Metabolic profile of patients with endometrial adenocarcinoma and association with tumor grade.

OBJECTIVE: To describe the prevalence of metabolic syndrome and other metabolic indicators in patients with endometrial cancer and its association with tumor grade. METHODS: This is a cross-sectional study of patients with endometrial cancer referred to the Brazilian National Cancer Institute. We collected data on sociodemographic variables, smoking, co-morbidities, physical activity level, menopausal status, and tumor characteristics (histological subtype, stage, and tumor grade). In addition, weight, height, and waist circumference were measured. Laboratory evaluation included lipid profile, fasting blood glucose and insulin, and C-reactive protein. Insulin resistance was estimated by the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). Characterization of metabolic syndrome and cardiovascular risk profile was performed. Binary logistic regression models were used to test the association between metabolic syndrome and its metabolic parameters, HOMA-IR, and C-reactive protein with tumor grade. RESULTS: We included a total of 313 patients, 245 (78.3%) aged <65 years, 262 (83.7%) with endometrioid adenocarcinoma, 193 (61.7%) early stage, and 201 (64.2%) with lower tumor grade (G1 and G2). Metabolic syndrome, insulin resistance, and low levels of leisure-time physical activity were highly prevalent (90.7%). In binary logistic regression models, an association was observed between HOMA-IR and lower tumor grade (p<0.05), while high-grade tumors were associated with the highest C-reactive protein values (p<0.05). CONCLUSION: The main finding of this study was the association between insulin resistance and low-grade tumors, and the association between high C-reactive protein levels and high-grade tumors.

The prevalence and prognostic impact of tumor-infiltrating lymphocytes in uterine carcinosarcoma.

OBJECTIVE: To examine the prevalence and prognostic role of tumor microenvironment (TME) markers in uterine carcinosarcoma (UCS) through immunohistochemical characterization. METHODS: The internal database of our institution was queried out for women with UCS who underwent surgery and thereafter postoperative chemotherapy with carboplatin and paclitaxel between January 2012 and December 2017. Tissue microarrays containing surgical samples of UCS from 57 women were assessed by immunohistochemistry for CD3, CD4, CD8, FOXP3, PD-1, PD-L1, and PD-L2. RESULTS: The mean age was 65.3 years (range, 49 to 79 years). For the epithelial component (E), CD3_E and CD4_E were highly expressed in 38 (66.7%) and in 40 (70.1%) patients, respectively, and were significantly associated with more advanced stages (p = 0.038 and p = 0.025, respectively). CD8_E was highly expressed in 42 (73.7%) patients, FOXP3_E 16 (28.1%), PD-1_E 35 (61.4%), PD-L1_E 27 (47.4%) and PD-L2_E 39 (68.4%). For the sarcomatous component (S), the prevalence of high expression was: CD3_S 6 (10.5%), CD4_S 20 (35.1%), CD8_S 44 (77.2%), FOXP3_S 8 (14%), PD-1_S 14 (24.6%), PD-L1_S 14 (24.6%) and PD-L2_S 8 (14%). By multivariate analysis, the CD8/FOXP3_S ratio (p = 0.026), CD4_E (p = 0.010), PD-L1_E (p = 0.013) and PD-L1_S (p = 0.008) markers significantly influenced progression-free survival. CD4/FOXP3_S ratio (p = 0.043), PD-1_E (p = 0.011), PD-L1_E (p = 0.036) and PD-L1_S (p = 0.028) had a significant association with overall survival. CONCLUSION: Some differences in UCS clinical outcomes may be due to the subtype of TILs and PD-1/PD-L1 axis immune checkpoint signaling.

The papillomavirus E5 gene does not affect EGFR transcription and overall survival in cervical cancer.

