Mutational Profiling of Driver Tumor Suppressor and Oncogenic Genes in Brazilian Malignant Pleural Mesotheliomas.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a highly lethal disease comprising a heterogeneous group of tumors with challenging to predict biological behavior. The diagnosis is complex, and the histologic classification includes 2 major subtypes of MPM: epithelioid (∼60% of cases) and sarcomatous (∼20%). Its identification depends upon pathological investigation supported by clinical and radiological evidence and more recently ancillary molecular testing. Treatment options are currently limited, with no known targeted therapies available. OBJECTIVES: To elucidate the mutation profile of driver tumor suppressor and oncogenic genes in a cohort of Brazilian patients. METHODS: We sequenced 16 driver genes in a series of 43 Brazilian malignant mesothelioma (MM) patients from 3 distinct Brazilian centers. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissue blocks, and the TERT promoter region was amplified by PCR followed by direct capillary sequencing. The Illumina TruSight Tumor 15 was used to evaluate 250 amplicons from 15 genes associated with solid tumors (AKT1, GNA11, NRAS, BRAF, GNAQ, PDGFRA, EGFR, KIT, PIK3CA, ERBB2, KRAS, RET, FOXL2, MET,and TP53). Library preparation with the TruSight Tumor 15 was performed before sequencing at the MiSeq platform. Data analysis was performed using Sophia DDM software. RESULTS: Out of 43 MPM patients, 38 (88.4%) were epithelioid subtype and 5 (11.6%) were sarcomatoid histotype. Asbestos exposure was present in 15 (39.5%) patients with epithelioid MPM and 3 (60%) patients with sarcomatoid MPM. We found a TERT promoter mutation in 11.6% of MM, and the c.-146C>T mutation was the most common event. The next-generation sequencing was successful in 33 cases. A total of 18 samples showed at least 1 pathogenic, with a median of 1.8 variants, ranging from 1 to 6. The most mutated genes were TP53 and ERBB2 with 7 variants each, followed by NRAS BRAF, PI3KCA, EGFR and PDGFRA with 2 variants each. KIT, AKT1, and FOXL2 genes exhibited 1 variant each. Interestingly, 2 variants observed in the PDGFRA gene are classic imatinib-sensitive therapy. CONCLUSIONS: We concluded that Brazilian MPM harbor mutation in classic tumor suppressor and oncogenic genes, which might help in the guidance of personalized treatment of MPM.

The Quality of Pap Smears from the Brazilian Cervical Cancer Screening Program According to the Human Development Index.

Brazil is a country with strong socioeconomic disparities, which may explain the different rates of cervical cancer incidence and mortality and influence the quality of cervical cancer screening tests. The aim of this study was to perform a trend analysis of some quality indicators of Pap smears according to the Municipal Human Development Index (MHDI). Information about cytopathological exams (approximately 65,000,000) performed from 2006 to 2014 in women ages 25 to 64 years was obtained from the Cervical Cancer Information System (SISCOLO). The average annual percentage change (AAPC) for each indicator was calculated using the Joinpoint Regression Program, according to MHDI levels. Very low frequencies of unsatisfactory cases (<5%) were observed at different MHDI levels. Although the positivity index in the low- and medium-MHDI groups has increased, the values remained below international recommendations (3%-10%). The HSIL (high-grade squamous intraepithelial lesion) percentage remained stationary at all levels of the MHDI. In the low- and medium-MHDI groups, most quality indicators were below the recommendations by Brazilian National Cancer Institute INCA, with no improvement trend; in the high-MHDI group, the majority of the indicators also presented no improvement, although they show slightly better quality indicators. The MHDI should be considered in the definition of the policies of the screening program for cervical cancer in Brazil, and the current program may require adjustments to achieve improved efficiency.

Trend analysis of the quality indicators for the Brazilian cervical cancer screening programme by region and state from 2006 to 2013.

