DNA methylation-based profiling reveals distinct clusters with survival heterogeneity in high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGSOC) is the most common type of epigenetically heterogeneous ovarian cancer. Methylation typing has previously been used in many tumour types but not in HGSOC. Methylation typing in HGSOC may promote the development of personalized care. The present study used DNA methylation data from The Cancer Genome Atlas database and identified four unique methylation subtypes of HGSOC. With the poorest prognosis and high frequency of residual tumours, cluster 4 featured hypermethylation of a panel of genes, which indicates that demethylation agents may be tested in this group and that neoadjuvant chemotherapy may be used to reduce the possibility of residual lesions. Cluster 1 and cluster 2 were significantly associated with metastasis genes and metabolic disorders, respectively. Two feature CpG sites, cg24673765 and cg25574024, were obtained through Cox proportional hazards model analysis of the CpG sites. Based on the methylation level of the two CpG sites, the samples were classified into high- and low-risk groups to identify the prognostic information. Similar results were obtained in the validation set. Taken together, these results explain the epigenetic heterogeneity of HGSOC and provide guidance to clinicians for the prognosis of HGSOC based on DNA methylation sites.

[Non endometroid endometrial cancer guidelines evaluation: A multicentric retrospective study]. / Évaluation de l'application des recommandations des cancers de l'endomètre de type 2 : étude rétrospective multicentrique.

INTRODUCTION: Non endometrioid endometrial cancer are infrequent and have poor prognosis. The aim of the study was to evaluate non endometrioid endometrial cancer managment by evaluating endometrial cancer guidelines application. MATERIAL AND METHODS: This multicentric retrospective study enrolled non endometrioid endometrial cancer between January 2009 to December 2019. Analyses adapted at last French guidelines applicated corresponding of year management. RESULTS: Seventy-four non endometrioid endometrial cancer analysed in 10 centers: 34 carcinosarcoma (45,9 %), 29 serous carcinoma (39,2 %), 9 clear cells carcinoma (12,2 %) and 2 undifferentiated carcinoma (2,7 %). For initial management, endometrial cancer guidelines applicated to 45,9 %. First reason of initial guidelines « non-application ¼ was lack of surgical lymph node stadification (57,1 %). For adjuvant management, endometrial cancer guidelines applicated to 38.7 %. First reason of adjuvant guidelines « non-application ¼ was lack lymph node stadification to complete staging when it previously incompletly operated (67,6 %). DISCUSSION: Non endometrioid endometrial cancer guidelines applicability is difficult. This explicated by high age and comorbidity when surgical lymph node stadification is necessary. Using new staging technic will allow target management and better select lymph node staging indication.

[A case of systemic sclerosis]. / U ne rémission « en peau de chagrin ¼.

In systemic sclerosis, the presence of an anti-RNA polymerase III antibody (ARNpol3) is associated with an increased risk of cancer. The characteristic picture of this serotype includes severe diffuse cutaneous involvement, a high risk of renal scleroderma crisis and a 10 year survival of only around 30%. Pulmonary involvement is less common. We report the case of a woman initially treated for drug-induced acute interstitial lung disease revealing chronic interstitial pneumonia with autoimmune features. The disease evolved in three stages with the occurrence of a rapidly progressive diffuse skin sclerosis with anti-ARNPol3 antibodies in the context of ovarian cancer remission.

