RESUMEN
PURPOSE: High-risk medulloblastomas (HR-MB) may not respond to induction chemotherapy, with either post-induction stable (SD) or progressive disease (PD). There is no consensus regarding their optimal management. METHODS: A retrospective, multicentre study investigated patients with non-responder HR-MB treated according to the PNET HR + 5 protocol (NCT00936156) between 01/01/2009 and 31/12/2018. After two courses of etoposide and carboplatin (induction), patients with SD or PD were analyzed. Upon clinician's decision, the PNET HR + 5 protocol was either pursued with tandem high-dose chemotherapy (HDCT) and craniospinal irradiation (CSI) (continuation group) or it was modified (switched group). RESULTS: Forty-nine patients were identified. After induction, 37 patients had SD and 12 had PD. The outcomes were better for the SD group: the 5-y PFS and OS were 52% (95% CI 35-67) and 70% (95% CI 51-83), respectively, in the SD group while the 2-y PFS and OS were 17% (95% CI 3-41) and 25% (95% CI 6-50), respectively, in the PD group (p < 0.0001). The PNET HR + 5 strategy was pursued for 3 patients in the PD group, of whom only one survived. In the SD group, it was pursued for 24/37 patients whereas 13 patients received miscellaneous treatments including a 36 Gy CSI in 12 cases. Despite that continuation and switched group were well-balanced for factors impacting the outcomes, the latter were better in the continuation group than in the switched group: the 5-y PFS were 78% (95% CI 54-90) versus 0% (p < 0.001), and the 5-y OS were 78% (95% CI 54-90) versus 56% (95% CI 23-79) (p = 0.0618) respectively. In the SD group, multivariate analysis revealed that MYC amplification, molecular group 3, and a switched strategy were independent prognostic factors for progression. CONCLUSION: Patients with post-induction SD may benefit from HDCT and CSI, whereas patients with early PD will require new therapeutic approaches.
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Neoplasias Cerebelosas , Meduloblastoma , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Cerebelosas/tratamiento farmacológico , Neoplasias Cerebelosas/radioterapia , Humanos , Quimioterapia de Inducción , Meduloblastoma/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
PURPOSES: The purpose of this study was to retrospectively study embryonal tumors with multilayered rosettes (ETMR), a rare new entity that gathers ETAN-TR (embryonal tumor with abundant neuropil and true rosettes), ependymoblastomas, and medulloepitheliomas, in order to improve their descriptions and try to better define therapeutic modalities. METHODS: Patients with ETMR, ETAN-TR, ependymoblastoma, and medulloepithelioma treated in SFCE centres (Société Française de lutte contre les Cancers et les leucémies de l'Enfant et de l'adolescent) since 2000 were collected. Data were retrieved from clinical charts. RESULTS: Thirty-eight patients were included in the analysis. Seventeen had an ETAN-TR, 13 had a medulloepithelioma, and 8 had an ETMR. No ependymoblastoma was included. The median age at diagnosis was 31 months (range, 2.8-141 months). The predominant tumor location was supratentorial (66%); 18.4% patients had metastatic lesion. LIN28A expression was positive in 11/11 patients. Amplification of the locus 19q13.42 was positive in 10/12 patients. Thirty patients were treated according to the primitive neuroectodermal tumors of high risk (PNET-HR) protocol. The median time of follow-up was 0.9 years (range 0.1 to 15.3 years). The 1-year event-free survival (EFS) and overall survival (OS) were, respectively, 36% CI 95% (23-55) and 45% CI 95% (31-64). On multivariate analysis, complete surgical resection, radiotherapy, and high-dose chemotherapy were associated with a better overall survival with a relative risk of, respectively, 7.9 CI 95% (2.6-23.5) p < 0.0002, 41.8 CI 95% (9.4-186) p < 0.0001, and 3.5 CI 95% (1.3-9.5) p = 0.012. CONCLUSION: Prognosis of ETMR remains dismal despite multimodal therapy. LIN28A immunostaining and 19q13.42 amplification should be systematically done to secure the diagnosis. Complete surgical resection, radiotherapy, and high-dose chemotherapy are associated with better outcome.
