Assuntos
Neoplasias do Sistema Nervoso Central/terapia , Irradiação Craniana , Meduloblastoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bussulfano/administração & dosagem , Carboplatina/administração & dosagem , Neoplasias do Sistema Nervoso Central/mortalidade , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Terapia Combinada , Irradiação Craniana/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/análogos & derivados , Intervalo Livre de Doença , Ependimoma/mortalidade , Ependimoma/terapia , Etoposídeo/administração & dosagem , Seguimentos , Humanos , Lactente , Meduloblastoma/mortalidade , Estudos Multicêntricos como Assunto , Tumores Neuroectodérmicos Primitivos/mortalidade , Tumores Neuroectodérmicos Primitivos/terapia , Projetos Piloto , Dosagem Radioterapêutica , Radioterapia Adjuvante/efeitos adversos , Risco , Taxa de Sobrevida , Tiotepa/administração & dosagem , Topotecan/administração & dosagem , Resultado do Tratamento , Vincristina/administração & dosagemRESUMO
PURPOSE: To test if methylphenidate (MPH) has an objective beneficial effect on immediate performance on tests of neurocognitive functions among learning-impaired survivors of childhood acute lymphoblastic leukemia (ALL) and malignant brain tumors (BT). PATIENTS AND METHODS: From July 1, 1997 through December 31, 1998, 104 long-term survivors of childhood ALL or a malignant BT completed neurocognitive screening for learning impairments and concurrent problems with sustained attention. Eligibility criteria for the MPH trial included an estimated intelligence quotient greater than 50, academic achievement in the 16(th) percentile or lower for age in reading, math, or spelling, and an ability to sustain attention on a computerized version of the Conners' Continuous Performance Test (CPT) in the 16(th) percentile or lower for age and sex. Of the 104, 32 (BT, n = 25; ALL, n = 7) were eligible on the basis of these a priori criteria for a randomized, double-blinded, placebo-controlled trial of MPH. The patients ingested a placebo (lactose) or MPH (0.6 mg/kg; 20 mg maximum) and repeated selected portions of the screening battery 90 minutes later. RESULTS: Compared to the 17 patients randomized to the placebo group, the 15 patients randomized to the MPH group had a significantly greater improvement on the CPT for sustained attention (errors of omission, P =.015) and overall index (P =.008) but not for errors of commission (indicative of impulsiveness) nor reaction times. A trend for greater improvement in the MPH group on a measure of verbal memory failed to reach statistical significance. No trend was observed for MPH effectiveness in improving learning of a word association task. No significant side effects from MPH were observed. CONCLUSION: MPH resulted in a statistically significant improvement on measures of attention abilities that cannot be explained by placebo or practice effects.
Assuntos
Atenção/efeitos dos fármacos , Neoplasias Encefálicas/psicologia , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/tratamento farmacológico , Metilfenidato/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/psicologia , Administração Oral , Adolescente , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/terapia , Criança , Método Duplo-Cego , Feminino , Humanos , Testes de Inteligência , Deficiências da Aprendizagem , Masculino , Memória/efeitos dos fármacos , Placebos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Resultado do TratamentoRESUMO
PURPOSE: The authors conducted a single-arm, prospective study using tamoxifen and carboplatin for the treatment of children with progressive or symptomatic low-grade gliomas. PATIENTS AND METHODS: Fourteen children with consecutively diagnosed cases of low-grade glioma were enrolled in this Study; all patients were younger than 14 years. One patient was excluded after induction chemotherapy because of the diagnosis of a nonmalignant condition. Patients were treated with daily tamoxifen (20 mg/m2 administered twice per day) in addition to targeted, monthly intravenous carboplatin at an area under the curve (AUC) exposure of 6.5 mg/mL x minute for 1 year or until they had clinical or radiologic evidence of disease progression. RESULTS: The median age at diagnosis was 5.3 years, the median age at initiation of chemotherapy was 8.3 years. Eight patients had tumors of the hypothalamus/optic pathway, two patients had thalamic tumors, and one patient each had tumors in the temporal lobe, tectum, and brain stem. Tumor histologic findings included fibrillary astrocytoma (n = 2), juvenile pilocytic astrocytoma (n = 6), and oligodendroglioma (n = 1). The best response to therapy was a partial response in two patients, stable disease in nine patients, and progressive disease in two patients. The overall survival at 3 years is 69%. The 3-year progression-free survival is 47%. Tamoxifen and carboplatin chemotherapy did not result in a significant number of objective responses in children with low-grade gliomas. The progression-free survival is similar to that of other published series. Nonmyelosuppressive agents such as tamoxifen deserve additional evaluation in the treatment of children with low-grade gliomas.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Astrocitoma/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Oligodendroglioma/tratamento farmacológico , Astrocitoma/mortalidade , Neoplasias Encefálicas/mortalidade , Carboplatina/administração & dosagem , Criança , Pré-Escolar , Progressão da Doença , Intervalo Livre de Doença , Inibidores Enzimáticos/administração & dosagem , Feminino , Humanos , Tábuas de Vida , Masculino , Oligodendroglioma/mortalidade , Estudos Prospectivos , Proteína Quinase C/antagonistas & inibidores , Análise de Sobrevida , Taxa de Sobrevida , Tamoxifeno/administração & dosagem , Resultado do TratamentoRESUMO
