Clinical Characteristics and Outcomes of a High-grade Endometrial Cancer Cohort Treated at Instituto Nacional de Câncer, Brazil.

OBJECTIVE: To analyze the outcomes of a cohort of patients with high-risk histologies of endometrial cancer (EC) treated at Instituto Nacional de Câncer (National Cancer Institute, INCA, in Portuguese), in Brazil. MATERIALS AND METHODS: We reviewed the medical records of patients with high-risk histologies of EC in any stage registered at INCA between 2010 and 2016 to perform a clinical and demographic descriptive analysis and to evaluate the outcomes in terms of recurrence and survival. RESULTS: From 2010 to 2016, 2,145 EC patients were registered and treated at INCA, and 466 had high-grade histologies that met the inclusion criteria. The mean age of the patients was 65 years, 44.6% were Caucasian, and 90% had a performance status of 0 or 1. The most common histology was high-grade endometrioid (31.1%), followed by serous carcinoma (25.3%), mixed (20.0%), carcinosarcoma (13.5%), and clear cell carcinoma (9.4%). Considering the 2018 Fédération Internationale de Gynécologie et d'Obstétrique (International Federation of Gynecology and Obstetrics, FIGO, in French) staging system, 44.8%, 12.4%, 29.8%, and 12.9% of the patient were in stages I, II, III or IV respectively. Age (> 60 years), more than 50% of myoinvasion, higher stage, poor performance status, serous and carcinosarcoma histologies, and adjuvant treatment were independent factors associated with recurrence-free survival (RFS) and overall survival (OS) in the multivariate analysis. CONCLUSION: The current findings reinforced the international data showing poor outcomes of these tumors, especially for serous and carcinosarcomas and tumors with advanced stages, with shorter survival and high recurrence rates in distant sites, independently of the FIGO stage. Adjuvant therapy was associated with better survival.

OBJETIVO: Analisar os desfechos de uma coorte de pacientes com câncer de endométrio (CE) e histologias de alto risco atendida no Instituto Nacional do Câncer (INCA) entre 2010 e 2016. MATERIAIS E MéTODOS: Foram revisados prontuários de pacientes com histologias de alto risco de CE em qualquer estágio cadastradas no INCA entre 2010 e 2016 para realizar uma análise descritiva clínica e demográfica e avaliar os resultados em termos de recorrência e sobrevida. RESULTADOS: De 2010 a 2016, 2.145 pacientes com CE foram cadastradas e atendidas no INCA, e 466 tinham histologias de alto grau e atendiam aos critérios de inclusão. A média de idade das pacientes foi de 65 anos, 44,6% eram brancas, e 90% tinham performance status de 0 ou 1. A histologia mais comum foi endometrioide de alto grau (31,1%), seguida de carcinoma seroso (25,3%), misto (20,0%), carcinossarcoma (13,5%) e carcinoma de células claras (9,4%). Considerando o estadiamento da Fédération Internationale de Gynécologie et d'Obstétrique (Federação Internacional de Ginecologia e Obstetrícia, FIGO, em francês) de 2018, 44,8%, 12,4%, 29,8% e 12,9% apresentaram estágios I, II, III ou IV, respectivamente. Idade (> 60 anos), mais de 50% de mioinvasão, estágio avançado, performance status ruim, histologias serosas e carcinossarcoma, e tratamento adjuvante foram fatores independentes associados à sobrevida livre de recorrência e sobrevida global na análise multivariada. CONCLUSãO: Os achados atuais reforçam os dados internacionais que demonstram o prognóstico ruim desses tumores, principalmente para as histologias serosas e carcinossarcomas e para estágios avançados, com menor sobrevida e altas taxas de recorrência à distância, independentemente do estágio da FIGO. A terapia adjuvante foi associada a melhor sobrevida.

Social, Genetics and Histopathological Factors Related to Titin (TTN) Gene Mutation and Survival in Women with Ovarian Serous Cystadenocarcinoma: Bioinformatics Analysis.

Several factors may increase the risk of development of ovarian cancer. In this study, we investigated the relationship between social, genetic, and histopathologic factors in women with ovarian serous cystadenocarcinoma and titin (TTN) mutations, whether the TTN gene mutation may be a predictor, and its impact on mortality and survival in these patients. A total of 585 samples from patients with ovarian serous cystadenocarcinoma were collected from The Cancer Genome Atlas and PanCancer Atlas through the cBioPortal for analysis of social, genetic, and histopathological factors. Logistic regression was used to investigate whether TTN mutation could be a predictor, and the Kaplan-Meier method was applied to analyze survival time. TTN mutation frequency did not differ between age at diagnosis, tumor stage, and race, and was related to increased Buffa hypoxia score (p = 0.004), mutation count (p < 0.0001), Winter hypoxia Score (p = 0.030), nonsynonymous tumor mutation burden (TMB) (p < 0.0001), and reduced microsatellite instability sensor score (p = 0.010). The number of mutations (p < 0.0001) and winter hypoxia score (p = 0.008) were positively associated with TTN mutations, and nonsynonymous TMB (p < 0.0001) proved to be a predictor. Mutated TTN affects the score of genetic variables involved in cancer cell metabolism in ovarian cystadenocarcinoma.

Fusion Cell Markers in Circulating Tumor Cells from Patients with High-Grade Ovarian Serous Carcinoma.

