Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 20
Filtrar
1.
Curr Med Res Opin ; 31(1): 99-106, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25215428

RESUMO

AIMS: To evaluate the efficacy and safety of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin in Asian patients with type 2 diabetes mellitus (T2DM), a rapidly increasing population. METHODS: Data were pooled for Asian patients receiving linagliptin orally once daily, as monotherapy or added to existing oral antidiabetes therapies, in multinational randomized placebo-controlled clinical trials. Efficacy data were taken from four pivotal trials with 24-week durations to allow for robust efficacy assessment. Safety data were pooled from a wider group of 10 trials with varying durations to capture the largest possible incidence of adverse events (AEs). The primary efficacy endpoint was change from baseline to week 24 in HbA1c. AEs were analyzed descriptively. RESULTS: Mean baseline HbA1c (±SD) in this population was 8.2 ± 0.9%. Placebo-corrected mean change in HbA1c after 24 weeks was -0.79% (95% confidence interval [CI]: -0.92 to -0.67; p < 0.0001). Placebo-corrected mean change in fasting plasma glucose was -17.8 ± 2.4 mg/dL (95% CI: -22.6, -13.0; p < 0.0001). In a small subgroup, mean post-prandial glucose was reduced by a placebo-corrected -56.9 ± 14.0 mg/dL (95% CI: -85.2, -28.5). AEs occurred in 58.0% of linagliptin patients (serious AEs in 2.4%) and 58.2% of placebo patients (serious AEs in 3.0%). CONCLUSIONS: This study was limited by the post hoc nature of the analysis, and because the pooling did not differentiate between geographically distant Asian regions. Nonetheless, this analysis provides evidence that linagliptin was efficacious and well tolerated as monotherapy or added to other oral antidiabetes therapies in Asian patients with T2DM.


Assuntos
Povo Asiático , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/etnologia , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Purinas/administração & dosagem , Quinazolinas/administração & dosagem , Adulto , Idoso , Glicemia/metabolismo , Quimioterapia Combinada , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Linagliptina , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
2.
Diabetes Care ; 36(11): 3460-8, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24026560

RESUMO

OBJECTIVE: Preclinical data suggest that linagliptin, a dipeptidyl peptidase-4 inhibitor, may lower urinary albumin excretion. The ability of linagliptin to lower albuminuria on top of renin-angiotensin-aldosterone system (RAAS) inhibition in humans was analyzed by pooling data from four similarly designed, 24-week, randomized, double-blind, placebo-controlled, phase III trials. RESEARCH DESIGN AND METHODS: A pooled analysis of four completed studies identified 217 subjects with type 2 diabetes and prevalent albuminuria (defined as a urinary albumin-to-creatinine ratio [UACR] of 30-3,000 mg/g creatinine) while receiving stable doses of RAAS inhibitors. Participants were randomized to either linagliptin 5 mg/day (n = 162) or placebo (n= 55). The primary end point was the percentage change in geometric mean UACR from baseline to week 24. RESULTS: UACR at week 24 was reduced by 32% (95% CI -42 to -21; P < 0.05) with linagliptin compared with 6% (95% CI -27 to +23) with placebo, with a between-group difference of 28% (95% CI -47 to -2; P = 0.0357). The between-group difference in the change in HbA1c from baseline to week 24 was -0.61% (-6.7 mmol/mol) in favor of linagliptin (95% CI -0.88 to -0.34% [-9.6 to -3.7 mmol/mol]; P < 0.0001). The albuminuria-lowering effect of linagliptin, however, was not influenced by race or HbA1c and systolic blood pressure (SBP) values at baseline or after treatment. CONCLUSIONS: Linagliptin administered in addition to stable RAAS inhibitors led to a significant reduction in albuminuria in patients with type 2 diabetes and renal dysfunction. This observation was independent of changes in glucose level or SBP. Further research to prospectively investigate the renal effects of linagliptin is underway.


Assuntos
Albuminúria/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Purinas/uso terapêutico , Quinazolinas/uso terapêutico , Idoso , Albuminúria/etiologia , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Linagliptina , Masculino , Pessoa de Meia-Idade , Sistema Renina-Angiotensina/efeitos dos fármacos , Resultado do Tratamento
3.
Cardiovasc Diabetol ; 12: 60, 2013 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-23570327