BACKGROUND: Quality indicators for the Brazilian cervical cancer screening programme can provide a perspective on its effectiveness in Brazilian macro-regions and states. The aim of this study was to perform a trend analysis of the cervical cancer screening program's quality indicators, according to Brazilian regions and states, from 2006 to 2013. METHODS: Using information from approximately 62,000,000 exams obtained from the Information System of Cervical Cancer Screening (SISCOLO), joinpoint analysis was used to calculate the Annual Percentage Change (APC). RESULTS: The estimated number of women in the target age group (25-64 years) who underwent Pap testing over a three-year interval was lower than that recommended by international guidelines in the North, Northeast and Midwest regions, and the trends for this indicator remained stationary over the years in all regions of Brazil. Overall, the index of positivity in Brazilian regions and states is below that preconized by the Brazilian National Cancer Institute (INCA). Additionally, the frequencies of unsatisfactory cases are in line with international guidelines but above those preconized by INCA guidelines. All positive cytological diagnoses were lower than those preconized by INCA. CONCLUSIONS: The results show that the cervical cancer screening programme is still far from efficient because most of the quality indicators in Brazilian regions and states are outside of the parameters preconized by national and international organizations.

Retrospective analysis of breast cancer prognosis among young and older women in a Brazilian cohort of 738 patients, 1985-2002.

Invasive breast cancer (BC) is infrequent among women aged ≤40 years, however, the disease outlook in these younger patients is generally worse than among older women. The present study aimed to compare socio-demographic, clinical and pathological characteristics, and their association with long-term survival, between two random cohorts of young (≤40 years) and older (50-69 years) Brazilian patients with BC. The cohort comprised of 738 randomly selected women who were diagnosed with BC at Barretos Cancer Hospital, Pio XII Foundation (Barretos, Brazil) between January 1985 and December 2002; the patients included young women (n=376) and older women (n=362). The current analysis suggested that BC in young women is associated with numerous pathological features of aggressiveness. Second cancer and bilateral BC were independent predictors of a poor outcome in the younger group. Furthermore, C-erB-2 was positively correlated with poor outcome in the older group, whereas estrogen receptor status and TNM stage were associated with disease prognosis in both groups. The overall survival rates of the two age groups were similar except when analyzed according the treatment period (1997-2002). Although patients aged ≤40 years harbored tumors with more aggressive clinicopathological characteristics, these characteristics were not independent predictors of overall survival. The present study indicates that medical advances associated with prevention of breast cancer may improve screening programs, which may therefore increase early diagnosis and subsequently lower mortality rates.

Influência dos determinantes subjetivos para a decisão de tratamento ortodôntico, em diferentes prevalências de cárie dentária / Influence of subjective determinants on the decision for orthodontic treatment in different dental caries prevalence

Objetivo: Este estudo objetivou avaliar a influência dos determinantes subjetivos no tratamento ortodôntico, em diferentes prevalências de cárie dentária em adolescentes de 15 anos do município de Piracicaba - SP. Métodos: O delineamento obedeceu à seguinte ordem: calibração dos examinadores; avaliação da prevalência de cárie; necessidade de tratamento ortodôntico (índice DAI e DHC-IOTN) e de variáveis subjetivas (autoestima: GSE, autoavaliação: AC-IOTN, autopercepção: OASIS e interesse ortodôntico declarado). Tratou-se de um estudo transversal observacional com amostra por conglomerados de 528 adolescentes selecionados em dez escolas públicas. Resultados: Quando se considerou a influência da cárie dentária, autoestima e interesse ortodôntico à necessidade de tratamento determinada pelos índices DAI e IOTN, não se observou significância estatística. Ao considerar a autopercepção, essa teve influência estatística para a necessidade de tratamento determinada pelos índices DAI e IOTN. Conclusão: Conclui-se que a prevalência de cárie dentária não foi associada à necessidade de tratamento ortodôntico e que, das variáveis subjetivas, a autopercepção foi importante na decisão do tratamento ortodôntico.