Cancer is primarily a disease in which late diagnosis is linked to poor prognosis, and unfortunately, detection and management are still challenging. Circulating tumor cells (CTCs) are a potential resource to address this disease. Cell fusion, an event discovered recently in CTCs expressing carcinoma and leukocyte markers, occurs when ≥2 cells become a single entity (hybrid cell) after the merging of their plasma membranes. Cell fusion is still poorly understood despite continuous evaluations in in vitro/in vivo studies. Blood samples from 14 patients with high-grade serous ovarian cancer (A.C. Camargo Cancer Center, São Paulo, Brazil) were collected with the aim to analyze the CTCs/hybrid cells and their correlation to clinical outcome. The EDTA collected blood (6 mL) from patients was used to isolate/identify CTCs/hybrid cells by ISET. We used markers with possible correlation with the phenomenon of cell fusion, such as MC1-R, EpCAM and CD45, as well as CEN8 expression by CISH analysis. Samples were collected at three timepoints: baseline, after one month (first follow-up) and after three months (second follow-up) of treatment with olaparib (total sample = 38). Fourteen patients were included and in baseline and first follow-up all patients showed at least one CTC. We found expression of MC1-R, EpCAM and CD45 in cells (hybrid) in at least one of the collection moments. Membrane staining with CD45 was found in CTCs from the other cohort, from the other center, evaluated by the CellSearch® system. The presence of circulating tumor microemboli (CTM) in the first follow-up was associated with a poor recurrence-free survival (RFS) (5.2 vs. 12.2 months; p = 0.005). The MC1-R expression in CTM in the first and second follow-ups was associated with a shorter RFS (p = 0.005). CEN8 expression in CTCs was also related to shorter RFS (p = 0.035). Our study identified a high prevalence of CTCs in ovarian cancer patients, as well as hybrid cells. Both cell subtypes demonstrate utility in prognosis and in the assessment of response to treatment. In addition, the expression of MC1-R and EpCAM in hybrid cells brings new perspectives as a possible marker for this phenomenon in ovarian cancer.

Expression of DNA Methyltransferase 3B Isoforms Is Associated with DNA Satellite 2 Hypomethylation and Clinical Prognosis in Advanced High-Grade Serous Ovarian Carcinoma.

Alterations in DNA methylation are critical for the carcinogenesis of ovarian tumors, especially ovarian carcinoma (OC). DNMT3B, a de novo DNA methyltransferase (DNMT), encodes for fifteen spliced protein products or isoforms. DNMT3B isoforms lack exons for the catalytic domain, with functional consequences on catalytic activity. Abnormal expression of DNMT3B isoforms is frequently observed in several types of cancer, such as breast, lung, kidney, gastric, liver, skin, leukemia, and sarcoma. However, the expression patterns and consequences of DNMT3B isoforms in OC are unknown. In this study, we analyzed each DNMT and DNMT3B isoforms expression by qPCR in 63 OC samples and their association with disease-free survival (DFS), overall survival (OS), and tumor progression. We included OC patients with the main histological subtypes of EOC and patients in all the disease stages and found that DNMTs were overexpressed in advanced stages (p-value < 0.05) and high-grade OC (p-value < 0.05). Remarkably, we found DNMT3B1 overexpression in advanced stages (p-value = 0.0251) and high-grade serous ovarian carcinoma (HGSOC) (p-value = 0.0313), and DNMT3B3 was overexpressed in advanced stages (p-value = 0.0098) and high-grade (p-value = 0.0004) serous ovarian carcinoma (SOC). Finally, we observed that overexpression of DNMT3B isoforms was associated with poor prognosis in OC and SOC. DNMT3B3 was also associated with FDS (p-value = 0.017) and OS (p-value = 0.038) in SOC patients. In addition, the ovarian carcinoma cell lines OVCAR3 and SKOV3 also overexpress DNMT3B3. Interestingly, exogenous overexpression of DNMT3B3 in OVCAR3 causes demethylation of satellite 2 sequences in the pericentromeric region. In summary, our results suggest that DNMT3B3 expression is altered in OC.

Somatic Mutational Profile of High-Grade Serous Ovarian Carcinoma and Triple-Negative Breast Carcinoma in Young and Elderly Patients: Similarities and Divergences.

