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Simple Summary: High-grade serous ovarian cancer (HGSOC) remains a lethal malignancy. There is an urgent need to establish whether a mass is benign or malignant prior to surgery. The HGSOC microenvironment harbours a mixture of immunosuppressive and inflammatory immune parameters that correlate independently with disease progression; however, their relationship is not well understood. We hypothesised that the inclusion of such diverse biomarkers would improve the prediction of ovarian malignancy. We quantified 29 soluble factors in blood, as well as the proportions of circulating T cell subsets using 16 phenotypic markers by multiparameter flow cytometry, in patients with suspected ovarian cancer or volunteers undergoing ovarian cancer risk reduction surgery. Out of all the soluble and cellular subsets tested, a combination of tumour necrosis factor receptor type 2 (TNFR2)-expressing regulatory T cells (Tregs) and interleukin 6 (IL-6) showed superior predictive ability over the biomarkers currently used to discriminate between benign and malignant tumors. We propose combining soluble and cellular circulating biomarkers as a useful approach to improve cancer diagnoses. We hypothesised that the inclusion of immunosuppressive and inflammatory biomarkers in HGSOC patients would improve the sensitivity and specificity of the preoperative marker prediction of malignancy in patients with ovarian masses. We tested a panel of 29 soluble immune factors by multiplex bead immunoassay and 16 phenotypic T cell markers by flow cytometry in pre-treatment blood samples from 66 patients undergoing surgery for suspected ovarian cancer or ovarian cancer risk reduction. The potential diagnostic utility of all parameters was explored using Volcano plots, principal component analysis (PCA) and receiver operator characteristic (ROC) analysis. We also assessed the effect of culturing PBMCs from 20 healthy donors in the presence of malignant ascites fluid. The combination of TNFR2+ Tregs and IL-6 in the pre-treatment blood of patients with advanced HGSOC effectively discriminated patients with benign or malignant ovarian masses. In vitro culturing of the PBMCs of healthy donors in malignant ascites promoted an increase in TNFR2-expressing Tregs, which were decreased following blockade with IL-6 or STAT3 activity. Pre-treatment serum IL-6 and peripheral blood TNFR2+ Tregs may be potential clinical biomarkers that can discriminate patients with malignant compared to benign ovarian cancer masses, and the relationship between IL-6 and TNFR2+ Treg is likely to be mediated via the STAT3 signalling pathway. [ABSTRACT FROM AUTHOR]

Pre-operative discrimination of malignant masses is crucial for accurate diagnosis and prompt referral to a gynae oncology centre for optimal surgical intervention. HGSOC progression is correlated with local and systemic inflammation. We hypothesised that inclusion of inflammatory biomarkers in sera may improve diagnostic tests. In the training cohort, we tested four existing clinical tests (RMI score and ROMA, CA125 and HE4) and a panel of 28 immune soluble biomarkers in sera from 66 patients undergoing surgery for suspected ovarian cancer. Six promising immune biomarkers alone, or in combination with conventional tests, were subsequently analysed in an independent validation cohort (n = 69). IL-6 was identified as the main driver of variability followed closely by conventional diagnostic tests. Median sera IL-6 was higher in HGSOC patients compared to those with a benign mass or controls with normal ovaries (28.3 vs 7.3 vs 1.2 pg/ml, p < 0.0001). The combination of IL-6 further improved the overall predictive probability of the conventional tests. Modelling a two-step triage of women with a suspicious ovarian mass, with IL-6 > 3.75 pg/ml as primary triage followed by conventional tests (CA125 or RMI score) identified ovarian cancer in patients with a misclassification rate of 4.54–3.03%, superior to the use of CA125 or RMI alone (9.09 to 10.60). The validation cohort demonstrated a similar improvement in the diagnostic sensitivity following addition of IL-6. IL-6 in combination with conventional tests may be a useful clinical biomarker for triage of patients with a suspected malignant ovarian mass. [ABSTRACT FROM AUTHOR]

The article presents a study on the survival patterns of Australian women with epithelial ovarian cancer, by clinical and sociodemographic factors. Topics discussed include 1,192 women with invasive epithelial ovarian cancer diagnosed in 2005 and were identified through state-based cancer registries, survival differences by histological subtype, presence of ascites and comorbidities, and the ongoing poor long-term prognosis for women with ovarian cancer.

Over 80% of women diagnosed with advanced-stage ovarian cancer die as a result of disease recurrence due to failure of chemotherapy treatment. In this study, using two distinct ovarian cancer cell lines (epithelial OVCA 433 and mesenchymal HEY) we demonstrate enrichment in a population of cells with high expression of CSC markers at the protein and mRNA levels in response to cisplatin, paclitaxel and the combination of both. We also demonstrate a significant enhancement in the sphere forming abilities of ovarian cancer cells in response to chemotherapy drugs. The results of these in vitro findings are supported by in vivo mouse xenograft models in which intraperitoneal transplantation of cisplatin or paclitaxel-treated residual HEY cells generated significantly higher tumor burden compared to control untreated cells. Both the treated and untreated cells infiltrated the organs of the abdominal cavity. In addition, immunohistochemical studies on mouse tumors injected with cisplatin or paclitaxel treated residual cells displayed higher staining for the proliferative antigen Ki67, oncogeneic CA125, epithelial E-cadherin as well as cancer stem cell markers such as Oct4 and CD117, compared to mice injected with control untreated cells. These results suggest that a short-term single treatment of chemotherapy leaves residual cells that are enriched in CSC-like traits, resulting in an increased metastatic potential. The novel findings in this study are important in understanding the early molecular mechanisms by which chemoresistance and subsequent relapse may be triggered after the first line of chemotherapy treatment. [ABSTRACT FROM AUTHOR]

Objectives: In view of the recent association of Brn-3 transcription factors with neuroblastomas, cervical, breast, and prostate cancers we examined the expression of Brn-3a(l) in normal ovaries and in different histological grades of ovarian tumors. The expression of Brn-3a(l) was also evaluated in normal ovarian and cancer cell lines and tumor cells isolated from the ascites of advanced-stage ovarian cancer patients. Methods: Normal ovaries, benign, borderline, grades 1, 2 and 3 ovarian tumors were analyzed by immunohistochemistry for Brn-3a(l) expression. A total of 46 ovarian specimens were included in the study. Immunofluorescence was used to investigate the expression of Brn-3a in normal ovarian and cancer cell lines. Brn- 3a(l) expression was also evaluated by Western blot in tumor cells isolated from ascites of advanced-stage ovarian cancer patients and also in ovarian cancer cell lines. Results: Nearly 12% of normal and benign ovarian tissues and 57% of borderline ovarian tumors were positive for epithelial Brn-3a(l) expression. Stromal staining was higher and it constituted 40% of normal non-cancerous ovaries compared to 50 and 86% in benign and borderline tumors. On the other hand, 85-100% of grades 1, 2 & 3 ovarian tumors demonstrated nuclear and cytoplasmic Brn-3a(l) staining in the epithelium. Stromal staining in grades1, 2 and 3 tumors constituted 71-88% of total staining. Overall, immunoreactive Brn-3a was present in all grades of ovarian tumors. The extent of epithelial and stromal Brn-3a staining was significantly different between the normal and histological grades of tumors (epithelial-χ² = 41.01, df = 20, P = 0.004, stromal-χ² = 24.66. df = 15, P = 0.05). The extent of epithelial staining was significantly higher in grades 1 and 2 ovarian tumors compared to normal ovaries and benign ovarian tumors (p < 0.05). In parallel, stromal staining was significantly higher in grade 3 tumors compared to normal ovaries (p < 0.05). In addition, cytoplasmic and nuclear Brn-3a expression was evident in ovarian cancer cell lines while no such expression was observed in SV40 antigen immortalized normal ovarian cell lines. Conclusion: These data suggest that like other cancers, Brn-3a(l) expression is enhanced in ovarian tumors and its expression is consistent with its known role in inhibiting apoptosis and enhancing tumorigenesis. Specific targeting of Brn-3a may provide a useful strategy for regulating multiple tumor related genes involved with ovarian carcinomas. [ABSTRACT FROM AUTHOR]

: Persistent infection of cervical epithelium with “high risk” human papillomavirus (HPV) results in cervical intraepithelial neoplasia (CIN) from which squamous cancer of the cervix can arise. A study was undertaken to evaluate the safety and immunogenicity of an HPV16 immunotherapeutic consisting of a mixture of HPV16 E6E7 fusion protein and ISCOMATRIX™ adjuvant (HPV16 Immunotherapeutic) for patients with CIN.: Patients with CIN (n = 31) were recruited to a randomised blinded placebo controlled dose ranging study of immunotherapy.: Immunotherapy was well tolerated. Immunised subjects developed HPV16 E6E7 specific immunity. Antibody, delayed type hypersensitivity, in vitro cytokine release, and CD8 T cell responses to E6 and E7 proteins were each significantly greater in the immunised subjects than in placebo recipients. Loss of HPV16 DNA from the cervix was observed in some vaccine and placebo recipients.: The HPV16 Immunotherapeutic comprising HPV16E6E7 fusion protein and ISCOMATRIX™ adjuvant is safe and induces vaccine antigen specific cell mediated immunity. [Copyright &y& Elsevier]

This qualitative study investigated women's participation in decisions regarding treatment of gynaecological cancer. Thirty women, receiving health care in two tertiary hospitals in Australia, were interviewed face-to-face. For women with gynaecological cancer, the most influential factors in treatment decisions are still the surgeon's recommendation and fear of dying from cancer. [ABSTRACT FROM AUTHOR]