Early onset neutropenia: a useful predictor of chemosensitivity and favorable prognosis in patients with serous ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer-associated deaths and a majority of its histological type is manifested as serous ovarian cancer (SOC). In this study, we investigated whether the timing of onset of chemotherapy-induced neutropenia (CIN) is related to chemotherapeutic response and disease outcome of SOC. METHODS: One hundred sixty-nine primary SOC patients receiving six doses of carboplatin plus paclitaxel adjuvant chemotherapy following cytoreductive surgery were retrospectively included in this research. CIN was grouped as early onset and late onset neutropenia depending on the timing of development. Development of CIN prior to or with administration of 3rd cycle of chemotherapy was listed as early onset neutropenia, while those CIN due to later stage chemotherapy were grouped into non-early type. The relevance of time of CIN onset with the clinical characteristics, chemotherapeutic response, progression free survival (PFS) and overall survival (OS) were determined and analyzed by using Kaplan-Meier curves, Logistic regression method, Cox proportional hazards models, and Chi-square tests. RESULTS: The age distribution of the patients was between 27 to 77 years. Fifty years was the median. No statistical significances of difference in age, FIGO stage, histological grade, tumor residual and lymph node invasion, as well as CA125 level in each CIN group were found (all P>0.05). The patients from non-early onset group showed higher chemoresistance rates (78.33%) compared to those from early onset group (9.17%). Additionally, patients in early onset group showed improved median PFS (23 vs. 9 months; P<0.001) and median OS (55 vs.24 months; P<0.001). CONCLUSIONS: Early onset neutropenia may be potentially used as a potential indicator for chemosensitivity and favorable prognosis of SOC in patients who underwent six cycles of carboplatin plus paclitaxel adjuvant chemotherapy following primary cytoreductive surgery.

Metabolic syndrome affects the long-term survival of patients with non-endometrioid carcinoma of the uterine corpus.

OBJECTIVE: To probe the influence of metabolic syndrome (MS) on the long-term survival of patients with non-endometrioid adenocarcinoma. METHODS: Between January 2003 and December 2012, 139 Chinese patients with non-endometrial adenocarcinoma were analyzed in a retrospective study. Patients who had received any treatment before surgery were excluded. Survival times were compared between patients with and without MS. RESULTS: Overall, 41 (29.5%) patients had MS; the highest incidence of MS was observed in those with uterine serous carcinoma (19/45, 42.2%). For uterine serous carcinoma or adenosquamous carcinoma, MS was an independent predictive factor of morbidity (P=0.023 and 0.016, respectively). For the overall population, those with MS had a significantly lower survival rate than those without MS (P=0.008), and the median overall survival (mOS) was 15 months versus 55 months (P<0.001, hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.29-0.69). Similarly, a lower survival rate (P=0.020) and shorter mOS (19 months vs 55 months, P=0.007, HR 0.41, 95% CI 0.20-0.83) were also found in the uterine serous carcinoma population with MS. Multivariate Cox regression analyses showed that disease stage (P=0.023) and MS (P=0.008) were independent prognostic factors for uterine serous carcinoma. CONCLUSION: The present study suggests that MS is a prognostic factor for non-endometrioid adenocarcinoma, especially uterine serous carcinoma.

Risk of epithelial ovarian cancer among women with benign ovarian tumors: a follow-up study.

PURPOSE: The importance of benign ovarian tumors as precursors or risk markers for ovarian cancer is not fully understood. Studies on the association between benign ovarian tumors and ovarian cancer have provided inconclusive results. We examined the overall and histological type-specific risk of ovarian cancer among 158,221 Danish women diagnosed with a benign ovarian tumor during 1978-2016. METHODS: The study cohort was linked to the Danish Cancer Register to identify all cases of epithelial ovarian cancer, and standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated. RESULTS: After excluding the first year of follow-up, women with benign ovarian tumors did not have an increased risk for overall epithelial ovarian cancer (SIR 1.02; 95% CI 0.93-1.11), as compared with women in the general population. However, we found an increased risk for mucinous ovarian cancer (SIR 2.06; 95% CI 1.67-2.52); both solid and cystic benign ovarian tumors were associated with an increased risk. The risk for mucinous ovarian cancer was increased irrespective of the age at benign ovarian tumors diagnosis and persisted for up to 20 years after the benign ovarian tumor diagnosis. No clear associations for other histological types of ovarian cancer were observed, except for an increased risk for serous ovarian cancer among women diagnosed with benign ovarian tumors at an young age. CONCLUSIONS: Benign ovarian tumors may be associated with long-term increased risk for mucinous ovarian cancer.