BACKGROUND: Triple-negative breast cancer (TNBC) and High-Grade Serous Ovarian Cancer (HGSOC) are aggressive malignancies that share similarities; however, different ages of onset may reflect distinct tumor behaviors. Thus, our aim was to compare somatic mutations in potential driver genes in 109 TNBC and 81 HGSOC from young (Y ≤ 40 years) and elderly (E ≥ 75 years) patients. METHODS: Open access mutational data (WGS or WES) were collected for TNBC and HGSOC patients. Potential driver genes were those that were present in the Cancer Gene Census-CGC, the Candidate Cancer Gene Database-CCGD, or OncoKB and those that were considered pathogenic in variant effect prediction tools. RESULTS: Mutational signature 3 (homologous repair defects) was the only gene that was represented in all four subgroups. The median number of mutated CGCs per sample was similar in HGSOC (Y:3 vs. E:4), but it was higher in elderly TNBC than it was in young TNBC (Y:3 vs. E:6). At least 90% of the samples from TNBC and HGSOC from Y and E patients presented at least one known affected TSG. Besides TP53, which was mutated in 67-83% of the samples, the affected TSG in TP53 wild-type samples were NF1 (yHGSOC and yTNBC), PHF6 (eHGSOC and yTNBC), PTEN, PIK3R1 and ZHFX3 (yTNBC), KMT2C, ARID1B, TBX3, and ATM (eTNBC). A few samples only presented one affected oncogene (but no TSG): KRAS and TSHR in eHGSOC and RAC1 and PREX2 (a regulator of RAC1) in yTNBC. At least ⅔ of the tumors presented mutated oncogenes associated with tumor suppressor genes; the Ras and/or PIK3CA signaling pathways were altered in 15% HGSOC and 20-35% TNBC (Y vs. E); DNA repair genes were mutated in 19-33% of the HGSOC tumors but were more frequently mutated in E-TNBC (56%). However, in HGSOC, 9.5% and 3.3% of the young and elderly patients, respectively, did not present any tumors with an affected CGC nor did 4.65% and none of the young and elderly TNBC patients. CONCLUSION: Most HGSOC and TNBC from young and elderly patients present an affected TSG, mainly TP53, as well as mutational signature 3; however, a few tumors only present an affected oncogene or no affected cancer-causing genes.

Ovarian Cancer-Associated Ascites Have High Proportions of Cytokine-Responsive CD56bright NK Cells.

Ovarian cancer is the most lethal gynecological malignancy, with serous histotype as the most prevalent epithelial ovarian cancer (EOC). Peritoneal ascites is a frequent comorbidity in advanced EOC. EOC-associated ascites provide a reliable sampling source for studying lymphocytes directly from tumor environment. Herein, we carried out flow cytometry-based analysis to readdress issues on NK and T lymphocyte subsets in women with advanced EOC, additionally evaluating phenotypic modulation of their intracellular pathways involved in interleukin (IL)-2 and IL-15 signaling. Results depicted ascites as an inflammatory and immunosuppressive environment, presenting significantly (p < 0.0001) higher amounts of IL-6 and IL-10 than in the patients' blood, as well as significantly (p < 0.05) increased expression of checkpoint inhibitory receptors (programmed death protein-1, PD-1) and ectonucleotidase (CD39) on T lymphocytes. However, NK lymphocytes from EOC-associated ascites showed higher (p < 0.05) pS6 phosphorylation compared with NK from blood. Additionally, in vitro treatment of lymphocytes with IL-2 or IL-15 elicited significantly (p < 0.001) phosphorylation of the STAT5 protein in NK, CD3 and CD8 lymphocytes, both from blood and ascites. EOC-associated ascites had a significantly (p < 0.0001) higher proportion of NK CD56bright lymphocytes than blood, which, in addition, were more responsive (p < 0.05) to stimulation by IL-2 than CD56dim NK. EOC-associated ascites allow studies on lymphocyte phenotype modulation in the tumor environment, where inflammatory profile contrasts with the presence of immunosuppressive elements and development of cellular self-regulating mechanisms.

Analysis of ovarian cancer cell secretome during epithelial to mesenchymal transition reveals a protein signature associated with advanced stages of ovarian tumors.

Ovarian cancer (OvCA) is the most lethal neoplasia among gynecologic malignancies and faces high rates of new cases particularly in South America. In special, the High Grade Serous Ovarian Carcinoma (HGSC) presents very poor prognosis with deaths caused mainly by metastasis. Among several mechanisms involved in metastasis, the Epithelial to Mesenchymal Transition (EMT) molecular reprogramming represents a model for latest stages of cancer progression. EMT promotes important cellular changes in cellular adhesion and cell-cell communication, which particularly depends on the paracrine signaling from neighbor cells. Considering the importance of cellular communication during EMT and metastasis, here we analyzed the changes in the secretome of the ovarian cancer cell line Caov-3 induced to EMT by Epidermal Growth Factor (EGF). Using a combination of GEL-LC-MS/MS and stable isotopic metabolic labelling (SILAC), we identified up-regulated candidates during EMT as a starting point to identify relevant proteins for HGSC. Based on public databases, our candidate proteins were validated and prioritized for further analysis. Importantly, several of the protein candidates were associated with cellular vesicles, which are important to the cell-cell communication and metastasis. Furthermore, the association of candidate proteins with gene expression data uncovered a subset of proteins correlated with the mesenchymal subtype of ovarian cancer. Based on this relevant molecular signature for aggressive ovarian cancer, supported by protein and gene expression data, we developed a targeted proteomic method to evaluate individual OvCA clinical samples. The quantitative information obtained for 33 peptides, representative of 18 proteins, was able to segregate HGSC from other tumor types. Our study highlighted the richness of the secretome and EMT to reveal relevant proteins for HGSC, which could be used in further studies and larger patient cohorts as a potential stratification signature for ovarian cancer tumor that could guide clinical conduct for patient treatment.

Bevacizumab in recurrent ovarian cancer: could it be particularly effective in patients with clear cell carcinoma?

