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São Paulo, Brazil

Barros M.H.M.,Instituto Nacional Of Cancer Inca | Scheliga A.,Instituto Nacional Of Cancer Inca | De Matteo E.,Ricardo Gutierrez Childrens Hospital | Minnicelli C.,Instituto Nacional Of Cancer Inca | And 3 more authors.
Leukemia and Lymphoma | Year: 2010

We investigated the correlation of tumor characteristics with clinico-biological markers of aggressive disease, evaluated by Ann Arbor stage, risk group, B-symptoms, number of involved anatomic areas, mediastinal mass, nodular sclerosis (NS) grade, and risk, in pediatric Hodgkin lymphoma (HL). Leukopenia and extranodal disease influenced event-free survival (p0.032 and p0.041). In multivariate analysis, extranodal disease was associated with high number of tumor-infiltrating eosinophils (p0.035) and Ki67<50 (p0.024); B-symptoms with Ki67≥75 (p0.027) and high LDH levels (p0.001); and mediastinal mass with leukopenia (p0.048), NS grade II (p0.025), and high-risk (p0.046). Furthermore, low stages correlated with Ki67≥50 (p0.005) and EpsteinBarr virus (EBV) (p0.065). Low-risk NS was associated with EBV (p0.014). Hierarchical cluster analysis identified two clusters, one composed of high-risk patients and cell cycle and apoptosis features, and the other including low-risk patients, EBV, and low-risk NS. Our results show the association of biological markers with disease aggressiveness in pediatric HL. © 2010 Informa UK, Ltd.

Pimenta S.P.,A. C. Camargo Hospital | Baldi B.G.,University of Sao Paulo | Kairalla R.A.,University of Sao Paulo | Carvalho C.R.R.,University of Sao Paulo
Jornal Brasileiro de Pneumologia | Year: 2013

Objective: To assess blockade of matrix metalloproteinase (MMP)-2 and MMP-9, as well as the variation in FEV1, in patients with lymphangioleiomyomatosis (LAM) treated with doxycycline (a known MMP inhibitor) for 12 months. Methods: An open-label, single-arm, interventional clinical trial in which LAM patients received doxycycline (100 mg/day) for 12 months. Patients underwent full pulmonary function testing, a six-minute walk test, and quality of life assessment, as well as blood and urine sampling for quantification of MMP-2, MMP-9, and VEGF-D levels-at baseline, as well as at 6 and 12 months after the initiation of doxycycline. Results: Thirty-one LAM patients received doxycycline for 12 months. Although there was effective blockade of urinary MMP-9 and serum MMP-2 after treatment, there were no significant differences between pre--and post-doxycycline serum levels of MMP-9 and VEGF-D. On the basis of their response to doxycycline (as determined by the variation in FEV1), the patients were divided into two groups: the doxycycline-responder (doxy-R) group (n = 13); and the doxycycline-nonresponder (doxy-NR) group (n = 18). The patients with mild spirometric abnormalities responded better to doxycycline. The most common side effects were mild epigastric pain, nausea, and diarrhea. Conclusions: In patients with LAM, doxycycline treatment results in effective MMP blockade, as well as in improved lung function and quality of life in those with less severe disease. However, these benefits do not seem to be related to the MMP blockade, raising the hypothesis that there is a different mechanism of action.

Torrezan G.T.,Laboratory of Genomics and Molecular Biology | Da Silva F.C.C.,Laboratory of Genomics and Molecular Biology | Santos E.M.M.,National Institute of Science and Technology in Oncogenomics INCITO | Krepischi A.C.V.,National Institute of Science and Technology in Oncogenomics INCITO | And 6 more authors.
Orphanet Journal of Rare Diseases | Year: 2013

