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STUDY QUESTION: Which chemotherapeutic agents and body site-specific radiation fields are dose-dependently associated with an increased risk of fertility impairment in long-term female childhood, adolescent and young adulthood (CAYA) cancer survivors? SUMMARY ANSWER: Busulfan, lower abdominal radiotherapy (RT) and total body irradiation (TBI) seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. WHAT IS KNOWN ALREADY: Several treatment-related fertility deficits, as assessed by both self-reported outcomes and hormonal markers are known to occur following treatment of CAYA cancer. However, knowledge regarding precise dose-related estimates of these treatment-related risks are scarce. STUDY DESIGN, SIZE, DURATION: The current case-control study was nested within the PanCareLIFE cohort study. In total, 1332 CAYA survivors from 8 countries, 9 institutions and 11 cohorts, participated in and contributed data to the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants were female 5-year CAYA cancer survivors. In total, 450 cases (fertility impaired survivors) and 882 matched controls (not fertility impaired survivors) were included. Fertility impairment was defined using both questionnaire data (primary or secondary amenorrhea; use of artificial reproductive techniques; unfulfilled wish to conceive) and hormonal data (FSH and anti-Müllerian hormone (AMH)). Multivariable logistic regression models were used to investigate the effect of (i) alkylating agent exposure, and (ii) dose categories for individual chemotherapeutic agents and for RT-exposed body sites. MAIN RESULTS AND THE ROLE OF CHANCE: A positive dose-effect relationship between cyclophosphamide equivalent dose (CED) score and fertility impairment was found, with survivors with a CED score > 7121 mg/m2 being at a significantly increased risk of fertility impairment (odds ratio (95% CI) = 2.6 (1.9-3.6) P < 0.001). Moreover, cumulative dose variables of the following treatments were significantly associated with fertility impairment: busulfan, carmustine, cyclophosphamide, melphalan, procarbazine, lower abdominal RT and TBI. Busulfan, lower abdominal RT and TBI seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. LIMITATIONS, REASONS FOR CAUTION: Our study may have been subject to selection bias since data from about half of the original base cohorts were available for the current study. This could impact the generalizability of our study results. WIDER IMPLICATIONS OF THE FINDINGS: We identified survivors at high risk for fertility impairment and, consequently, for a reduced or even absent reproductive life span. Both girls and young women who are about to start anti-cancer treatment, as well as adult female survivors, should be counselled about future parenthood and referred to a reproductive specialist for fertility preservation, if desired. STUDY FUNDING/COMPETING INTEREST(S): This study has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030. There are no competing interests. TRIAL REGISTRATION NUMBER: n/a.
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Sobreviventes de Câncer , Preservação da Fertilidade , Neoplasias , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Estudos de Coortes , Feminino , Fertilidade , Humanos , Masculino , Neoplasias/tratamento farmacológico , Adulto JovemRESUMO
BACKGROUND: The outcome of children with refractory/relapsed malignancies remains poor and novel therapies are urgently required. One of the promising approaches is metronomic chemotherapy. We present the clinical results of 74 children with advanced solid tumors treated according to treatment recommendation with data registry in three European pediatric centers. METHODS: COMBAT (Combined Oral Metronomic Biodifferentiating Antiangiogenic Treatment) included low-dose daily temozolomide, etoposide, celecoxib, vitamin D, fenofibrate and retinoic acid. From 2004 to 2010, 74 children were enrolled. RESULTS: The 2-year overall survival (OS) was 43.1% (median 15.4, range 1.3-69.9 months). Of the 74 patients, 50 patients (68%) died and 24 are alive: 6 (8%) with progressive disease, 7 (9%) with stable disease/partial response and 11 (15%) in complete response. Median time to response was 6 months. Of 62 patients with initially measurable disease, 25 (40%) had radiological response or stable disease. Fourteen of 25 showing clinical benefit responded within the first 6 months. The treatment was well tolerated on an outpatient basis. Regarding non-hematological toxicity of grade ≥2, hepatotoxicity of grade 3 occurred in 8 children and grade 3 cheilitis in 16 children. CONCLUSION: COMBAT is a feasible and effective treatment option for patients with relapsing/refractory malignancies. The treatment is well tolerated with a low acute toxicity profile.
