RESUMEN
Chordomas are rare, malignant bone tumors of the skull-base and axial skeleton. Until recently, there was no consensus among experts regarding appropriate clinical management of chordoma, resulting in inconsistent care and suboptimal outcomes for many patients. To address this shortcoming, the European Society of Medical Oncology (ESMO) and the Chordoma Foundation, the global chordoma patient advocacy group, convened a multi-disciplinary group of chordoma specialists to define by consensus evidence-based best practices for the optimal approach to chordoma. In January 2015, the first recommendations of this group were published, covering the management of primary and metastatic chordomas. Additional evidence and further discussion were needed to develop recommendations about the management of local-regional failures. Thus, ESMO and CF convened a second consensus group meeting in November 2015 to address the treatment of locally relapsed chordoma. This meeting involved over 60 specialists from Europe, the United States and Japan with expertise in treatment of patients with chordoma. The consensus achieved during that meeting is the subject of the present publication and complements the recommendations of the first position paper.
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Cordoma/terapia , Guías de Práctica Clínica como Asunto , Humanos , Recurrencia Local de NeoplasiaRESUMEN
PURPOSE: Monte Carlo (MC) simulations can be used to accurately simulate dose and linear energy transfers (LET) distributions, thereby allowing for the calculation of the relative biological effectiveness (RBE) of protons. We present hereby the validation and implementation of a workflow for the Monte Carlo modelling of the double scattered and pencil beam scanning proton beamlines at our institution. METHODS: The TOPAS/Geant4 MC model of the clinical nozzle has been comprehensively validated against measurements. The validation also included a comparison between simulated clinical treatment plans for four representative patients and the clinical treatment planning system (TPS). Moreover, an in-house tool implemented in Python was tested to assess the variable RBE-weighted dose in proton plans, which was illustrated for a patient case with a developing radiation-induced toxicity. RESULTS: The simulated range and modulation width closely matches the measurements. Gamma-indexes (3%/3mm 3D), which compare the TPS and MC computations, showed a passing rate superior to 98%. The calculated RBE-weighted dose presented a slight increase at the necrosis location, within the PTV margins. This indicates the need for reporting on the physical and biological effects of irradiation in high dose regions, especially at the healthy tissues and increased LET distributions location. CONCLUSION: The results demonstrate that the Monte Carlo method can be used to independently validate a TPS calculation, and to estimate LET distributions. The features of the in-house tool can be used to correlate LET and RBE-weighted dose distributions with the incidence of radiation-induced toxicities following proton therapy treatments.
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Terapia de Protones , Traumatismos por Radiación , Humanos , Terapia de Protones/efectos adversos , Terapia de Protones/métodos , Protones , Estudios Retrospectivos , Dosificación Radioterapéutica , Método de Montecarlo , Flujo de Trabajo , Planificación de la Radioterapia Asistida por Computador/métodos , AlgoritmosRESUMEN
PRIMARY OBJECTIVE: Childhood craniopharyngioma, a benign tumour with a good survival rate, is associated with important neurocognitive and psychological morbidity, reducing quality-of-life (QoL). METHOD: This retrospective study analysed QoL, mood disorders, everyday executive functioning and disease's impact on family life in 29 patients (mean age at diagnosis 7 years 10 months (SD = 4.1); mean follow-up period 6 years 2 months (SD = 4.5)) treated for childhood craniopharyngioma by surgery combined with radiotherapy using proton beam. Assessment included a semi-structured interview and standardized scales evaluating self-report of QoL (Kidscreen 52) and depression (MDI-C) and proxy-reports of QoL (Kidscreen 52), executive functioning (BRIEF) and disease's impact (Hoare and Russel Questionnaire). RESULTS: Twenty-three families answered the questionnaires completely. Overall QoL self-report was within the normal range. QoL proxy-report was lower than self-report. Eleven patients reported depression; 24-38% had dysexecutive symptoms. A majority of families felt 'very concerned' by the disease. Depression and low parental educational level were associated with lower QoL and higher levels of executive dysfunction. CONCLUSION: Given the high morbidity of childhood craniopharyngioma, screening for psychosocial outcome, cognitive functioning, including executive functions, mood and QoL should be systematic and specific interventions should be developed and implemented.
