TIMP3 and CCNA1 hypermethylation in HNSCC is associated with an increased incidence of second primary tumors

Background: Hypermethylation in the promoter regions is associated with the suppression of gene expression and has been considered a potential molecular marker for several tumor types, including head and neck squamous cell carcinomas (HNSCC).Methods: To evaluate the gene hypermethylation profile as a prognostic marker, this retrospective study used a QMSP approach to determine the methylation status of 19 genes in 70 HNSCC patients.Results: the methylation profile analysis of primary HNSCC revealed that genes CCNA1, DAPK, MGMT, TIMP3 and SFRP1 were frequently hypermethylated, with high specificity and sensitivity. TIMP3 and CCNA1 hypermethylation was significantly associated with lower rates of second primary tumor-free survival (p = 0.007 and p = 0.001; log-rank test, respectively).Conclusion: This study, for the first time, presents CCNA1 and TIMP3 hypermethylation as a helpful tool to identify HNSCC subjects at risk of developing second primary carcinomas.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo, Dept Biol Sci, Lab Mol Canc Biol, BR-04039020 São Paulo, BrazilBarretos Canc Hosp, Stat & Epidemiol Ctr, BR-14784400 Barretos, BrazilAC Camargo Hosp, Dept Head & Neck Surg, BR-01509010 São Paulo, BrazilBarretos Canc Hosp, Dept Head & Neck Surg, BR-14784400 Barretos, BrazilDuke NUS Grad Med Sch, Canc & Stem Cell Biol Program, Singapore 169857, SingaporeUniversidade Federal de São Paulo, Dept Biol Sci, Lab Mol Canc Biol, BR-04039020 São Paulo, BrazilWeb of Scienc

Ki-67 and CD100 immunohistochemical expression is associated with local recurrence and poor prognosis in soft tissue sarcomas, respectively

Soft tissue sarcomas (STSs) are a heterogeneous group of mesenchymal tumors of >50 subtypes. However, STSs represent <1% of types of cancer. Despite this low frequency, the disease is aggressive and treatment, when possible, is based on traditional chemotherapies. A number of cases of resistance to adjuvant therapies have been reported. Metastases are commonly identified in STS patients during diagnosis and the development of effective clinical parameters is crucial for correct management of the disease. The use of biological markers in cancer is a useful tool to determine patient prognosis. Ki-67 is a protein marker for proliferation of somatic cells and is widely used in prognostic studies of various types of tumor, including STSs. Cluster of differentiation 100 (CD100) is a member of the semaphorin family. The family was initially described as axon guidance molecules important for angiogenesis, organogenesis, apoptosis and neoplasia. CD100 was previously utilized as a prognostic factor in tumors and also in STSs. In the present study, protein expression of Ki-67 and CD100 was analyzed by immunohistochemistry in samples of STS patients of the Barretos Cancer Hospital (Barretos, Brazil) to establish prognostic criteria of the disease. Results demonstrate a correlation between CD100 expression and poor prognosis, consistent with a previous study. Moreover, the expression of Ki-67 was identified to correlate with presence of local or locoregional recurrence. To the best of our knowledge, no large casuistic study has revealed this correlation between Ki-67 and local recurrence in STSs. The use of Ki-67 and CD100 as markers in clinical pathological analysis may be suitable as a prognostic criterion in disease progression