INTRODUCTION: The human papillomavirus (HPV) E5 gene encodes a small and highly hydrophobic oncoprotein that affects immune evasion, cell proliferation, loss of apoptotic capacity and angiogenesis in tumors. E5 shows an affinity for biological membranes and was associated with an increase of epidermal growth factor/epidermal growth factor receptor (EGF/EGFR) signaling through the accumulation of EGFR in cellular membranes. Due to the frequent integration of the HPV genome into the host cell genome, E5 is frequently not transcribed in cervical tumors. AIM: In this study we looked forward to verifying whether the potential expression of E5 protein in human papillomavirus 16 positive (HPV16+ ) and human papillomavirus 18 positive (HPV18+ ) cervical tumors was associated with levels of EGFR and vascular endothelial growth factor A (VEGFA) transcription and with patients overall survival. RESULTS: Association between the presence of E5 transcripts and viral genome disruption was observed for HPV16+ and HPV18+ tumors. Association was not observed between tumors potentially capable of translating E5 and EGFR or VEGFA transcriptional levels. Similarly, the capability of translating E5 and overall survival in patients with HPV16+ squamous cell carcinoma tumors stage ≥ IB2 were not associated. CONCLUSION: The likely presence of E5 transcripts was neither associated to a higher activity of the EGFR-VEGFA pathway nor to the overall survival of patients with HPV16+ squamous cell carcinoma in stages ≥ IB2.

Overweight and obesity do not determine worst prognosis in endometrioid endometrial carcinoma.

PURPOSE: The aim of this study was to investigate the impact of body mass index (BMI) on disease-free survival (DFS) and overall survival (OS) in women diagnosed with EEC and treated at the Brazilian National Cancer Institute. METHODS: The study comprised 849 women diagnosed with EEC who underwent surgical treatment between January, 2000 and December, 2011. The demographic and clinical characteristics of these patients were collected from medical records and their nutritional status was based on the BMI criteria. Univariate (OS and DFS) and multivariate analyses were performed using the Kaplan-Meier method and Cox proportional hazards models, respectively. RESULTS: About 83.2% of patients were obese or overweight at time of diagnosis, with a mean BMI of 31.83. Patients were followed for an average of 34.97 months. There were 111 recurrences (13.1%) and 140 deaths (16.5%), with mean DFS of 51.90 months and mean OS of 52.25 months. There was no significant association between BMI and DFS or OS. In multivariate analysis we did not find an increased hazard of recurrence or death among overweight or obese patients. CONCLUSION: Overweight and obesity had no impact on EEC prognosis on the assessed cohort. Further studies are warranted.

Genetic diversity of human papillomavirus types 35, 45 and 58 in cervical cancer in Brazil.

In Brazil, most studies of intra-type variants of human papillomavirus (HPV) have focused on HPV16 and HPV18, but other high-risk HPV types have not been studied. Here, we report the prevalence of lineages and variants of HPV35, HPV45 and HPV58 in cervical cancers from the Amazonian and Southeast Brazilian regions. The most frequent sublineages were A1 for HPV35, B2 for HPV45, and A2 for HPV58. The Southeast region had a higher frequency of the B2 sublineage of HPV45, and for HPV35, the genetic and nucleotide sequence diversity were higher in the Southeast region, suggesting that regional factors are influencing the diversity and lineage prevalence.

ERM/ETV5 and RUNX1/AML1 expression in endometrioid adenocarcinomas of endometrium and association with neoplastic progression.

The majority of endometrioid endometrial carcinomas (EEC) is diagnosed at stage I. Among these, 30% present myometrial invasion (stage IB), which is associated with tumor spread and relapse after primary treatment. Although an increased expression of RUNX1/AML1 and ERM/ETV5 in EEC have been suggested to be associated with early events of myometrial infiltration, there is no data regarding its expression along the evolution of EEC and possible associations with other clinicopathological parameters. Therefore, ERM/ETV5 and RUNX1/AML1 protein and gene expression profiles were assessed in different EEC stages to evaluate their role in endometrial carcinogenesis. RUNX1/AML1 and ERM/ETV5 proteins were analyzed by immunohistochemistry in 219 formalin fixed paraffin embedded endometrioid tumors and in 12 normal atrophic and proliferative endometrium samples. RUNX1/AML1 and ERM/ETV5 genes expression were analyzed by RT-qPCR. RUNX1/AML1 and ERM/ETV5 expression were decreased with increasing EEC stage, with a positive correlation between protein and gene expression for ERM/ETV5, but not for RUNX1/AML1. Both proteins were present in the nucleus of the tumor cells, whereas RUNX1/AML1, but not ERM/ETV5, was expressed in 7 out of 12 normal endometrial samples, with its expression being restricted to the cytoplasm of the positive cells. We concluded that there is a higher expression of ERM/ETV5 in early stages of EEC, whereas there seems to be a RUNX1/AML1 translocation from cytoplasm to nucleus in EEC neoplastic transformation.

