Natural history of pelvic floor disorders before and after hysterectomy for gynaecological cancer.

OBJECTIVE: To investigate the prevalence and severity of pelvic floor disorders (PFD), and the associations between treatment type and PFD, and cancer stage and PFD in patients before and after hysterectomy for gynaecological cancer; and the changes in outcomes over time. DESIGN: Longitudinal cohort study. SETTING: Gynaecological oncology outpatient clinics. POPULATION: Patients undergoing hysterectomy for endometrial, uterine, ovarian or cervical cancer. METHODS: Participants were assessed before, and 6 weeks and 3 months after hysterectomy. Changes over time were analysed using generalised estimating equations or linear mixed models. Associations were analysed using logistic regression models and analyses of variance. MAIN OUTCOME MEASURES: Incontinence Severity Index, Pelvic Floor Distress Inventory-short form (PFDI-20), Female Sexual Function Index. RESULTS: Of 277 eligible patients, 126 participated. Prevalence rates of PFD were high before (urinary incontinence [UI] 66%, faecal incontinence [FI] 12%, sexual inactivity 73%) and after (UI 59%, FI 14%, sexual inactivity 58%) hysterectomy. Receiving adjuvant therapy led to moderate-to-very severe UI 3 months after surgery compared with surgery only (odds ratio 4.98, 95% CI 1.63-15.18). There was no association between treatment type and other PFD, or cancer stage and any PFD. CONCLUSION: Prevalence of PFD was high before and after hysterectomy for gynaecological cancer. Moderate-to-very-severe UI was associated with adjuvant therapy.

Pelvic floor muscle training delivered via telehealth to treat urinary and/or faecal incontinence after gynaecological cancer surgery: a single cohort feasibility study.

PURPOSE: To assess the feasibility and clinical outcomes of telehealth-delivered pelvic floor muscle training (PFMT) for urinary incontinence (UI) and/or faecal incontinence (FI) after gynaecological cancer surgery. METHODS: In this pre-post cohort clinical trial, patients with incontinence after gynaecological cancer surgery underwent a 12-week physiotherapist-supervised telehealth-delivered PFMT program. The intervention involved seven videoconference sessions with real-time feedback from an intra-vaginal biofeedback device and a daily home PFMT program. Feasibility outcomes included recruitment, retention, engagement and adherence rates. Clinical outcomes were assessed at baseline, immediately post-intervention and a 3-month post-intervention using International Consultation on Incontinence questionnaires for UI (ICIQ-UI-SF) and Bowel function (ICIQ-B) and the intra-vaginal biofeedback device. Means and 95%CIs for all time points were analysed using bootstrapping methods. RESULTS: Of the 63 eligible patients, 39 (62%) consented to the study. Three participants did not complete baseline assessment and were not enrolled in the trial. Of the 36 participants who were enrolled, 32 (89%) received the intervention. Retention was 89% (n=32/36). The majority of participants (n=30, 94%) demonstrated high engagement, attending at least six videoconference sessions. Adherence to the daily PFMT program was moderate, with 24 participants (75%) completing five-to-seven PFMT sessions per week during the intervention. All clinical outcomes improved immediately post-intervention; however, the magnitude of these improvements was small. CONCLUSION: Telehealth-delivered PFMT may be feasible to treat incontinence after gynaecological cancer surgery. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: ACTRN12621000880842).

ConCerv: a prospective trial of conservative surgery for low-risk early-stage cervical cancer.