Prediagnostic Proinflammatory Dietary Potential Is Associated with All-Cause Mortality among African-American Women with High-Grade Serous Ovarian Carcinoma.

BACKGROUND: Chronic inflammation is associated with ovarian carcinogenesis; yet, the impact of inflammatory-related exposures on outcomes has been understudied. OBJECTIVE: Given the poor survival of women diagnosed with ovarian cancer, especially African-Americans, we examined whether diet-associated inflammation, a modifiable source of chronic systemic inflammation measured by the dietary inflammatory index (DII), was associated with all-cause mortality among African-American women with ovarian carcinoma. METHODS: Data were available from 490 ovarian carcinoma patients enrolled in a population-based case-control study of African-American women with ovarian cancer, the African-American Cancer Epidemiology Study. Energy-adjusted DII (E-DII) scores were calculated based on prediagnostic dietary intake of foods alone or foods and supplements, which was self-reported using the 2005 Block Food Frequency Questionnaire. Cox proportional hazards regression was used to estimate risk of mortality overall and for the most common histotype, high-grade serous carcinoma. Additionally, we assessed interaction by age at diagnosis and smoking status. RESULTS: Women included in this study had a median age of 57 y, and the majority of women were obese (58%), had late-stage disease (Stage III or IV, 66%), and had high-grade serous carcinoma (64%). Greater E-DII scores including supplements (indicating greater inflammatory potential) were associated with an increased risk of mortality among women with high-grade serous carcinoma (HR1-unit change: 1.08; 95% CI: 1.01, 1.17). Similar associations were observed for the E-DII excluding supplements, although not statistically significant (HR1-unit change: 1.07; 95% CI: 0.97, 1.17). There was an interaction by smoking status, where the positive association with mortality was present only among ever smokers (HRQuartile 4/Quartile 1: 2.36; 95% CI: 1.21, 4.60) but not among never smokers. CONCLUSIONS: Greater inflammatory potential of prediagnostic diet may adversely impact prognosis among African-American women with high-grade serous carcinoma, and specifically among ever smokers.

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.

Malignant ascites occurs most often in patients with high-grade serous papillary ovarian cancer at initial diagnosis: a retrospective analysis of 191 women treated at Bayreuth Hospital, 2006-2015.

BACKGROUND: Malignant ascites often develops in patients with ovarian cancer, but there is a lack of more detailed characterization of the different histological subtypes. METHODS: Ascites specimens from patients with ovarian cancer who were treated at Bayreuth Hospital from 2006 to 2015, with follow-up until December 2016, were reevaluated retrospectively. RESULTS: A total of 191 women (mean age 64 years, range 48-79) were included, of whom 180 (94.2%) had carcinoma, three (1.6%) had malignant mixed müllerian tumors (MMMTs), four (2.1%) had sex cord-stromal tumors (SCSTs), three (1.6%) had germ cell tumors (GCTs), and one (0.5%) had a sarcoma. The carcinoma group comprised 134 (70.1%) patients with high-grade serous papillary ovarian cancer, 17 (8.9%) with low-grade serous papillary ovarian cancer, 10 (5.3%) with mucinous carcinomas, nine (4.7%) with endometrioid carcinomas, six (3.1%) with clear cell carcinomas, and four (2.1%) with neuroendocrine tumors. The latter group consisted of two patients with mixed neuroendocrine-nonneuroendocrine tumors (MiNENs), one with only a small cell carcinoma (SCCO), and one with a mucinous carcinoid. The noncarcinomatous group of eight patients (4.2%) included three (1.6%) with Sertoli-Leydig cell tumor and mature cystic teratoma (MCT), one (0.5%) with a granulosa cell tumor, and one with a leiomyosarcoma. A statistically significant difference in the proportion of patients with malignant ascites was observed, at 17.7% (3/17) in those with low-grade serous papillary ovarian cancer and 91.8% (123/134) in those with high-grade serous papillary ovarian carcinomas. In both patients with MiNEN, the glandular tumor cell component was found in the ascites. Tumor cells were found in the ascitic fluid in 50% (5/10) of patients with mucinous ovarian carcinomas, 16.7% (1/6) of those with clear cell carcinomas, and 33.3% (1/3) of those with MMMTs. The two patients (2/3; 66.7%) with neoplastic squamous cell components in MCT and the only patient with a granulosa cell tumor in the SCST group (1/4; 25%) had malignant cell populations in the ascites, whereas patients with endometrioid cell carcinoma and leiomyosarcoma lacked tumor cells in the ascites. The malignant ascites was detected at the initial diagnosis in all 138 (100%) patients with ovarian neoplasms. CONCLUSIONS: High-grade serous papillary ovarian cancer was the main histological subtype most frequently found in ascites fluid in this series. The significant difference (P < 0.00001) in the malignancy rate in comparison with low-grade serous papillary carcinoma confirms the histological distinction between the two entities. Initial evidence of ovarian cancer in ascites fluid allows correct primary diagnosis in cytology specimens and is important for staging and prognosis.