RESUMO

BACKGROUND: In patients with type 2 diabetes mellitus (T2DM), hypertension and microalbuminuria are predictive markers for increased renal and cardiovascular risk. This post hoc analysis of data from a global development program aimed to evaluate the efficacy and safety of linagliptin in a population with joint prevalence of these two vascular risk factors. METHODS: Data for patients with baseline microalbuminuria (urine albumin-to-creatinine ratio 30-300 mg/g) and hypertension (systolic blood pressure ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg and/or a history of hypertension; and/or an antihypertensive treatment at baseline) who participated in any of six randomized, placebo-controlled, phase III trials were analyzed. Participants received linagliptin 5 mg daily (alone or in combination with other oral antidiabetic drugs) or placebo for 18 to 24 weeks. RESULTS: Of 3,119 patients, 512 had both microalbuminuria and hypertension (linagliptin, 366; placebo, 146). Baseline mean (SD) HbA1c was 8.3 (0.9)% and 8.4 (0.9)%; median (range) urine albumin-to-creatinine ratio was 60 (30-292) mg/g and 64 (30-298) mg/g; mean (SD) systolic blood pressure was 138 (15) mm Hg and 135 (16) mm Hg; and mean (SD) diastolic blood pressure was 81 (10) mm Hg and 81 (10) mm Hg, for linagliptin and placebo, respectively. Placebo-corrected mean change in HbA1c from baseline to week 18 and week 24 was -0.57% (95% CI: -0.75, -0.39; P < 0.0001) and -0.59% (95% CI: -0.80, -0.39; P < 0.0001), respectively. Placebo-corrected mean change in FPG from baseline to week 24 was -21.3 mg/dl (95% CI: -31.0, -11.6; P < 0.0001). The incidence of drug-related adverse events was similar for linagliptin and placebo (10.4% and 8.2%, respectively). Changes in systolic and diastolic blood pressure, cholesterol and triglyceride levels were similar between linagliptin and placebo. CONCLUSION: In T2DM patients with the two common vascular risk factors of hypertension and microalbuminuria, linagliptin achieved significant improvements in glycemic control. In this vulnerable patient population at high risk for micro- and macrovascular complications, linagliptin was well tolerated.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Nefropatias/tratamento farmacológico , Purinas/uso terapêutico , Quinazolinas/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Ensaios Clínicos Fase III como Assunto/métodos , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Nefropatias/epidemiologia , Linagliptina , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Fatores de Risco , Resultado do Tratamento
4.
J Diabetes Complications ; 27(3): 274-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23403068

RESUMO

AIMS: To evaluate the efficacy/safety of dipeptidyl peptidase-4 inhibitor, linagliptin, in subjects with insufficiently controlled type 2 diabetes mellitus (T2DM), and factors influencing treatment response. METHODS: Pooled analysis of data from 2258 subjects in three 24-week phase III, randomized, placebo-controlled, parallel-group studies, who received oral linagliptin (5 mg/day) or placebo as monotherapy, added-on to metformin, or added-on to metformin plus sulfonylurea was performed. RESULTS: Among 388 subjects with HbA1c ≥9.0%, adjusted mean baseline HbA1c (9.4% both groups) declined to 8.3% in linagliptin group and 9.1% in placebo group at 24 weeks (P<.0001) and adjusted mean change from baseline was 1.2% (vs. 0.4%, placebo). Linagliptin significantly lowered fasting plasma glucose levels vs. placebo (1.6 mmol/l vs. 0.4 mmol/l); treatment difference, 1.1 mmol/l (95% CI, -1.7 to -0.5). Treatment and washout of previous oral antidiabetes drugs were the only factors to independently affect HbA1c change at week 24. Adverse event rates were similar for linagliptin (61.9%) and placebo (62.7%). Hypoglycemia was rare with linagliptin monotherapy/add-on to metformin (≤1%) and increased when linagliptin was added to metformin plus sulfonylurea (linagliptin, 17.9% vs. placebo, 8.3%). CONCLUSIONS: Linagliptin was an effective, well-tolerated treatment in subjects with T2DM and insufficient glycemic control, both as monotherapy or added-on to metformin/metformin plus sulfonylurea.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hiperglicemia/prevenção & controle , Hipoglicemia/prevenção & controle , Purinas/uso terapêutico , Quinazolinas/uso terapêutico , Idoso , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/fisiopatologia , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Método Duplo-Cego , Resistência a Medicamentos , Quimioterapia Combinada/efeitos adversos , Feminino , Hemoglobinas Glicadas/análise , Humanos , Hiperglicemia/induzido quimicamente , Hiperglicemia/epidemiologia , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Incidência , Rim/efeitos dos fármacos , Rim/fisiopatologia , Linagliptina , Masculino , Metformina/efeitos adversos , Metformina/uso terapêutico , Pessoa de Meia-Idade , Purinas/efeitos adversos , Quinazolinas/efeitos adversos , Compostos de Sulfonilureia/efeitos adversos , Compostos de Sulfonilureia/uso terapêutico
5.
Am J Ther ; 20(6): 618-21, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23411609

RESUMO

Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor with a primarily nonrenal route of excretion. Consequently, renal impairment should not substantially affect drug exposure. This analysis was undertaken to compare steady-state trough concentrations of linagliptin among patients with type-2 diabetes receiving linagliptin 5 mg in phase 3 studies. Data were pooled from 3 randomized studies from the global phase 3 program of linagliptin (5 mg daily in each) in patients with type-2 diabetes. These studies were selected for their inclusion of pharmacokinetic data. Linagliptin plasma concentrations were available for 969 patients who were determined by estimated glomerular filtration rate to have normal renal function (n = 438), mild renal impairment (RI) (n = 429), moderate RI (n = 44), or severe RI (n = 58). In patients with normal renal function, the geometric mean linagliptin trough concentration (coefficient of variation) was 5.93 nmol/L (56.3%); in patients with mild, moderate, or severe RI, geometric mean concentrations were 6.07 nmol/L (62.9%), 7.34 nmol/L (58.6%), and 8.13 nmol/L (49.8%), respectively. In patients with type-2 diabetes, RI had a minor effect on linagliptin exposure. Therefore, neither dose-adjustment nor drug-related monitoring of estimated glomerular filtration rate is necessary for patients with RI.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacocinética , Purinas/farmacocinética , Quinazolinas/farmacocinética , Insuficiência Renal/fisiopatologia , Idoso , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Feminino , Taxa de Filtração Glomerular , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Linagliptina , Masculino , Pessoa de Meia-Idade , Purinas/administração & dosagem , Purinas/uso terapêutico , Quinazolinas/administração & dosagem , Quinazolinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença
6.
Pediatr Blood Cancer ; 57(6): 978-85, 2011 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-21796761