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Afecto , Craneofaringioma/psicología , Craneofaringioma/terapia , Función Ejecutiva , Neoplasias Hipofisarias/psicología , Neoplasias Hipofisarias/terapia , Terapia de Protones , Calidad de Vida , Actividades Cotidianas , Adolescente , Niño , Preescolar , Depresión/etiología , Femenino , Humanos , Lactante , Masculino , Pruebas Neuropsicológicas , Radioterapia Adyuvante , Estudios Retrospectivos , Autoinforme , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
Medulloblastoma patients treated at the Institute Curie between 1980 and 2000 were reviewed. Only patients whose primary treatment included craniospinal radiation were considered. Surviving patients were identified and evaluated by means of self-report questionnaires using the Health Utility Index (HUI). Psychosocial functioning, employment, and other health-related indicators were recorded. Seventy-three patients were treated during the study period. At a median follow-up from diagnosis of 14.4 years, 49 patients were alive and 45 surviving patients could be contacted. Late sequelae were frequent, particularly neurological deficits (71%) and endocrine complications (52%). Impairments of psychosocial functioning, including employment, driving capacity, independent living, and marital status, were identified in most patients. Most long-term medulloblastoma survivors suffer persistent deficits in several domains, with a significant impact on their psychosocial functioning. These findings reinforce the importance of early intervention programs for all survivors in order to reduce the psychosocial impacts of their disease.
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Neoplasias Cerebelosas/radioterapia , Irradiación Craneana , Meduloblastoma/radioterapia , Calidad de Vida , Neoplasias de la Médula Espinal/radioterapia , Adolescente , Neoplasias Cerebelosas/mortalidad , Neoplasias Cerebelosas/psicología , Niño , Preescolar , Femenino , Estudios de Seguimiento , Estado de Salud , Humanos , Lactante , Masculino , Meduloblastoma/mortalidad , Meduloblastoma/psicología , Pronóstico , Neoplasias de la Médula Espinal/mortalidad , Neoplasias de la Médula Espinal/psicología , Encuestas y Cuestionarios , Tasa de Supervivencia , Sobrevivientes , Resultado del TratamientoRESUMEN
Among over 100 proton therapy centres worldwide in operation or under construction, French proton therapy is coming to full maturity with the recent opening of the Nice (1991, upgrade in 2016) and Caen (2018) facilities next to the Orsay (1991, upgrade in 2010) centre. Proton therapy is a national priority for children and young adults in all three centres. The patient-related activity of the three French centres is coordinated via the Protonshare portal to optimise referral by type of indication and available expertise in coordination with the French society of radiation oncology SFRO and French radiotherapy centres. The centres are recognised by the French Health Care excellence initiative, promoted by the ministry of Foreign Affairs. The three centres collaborate structurally in terms of clinical research and are engaged at the international level in the participation to European databases and research initiatives. Concerted actions are now also promoted in preclinical research via the Radiotransnet network. Ongoing French developments in proton therapy are well presented in international hadron therapy meetings, including European Proton Therapy Network and Particle Therapy Cooperative Oncology Group. Proton therapy teaching in France is offered at several levels and is open to colleagues from all radiation oncology centres, so that they are fully informed, involved and trained to facility recognition of possible indications and thereby to contribute to appropriate patient referral. This close collaboration between all actors in French radiation oncology facilitates the work to demonstrate the required level of medical and scientific evidence for current and emerging indications for particle therapy. Based on that, the future might entail a possible creation of more proton therapy facilities in France.
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Instituciones Oncológicas , Neoplasias/radioterapia , Terapia de Protones , Oncología por Radiación , Adolescente , Adulto , Investigación Biomédica/organización & administración , Instituciones Oncológicas/organización & administración , Instituciones Oncológicas/provisión & distribución , Niño , Ciclotrones/provisión & distribución , Apoyo Financiero , Francia , Humanos , Cooperación Internacional , Terapia de Protones/economía , Terapia de Protones/instrumentación , Terapia de Protones/métodos , Oncología por Radiación/educación , Oncología por Radiación/organización & administración , Adulto JovenRESUMEN
After a request for proposal initiated by National Institute against cancer (INCa) in 2005, three French centers in France started tomotherapy in the first semester of 2007. A national policy of evaluation was performed to study the feasibility of this innovative technique and to compare the interest of helicoidal tomotherapy with other modalities of conformal therapy. Common protocols have been designed to facilitate this evaluation. Description of dose, IMRT levels and constraints are achieved according to each selected indication as: sarcoma, head and neck tumors, lung cancer, mesothelioma, bone metastases, anal carcinoma and craniospinal irradiation.