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Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/tratamento farmacológico , Sistema de Registros , Administração Metronômica , Adolescente , Adulto , Celecoxib , Criança , Pré-Escolar , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Etoposídeo/administração & dosagem , Europa (Continente) , Estudos de Viabilidade , Feminino , Fenofibrato/administração & dosagem , Humanos , Lactente , Isotretinoína/administração & dosagem , Masculino , Pirazóis/administração & dosagem , Sulfonamidas/administração & dosagem , Temozolomida , Vitamina D/administração & dosagem , Adulto JovemRESUMO
In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.
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AIM OF STUDY: An analysis of birth defects incidences in a co-incidence with children age tumors in the Czech Republic in 1994 - 2005. Some bio-social factors (maternal age, birth weight, gestational week at birth) and their roles were studied as well. TYPE OF STUDY: Retrospective demografic-epidemiological analysis of birth defects and children age tumors incidences in children born in the Czech Republic during 1994 - 2005. MATERIAL AND METHODS: Data from the National Birth Defects Register and National Oncological Register (both run in the Institute for Health Information and Statistics) in the Czech Republic were used along with some additional data from the Register of newborns and Register of mothers at childbirth. Out of these data, a group of children with both birth defect and tumor was analyzed according to particular diagnoses and to some selected bio-social factors. Out of the total number 1707 children with tumor (934 (54.7%) boys and 773 (45.3%) girls) were 1572 children without birth defect and 135 with both tumor and birth defect. Total number of children with birth defect were 39 197 (39 059 live births and 138 stillbirths), 22 741 (58.1%) boys and 16 435 (41.9%) girls (in 21 cases the sex was not specified). In these children totally 53 539 birth defect diagnoses were registered (30 739 in boys, 22 781 in girls and 19 in children with unspecified sex). RESULTS: In 1572 children without birth defect and with tumor, a mean age at time of tumor diagnosis was 3.6 years, in 135 children with both tumor and birth defect was 2.2 years, which is significantly lower (p < 0.001, Mann-Whitney U test). No statistically significant difference was found in birthweight and birthlenght and gestational week and maternal age at time of delivery. An increased frequency of tumors in the group of children with birth defect was found in groups mesothelial tumors (C45 - C49), tumors of urinary tract (C64 - C68) and tumors of head and neck (C00 - C14, C30 - C31). On the other hand, a decreased tumor frequency in the group of children with birth defect was found in groups of lymfoid and haematopoietic tumors ((C81 - C96) and tumors of eye and brain (C69 - C72). As a risk factor of tumorigenesis in in children with birth defect was a birth defect from groups of defects of cardiovascular system, uropoietic system, chromosal aberrations and other unspecified defects. In children with both birth defect and tumor a decreased survival rate (p = 0.0437, Log-rank test) was found. A decreased survival rate was also confirmed after tumor diagnosis, although this decrease was not statistically significant (p = 0.2021, Log-rank test). There is also a highly statistically significant difference (p < 0.001, Log-rank test) in survival between groups with and without a birth defect prior to tumor diagnosis. CONCLUSIONS: A higher risk of tumorigenesis in children with birth defect (compared to children without birth defect) was confirmed. There was also a lower survival in a group of children with tumor and birth defect compared to those with tumor and without birth defects. A higher risk of tumorigenesis in some types of birt defects was also found.
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Anormalidades Congênitas/epidemiologia , Neoplasias/complicações , Neoplasias/epidemiologia , Criança , Pré-Escolar , República Tcheca/epidemiologia , Feminino , Humanos , Incidência , Lactente , MasculinoRESUMO
BACKGROUND: The monitoring of the late effects of childhood cancer treatments was established approximately in the 1970s. With an increasing number of children cancer survivors the identification of the short-term or late effects becomes more detailed. The psychosocial and cognitive problems are of the most frequent sequelae of the cancer treatment and their prevalence is nearly 20% in survivors of childhood cancer. These problems can have an adverse impact on further professional career or private life in the childhood cancer survivors. The most threatened group of patients are children treated for brain tumors and acute lymphoblastic leukemia. DESIGN: The object of this paper is to review the present information in the area of the neuropsychological sequelae in the childhood cancer survivors. CONCLUSIONS: Identification of the specific cognitive problems in childhood cancer survivors can have the profound impact on improvement of the support delivered to the children and adolescents by their families, in the school and further career. Tailored interventions can have the positive impact on the quality of life of this subgroup of children. Multidisciplinary approach including routine psychological screening is necessary for addressed follow-up care concerning this vulnerable at-risk population.