OBJECTIVE: The objective of the ConCerv Trial was to prospectively evaluate the feasibility of conservative surgery in women with early-stage, low-risk cervical cancer. METHODS: From April 2010 to March 2019, a prospective, single-arm, multicenter study evaluated conservative surgery in participants from 16 sites in nine countries. Eligibility criteria included: (1) FIGO 2009 stage IA2-IB1 cervical carcinoma; (2) squamous cell (any grade) or adenocarcinoma (grade 1 or 2 only) histology; (3) tumor size <2 cm; (4) no lymphovascular space invasion; (5) depth of invasion <10 mm; (6) negative imaging for metastatic disease; and (7) negative conization margins. Cervical conization was performed to determine eligibility, with one repeat cone permitted. Eligible women desiring fertility preservation underwent a second surgery with pelvic lymph node assessment, consisting of sentinel lymph node biopsy and/or full pelvic lymph node dissection. Those not desiring fertility preservation underwent simple hysterectomy with lymph node assessment. Women who had undergone an 'inadvertent' simple hysterectomy with an unexpected post-operative diagnosis of cancer were also eligible if they met the above inclusion criteria and underwent a second surgery with pelvic lymph node dissection only. RESULTS: 100 evaluable patients were enrolled. Median age at surgery was 38 years (range 23-67). Stage was IA2 (33%) and IB1 (67%). Surgery included conization followed by lymph node assessment in 44 women, conization followed by simple hysterectomy with lymph node assessment in 40 women, and inadvertent simple hysterectomy followed by lymph node dissection in 16 women. Positive lymph nodes were noted in 5 patients (5%). Residual disease in the post-conization hysterectomy specimen was noted in 1/40 patients-that is, an immediate failure rate of 2.5%. Median follow-up was 36.3 months (range 0.0-68.3). Three patients developed recurrent disease within 2 years of surgery-that is, a cumulative incidence of 3.5% (95% CI 0.9% to 9.0%). DISCUSSION: Our prospective data show that select patients with early-stage, low-risk cervical carcinoma may be offered conservative surgery.

Primary HPV cervical screening: Clinical audit of outcomes of women seen at a tertiary referral centre for colposcopy in Australia.

BACKGROUND: Primary human papillomavirus (HPV) screening was introduced in Australia in December 2017. AIMS: Outcomes for women after positive HPV in their cervical screening test (CST). MATERIALS AND METHODS: A retrospective observational study of 4458 women seen at the Royal Women's Hospital Colposcopy Clinic from 1 January 2018 to 31 July 2020. RESULTS: HPV16/18 was positive (considered higher-risk CST) in 42.2% of women in the study, 16.6% with reflex possible with high-grade squamous intraepithelial lesions (pHSIL) or worse and 54.9% with normal cytology. There were 24.8% of women with positive HPV16/18 who had histological confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+), 10.3% CIN2+ (including six cancers) among women with reflex negative cytology and 87.7% CIN2+ among women with reflex HSIL cytology. In women with positive HPV (not 16/18), CIN2+ was found in 60.2% with reflex pHSIL or worse cytology (higher risk) and 10.2% with reflex low-grade SIL (LSIL) or normal cytology (intermediate risk). Median waiting time to colposcopy with the intermediate-risk group went up to 181 days. Our colposcopists were able to achieve a positive predictive value (PPV) for CIN2+ of 69.9%, higher than 57.8% PPV in the National Cervical Screening Program (NCSP) 2020 monitoring report. Women with type 3 transformation zone on colposcopy could be followed up with CST if no HSIL was suspected on screening or at colposcopy as their risk of CIN2+ was only 2.5%. CONCLUSIONS: Our findings support direct referral to colposcopy for women with higher-risk CST, with all cancers confined to this group. The NCSP recommendation to refer for colposcopy only after three intermediate-risk CST will need monitoring with the LSIL triage group.

Therapeutic options for mucinous ovarian carcinoma.

OBJECTIVE: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. METHODS: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). RESULTS: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). CONCLUSIONS: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition.

Paragon (ANZGOG-0903): Phase 2 Study of Anastrozole in Women With Estrogen or Progesterone Receptor-Positive Platinum-Resistant or -Refractory Recurrent Ovarian Cancer.