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Neoplasias/radioterapia , Radioterapia Conformacional/métodos , Tomografía Computarizada Espiral/métodos , Adulto , Factores de Edad , Protocolos Clínicos , Irradiación Craneana/métodos , Estudios de Factibilidad , Femenino , Francia , Humanos , Masculino , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador , Radioterapia Conformacional/efectos adversos , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Factores de Riesgo , Factores Sexuales , Factores de TiempoRESUMEN
AIM: Improvement of EFS of children older than 3 years with high risk medulloblastoma. METHODS: Between 1993 and 1999, 115 patients (3-18 years, mean 8 years) with high risk medulloblastoma were included. After surgery treatment consisted of chemotherapy ('8in1' and etoposide/carboplatin) before and after craniospinal radiotherapy. RESULTS: Patients were staged using Chang-criteria (PF residue only, M1 and M2/M3) by local investigator as well as by central review panel (82.4% concordance). Chemotherapy was well tolerated without major delays in radiotherapy. With a mean follow up of 81 months (9-119), 5-year EFS was 49.8% and OS 60.1%. In detail according to subgroups EFS was 68.8% for PF residue only, 58.8% for M1 disease and 43.1% for M2/M3. CONCLUSION: M1 patients are legitimate high risk patients. Survival rates are still very low for high risk medulloblastoma patients and future trials should therefore focus on more intensive (chemotherapy/radiotherapy) treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Cerebelosas , Meduloblastoma , Adolescente , Carboplatino/administración & dosificación , Neoplasias Cerebelosas/tratamiento farmacológico , Neoplasias Cerebelosas/radioterapia , Neoplasias Cerebelosas/cirugía , Niño , Preescolar , Terapia Combinada/métodos , Supervivencia sin Enfermedad , Etopósido/administración & dosificación , Humanos , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/radioterapia , Meduloblastoma/cirugía , Cuidados Posoperatorios , Estudios Prospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
PURPOSE: Radiotherapy is a rare indication in paediatric oncology, with 800 to 900 children in treatment per year in France. Child cancers represent approximately 1% of cancers in France and half occur before the age of 5 years. Paediatric radiation requires appropriate tools, local, time and specific training. In France, in 2015, 18 centres are accredited by the French National Cancer Institute (INCa) for this activity. MATERIAL AND METHODS: Survey conducted in February 2015 on the care of children (0 to 18 years) in radiotherapy departments in France. The survey was sent to the radiation oncologists involved in the 18 centres. The questions concerned the qualitative and quantitative aspect, medical and organizational aspects, and the involvement of assistant practitioners in the management of this activity. RESULTS: Seventeen centres responded. In 2014, 889 children under 18 were treated in radiotherapy departments. These departments are working together with one to four paediatric oncology departments. Regarding access to general anaesthesia: three centres perform one to seven treatment(s) under anaesthesia per year, three centres eight to ten treatments under anaesthesia per year, three centres ten to 24 treatments under anaesthesia per year and nine centres out of 17 use hypnosis techniques. In terms of human resources, in 2015, 29 radiation therapists have a paediatric radiotherapy activity. Involvement of assistant practitioners is growing and specific training are desired. Regarding treatment preparation and delivery, 13 centres have specific paediatric contentions, 14 of 16 centres employ radiation intensity modulated if dosimetry is more satisfying with 11 regularly to the craniospinal irradiation. Radiotherapy on moving areas with respiratory gating or hypofractionation is under developed. CONCLUSION: Paediatric radiation therapy is a specific activity requiring a dedicated management, both in human, organizational, medical and scientific aspects.