To determine how often central hypothyroidism remains undetected by routine out-patient tests of thyroid hormone, we studied 208 pediatric cancer survivors referred for evaluation because of signs of subtle hypothyroidism or hypopituitarism. Of the 208 (68 females and 140 males), 110 had brain tumors, 14 had other head/neck tumors, 11 had solid tumors remote from head and neck, and 73 had leukemia. Patients were evaluated 1-16 yr (mean, 6.1+/-4.1 yr) after tumor diagnosis. The nocturnal TSH surge and response to TRH were measured. Of 160 patients with free T4 in lowest third of normal, 34% had central hypothyroidism (blunted TSH surge or low/delayed TSH peak or delayed TSH decline after TRH); 9% had central hypothyroidism with mild TSH elevation (mixed hypothyroidism). Another 16% had mild primary hypothyroidism (TSH, 5-15 mU/L). Of 48 with free T4 in the upper two thirds of normal, 14% had central hypothyroidism; 17% had mild primary hypothyroidism. Incidence of central, mixed, and mild primary hypothyroidism 10 yr after tumor diagnosis was significantly related to total cranial radiation dose (P < 0.0001). Of 62 patients with central hypothyroidism, 34% had not developed GH deficiency. TSH surge identified 71%, and response to TRH identified 60% of those with central hypothyroidism. More than half of the slowly growing patients who have received cranial or craniospinal radiation for childhood cancer develop subtle hypothyroidism. In our study group, 92% of patients with central hypothyroidism and 27% with mixed hypothyroidism would have remained undiagnosed using baseline thyroid function tests alone. Both TSH surge and response to TRH must be evaluated to identify all of these patients.
Assuntos
Hipotireoidismo/diagnóstico , Neoplasias/complicações , Adolescente , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/radioterapia , Criança , Pré-Escolar , Feminino , Neoplasias de Cabeça e Pescoço/complicações , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Hipotireoidismo/etiologia , Lactente , Leucemia/complicações , Leucemia/terapia , Masculino , Neoplasias/radioterapia , Radioterapia/efeitos adversos , Tireotropina/sangue , Hormônio Liberador de Tireotropina , Tiroxina/sangueRESUMO
PURPOSE: Young children treated for medulloblastoma are at especially high risk for morbidity and mortality from their disease and therapy. This study sought to assess the relationship, if any, between patient outcome and M stage. Neuropsychologic and endocrine outcomes were also assessed. PATIENTS AND METHODS: Twenty-nine consecutively diagnosed infants and young children were treated for medulloblastoma at St Jude Children's Research Hospital between November 1984 and December 1995. All patients were treated with the intent of using postoperative chemotherapy to delay planned irradiation. RESULTS: The median age at diagnosis was 2.6 years. Six patients completed planned chemotherapy without progressive disease and underwent irradiation at completion of chemotherapy. Twenty-three children experienced disease progression during chemotherapy and underwent irradiation at the time of progression. The 5-year overall survival rate for the entire cohort was 51% +/- 10%. The 5-year progression-free survival rate was 21% +/- 8%. M stage did not impact survival. All patients lost cognitive function during and after therapy at a rate of -3.9 intelligence quotient points per year (P =.0028). Sensory functions declined significantly after therapy (P =.007). All long-term survivors required hormone replacement therapy and had growth abnormalities. CONCLUSION: The majority of infants treated for medulloblastoma experienced disease progression during initial chemotherapy. However, more than half of these patients can be cured with salvage radiation therapy, regardless of M stage. The presence of metastatic disease did not increase the risk of dying from medulloblastoma. All patients treated in this fashion have significant neuropsychologic deficits. Our experience demonstrates that medulloblastoma in infancy is a curable disease, albeit at a significant cost.
Assuntos
Neoplasias Cerebelares/mortalidade , Meduloblastoma/mortalidade , Fatores Etários , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/cirurgia , Neoplasias Cerebelares/terapia , Pré-Escolar , Feminino , Hormônio do Crescimento/metabolismo , Humanos , Lactente , Masculino , Meduloblastoma/patologia , Meduloblastoma/cirurgia , Meduloblastoma/terapia , Estadiamento de Neoplasias , Avaliação de Resultados em Cuidados de Saúde , Análise de SobrevidaRESUMO
PURPOSE: Leptomeningeal disease (LMD) significantly affects the prognosis and treatment of pediatric patients with primary CNS tumors. Cytologic examination of lumbar CSF is routinely used to detect LMD. To determine whether examination of CSF obtained from ventricular shunt taps is a more sensitive method of detecting LMD in these patients, we designed a prospective study to compare the findings of cytologic examinations of CSF obtained from concurrent lumbar and ventriculoperitoneal (VP) shunt taps. PATIENTS AND METHODS: As a part of diagnostic staging, follow-up testing, or both, 52 consecutive patients underwent concurrent lumbar and shunt taps on 90 separate occasions, ranging from the time of diagnosis to treatment follow-up. CSF from both sites was examined cytologically for malignant cells. RESULTS: The median age of the 28 males and 24 females was 7.5 years (range, 0.6 to 21.4 years). The primary CNS tumors included medulloblastoma (n = 29), astrocytoma (n = 10), ependymoma (n = 5), germinoma (n = 3), atypical teratoid rhabdoid tumor (n = 2), choroid plexus carcinoma (n = 2), and pineoblastoma (n = 1). Each site yielded a median CSF volume of 1.0 mL. Fourteen of 90 paired CSF test results were discordant: in 12, the cytologic findings from shunt CSF were negative for malignant cells, but those from lumbar CSF were positive; in two, the reverse was true. Malignant cells were detected at a higher rate in lumbar CSF than in shunt CSF (P =.0018). When repeat analyses were excluded, examination of lumbar CSF remained significantly more sensitive in detecting malignant cells (P =.011). Analysis of the subset of patients with embryonal tumors showed similar results (P =.0008). CONCLUSION: Cytologic examination of lumbar CSF is clearly superior to cytologic examination of VP shunt CSF for detecting leptomeningeal metastases in pediatric patients with primary CNS tumors.