RESUMO

PURPOSE: To analyze the frequency, prognostic factors, and outcome of children with atypical teratoid/rhabdoid tumors (AT/RT), a rare and highly malignant embryonal brain tumor. MATERIALS AND METHODS: Clinical data of patients diagnosed between 1988 and 2004 with AT/RT who were registered to the German HIT trial center, were correlated with outcome. Patient numbers for AT/RT were compared to numbers for primitive neuroectodermal tumors and medulloblastomas (PNET/MB) registered to the population-based HIT trials. RESULTS: We identified 56 patients with the centrally confirmed histopathological diagnosis of AT/RT with a median age of 1.2 years (range, 0.1-14.0 years). The AT/RT:PNET/MB ratio was 1:12.2 for all children, and 1:1.5 for children younger than 1 year at diagnosis. Three-year overall survival (OS) and event-free survival (EFS) for all patients were 22% and 13%, respectively. Eight patients (14%) are considered long-term event-free survivors (follow-up 1.4-10.6 years). By univariable analyses, younger age, metastatic disease, infratentorial location, and less than complete remission at the end of chemotherapy were identified as negative influencing factors for OS. By multivariable analyses, younger age (OS, EFS) and metastatic disease (OS) were identified as independent risk factors. CONCLUSION: The incidence of AT/RT in children below 1 year is higher than previously reported. A subset of patients with favorable clinical risk factors profits from intensive multimodal treatment. Prospective clinical and biological studies are needed to further define prognostic factors and optimize therapy.


Assuntos
Neoplasias do Sistema Nervoso Central/epidemiologia , Bases de Dados Factuais , Tumor Rabdoide/epidemiologia , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/mortalidade , Neoplasias do Sistema Nervoso Central/terapia , Criança , Pré-Escolar , Feminino , Alemanha , Humanos , Lactente , Masculino , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/mortalidade , Tumor Rabdoide/terapia , Fatores de Risco , Análise de Sobrevida
7.
J Neurooncol ; 102(3): 459-69, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21308398

RESUMO

Ependymoblastoma is a rare malignant brain tumor of early childhood. Data on clinical behavior and optimal treatment strategies are scarce. We report on 11 consecutively treated children with centrally confirmed diagnosis of CNS ependymoblastoma, registered between February 1994 and October 2006 to the prospective GPOH-HIT multicenter brain tumor trials, and treated by multimodal regimens. Median age at diagnosis was 3.5 years (range, 1.8-5.6 years), and the median follow-up of survivors was 5.9 years (range, 2.2-12.7 years). Initial stage was M0 in 9, and M0/1 (no cerebrospinal fluid examination done) in 2 patients. Gross-total tumor resection was achieved in 7 patients, incomplete resection in 4 patients. Further primary therapy included chemotherapy in all patients, craniospinal radiotherapy in 5 patients and high-dose chemotherapy in 2 patients. Tumor response to chemotherapy was observed in 1 of 4 evaluable patients. Tumor progression occurred in 7 patients after a median time of 5.0 months (range, 2.5-19.2 months). Five-year progression-free survival was 36.4% (±14.5%), 5-year overall survival 30.3% (±15.9%). Of 4 survivors, 3 had gross-total tumor resection, and all were treated by either craniospinal radiotherapy and/or high-dose chemotherapy with autologous blood stem cell rescue. Prognosis of children with ependymoblastoma is poor, but sustained remissions have been achieved after multimodal treatment. Considerable diagnostic discrepancies between local and central pathologists underscore the importance of central review. Further studies are needed to improve survival of children with this rare malignant central nervous system tumor.


Assuntos
Neoplasias Encefálicas , Tumores Neuroectodérmicos Primitivos , Resultado do Tratamento , Adolescente , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/cirurgia , Criança , Pré-Escolar , Terapia Combinada , Irradiação Craniana/métodos , Humanos , Lactente , Estimativa de Kaplan-Meier , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Tumores Neuroectodérmicos Primitivos/diagnóstico , Tumores Neuroectodérmicos Primitivos/mortalidade , Tumores Neuroectodérmicos Primitivos/cirurgia , Neurocirurgia/métodos
8.
Pediatr Blood Cancer ; 56(7): 1046-54, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21319282