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Pediatría , Pautas de la Práctica en Medicina/estadística & datos numéricos , Radioterapia/métodos , Radioterapia/estadística & datos numéricos , Técnicos Medios en Salud/estadística & datos numéricos , Anestesia General/estadística & datos numéricos , Niño , Francia , Humanos , Neoplasias/radioterapia , Sociedades Médicas , Encuestas y Cuestionarios , Tecnología Radiológica , Recursos HumanosRESUMEN
A survey was conducted in 2015 in France on the care of children in radiotherapy services. We present the results for total body irradiation in children, a specific technique of radiation treatment, which needs dedicated controls for this particular population. Of the 17 centres interviewed, 16 responded, and 13 practiced total body irradiation. Patients are positioned in lateral decubitus in 11 centres and supine/prone in two centres. Doses used for total body irradiation in myeloablative bone marrow transplantation are the same in all centres (12Gy); treatments are always fractionated. Lung shielding is positioned to limit the dose at an average of 8Gy with extremes ranging from 6 to 10Gy. The shape of the shieldings varies depending on departments' protocol, with a smaller size in case of mediastinal mass. Four centres have experience of total body irradiation under general anaesthesia, despite twice-daily fractions. In total, practice is relatively homogeneous throughout France and is inspired by the knowledge obtained in adults.
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Pautas de la Práctica en Medicina/estadística & datos numéricos , Irradiación Corporal Total/estadística & datos numéricos , Anestesia General/estadística & datos numéricos , Niño , Francia , Humanos , Órganos en Riesgo , Posicionamiento del Paciente/estadística & datos numéricos , Protección Radiológica/estadística & datos numéricos , Dosificación Radioterapéutica , Encuestas y CuestionariosRESUMEN
Fanconi anemia belongs to a group of human genetic diseases characterized by chromosomal instability, sensitivity to genotoxic agents associated to impaired processing of DNA lesions, cell cycle anomalies and cancer predisposition. We recently added to this list of distinctive features reduced production of interleukin 6 and overproduction of tumor necrosis factor alpha. Since growth factor deprivation, TNF alpha treatment or DNA damage can trigger apoptosis, we monitored the apoptotic response of FA cell lines. We show here that, although the spontaneous rate of apoptosis is slightly more elevated in FA than in normal cell cultures, the apoptosis induced by gamma-irradiation is drastically reduced in FA. Since the induction of apoptosis by radiation is a p53-dependent mechanism, the induction of this protein in FA cells was also examined. We found that the p53 protein is not radio-induced in FA cells belonging to the two genetic complementation groups examined (C and D), in contrast to normal cells. Moreover, the same impairment in p53 induction is observed after exposure to mitomycin C, a chemical agent for which FA cells demonstrate a specific cellular and chromosomal hypersensitivity, as well as after u.v.-B irradiation, an agent known to cause oxidative stress. These observations are in line with recent reports showing that at least certain cell lines from other chromosome breakage syndromes, such as ataxia telangiectasia and Bloom syndrome, may be also defective for radiation-induced increase of p53 protein. As the p53 tumor suppressor gene encodes a transcriptional activator whose targets include genes that regulate genomic stability, cellular response to DNA damage and cell cycle progression, we suggest that altered expression of p53 may be relevant to the FA phenotype.
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Anemia de Fanconi/patología , Genes p53 , Linfocitos/efectos de la radiación , Ciclo Celular , Células Cultivadas , Anemia de Fanconi/genética , Humanos , Linfocitos/metabolismo , Linfocitos/patología , FenotipoRESUMEN
Medulloblastoma are cerebellar tumours belonging to the group of primitive neuroectodermal tumours (PNET) and are the most common malignant brain tumours of childhood. These tumours are rare and heterogeneous, requiring some multicentric prospective studies and multidisciplinary care. The classical therapeutic approaches are based on clinical, radiological and surgical data. They involve surgery, radiation therapy and chemotherapy. Some histological features were added to characterize risk. More recently, molecular knowledge has allowed to devise risk-adapted strategies and helped to define groups with good outcome and reduce long-term sequelae, improve the prognostic of high-risk medulloblastoma and develop new therapeutic tools.
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Neoplasias Cerebelosas/terapia , Meduloblastoma/terapia , Adulto , Neoplasias Cerebelosas/clasificación , Neoplasias Cerebelosas/diagnóstico , Neoplasias Cerebelosas/metabolismo , Quimioterapia Adyuvante , Niño , Discapacidades del Desarrollo/etiología , Predisposición Genética a la Enfermedad , Proteínas Hedgehog/metabolismo , Humanos , Imagen por Resonancia Magnética , Meduloblastoma/clasificación , Meduloblastoma/diagnóstico , Meduloblastoma/metabolismo , Mutismo/etiología , Recurrencia Local de Neoplasia , Cuidados Posoperatorios , Pronóstico , Radioterapia Adyuvante , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Proteínas Wnt/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Brain tumours are the most frequent solid tumours in children and the most frequent radiotherapy indications in paediatrics, with frequent late effects: cognitive, osseous, visual, auditory and hormonal. A better protection of healthy tissues by improved beam ballistics, with particle therapy, is expected to decrease significantly late effects without decreasing local control and survival. This article reviews the scientific literature to advocate indications of protontherapy and carbon ion therapy for childhood central nervous system cancer, and estimate the expected therapeutic benefits. MATERIALS AND METHODS: A systematic review was performed on paediatric brain tumour treatments using Medline (from 1966 to March of 2014). To be included, clinical trials had to meet the following criteria: age of patients 18 years or younger, treated with radiation, and report of survival. Studies were also selected according to the evidence level. A secondary search of cited references found other studies about cognitive functions, quality of life, the comparison of photon and proton dosimetry showing potential dose escalation and/or sparing of organs at risk with protontherapy; and studies on dosimetric and technical issues related to protontherapy. RESULTS: A total of 7051 primary references published were retrieved, among which 40 clinical studies and 60 papers about quality of life, dose distribution and dosimetry were analysed, as well as the ongoing clinical trials. These papers have been summarized and reported in a specific document made available to the participants of a final 1-day workshop. Tumours of the meningeal envelop and bony cranial structures were excluded from the analysis. Protontherapy allows outstanding ballistics to target the tumour area, while substantially decreasing radiation dose to the normal tissues. There are many indications of protontherapy for paediatric brain tumours in curative intent, either for localized treatment of ependymomas, germ-cell tumours, craniopharyngiomas, low-grade gliomas; or panventricular irradiation of pure non-secreting germinoma; or craniospinal irradiation of medulloblastomas and metastatic pure germinomas. Carbon ion therapy is just emerging and may be studied for highly aggressive and radioresistant tumours, as an initial treatment for diffuse brainstem gliomas, and for relapse of high-grade gliomas. CONCLUSION: Both protontherapy and carbon ion therapy are promising for paediatric brain tumours. The benefit of decreasing late effects without altering survival has been described for most paediatric brain tumours with protontherapy and is currently assessed in ongoing clinical trials with up-to-date proton devices. Unfortunately, in 2015, only a minority of paediatric patients in France can receive protontherapy due to the lack of equipment.
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Neoplasias Encefálicas/radioterapia , Niño , Predicción , Radioterapia de Iones Pesados , Humanos , Guías de Práctica Clínica como Asunto , Terapia de ProtonesRESUMEN
Xeroderma pigmentosum (XP) and trichothiodystrophy (TTD) are autosomal recessive diseases associated with extreme cutaneous photosensitivity, a defect in nucleotide excision repair (NER), and genetic complexity. Severe prognosis and lack of treatment led families at risk to request genetic counseling. Unscheduled DNA synthesis (UDS) is the classic method for diagnosis and requires 4 to 5 wk before conclusion. The use of the alkaline comet assay (single cell gel electrophoresis assay) is proposed as a simple repair test for earlier prenatal diagnosis. Amniotic or chorionic villus cells in two pregnancies at risk for XP and one for TTD were examined in comparison with skin fibroblasts of family members or with repair-proficient or -deficient control cells. The comet assay and the UDS test were performed in parallel. In repair-proficient cells, DNA strand breaks due to the incision of UV-induced DNA damage result in increased migration of high molecular weight DNA in the comet assay. Fetal cells demonstrate repair capacity similar to that of fibroblasts. In incision repair-deficient XP and TTD cells, after post-UV incubation, migration does not occur and comet moments are reduced. Two fetuses belonging to two XP families responded normally and were diagnosed as unaffected. Fetal cells in a TTD family had reduced comet moments and a low UDS. This fetus was diagnosed and confirmed later as affected. Heterozygotes had normal responses with both assays. The comet assay offers discrimination similar to that of the UDS assay in identifying NER-deficient phenotypes. Practical advantages in view of prenatal diagnosis include the reduced number of cells required, a 24-h delay in obtaining results, and no need for radioactivity.
