RESUMO
Differential diagnosis between constitutional mismatch repair deficiency (CMMRD) and neurofibromatosis type 1 (NF1) is crucial as treatment and surveillance differ. We report the case of a girl with a clinical diagnosis of sporadic NF1 who developed a glioblastoma. Immunohistochemistry for MMR proteins identified PMS2 loss in tumour and normal cells and WES showed the tumour had an ultra-hypermutated phenotype, supporting the diagnosis of CMMRD. Germline analyses identified two variants (one pathogenic variant and one classified as variant(s) of unknown significance) in the PMS2 gene and subsequent functional assays on blood lymphocytes confirmed the diagnosis of CMMRD. The large plexiform neurofibroma of the thigh and the freckling were however more compatible with NF1. Indeed, a NF1 PV (variant allele frequencies of 20%, 3% and 9% and in blood, skin and saliva samples, respectively) was identified confirming a mosaicism for NF1. Retrospective analysis of a French cohort identified NF1 mosaicism in blood DNA in 2 out of 22 patients with CMMRD, underlining the existence of early postzygotic PV of NF1 gene in patients with CMMRD whose tumours have been frequently reported to exhibit somatic NF1 mutations. It highlights the potential role of this pathway in the pathogenesis of CMMRD-associated gliomas and argues in favour of testing MEK inhibitors in this context.
Assuntos
Neoplasias Encefálicas , Neoplasias Colorretais , Síndromes Neoplásicas Hereditárias , Neurofibromatose 1 , Feminino , Humanos , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/genética , Mosaicismo , Estudos Retrospectivos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Encefálicas/genética , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA/genéticaRESUMO
OBJECTIVES: Posterior fossa ependymoma group A (EPN_PFA) and group B (EPN_PFB) can be distinguished by their DNA methylation and give rise to different prognoses. We compared the MRI characteristics of EPN_PFA and EPN_PFB at presentation. METHODS: Preoperative imaging of 68 patients with posterior fossa ependymoma from two centers was reviewed by three independent readers, blinded for histomolecular grouping. Location, tumor extension, tumor volume, hydrocephalus, calcifications, tissue component, enhancement or diffusion signal, and histopathological data (cellular density, calcifications, necrosis, mitoses, vascularization, and microvascular proliferation) were compared between the groups. Categorical data were compared between groups using Fisher's exact tests, and quantitative data using Mann-Whitney tests. We performed a Benjamini-Hochberg correction of the p values to account for multiple tests. RESULTS: Fifty-six patients were categorized as EPN_PFA and 12 as EPN_PFB, with median ages of 2 and 20 years, respectively (p = 0.0008). The median EPN_PFA tumoral volume was larger (57 vs 29 cm3, p = 0.003), with more pronounced hydrocephalus (p = 0.002). EPN_PFA showed an exclusive central position within the 4th ventricle in 61% of patients vs 92% for EPN_PFB (p = 0.01). Intratumor calcifications were found in 93% of EPN_PFA vs 40% of EPN_PFB (p = 0.001). Invasion of the posterior fossa foramina was mostly found for EPN_PFA, particularly the foramina of Luschka (p = 0.0008). EPN_PFA showed whole and homogeneous tumor enhancement in 5% vs 75% of EPN_PFB (p = 0.0008). All mainly cystic tumors were EPN_PFB (p = 0.002). The minimal and maximal relative ADC was slightly lower in EPN_PFA (p = 0.02 and p = 0.01, respectively). CONCLUSION: Morphological characteristics from imaging differ between posterior fossa ependymoma subtypes and may help to distinguish them preoperatively. CLINICAL RELEVANCE STATEMENT: This study provides a tool to differentiate between group A and group B ependymomas, which will ultimately allow the therapeutic strategy to be adapted in the early stages of patient management. KEY POINTS: ⢠Posterior fossa ependymoma subtypes often have different imaging characteristics. ⢠Posterior fossa ependymomas group A are commonly median or lateral tissular calcified masses, with incomplete enhancement, affecting young children and responsible for pronounced hydrocephalus and invasion of the posterior fossa foramina. ⢠Posterior fossa ependymomas group B are commonly median non-calcified masses of adolescents and adults, predominantly cystic, and minimally invasive, with total and homogeneous enhancement.