RESUMO

BACKGROUND: We describe demographic data of disseminated childhood low-grade glioma (DLGG) prospectively recruited in the HIT-LGG 1996 study and evaluate the impact of primary chemotherapy (CT) on the outcome of these tumors, which have previously only been described in small and retrospective series. PATIENTS AND METHODS: The multicenter study HIT-LGG 1996 accrued 1181 children and adolescents with low-grade glioma. 61 patients (5.2%) had tumor dissemination, with 2.8% being present at diagnosis. Frequencies of dissemination for different subgroups were calculated. Efficiency of first-line CT with vincristine/carboplatin was defined in 24 children with dissemination prior to first-line non-surgical-treatment. RESULTS: Incidence of dissemination was high among infants (16%) with hypothalamic-chiasmatic-glioma (HCG) and diencephalic syndrome. A relevant percentage of HCG showed isolated spinal dissemination. CT achieved objective and overall response rates of 25% and 79% of the primary tumor and a similar response of disseminated lesions. Clinical stabilization or improvement could be achieved in the majority of patients during treatment. However, 20 of 24 patients experienced further progression and 5-year PFS was 6%. Dissemination prior to CT was a negative prognostic factor for PFS within the study (P = 0.005). Overall-survival of primary DLGG was inferior compared to LGG without dissemination at diagnosis (P < 0.001). CONCLUSION: Complete MRI scan should be a standard diagnostic procedure in young children with hypothalamic-chiasmatic tumors especially if presenting with diencephalic syndrome. Dissemination in childhood LGG relates to impaired PFS. CT delays progression for responders. Multicenter studies have to evaluate the efficacy of extended treatment strategies in DLGG to improve outcome.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/terapia , Glioma/terapia , Adolescente , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Carboplatina/administração & dosagem , Criança , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Glioma/tratamento farmacológico , Glioma/patologia , Glioma/radioterapia , Humanos , Lactente , Masculino , Estudos Prospectivos , Radioterapia , Taxa de Sobrevida , Resultado do Tratamento , Vincristina/administração & dosagem
9.
J Clin Oncol ; 28(33): 4961-8, 2010 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-20940197

RESUMO

PURPOSE: To assess the prognostic role of clinical parameters and histology in early childhood medulloblastoma. PATIENTS AND METHODS: Clinical and histologic data from 270 children younger than age 5 years diagnosed with medulloblastoma between March 1987 and July 2004 and treated within prospective trials of five national study groups were centrally analyzed. RESULTS: Two hundred sixty children with medulloblastoma and specified histologic subtype were eligible for analysis (median age, 1.89 years; median follow-up, 8.0 years). Rates for 8-year event-free survival (EFS) and overall survival (OS) were 55% and 76%, respectively, in 108 children with desmoplastic/nodular medulloblastoma (DNMB) or medulloblastoma with extensive nodularity (MBEN); 27% and 42%, respectively, in 145 children with classic medulloblastoma (CMB); and 14% and 14%, respectively, in seven children with large-cell/anaplastic (LC/A) medulloblastoma (P < .001). Histology (DNMB/MBEN: hazard ratio [HR], 0.44; 95% CI, 0.31 to 0.64; LC/A medulloblastoma: HR, 2.27; 95% CI, 0.95 to 5.54; P < .001 compared with CMB), incomplete resection and metastases (M0R1: HR, 1.86; 95% CI, 1.29 to 2.80; M+: HR, 2.28; 95% CI, 1.50 to 3.46; P < .001 compared with M0R0), and national group were independent prognostic factors for EFS, and OS. The HRs for OS ranged from 0.14 for localized M0 and DNMB/MBEN to 13.67 for metastatic LC/A medulloblastoma in different national groups. CONCLUSION: Our results confirm the high frequency of desmoplastic variants of medulloblastomas in early childhood and histopathology as a strong independent prognostic factor. A controlled de-escalation of treatment may be appropriate for young children with DNMB and MBEN in future clinical trials.


Assuntos
Neoplasias Cerebelares/mortalidade , Meduloblastoma/mortalidade , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Análise Multivariada , Prognóstico , Taxa de Sobrevida
10.
J Neurooncol ; 100(2): 199-207, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20352473

RESUMO

Pediatric neurofibromatosis type 1 (NF-1) patients are prone to developing low-grade glioma (LGG). The HIT-LGG study 1996 aimed to observe the natural history of pediatric LGG and to postpone irradiation in younger children by using carboplatinum and vincristine in case non-surgical treatment was required. A total of 109 of 1,044 (10.4%) protocol patients had a genetic NF-1 trait [57 female patients; median age 5.1 years (range 1-15.4 years)]. Eighty-three patients (76%) suffered from an optic pathway tumor. Neuroimaging only allowed diagnosis in 67 patients. Histology revealed pilocytic astrocytoma WHO grade I in 38 of 42 biopsied patients. Sixty-five (60%) patients received non-surgical treatment, either chemotherapy (n = 55) or irradiation (n = 10). The overall survival rate of 96% after a median observation time of 5.25 years contrasts with an event free survival rate (EFS) of 0.24 at 5 years. Progressive LGG were observed even in children older than 11 years. Chiasmatic/postchiasmatic localization was a univariate risk factor for progressive disease. In the chemotherapy group, we observed a 5-year progression-free survival (PFS) rate of 0.73. Similarly, the PFS rate in the irradiation group was 0.78. Multivariate analysis revealed surgical intervention and localization within the optic pathway as factors that increased the risk of tumor progression. In this large prospective multinational study, LGG in NF-1 patients did progress in 75% of patients. Chemotherapy yielded acceptable PFS. The biological factors determining progression remain poorly understood.