BACKGROUND: There is some evidence that a subset of patients with recurrent ovarian cancer may benefit from antiestrogen therapy. The Paragon study is a basket protocol that includes a series of phase 2 trials investigating the activity of anastrozole in patients with estrogen or progesterone receptor-positive recurrent gynecological cancers. We report the results of treatment in patients with platinum-resistant or -refractory recurrent epithelial ovarian cancer. METHODS: Postmenopausal women who had estrogen and/or progesterone receptor-positive platinum-resistant or platinum-refractory recurrent ovarian cancer and disease measurable by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 or GCIG (Gynecologic Cancer InterGroup) CA-125 criteria were eligible. Patients received anastrozole 1 mg daily until progression or unacceptable toxicity. The study was prospectively registered (ACTRN12610000796088). RESULTS: There were 49 evaluable patients, and clinical benefit was observed in 13 (27%; 95% confidence interval [CI], 16%-40%). There were no complete or partial RECIST version 1.1 responses. Clinical benefit was associated with higher global quality-of-life scores. Median progression-free survival was 2.7 months (95% CI, 2.0-2.8 months). The median duration of clinical benefit was 2.8 months (95% CI, 2.6-5.7 months). Most patients (83%) progressed within 6 months. Seven patients continued on treatment for longer than 6 months. Anastrozole was well tolerated in most patients. Subgroup analysis suggested greater clinical benefit in patients with tumors with estrogen-receptor histoscore of more than 200, but this difference was not statistically significant. CONCLUSIONS: A subset of patients with estrogen- or progesterone-positive platinum-resistant or platinum-refractory recurrent epithelial ovarian cancers derives clinical benefit from anastrozole, with acceptable toxicity. The challenge remains how to identify them.

Identification of patients with persistent trophoblastic disease after complete hydatidiform mole by using a normal 24-hour urine hCG regression curve.

OBJECTIVE: The aim of this study was to establish a reference 24-hour urine human chorionic gonadotropin (hCG) regression curve in patients with complete hydatidiform mole (CHM) as diagnostic tool in the prediction of persistent trophoblastic disease (PTD). METHODS: From 2004 to 2011, 312 cases suitable for this study were registered at the Hydatidiform Mole Registry of the Royal Women's Hospital Melbourne, Australia. hCG levels of 61 patients diagnosed as having PTD according to FIGO 2000 criteria were compared with the 95th-percentile (p95) of the normal regression curve derived from hCG levels of 251 cases of uneventful CHM. RESULTS: In the test group of 61 patients PTD was diagnosed by FIGO 2000 criteria after a mean (±SD, min.-max.) of 7.6 (±3.4, 3.0-16.7) weeks after evacuation of the mole while in the same group hCG values for the first time exceeded the upper limit of the 95th percentile significantly earlier after 4.5 (±1.9, 2.0-9.9) weeks (P<0.001). However, hCG levels of 14% of the cases of uneventful CHM at least once exceeded the upper limit of p95, showing that one single value above p95 is not accurate enough for the diagnosis of PTD. CONCLUSIONS: The normal 24-hour urine hCG regression curve may be used as a tool in the follow-up of an individual case of CHM after evacuation. At least one hCG level exceeding the upper limit of p95 within 11weeks after evacuation could be added to the current FIGO criteria, in order to diagnose PTD early, but the lack of it may also prevent unnecessary treatment.

Combining TNFR2-Expressing Tregs and IL-6 as Superior Diagnostic Biomarkers for High-Grade Serous Ovarian Cancer Masses.

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.

Routine hysterectomy in the surgical management of ovarian cancer: a retrospective case series, physician opinion survey, and review of the literature.

Current international guidelines recommend routine hysterectomy in the initial surgical management of epithelial ovarian cancer. However, there seems to be limited evidence to support these recommendations. We examined the data for a series of women undergoing hysterectomy as part of surgical management of ovarian cancer. Most of the women who underwent hysterectomy had no macroscopic uterine involvement in the ovarian cancer. However, almost half of them had macroscopic residual disease at completion of cytoreductive surgery. The incidence of synchronous primary endometrial cancers was 5%, and preoperative ultrasound had a sensitivity of 82% for predicting endometrial pathology. We also surveyed the members of the Australian Society of Gynaecological Oncologists (ASGO) regarding the role of hysterectomy in the management of ovarian cancer. Most of the respondents indicated that they believe hysterectomy should be routinely performed in the management of ovarian cancer but acknowledge that there is a lack of evidence to support the practice.

Long-term psychological morbidity, sexual functioning, and relationship outcomes in women with gestational trophoblastic disease.

OBJECTIVE: Clinical observation suggests a protracted psychosocial recovery after gestational trophoblastic disease (GTD), although this has not been well studied. We describe long-term psychological morbidity, sexual functioning, and relationship outcomes after GTD. MATERIALS AND METHODS: Cross-sectional analysis was made of 176 Australian women previously diagnosed with GTD recruited from a statewide registry. Participants comprised 149 women (85%) who did not require chemotherapy and 27 women (15%) who required chemotherapy for malignant or persistent GTD/molar disease (gestational trophoblastic tumor [GTT]). Data were collected from medical records and via validated self-report questionnaires. RESULTS: The participants were 94 women (53%) with partial mole, 75 women (43%) with complete mole, 4 women (2%) with choriocarcinoma, and 3 women (2%) with hydatidiform mole not otherwise specified. The mean (SD) age at diagnosis and time since diagnosis were 32.1 (6.3) and 4.7 (3.3) years, respectively. Elevated levels of depression and anxiety were reported by 22% and 26% of the women, respectively. One fifth to half of the women experienced some GTD-related avoidant and intrusive phenomena, the latter being more prominent among women who had not had chemotherapy. Sexual dysfunction was reported by 52% of the women. Most women (81%) felt well supported by their partners during the illness, 19% thought the relationship had changed, and 26% perceived that GTD had negatively affected sex life. This perception was stronger in those who received chemotherapy, although objective measures of sexual morbidity showed no group differences. Socially disadvantaged women and those who did not conceive subsequent to the diagnosis had poorer psychosocial outcomes. CONCLUSIONS: Notwithstanding limitations, this study is the largest of its type to date. Psychological morbidity rates exceeded community norms, but sexual dysfunction rates, although high, are likely consistent with local norms. These findings highlight the long-term burden of GTD and the importance of a supportive care component in management, even among those who do not require chemotherapy. Socially disadvantaged women and those who do not conceive subsequent to GTD diagnosis require greater psychosocial support.

Mapping Epitopes Recognised by Autoantibodies Shows Potential for the Diagnosis of High-Grade Serous Ovarian Cancer and Monitoring Response to Therapy for This Malignancy.

Autoantibodies recognising phosphorylated heat shock factor 1 (HSF1-PO4) protein are suggested as potential new diagnostic biomarkers for early-stage high-grade serous ovarian cancer (HGSOC). We predicted in silico B-cell epitopes in human and murine HSF1. Three epitope regions were synthesised as peptides. Circulating immunoglobulin A (cIgA) against the predicted peptide epitopes or HSF1-PO4 was measured using ELISA, across two small human clinical trials of HGSOC patients at diagnosis. To determine whether chemotherapy would promote changes in reactivity to either HSF1-PO4 or the HSF-1 peptide epitopes, IgA responses were further assessed in a sample of patients after a full cycle of chemotherapy. Anti-HSF1-PO4 responses correlated with antibody responses to the three selected epitope regions, regardless of phosphorylation, with substantial cross-recognition of the corresponding human and murine peptide epitope variants. Assessing reactivity to individual peptide epitopes, compared to HSF1-PO4, improved assay sensitivity. IgA responses to HSF1-PO4 further increased significantly post treatment, indicating that HSF1-PO4 is a target for immunity in response to chemotherapy. Although performed in a small cohort, these results offer potential insights into the interplay between autoimmunity and ovarian cancer and offer new peptide biomarkers for early-stage HGSOC diagnosis, to monitor responses to chemotherapy, and widely for pre-clinical HGSOC research.