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Ependimoma , Hidrocefalia , Criança , Adulto , Adolescente , Humanos , Pré-Escolar , Adulto Jovem , Imageamento por Ressonância Magnética , Prognóstico , Ependimoma/diagnóstico por imagem , Ependimoma/genética , Ependimoma/patologia , CabeçaRESUMO
Somatic gene translocations are key to making an accurate diagnosis in many cancers including many pediatric sarcomas. Currently available molecular diagnostic approaches to identifying somatic pathognomonic translocations have limitations such as minimal multiplexing, high cost, complex computational requirements, or slow turnaround times. We sought to develop a new fusion-detection assay optimized to mitigate these challenges. To accomplish this goal, we developed a highly sensitive multiplexed digital PCR-based approach that can identify the gene partners of multiple somatic fusion transcripts. This assay was validated for specificity with cell lines and synthetized DNA fragments. Assay sensitivity was optimized using a tiered amplification approach for fusion detection from low input and/or degraded RNA. The assay was then tested for the potential application of fusion detection from FFPE tissue and liquid biopsy samples. We found that this multiplexed PCR approach was able to accurately identify the presence of seven different targeted fusion transcripts with a turnaround time of 1 to 2 days. The addition of a tiered amplification step allowed the detection of targeted fusions from as little as 1 pg of RNA input. We also identified fusions from as little as two unstained slides of FFPE tumor biopsy tissue, from circulating tumor cells collected from tumor-bearing mice, and from liquid biopsy samples from patients with known fusion-positive cancers. We also demonstrated that the assay could be easily adapted for additional fusion targets. In summary, this novel assay detects multiple somatic fusion partners in biologic samples with low tumor content and low-quality RNA in less than two days. The assay is inexpensive and could be applied to surgical and liquid biopsies, particularly in places with inadequate resources for more expensive and expertise-dependent assays such as next-generation sequencing.
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Fusão Gênica , Sarcoma , Animais , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Camundongos , Reação em Cadeia da Polimerase Multiplex , Proteínas de Fusão Oncogênica/genética , RNA/genética , Sarcoma/genéticaRESUMO
Circulating tumor DNA can be detected in the blood and body fluids of patients using ultrasensitive technologies, which have the potential to improve cancer diagnosis, risk stratification, noninvasive tumor profiling, and tracking of treatment response and disease recurrence. As we begin to apply "liquid biopsy" strategies in children with cancer, it is important to tailor our efforts to the unique genomic features of these tumors and address the technical and logistical challenges of integrating biomarker testing. This article reviews the literature demonstrating the feasibility of applying liquid biopsy to pediatric solid malignancies and suggests new directions for future studies.
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Biomarcadores Tumorais/análise , DNA Tumoral Circulante/análise , Neoplasias/sangue , Neoplasias/diagnóstico , Medicina de Precisão , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Humanos , Biópsia Líquida , Neoplasias/genéticaRESUMO
Advanced stage nodular lymphocyte predominant Hodgkin lymphoma (nLPHL) is extremely rare in children and as a consequence, optimal treatment for this group of patients has not been established. Here we retrospectively evaluated the treatments and treatment outcomes of 41 of our patients from the UK and France with advanced stage nLPHL. Most patients received chemotherapy, some with the addition of the anti CD20 antibody rituximab or radiotherapy. Chemotherapy regimens were diverse and followed either classical Hodgkin lymphoma or B non-Hodgkin lymphoma protocols. All 41 patients achieved a complete remission with first line treatment and 40 patients are alive and well in remission. Eight patients subsequently relapsed and 1 patient died of secondary cancer (9 progression-free survival events). The median time to progression for those who progressed was 21 months (5·9-73·8). The median time since last diagnosis is 87·3 months (8·44-179·20). Thirty-six (90%), 30 (75%) and 27 (68%) patients have been in remission for more than 12, 24 and 36 months, respectively. Overall, the use of rituximab combined with multi-agent chemotherapy as first line treatment seems to be a reasonable therapeutic option.
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Doença de Hodgkin/diagnóstico , Doença de Hodgkin/terapia , Adolescente , Biópsia , Criança , Pré-Escolar , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Feminino , Doença de Hodgkin/mortalidade , Humanos , Masculino , Imagem Multimodal , Estadiamento de Neoplasias , Recidiva , Retratamento , Resultado do TratamentoRESUMO
To study the management of acute appendicitis in neutropenic patients, we retrospectively reviewed cases of acute appendicitis in neutropenic children treated for cancer. The patients' demographics, medical records, and outcomes were tracked. We compared nonoperative treatment versus emergency or delayed surgery. The cases of 30 patients with a mean age of 8.8 years in 12 French departments of Pediatric Hematology/Oncology between 1995 and 2013 were studied. Most patients (90%) were treated for hematological malignancies. Seven of the 30 children were successfully treated with exclusive medical treatment. Early surgery was performed in 6 patients, and the remaining 17 underwent combined management with a first-line antibiotic treatment and delayed appendectomy. Treatments were successful in all cases with transitory complications in only 3 patients. No death linked to infection was reported. Surgery was well tolerated even in the neutropenic period. Appendix perforation was a major risk factor of prolonged hospitalization. Histologic as well as bacteriologic and mycologic/parasitologic analyses were required in case of surgery. Analysis of diagnostic assessments showed the major importance of imaging (ultrasonography and tomography) on diagnosis confirmation. We could not come to a conclusion in the few numbers of reviewed cases because of a significant difference in management strategies, but we can conclude that early surgery after adequate supportive care is an acceptable modality of treatment and must be chosen in the face of life-threatening conditions.
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Apendicite/complicações , Apendicite/terapia , Neutropenia/complicações , Adolescente , Apendicite/cirurgia , Criança , Pré-Escolar , Diagnóstico por Imagem , Feminino , Humanos , Lactente , Tempo de Internação , Masculino , Estudos Retrospectivos , Tempo para o Tratamento , Resultado do TratamentoAssuntos
Neoplasias Encefálicas/patologia , Glândula Pineal/patologia , Rabdomiossarcoma Alveolar/patologia , Biomarcadores Tumorais/líquido cefalorraquidiano , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Sistema Nervoso Central/patologia , Criança , Diagnóstico Diferencial , Regulação Neoplásica da Expressão Gênica/genética , Glioma/diagnóstico , Glioma/patologia , Humanos , Hipertensão Intracraniana , Masculino , Coativador 2 de Receptor Nuclear/genética , Coativador 2 de Receptor Nuclear/metabolismo , Fator de Transcrição 2 de Oligodendrócitos/metabolismo , Proteínas de Fusão Oncogênica/genética , Fator de Transcrição PAX3/genética , Fator de Transcrição PAX3/metabolismo , Rabdomiossarcoma Alveolar/diagnóstico , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Alveolar/metabolismoRESUMO
PURPOSE: To evaluate, in children with Hodgkin lymphoma (HL), the frequency and intensity of visually diffuse FDG uptake by selected organs at baseline (bPET) and on interim PET/CT (iPET), and to evaluate the relation between FDG uptake, metabolic response and evolution of the disease with treatment. PATIENTS AND METHODS: Thirty children with HL had bPET and then iPET after two cycles of treatment, which were blind-read retrospectively. Excluding sites with focal uptake, diffuse FDG uptake by thymus, bone marrow at iliac crests, liver, spleen, and the spinal cord at the 12th thoracic vertebra (Th12) was evaluated visually using a three-point scoring method and semiquantitatively by measuring SUVmax. Visualisation of activated brown adipose tissue (BAT) was also quoted. Five children had refractory HL. Recurrence-free survival was determined for each patient. Nine patients relapsed; in 21 non-relapsing patients, the median follow-up period was 43 months (range: 28-61). RESULTS: On bPET, the rate of diffuse and intense (visual score = 3) FDG uptake was 48 % in the spleen, 43 % in the spinal cord at Th12, 37 % in bone marrow, 21 % in the thymus and 7 % in BAT. At least one of those sites showed diffuse and intense FDG uptake in 77 % of patients. On iPET, a significant decrease in SUVmax was observed in thymus, iliac crest bone marrow and spleen, but not in spinal cord. In contrast, the FDG uptake by the liver significantly increased. The absence of SUVmax increase in the liver between bPET and iPET was the best criterion to predict a refractory disease (PPV = 55 %, NPV = 100 %). Its area under ROC (AUC) was 0.9 vs. 0.73 for five-point Deauville criteria. For prediction of relapse, two criteria were derived from the evolution of diffuse uptake between bPET and iPET: no increase in liver uptake and an increase > 5 % in spinal cord uptake. As compared with 13 patients who matched none of those criteria, the hazard ratio (HR) for relapse was 2.1 in 13 patients who matched one criterion, and 10.3 in four patients who matched both (Kaplan-Meier analysis p = 0.005). CONCLUSION: Diffuse and intense FDG uptake by organs is frequent in children with HL on bPET. On iPET, it is frequently reduced in all sites except the liver, which may pose problems for visual quotation of the FDG intensity of HL foci. The variation of SUVmax between bPET and iPET permitted us to achieve a prediction of refractory or relapsing HL that was at least as effective as using criteria based on FDG uptake by the HL lesions. The results of this retrospective pilot study need further validation.
Assuntos
Fluordesoxiglucose F18/metabolismo , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Adolescente , Transporte Biológico , Criança , Pré-Escolar , Difusão , Feminino , Doença de Hodgkin/terapia , Humanos , Masculino , Projetos PilotoRESUMO
High-grade osteosarcoma is the most common paediatric bone cancer. More than one third of patients relapse and die of osteosarcoma using current chemotherapeutic and surgical strategies. To improve outcomes in osteosarcoma, two crucial challenges need to be tackled: 1-the identification of hard-to-treat disease, ideally from diagnosis; 2- choosing the best combined or novel therapies to eradicate tumor cells which are resistant to current therapies leading to disease dissemination and metastasize as well as their favorable microenvironment. Genetic chaos, tumor complexity and heterogeneity render this task difficult. The development of new technologies like next generation sequencing has led to an improvement in osteosarcoma oncogenesis knownledge. This review summarizes recent biological and therapeutical advances in osteosarcoma, as well as the challenges that must be overcome in order to develop personalized medicine and new therapeutic strategies and ultimately improve patient survival.
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Neoplasias Ósseas , Osteossarcoma , Medicina de Precisão , Osteossarcoma/genética , Osteossarcoma/patologia , Humanos , Medicina de Precisão/métodos , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapiaRESUMO
BACKGROUND: Optic pathway gliomas (OPGs) represent 5% of childhood brain tumors. Successive relapses lead to multiple treatments exposing to late complications. METHODS: We included patients treated at Gustave Roussy (GR) between January 1980 and December 2015 for OPG, before 18 years old and alive at 5 years from diagnosis. Mortality and physical health conditions data were extracted from medical data files and updated, thanks to the GR long-term follow-up program and French national mortality registry for patients included in the French Childhood Cancer Survivor Study. RESULTS: We included 182 5-year OPG-childhood survivors in the analysis (sex ratio M/F 0.8, 35% with neurofibromatosis type 1 [NF1]). With a median follow-up of 17.2 years (rangeâ =â 5-41), we registered 82 relapses, 9 second malignancies, and 15 deaths as first events after 5 years, resulting in 20-year conditional overall survival (C-OS) and late events-free survival of 79.9% (95% confidence interval [CI]â =â 71-86) and 43.5% (95% CIâ =â 36-51), respectively. Radiotherapy exposure in NF1 patients (hazard ratio [HR] = 6, 95% CI = 1.7-21.2) and hypothalamic involvement (HR = 3.2, 95% CI = 1.4-7.3) were significantly associated with C-OS in multivariable analyses. Ninety-five percent of 5-year OPG survivors suffered from any health condition, especially visual acuity "<1/10" (nâ =â 109), pituitary deficiency (nâ =â 106), and neurocognitive impairment (nâ =â 89). NF1 (HR 2.1) was associated with precocious puberty. With a median time post-diagnosis of 4.2 years, 33 cerebrovascular events were observed in 21 patients. CONCLUSIONS: Late relapses, second malignancies, and cerebrovascular diseases are severe late events resulting in premature mortality. Morbidity is high and needs after-cancer care to improve quality of life. Risk factors could be considered to better stratify long-term follow-up.