Assuntos
Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Glioma/mortalidade , Glioma/terapia , Neurofibromatose 1/mortalidade , Neurofibromatose 1/terapia , Adolescente , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Progressão da Doença , Intervalo Livre de Doença , Feminino , Glioma/patologia , Humanos , Lactente , Masculino , Procedimentos Neurocirúrgicos , Radioterapia , Fatores de Risco
11.
Neuro Oncol ; 11(2): 201-10, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18818397

RESUMO

To investigate the utility of postoperative chemotherapy in delaying radiotherapy and to identify prognostic factors in early childhood medulloblastoma, we studied children younger than 3 years of age registered to the HIT-SKK'87 (Therapieprotokoll für Säuglinge und Kleinkinder mit Hirntumoren [Brain Tumor Radiotherapy for Infants and Toddlers with Medulloblastoma] 1987) trial who received systemic interval chemotherapy until craniospinal radiotherapy was applied at 3 years of age or at relapse, from 1987 to 1993. Children with postoperative residual tumor or metastatic disease received systemic induction chemotherapy prior to interval chemotherapy. Twenty-nine children were eligible for analyses (median age, 1.7 years; median follow-up, 12.6 years). In children without macroscopic metastases, rates (+/-SEM) for 10-year progression-free survival (PFS) and overall survival (OS) were 52.9% +/- 12.1% and 58.8% +/- 11.9% (complete resection), and 55.6% +/- 16.6% and 66.7% +/- 15.7% (incomplete resection), compared with 0% and 0% in children with macroscopic metastases. Survival was superior in nine children with desmoplastic or extensive nodular histology compared with 20 children with classic medulloblastoma (10-year PFS, 88.9% +/- 10.5% and 30.0% +/- 10.3%, p = 0.003; OS, 88.9% +/- 10.5% and 40.0% +/- 11.0%, p = 0.006). Eleven of 12 children with tumor progression during chemotherapy had classic medulloblastoma. After treatment, IQ scores were inferior compared with nonirradiated children from the subsequent study, HIT-SKK'92. Classic histology, metastatic disease, and male gender were independent adverse risk factors for PFS and OS in 72 children from HIT-SKK'87 and HIT-SKK'92 combined. In terms of survival, craniospinal radiotherapy was successfully delayed especially in young children with medulloblastoma of desmoplastic/extensive nodular histology, which was a strong independent favorable prognostic factor. Because of the neurocognitive deficits of survivors, the emerging concepts to avoid craniospinal radiotherapy should rely on the histological medulloblastoma subtype.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/radioterapia , Irradiação Craniana , Meduloblastoma/tratamento farmacológico , Meduloblastoma/radioterapia , Recidiva Local de Neoplasia/terapia , Neoplasias Cerebelares/cirurgia , Pré-Escolar , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Meduloblastoma/cirurgia , Recidiva Local de Neoplasia/diagnóstico , Projetos Piloto , Prognóstico , Taxa de Sobrevida , Resultado do Tratamento
12.
Clin Cancer Res ; 13(9): 2651-7, 2007 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-17473196

RESUMO

PURPOSE: To identify better risk stratification systems in childhood medulloblastoma based on clinical factors and analysis of routinely processed formalin-fixed tumor material. EXPERIMENTAL DESIGN: Formalin-fixed paraffin-embedded tumor samples from well-documented patients treated within the prospective randomized multicenter trial HIT'91 were analyzed for DNA amplification of c-myc and N-myc (n=133) and mRNA expression of c-myc and trkC (n=104; compared with human cerebellum) using validated methods of quantitative PCR and reverse transcription-PCR. Results were related to clinical data and outcome. RESULTS: TrkC and c-myc mRNA expression were identified as independent prognostic factors by multivariate analysis. Three risk groups were identified. (a) Favorable risk group: all 8 patients (2 metastatic) with high trkC (>1x human cerebellum) and low c-myc mRNA expression (

Assuntos
Biomarcadores Tumorais/análise , Neoplasias Cerebelares/diagnóstico , Meduloblastoma/diagnóstico , Adolescente , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , DNA de Neoplasias/análise , Feminino , Humanos , Masculino , Meduloblastoma/patologia , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-myc/genética , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Receptor trkC/genética , Fatores de Risco
13.
Cancer Causes Control ; 17(4): 583-9, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16596314

RESUMO

Craniopharyngioma is a rare dysontogenetic benign tumor. Patients frequently suffer from endocrine deficiencies, sleep disturbances and obesity due to pituitary and hypothalamic lesions. A self-assessment daytime sleepiness questionnaire (German version of the Epworth Sleepiness Scale [ESS]) was used to evaluate 79 patients with childhood craniopharyngioma. Because hypothalamic lesions may explain daytime sleepiness in craniopharyngioma patients, salivary melatonin and cortisol concentrations were examined in severely obese (BMI>or=4SD) and non severely obese (BMI<4SD) craniopharyngioma patients (n=79), patients with hypothalamic pilocytic astrocytoma (n=19), and control subjects (n=30). Using a general linear model procedure analyzing the influence of BMI and tumor diagnosis on diurnal salivary melatonin we found that morning salivary melatonin levels were related to BMI (F test: p-value=0.004) and tumor diagnosis (F-test: p-value=0.032). Also for nighttime salivary melatonin levels significant relations with BMI (p-value in F-test: <0.001) and tumor diagnosis (p-value in F-test: 0.025) were detectable. Melatonin concentrations in saliva of craniopharyngioma patients collected at nighttime or in the morning showed a negative correlation (Spearman's rho: -0.42; p=0.001; Spearman's rho: -0.31; p=0.020) with the patient's ESS score. Severely obese craniopharyngioma patients and severely obese hypothalamic tumor patients had similar patterns of melatonin secretion. Differences in terms of diurnal salivary cortisol concentrations were not detectable when patient groups and controls were compared. As decreased nocturnal melatonin levels were associated with increased daytime sleepiness, BMI and hypothalamic tumor diagnosis, we initiated an experimental melatonin substitution in 10 adult obese patients (5f/5m) with childhood craniopharyngioma. In all 10 patients with childhood craniopharyngioma the degree of daytime sleepiness significantly improved based on activity diaries, ESS, self assessment questionnaires and actimetry. We speculate that hypothalamic lesions might be responsible for both obesity and daytime sleepiness. As first experiences with experimental melatonin substitution were promising, further randomized double-blinded studies on the beneficial effects of melatonin substitution on daytime sleepiness and weight control in these patients are warranted.