Predictive value of magnetic resonance imaging in assessing myometrial invasion in endometrial cancer: is radiological staging sufficient for planning conservative treatment?

OBJECTIVES: There has been an increasing interest in accurately assessing tumors preoperatively to plan appropriate surgery or, in some low-risk patients, conservative treatment. We wish to determine the accuracy of magnetic resonance imaging (MRI) in predicting myometrial invasion in endometrial cancer and whether it is a safe and suitable tool for planning conservative treatment. MATERIALS AND METHODS: We compared MRI scans and final histopathologic diagnoses of 111 patients with endometrioid adenocarcinoma over a 6-year period at a major tertiary centre. Data were analyzed collectively and according to histological differentiation and types of MRI scans (1.5 vs 3 T). Outcomes were presence versus absence of myometrial invasion and recently revised International Federation of Gynecology and Obstetrics stage IA (up to 50% myometrial invasion) versus deep invasion. RESULTS: Magnetic resonance imaging had a high negative predictive value for the presence of deep invasion (87% overall and 95% for grade 1 disease). However, although the positive predictive value for the presence of any myometrial invasion was high, negative predictive values were poor (35% for all grades and 46% for grade 1). There was no difference between 1.5- and 3-T scanning. CONCLUSIONS: Magnetic resonance imaging is a suitable screening tool for the presence of stage IA disease under the newly revised International Federation of Gynecology and Obstetrics staging system. The significance of this finding will depend on whether clinicians are willing to treat all grade 1 stage IA disease (under the revised system) as low risk and to deem selected patients in this group suitable for more conservative treatment.

Pre-operative sera interleukin-6 in the diagnosis of high-grade serous ovarian cancer.

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.

The molecular origin and taxonomy of mucinous ovarian carcinoma.

Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. In addition, the molecular drivers of invasive progression, high-grade and metastatic disease are poorly defined. We perform genetic analysis of MOC across all histological grades, including benign and borderline mucinous ovarian tumors, and compare these to tumors from other potential extra-ovarian sites of origin. Here we show that MOC is distinct from tumors from other sites and supports a progressive model of evolution from borderline precursors to high-grade invasive MOC. Key drivers of progression identified are TP53 mutation and copy number aberrations, including a notable amplicon on 9p13. High copy number aberration burden is associated with worse prognosis in MOC. Our data conclusively demonstrate that MOC arise from benign and borderline precursors at the ovary and are not extra-ovarian metastases.

Immunotherapeutic Interleukin-6 or Interleukin-6 Receptor Blockade in Cancer: Challenges and Opportunities.

Interleukin 6 (IL-6), a well-known pro-inflammatory cytokine with pleiotropic activity is a central player in chronic inflammatory diseases including cancers. Therefore, blockade of the IL-6 signalling pathway has become a target for the therapy of diverse cancers such as multicentric Castleman's disease (CD), multiple myeloma and solid tumours including renal, prostate, lung, colorectal and ovarian cancers. Monoclonal antibodies against IL-6 (Siltuximab) and the IL-6 receptor (IL-6R) (Tocilizumab) have emerged as potential immunotherapies, alone or in combination with conventional chemotherapy. Human trials have demonstrated the ability to block IL-6 activity and in multicentric CD lead to durable clinical response and longer disease stabilisation. However, the efficacy of these treatments is still debatable for other cancers. New generation therapeutics in development such as Clazakizumab, Sarilumab, and soluble gp130-Fc have the additional features of improved binding affinity, better specificity with reduced adverse effects. A deeper understanding of the immunological basis of these agents, as well as of the challenges that are faced by immunotherapy-based products in clinical trials, will help select the most promising anti-IL-6/IL-6R therapies for large scale use. Concurrently, current research efforts to personalize treatments may help in the treatment of patients that would greatly benefit from IL-6 blocking therapies.

Interleukin 6 Present in Inflammatory Ascites from Advanced Epithelial Ovarian Cancer Patients Promotes Tumor Necrosis Factor Receptor 2-Expressing Regulatory T Cells.

BACKGROUND: Epithelial ovarian cancer (EOC) remains a highly lethal gynecological malignancy. Ascites, an accumulation of peritoneal fluid present in one-third of patients at presentation, is linked to poor prognosis. High levels of regulatory T cells (Tregs) in ascites are correlated with tumor progression and reduced survival. Malignant ascites harbors high levels of Tregs expressing the tumor necrosis factor receptor 2 (TNFR2), as well as pro-inflammatory factors such as interleukin 6 (IL-6) and tumor necrosis factor (TNF). IL-6 is also associated with poor prognosis. Herein, we study the effect of IL-6 and TNF present in ascites on the modulation of TNFR2 expression on T cells, and specifically Tregs. METHODS: Ascites and respective peripheral blood sera were collected from 18 patients with advanced EOC and soluble biomarkers, including IL-6, sTNFR2, IL-10, TGF-ß, and TNF, were quantified using multiplexed bead-based immunoassay. Peripheral blood mononuclear cells (PBMC) from healthy donors were incubated with cell-free ascites for 48 h (or media as a negative control). In some experiments, IL-6 or TNF within the ascites were neutralized by using monoclonal antibodies. The phenotype of TNFR2+ Tregs and TNFR2- Tregs were characterized post incubation in ascites. In some experiments, cell sorted Tregs were utilized instead of PBMC. RESULTS: High levels of immunosuppressive (sTNFR2, IL-10, and TGF-ß) and pro-inflammatory cytokines (IL-6 and TNF) were present in malignant ascites. TNFR2 expression on all T cell subsets was higher in post culture in ascites and highest on CD4+CD25hiFoxP3+ Tregs, resulting in an increased TNFR2+ Treg/effector T cell ratio. Furthermore, TNFR2+ Tregs conditioned in ascites expressed higher levels of the functional immunosuppressive molecules programmed cell death ligand-1, CTLA-4, and GARP. Functionally, TNFR2+ Treg frequency was inversely correlated with interferon-gamma (IFN-γ) production by effector T cells, and was uniquely able to suppress TNFR2+ T effectors. Blockade of IL-6, but not TNF, within ascites decreased TNFR2+ Treg frequency. Results indicating malignant ascites promotes TNFR2 expression, and increased suppressive Treg activity using PBMC were confirmed using purified Treg subsets. CONCLUSION: IL-6 present in malignant ovarian cancer ascites promotes increased TNFR2 expression and frequency of highly suppressive Tregs.

Paclitaxel and Its Evolving Role in the Management of Ovarian Cancer.

Paclitaxel, a class of taxane with microtubule stabilising ability, has remained with platinum based therapy, the standard care for primary ovarian cancer management. A deeper understanding of the immunological basis and other potential mechanisms of action together with new dosing schedules and/or routes of administration may potentiate its clinical benefit. Newer forms of taxanes, with better safety profiles and higher intratumoural cytotoxicity, have yet to demonstrate clinical superiority over the parent compound.

Intravenous leiomyomatosis with intracardiac extension - a review of diagnosis and management with an illustrative case.

Intravenous leiomyomatosis with intracardiac extension is an uncommon pathologic progression of uterine leiomyomata. It is a histologically benign condition, however due to interfence with right sided cardiac function patients may present with marked cardiovascular compromise and present a diagnostic dilemma to clinicians who are unfamiliar with this condition. Given the rarity of this condition, experience in individual institutions is usually limited to a few cases. We present an illustrative case and provide a review of the clinical presentation, preoperative assessment, operative approach, pathology and postoperative issues. The importance of a multidisciplinary approach to diagnosis and management is highlighted. Operative management aims to completely resect all tumour in the safest manner for the patient, most commonly via single or two stage operation. Where complete resection is achieved, recurrence appears to be a rare event.