Assuntos
Neoplasias Encefálicas/líquido cefalorraquidiano , Neoplasias Encefálicas/patologia , Líquido Cefalorraquidiano/citologia , Neoplasias Meníngeas/líquido cefalorraquidiano , Neoplasias Meníngeas/diagnóstico , Adolescente , Adulto , Neoplasias Encefálicas/diagnóstico , Criança , Pré-Escolar , Estudos de Avaliação como Assunto , Feminino , Humanos , Lactente , Região Lombossacral , Masculino , Neoplasias Meníngeas/secundário , Valor Preditivo dos Testes , Estudos Prospectivos , Sensibilidade e Especificidade , Derivação VentriculoperitonealRESUMO
PURPOSE: Leptomeningeal disease (LMD) significantly affects the prognosis and treatment of pediatric patients with medulloblastoma or primitive neuroectodermal tumor (PNET). Examination of CSF for malignant cells, detection of LMD on spinal magnetic resonance imaging (MRI), or both are the methods routinely used to diagnose LMD. A recent study suggested 100% correlation between CSF and MRI findings in children with medulloblastoma. To determine the validity of this hypothesis, we compared the rate of detection of LMD between concurrent lumbar CSF cytology and spinal MRI performed at diagnosis in patients with medulloblastoma or PNET. PATIENTS AND METHODS: As a part of diagnostic staging, 106 consecutive patients newly diagnosed with medulloblastoma or PNET were evaluated with concurrent lumbar CSF cytology and spinal MRI. CSF cytology was examined for the presence of malignant cells and spinal MRI was reviewed independently for the presence of LMD. RESULTS: Thirty-four patients (32%) were diagnosed with LMD based on CSF cytology, spinal MRI, or both. There were 21 discordant results. Nine patients (8.5%) with positive MRI had negative CSF cytology. Twelve patients (11.3%) with positive CSF cytology had negative MRIs. The exact 95% upper bounds on the proportion of patients with LMD whose disease would have gone undetected using either CSF cytology or MRI as the only diagnostic modality were calculated at 14.4% and 17.7%, respectively. CONCLUSION: With the use of either CSF cytology or spinal MRI alone, LMD would be missed in up to 14% to 18% of patients with medulloblastoma or PNET. Thus, both CSF cytology and spinal MRI should routinely be used to diagnose LMD in patients with medulloblastoma or PNET.
Assuntos
Neoplasias Cerebelares/diagnóstico , Líquido Cefalorraquidiano/citologia , Meduloblastoma/diagnóstico , Neoplasias Meníngeas/secundário , Tumores Neuroectodérmicos Primitivos/diagnóstico , Adolescente , Adulto , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Meduloblastoma/patologia , Neoplasias Meníngeas/diagnóstico , Meninges/patologia , Tumores Neuroectodérmicos Primitivos/patologia , Prognóstico , Sensibilidade e EspecificidadeRESUMO
Topotecan was studied as a 72 h infusion given every 3 weeks. Treatment began at a dose of 1.0 mg/m2/day and was increased to 1.25 mg/m2/day after the first 6 patients tolerated this higher dose without excessive toxicities. Eighty-eight evaluable children were accrued in 6 strata. There were no complete nor partial responses. Twenty subjects had stable disease (astrocytoma 5/11, malignant glioma 5/13, medulloblastoma 0/12, brain stem tumor 4/19, ependymoma 5/17, and miscellaneous histologies 1/16). Two patients (astrocytoma, ependymoma) completed the maximum 18 topotecan courses. The remaining 68 children developed progressive disease within 2 months. Myelosuppression was the main toxicity. Grade 4 leukopenia, neutropenia, anemia, and thrombocytopenia were observed in 18, 32, 5, and 23 participants, respectively. It was concluded that topotecan as given according to this schedule showed insufficient activity to promote it to frontline protocol usage.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Topotecan/uso terapêutico , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Criança , Progressão da Doença , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Humanos , Imageamento por Ressonância Magnética , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Tomografia Computadorizada por Raios X , Topotecan/efeitos adversos , Topotecan/farmacocinéticaRESUMO