Therapeutic Use of Metformin in Diabetes and Survival Outcomes in Endometrial Cancer Patients with Diabetes

Objectives: To compare survival outcomes between endometrial cancer (EC) patients with diabetes who used metformin to those who did not use metformin. Materials and Methods: A retrospective cohort study was conducted of EC patients who were diabetes at the time of their cancer diagnosis and had been scheduled for elective surgery at Rajavithi Hospital between 1 January 2003 and 31 December 2013. The patients were excluded if they had type I diabetes mellitus and a history of other cancers. Results: Of 1,262 EC patients in the study period, there was 212 (16.8%) patients who met the inclusion criteria. Among them, 90 (42.5%) were non-metformin users and 122 (57.5%) were metformin users. With a median follow-up of 47 months, the 5-year overall survivals (76.4% vs 77.9%, p=0.959) and the 5-year progression-free survivals (92.6% vs 84.7%, p=0.091) did not significantly differ between the both groups. On Cox proportional-hazards regression analysis, independent prognostic factors for overall survival (OS) were FIGO stage, depth of myometrial invasion, and cervical involvement. Patients with non-endometrioid histology and advanced stage were found to have a significant effect on progression-free survival (PFS). However, metformin used did not predict either OS (HR, 0.99; 95%CI, 0.56-1.73; p=0.959) or PFS (HR, 2.19; 95%CI, 0.86-5.55; p=0.099). Conclusion: Overall, a significant effect of metformin on survival outcomes in EC patients with diabetes was not found in the current study. Larger studies with a prospective randomized control design are needed to clarify the benefit of metformin as a strategy for endometrial cancer prevention and treatment.

Surgical Findings and Outcomes in Premenopausal Breast Cancer Patients Undergoing Oophorectomy: A Multicenter Review From the Society of Gynecologic Surgeons Fellows Pelvic Research Network.