PURPOSE: Treatment of recurrent ovarian carcinoma is a challenge, particularly for the clear cell (CCC) subtype. However, there is a preclinical rationale that these patients could achieve a benefit from antiangiogenic therapy. To assess this hypothesis, we used the growth modulation index (GMI), which represents an intrapatient comparison of two successive progression-free survival (PFS). METHODS: We conducted a retrospective real-world study performed on 34 patients with recurrent ovarian cancer, treated with bevacizumab-containing regimens from January 2009 to December 2017. The primary endpoint was GMI. An established cut-off > 1.33 was defined as a sign of drug activity. RESULTS: 73.5% of patients had high-grade serous ovarian carcinoma (HGSOC), and 17.7% had CCC; 70.6% of patients received carboplatin/gemcitabine/bevacizumab, and 29.4% received weekly paclitaxel/bevacizumab. According to histological subtype, the overall response rate and median PFS were 52% and 14 months for HGSOC and 83.3% and 20 months for CCC, respectively. The overall population median GMI was 0.99; it was 0.95 and 2.36 for HGSOC and CCC, respectively. CCC subtype was significantly correlated with GMI > 1.33 (odds ratio 41.67; 95% confidence interval 3.6-486.94; p = .03). CONCLUSION: Adding bevacizumab to chemotherapy in recurrent CCC is associated with a remarkable benefit in this cohort. The efficacy of antiangiogenic drugs in CCC warrants further prospective evaluation.

Analysis of the relationship between hospital characteristics and survival in ovarian cancer: A historical cohort.

BACKGROUND AND OBJECTIVES: The management of ovarian cancer requires complex surgical and medical interventions. Specialized care is associated with superior outcomes in early and advanced stages. This study aimed to estimate the effect of hospital characteristics on the overall survival of women with epithelial ovarian cancer. METHODS: We established a cohort with data recorded by the Fundação Oncocentro de São Paulo cancer registry. We included 6111 women treated for ovarian cancer in the state of Sao Paulo from January 2000 to December 2018. From 76 hospitals analyzed, 7 were high volume (20 or more cases a year) and 69 low volume. Twenty-nine were teaching and 47 community hospitals. A 10-year survival was analyzed using the Kaplan-Meyer estimator and the Cox model. RESULTS: Fifty-two percent of the epithelial ovarian cancer patients were treated in high-volume hospitals. High-volume - (HR, 0.86; 95% CI, 0.8-0.92; P < .001) and teaching - (HR, 0.91; 95% CI, 0.85-0.99; P = .019) were hospital characteristics associated with low risk of death in 10 years. CONCLUSIONS: High-volume and teaching hospitals are associated with better overall survival in ovarian cancer. Our data suggest that both hospital characteristics are important indicators of good quality of care in ovarian cancer treatment.

Follicle-stimulating hormone promotes nerve growth factor and vascular endothelial growth factor expression in epithelial ovarian cells.

Ovarian cancer is the first cause of death for gynecological malignances in developed countries and around 80% correspond to Epithelial Ovarian Cancer (EOC). Overexpression of Nerve Growth Factor (NGF) and its high affinity receptor TRKA are involved in EOC progression, modulating several oncogenic processes such as angiogenesis by the increase of Vascular Endothelial Growth Factor (VEGF). FSH receptors (FSH-R) are present in EOC, but their changes and contribution during EOC progression are still not thoroughly known. The aims of this study were to evaluate the abundance of FSH receptors during EOC differentiation and to determine whether FSH modulates oncoproteins such as NGF and VEGF in ovarian cells. FSH-R expression in EOC tissues and cell lines (A2780, poorly differentiated EOC cells and HOSE, non-tumoral ovarian surface epithelial cells) were measured by RT-PCR and laser capture of epithelial cells from EOC samples by qPCR. FSH-R protein levels were evaluated by immunohisto/cytochemistry. Additionally, ovarian explants and ovarian cell lines were stimulated with FSH and/or FSH-R inhibitor to assess NGF and VEGF mRNA and protein levels. The results showed that FSH-R levels decreased during EOC progression, nevertheless these receptors are still present in poorly differentiated EOC. FSH increased NGF expression in ovarian cells, which was prevented using a FSH-R inhibitor. Similarly, in ovarian cancer explants, FSH increased NGF and VEGF mRNA, as well as NGF protein levels. These results suggest that FSH would display a key role not only in initial stages of EOC, but also in late stages of this disease, by modulation of NGF and VEGF levels in EOC cells.

Impacto prognóstico de marcadores do ciclo celular em pacientes com carcinoma de ovário / Prognostic impact of cell cycle markers in ovarian cancer patients

