High-dose cyclosporin with etoposide--toxicity and pharmacokinetic interaction in children with solid tumours.

The tolerability, anti-tumour activity and pharmacokinetic interaction of high-dose intravenous cyclosporin combined with intravenous etoposide was evaluated in children. Eighteen patients with recurrent or refractory tumours, all of whom had previously received etoposide, were treated with a combination of high-dose cyclosporin and etoposide. In 13, cyclosporin was given as a continuous infusion (15 mg kg(-1) per 24 h for 60 h) and in five a short 3-hour infusion of 30 mg kg(-1) day(-1) on three consecutive days. Pharmacokinetic profiles of etoposide were determined with and without cyclosporin. Cyclosporin levels ranged from 1359 to 4835 ng ml(-1) and cyclosporin increased the median area under the concentration time for etoposide curve from 7.2 to 12.5 mg ml(-1) min. The major toxicity was acute with varying forms of hypersensitivity reactions. In four cases this was severe. Hyperbilirubinaemia was present in 25 of 32 courses but was of short duration. In 14 courses, creatinine and/or urea was elevated, but was also transient. Significant hypertension was seen in six courses. Four of 17 patients evaluable for response obtained a partial response and one showed stable disease. It is concluded that in children given the combination of high-dose cyclosporin and etoposide, the etoposide dose should be halved in order to achieve an area under the drug concentration-time curve similar to that with etoposide alone. A continuous infusion schedule of cyclosporin is better tolerated during the period of administration but is associated with similar hepatic and renal dysfunction to a short schedule. The 24% response rate in children who had previously received etoposide suggests that this may be an effective method of enhancing drug sensitivity and further phase II evaluation is justified

Veno-occlusive disease of the liver in children treated for Wilms tumor

Hepatotoxicity consistent with the clinical diagnosis of veno-occlusive disease (VOD) of the liver has been suspected after conventional anti-cancer chemotherapy in children. To establish the incidence of hepatotoxicity and its relationship with VOD, we analyzed toxicity data obtained on 511 children affected by Wilms tumor and treated according to the SIOP-9 protocol. They all received pre- and postnephrectomy chemotherapy using dactinomycin (AD) and vincristine (VCR) +/- other drugs +/- radiotherapy according to surgical stage and histology. Sixty-four patients suffered at least one episode of hepatotoxicity and 41 satisfied the criteria for a clinical diagnosis of VOD. In this latter group, toxicity occurred during preoperative treatment in 15 patients and was confirmed histopathologically in 9 of the 16 liver biopsies obtained. There was a higher percentage of children aged less than 1 year at diagnosis in the VOD group than in the other patients (24% vs. 11.4%). The degree of liver damage in the younger patients seems important, as suggested by a higher increase in transaminases. VOD developed in 12% of the 68 irradiated children vs. 7% in the non-irradiated group. Statistical analysis showed an increased risk of VOD in younger patients (p < 0.001) and in those receiving radiotherapy (p < 0.001). All patients recovered after 6-180 days using supportive therapy only. (1) 8% of children treated according to the SIOP-9 protocol, developed hepatotoxicity consistent with VOD. Excluding patients who received radiotherapy, the incidence was 6%. These figures are much higher than in earlier reports, though different diagnostic criteria were used. (2) Chemotherapy with AD and VCR seems to be a major cause of VOD. (3) Risk factors are young age and concomitant radiotherapy. (4) VOD does not prejudice positive outcome for these patient