STUDY OBJECTIVE: To describe the procedures performed, intra-abdominal findings, and surgical pathology in a cohort of women with premenopausal breast cancer who underwent oopherectomy. DESIGN: Multicenter retrospective chart review (Canadian Task Force classification II-3). SETTING: Nine US academic medical centers participating in the Fellows' Pelvic Research Network (FPRN). PATIENTS: One hundred twenty-seven women with premenopausal breast cancer undergoing oophorectomy between January 2013 and March 2016. INTERVENTION: Surgical castration. MEASUREMENTS AND MAIN RESULTS: The mean patient age was 45.8 years. Fourteen patients (11%) carried a BRCA mutations, and 22 (17%) carried another germline or acquired mutation, including multiple variants of uncertain significance. There was wide variation in surgical approach. Sixty-five patients (51%) underwent pelvic washings, and 43 (35%) underwent concurrent hysterectomy. Other concomitant procedures included midurethral sling placement, appendectomy, and hysteroscopy. Three patients experienced complications (transfusion, wound cellulitis, and vaginal cuff dehiscence). Thirteen patients (10%) had ovarian pathology detected on analysis of the surgical specimen, including metastatic tumor, serous cystadenomas, endometriomas, and Brenner tumor. Eight patients (6%) had Fallopian tube pathology, including 3 serous tubal intraepithelial cancers. Among the 44 uterine specimens, 1 endometrial adenocarcinoma and 1 multifocal endometrial intraepithelial neoplasia were noted. Regarding the entire study population, the number of patients meeting our study criteria and seen by gynecologic surgeons in the FPRN for oophorectomy increased by nearly 400% from 2013 to 2015. CONCLUSION: Since publication of the Suppression of Ovarian Function Trial data, bilateral oophorectomy has been recommended for some women with premenopausal breast cancer to facilitate breast cancer treatment with aromatase inhibitors. These women may be at elevated risk for occult abdominal pathology compared with the general population. Gynecologic surgeons often perform castration oophorectomy in patients with breast cancer as an increasing number of oncologists are using aromatase inhibitors to treat premenopausal breast cancer. Our data suggest that other abdominal/pelvic cancers, precancerous conditions, and previously unrecognized metastatic disease are not uncommon findings in this patient population. Gynecologists serving this patient population may consider a careful abdominal survey, pelvic washings, endometrial sampling, and serial sectioning of fallopian tube specimens for a thorough evaluation.

Clinical and genetic predictors of paclitaxel neurotoxicity based on patient- versus clinician-reported incidence and severity of neurotoxicity in the ICON7 trial.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of paclitaxel, with no reliable method to identify at-risk patients. We investigated the incidence and risk factors including genetic polymorphisms associated with the development of CIPN based on clinician and patient reporting of neuropathic symptoms. PATIENTS AND METHODS: Risk factors for the development of CIPN were examined in 454 patients treated with paclitaxel/carboplatin from the International Collaboration on Ovarian Neoplasms 7 (ICON7) trial. Neuropathy was graded by clinicians by standard adverse event reporting and by patients utilising OV28 questionnaire. Genetic risk factors were examined by selecting six single nucleotide polymorphisms in genes associated with microtubule function. Risk factors were assessed via dose-to-event cox regression models. RESULTS: Grade >2 neuropathy was reported by clinicians in 28% of patients, while 67% of patients reported 'quite a bit' or 'very much' tingling or numbness. Agreement between clinicians and patients was poor (κ = 0.236, 95% confidence interval, 0.177-0.296, P < 0.001). Older age, bevacizumab treatment and bowel resection were associated with clinician reported CIPN, while older age and volume of residual disease were associated with patient-reported neuropathy. There were no significant associations between clinician-reported neuropathy or patient-reported neuropathy and TUBB2, CEP72 or individual MAPT or GSK3B SNPs, however MAPT additive polymorphisms were associated with patient-reported neuropathy and GSK3B additive polymorphisms were associated with clinician reported CIPN. CONCLUSIONS: There was significant discordance between patient- and clinician-reported neurotoxicity. The lack of consensus regarding optimal outcome measures and whose opinion with regard to CIPN takes precedence is a limitation in the investigation of risk factors for CIPN. Care must be taken to select and include patient-reported outcome measures in CIPN assessment to enable accurate identification of genetic and other risk factors for neuropathy.

Type II Endometrial Cancer Overexpresses NILCO: A Preliminary Evaluation.