Assuntos
Craniofaringioma/metabolismo , Melatonina/metabolismo , Melatonina/uso terapêutico , Obesidade/metabolismo , Neoplasias Hipofisárias/metabolismo , Fases do Sono , Adolescente , Adulto , Astrocitoma/complicações , Astrocitoma/metabolismo , Criança , Pré-Escolar , Ritmo Circadiano , Craniofaringioma/complicações , Distúrbios do Sono por Sonolência Excessiva/complicações , Distúrbios do Sono por Sonolência Excessiva/tratamento farmacológico , Feminino , Humanos , Hidrocortisona/sangue , Neoplasias Hipotalâmicas/metabolismo , Masculino , Obesidade/complicações , Neoplasias Hipofisárias/complicações , Saliva/química , Fases do Sono/efeitos dos fármacos
14.
J Neurooncol ; 79(3): 281-7, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16598416

RESUMO

BACKGROUND: Pontine gliomas are the subgroup of brainstem gliomas with the worst prognosis. Controversial treatment approaches are discussed. PATIENTS AND METHODS: Data of children with pontine gliomas treated in different prospective multi-center studies who were registered in the HIT-GBM database were pooled and analyzed addressing prognostic factors and the relevance of intensive treatment using contingency tables, Kaplan-Meier curves and Cox regression analyses. RESULTS: From 1983 to 2001, 153 patients (74 males, 79 females, mean age: 8.1 years) with pontine gliomas were registered. Twenty-one tumors were low-grade and 60 were high-grade gliomas (72 undefined histology: 67 no surgery, 5 incomplete data). Sixteen tumors were partially resected, and 125 were irradiated. Ninety children received chemotherapy according to the "HIT-GBM" protocols ("Hirntumor-Glioblastoma multiforme"). The one-year overall survival rate (1YOS) of all patients with pontine glioma was 39.9+/-4.3%. None of the surviving patients had an observation time longer than 3.9 years. Favorable prognostic factors seemed to be age younger than 4 years, low-grade histology and smaller tumor. All three major treatment modalities including resection, irradiation and chemotherapy had prognostic relevance in univariable analysis. Chemotherapy remained beneficial, even if the analysis was restricted to the subgroup of irradiated tumors (1YOS 45.8+/-5.4% vs. 34.4+/-13.5%, P=0.030). CONCLUSION: Irradiation is an effective element for the treatment of pontine gliomas. Intensive chemotherapy seems to be important in achieving a better OS.


Assuntos
Neoplasias do Tronco Encefálico/mortalidade , Neoplasias do Tronco Encefálico/terapia , Glioma/mortalidade , Glioma/terapia , Ponte/patologia , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Tronco Encefálico/patologia , Criança , Ensaios Clínicos como Assunto , Feminino , Glioma/patologia , Humanos , Masculino , Estudos Multicêntricos como Assunto , Procedimentos Neurocirúrgicos , Prognóstico , Radioterapia , Estudos Retrospectivos , Análise de Sobrevida
15.
Eur J Neurosci ; 23(1): 105-11, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16420420

RESUMO

The influence of seasonal lighting conditions on expression of clock genes and the circadian pacemaker was investigated in the rat retina. For this purpose, the 24-h profiles of nine clock genes (bmal1, clock, per1, per2, per3, dec1, dec2, cry1 and cry 2) and the arylalkylamine N-acetyltransferase gene as an indicator of the circadian pacemaker output were compared between light-dark periods of 8 : 16 and 16 : 8 h. The photoperiod influenced the daily patterns of the amount of transcript for per1, per3, dec2 and arylalkylamine N-acetyltransferase. This indicates that photoperiodic information modulates clock gene expression in addition to the circadian pacemaker of the retina. Under constant darkness, photoperiod-dependent changes in the daily profile of the level of transcript persisted for the arylalkylamine N-acetyltransferase gene but not for any of the clock genes. Hence, quantitative expression of each clock gene is influenced by the photoperiod only under the acute light-dark cycle, whereas the pacemaker is capable of storing photoperiodic information from past cycles.