A hiperexpressão da ciclina E1 (CCNE1h) foi identificada como um marcador de um subgrupo distinto de carcinoma ovariano seroso de alto grau (HGSC), caracterizado por ausência de deficiência de recombinação homóloga. Os inibidores Wee1 são inibidores do checkpoint G2-M e atuam principalmente em pacientes com tumores com defeitos no checkpoint G1-S. A associação entre CCNE1h e Wee1 ainda não foi avaliada. O objetivo deste estudo é avaliar a a expressão de ciclina E1 e Wee1 sua associação com as características clínicas e seu impacto prognóstico em um subconjunto institucional de pacientes brasileiras com diagnóstico de carcinoma de ovário.Também avaliamos em todo grupo institucional as características clínicas e seu impacto prognóstico e em um segundo subgrupo desta população o papel preditivo da expressão do intervalo livre de platina (PFI) e da ciclina E1 na eficácia do bevacizumabe. Realizamos uma revisão retrospectiva de dados clínicos de pacientes com câncer epitelial de ovário (EOC), tratados de janeiro de 2007 a janeiro de 2017 no A.C.Camargo Cancer Center. A CCNE1h e Wee1 foi avaliada por imunoistoquímica (IHC). As características das pacientes foram coletadas e os resultados clínicos medidos foram sobrevida livre de progressão (SLP), sobrevida global (SG), tempo para recidiva platino resistente, e intervalo livre de platina (PFI). Dos 196 pacientes com EOC, a ciclina E1 foi hiperexpressada em 83 pacientes (42%) e esse grupo apresentou características clínicas semelhantes as pacientes sem hiperexpressão. CCNE1h foi associada a menor mediana SGm 56,34 vs 88,08 meses (p = 0,06), menor SLP mediana (mSLP) 19,41 vs 22,47 meses (p = 0,37) e menor tempo mediano para recidiva platino resistente 50,72 vs 97,54 meses (p = 0,001). Foi feita uma subanálise das pacientes com recidiva platina sensível, tratadas com bevacizumabe e quimioterapia (grupo Bev) comparando-as com as tratadas apenas com quimioterapia (grupo CT) pareadas 1: 1 quanto ao intervalo livre de platina, número de linhas anteriores de quimioterapia e histologia. 124 pacientes foram pareadas, 62 em cada grupo. A SLPm foi de 19,5 meses para o grupo Bev vs. 16,0 meses para o grupo CT (p = 0,150). Na análise multivariada para SLP, o HR foi de 2,25 (IC95% 1,10-4,60) para a CCNE1h. O benefício do bevacizumabe estava presente apenas no subgrupo de pacientes com PFI <12 meses (SLPm 18,6 versus 10,4 meses, p = 0,002) e no subgrupo de pacientes com CCNE1h (mSLP 16,3 versus 7,0 meses, p = 0,010). As pacientes com CCNE1h apresentam pior tempo mediano para recidiva platino resistente. A expressão de Wee1 foi constante e na mesma intensidade para todas as pacientes. A IHC não parece ser um método apropriado para avaliar a atividade Wee1 no tecido tumoral. Concluimos portanto que a CCNE1h está associada à resistência à platina e à sobrevida global e que a CCNE1h e o PFI podem identificar pacientes com o maior benefício do bevacizumabe. Esses dados se confirmados em novos estudos podem ajudar a selecionar melhor os pacientes para terapia antiangiogênica.

Cyclin E1 overexpression (CCNE1h) has been identified as a marker of a distinct subgroup of high-grade serous ovarian carcinoma (HGSC) characterized by no homologous recombination deficiency. Wee1 inhibitors are G2-M check point inhibitors and act mostly in patients with tumors with G1-S defects. Association between CCNE1 and Wee1 has not been evaluated yet. The objective of this study is to evaluate the expression of cyclin E1 and Wee1 and their association with the clinical characteristics of patients and their prognostic impact in an institutional subset of Brazilian patients diagnosed with ovarian carcinoma. We also evaluated the clinical characteristics and their prognostic impact in every institutional group and in a second subgroup of this population the predictive role of platinum free interval (PFI) and E1 cyclin expression in the effectiveness of bevacizumab. A retrospective review of clinical data from epithelial ovarian cancer (EOC) patients treated from January 2007 to January 2017 at A.C.Camargo Cancer Center. CCNE1h and Wee1 overexpression were assessed by immunohistochemistry (IHC). Patients characteristics were collected, and measured clinical outcomes were progression-free survival (PFS), overall survival (OS), platinum resistant free survival (PRFS), platinum-free interval (PFI). Among 196 patients with EOC, cyclin E1 was overexpressed in 83 patients (42%) and this group had similar clinical characteristics to patients without CCNE1h. CCNE1h was associated with shorter median OS 56,34 vs 88,08 months (p =0.06), shorter mPFS 19,41 vs 22,47 months (p =0.37) and shorter mPRFS 50,72 vs 97,54 months (p =0.001). A subanalysis of patients with sensitive platinum recurrence treated with bevacizumab and chemotherapy (group Bev) was performed, comparing them with those treated only with chemotherapy (group CT) paired 1: 1 regarding the platinum free interval, number of previous lines of chemotherapy and histology. 124 patients were paired, 62 in each group.. Median PFS (mPFS) was 19.5 months for the Bev group vs. 16.0 months for CT group (p = 0.150). On multivariate analysis for PFS HR was 2.25 (95%CI 1.10-4.60) for CCNE1 overexpression. Benefit of bevacizumab was present only in the subgroup of patients with PFI < 12 months (mPFS 18.6 versus 10.4 months, p=0.002) and in the subgroup of patients with CCNE1 overexpression (mPFS 16.3 versus 7.0 months, p=0.010). CCNE1 overexpressed tumors have worse median time for resistant platinum recurrence. IHC does not seem to be an appropriate method to evaluate Wee1 activity in tumor tissue. We therefore conclude that CCNE1h is associated with platinum resistance and overall survival and that CCNE1h and PFI can identify patients with the greatest benefit from bevacizumab. These data if confirmed in new studies may help to better select patients for antiangiogenic therapy.

Brain Metastasis in Papillary Serous Adenocarcinoma of the Endometrium.

BACKGROUND: Most endometrial cancers (75%) are diagnosed in early stages (stages I and II), in which abnormal uterine bleeding is the most frequent clinical sign. When the diagnosis is performed in stage IV, the most common sites of metastasis are the lungs, liver and bones. Central nervous system (CNS) metastasis is a rare condition. The aim of this study is to describe a case of uterine papillary serous adenocarcinoma of the endometrium that progressed to brain and bone metastases. CASE REPORT: We present the case of a 56-year-old woman with abnormal uterine bleeding and endometrial thickened echo (1.8 cm). A hysteroscopy with biopsy was performed, which identified poor differentiated serous adenocarcinoma of the endometrium. A total abdominal hysterectomy, with pelvic and para-aortic lymphadenectomy, was performed. Analysis of the surgical specimen revealed a grade III uterine papillary serous adenocarcinoma. Adjuvant radio/chemotherapy (carboplatin and paclitaxel-six cycles) was indicated. Sixteen months after the surgery, the patient began to complain of headaches. Brain magnetic resonance imaging demonstrated an expansile mass in the right parietal lobe, suggesting a secondary hematogenous implant subsequently confirmed by biopsy. She underwent surgery for treatment of brain metastasis, followed by radiotherapy. She died 12 months after the brain metastasis diagnosis due to disease progression. CONCLUSION: Uterine papillary serous adenocarcinoma of the endometrium has a low propensity to metastasize to the brain. To the best of our knowledge, this is the fifth documented case of uterine papillary serous adenocarcinoma of the endometrium with metastasis to the CNS.

FUNDAMENTOS: A maioria dos cânceres de endométrio (75%) é diagnosticada em estágios iniciais (estágios I e II), nos quais o sangramento uterino anormal é o sinal clínico mais frequente. Quando o diagnóstico é realizado no estágio IV, os locais mais comuns de metástase são os pulmões, o fígado e os ossos. A metástase para o sistema nervoso central (SNC) é uma condição rara. O objetivo deste estudo é descrever um caso de adenocarcinoma seroso-papilífero do endométrio que progrediu para metástases cerebral e óssea. RELATO DE CASO: Apresentamos o caso de uma mulher de 56 anos com sangramento uterino anormal e eco endometrial espessado (1,8 cm). Foi realizada histeroscopia com biópsia que identificou adenocarcinoma seroso-papilífero pouco diferenciado do endométrio. Uma histerectomia abdominal total, com linfadenectomia pélvica e para-aórtica, foi realizada. A análise da peça cirúrgica revelou adenocarcinoma seroso-papilífero do endométrio grau III. Radioterapia adjuvante/quimioterapia (carboplatina e paclitaxel­seis ciclos) foi indicada. Dezesseis meses após a cirurgia, a paciente começou a se queixar de dores de cabeça. A ressonância magnética cerebral demonstrou uma massa expansiva no lobo parietal direito, sugerindo um implante hematogênico secundário posteriormente confirmado por biópsia. A paciente foi submetida a cirurgia para tratamento de metástase cerebral, seguida de radioterapia. A paciente morreu 12 meses após o diagnóstico de metástase cerebral devido à progressão da doença. CONCLUSãO: O adenocarcinoma seroso-papilífero do endométrio tem uma baixa propensão a metastizar para o cérebro. Até onde sabemos, este é o quinto caso documentado de adenocacinoma seroso-papilífero do endométrio com metástase para o SNC.

Brain metastasis in papillary serous adenocarcinoma of the endometrium / Metástase cerebral do adenocarcinoma seroso-papilífero do endométrio

Abstract Background Most endometrial cancers (75%) are diagnosed in early stages (stages I and II), in which abnormal uterine bleeding is the most frequent clinical sign.When the diagnosis is performed in stage IV, the most common sites of metastasis are the lungs, liver and bones. Central nervous system (CNS)metastasis is a rare condition. The aim of this study is to describe a case of uterine papillary serous adenocarcinoma of the endometrium that progressed to brain and bone metastases. Case Report We present the case of a 56-year-old woman with abnormal uterine bleeding and endometrial thickened echo (1.8 cm). A hysteroscopy with biopsy was performed, which identified poor differentiated serous adenocarcinoma of the endometrium. A total abdominal hysterectomy, with pelvic and para-aortic lymphadenectomy, was performed. Analysis of the surgical specimen revealed a grade III uterine papillary serous adenocarcinoma. Adjuvant radio/chemotherapy (carboplatin and paclitaxel-six cycles) was indicated. Sixteen months after the surgery, the patient began to complain of headaches. Brain magnetic resonance imaging demonstrated an expansile mass in the right parietal lobe, suggesting a secondary hematogenous implant subsequently confirmed by biopsy. She underwent surgery for treatment of brain metastasis, followed by radiotherapy. She died 12 months after the brain metastasis diagnosis due to disease progression. Conclusion Uterine papillary serous adenocarcinoma of the endometrium has a low propensity to metastasize to the brain. To the best of our knowledge, this is the fifth documented case of uterine papillary serous adenocarcinoma of the endometrium with metastasis to the CNS.