OBJECTIVE: The expression of NILCO molecules (Notch, IL-1, and leptin crosstalk outcome) and the association with obesity were investigated in types I and II endometrial cancer (EmCa). Additionally, the involvement of NILCO in leptin-induced invasiveness of EmCa cells was investigated. METHODS: The expression of NILCO mRNAs and proteins were analyzed in EmCa from African-American (n = 29) and Chinese patients (tissue array, n = 120 cases). The role of NILCO in leptin-induced invasion of Ishikawa and An3ca EmCa cells was investigated using Notch, IL-1, and leptin signaling inhibitors. RESULTS: NILCO molecules were expressed higher in type II EmCa, regardless of ethnic background or obesity status of patients. NILCO proteins were mainly localized in the cellular membrane and cytoplasm of type II EmCa. Additionally, EmCa from obese African-American patients showed higher levels of NILCO molecules than EmCa from lean patients. Notably, leptin-induced EmCa cell invasion was abrogated by NILCO inhibitors. CONCLUSION: Type II EmCa expressed higher NILCO molecules, which may suggest it is involved in the progression of the more aggressive EmCa phenotype. Obesity was associated with higher expression of NILCO molecules in EmCa. Leptin-induced cell invasion was dependent on NILCO. Hence, NILCO might be involved in tumor progression and could represent a new target/biomarker for type II EmCa.

Utility of human epididymis protein 4 serum marker for the detection of adnexal malignancy: a multicentric prospective study.

The aim of this study was to assess the usefulness of the human epididymis protein 4 (HE4) serum biomarker in predicting malignant disease in a clinical setting in comparison with other diagnostic tools, such as serum CA125 and ROMA score. A multicentric prospective observational study was carried out between January 2010 and December 2011 in four European centres (Italy, Portugal, Latvia and Spain). Data from 981 healthy controls and patients diagnosed with adnexal pathology were collected. Data on the ROMA index, CA124 and HE4 tumour markers were analysed. The receiver-operator characteristics curve and the area under the curve were analysed to discriminate between malignant and nonmalignant disease. Predictive values were also calculated. In total, 642 (65.4%) patients presented with a pelvic mass, with 324 (33%) of them being diagnosed with malignant disease. Sensitivity for HE4 was 64.1%; specificity was 95.7%; and positive predictive value was 88.1%, with a 4.3% false-positive rate. On comparing malignant disease versus nonmalignant/healthy patients, there was a significant difference (P<0.001) in the area under the curve. The receiver-operator characteristic for CA125 was 0.79 [95% confidence interval (CI): 0.76-0.83], for HE4 was 0.89 (95% CI: 0.87-0.91) and for ROMA was 0.71 (95% CI: 0.68-0.75). The HE4 serum marker showed similar sensitivity, but better specificity, than CA125 and can improve the detection of malignant pathology in women diagnosed with adnexal pathology.

SIADH secundario a adenocarcinoma seroso de ovario tratado con tolvaptán / SIADH secondary to serous ovarian adenocarcinoma treated with tolvaptan

La hiponatremia es la alteración electrolítica más frecuente en el medio hospitalario, y en un 30% de los casos se debe a un síndrome de secreción inapropiada de vasopresina (SIADH). El SIADH está descrito como cuadro paraneoplásico endocrinológico en múltiples tumores, entre los que excepcionalmente se encuentra el de ovario y las neoplasias ginecológicas en general. Presentamos un caso de SIADH paraneoplásico por un citoadenocarcinoma seroso de ovario de alto grado, estadio IV. Se trata del primer caso de SIADH crónico por cáncer de ovario tratado con Tolvaptán. En el presente caso el objetivo de eunatremia se alcanzó con una dosis baja de acuarético, lo que apoya la elevada sensibilidad, ya previamente documentada, de los SIADH tumorales al tratamiento con Tolvaptán.

Hyponatremia is the most common electrolyte disturbance in hospitals, and 30% of cases are due to syndrome of inappropriate secretion of antidiuretic hormone (SIADH). SIADH is described as an endocrine paraneoplastic syndrome in multiple tumors including, ovary and gynecological malignancies in general, although these are exceptional. We report a case of paraneoplastic SIADH for high-grade serous ovarian cystoadenocarcinoma stage IV. This is the first case of chronic SIADH for ovarian cancer treated with Tolvaptan. In this case the target of eunatremia was reached with a low dose of aquaretic, which supports the high sensitivity, as previously documented, of paraneoplasic SIADH to Tolvaptan.