OBJECTIVE: Hypothalamic obesity is a rare sequela of cranial insult, for which pathogenesis and treatment remain obscure. In rodents ventromedial hypothalamic damage causes hyperphagia, obesity, hyperinsulinism, and insulin resistance. Reduction of insulin secretion in humans may attenuate weight gain. METHODS: Eight children with intractable obesity after therapy for leukemia or brain tumors underwent oral glucose tolerance testing (OGTT) with simultaneous insulin levels before and after treatment with octreotide for 6 months. RESULTS: In comparison with a 6-month pre-study observation period, patients exhibited weight loss (+6.0 +/- 0.7 kg vs -4.8 +/- 1.8 kg; P =.04) and decrease in body mass index (+2.1 +/- 0.3 kg/m(2) vs -2.0 +/- 0.7 kg/m(2); P =.0001). Recall calorie count decreased during the 6 months of treatment (P =. 015). OGTT demonstrated biochemical glucose intolerance in 5 of 8 patients initially and in 2 of 7 at study end, whereas insulin response was decreased (281 +/- 47 microU/mL vs 114 +/- 35 microU/mL; P =.04). Percent weight change correlated with changes in insulin response (r = 0.72, P =.012) and changes in plasma leptin r = 0.76, P =.0004). CONCLUSIONS: Patients with hypothalamic obesity demonstrate excessive insulin secretion. Octreotide administration promoted weight loss, which correlated with reduction in insulin secretion on OGTT and with reduction in leptin levels. Pre-study biochemical glucose tolerance improved in several patients while they were receiving octreotide. These results suggest that normalization of insulin secretion may be an effective therapeutic strategy in this syndrome.
Assuntos
Dano Encefálico Crônico/complicações , Hormônios/uso terapêutico , Doenças Hipotalâmicas/tratamento farmacológico , Obesidade/tratamento farmacológico , Octreotida/uso terapêutico , Somatostatina/agonistas , Adolescente , Animais , Criança , Modelos Animais de Doenças , Feminino , Humanos , Hiperfagia/tratamento farmacológico , Hiperfagia/etiologia , Hiperfagia/fisiopatologia , Doenças Hipotalâmicas/etiologia , Doenças Hipotalâmicas/fisiopatologia , Insulina/sangue , Masculino , Obesidade/etiologia , Obesidade/fisiopatologia , RatosRESUMO
PURPOSE: Evaluation of inter- and intrapatient variability of topotecan oral bioavailability and disposition was performed in children with malignant solid tumors. PATIENTS AND METHODS: Topotecan i.v. formulation was given orally on schedules of daily for 21 consecutive days (d x 21) or daily for 5 days per week for 3 weeks [(d x 5)3], in both cases repeated every 28 days. Topotecan doses of 0.8 and 1.1 mg/m2 per day were evaluated on both schedules. Serial plasma samples were obtained after oral and i.v. administration of topotecan at the beginning and end of the first course of therapy. Topotecan lactone and total concentrations were measured by a high-performance liquid chromatography (HPLC) assay, and a one-or two-compartment model was fit to the plasma concentration-time data after oral or i.v. administration, respectively. Topotecan oral bioavailability (F) was calculated as the ratio of the AUC determined after oral treatment (AUCpo) divided by the AUC calculated after i.v. administration. RESULTS: Pharmacokinetics studies were performed on 15 and 11 patients receiving 0.8 and 1.1 mg/m2 per day, respectively. After oral administration the topotecan lactone AUCpo and F determined for 0.8 and 1.1 mg/m2 per day were 13.6 +/- 5.8 and 25.1 +/- 12.9 ng ml(-1) h and 0.34 +/- 0.14 and 0.34 +/- 0.16, respectively. The within-patient variance for AUCpo and F was much smaller than the between-patient variance. The ratio of topotecan lactone to total concentration was consistently higher after oral as compared with i.v. administration. CONCLUSIONS: Large interpatient variability was noted in topotecan pharmacokinetics, whereas intrapatient variability was relatively small. Further studies of oral topotecan are warranted to evaluate the tolerance of shorter courses and to define further the interpatient variability.
Assuntos
Antineoplásicos/farmacocinética , Neoplasias/tratamento farmacológico , Topotecan/farmacocinética , Administração Oral , Adolescente , Adulto , Disponibilidade Biológica , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Injeções Intravenosas , Masculino , Recidiva Local de Neoplasia , Neoplasias/metabolismo , Topotecan/administração & dosagemRESUMO
PURPOSE: Choroid plexus tumors (CPT) are rare childhood neoplasms. The relatively small number of reported cases and the controversies surrounding the clinical and pathological classification of these tumors have made it difficult to define a standard of care for these patients. Our intention is to contribute to the body of knowledge of these tumors and further define the role of adjuvant therapy. METHODS AND MATERIALS: We performed a retrospective review of 14 children with choroid plexus neoplasms referred to St. Jude Children's Research Hospital between October 1985 and December 1987. Ten patients had choroid plexus carcinoma (CPC) based on pathologic criteria and evidence of brain invasion at surgery or leptomeningeal disease (M+); 4 patients had choroid plexus papilloma (CPP). Patients with CPP were initially treated with surgery alone whereas patients with CPC were generally treated with postoperative therapy that included chemotherapy (CT) and/or craniospinal irradiation (CSI) with a focal boost to the primary site. For most patients CT consisted of combinations of cyclophosphamide, etoposide, vincristine, and a platinum agent. The median CSI dose was 35.2 Gy (range 24-46.2 Gy). The median primary site dose was 55.2 Gy (range 49.6-64 Gy). RESULTS: Seven of the 10 CPC cases presented with leptomeningeal dissemination; two of these patients have succumbed to disease. Of the 3 patients with M0 status, all are alive with no evidence of disease (NED). The medial time to relapse from the time of surgery was 5.3 mo (range 3-25 mo). Seven CPC patients were treated with gross total resection (GTR). Three of these patients (2 M0, 1 M+) received CT without CSI and are currently NED (27, 69, and 60 mo respectively). One M+ patient progressed on CT and has stable disease after CSI (6 mo), one (M0) received CT and CSI and is NED (120 mo), one (M+) is currently on CT with objective response (3 mo) and one (M+) died of progressive disease (24.5 mo) despite CT and CSI. Three patients with CPC had subtotal resection (STR). One of these patients (M+) received CT and CSI and is NED (23 mo), one (M0) had an elective second resection GTR alone and is currently NED (153 mo), and one (M+) developed progressive disease (13.5 mo) while on CT and died despite CSI. Among the 4 CPP patients, GTR was performed in two; both were NED at 54 and 81 mo. Two patients with CPP (one with focal atypia) were treated with STR initially; both transformed to CPC at 7 and 27 mo, respectively. Both were currently NED following salvage with (1) GTR and CSI alone (98 mo) or (2) STR, CT, and CSI (62 mo). Six of the 12 survivors in this series had significant neuropsychological sequelae. CONCLUSION: The prognosis of CPP is good for patients treated with GTR. Malignant transformation occurred in 2 CPP patients with less than GTR. Patients with localized CPC who undergo GTR have had a favorable outcome with the addition of chemotherapy or irradiation. CSI may not be routinely indicated in M0 children following GTR. There is evidence that salvage with radiation therapy may be successful following progression on chemotherapy. For patients treated with STR, the use of CT and CSI appears to be necessary.
Assuntos
Neoplasias do Plexo Corióideo/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Quimioterapia Adjuvante , Pré-Escolar , Neoplasias do Plexo Corióideo/patologia , Neoplasias do Plexo Corióideo/cirurgia , Ciclofosfamida/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Lactente , Masculino , Neoplasias Meníngeas/terapia , Papiloma do Plexo Corióideo/patologia , Papiloma do Plexo Corióideo/cirurgia , Papiloma do Plexo Corióideo/terapia , Radioterapia Adjuvante , Estudos Retrospectivos , Vincristina/administração & dosagemRESUMO
Choroid plexus tumors are rare CNS neoplasms. The distinction between choroid plexus papilloma (CPP) and choroid plexus carcinoma (CPC) is made on the basis of clinical and histological criteria. Malignant evolution of CPP may occur, and the presence of mitotic figures in CPP may predict the likelihood of recurrence or malignant evolution. Close surveillance is mandated for these patients. We report on two such cases of CPP that transformed to CPC at the time of recurrence.
Assuntos
Transformação Celular Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Papiloma do Plexo Corióideo/patologia , Pré-Escolar , Plexo Corióideo/patologia , Plexo Corióideo/cirurgia , Feminino , Seguimentos , Humanos , Lactente , Invasividade Neoplásica , Recidiva Local de Neoplasia/cirurgia , Papiloma do Plexo Corióideo/cirurgia , ReoperaçãoRESUMO
The purpose of this study was to define the length of topotecan (TPT) i.v. infusion necessary to attain a cytotoxic exposure for medulloblastoma cells throughout the neuraxis. In vitro studies of human medulloblastoma cell lines (Daoy, SJ-Med3) were used to estimate the length and extent of TPT systemic exposure associated with inhibition of tumor cell growth or the exposure duration threshold (EDT). We evaluated TPT systemic and cerebrospinal fluid (CSF) disposition in six male rhesus monkeys (8-12 kg) that received TPT 2.0 mg/m2 i.v. as a 30-min or 4-h infusion. Plasma and CSF samples were assayed for TPT lactone by high-performance liquid chromatography, and the CSF exposures were compared with the estimated EDT. Results of the in vitro studies defined an EDT as a TPT lactone concentration of > 1 ng/ml for 8 h (IC99) daily for 5 days. The mean +/- SD for systemic clearance (CL(SYS)), penetration into fourth ventricle (%CSF(4th)), and penetration into lumbar space (%CSF(LUM)) were similar for the 30-min and the 4-h infusions. At a TPT lactone systemic exposure (AUC(PL)) of 56.7 +/- 19.9 ng/ml x h, time above 1 ng/ml in the fourth ventricle was 1.4-fold greater for a 4-h infusion compared with a 30-min infusion. At a TPT lactone AUC(PL) of 140 ng/ml x h, the 4-h infusion achieved the desired TPT exposure throughout the neuraxis (lateral and fourth ventricles and lumbar space), whereas the 30-min infusion failed to achieve it in the lumbar space. In conclusion, prolonging TPT i.v. infusion from 30-min to 4-h at a targeted AUC(PL) achieves the EDT throughout the neuraxis and represents an alternative method of TPT administration that will be tested prospectively in patients with high-risk medulloblastoma.