Mecanismos Moleculares Envolvidos na Progressão e Recidiva do Câncer de Endométrio / [Molecular Mechanisms Involved in Endometrial Cancer Progression and Relapse]

O câncer de endométrio é responsável por mais de 90% dos casos de câncer de corpo de útero. É considerada a quinta neoplasia maligna mais incidente entre mulheres no mundo, sendo estimados 319.605 novos casos e 76.155 óbitos para o ano de 2012 (IARC). A maior ocorrência é observada nos países desenvolvidos, mas a doença vem progredindo em alguns países em desenvolvimento. No Brasil, é observado um crescente aumento com 5.900 novos casos estimados para 2014. O tipo histológico mais frequente é o adenocarcinoma, sendo o tipo endometrioide (Tipo I) o mais comum. A sobrevida na doença localizada, na localmente avançada e na metastática é de 96%, 66% e 24%, respectivamente. Entretanto, uma parcela das pacientes com critérios clínico-patológicos debom prognóstico pode evoluir com recidiva e apresentar resposta limitada ao tratamento. Por isto, a identificação e compreensão das características clínico-patológicas e da biologia molecular do câncer de endométrio são fundamentais para o entendimento da evolução da doença. Já foram descritas algumas alterações moleculares características dos subtipos de adenocarcinoma, porém ainda não está bem estabelecida associação destes marcadores ao risco de progressão e recidiva. Assim, o objetivo principal deste estudo foi identificar tanto fatores clínico-patológicos quanto alterações moleculares que possam predizer um pior prognóstico das pacientes com câncer de endométrio. Para tal, inicialmente foram analisadas as frequências descritivas, a sobrevida livre de doença (SLD) e a sobrevida global (SG) de 1.132 pacientes com o diagnóstico de “adenocarcinoma de endométrio”, matriculadas e tratadas no período de 2000 a 2011. A idade mediana foi de 63,7 anos. Os tumores Tipo I, de baixo grau e diagnosticados nos estádios precoces foram os mais frequentes. Recidiva e óbito ocorreram mais nos tumores Tipo II (p<0,001 cada)...

Endometrial cancer accounts for over 90% of corpus uteri cancer. It is the fifth malignancy among women, with 319,605 new cases and 76,155 related deaths worldwide in 2012 (IARC). Most cases occur in developed countries, but its incidence is increasing in developing countries as well. Incidence rates in Brazil are raising and 5,900 new cases are expected for 2014. Adenocarcinomas are the most common histologic type and endometrioid adenocarcinomas (Type I) are diagnosed more often. Overall survival in disease confined in the uterus, in locally advanced disease and in metastatic disease is 96%, 66% and 24%, respectively. However, a group of patients whom present clinicopathological characteristics of good prognosis can develop recurrence with poor response to treatment. For this reason it is essential to improve knowledge about clinicopathological features and molecular biology of endometrial cancer. Some molecular aberrations on specific histologic subtypes have already been reported, but its association with risk of progression and relapse has not been determined yet. Therefore, the main purpose of this study was the evaluation of possible associations of clinicopatological variables, as well as molecular alterations that can predict a worse prognosis for endometrial cancer patients. For this, firstly, clinical and pathological frequencies, disease-free survival (DFS) and overall survival (OS) were studied in a population of 1,132 patients who were diagnosed on “endometrial adenocarcinoma” and underwent surgical treatment from 2000 to 2011. Median age was 63.7 years-old. Type I, low grade and early stage tumors were more frequent. Relapse and death occurred more often in Type II tumors (p<0,001 each). Staging and lymphovascular invasion emerged as independent prognostic factors for recurrence when DFS was assessed by multivariate analysis in all groups, and staging was considered an independent prognostic factor for death when OS was evaluated...