The adverse event profile of zonisamide: a meta-analysis.

The first aim of our study was to analyze the adverse events statistically significantly associated with zonisamide, through a systematic review and meta-analysis of available randomized placebo-controlled trials (RCTs). The second aim was to compare these results with those obtained from an analysis of non-RCTs and observational studies. Randomized controlled trials were identified using Medline (PubMed), EMBASE (Ovid), and Cochrane CENTRAL, from 1990 to September 2012. RevMan version 5.1 and OpenMeta[Analyst] were used for analyses of RCT and non-RCTs, respectively. Six eligible studies with 1184 patients between 12 and 80 years of age were included in RCTs analysis. Fifteen adverse events were investigated. In this first part of the analysis, no adverse events were statistically significantly associated with zonisamide. In the non-RCT analysis, a high incidence of weight loss and headache was found. In RCTs, zonisamide was statistically significantly associated with an increased risk of adverse event-related study withdrawals [RR (99% CI) = 1.81 (1.07-3.08)]. Although our study revealed no statistically significantly associated adverse effects (AEs) with zonisamide, this is very likely a consequence of the small numbers in the RCTs available. The limited data available from the studies appear to reveal no major safety concerns related to zonisamide. However, the high incidence of weight loss and headache in the non-RCTs suggests that these AEs could be of clinical significance.

New insights in diabetic autonomic neuropathy in children and adolescents.

Diabetic autonomic neuropathy (DAN) represents a major complication of diabetes mellitus but there is considerable uncertainty about its incidence, prevalence, pathogenesis, diagnosis, and prognosis. There are conflicting opinions about the pathogenesis of DAN: the 'classical hypothesis' has been supplemented by some new insights. Clinical symptoms of autonomic neuropathy do not generally occur until long after the onset of diabetes. DAN seems to be detectable even in asymptomatic children and adolescents with diabetes and is associated with the most serious consequences, such as cardiovascular dysfunction. Because of its association with a variety of adverse outcomes, including cardiovascular deaths, cardiovascular autonomic neuropathy is the most clinically important and well-studied form of DAN. No form of therapy in DAN has been identified that provides unequivocal, safe, and effective stabilization or reversal of the condition, just a near normal control of blood glucose in the early years after the onset of diabetes that may delay the development of clinically significant nerve impairment. This article reviews recent developments in knowledge of epidemiology, pathogenesis, clinical symptoms, diagnosis, and therapy of DAN.

Levetiracetam monotherapy for childhood occipital epilepsy of gastaut.

OBJECTIVES: The aim of this open label pilot study was to evaluate the efficacy and tolerability of levetiracetam (LEV) as 'de novo' monotherapy in children and adolescents with late onset childhood occipital epilepsy-Gastaut type (COE-G). MATERIAL AND METHODS: Twelve patients suffering from COE-G were enrolled in this prospective study. The age of seizures onset ranged from 6.1 to 16.2 years with a peak of frequency at mean (+/-SD) 10.54 +/- 2.77 years. Therapy with LEV was started at 10 mg/kg/day and, after titration, the final dose was generally achieved within 4 weeks and ranged from 20.7 to 45.2 mg/kg/day. RESULTS: At the 6 month evaluation, 11 (91.6%) of the 12 patients studied were seizure free, and one (8.3%) showed four additional episodes. Electroencephalography (EEG) activity was normal in six (54.5%) patients, unchanged in two (18.1%) children, and in four (33.3%) patients sporadic occipital abnormalities persisted. At the 12-month evaluation all patients were completely seizure free. Four patients (33.3%) continued to show some EEG abnormalities, while eight (72.8%) patients had normal EEG. At the 18-month evaluation all patients were seizure free and 10 patients (83.3%) showed a complete normalization of EEG abnormalities. DISCUSSION: Monotherapy with LEV was effective and well tolerated in patients with COE-G. Nevertheless, prospective, large, long-term double-blind studies are needed to confirm these findings.

Ear involvement in childhood Langerhans' cell histiocytosis.

BACKGROUND: Ear involvement (EI) in Langerhans' cell histiocytosis (LCH) occurs quite often. We reviewed the Italian pediatric population of 251 children with LCH diagnosed between 1982 and 1995, focusing on EI, to highlight the prevalence, the clinical presentation, the outcome during follow-up, and the prognostic impact of otologic LCH. METHODS: EI was defined by chronic otorrhea and/or mastoid infiltration, external auditory meatus lesions, and middle/internal EI. The age at diagnosis, sex, system involved, organ dysfunction, treatment, disease control, and outcome were recorded. RESULTS: EI was noted at presentation in 34 children (13. 5%). They had a younger age at diagnosis (p=.0013) and near totality of multisystem disease (93.8% of patients with EI). Among patients with multisystem disease, children with EI seemed to have a higher risk of poor response and a higher percentage of second line treatment (p=.003). CONCLUSIONS: EI seems to identify patients with a particular disease behavior, which requires a more accurate evaluation at diagnosis, staging and treatment, and a strict follow-up, considering the possibility of an unfavorable outcome.