Assuntos
Ritmo Circadiano/genética , Regulação da Expressão Gênica/efeitos da radiação , Expressão Gênica/efeitos da radiação , Proteínas Nucleares/metabolismo , Fotoperíodo , Retina/metabolismo , Análise de Variância , Animais , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Feminino , Expressão Gênica/fisiologia , Regulação da Expressão Gênica/fisiologia , Masculino , Proteínas Nucleares/genética , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Fatores de Tempo
16.
Childs Nerv Syst ; 21(11): 975-80, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16075216

RESUMO

OBJECTS: We longitudinally analysed functional capacity and quality of life (QoL) in 102 patients with a childhood craniopharyngioma during follow-up. METHODS: The Fertigkeitenskala Münster-Heidelberg (FMH) ability scale was used for QoL assessment. Multivariate analysis evaluated FMH scores at various time points, examining hypothalamus involvement (HI), body mass index (BMI), degree of resection, tumour progression, relapse and irradiation. RESULTS AND CONCLUSION: Patients without HI (n=60) self-assessed higher QoL at baseline (p=0.001) and follow-up (p<0.001) than patients with HI (n=42). Only patients without HI evaluated at baseline >12 months after diagnosis showed longitudinal improvement in FMH scores (p=0.040). Rates of incomplete resection and irradiation were higher (p=0.070 and p=0.002 respectively) in patients with HI. In multivariate analysis, only HI, tumour relapse, progression, baseline FMH score, and time between diagnosis and baseline evaluation had independent impact on QoL. HI, tumour progression, and relapse had long-term QoL affects-most notably, severe obesity.


Assuntos
Craniofaringioma/psicologia , Hipofisectomia/psicologia , Neoplasias Hipofisárias/psicologia , Qualidade de Vida/psicologia , Sobreviventes/psicologia , Atividades Cotidianas/classificação , Atividades Cotidianas/psicologia , Adolescente , Adulto , Índice de Massa Corporal , Criança , Pré-Escolar , Terapia Combinada , Craniofaringioma/radioterapia , Craniofaringioma/cirurgia , Progressão da Doença , Feminino , Seguimentos , Humanos , Hipotálamo/patologia , Lactente , Estudos Longitudinais , Masculino , Invasividade Neoplásica , Recidiva Local de Neoplasia/psicologia , Obesidade/psicologia , Irradiação Hipofisária , Neoplasias Hipofisárias/radioterapia , Neoplasias Hipofisárias/cirurgia , Complicações Pós-Operatórias/psicologia , Psicometria/estatística & dados numéricos , Radioterapia Adjuvante , Reprodutibilidade dos Testes , Autoavaliação (Psicologia) , Perfil de Impacto da Doença
17.
Childs Nerv Syst ; 21(7): 539-45, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15889310

RESUMO

RATIONALE: We analyzed the impact of tumour localization and histology on functional capacity (FC) and body mass index (BMI) in children with sellar masses. METHODS: FC was evaluated using the ability scale Fertigkeitenskala Münster-Heidelberg in 403 children and adolescents with sellar masses (276 craniopharyngioma, 14 germinoma, 21 optic/chiasmatic glioma, 40 hypothalamic glioma, 13 cysts of Rathke's cleft and 39 other sellar masses). Besides tumour localization, the influence of gender, irradiation and age at diagnosis and at evaluation on FC and BMI was analyzed. General linear models with explanatory influential variables were built. RESULTS: In multivariate analysis, only age at diagnosis (p<0.001) and hypothalamic involvement (p=0.005) had relevant impact on FC. The second model showed BMI at diagnosis (p<0,001), hypothalamic involvement (p<0.001) and craniopharyngioma (p=0,004) to influence BMI at the latest evaluation. CONCLUSION: We conclude that hypothalamic involvement and young age at diagnosis had major impact on FC and BMI and should be considered as risk factors for impaired rehabilitation.


Assuntos
Índice de Massa Corporal , Craniofaringioma/diagnóstico , Craniofaringioma/fisiopatologia , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/fisiopatologia , Adolescente , Adulto , Distribuição de Qui-Quadrado , Criança , Craniofaringioma/classificação , Estudos Transversais , Feminino , Humanos , Hipotálamo/patologia , Hipotálamo/fisiopatologia , Masculino , Testes Neuropsicológicos , Neoplasias Hipofisárias/classificação , Estudos Prospectivos , Qualidade de Vida , Estudos Retrospectivos
18.
N Engl J Med ; 352(10): 978-86, 2005 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-15758008

RESUMO

BACKGROUND: The prognosis for young children with medulloblastoma is poor, and survivors are at high risk for cognitive deficits. We conducted a trial of the treatment of this brain tumor by intensive postoperative chemotherapy alone. METHODS: After surgery, children received three cycles of intravenous chemotherapy (cyclophosphamide, vincristine, methotrexate, carboplatin, and etoposide) and intraventricular methotrexate. Treatment was terminated if a complete remission was achieved. Leukoencephalopathy and cognitive deficits were evaluated. RESULTS: Forty-three children were treated according to protocol. In children who had complete resection (17 patients), residual tumor (14), and macroscopic metastases (12), the five-year progression-free and overall survival rates (+/-SE) were 82+/-9 percent and 93+/-6 percent, 50+/-13 percent and 56+/-14 percent, and 33+/-14 percent and 38+/-15 percent, respectively. The rates in 31 patients without macroscopic metastases were 68+/-8 percent and 77+/-8 percent. Desmoplastic histology, metastatic disease, and an age younger than two years were independent prognostic factors for tumor relapse and survival. Treatment strategies at relapse were successful in 8 of 16 patients. There were no major instances of unexpected toxicity. In 19 of 23 children, asymptomatic leukoencephalopathy was detected by magnetic resonance imaging. After treatment, the mean IQ was significantly lower than that of healthy controls within the same age group but higher than that of patients in a previous trial who had received radiotherapy. CONCLUSIONS: Postoperative chemotherapy alone is a promising treatment for medulloblastoma in young children without metastases.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Cerebelares/tratamento farmacológico , Meduloblastoma/tratamento farmacológico , Análise de Variância , Carboplatina/administração & dosagem , Neoplasias Cerebelares/psicologia , Neoplasias Cerebelares/cirurgia , Quimioterapia Adjuvante , Pré-Escolar , Ciclofosfamida/administração & dosagem , Etoposídeo/administração & dosagem , Seguimentos , Humanos , Lactente , Inteligência/efeitos dos fármacos , Meduloblastoma/psicologia , Meduloblastoma/secundário , Meduloblastoma/cirurgia , Metotrexato/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Testes Neuropsicológicos , Cuidados Pós-Operatórios , Modelos de Riscos Proporcionais , Indução de Remissão , Análise de Sobrevida , Vincristina/administração & dosagem
19.
J Clin Endocrinol Metab ; 89(7): 3298-305, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15240606