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Reparación del ADN , Electroforesis/métodos , Enfermedades del Cabello/diagnóstico , Enfermedades del Cabello/genética , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/genética , Diagnóstico Prenatal , Xerodermia Pigmentosa/diagnóstico , Xerodermia Pigmentosa/genética , Células Cultivadas/efectos de la radiación , Daño del ADN/efectos de la radiación , Femenino , Feto/citología , Humanos , Masculino , Microscopía Fluorescente , Embarazo , Azufre/metabolismo , Rayos UltravioletaRESUMEN
Childhood malignant brain stem tumours have a very poor prognosis with a median survival of 9 months despite radiotherapy. No chemotherapy has improved survival. However, carboplatin has been reported to have activity in glial tumours as well as antitumour synergy with radiation. Our aims were to test the response rate of these tumours to carboplatin alone and to evaluate the efficacy on survival of carboplatin alone followed by concurrent carboplatin and radiotherapy. Patients younger than 16 years with typical clinical and radiological presentation of infiltrating brain stem tumour, as well as histologically-documented cases in the atypical forms, were eligible. Two courses of carboplatin (1050 mg/m2 over 3 days) were administered initially. This treatment was followed by a chemoradiotherapy phase including five weekly carboplatin courses (200 mg/m2) and conventional radiotherapy. 38 eligible patients were included. No tumour response was observed after the initial phase. This schedule of first-line carboplatin followed by concurrent carboplatin and radiotherapy did not improve survival.
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Antineoplásicos/uso terapéutico , Neoplasias del Tronco Encefálico/tratamiento farmacológico , Neoplasias del Tronco Encefálico/radioterapia , Carboplatino/uso terapéutico , Adolescente , Niño , Preescolar , Terapia Combinada/métodos , Femenino , Humanos , Masculino , Análisis de SupervivenciaRESUMEN
PURPOSE: Patients with a history of head and neck irradiation in childhood are at risk to develop thyroid tumors. The aim of this study was to determine if an impairement of DNA strand breaks repair could account for this observation. METHODS AND MATERIALS: Circulating unstimulated lymphocytes of a group of 13 patients who developed thyroid tumors after radiotherapy were submitted to the alkaline single-cell gel electrophoresis assay (SCGE or "comet" assay) after in vitro exposure to 2 and 5 Gy of gamma-rays. A control group of 8 healthy donors and 2 cases with a history of neck irradiation who did not develop a thyroid tumor were also analysed. The immediate response was compared to that observed after 15, 30, and 60 min of postexposure incubation periods. RESULTS: Induction of DNA strand breaks is a dose-dependent process. The SCGE assay parameters did not differ significantly between patients and controls immediately (t=0) after irradiation at the two doses used. As compared to healthy donors, a slower kinetics of repair was found in the patients. The proportion of residual damage at 60 min postirradiation was significantly (p < 0.01) higher in patients than in controls, at both doses analysed. Flow cytometric analysis of apoptosis and p53 protein status studied before and after irradiation showed no apparent relationship with the repair capacity. CONCLUSION: This preliminary study suggests that a subgroup of patients who develop thyroid tumors after a history of irradiation are partially defective in the late restitution of in vitro radiation-induced DNA strand breaks. This deficiency could be a predisposing factor to radiation-associated thyroid tumorigenesis. Detection of susceptible individuals using the simple and rapid comet assay, especially children receiving radiotherapeutic treatment, may allow a preventive surveillance for radiation-associated epithelial thyroid tumor development.
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Reparación del ADN , Neoplasias Inducidas por Radiación/genética , Neoplasias de la Tiroides/genética , Adulto , Apoptosis , ADN/efectos de la radiación , Daño del ADN , Electroforesis/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Glándula Tiroides/efectos de la radiaciónRESUMEN
PURPOSE: Using magnetic resonance (MR) and isotopic imaging to investigate the cerebral alterations after highdose single-fraction irradiation on a pig model. We assessed the nuclear magnetic resonance (NMR) relaxation times as early markers of radiation injury to the healthy brain. METHODS AND MATERIALS: A total of 17 animals was studied; 15 irradiated and 2 unirradiated controls. Pigs were irradiated with a 12 MeV electron beam at a rate of 2 Gy/min. Ten animals received 40 Gy at the 90% isodose, five animals received 60 Gy, and two animals were unirradiated. The follow-up intervals ranged from 2 days to 6 months. T1-weighted scans, T2-weighted scans, and scintigrams were performed on all animals to study neurological abnormalities, cerebral blood flow, and blood-brain barrier (BBB) integrity. T1 and T2 relaxation times were measured in selected regions of interest (ROIs) within the irradiated and contralateral hemispheres. A ratio T1 after irradiation/T1 before irradiation, and a ratio T2 after irradiation/T2 before irradiation, were calculated, pooled for each dose group, and followed as a function of time after irradiation. RESULTS: Scintigraphy visualized the brain perfusion defect and BBB disruption in all irradiated brains. The ratio T2 after irradiation/T2 before irradiation was proportional to the effective dose received. The T2 ratio kinetics could be analyzed in three phases:an immediate and transient phase, two long-lasting phases, which preceded compression of the irradiated lateral ventricle, and edema and necrosis at later stages of radiation injury, respectively. The magnetic resonance imaging (MRI) observations correlated well with histological analysis. CONCLUSION: The results show that quantitative imaging is a sensitive in vivo method for early detection of cerebral radiation injury. The reliability and dose dependence of T2 relaxation time may offer new opportunities to detect and understand brain pathophysiology after high-dose single-fraction irradiation.
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Encéfalo/efectos de la radiación , Imagen por Resonancia Magnética , Traumatismos Experimentales por Radiación/diagnóstico , Animales , Barrera Hematoencefálica/efectos de la radiación , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Espectroscopía de Resonancia Magnética , Masculino , Dosis de Radiación , Traumatismos Experimentales por Radiación/diagnóstico por imagen , Traumatismos Experimentales por Radiación/patología , Cintigrafía , Pentetato de Tecnecio Tc 99m , Factores de TiempoRESUMEN
PURPOSE: To correlate targeting deviation in external beam radiation therapy with site of relapse in a prospective study of 174 patients treated for medulloblastoma. METHODS AND MATERIALS: Between February 1992 and February 1998 the radiotherapy treatment records were reviewed by a panel of radiation oncologists for 174 children treated with radiation therapy for medulloblastoma. The review was done without knowledge of patient outcome. Patterns of relapse were correlated with the results of the quality control review. RESULTS: Among the 174 patients five relapsed before the start of radiotherapy. One hundred sixty-nine patients were evaluable for correlation between targeting deviation and site of relapse. Number of major deviations in radiation therapy treatment is strongly correlated with the risk of tumor relapse (67% [95% CI: 28-91] of 3-year relapse rate in patient group with 2 major deviations and 78% [95% CI: 35-96] with 3 major deviations). This is particularly correlated with relapse in the frontal region of the brain: 5 relapses occurred in the frontal region in patients with major deviation in this area. An erroneous choice of electron beam energy is also linked with craniospinal fluid (CSF) relapse (3-year relapse rate of 68% [95% CI: 42-86]). Minor deviations in therapy technique are slightly associated with an increased risk of relapse in the same range as the group with only one major deviation. CONCLUSION: The quality of medulloblastoma radiation therapy technique is strongly correlated with outcome. Pretreatment central quality assurance review or standardized computer-designed blocks would improve survival to an extent equivalent to that attributed to adjuvant chemotherapy.