Abstract: Objectives.: To evaluate the impact of PET/CT on the restaging and management of recurrent ovarian cancer. Methods. : From January 2002 to July 2003, all women undergoing either surveillance or investigation of possible recurrent ovarian cancer at the Centre for Molecular Imaging, The Peter MacCallum Cancer Centre, were invited to take part in a prospective evaluation of the clinical impact of PET/CT. Results.: Fifty-six women having 66 scans were available for analysis. All patients had at least 12months follow-up after the PET/CT unless they died before that time. Apart from one equivocal scan, all scans performed in women with a CA125 higher than 35IU/ml had a positive PET/CT. PET/CT altered the known disease distribution in 40 scans (64%). Overall, PET/CT showed less disease in six scans (9%) and more disease in 34 scans (52%). Regardless of the value of CA125, PET/CT identified a sub group of women with apparently localized disease or no definite evidence of disease. This group showed improved survival compared with women shown to have systemic disease. PET/CT resulted in a major change of management plan in 34 patients (58%). Conclusion. : PET/CT modifies the assessment of the distribution of recurrent ovarian cancer and alters patient management in a substantial proportion of patients. PET/CT appears to offer prognostic information. [Copyright &y& Elsevier]

Women in low- and middle-income countries (LMICs) are significantly more likely to develop and die from invasive cervical cancer, while rates of other gynecologic malignancies are comparable to those faced by women in high-income countries. Despite this increased need, there are few specialist physicians in LMICs available to treat women with gynecologic cancers. Training specialists in low-resource settings faces multiple challenges, including ensuring protected time from other clinical demands, access to best practice guidelines, training that is tailored to the specific challenges faced in the trainee's environment, and isolation from other fully trained professionals and securing support services. In addition, training specialists from LMICs in high-resource settings is costly and return of trainees to their own country is not guaranteed. Here we describe two approaches to gynecologic oncology training in LMICs. The International Gynecologic Cancer Society (IGCS) developed the Global Curriculum Mentorship and Training Program (Global Curriculum) to support gynecologic oncology fellowships in regions of the world that do not currently have formal training in gynecologic oncology. In India, on the other hand, leaders in world-class gynecologic oncology centers must find a way to meet the training needs of a vast and disparate country. [ABSTRACT FROM AUTHOR]

Abstract: Objective : To investigate the efficacy of different treatment modalities used in microinvasive adenocarcinoma (AC) of the uterine cervix (FIGO stage IA1 and IA2), and review the literature. Methods : Medical and histopathological records of 38 patients treated for microinvasive AC of the cervix were studied retrospectively, and compared with the literature. Results : Twenty-nine patients had stage IA1 and nine stage IA2 cancers. Treatment modalities ranged from radical hysterectomy with pelvic lymph node dissection (PLND) to conization only. Eighteen patients underwent a conization, including two patients with stage IA2 disease, of whom 11 had 18 pregnancies in total, resulting in 13 live births, two terminations and three spontaneous abortions. In two patients a hysterectomy was performed after pregnancy. No recurrences were noted during an average follow-up of 72 months. In the literature 1565 patients were reported. Of the 814 patients undergoing PLND, 12 had positive nodes. Lymphvascular space invasion (LVSI) was present in 25 patients, all without node involvement. None of the 356 described parametria were involved. Twenty-nine recurrences occurred. In total, 21 pregnancies with 16 live births occurred in those patients treated to preserve fertility. Conclusions : There is no uniformity in the treatment of microinvasive AC of the uterine cervix. For stage IA1 disease, conization seems to be safe and PLND is only recommended where LVSI is present. Although the number of reported cases is small, for stage IA2 disease, conization with PLND in case of LVSI seems advisable. More studies are desirable to define the optimal treatment for patients with microinvasive AC of the cervix, especially with regard to those patients with stage IA2 disease. [Copyright &y& Elsevier]

Abstract: Background. : No consensus exists which patients with surgical stage 1 epithelial ovarian should receive postoperative chemotherapy. The purpose of this study was to evaluate the prognostic impact of preoperative CA-125 and to establish a prognostic index to identify patients in different risk categories. Methods. : Data of 600 surgically staged patients with FIGO stage 1 EOC treated in eleven gynecological cancer centers in Australia, the USA and Europe were analyzed. Eligible patients include those with invasive EOC where a preoperative CA-125 was obtained and standard surgical staging performed. Overall survival (OS) was chosen as study endpoint. Preoperative CA-125 values were compared with other prognostic factors, and univariate and multivariate Cox models were calculated. Results. : Two hundred and one patients (33.5%) had preoperative CA-125 ≤30 U/ml and CA-125 levels ≤30 U/ml were associated with lower grade, substage 1A and mucinous histologic cell type. Patients with elevated CA-125 levels were more likely to receive chemotherapy. OS probability was 95% and 85% for patients with pretreatment CA-125 ≤30 U/ml and >30 U/ml, respectively (p 0.003). Multivariate analysis confirmed preoperative serum CA-125 >30 U/ml (OR 2.7) and age at diagnosis >70 years (OR 2.6) as the only independent predictors for overall survival. Conclusion. : Pretreatment of CA-125 ≤30 U/ml dominates over histologic cell type, substage and grade to identify a subgroup of FIGO stage 1 patients with a genuinely good prognosis with extremely good survival and who could possibly be spared with adjuvant chemotherapy. [Copyright &y& Elsevier]