Resumo Fundamentos A maioria dos cânceres de endométrio (75%) é diagnosticada em estágios iniciais (estágios I e II), nos quais o sangramento uterino anormal é o sinalclínico mais frequente. Quando o diagnóstico é realizado no estágio IV, os locais mais comuns de metástase são os pulmões, o fígado e os ossos. A metástase para o sistema nervoso central (SNC) é uma condição rara. O objetivo deste estudo é descrever um caso de adenocarcinoma seroso-papilífero do endométrio que progrediu para metástases cerebral e óssea. Relato de Caso Apresentamos o caso de uma mulher de 56 anos com sangramento uterino anormal e eco endometrial espessado (1,8 cm). Foi realizada histeroscopia com biópsia que identificou adenocarcinoma seroso-papilífero pouco diferenciado do endométrio. Uma histerectomia abdominal total, com linfadenectomia pélvica e para-aórtica, foi realizada. A análise da peça cirúrgica revelou adenocarcinoma seroso-papilífero do endométrio grau III. Radioterapia adjuvante/quimioterapia (carboplatina e paclitaxel- seis ciclos) foi indicada.Dezesseismeses após a cirurgia, a paciente começou a se queixar de dores de cabeça. A ressonância magnética cerebral demonstrou uma massa expansiva no lobo parietal direito, sugerindo um implante hematogênico secundário posteriormente confirmado por biópsia. A paciente foi submetida a cirurgia para tratamento de metástase cerebral, seguida de radioterapia. A paciente morreu 12 meses após o diagnóstico de metástase cerebral devido à progressão da doença. Conclusão O adenocarcinoma seroso-papilífero do endométrio tem uma baixa propensão a metastizar para o cérebro. Até onde sabemos, este é o quinto caso documentado de adenocacinoma seroso-papilífero do endométrio com metástase para o SNC.

Prostaglandin D2 expression is prognostic in high­grade serous ovarian cancer.

To identify biomarkers that could predict response or lack of response to conventional chemotherapy at the time of diagnosis of high­grade serous ovarian carcinoma (HGSOC), the present study compared large­scale gene expression from patients with short or long disease­free survival times, according to the last cycle of chemotherapy, and validated these findings using reverse transcription­quantitative polymerase chain reaction (RT­qPCR) and conventional immunohistochemical (IHC) analysis. Samples were selected for microarray evaluation, at the time of diagnosis, using the following criteria: Identical debulking primary surgery, International Federation of Gynaecology and Obstetrics staging, histological subtype and grade. These were divided into 2 groups, regarding the outcome after 2 years of follow-up. Prostaglandin D2 synthase 21 kDa (brain) (PTGDS) was found to be expressed at a significantly higher level in the tumours of patients with a short disease­free survival time, and this was validated by RT­qPCR in all samples. Furthermore, the study evaluated PGD2, the protein product of the PTGDS gene, in a large cohort of 114 HGSOC patients using the Ventana Benchmark automated platform, and IHC positivity was correlated with clinicopathological data and outcome. The global gene expression analysis identified 1,149 genes that were differentially expressed in microarray data, according to the patient outcome. Further analysis RT­qPCR validated PTGDS gene expression in the same samples (r=0.945; P<0.001). IHC analysis showed an inverse profile, with positivity for PGD2 strongly associated with an increase in disease­free survival (P=0.009), the absence of relapse (P=0.039) and sensitivity to platinum­based therapy (P=0.016). Multiple Cox regression showed that IHC evaluation of PGD2 was also a prognostic marker associated with relapse (hazard ratio, 0.37; P=0.002). Overall, the results showed that IHC evaluation of PGD2 is an independent marker of good prognosis in HGSOC. This finding contributes to our understanding of the mechanism of tumour regulation and to investigations into biomarkers that predict response to chemotherapy.

Cardiophrenic lymph node resection in cytoreduction for primary advanced or recurrent epithelial ovarian carcinoma: a cohort study.

OBJECTIVES: To evaluate the clinical outcomes of epithelial ovarian carcinoma patients who underwent cardiophrenic lymph node resection. METHODS: We retrospectively reviewed the records of all surgically treated patients with advanced epithelial ovarian carcinoma (stages IIIC-IV) who underwent cardiophrenic lymph node resection between 2002 and 2018. Only those in whom cardiophrenic lymph node involvement was the only detectable extra-abdominal disease were included. Patients with suspected cardiophrenic lymph node metastasis on staging images underwent a transdiaphragmatic incision to access the para-cardiac space after complete abdominal cytoreduction achievement. Data on disease-free survival, overall survival, and surgical procedures performed concurrently with cardiophrenic lymph node resection were collected. RESULTS: Of the total 456 patients, 29 underwent cardiophrenic lymph node resection; of these, 24 patients met the inclusion criteria. Twenty-two, one, and one patients had high grade serous epithelial ovarian carcinoma, low grade epithelial ovarian carcinoma, and ovarian carcinosarcoma, respectively. Ten patients had recurrent disease (recurrence group). Fourteen patients underwent cytoreduction during primary treatment (primary debulking group); four underwent cytoreduction after neoadjuvant chemotherapy. Cardiophrenic lymph node resection was performed on the right side in 19 patients, left side in three, and bilaterally in two. The average procedural duration was 28 minutes, with minimal blood loss and no severe complications. Twenty-one patients had cardiophrenic lymph node positivity. The median disease-free intervals were 17 and 12 months in the recurrent and primary debulking surgery groups, respectively. The mediastinum was the first recurrence site in 10 patients. Five patients developed brain metastases. Five patients had an overall survival beyond 50 months. CONCLUSIONS: Although rare, the cardiophrenic lymph nodes may be a site of metastasis of ovarian cancer. Although their presence might indicate future recurrence, some patients may achieve long-term survival. Resection should be considered in cases of suspicious involvement to confirm extra-abdominal disease and achieve complete cytoreduction.