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Neoplasias Encefálicas/terapia , Quimioterapia Adyuvante , Tumores Neuroectodérmicos Primitivos/terapia , Procedimientos Neuroquirúrgicos , Radioterapia Adyuvante , Neoplasias de la Médula Espinal/terapia , Neoplasias Encefálicas/patología , Niño , Preescolar , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Masculino , Análisis Multivariante , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias de Células Germinales y Embrionarias/terapia , Tumores Neuroectodérmicos Primitivos/patología , Neurópilo/patología , Pronóstico , Estudios Retrospectivos , Neoplasias de la Médula Espinal/patologíaRESUMEN
Background: SIOP-CNS-GCT-II European trial was opened for the treatment of patients of any age with central nervous system germ cell tumour (CNS-GCT). Four courses of pre-irradiation chemotherapy were delivered. The influence of patient age on chemotherapy related acute toxicity (CRAT) was assessed. Methods: CRAT was analysed according to age-groups: children (aged ≤11 years), adolescents (aged 12-17 years), adults (aged ≥18 years) and to chemotherapy type: CarboPEI (alternating etoposide-carboplatin/etoposide-ifosfamide) for non-metastatic germinoma; PEI (cisplatin-etoposide-ifosfamide) for standard-risk non-germinomatous GCT (NGGCT); PEI and high-dose PEI (HD-PEI), for high-risk or poorly responsive NGGCTs. Results: 296 patients were assessable for CRAT: 105 children, 121 adolescents, 70 adults (max age: 41 years). Median cumulative doses/m² of chemotherapy were similar among age-groups. The proportion of germinoma over NGGCT (and accordingly use of CarboPEI chemotherapy) was higher in the adult groups (79%) versus the other two groups (62%). Delay in chemotherapy ≥7 days was noticed in 27%, 38%, and 19% of children, adolescents, and adults, respectively. Grade ≥3 haematological and non-haematological adverse events (AEs) were observed in 94%/31%, 97%/36%, and 77%/21% of children, adolescents, and adults, respectively. No toxic death was reported. Grade ≥3 AEs and delayed chemotherapies were significantly rarer in adults when compared with adolescents, even when adjusted on chemotherapy type: odds ratio: 0.1 [95%CI 0.02-0.4], and 0.2 [95%CI 0.1-0.4] in the group treated with CarboPEI. Conclusion: Adult patients can be treated safely with a chemotherapy intensive protocol, with even less toxicity than that observed in adolescents. Further work is required to understand age-related differences regarding toxicity.
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A 9-year-old girl was managed according to the COPRALL 04 protocol for treatment of a relapse of acute lymphoblastic leukemia. Owing to a previous case of disseminated fusariosis, posaconazole was started 5 days before initiation of chemotherapy. Six days after the last dose of vincristine, the child reported symptoms of severe peripheral neuropathy, abdominal cramps, and constipation. After this, she developed fluctuations in her level of consciousness and seizures. After cessation of therapy with posaconazole, a complete resolution of the above occurred within 7 days. This case illustrates the possibility of vincristine toxicity exacerbated by coadministration of posaconazole. As posaconazole is an inhibitor of the isoenzyme CYP3A4, interactions with drugs that are metabolized via this pathway, such as vincristine, can be anticipated. Another possibility is that, like itraconazole, posaconazole may also inhibit P-glycoprotein-mediated vincristine efflux. Although case reports of neurotoxicity owing to possible interaction between itraconazole and vincristine exist in the literature, only 1 case report relating to the possible interaction between posaconazole and vincristine exists. Clinicians should be made aware of this possible drug-drug interaction.
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Antifúngicos/efectos adversos , Antineoplásicos Fitogénicos/efectos adversos , Micosis/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Triazoles/efectos adversos , Vincristina/efectos adversos , Antineoplásicos Fitogénicos/toxicidad , Niño , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Interacciones Farmacológicas , Femenino , Humanos , Micosis/complicaciones , Enfermedades del Sistema Nervioso/inducido químicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Recurrencia , Vincristina/toxicidadRESUMEN
BACKGROUND: The management of malignant germ cell tumors of the ovary (OMGCT) requires multidisciplinary expertise. We analyze the surgical and medical outcomes of a cohort of patients treated for OMGCT. PATIENTS AND METHODS: Data concerning diagnosis, surgery, and medical decisions were reviewed for all patients seen for postoperative management of OMGCT at the Centre Léon Bérard in Lyon and the Institut Curie in Paris between 1985 and 2003. Sixty patients aged 0.4 to 27.9 years (mean 12.8 years) at diagnosis were included. RESULTS: Twenty (53%) of 38 the International Federation of Gynecology and Obstetrics (FIGO) stage I tumors were staged Ix. All stage Ix tumors had been operated by a nongynecologic surgeon. Relapses occurred in 8 of 24 stage I tumors that were observed (0/8 stage Ia; 5/13 stage Ix (P = 0.044) and 3/3 stage Ic) versus 0/14 stage I treated by adjuvant chemotherapy (P = 0.0015). The risk of relapse was significantly increased if patients underwent postsurgical observation ((HR) = 4.5 (95% CI, 1.5 to 13.3)), and when the tumor contained yolk sac tumor (HR = 7.3 (95% CI, 2.3 to 22.7)). There was no significant prognostic value for age, stage, level of tumor markers at diagnosis, type of surgery, and type of chemotherapy. Five-year overall survival was 96.7%, and event free survival was 83.3%. CONCLUSION: Comprehensive staging after removal of localized OMGCT is crucial. It allows a safe observation strategy in stage Ia tumors. Patients with stages Ix and Ic tumors may benefit from adjuvant chemotherapy.
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Neoplasias de Células Germinales y Embrionarias/cirugía , Neoplasias Ováricas/cirugía , Quimioterapia Adyuvante , Niño , Disgerminoma/diagnóstico , Disgerminoma/cirugía , Tumor del Seno Endodérmico/patología , Tumor del Seno Endodérmico/cirugía , Trompas Uterinas/cirugía , Femenino , Humanos , Estadificación de Neoplasias , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Neoplasias Ováricas/diagnóstico , Ovariectomía , Radioterapia Adyuvante , Estudios Retrospectivos , Teratoma/diagnóstico , Teratoma/patología , Teratoma/cirugía , Resultado del TratamientoRESUMEN
Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6-dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96% of the patients), memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67%), as well as secondary aspergillosis (22%). Up to 92% of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95%), retention of decidual teeth (65%), osteopenia (50%), and hyperextensibility (50%). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90% of patients), antifungal prophylaxis (50%), and IgG infusions (53%) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic measures, including IgG infusions, are implemented.
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Huésped Inmunocomprometido/genética , Síndrome de Job/epidemiología , Síndrome de Job/genética , Factor de Transcripción STAT3/deficiencia , Factor de Transcripción STAT3/genética , Adolescente , Adulto , Distribución por Edad , Niño , Preescolar , Estudios Transversales , Análisis Mutacional de ADN , Bases de Datos Factuales , Eccema/epidemiología , Eccema/etiología , Femenino , Francia/epidemiología , Predisposición Genética a la Enfermedad/epidemiología , Heterocigoto , Humanos , Incidencia , Lactante , Recién Nacido , Síndrome de Job/complicaciones , Síndrome de Job/inmunología , Masculino , Persona de Mediana Edad , Fosforilación , Neumonía Bacteriana/epidemiología , Neumonía Bacteriana/etiología , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/etiología , Medición de Riesgo , Índice de Severidad de la Enfermedad , Distribución por Sexo , Transducción de Señal , Enfermedades Cutáneas Bacterianas/epidemiología , Enfermedades Cutáneas Bacterianas/etiología , Infecciones Estafilocócicas/epidemiología , Infecciones Estafilocócicas/etiología , Análisis de Supervivencia , Adulto JovenRESUMEN
PURPOSE: To determine whether the clinical and molecular biologic characteristics of the alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) subtypes have relevance independent of the presence or absence of the PAX/FOXO1 fusion gene. PATIENTS AND METHODS: The fusion gene status of 210 histopathologically reviewed, clinically annotated rhabdomyosarcoma samples was determined by reverse transcriptase polymerase chain reaction. Kaplan-Meier analysis was used to assess event-free survival and overall survival in fusion gene-negative ARMS (ARMSn; n = 39), fusion gene-positive ARMS (ARMSp; n = 94), and ERMS (n = 77). A total of 101 RMS samples were also profiled for whole-genome expression, and 128 were profiled for genomic copy number imbalances. Profiling data were analyzed by supervised and unsupervised methods to compare features related to histopathology and fusion gene status. Results were also projected by meta-analysis techniques across three separate publically available data sets. RESULTS: Overall and event-free survival, frequency of metastases, and distribution of site at initial presentation were not significantly different between ARMSn and ERMS. Consistent with this, analysis of gene expression signatures could not reproducibly distinguish ARMSn from ERMS whereas fusion gene-positive cases were distinct. ARMSn and ERMS frequently show whole-chromosome copy number changes, notably gain of chromosome 8 with associated high levels of expression of genes from this chromosome. CONCLUSION: The clinical behavior and molecular characteristics of alveolar cases without a fusion gene are indistinguishable from embryonal cases and significantly different from fusion-positive alveolar cases. This implies that fusion gene status irrespective of histology is a critical factor in risk stratification of RMS.
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Cromosomas Humanos Par 8 , Pruebas Genéticas , Proteínas de Fusión Oncogénica/genética , Factor de Transcripción PAX7/genética , Factores de Transcripción Paired Box/genética , Rabdomiosarcoma Alveolar/diagnóstico , Rabdomiosarcoma Embrionario/diagnóstico , Niño , Preescolar , Diagnóstico Diferencial , Supervivencia sin Enfermedad , Femenino , Francia , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Masculino , Coactivador 1 de Receptor Nuclear/genética , Factor de Transcripción PAX3 , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rabdomiosarcoma Alveolar/genética , Rabdomiosarcoma Alveolar/mortalidad , Rabdomiosarcoma Alveolar/patología , Rabdomiosarcoma Alveolar/terapia , Rabdomiosarcoma Embrionario/genética , Rabdomiosarcoma Embrionario/mortalidad , Rabdomiosarcoma Embrionario/patología , Rabdomiosarcoma Embrionario/terapia , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Reino UnidoRESUMEN
This work was conducted by the French Brain Tumor Data Bank (FBTDB) and aims to prospectively record all primary central nervous system tumors (PCNST), in France, for which histological diagnosis is available. Results concerning children are presented. This study analyzes the childhood cases (0-19 years) of newly diagnosed and histologically confirmed PCNST (during the years 2004-2006) which have been recorded by the FBTDB. All French neuropathology and neurosurgery departments participated in this program. Neurosurgeons and neuropathologists completed a data file containing socio-demographic, clinical, radiologic and anatomopathologic information. The Tumor Registry from Herault was authorized to compile the data files with personal identifiers. About 1,017 cases (533 boys and 484 girls) of newly diagnosed childhood PCNST have been recorded (gliomas: 52%, all other neuroepithelial tumors: 31%, craniopharyngioma: 5%, germ cell tumors, meningioma and neurinoma: approximately 3% each, all histological subtypes have been detailed). Tumor resections were performed in 83.3%, and biopsies in 16.7%. The distributions by histology, cryopreservation of the samples, age, sex, tumor site and surgery have been detailed. To our knowledge, this work is the first databank in Europe dedicated to PCNST that includes the collection of clinical, radiological and histological data (including cryopreservation of the specimen). The long term goals of the FBTDB are to create a national registry and a network to perform epidemiological studies, to implement clinical and basic research protocols, and to evaluate and harmonize the healthcare of children and adult patients affected by PCNST.