Autologous bone marrow transplantation for treatment of isolated central nervous system relapse of childhood acute lymphoblastic leukemia. AIEOP/FONOP-TMO group. Associzione Italiana Emato-Oncologia Pediatrica.

The purpose of this study was to assess the role of ABMT in children with ALL who are in 2nd CR after an early isolated CNS relapse. All children experiencing an isolated CNS relapse at 10 AIEOP centers (Associazione Italiana Emato-Oncologia Pediatrica) from 1986 to 1992 were eligible for this study. The series included 69 patients who relapsed within 3 years from diagnosis: 19 underwent ABMT, nine patients underwent ALLO-BMT from an HLA-identical sibling, and 41 received conventional chemotherapy (CHEMO). Statistical analysis was performed using a Cox's regression model, adjusting for the waiting time before transplantation and prognostic factors. The 5 years DFS was 56.3% (s.e. 12.3) for patients in the ABMT group. This compared favorably with the poor result (12.6% (s.e. 5.9)) seen in the CHEMO group. The risk of failures was reduced by one-third in the ABMT group as compared to the CHEMO group in the multivariate analysis (P < 0.01). In the ALLO group four out of nine patients were in CCR 4-5 years post-transplant. This study suggests that ABMT may also represent a valuable therapeutic choice for patients lacking a matched familiar donor in 2nd CR after an early isolated CNS relapse.

High-average-power KTiOAsO4 optical parametric oscillator.

Using noncritically phase-matched 1-cm(2) -aperture KTiOAsO(4) (KTA) crystals in an optical parametric oscillator (OPO), we have demonstrated a sustained average signal power of 33 W at 1534.7 nm. To our knowledge, this is the highest-average-power signal ever generated by an OPO. The pump source was a 100-Hz Q -switched 1064-nm Nd:YAG laser. Compared with that of the similar and more-common material KTiOPO>(4) , idler absorption in KTA is negligible, allowing high-power operation with minimal thermally induced refractive distortion in the OPO crystal.

Risk of secondary leukemia after treatment with etoposide (VP-16) for Langerhans' cell histiocytosis in Italian and Austrian-German populations.

To estimate the risk of secondary leukemias after treatment with etoposide (VP-16), we evaluated subjects treated for Langerhans' cell histiocytosis (LCH) according to cooperative protocols in Italy or in Austria, Germany, Holland and Switzerland (AGDS). For each subject, information was collected on the cumulative dosages of chemotherapy and radiotherapy received, vital status and occurrence of secondary leukemia. The expected number of leukemias was estimated using age-specific incidence rates from the cancer registries in Italy and Germany. Standardized incidence ratios (SIR) were used to measure the risk of secondary leukemia among LCH patients. Five leukemias occurred among the 241 Italian study patients (SIR 520), whereas no cases were reported among the 363 AGDS patients. Interestingly, and in contrast to previous descriptions of epipodophyllotoxin-related leukemias which are mostly FAB M4 or M5, these leukemias showed typical FAB M3 features, and received a dose of VP-16 > 4,000 mg/m2. Among the AGDS cohort, very few subjects were exposed to high doses of VP-16. The risk of secondary acute non-lymphoblastic leukemia (s-ANLL) among the Italian subjects exposed to VP-16 was more than 1,000 times greater than expected. The study suggests that high doses of VP-16 appear to increase the risk of s-ANLL in LCH patients. The fact that all the leukemias described in the Italian LCH cohort were promyelocytic, and evidence of a higher incidence of promyelocytic leukemias among Italians and Latinos, suggest that high doses of etoposide in subjects of Latino origin may lead to aberrations on chromosomes 15 and 17.

Autologous bone marrow transplantation for extramedullary relapse in childhood leukemia. The AIEOP Group and the FONOP. Italian Association of Pediatric Hemato/Oncology.

The role of autologous bone marrow transplantation (ABMT) in childhood ALL after an isolated extramedullary (IE) relapse is controversial. Between December 1984 and November 1995, 52 children underwent ABMT because of an IE relapse. The data were stored in the AIEOP-BMT Registry. Thirty four children were transplanted in 2nd CR; eighteen > 2nd CR. The median duration of 1st CR was 24 (range 3-69) and 18 (range 3-59) months, respectively. The median interval from last CR to ABMT was 6 (range 1-28) and 3 (range 1-81) months, respectively. The 5 year EFS for patients transplanted in 2nd CR was 67.7%, while the 3 year EFS for patients in > 2nd CR was 16.7%. In conclusion, ABMT was an effective treatment in early IE relapse only if performed in 2nd CR.

CNS-85 trial: a cooperative pediatric CNS tumor study--results of treatment of medulloblastoma patients.

Between 1985 and 1989, 38 children with newly diagnosed medulloblastoma entered our therapeutic protocol. After surgery and postoperative staging assessments, patients were assigned to risk groups. Eleven with "standard-risk" (SR) tumors were treated with radiation therapy alone, while 27 with "high-risk" (HR) tumors received radiation therapy plus adjuvant chemotherapy with vincristine, methotrexate, VM-26, and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). After a minimum follow-up of 5 years (range 5-9 years) 21/38 children had developed a recurrence or progression of their disease and 19/38 patients had died. Five-year event-free survival rates and 5-year total survival rates for all 38 patients were 47.4% and 50% respectively. The event-free survival rates at 5 years for SR and HR patients separately were 27.3% and 55.6%, respectively. The corresponding 5-year total survival rates were 27.3% and 59.3%. The differences were not statistically significant. Univariate analysis showed age at diagnosis to be the most important prognostic factor. Infants aged 5 years or less had a significantly shorter event-free survival time than older patients (P = 0.00897). Similar effects were found when total survival time was considered. There were significant differences in outcome in patients receiving different doses of radiation, suggesting a dose-response relationship. A Cox stepwise multivariate analysis showed age at diagnosis as the only independent prognostic factor. Variables relating to treatment entered the model, suggesting that chemotherapy could play an important role in determining outcome.

[In vitro and in vivo effects of cefodizime and ceftriaxone on oxygen-dependent killing of neutrophils of elderly patients with exacerbation of chronic bronchitis]. / Effetto in vitro e in vivo del cefodizime e del ceftriaxone sul killing ossigeno-dipendente dei granulociti neutrofili di pazienti anziani con bronchite cronica riacutizzata.

The immunomodulating activity of some chemotherapeutic agents, is particularly interesting. Our study has evaluated the in vitro and in vivo effects of two third generation cephalosporins: cefodizime and ceftriaxone, on the chemiluminescence of polymorphonuclears of 20 elderly patients affected by acute exacerbation of bronchitis. Twenty healthy patients have been also evaluated in vitro. Antibiotics have been used in vitro at the concentration of 50 g/ml while in vivo a group of 10 patients have been treated with cefodizime (2g/daily in 2 divided doses), another group of 10 patients with ceftriaxone (2g/daily as a single dose); in both groups the antibiotic treatment was given for 7-10 days. A significant potentiation of chemiluminescence has been shown in both groups of patients treated in vivo; whereas the preincubation in vitro of the polymorphonuclear suspension, both in healthy patients and in elderly bronchopathic ones, with antibiotics, has not changed the activity of oxygen dependent killing. Finally, we believe that bactericidal properties of the antibiotic still remain now the most important criteria of choice in order to assure effective control of infections.

Increased risk of secondary leukemia after single-agent treatment with etoposide for Langerhans' cell histiocytosis.

The study evaluated 139 patients diagnosed with Langerhans' cell histiocytosis (LCH) and enrolled in any protocol of the Italian Association of Pediatric Hematology/Oncology since 1982. Treatment was etoposide (VP-16) only in 50 patients, VP-16 and other drugs with an already established leukemogenic effect in 17 patients, only drugs with leukemogenic effect in 6 patients, other drugs in 35 patients, and surgery only in 31 patients. Median length of follow-up after diagnosis was 65 months (range, 1 to 126 months) for a total of 742.5 person-years at risk (PYRs). Three cases of acute myelogenous leukemia (AML) were reported; only 0.0044 case was expected. The standard incidence ratio (SIR) of AML in this cohort was 680.5 [95% confidence interval (CI), 140.2-1988.5], and the incidence rate per 1000 PYRs was 4.0 (95% CI, 0.8-11.8). For the subgroup treated with single-agent VP-16, the SIR after treatment was 2270.0 (95% CI, 275-8199), and the incidence rate after treatment was 14.7 (95% CI, 1.8-42.8). The study confirms a higher risk of leukemia after LCH and supports the hypothesis of an association between treatment-related acute nonlymphocytic leukemia and single-agent treatment with VP-16.

Langerhans cell histiocytosis in childhood: results from the Italian Cooperative AIEOP-CNR-H.X '83 study.

Ninety patients with biopsy-proven Langerhans cell histiocytosis (LCH) were enrolled from June, 1983, to December, 1988, in the multicenter AIEOP-CNR-H.X. '83 study. They were divided into two groups: poor prognosis (PP), comprising 11 children with organ dysfunction (OD), and good prognosis (GP), made up of 79 patients without OD. Eighty-four patients were evaluable for treatment results. Among GP patients, 16 with a single lesion received only local treatment, while 59 entered a clinical trial of immunotherapy and/or monochemotherapy with vinblastine (VBL). Nonresponders, sequentially received doxorubicin (ADM) and then etoposide (VP16). PP patients were treated with 4 week cycles of vincristine, ADM, cyclophosphamide, and prednisone for nine courses. The overall survival was 92.8% (100% for GP patients and 45.5% for PP patients) at 48 months. The complete response (CR) rates for immunotherapy, VBL, ADM, and VP16 were 10%, 62.9%, 42.8%, and 88.2%, respectively. Two of the 11 PP patients had a CR (18.2%), while six died and three are still alive with recurrent disease. The overall incidence of disease-related disabilities was 47.7%, while that of diabetes insipidus was 20%. Monochemotherapy is probably adequate in GP patients, while more effective treatments are needed for PP patients.

High dose peptichemio in pretreated neuroblastoma.

The aim of this study was to evaluate the antitumor effect and toxicity of a single course of Peptichemio at high dose (450 mg/sq m) given to children with neuroblastoma resistant to first line treatment or at relapse. A total of 28 children were treated. Seven children showed partial response, 4 minor response, 8 had stable disease, and in 8 the tumor progressed. The principal toxic effect was myelosuppression. Hemorrhagic enteritis with liver failure and toxic death occurred in 1 patient. High dose Peptichemio can be administered with tolerable toxicity, inducing tumor regression in one third of previously treated patients.

Neurofibromatosis and malignant childhood cancers: a survey in Italy, 1970-83.

Neural tumors, Wilms' tumor, rhabdomyosarcoma and several types of leukemia have been previously described in association with neurofibromatosis (NF). In a nation-wide collection of cases in Italy, 15 children (0-14 years of age) with NF and cancer or leukemia were identified; 13 of them had been diagnosed with cancer between 1976-83. The expected number of children with cancer and NF in 1976-83 was 4.48. The distribution of tumor types was different from that found in the general population, with a higher proportion of tumors of neural crest origin as well as soft tissue sarcomas. In 7/15 the family history was positive for NF; in 5/7 the individuals affected included the mother and/or a maternal relative.

[Prognostic factors in non-Hodgkin's lymphoma in childhood]. / Fattori prognostici dei linfomi non-H. nell'infanzia.

38 children with Non-Hodgkin Lymphoma (age 15 months - 17 years; 27 males and 11 females) have been treated between 1974 and 1982. They have been divided in two different groups: a Good Prognosis group for patients with complete resectable disease and a Poor Prognosis group including patients with mediastinal, bone marrow or CNS involvement or with diffuse and non completely resectable localization. In the Good Prognosis group there were 100% Complete Remission, 12.5% Local Relapses and 12.5% deaths. 88% of patients are alive at 8 1/2 years follow-up. In the Poor Prognosis group there were 83% Complete Remission, 50% Relapses (8 in the first year, 2 in the second and 5 in the third and no more in the next years) and 60% Deaths; 30% of patients are off-therapy with a survival of 40% at 8 1/2 years follow-up. Among the 19 patients with mediastinal involvement there were 84.2% Complete Remission, 68.4% Relapses, 63.1% Deaths and 26.6% off therapy patients. Among the 19 patients with mediastinal involvement there were 84.2% Complete Remission, 68.4% Relapses, 63.1% Deaths and 26.6% off therapy patients. Survival is 70% for the group without mediastinal involvement and 35% for the group with mediastinal involvement. Burkitt-type Lymphoma has a survival of 30% in contrast to the 60% survival for all the others histological types. In summary we conclude that the distinction between Good Prognosis and Poor Prognosis groups, on the basis of a clinical stage involvement and Burkitt histology have an important role for prognosis of Non-Hodgkin Lymphoma in children.

Peptichemio in neuroblastoma at relapse.

Peptichemio (PTC), a multipeptidic complex of m-L-phenyl-alanine mustard, was administered to 39 children with neuroblastoma at relapse. The compound was given in two 5-day cycles at dosages varying from 1.0-1.5 mg/kg/day. We were able to evaluate 29 of the initial 39 children for PTC effect; 21 of them had received PTC as first therapy following diagnosis. Ten patients underwent other chemotherapy for relapse before PTC. Three patients were off therapy when relapse occurred. Subjective improvement was observed in 18 cases (62%). Eleven patients (38%) experienced an objective regression, which was scored as complete response in three cases, partial response in two, mixed response in six. In ten children no significant disease change was observed; the remaining eight had a progression of their disease while receiving PTC. The incidence of responses has been higher in patients off therapy at moment of relapse, and lower in those pretreated for their relapse. Previous administration of PTC did not reduce the chance of response at relapse. Major toxic effects were transient, mostly moderate myelodepression and phlebosclerosis. Allergic reactions, nausea, and vomiting, occurred in a few patients. These data indicate that PTC may exert objective antitumor activity in approximately one-third of neuroblastoma patients at relapse.