Cáncer de endometrio: reporte de un caso y revisión de la literatura / Endometrial Cancer. Case report and literature review

Antecedentes: El cáncer endometrial (CE) según las estadísticas es el tumor ginecológico más frecuente en países desarrollados, donde su incidencia ha ido en aumento. Históricamente, el CE se ha clasificado en dos tipos: Tipo I (endometrioide), representando el 80-90% de los casos; el tipo II (no endometrioide como el de células serosas y claras, carcinomas indiferenciados). Como dato importante, la mayoría de las pacientes son diagnosticadas cuando la enfermedad se encuentra en etapas tempranas o la lesión todavía está confinada al útero. El tratamiento convencional radica en una histerectomía primaria más salpingooforectomía bilateral, según el estadío de la enfermedad. Caso clínico: Paciente de 58 años de edad que ingresa al Hospital de San Marcos, Ocotepeque, con sangrado transvaginal de 1 mes de evolución, hipertensión crónica y obesidad tipo I. En el ultrasonido transvaginal se observó engrosamiento endometrial, pero en la biopsia se diagnosticó Adenocarcinoma Endometrial de tipo Endometroide Grado II-III de la FIGO. Conclusión: Ante la presencia de sangrado uterino anormal en mujeres peri y postmenopáusicas, con factores de riesgos asociados, se debe sospechar cáncer de endometrio...(AU)

Immunhistochemical analysis of Nuclear Factor Kappa Beta expression in etiopathogenesis of ovarian tumors1.

PURPOSE: To investigate the place of the transcription factor nuclear kappa B (NF-kB), which is a marker of chronic inflammation, in the etiology of the ovarian carcinoma. METHODS: NFkB analysis with the immunohistochemical method has been performed. To evaluate immunohistochemical NF-kB expression in the ovarian tissue, the H-score method. H-score = ∑ Pi (i+1), where ''Pi'' is the percentage of stained cells in each intensity category (0-100%) and ''i'' is the intensity indicating weak (i=1), moderate (i=2) or strong staining (i=3). RESULTS: It has been seen that, the mean H score is statistically significantly higher in the patient group with serous and musinous adenocarcinoma diagnosis than the two other patient groups (p<0.005). CONCLUSIONS: Factor nuclear kappa B is an important mediator that acts in the chronic inflammation. The highest expression rates are determined by the immunohistochemical method in the ovarian cancer group.

Patient inflammatory status and CD4+/CD8+ intraepithelial tumor lymphocyte infiltration are predictors of outcomes in high-grade serous ovarian cancer.

BACKGROUND: High-grade serous ovarian cancer (HGSOC) is the most prevalent and aggressive histologic type of ovarian cancer. To date, there are no reliable biomarkers to effectively predict patient prognosis. Studies have demonstrated inflammation and tumor infiltrating lymphocytes (TILs) correlate with a bad and good prognosis, respectively. Here, we sought to evaluate systemic inflammation and TILs as early prognostic markers of survival. METHODS: Neutrophil-to-lymphocyte ratio (NLR) and serum Lactate Dehydrogenase (LDH) were used as indicators of systemic inflammation. NLR, serum LDH, tumor infiltrating lymphocytes (TILs), PDL1 and quality of debulking surgery were evaluated as determinants of progression-free survival (PFS) and overall survival (OS) in a cohort of 128 HGSOC patients. RESULTS: Initial univariate analysis showed that systemic inflammation measures (NLR and serum LDH), debulking surgery, and intra-epithelial TILs have a significant impact on both PFS and OS. After adjustment for several variables, multivariate analyses confirmed intraepithelial CD4+ T-cells, systemic inflammation measures, PDL1 and debulking surgery as determinants of better OS and PFS. CONCLUSIONS: Systemic inflammation and TILs are early determinants of OS in HGSOC. Other variables such as the quality of debulking surgery and PDL1 also improve survival of patients. Regarding TIL sub-populations, intraepithelial CD4+ cells are associated to an increase in both PFS and OS. We also confirmed previous reports that demonstrate intraepithelial CD8+ cells correlate with an increase on PFS in ovarian cancer. A combined score using systemic inflammation and TILs may be of prognostic value for HGSOC patients.

Immunhistochemical analysis of Nuclear Factor Kappa Beta expression in etiopathogenesis of ovarian tumors

Abstract Purpose: To investigate the place of the transcription factor nuclear kappa B (NF-kB), which is a marker of chronic inflammation, in the etiology of the ovarian carcinoma. Methods: NFkB analysis with the immunohistochemical method has been performed. To evaluate immunohistochemical NF-kB expression in the ovarian tissue, the H-score method. H-score = ∑ Pi (i+1), where ''Pi'' is the percentage of stained cells in each intensity category (0-100%) and ''i'' is the intensity indicating weak (i=1), moderate (i=2) or strong staining (i=3). Results: It has been seen that, the mean H score is statistically significantly higher in the patient group with serous and musinous adenocarcinoma diagnosis than the two other patient groups (p<0.005). Conclusions: Factor nuclear kappa B is an important mediator that acts in the chronic inflammation. The highest expression rates are determined by the immunohistochemical method in the ovarian cancer group.