Assuntos
Glioma do Nervo Óptico , Humanos , Masculino , Feminino , Glioma do Nervo Óptico/patologia , Glioma do Nervo Óptico/terapia , Criança , Pré-Escolar , Adolescente , Estudos Longitudinais , Seguimentos , Taxa de Sobrevida , Sobreviventes de Câncer/estatística & dados numéricos , Lactente , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/epidemiologia , Prognóstico , Adulto , Neurofibromatose 1/terapia , Neurofibromatose 1/complicações , Neurofibromatose 1/mortalidade , Neurofibromatose 1/patologia , Recém-NascidoRESUMO
PURPOSE: Supratentorial (ST) ependymoma subgroups are defined by two different fusions with different prognoses. Astroblastomas, MN1-altered, have ependymal-like histopathologic features and represent a differential diagnosis in children. We hypothesized that ZFTA-fused ependymoma and YAP1-fused ependymoma on the one hand, and astroblastoma, MN1-altered, on the other hand, show different MRI characteristics. METHODS: We retrospectively analyzed the preoperative imaging of 45 patients with ST ependymoma or astroblastoma between January 2000 and September 2020, blinded to histomolecular grouping. Several characteristics, such as location, tumor volume, calcifications, solid/cystic component, and signal enhancement or diffusion were evaluated. We compared imaging characteristics according to their molecular subtype (ZFTA-fused, YAP1-fused, and astroblastoma, MN1-altered). RESULTS: Thirty-nine patients were classified as having an ependymoma, 35 with a ZFTA fusion and four with a YAP1 fusion, and six as having an astroblastoma, MN1-altered. YAP1-fused ependymomas were more likely to involve at least 3 lobes than ZFTA-fused ependymomas. Astroblastomas were located in the frontal lobe in 100% of the tumors versus 49% of the ependymomas. Cerebral blood flow by arterial spin labeling was higher in astroblastomas than in ependymomas. There were no differences in the other characteristics between the molecular groups. All the tumors showed common features: intra-axial extra-ventricular tumors, very frequent contrast enhancement (39/43, 91%), a cystic/necrotic component (41/45, 91%), restricted diffusion (32/36, 89%), calcifications (15/18, 83%), and peri-tumoral edema (38/44, 86%). CONCLUSION: The distinction between ST ependymoma subtypes and astroblastomas can be guided by several imaging features. These tumors share common imaging features that may help to differentiate ST ependymomas and astroblastomas from other pediatric ST tumors.
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Erythroblastic sarcoma (ES) (previously called chloroma or granulocytic sarcoma) are rare hematological neoplams characterized by the proliferation of myeloid blasts at extramedullary sites, and primarily involve the skin and soft tissue of middle-aged adults. ES may be concomitant with or secondary to myeloid neoplasms (mostly acute myeloid leukemia (AML)) or in isolated cases (de novo) without infiltration of the bone marrow by blasts. ES share cytogenetic and molecular abnormalities with AML, including RUNX1T1 fusions. Some of these alterations seem to be correlated with particular sites of involvement. Herein, we report an isolated erythroblastic sarcoma with NFIA::RUNX1T1 located in the central nervous system (CNS) of a 3-year-old boy. Recently, two pediatric cases of CNS MS with complete molecular characterization have been documented. Like the current case, they concerned infants (2 and 3 years-old) presenting a brain tumor (pineal involvement) with leptomeningeal dissemination. Both cases also harbored a NFIA::RUNX1T3 fusion. ES constitutes a diagnostic challenge for neuropathologists because it does not express differentiation markers such as CD45, and may express CD99 which could be confused with CNS Ewing sarcoma. CD43 is the earliest pan-hematopoietic marker and CD45 is not expressed by erythroid lineage cells. E-cadherin (also a marker of erythroid precursors) and CD117 (expressed on the surface of erythroid lineage cells) constitute other immunhistochemical hallmarks of ES. The prognosis of patients with ES is similar to that of other patients with AML but de novo forms seem to have a poorer prognosis, like the current case. To conclude, pediatric ES with NFIA::RUNX1T1/3 fusions seem to have a tropism for the CNS and thus constitute a potential pitfall for neuropathologists. Due to the absence of circulating blasts and a DNA-methylation signature, the diagnosis must currently be made by highlighting the translocation and expression of erythroid markers.
Assuntos
Neoplasias do Sistema Nervoso Central , Leucemia Mieloide Aguda , Sarcoma Mieloide , Sarcoma , Pré-Escolar , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Medula Óssea/patologia , Neoplasias do Sistema Nervoso Central/patologia , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Fatores de Transcrição NFI/genética , Fatores de Transcrição NFI/metabolismo , Proteína 1 Parceira de Translocação de RUNX1/metabolismo , Sarcoma/metabolismo , Sarcoma/patologia , Sarcoma Mieloide/genética , Sarcoma Mieloide/diagnóstico , Sarcoma Mieloide/metabolismoRESUMO
PURPOSE: AcSé-ESMART Arm C aimed to define the recommended dose and activity of the WEE1 inhibitor adavosertib in combination with carboplatin in children and young adults with molecularly enriched recurrent/refractory malignancies. PATIENTS AND METHODS: Adavosertib was administered orally, twice every day on Days 1 to 3 and carboplatin intravenously on Day 1 of a 21-day cycle, starting at 100 mg/m2/dose and AUC 5, respectively. Patients were enriched for molecular alterations in cell cycle and/or homologous recombination (HR). RESULTS: Twenty patients (median age: 14.0 years; range: 3.4-23.5) were included; 18 received 69 treatment cycles. Dose-limiting toxicities were prolonged grade 4 neutropenia and grade 3/4 thrombocytopenia requiring transfusions, leading to two de-escalations to adavosertib 75 mg/m2/dose and carboplatin AUC 4; no recommended phase II dose was defined. Main treatment-related toxicities were hematologic and gastrointestinal. Adavosertib exposure in children was equivalent to that in adults; both doses achieved the cell kill target. Overall response rate was 11% (95% confidence interval, 0.0-25.6) with partial responses in 2 patients with neuroblastoma. One patient with medulloblastoma experienced unconfirmed partial response and 5 patients had stable disease beyond four cycles. Seven of these eight patients with clinical benefit had alterations in HR, replication stress, and/or RAS pathway genes with or without TP53 alterations, whereas TP53 pathway alterations alone (8/10) or no relevant alterations (2/10) were present in the 10 patients without benefit. CONCLUSIONS: Adavosertib-carboplatin combination exhibited significant hematologic toxicity. Activity signals and identified potential biomarkers suggest further studies with less hematotoxic DNA-damaging therapy in molecularly enriched pediatric cancers.
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Braço , Carcinoma , Pirazóis , Pirimidinonas , Criança , Adulto Jovem , Humanos , Adolescente , Carboplatina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Proteínas Tirosina Quinases , Proteínas de Ciclo CelularRESUMO
OBJECTIVE: Adamantinomatous craniopharyngioma mainly affects children. Excessive weight gain is a major long-term complication. The primary objective of this study was to assess long-term weight changes in children treated for craniopharyngioma. The secondary objectives were to identify risk factors for excessive weight gain and to look for associations with hypothalamic damage by the tumour or treatment. DESIGN: Single-centre retrospective cohort study. METHOD: Children managed for craniopharyngioma at our centre between 1990 and 2019 were included. The body mass index (BMI) standard deviation scores (SDS) at baseline and at last follow-up were compared. Univariate and multivariate analyses were performed in order to identify variables associated with the long-term BMI-SDS variation. RESULTS: The 108 patients had a mean follow-up of 10.4 years. The mean BMI-SDS increase over time was 2.11 (P < .001) overall, 1.21 (P < .001) in the group without hypothalamic involvement by the tumour, and 1.95 (P < .001) in the group managed using intended hypothalamus-sparing surgery. The absence of hypothalamic involvement by the tumour or treatment was significantly associated with less weight gain (P = .046 and P < .01, respectively). After adjustment, factors associated with a BMI-SDS change greater than 2 were female sex (P = .023), tumour involving the hypothalamus (P = .04), and higher baseline BMI (P < .001). CONCLUSION: Clinically significant weight gain occurred in nearly all children treated for craniopharyngioma, including those whose hypothalamus was spared by the tumour and intentionally by treatment. However, hypothalamus integrity was associated with less weight gain. Despite hypothalamus-sparing strategies, hypothalamic obesity remains a major concern, indicating a need for novel treatment approaches.
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Índice de Massa Corporal , Craniofaringioma , Neoplasias Hipofisárias , Aumento de Peso , Humanos , Craniofaringioma/epidemiologia , Craniofaringioma/complicações , Aumento de Peso/fisiologia , Masculino , Feminino , Criança , Estudos Retrospectivos , Neoplasias Hipofisárias/epidemiologia , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/complicações , Adolescente , Pré-Escolar , Seguimentos , Fatores de Risco , Hipotálamo , Estudos de CoortesRESUMO
Background: ELP1 pathogenic variants (PV) have been recently identified as the most frequent variants predisposing to Sonic Hedgehog (SHH) medulloblastomas (MB); however, guidelines are still lacking for genetic counseling in this new syndrome. Methods: We retrospectively reviewed clinical and genetic data of a French series of 29 ELP1-mutated MB. Results: All patients developed SHH-MB, with a biallelic inactivation of PTCH1 found in 24 tumors. Other recurrent alterations encompassed the TP53 pathway and activation of MYCN/MYCL signaling. The median age at diagnosis was 7.3 years (range: 3-14). ELP1-mutated MB behave as sporadic cases, with similar distribution within clinical and molecular risk groups and similar outcomes (5 y - OSâ =â 86%); no unusual side effect of treatments was noticed. Remarkably, a germline ELP1 PV was identified in all patients with available constitutional DNA (nâ =â 26); moreover, all tested familial trio (nâ =â 11) revealed that the PVs were inherited. Two of the 26 index cases from the French series had a family history of MB; pedigrees from these patients and from 1 additional Dutch family suggested a weak penetrance. Apart from MB, no cancer was associated with ELP1 PVs; second tumors reported in 4 patients occurred within the irradiation fields, in the usual time-lapse for expected radiotherapy-induced neoplasms. Conclusions: The low penetrance, the "at risk' age window limited to childhood and the narrow tumor spectrum, question the actual benefit of genetic screening in these patients and their family. Our results suggest restricting ELP1 germline sequencing to patients with SHH-MB, depending on the parents" request.
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PURPOSE: The study of cell-free DNA (cfDNA) enables sequential analysis of tumor cell-specific genetic alterations in patients with neuroblastoma. EXPERIMENTAL DESIGN: Eighteen patients with relapsing neuroblastoma having received lorlatinib, a third-generation ALK inhibitor, were identified (SACHA national registry and/or in the institution). cfDNA was analyzed at relapse for nine patients and sequentially for five patients (blood/bone marrow plasma) by performing whole-genome sequencing library construction followed by ALK-targeted ddPCR of the hotspot mutations [F1174L, R1275Q, and I1170N; variant allele fraction (VAF) detection limit 0.1%] and whole-exome sequencing (WES) to evaluate disease burden and clonal evolution, following comparison with tumor/germline WES. RESULTS: Overall response rate to lorlatinib was 33% (CI, 13%-59%), with response observed in 6/10 cases without versus 0/8 cases with MYCN amplification (MNA). ALK VAFs correlated with the overall clinical disease status, with a VAF < 0.1% in clinical remission, versus higher VAFs (>30%) at progression. Importantly, sequential ALK ddPCR detected relapse earlier than clinical imaging. cfDNA WES revealed new SNVs, not seen in the primary tumor, in all instances of disease progression after lorlatinib treatment, indicating clonal evolution, including alterations in genes linked to tumor aggressivity (TP53) or novel targets (EGFR). Gene pathway analysis revealed an enrichment for genes targeting cell differentiation in emerging clones, and cell adhesion in persistent clones. Evidence of clonal hematopoiesis could be observed in follow-up samples. CONCLUSIONS: We demonstrate the clinical utility of combining ALK cfDNA ddPCR for disease monitoring and cfDNA WES for the study of clonal evolution and resistance mechanisms in patients with neuroblastoma receiving ALK-targeted therapy.
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Quinase do Linfoma Anaplásico , Ácidos Nucleicos Livres , Evolução Clonal , Mutação , Neuroblastoma , Humanos , Neuroblastoma/genética , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Evolução Clonal/genética , Masculino , Feminino , Criança , Pré-Escolar , Ácidos Nucleicos Livres/genética , Aminopiridinas/uso terapêutico , Pirazóis/uso terapêutico , Lactamas , Lactente , Adolescente , Sequenciamento do Exoma , Inibidores de Proteínas Quinases/uso terapêutico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Terapia de Alvo Molecular/métodos , Biomarcadores Tumorais/genética , Sequenciamento Completo do Genoma/métodosAssuntos
Quinase do Linfoma Anaplásico/metabolismo , Linfoma Anaplásico de Células Grandes , Proteínas de Neoplasias/metabolismo , Nivolumabe/administração & dosagem , Adolescente , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Humanos , Linfoma Anaplásico de Células Grandes/diagnóstico , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/enzimologia , Linfoma Anaplásico de Células Grandes/patologia , Masculino , Proteínas de Neoplasias/antagonistas & inibidoresRESUMO
Temozolomide (TMZ) is part of the therapeutic armamentarium used in managing pediatric cancers; however, available oral forms (capsules) are not adapted for use in children. Our aim was to assess the dose accuracy and stability of TMZ using capsule contents mixed with food compared with a novel, ready-to-use liquid formulation specifically developed for children (Ped-TMZ, brand name KIZFIZO). Dose accuracy and TMZ stability testing were performed with TMZ capsule contents (90 mg) mixed with food vehicles (apple juice, apple sauce, cream, milk, and mashed potatoes) and compared to an equivalent dose of Ped-TMZ. Acceptance criteria were predefined for TMZ (95.0-105.0%) and its degradation product amino-imidazole-carboxamide (AIC; <1%) content. The delivered dose was significantly higher using Ped-TMZ (96.6 ± 1.2%) and within the predefined criteria for TMZ content, whereas it was systematically under the lower specifications of 95% using capsule-derived preparations with apple juice (91.0 ± 1.5%) and apple sauce (91.6 ± 1.4%), respectively (p < 0.0001). In chemical stability tests, the four food vehicles (apple sauce, cream, milk, mashed potatoes) had a significant effect on TMZ stability (p = 0.0042), and the AIC significantly increased with time in three of the four vehicles (p < 0.0001). Only 1/72 of preparations from capsules met the predefined acceptance criteria, whereas Ped-TMZ showed no TMZ loss, and the AIC remained within specifications. In conclusion, mixing TMZ capsule content with food may result in significant underexposure, possibly even greater in routine practice, as complete food intake by the child is unlikely.
RESUMO
Background: The co-occurrence of moyamoya vasculopathy and extra-optic pathway tumors is rare in neurofibromatosis type 1 (NF1), with only four cases described in the literature. Brain surgery in these patients may be challenging because of the risk of brain infarction after skin and dural incision. Given its percutaneous and minimally invasive nature, laser interstitial thermal therapy (LITT) is an ideal option for the treatment of brain tumors in these patients. Here, we report on two patients with NF1 and moyamoya syndrome (MMS) treated for a brain glioma with LITT, after cerebral revascularization. Cases: The first patient, with familial NF1, underwent bilateral indirect revascularization with multiple burr holes (MBH) for symptomatic MMS. Two years later, she was diagnosed with a left temporal tumor, with evidence of radiologic progression over 10 months. The second patient, also with familial NF1, developed unilateral MMS when he was 6 years old and was treated with MBH. At the age of 15 years, MRI showed a right cingular lesion, growing on serial MRIs. Both patients underwent LITT with no perioperative complications; they are progression free at 10 and 12 months, respectively, and the tumors have decreased in volume. Discussion: While the association of extra-optic neoplasm and moyamoya angiopathy is seldom reported in NF1, tumor treatment is challenging in terms of both avoiding stroke and achieving oncological control. Here, we show in 2 cases, that LITT could be a safe and effective option in these rare conditions.