Mitotane Associated With Cisplatin, Etoposide, And Doxorubicin In Advanced Childhood Adrenocortical Carcinoma: Mitotane Monitoring And Tumor Regression

PURPOSE: To define a mitotane dose for pediatric patients with adrenocortical cancer (ACC) that maintains therapeutic plasma levels (TL) between 14 and 20 μg/mL and to verify its antitumor efficacy in association with 8 cycles of cisplatin, etoposide, and doxorubicin (CED). METHODS: Powdered mitotane was dissolved in a medium chain triglyceride oil and administered to 11 children with ACC (2.4 to 15.4 y of age); an initial low dose was increased to 4 g/m/d. Ten of the 11 children had a germline TP53 R337H mutation. Mitotane plasma levels were determined using high-performance liquid chromatography. RESULTS: The mitotane dose to maintain TL in 7 patients ranged from 1.0 to 5.3 g/m/d. Six children reached mitotane levels of 10 μg/mL in 3.6 months (1.5 to 5.0 mo), whereas 5 children took 8 months (6.5 to 12.5 mo). Minor to partial tumor remission was found in 5 patients (<1 y) and complete remission was found in 2 patients. Of the 3 patients who are alive at the time of report, 1 patient has been without disease for 16 months, and 2 patients have progressive disease. All patients had recurrent metastatic disease (2 to 9 times). Mitotane toxic effects were nausea, diarrhea, vomiting, neurologic alterations, gynecomastia, a rare case of hypertensive encephalopathy, and CED-related hematologic toxic effects. CONCLUSIONS: Mitotane daily dose to maintain TL is variable and monitoring should start 1.5 months after the beginning of treatment. CED combined with mitotane is the best available pharmacologic treatment for ACC, but further studies are required to characterize different profiles of therapeutic response. 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High frequency of loss of heterozygosity at 11p15 and IGF2 overexpression are not related to clinical outcome in childhood adrenocortical tumors positive for the R337H TP53 mutation

A germline TP53 R337H mutation is present in childhood adrenocortical tumors (ACT) from southern Brazil. Other genetic alterations are also frequently found in these tumors. This study was designed to assess whether alterations of the 11p15 region exist in childhood ACT, accounting for IGF2 overexpression in these tumors, and how they are related to clinical outcome. Tumor DNA of 12 children with ACT (4 adenomas and 8 carcinomas) and from the blood of their parents was analyzed. All patients showed 11p15 loss of heterozygosity (LOH) in the tumor. In contrast to the single case of paternal LOH, IGF2 was overexpressed in tumors with maternal allele loss. Our data show that 11p15 LOH is a widespread finding in childhood ACT not related with malignancy, contrary to adult ACT. Alterations in the expression of other genes in the same region (e.g., CDKN1C) may contribute to ACT tumorigenesis. ©2008 Elsevier Inc. All rights reserved. © 2008 Elsevier Inc. All rights reserved

Spatial trends in congenital malformations and stream water chemistry in Southern Brazil

The incidence of variable congenital malformation (CM) among 399 municipalities in the state of Paraná, southern Brazil, suggests the etiological role of environmental factors. This study examined a) environmental concentrations of chlorine anions (Cl−) associated with organochlorines (OCs) and b) associations between these chemicals and agricultural output with CMs using a geographical information system. In one of the three years during the sampling period (2008, 2009 or 2010) Cl−, dichlorodiphenyltrichloroethane (p,p′-DDT), dichlorodiphenyldichloroethylene (p,p′-DDE), dichlorodiphenyldichloroethane (p,p′-DDD), and endosulfan levels were measured in 465 (465/736, 63%) catchment basins. Agricultural outputs for crops during 2006–2010 were also evaluated (t/km2). Further, CM kernel density for the 399 municipalities in Paraná during 2007–2014 was investigated. Cl− levels increased significantly in one of the three years (2008, 2009 or 2010) in western catchment basins, compared to 1996 (p < 0.0001). The municipalities were divided according to the obtained Cl− levels, where sub-region C2 (central–southern) < 1.8 mg/L ≤ sub-regions C1 (northern–western) and C3 (eastern–southern). We identified 8756 cases of CMs among 1,221,287 newborns (NB) in all sub-regions. C1 had higher DDT-DDE-DDD (p,p′-DDT + p,p′-DDE + p,p′-DDD) concentrations, agricultural output, and CM kernel density. C2 and C3 had minor agricultural outputs (per square kilometer) and CM densities. A 2.96 mg/L increase in Cl− between sub-regions C1 and C2 was co-localized with a 45% increase in CM density (spatial relative risk = 1.45, CI 95%: 1.36–1.55). C1 had the highest log likelihood ratios (p = 0.001) identified via SaTScan clustering analyses. Organochlorines and other toxic chlorinated chemicals may contribute to CMs in humans, and these chemicals are ultimately transformed and release Cl− in rivers. Higher Cl− levels were correlated significantly with higher agricultural productivity, DDT-DDE-DDD levels, and CMs in some parts of the northern and western sub-regions (C1)650112781291CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESsem informaçãosem informaçãoThis project was funded by grants from the Paraná State Secretary of Science, Technology and Higher Education (No. 026/06/SETI/Geomedicina, 2006–2011), Brazilian National Council for Research and Development (CNPq, 2016–2018) and Coordenadoria de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES, 2011–2018