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Neoplasias Cerebelosas/radioterapia , Meduloblastoma/radioterapia , Adolescente , Neoplasias Encefálicas/secundario , Niño , Preescolar , Francia , Humanos , Oncología Médica , Meduloblastoma/secundario , Estudios Prospectivos , Control de Calidad , Radioterapia/normas , Sociedades MédicasRESUMEN
Between 06.86 and 11.89, 88 medulloblastoma or primitive neuroectodermic tumour (PNET) localised in the posterior fossa have been included in the M7 multicentric protocol, 82 received the totality of the radiotherapy treatment and were evaluable for this study. Twenty-two of these 82 patients relapsed: their radiotherapy treatment is analysed in the present study. In 10 cases out of the 22 relapses treatment failure was probably due to a radiotherapeutic imperfection. This study confirms the necessity of a strict radiotherapy control, particularly in multicentric study.
Asunto(s)
Neoplasias Cerebelosas/radioterapia , Meduloblastoma/radioterapia , Recurrencia Local de Neoplasia/epidemiología , Neoplasias de Células Germinales y Embrionarias/radioterapia , Garantía de la Calidad de Atención de Salud , Radioterapia/normas , Adolescente , Adulto , Neoplasias Cerebelosas/epidemiología , Niño , Preescolar , Protocolos Clínicos , Francia/epidemiología , Humanos , Lactante , Meduloblastoma/epidemiología , Persona de Mediana Edad , Neoplasias de Células Germinales y Embrionarias/epidemiología , Estudios RetrospectivosRESUMEN
The ubiquitin system regulates diverse biological processes such as DNA replication and repair, biogenesis of ribosome, peroxisome and nucleosome, cell cycle, stress response and signal transduction pathways. Thus, the reported role of the ubiquitin system in apoptotic death control as well the alteration of its control in carcinogenesis should come as no surprise. Indeed, we and other groups have reported that the ubiquitin system is involved in apoptotic cell death of normal human lymphocytes and that this control is altered in B lymphocytes derived from chronic lymphocytic leukemia patients (B-CLL), rendering these malignant cells hypersensitive to specific inhibition of protein degradation/processing through proteasomal function. This approach recently allowed us to demonstrate that the stability of the tumor suppressor and pro-apoptotic protein p53 is differentially regulated in B-CLL versus normal lymphocytes and that this difference might at least partly explain the impaired response of B-CLL lymphocytes to apoptotic death activation. These results strongly suggest an imbalance in p53 regulation in B-CLL cells that leads to a variable response to DNA damage and constitutively expressed chromosomal instability. The question we and others would like to address is whether this alteration, or more likely a subset of alterations of the ubiquitin-proteasome pathway, is specific to B-CLL malignancy or if it is a hallmark of cancer cells in general. In either case, a better understanding of the ubiquitin-dependent control of apoptosis should pave the way towards a methodological approach for in vitro development of discriminating treatments which may be of potential usefulness in clinical trials of B-CLL.
Asunto(s)
Apoptosis , Cromosomas Humanos/genética , Leucemia Linfocítica Crónica de Células B/genética , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitina/metabolismo , Cisteína Endopeptidasas/fisiología , Daño del ADN , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Complejos Multienzimáticos/fisiología , Complejo de la Endopetidasa ProteasomalRESUMEN
PURPOSE: To investigate the MR T2 relaxation time and histologic changes after a single-fraction 25-Gy dose of radiation to the brain of pigs. METHODS: The right hemisphere of 10 Meishan pigs was irradiated with a single dose of 25 GY at the 90% isodose, using a 12-MeV electron beam. T2 relaxation time was measured within three regions of interest in the brain: those that had received 90%, 70%, and 40% of the total dose, respectively. T2 kinetics over time was compared with histologic studies. RESULTS: Brain T2 values were noted to increase within the irradiated areas. T2 kinetics were analyzed in three phases: an immediate transient phase and two long-lasting phases. These two long-lasting phases were correlated with the detection of ventricular compression and necrosis, respectively. The T2 increase within the 90% region of interest was 19%, 22%, and 26% for phases I, II, and III, respectively. T2 measurements within other regions of interest were not significant. CONCLUSION: Although our results suggest a dose threshold for T2 variations, brain T2 values increased after irradiation at a level at which disease could not be seen on conventional MR images. This illustrates the value of using conventional MR imaging in a quantitative manner to assess molecular tissue abnormalities at earlier stages of developing diseases.