RESUMO

We analyzed whether childhood craniopharyngioma predisposes to obesity and growth impairment. Height/length, body mass index (BMI), and hypothalamic involvement were evaluated in 90 patients at standardized ages and time points before, after, and at the time of diagnosis. Relevant decreases in height sd score (SDS) started at 10-12 months of age and persisted until diagnosis of childhood craniopharyngioma. Relevant increases in BMI SDS were detectable between 4 and 5 yr of age. Postoperative BMI SDS (yr 1-6) had a weak positive correlation with BMI SDS at the time of diagnosis. In linear regression analysis, hypothalamic tumor involvement (P < 0.001), ponderal index at birth (P = 0.014), and BMI SDS at age 6-7 months (P = 0.029) and at age 5 yr (P < 0.001) had relevant and independent impacts on the development of obesity. Patients with hypothalamic involvement (n = 48) presented lower ponderal index and BMI SDS at birth and higher BMI SDS at the time of diagnosis (P < 0.001) as well as during annual follow-up (P < 0.001) compared with patients without hypothalamic involvement (n = 42). From childhood (3.5-4 yr) to the time of diagnosis, growth rates were reduced for patients with hypothalamic tumor involvement. Patients without hypothalamic involvement presented reduced growth rates in early infancy (age 10-12 months) that persisted until diagnosis. We conclude that reduced growth rates occur quite early in history; BMI SDS increases occur later and are predictive of obesity. Hypothalamic involvement is the major risk factor for obesity in patients with childhood craniopharyngioma.


Assuntos
Índice de Massa Corporal , Desenvolvimento Infantil , Craniofaringioma/complicações , Transtornos do Crescimento/etiologia , Obesidade/etiologia , Neoplasias Hipofisárias/complicações , Estatura , Peso Corporal , Craniofaringioma/patologia , Craniofaringioma/fisiopatologia , Craniofaringioma/cirurgia , Suscetibilidade a Doenças , Humanos , Hipotálamo/patologia , Lactente , Estudos Longitudinais , Análise Multivariada , Invasividade Neoplásica , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/fisiopatologia , Neoplasias Hipofisárias/cirurgia , Estudos Retrospectivos , Fatores de Risco
20.
Cancer ; 100(8): 1750-7, 2004 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-15073866

RESUMO

BACKGROUND: Continuous oral treatment with topotecan may be more effective than the typical 1-day and 5-day treatment schedules. In previous studies of continuous treatment with topotecan, increased intestinal side effects were reported in adult patients; however, the experience in pediatric patients and patients with high-grade glioma is quite limited. METHODS: Thirty-two pediatric patients with recurrent high-grade glioma (16 females and 16 males; median age, 9.5 years) were enrolled in the current Phase I/II study. Tumor locations included the cerebral cortex (n = 5), pons (n = 18), and other sites (n = 9). An injectable formulation of topotecan was administered orally, in ice-cold orange juice, once daily. The starting dose of 0.4 mg/m(2) per day was escalated on a patient-by-patient basis. At each patient's maximum dose, blood samples were obtained for the determination of plasma hydroxytopotecan and topotecan lactone concentrations and for the calculation of pharmacokinetic quantities. RESULTS: The toxicity criteria for a maximum tolerated topotecan dose were met in only 19 patients. The primary toxicity type was hematologic. The median maximum tolerated dose was 0.9 mg/m(2) per day (n = 19). The calculated maximum total plasma topotecan concentration was 3.8 ng/mL (n = 7), with an area under the concentration-time curve of 38.4 ng. hours/mL and a half-life of 4.1 hours, which would result in the complete disappearance of topotecan from the plasma after 12 hours. Objective responses were observed in 2 of 13 evaluable patients and lasted for 2.5 and 9 months, respectively (continuous clinical remission, 1 of 14 patients; partial response, 2 of 14 patients; stable disease, 7 of 14 patients; progressive disease, 4 of 14 patients). CONCLUSIONS: Oral topotecan (median dose, 0.9 mg/m(2) per day) administered once daily was well tolerated and somewhat effective in children with recurrent high-grade glioma. A schedule in which the daily dose is split so that dosing is performed twice daily may be superior to the current schedule.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Topotecan/uso terapêutico , Administração Oral , Adolescente , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Glioma/patologia , Humanos , Masculino , Topotecan/administração & dosagem , Topotecan/efeitos adversos , Topotecan/farmacocinética , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...