Modelo Weibull modificado de longa duração

When a group of patients is monitored until a pre-established date for observation of the recurrence time of an event, it is possible that, at the end of the monitoring period, a parcel of such group has not yet suffered the event of interest. When that happens, even if the period is extended, there is evidence that an appropriate model for the theoretical survival function of the time until the event occurs would be one model able to bear this kind of data. This class of long duration models will be defined because the form presented by the nonparametric estimation of hazard function in this type of study indicates that the model should be flexible to allow such function to be increasing, decreasing, constant or U-shaped. In this report, we present the long duration modified Weibull model (LDMW) as a proposal to contemplate the issues in the medicine area. The LDMW model has a flexible hazard curve, which enables adjustment when the hazard is decreasing, increasing, U-shaped, unimodal, initially decreasing and posteriorly unimodal and constant. The report also particularizes models already known in the literature that contemplate long duration, such as the long duration Weibull (LDW), long duration Exponential (LDE) and short duration models, such as the modified Weibull (MW), Weibull and Exponential. The simulations showed that the odds of coverage reach the nominal probability of 95% for moderately to big sized samples, that the LDMW p model parameters estimation is costless when compared to the MW and that the selection criteria of the AIC and BIC models are not adequate to discriminate the LDMW model adjustment when compared to the LDW model adjustment for small or moderately sized samples. The LDMW model and its particular cases were adjusted into two sets of real data considering the Classic and Bayesian Inference. The first data set is about the time until the seroreversion of children born from HIV-positive mothers and the second data set is about the recurrence time of breast cancer in women.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Quando um grupo de pacientes é seguido até uma data pré-estabelecida, para a observação do tempo até a ocorrência de um evento, pode acontecer que, na data de término do acompanhamento, uma parcela do grupo não tenha sofrido o evento de interesse. Quando ocorre, ainda que se estenda o prazo, existem indícios de que um modelo adequado para a função de sobrevivência teórica do tempo até a ocorrência do evento seja um modelo que comporte esse tipo de dados. Será definida essa classe de modelos de longa duração, pois a forma apresentada pela estimativa não paramétrica da função de risco, nesse tipo de estudo, indica que o modelo deve ser flexível no sentido de permitir que a função de risco seja uma função crescente, decrescente, constante ou em forma de U. Nesta dissertação, apresenta-se o modelo Weibull modificado de longa duração (WMLD) como proposta para contemplar os problemas na área médica. O modelo WMLD possui curva de risco flexível, possibilitando o ajuste quando há o risco decrescente, crescente, forma de U, unimodal, inicialmente decrescente e, posteriormente, descrevendo forma unimodal e constante. Particulariza modelos já conhecidos na literatura que contemplam a longa duração como o Weibull de longa duração (WLD), exponencial de longa duração (ELD) e modelos de curta duração, como Weibull modificado (WM), Weibull e exponencial. As simulações feitas mostraram que as probabilidades de cobertura atingem a probabilidade nominal de 95% para amostras moderadas a grandes, que não existe custo de estimação do parâmetro p do modelo WMLD, quando comparado com o WLD, e que os critérios de seleção de modelos AIC e BIC não são adequados para discriminar o ajuste do modelo WMLD comparado com o ajuste do modelo WLD, para tamanhos de amostras pequenos ou moderados. Ajustou-se o modelo WMLD e seus casos particulares em dois conjuntos de dados reais, considerando a inferência clássica e a bayesiana. O primeiro conjunto de dados trata-se do tempo até a sororreversão de crianças que nasceram de mães portadoras do vírus HIV e o segundo trata-se do tempo até a recidiva em mulheres com câncer de mama

Curative-intent surgery for pancreatic tumors: A review of 3,386 procedures from the Brazilian National Health System

246 Background: In Brazil, a large country with major socioeconomic and health access disparities, resource limitations make the management of pancreatic tumors challenging. We aimed to evaluate curative-intent surgical procedures for pancreatic cancer (PC) in the public health care system. Methods: Based on Brazilian’s public health system database (DATASUS) and demographic database (IBGE), we collected data for curative-intent surgical procedures for pancreatic tumors. Information about number of procedures, costs, length of stay, number of perioperative deaths and PC deaths were analyzed for each State and Region and then correlated to State specific population, gross domestic product (GDP) per capita and number of procedures. Results: Between 2008 and 2012, 37,142 patients died due to PC in Brazil, with an increase of 6.3% in mortality annually. Mortality (per 100,000 persons-year) increases from North to South States. GPD per capita (rho=0.636, 2-tailed p<0.001) was associated to PC mortality. Between January 2008 and July 2014, 3,386 procedures were performed, the majority (51.2%) in the Southeast region (particularly in São Paulo State, 32.7%). Total cost was US$9,741,315.28, average cost per admission was US$ 2,876.94. The number of procedures per 100,000 residents was higher in Southeast and South Brazil. On multivariate analysis, average cost in each State was only correlated to the number of procedures (β=0.568, p=0.029). The mean length of hospital stay was 16.9 days, with no major differences across regions. The mean length of hospital stay was correlated to GDP per capita and number of procedures. However, no independent association was found on multivariate analysis. A total of 493 patients died, translating into an inpatient mortality rate of 14.55%, higher than observed in high-income countries. The Northern States have the highest mortality rates (mean 25%, and 33% for the State with highest mortality). Neither characteristic was associated to perioperative mortality. Conclusions: This is the first study to evaluate regional disparities in PC care and mortality in Brazil. These disparities calls for regionalized policies aiming the improvement of PC care

The Brazilian version of Skindex-16 is a valid and reliable instrument to assess the health-related quality of life of patients with skin diseases

