nuclear immunopositivity was observed in all (16/16) neuroblastomas (primary and metastatic). Among CNS embryonal tumors, focal immunoreactivity for PHOX2B was observed in most (5/7) embryonal tumors with multilayered rosettes (ETMR) and a single high-grade neuroepithelial tumor (HGNET) with PLAGL2 amplification; the remaining 27 CNS tumors were essentially immunonegative (<0.05% positive). Among ETMR, PHOX2B expression was observed in a small overall proportion (0.04%-4.94%) of neoplastic cells but focally reached up to 39% in 1 mm 'hot spot' areas. In the PLAGL2-amplified case, 0.09% of the total neoplastic population was immunoreactive, with 0.53% in the 'hot spot' area. Care should be taken in interpreting PHOX2B immunopositivity in a differential diagnosis that includes metastatic neuroblastoma and CNS tumors; focal or patchy expression should not be considered definitively diagnostic of metastatic peripheral neuroblastoma.
Assuntos
Neoplasias Encefálicas , Proteínas de Homeodomínio , Neoplasias Embrionárias de Células Germinativas , Neuroblastoma , Tumores Neuroectodérmicos Primitivos , Fatores de Transcrição , Neoplasias Encefálicas/genética , Criança , Proteínas de Ligação a DNA/metabolismo , Genes Homeobox , Proteínas de Homeodomínio/genética , Humanos , Neoplasias Embrionárias de Células Germinativas/genética , Neuroblastoma/genética , Tumores Neuroectodérmicos Primitivos/genética , Proteínas de Ligação a RNA , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
DICER1 syndrome is a hereditary cancer predisposition syndrome caused by deleterious germline DICER1 mutations. Characteristic "hotspot" somatic mutations of DICER1 have been identified in DICER1-associated tumors. With the exception of genitourinary embryonal rhabdomyosarcoma and anaplastic sarcoma of the kidney, sarcomas are rarely reported in DICER1 syndrome. Herein, we report the clinical, histopathologic, and molecular findings of a germline DICER1-associated ovarian sarcoma in a 5-year-old female, a somatic DICER1-associated metastatic peritoneal sarcoma in a 16-year-old female, and a somatic DICER1-associated primary intracranial sarcoma in a 4-year-old male. A comprehensive review of the literature, including 83 DICER1-associated sarcomas, illustrates an unequivocal histologic pattern mimicking pleuropulmonary blastoma, regardless of the site of origin. The features include undifferentiated small round blue cells, poorly differentiated spindle cells, and large bizarre pleomorphic cells (anaplasia), often with rhabdomyoblastic and/or chondroid differentiation, and rare bone/osteoid formation. This unique heterogeneous histologic pattern should raise suspicion for pathogenic DICER1 mutation(s) warranting a detailed review of the family history and DICER1 mutation analysis. In addition to expanding the phenotypic spectrum of DICER1-associated conditions, identification of pathogenic DICER1 variants facilitates optimized genetic counseling, caregiver education and judicious imaging-based surveillance.
Assuntos
Neoplasias Encefálicas/genética , RNA Helicases DEAD-box/genética , Predisposição Genética para Doença/genética , Neoplasias Ovarianas/genética , Neoplasias Peritoneais/genética , Ribonuclease III/genética , Sarcoma/genética , Adolescente , Pré-Escolar , Feminino , Humanos , Masculino , MutaçãoRESUMO
The autosomal dominant disorder tuberous sclerosis complex (TSC) is characterized by an array of manifestations both within and outside of the central nervous system (CNS), including hamartomas and other malformations. TSC is caused by mutations in the TSC1 or TSC2 gene resulting in activation of the mechanistic target of rapamycin (mTOR) signaling pathway. Study of TSC has shed light on the critical role of the mTOR pathway in neurodevelopment. This update reviews the genetic basis of TSC, its cardinal phenotypic CNS features, and recent developments in the field of TSC and other mTOR-altered disorders.
Assuntos
Doenças do Sistema Nervoso Central/genética , Doenças do Sistema Nervoso Central/patologia , Esclerose Tuberosa/complicações , Esclerose Tuberosa/patologia , Predisposição Genética para Doença , HumanosRESUMO
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
Plants utilize variation in day length (photoperiod) to anticipate seasonal changes. They respond by modulating their growth and development to maximize seed production, which in cereal crops is directly related to yield. In wheat (Triticum aestivum), the acceleration of flowering under long days (LD) is dependent on the light induction of PHOTOPERIOD1 (PPD1) by phytochromes. Under LD, PPD1 activates FLOWERING LOCUS T1 (FT1), a mobile signaling protein that travels from the leaves to the shoot apical meristem to promote flowering. Here, we show that the interruption of long nights by short pulses of light ("night-break" [NB]) accelerates wheat flowering, suggesting that the duration of the night is critical for wheat photoperiodic response. PPD1 transcription was rapidly upregulated by NBs, and the magnitude of this induction increased with the length of darkness preceding the NB Cycloheximide abolished the NB up-regulation of PPD1, suggesting that this process is dependent on active protein synthesis during darkness. While one NB was sufficient to induce PPD1, more than 15 NBs were required to induce high levels of FT1 expression and a strong acceleration of flowering. Multiple NBs did not affect the expression of core circadian clock genes. The acceleration of flowering by NB disappeared in ppd1-null mutants, demonstrating that this response is mediated by PPD1 The acceleration of flowering was strongest when NBs were applied in the middle of the night, suggesting that in addition to PPD1, other circadian-controlled factors are required for the up-regulation of FT1 expression and the acceleration of flowering.
Assuntos
Escuridão , Flores/fisiologia , Fotoperíodo , Proteínas de Plantas/metabolismo , Triticum/fisiologia , Alelos , Relógios Circadianos/genética , Flores/genética , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Modelos Biológicos , Fitocromo/metabolismo , Proteínas de Plantas/genética , Biossíntese de Proteínas , Fatores de Tempo , Transcrição Gênica , Triticum/genéticaRESUMO
BACKGROUND: Despite its global recognition as a ruminant pathogen, cases of Chlamydia pecorum infection in Australian livestock are poorly documented. In this report, a C. pecorum specific Multi Locus Sequence Analysis scheme was used to characterise the C. pecorum strains implicated in two cases of sporadic bovine encephalomyelitis confirmed by necropsy, histopathology and immunohistochemistry. This report provides the first molecular evidence for the presence of mixed infections of C. pecorum strains in Australian cattle. CASE PRESENTATION: Affected animals were two markedly depressed, dehydrated and blind calves, 12 and 16 weeks old. The calves were euthanized and necropsied. In one calf, a severe fibrinous polyserositis was noted with excess joint fluid in all joints whereas in the other, no significant lesions were seen. No gross abnormalities were noted in the brain of either calf. Histopathological lesions seen in both calves included: multifocal, severe, subacute meningoencephalitis with vasculitis, fibrinocellular thrombosis and malacia; diffuse, mild, acute interstitial pneumonia; and diffuse, subacute epicarditis, severe in the calf with gross serositis. Immunohistochemical labelling of chlamydial antigen in brain, spleen and lung from the two affected calves and brain from two archived cases, localised the antigen to the cytoplasm of endothelium, mesothelium and macrophages. C. pecorum specific qPCR, showed dissemination of the pathogen to multiple organs. Phylogenetic comparisons with other C. pecorum bovine strains from Australia, Europe and the USA revealed the presence of two genetically distinct sequence types (ST). The predominant ST detected in the brain, heart, lung and liver of both calves was identical to the C. pecorum ST previously described in cases of SBE. A second ST detected in an ileal tissue sample from one of the calves, clustered with previously typed faecal bovine isolates. CONCLUSION: This report provides the first data to suggest that identical C. pecorum STs may be associated with SBE in geographically separated countries and that these may be distinct from those found in the gastrointestinal tract. This report provides a platform for further investigations into SBE and for understanding the genetic relationships that exist between C. pecorum strains detected in association with other infectious diseases in livestock.
Assuntos
Doenças dos Bovinos/microbiologia , Infecções por Chlamydia/veterinária , Chlamydia/classificação , Encefalomielite/veterinária , Animais , Bovinos , Doenças dos Bovinos/epidemiologia , Doenças dos Bovinos/patologia , Chlamydia/genética , Infecções por Chlamydia/epidemiologia , Infecções por Chlamydia/microbiologia , Encefalomielite/epidemiologia , Encefalomielite/microbiologia , Filogenia , Reação em Cadeia da Polimerase/métodos , Austrália Ocidental/epidemiologiaRESUMO
This study evaluates the diagnostic utility of OLIG2 immunohistochemistry for distinguishing between pediatric high-grade gliomas (pHGG) and embryonal tumors (ETs) of the CNS. Utilizing a retrospective pediatric cohort (1990-2021) of 56 CNS tumors, classified initially as primitive neuroectodermal tumors or CNS ET, we reclassified the cases based on WHO CNS5 criteria after comprehensive review and additional molecular testing that included next-generation sequencing and DNA methylation profiling. Our results indicate that OLIG2 immunopositivity was negative or minimal in a significant subset of pHGG cases (6 out of 11). At the same time, it showed diffuse expression in all cases of CNS neuroblastomas with FOXR2 activation (5/5), demonstrating its limited specificity in differentiating between pHGG and ET. Variable OLIG2 expression in other ETs, ATRT, and ETMR suggests the broader diagnostic implications of the marker. Furthermore, incidental findings of OLIG2 positivity in cases traditionally expected to be negative, such as medulloblastoma and ependymoma, introduce an additional layer of complexity. Together, these findings highlight the challenges of relying solely on OLIG2 immunostaining for accurate tumor classification in pediatric CNS neoplasms and underscore the importance of an integrated diagnostic approach.
RESUMO
The mitochondrion is a multifunctional organelle that modulates multiple systems critical for homeostasis during pathophysiological stress. Variation in mitochondrial DNA (mtDNA) copy number (mtDNAcn), a key mitochondrial change associated with chronic stress, is an emerging biomarker for disease pathology and progression. mtDNAcn can be quantified from whole blood samples using qPCR to determine the ratio of mtDNA to nuclear DNA. However, the collection of blood samples in pediatric populations, particularly in infants and young children, can be technically challenging, yield much smaller volume samples, and can be distressing for the patients and their caregivers. Therefore, we have validated a mtDNAcn assay utilizing DNA from simple buccal swabs (Isohelix SK-2S) and report here it's performance in specimens from infants (age = <12 months). Utilizing qPCR to amplify â¼200â bp regions from two mitochondrial (ND1, ND6) and two nuclear (BECN1, NEB) genes, we demonstrated absolute (100%) concordance with results from low-pass whole genome sequencing (lpWGS). We believe that this method overcomes key obstacles to measuring mtDNAcn in pediatric populations and creates the possibility for development of clinical assays to measure mitochondrial change during pathophysiological stress.
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Integration of molecular data with histologic, radiologic, and clinical features is imperative for accurate diagnosis of pediatric central nervous system (CNS) tumors. Whole transcriptome RNA sequencing (RNAseq), a genome-wide and non-targeted approach, allows for the detection of novel or rare oncogenic fusion events that contribute to the tumorigenesis of a substantial portion of pediatric low- and high-grade glial and glioneuronal tumors. We present two cases of pediatric glioneuronal tumors occurring in the occipital region with a CLIP2::MET fusion detected by RNAseq. Chromosomal microarray studies revealed copy number alterations involving chromosomes 1, 7, and 22 in both tumors, with Case 2 having an interstitial deletion breakpoint in the CLIP2 gene. By methylation profiling, neither tumor had a match result, but both clustered with the low-grade glial/glioneuronal tumors in the UMAP. Histologically, in both instances, our cases displayed characteristics of a low-grade tumor, notably the absence of mitotic activity, low Ki-67 labeling index and the lack of necrosis and microvascular proliferation. Glial and neuronal markers were positive for both tumors. Clinically, both patients achieved clinical stability post-tumor resection and remain under regular surveillance imaging without adjuvant therapy at the last follow-up, 6 months and 3 years, respectively. This is the first case report demonstrating the presence of a CLIP2::MET fusion in two pediatric low-grade glioneuronal tumors (GNT). Conservative clinical management may be considered for patients with GNT and CLIP2:MET fusion in the context of histologically low-grade features.
Assuntos
Neoplasias Encefálicas , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Glioma/genética , Glioma/patologia , Glioma/diagnóstico por imagem , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-met/genéticaRESUMO
Little is known about the genomic alterations in chordoma, with the exception of loss of SMARCB1, a core member of the SWI/SNF complex, in poorly differentiated chordomas. A TBXT duplication and rs2305089 polymorphism, located at 6q27, are known genetic susceptibility loci. A comprehensive genomic analysis of the nuclear and mitochondrial genomes in pediatric chordoma has not yet been reported. In this study, we performed WES and mtDNA genome sequencing on 29 chordomas from 23 pediatric patients. Findings were compared with that from whole-genome sequencing datasets of 80 adult patients with skull base chordoma. In the pediatric chordoma cohort, 81% of the somatic mtDNA mutations were observed in NADH complex genes, which is significantly enriched compared with the rest of the mtDNA genes (P = 0.001). In adult chordomas, mtDNA mutations were also enriched in the NADH complex genes (P < 0.0001). Furthermore, a progressive increase in heteroplasmy of nonsynonymous mtDNA mutations was noted in patients with multiple tumors (P = 0.0007). In the nuclear genome, rare likely germline in-frame indels in ARID1B, a member of the SWI/SNF complex located at 6q25.3, were observed in five pediatric patients (22%) and four patients in the adult cohort (5%). The frequency of rare ARID1B indels in the pediatric cohort is significantly higher than that in the adult cohort (P = 0.0236, Fisher's exact test), but they were both significantly higher than that in the ethnicity-matched populations (P < 5.9e-07 and P < 0.0001174, respectively). Implications: germline ARID1B indels and mtDNA aberrations seem important for chordoma genesis, especially in pediatric chordoma.
Assuntos
Cordoma , Humanos , Cordoma/genética , Cordoma/patologia , Criança , Feminino , Masculino , Pré-Escolar , Adolescente , Lactente , Adulto , Mutação , DNA Mitocondrial/genética , Proteínas de Ligação a DNA/genéticaRESUMO
Background: There is no standard treatment for the recurrence of medulloblastoma, the most common malignant childhood brain tumor, and prognosis remains dismal. In this study, we introduce a regimen that is well-tolerated and effective at inducing remission. Methods: The primary objectives of this study were to assess tolerability of the regimen and overall response rate (ORR). A retrospective chart review of patients with recurrent medulloblastoma, treated at two institutions with a re-induction regimen of intravenous irinotecan and cyclophosphamide with oral temozolomide and etoposide, was performed. Demographic, clinicopathologic, toxicity, and response data were collected and analyzed. Results: Nine patients were identified. Median age was 5.75 years. Therapy was well-tolerated with no therapy-limiting toxicities and no toxic deaths. Successful stem cell collection was achieved in all 5 patients in whom it was attempted. ORR after 2 cycles was 78%. Three patients had a complete response, 4 patients had a partial response, 1 patient had stable disease, and 1 patient had progressive disease. Four patients are alive with no evidence of disease (NED), 2 patients are alive with disease, 2 patients have died of disease, and 1 patient died of toxicity related to additional therapy (NED at time of death). Conclusions: This regimen is well-tolerated and effective. Tumor response was noted in the majority of cases, allowing patients to proceed to additional treatment with no or minimal disease. Further study of this regimen in a clinical trial setting is an important next step.