Estudio macro y microscópico de salpingectomías profilácticas en mujeres BRCA positivo / Macro and microscopic study of prophylactic salpingectomy in women with BRCA mutations

El cáncer seroso ovárico está englobado dentro del carcinoma de ovario. Se distinguen 1 tipos de carcinomas serosos: tipo 1 (mutación frecuente de PTEN, KRAS y BRAF) que corresponde al carcinoma seroso de bajo grado y tipo 2 (mutación frecuente de p53) que corresponde al carcinoma seroso de alto grado. Su origen ha sido motivo de controversia; clásicamente predominaba la hipótesis de la ovulación incesante, que atribuía el origen a daños en la superficie ovárica durante la ovulación y metaplasias posteriores. Actualmente se han propuesto hipótesis que sitúan a la trompa de Falopio como el origen del carcinoma seroso ovárico de alto grado. Con el fin de demostrar esta hipótesis, se analizaron 20 muestras consecutivas de pacientes salpingooforectomizadas bilateralmente con mutaciones en BRCA1-2 conocidas. Se estudió la trompa macroscópicamente según el protocolo SEE-FIM y se siguió el algoritmo diagnóstico de carcinoma intraepitelial tubárico seroso de Kurman. Se realizó inmunohistoquímica para Ki-67 y p53 en todas las secciones. Así encuadramos a todas las trompas estudiadas en 4 categorías: normal, STIC (carcinoma intraepitelial), STIL (lesión tubárica intraepitelial en transición) y señal p53. En nuestra serie hemos obtenido 7 casos con diagnósticos diferentes al normal (35%): 2 STIL (10%) y 5 señal p53 (25%). El resto de trompas no mostraron atipia citológica ni inmunotinción con los anticuerpos usados. El estudio de los ovarios no mostró lesiones en ninguno de los casos. Estos resultados están de acuerdo con los obtenidos por otros investigadores, reflejando una lesión tubárica inicial, que revela una mutación del gen supresor de tumores (p53) que podría jugar un papel importante en la tumorogénesis del carcinoma seroso ovárico de alto grado (AU)

Serous ovarian cancer is a type of ovarian carcinoma. Two subtypes of serous carcinoma can be distinguished: Type 1 (frequent mutation of PTEN, KRAS and BRAF), corresponding to low-grade serous carcinoma, and Type 2 (frequent mutation of p53), corresponding to high-grade serous carcinoma. Its origin is not clear; classically causative factors included continuous ovulation, damage to the ovarian surface during ovulation and subsequent metaplasia. However, recently it has been proposed that the fallopian tube may be the origin of high-grade serous carcinoma. In order to test this hypothesis, we analyzed samples from 20 patients with known mutations in BRCA1-2 who had undergone bilateral salpingo-oophorectomy. The fallopian tube was studied macroscopically following the SEE-FIM protocol and Kurman's algorithm for the diagnosis of serous tubal intraepithelial carcinoma. All the sections were tested immunohistochemically with Ki-67 and p53 and the fallopian tubes were classified into 4 categories: normal, STIC (intraepithelial carcinoma), STIL (intraepithelial tubal lesion in transition) and p53 signature. In the series studied, 7 cases (35%) were diagnosed as abnormal: 2 STIL (10%) and 5 p53 signature (25%). The rest of the fallopian tubes showed no cytological atypia or immunostaining with the antibodies used. A study of the ovaries found no lesions in any of the cases. These findings agree with the results of other authors, and point to an initial lesion in the tube, reflecting a mutation of a tumour-suppressing gene (p53), which might play an important role in the development of high grade ovarian serous carcinoma (AU)