Background: Patients with multiple colorectal adenomas are currently screened for germline mutations in two genes, APC and MUTYH. APC-mutated patients present classic or attenuated familial adenomatous polyposis (FAP/AFAP), while patients carrying biallelic MUTYH mutations exhibit MUTYH-associated polyposis (MAP). The spectrum of mutations as well as the genotype-phenotype correlations in polyposis syndromes present clinical impact and can be population specific, making important to obtain genetic and clinical data from different populations. Methods. DNA sequencing of the complete coding region of the APC and MUTYH genes was performed in 23 unrelated Brazilian polyposis patients. In addition, mutation-negative patients were screened for large genomic rearrangements by multiplex ligation-dependent probe amplification, array-comparative genomic hybridization, and duplex quantitative PCR. Biallelic MUTYH mutations were confirmed by allele-specific PCR. Clinical data of the index cases and their affected relatives were used to assess genotype-phenotype correlations. Results: Pathogenic mutations were identified in 20 of the 23 probands (87%): 14 in the APC gene and six in the MUTYH gene; six of them (30%) were described for the first time in this series. Genotype-phenotype correlations revealed divergent results compared with those described in other studies, particularly regarding the extent of polyposis and the occurrence of desmoid tumors in families with mutations before codon 1444 (6/8 families with desmoid). Conclusions: This first comprehensive investigation of the APC and MUTYH mutation spectrum in Brazilian polyposis patients showed a high detection rate and identified novel pathogenic mutations. Notably, a significant number of APC-positive families were not consistent with the predicted genotype-phenotype correlations from other populations. © 2013 Torrezan et al.; licensee BioMed Central Ltd.

Braga J.C.T.,A. C. Camargo Hospital | Macedo M.P.,A. C. Camargo Hospital | Pinto C.,A. C. Camargo Hospital | Duprat J.,A. C. Camargo Hospital | And 3 more authors.
PLoS ONE | Year: 2013

Histopathologic interpretation of dermoscopic and reflectance confocal microscopy (RCM) features of cutaneous melanoma was timidly carried out using perpendicular histologic sections, which does not mimic the same plane of the image achieved at both techniques (horizontal plane). The aim of this study was to describe the transverse histologic sections research technique and correlate main dermoscopic features characteristic of cutaneous melanoma (atypical network, irregular globules and pseudopods) with RCM and histopathology in perpendicular and transverse sections in order to offer a more precise interpretation of in vivo detectable features. Four melanomas and 2 nevi with different dermoscopic clues have been studied. Lesion areas that showed characteristic dermoscopic features were imaged by dermoscopy and confocal microscopy and directly correlated with histopathology in perpendicular and transverse sections. We presented the possibility to perform transverse sections as a new approach to understand RCM features. Atypical network showed different aspects in the 2 melanomas: in one case it was characterized by pleomorphic malignant melanocytes with tendency to form aggregates, whereas in the other elongated dendritic cells crowded around dermal papillae, some of them forming bridges that resembled the mitochondrial aspect at confocal and histopathology transversal sections. Pigment globules in melanomas and nevi differed for the presence of large atypical cells in the former, and pseudopods showed up as elongated nests protruded toward the periphery of the lesion. Transverse histologic research sections have a consistent dermoscopic and confocal correlate, and it may represent an help in confocal feature interpretation and an advance in improving melanoma diagnosis and knowledge of the biology of melanocytic lesions. © 2013 Braga et al.

Faucz F.R.,U.S. National Institutes of Health | Faucz F.R.,Pontifical Catholic University of Parana | Horvath A.,U.S. National Institutes of Health | Rothenbuhler A.,U.S. National Institutes of Health | And 14 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: Among the genomic loci harboring potential candidate genes for prostatic cancer (PCa) is the 2q31-33 chromosomal region that harbors the gene encoding phosphodiesterase 11A (PDE11A). In addition, the combined cancer genome expression metaanalysis datasets included PDE11A among the top 1% down-regulated genes in PCa. Objective: In the present study, we screened 50 unrelated PCa patients of Brazilian descent for PDE11A coding defects. Design: The study consisted of PDE11A sequencing, in vitro functional assays, and immunostaining analysis. Results: We identified eight different sequence alterations in 15 patients (30%): one stop-codon and seven missense mutations. Three of the variants (R202C, Y658C, and E840K) were novel, and the remaining five (Y727C, R804H, R867G, M878V, and R307X) have been associated with predisposition to adrenal or testicular tumors. The overall prevalence of PDE11A-inactivating sequence variants among PCa patients was significantly higher than in 287 healthy controls (0.16 vs. 0.051, respectively, P < 0.001, odds ratio 3.81, 95% confidence interval 1.86-7.81) and the R202C, Y658C, and E840K substitutions were not found in controls. All missense mutations led to decreased PDE11A activity in human embryonic kidney 293 and PC3M cells and immunostaining of PCa samples with sequence changes showed decreased PDE11A protein expression. Conclusion: Our data suggest that, like in the adrenal cortex and the testicular germ cells, PDE11Ainactivating genetic alterations may play a role in susceptibility to PCa. Copyright © 2011 by The Endocrine Society.

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