Assuntos
Antineoplásicos/administração & dosagem , Meduloblastoma/tratamento farmacológico , Topotecan/administração & dosagem , Animais , Ventrículos Cerebrais/metabolismo , Criança , Humanos , Infusões Intravenosas , Região Lombossacral , Macaca mulatta , Masculino , Topotecan/farmacocinética , Células Tumorais CultivadasRESUMO
Clinical features and treatment of 36 consecutive pediatric patients with thalamic glial tumors confirmed by histology and characterized by neuroimaging were reviewed to identify prognostic factors. The median age at diagnosis was 10 years (range 1-18 years). Twenty-four patients had low-grade tumors (juvenile pilocytic astrocytoma n = 9, fibrillary astrocytoma n = 6, astrocytomas not otherwise specified n = 6, ganglioglioma n = 2 and oligodendroglioma n = 1) and 12 patients had high-grade tumors (glioblastoma multiforme n = 7, anaplastic astrocytoma n = 4 and unclassified malignant tumor n = 1). With a median follow-up of 4.3 years among survivors, estimates of 4-year progression-free survival (PFS) and overall survival (OS) for the entire group are 28+/-10 and 37 +/- 10%, respectively. Low-grade tumors were associated with a significantly better 4-year PFS (36 +/- 12 vs. 0% for the high-grade group; p = 0.03) and OS (52 +/- 12 vs. 0%; p < 0.001). This review identified that bithalamic involvement, characterized by neuroimaging, exerted an independent and significant negative impact on PFS and OS for patients with low-grade tumors. Estimates of 4-year PFS and OS among patients with tow-grade bithalamic versus monothalamic tumors were 58 +/- 15 vs. 0% and 85 +/- 11 vs. 0% (p < 0.00001), respectively. The presence of bithalamic involvement did not affect outcome among patients with high-grade tumors. Additionally, age at diagnosis, enhancement with neuroimaging contrast, extension beyond the thalamus and extent of surgical resection did not correlate with overall outcome. Because treatment approaches varied during the study period, the impact of radiation therapy or chemotherapy could not be assessed. This contemporary, single-institution series of pediatric thalamic glial tumors demonstrates, for the First time, the statistical significance of bithalamic involvement as a marker of poor prognosis among patients with low-grade glial lesions.
Assuntos
Neoplasias Encefálicas/patologia , Glioma/patologia , Tálamo/patologia , Adolescente , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Criança , Pré-Escolar , Feminino , Glioma/diagnóstico , Glioma/mortalidade , Glioma/terapia , Humanos , Lactente , Masculino , Estadiamento de Neoplasias , Prognóstico , Estudos RetrospectivosRESUMO
Topotecan undergoes both renal and hepatic elimination, with topotecan urinary recovery ranging from 60 to 70%. We evaluated the potential of phenytoin to alter the disposition of topotecan and its N-desmethyl metabolite. A 5-year-old child with high-risk medulloblastoma received the first course of topotecan with phenytoin and the second course without phenytoin. For both courses, topotecan doses were adjusted to achieve a target topotecan lactone plasma area under the curve (AUC). Serial plasma samples were obtained, and lactone and total plasma concentrations of topotecan, as well as total plasma and cerebrospinal fluid concentrations of N-desmethyl topotecan, were measured by high-performance liquid chromatography. Phenytoin coadministration increased lactone and total topotecan clearance from 43.4 +/- 1.9 L/h/m2 to 62.9 +/- 6.4 L/h/m2, and 20.8 +/- 2.8 L/h/m2 to 30.6 +/- 4.1 L/h/m2, respectively (P < 0.05). Concomitant phenytoin increased the plasma AUC of total N-desmethyl topotecan from 7.5 +/- 0.68 ng/ml x h to 16.3 +/- 0.53 ng/ml x h (P < 0.05) at plasma AUC of total topotecan of 226.0 +/- 5.5 ng/ml x h and 240.9 +/- 39.8 ng/ml x h, respectively. N-Desmethyl topotecan penetrated into the cerebrospinal fluid (0.12 +/- 0.01). The patient experienced no grade 3 or 4 toxicity. These are the first data documenting altered topotecan and N-desmethyl topotecan disposition when coadministered with phenytoin and suggests that topotecan may undergo further hepatic metabolism. Although there is an increase in exposure to the active N-desmethyl topotecan metabolite, it is less than the decrease in exposure to topotecan lactone. Therefore, patients concomitantly administered phenytoin may require an increase in topotecan dose to achieve a similar pharmacological effect as a patient not receiving phenytoin.
Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Neoplasias Cerebelares/tratamento farmacológico , Meduloblastoma/tratamento farmacológico , Fenitoína/uso terapêutico , Topotecan/análogos & derivados , Topotecan/farmacocinética , Topotecan/uso terapêutico , Anticonvulsivantes/uso terapêutico , Antineoplásicos/sangue , Neoplasias Cerebelares/sangue , Neoplasias Cerebelares/cirurgia , Pré-Escolar , Interações Medicamentosas , Humanos , Lactonas , Masculino , Meduloblastoma/sangue , Meduloblastoma/cirurgia , Taxa de Depuração Metabólica , Modelos Biológicos , Topotecan/sangue , Topotecan/líquido cefalorraquidianoRESUMO
We analyzed 27 samples of primary medulloblastoma, using comparative genomic hybridization and a novel statistical approach to evaluate chromosomal regions for significant gain or loss of genomic DNA. An array of nonrandom changes was found in most samples. Two discrete regions of high-level DNA amplification of chromosome bands 5p15.3 and 11q22.3 were observed in 3 of 27 tumors. Nonrandom genomic losses were most frequent in regions on chromosomes 10q (41% of samples), 11 (41%), 16q (37%), 17p (37%), and 8p (33%). Regions of DNA gain most often involved chromosomes 17q (48%) and 7 (44%). These findings suggest a greater degree of genomic imbalance in medulloblastoma than has been recognized previously and highlight chromosomal loci likely to contain oncogenes or tumor suppressor genes that may contribute to the molecular pathogenesis of this tumor.
Assuntos
Aberrações Cromossômicas/genética , DNA de Neoplasias/genética , Meduloblastoma/genética , Adolescente , Criança , Pré-Escolar , Transtornos Cromossômicos , Mapeamento Cromossômico , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Lactente , Masculino , Hibridização de Ácido Nucleico/métodosRESUMO
BACKGROUND: A retrospective study evaluated the clinical characteristics, prognostic factors, and outcome of patients with newly diagnosed supratentorial malignant gliomas treated with preirradiation chemotherapy. METHODS: Of 41 patients with supratentorial malignant gliomas accrued between 1984-1994, all had neuroimaging documentation of the extent of resection and 37 had complete neuraxis staging prior to treatment; 80% were treated with one of a variety of neoadjuvant chemotherapy regimens. RESULTS: Thirteen patients had anaplastic astrocytoma (AA), 25 had glioblastoma multiforme (GBM), and 3 had anaplastic oligodendroglioma. Gross total resection (GTR) was performed in 10 patients, subtotal resection (STR) in 22 patients, and biopsy (Bx) alone in 9 patients. For the entire group the 3-year overall and progression free survivals were 35 +/- 8% and 18 +/- 6%, respectively. Tumor recurrence was dominantly local. However, 9 patients with initially local disease failed at a distant neuraxis site, giving a 26 +/- 7% actuarial risk of dissemination at 3 years. The only significant prognostic factor was extent of tumor resection: patients who underwent GTR survived longer than those who underwent STR or Bx (P = 0.004). Histology (GBM vs. AA), age, and the use of enhanced local dose radiation therapy (brachytherapy or stereotactic irradiation) did not affect survival. CONCLUSIONS: Neoadjuvant chemotherapy was not associated with a survival rate significantly different from that observed in adjuvant chemotherapy studies. Systematic neuraxis staging at diagnosis and recurrence revealed a rate of neuraxis dissemination as a component of recurrence that was higher than previously reported; the utility of craniospinal irradiation in preventing isolated dissemination remains uncertain.
Assuntos
Glioma , Neoplasias Supratentoriais , Adolescente , Criança , Pré-Escolar , Terapia Combinada , Feminino , Glioma/tratamento farmacológico , Glioma/mortalidade , Glioma/radioterapia , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia , Prognóstico , Estudos Retrospectivos , Neoplasias Supratentoriais/tratamento farmacológico , Neoplasias Supratentoriais/mortalidade , Neoplasias Supratentoriais/radioterapia , Análise de SobrevidaRESUMO
Individuals affected with tuberous sclerosis complex (TSC) develop several benign and malignant tumors at increased frequency, including astrocytomas. Tuberin, the protein product of the tuberous sclerosis complex-2 (TSC2) tumor suppressor gene, has been shown to directly inhibit cell growth and is expressed at high levels in normal central nervous system neurons and astrocytes. To determine whether TSC2 RNA and protein are reduced in astrocytomas from individuals without tuberous sclerosis, reverse transcriptase-polymerase chain reaction and immunoblotting analyses were performed on 49 adult astrocytomas, 10 pediatric astrocytomas, and 13 ependymomas. Eighteen of 40 (45%) high-grade (World Health Organization [WHO] grade III/IV) astrocytomas and 4 of 8 (50%) adult low-grade (WHO grade II) astrocytomas demonstrated reduced or absent TSC2 expression, including 1 giant cell astrocytoma, whereas none of the 10 pediatric low-grade astrocytomas analyzed showed a reduction in TSC2 expression. Reduced or absent tuberin was observed in 2 of 6 (33%) ependymomas analyzed. These data demonstrate, for the first time, that reduced or absent TSC2 expression may represent one of the critical genetic events associated with the development of sporadic adult, but not pediatric, astrocytomas.
Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Ependimoma/genética , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Proteínas Repressoras/biossíntese , Adulto , Fatores Etários , Astrocitoma/metabolismo , Astrocitoma/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Criança , Primers do DNA , Ependimoma/metabolismo , Ependimoma/patologia , Éxons , Humanos , Reação em Cadeia da Polimerase , Biossíntese de Proteínas , RNA Mensageiro/biossíntese , Proteínas Repressoras/genética , Transcrição Gênica , Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de TumorRESUMO
PURPOSE: To evaluate the effects of preirradiation chemotherapy on patterns of failure in children with medulloblastoma. METHODS AND MATERIALS: Fifty-three patients (pts) with medulloblastoma were given preirradiation chemotherapy as initial postoperative treatment at St. Jude Children's Research Hospital from November 1984 to September 1993. Patients < or = 3 years of age (n = 23) received chemotherapy (CH) with delayed craniospinal irradiation (CSI). Children > or = 3 years with more advanced disease (T3b-T4, M+ or measurable residual after resection) were given CH followed by CSI (30 patients). Chemotherapy regimen depended on protocol, but usually included cis- or carboplatin and etoposide, +/- cyclophosphamide and vincristine. RESULTS: Actuarial overall survival and event-free survival rates are 60% (95% confidence interval [41,79]) and 37% [19,55] at 5 years. Children < or = 3 at diagnosis: six of 23 pts completed CH without progression and received consolidative CSI; all six are alive with no evidence of disease (NED) at 2.4-9.1 years. Seventeen patients progressed during CH and were then given CSI. Sites of progression during CH were posterior fossa (PF) in 11 patients, neuraxis (NEUR) in 4, and PF+NEUR in 2. Following CSI, 7 patients are alive NED at 2.0-8.6 years; 10 patients died of progressive disease. Eleven patients had M0 disease at diagnosis; 8 (73%) progressed during CH, 3 in the neuraxis. Children > or = 3 at diagnosis: 20 of 30 patients completed pre-CSI CH without progression; 15 are alive NED at 1.3-9.2 years, and 5 showed post-CSI progression in the PF (n = 3), in the NEUR (n = 1) and in bone marrow (n = 1). Ten of the 30 (33%) patients progressed on CH (6 in NEUR, 4 in PF); 5 are alive and NED or with stable disease. Seventeen patients had M0 disease at diagnosis; 3 out of 17 (18%) progressed during CH, 2 in NEUR and 1 in an extraneural site. In the total group of 30 patients, 11 have had disease recurrence after completion of XRT. The actuarial rate of failure was 23 +/- 9% for the patients < or = 3 years of age and 21 +/- 8% for the older children when evaluated at 4 months after diagnosis (at the completion of chemotherapy in the older children but during the ongoing chemotherapy in the younger children). CONCLUSIONS: In patients presenting with M0 disease and receiving pre-CSI chemotherapy, the risk of neuraxis progression seems to increase with duration of chemotherapy. The sites of progression during preirradiation chemotherapy are nearly equally divided between posterior fossa and other neuraxis sites. CSI salvage of patients progressing on chemotherapy is possible in approximately 50% of patients. Following CSI, neuraxis progression is more frequent than posterior fossa relapse.
Assuntos
Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/radioterapia , Meduloblastoma/tratamento farmacológico , Meduloblastoma/radioterapia , Adolescente , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Cerebelares/mortalidade , Criança , Pré-Escolar , Terapia Combinada , Irradiação Craniana , Progressão da Doença , Intervalo Livre de Doença , Humanos , Lactente , Recém-Nascido , Meduloblastoma/mortalidade , Falha de TratamentoRESUMO
We discuss the surgical approach used for and outcome in 11 infants (< or =3 years) who were treated at our institution for ependymomas arising in the cerebellar-pontine (C-P) angle. The median age of the group was 19 months (range: 6-26 months). Of these 11 patients, the initial surgery for 8 was performed at our center and achieved a gross total resection (GTR) in 4 patients and a subtotal resection (STR) in the remaining 4. The 3 patients who had tumor debulking performed elsewhere were subsequently referred to our institution and had definitive surgery after receiving 3-4 courses of chemotherapy; one of these children had a GTR, whereas the remaining 2 had an STR. During the immediate postoperative period, 9 patients had cranial nerve deficits that necessitated placement of a tracheostomy and a gastrostomy feeding tube; these were discontinued in 6 of the 9 patients as the deficits resolved. The majority of the permanent cranial nerve deficits involved the sixth and seventh cranial nerves. Of the 11 patients, 4 have died (progressive disease, n = 1; accidental death, n = 2; withdrawal of life support, n = 1); the remaining 7 patients are alive, with a median follow-up of 37 months (range: 20-73 months). Aggressive surgical resection for tumors arising in the C-P region is associated with postoperative deficits, which resolve over time with appropriate supportive care. This approach may increase the number of children in whom GTR is achieved, thereby potentially increasing the cure rate for these patients.