Renal cell carcinoma in children: A clinicopathologic study

Purpose: To identify the prognostic factors, treatment, and outcome of children affected by renal cell carcinoma (RCC). Patients and Methods: The series included 41 patients (18 males and 23 females) with a median age of 124 months observed at the 11 Italian Association for Pediatric Hematology and Oncology centers from January 1973 to January 2001. Clinical data, surgical notes, pathologic findings, and summaries of therapy were taken from the charts. Results: Seven (17%) of the 41 patients had a papillary histology, and 34 (82.4%) had nonpapillary histology. Eighteen patients (43.9%) had stage I, one patient (2.4%) had stage II, two patients (4.8%) had stage IIIA, 10 patients (24.3%) had stage IIIB, and nine patients (21.9%) had stage IV disease. One patient had a bilateral involvement at diagnosis. Seven patients experienced disease recurrence. Lung and liver were the most common distant lesions and usually were fatal. In this study, the major factor influencing the prognosis was the stage. Event-free survival at 20 years was 53.5% for all patients. Overall survival at 20 years was 54.9% for all patients. Conclusion: RCC is a rare disease in children and adolescents. This neoplasm has a different clinical presentation in children compared with adults but the same outcome. In our experience, patients with localized disease could be cured by nephrectomy alone. Prospective studies in a larger number of patients are needed to confirm radiation therapy and biologic response modifiers as effective adjunct therapy in RCC stage III. The alternative therapy seems warranted in patients with advanced disease. © 2003 by American Society of Clinical Oncology

Childhood leiomyosarcoma: A report from the Soft Tissue Sarcoma Italian Cooperative Group

n/

Bundling of Services and Household Welfare in Developing Countries Using Panel Data: The Case of Peru

Using panel data for Peru for the period 1994-2000, we find that when households receive two or more services jointly, the welfare increases of the household, as measured by changes in consumption, are larger than when services are provided separately. Such an increase appears to be more than proportional, as F-tests on the coefficients of the corresponding regressors confirm. Thus, we find that bundling of services may help realize welfare effects

Obstructive sleep apnoea/hypopnoea syndrome: Relationship with obesity and management in obese patients

SUMMARY Obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is a disease characterised by upper airway obstruction during sleep, quite frequent in the general population, even if underestimated. Snoring, sleep apnoea and diurnal hypersomnia are common in these patients. Central obesity plays a key role: it reduces the size and changes the conformation of the upper airways, besides preventing lung expansion, with consequent reduction of lung volumes. Furthermore, obese people are also resistant to leptin, which physiologically stimulates ventilation; as a result, this causes scarce awakening during apnoea. OSAHS diagnosis is based on the combination of clinical parameters, such as apnoea/hypopnoea index (AHI), medical history, physical examination and Mallampati score. The first objective reference method to identify OSAHS is polysomnography followed by sleep endoscopy. Therapy provides in the first instance reduction of body weight, followed by continuous positive airway pressure (CPAP), which still remains the treatment of choice in most patients, mandibular advancement devices (MAD) and finally otolaryngology or maxillofacial surgery. Among surgical techniques, central is barbed reposition pharyngoplasty (BRP), used in the field of multilevel surgery

Salvage rates and prognostic factors after relapse in children and adolescents with initially localised synovial sarcoma

Background: Previous studies have reported a poor outcome for synovial sarcoma patients whose tumours relapse. Methods: This study analysed 44 relapsing cases in a series of 118 consecutive patients&lt;21 yr of age with non-metastatic synovial sarcoma prospectively enrolled in Italian paediatric protocols between 1979 and 2006. In an effort to identify a possible risk-adapted stratification enabling a better planning of second-line treatment, the relapsing patients' outcome was analysed vis-à-vis their clinical picture at onset, first-line treatments, clinical findings at the time of first relapse and second-line treatment modalities. Results: The first event was a local recurrence in only 15 cases, and metastatic in 29 (associated with local relapse too in 7 cases). The time to relapse ranged from 4 to 108 months (median 20 months). Overall survival was 29.7% and 21.0% five and ten years after relapsing, respectively. The variables influencing survival were the timing and type of relapse (combined) and the chances of a secondary remission, which correlated strongly with the feasibility of complete surgery. Conclusions: Our study confirmed a largely unsatisfactory prognosis after recurrences in children and adolescents with synovial sarcoma: the chances of survival can be estimated on the basis of several variables for the purposes of planning risk-adapted salvage protocols. An aggressive surgical approach should be recommended. New effective systemic agents are warranted, and experimental therapies can be offered to patients with little chance of salvage. © 2012 Elsevier Ltd. All rights reserved