<div><p>Introduction</p><p>The aim of this study was to assess the psychometric properties of the Brazilian version of Skindex-16 in patients with various skin diseases.</p><p>Methods</p><p>Dermatologic assessments were performed for the diagnosis and classification of the severity of skin conditions. The clinical feasibility of Skindex-16 was assessed based on the time required to complete the questionnaire and the number of unanswered items. The participants (n = 110) answered the Hospital Anxiety and Depression Scale (HADS), the Dermatology Life Quality Index (DLQI) and the Skindex-16 (Portuguese/Brazil version) questionnaires. Convergent validity was assessed based on the correlation of the Skindex-16 with the DLQI and HADS subscales. Known-groups validity was assessed based on the comparison of the mild, moderate and severe disease groups using the Kruskal-Wallis test. Internal consistency was assessed using Cronbach’s alpha and test-retest reproducibility using the intraclass correlation coefficient (ICC) obtained with 29 participants who answered the Skindex-16 a second time 3 to 10 days after the first assessment.</p><p>Results</p><p>The mean time to answer the questionnaire was 2 min 41 sec. Cronbach’s alpha scores were 0.867, 0.930 and 0.888 for the Skindex-16 domains symptoms, emotions and functioning, respectively. The ICCs were 0.947, 0.860 and 0.843 for the Skindex-16 domains symptoms, emotions and functioning, respectively. All three Skindex-16 scales exhibited strong correlations with DLQI. Moderate correlations were found between HADS subscales and the Skindex-16 emotions domain. Known-groups validity showed differences in all three Skindex-16 domains between the mild and moderate skin disease groups (emotions: p < 0.001; symptoms: p = 0.049; functioning: p < 0.001) and between the mild and severe skin disease groups (emotions: p = 0.002; symptoms: p = 0.001; functioning: p = 0.002).</p><p>Conclusion</p><p>The Portuguese/Brazil version of Skindex-16 is a valid and reliable instrument to assess the quality of life of patients with skin diseases.</p></div

Known-groups validation analyses of Skindex-16.

<p>Known-groups validation analyses of Skindex-16.</p

Convergent analyses between Skindex-16, HADS and DLQI.

<p>Convergent analyses between Skindex-16, HADS and DLQI.</p

Genotype‐phenotype correlation in 99 familial adenomatous polyposis patients: A prospective prevention protocol

Abstract Background Familial adenomatous polyposis (FAP) is a syndrome caused by germline pathogenic variants in the tumor suppressor gene adenomatous polyposis coli (APC). Identification of APC pathogenic variants sites and the genotype‐phenotype correlation are important for characterizing, monitoring, and treating members of affected families. The aim of this study was to correlate genotype‐phenotype of Brazilian individuals carrying APC pathogenic germline variants and that have FAP. Methods The polyposis phenotype of 99 individuals from 35 families between July 2013 and December 2014 were prospectively evaluated based on the InSIGHT polyposis staging classification. Seven extra‐colonic manifestations were assessed and the clinical manifestations correlated with the APC genotype. Results The age of the study participants ranged from 12 to 67 years (median of 29 years). Twenty‐six APC pathogenic variants were identified. Fifty‐five cases harbored nonsense pathogenic variants (55.6%). Frameshift alterations were noted in 39 cases (39.4%). Aberrant splicing was noted in 1 case (1%). Rearrangements were observed in 3 cases (3%). An association between nonsense variants and rearrangement was noted in 1 case (1%). The genotype‐phenotype correlation analysis led the identification of classic FAP in 94 cases (94.9%). Profuse polyposis was identified in 5 cases (5.1%). Thirty‐six cases were diagnosed with cancer of which 29 cases (80.6%) were colorectal cancer, 1 case (2.7%) was brain cancer, 4 cases (11.2%) were papillary thyroid cancer, and 2 cases (5.5%) were stomach cancer. The extra‐colonic manifestations included 9 individuals with desmoids tumors, 10 with osteomas, and 9 with congenital hypertrophy of the retinal pigment epithelium. Conclusions The genotype‐phenotype correlation in Brazilian individuals with FAP revealed specific findings not previously reported for other cohorts, demonstrating the relevance of knowledge regarding the variable pathogenic variants and clinical presentation in different populations for adequate individual clinical management of patients harboring this medical condition

The role of TMPRSS2:ERG in molecular stratification of PCa and its association with tumor aggressiveness: a study in Brazilian patients

Recurrent gene fusions between the genes TMPRSS2 and ERG have been described in prostate cancer (PCa) and are found in 27% to 79% of radical prostatectomy. This fusion transcription results in ERG overexpression, which can be detected by immunohistochemistry (IHC) and provide a potential diagnostic marker for PCa. Three tissue microarrays (TMAs) containing samples from 98 patients with PCa and one TMA of 27 samples from individuals without PCa were tested for ERG immunostaining, and the presence of TMPRSS2: ERG transcripts was confirmed by quantitative real time PCR (qRT-PCR). The results showed that 46.9% of tumors tested positive for ERG immunostaining, and this finding was consistent with the results of qRT-PCR testing (k = 0.694, p < 0.001). IHC had a specificity of 83.3% and a sensitivity of 81% in detecting TMPRSS2:ERG fusion. Patients with PSA < 4.0 ng/mL showed positive immunoreactivity for ERG (p = 0.031). Kaplan-Meier analysis suggested that ERG expression did not influence the time of biochemical recurrence. This study demonstrates that both IHC and qRT-PCR are useful tools in detecting TMPRSS2: ERG fusions. A correlation between ERG expression and clinical and pathological parameters was not found, but the frequency, specificity and recurrence of ERG in PCa suggests that it may be a potential adjunct diagnostic tool.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq