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PurposeThe Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V)-II investigated whether inguinofemoral radiotherapy is a safe alternative to inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN).MethodsGROINSS-V-II was a prospective multicenter phase-II single-arm treatment trial, including patients with early-stage vulvar cancer (diameter < 4 cm) without signs of lymph node involvement at imaging, who had primary surgical treatment (local excision with SN biopsy). Where the SN was involved (metastasis of any size), inguinofemoral radiotherapy was given (50 Gy). The primary end point was isolated groin recurrence rate at 24 months. Stopping rules were defined for the occurrence of groin recurrences.ResultsFrom December 2005 until October 2016, 1,535 eligible patients were registered. The SN showed metastasis in 322 (21.0%) patients. In June 2010, with 91 SN-positive patients included, the stopping rule was activated because the isolated groin recurrence rate in this group went above our predefined threshold. Among 10 patients with an isolated groin recurrence, nine had SN metastases > 2 mm and/or extracapsular spread. The protocol was amended so that those with SN macrometastases (> 2 mm) underwent standard of care (IFL), whereas patients with SN micrometastases (≤ 2 mm) continued to receive inguinofemoral radiotherapy. Among 160 patients with SN micrometastases, 126 received inguinofemoral radiotherapy, with an ipsilateral isolated groin recurrence rate at 2 years of 1.6%. Among 162 patients with SN macrometastases, the isolated groin recurrence rate at 2 years was 22% in those who underwent radiotherapy, and 6.9% in those who underwent IFL (P = .011). Treatment-related morbidity after radiotherapy was less frequent compared with IFL.ConclusionInguinofemoral radiotherapy is a safe alternative for IFL in patients with SN micrometastases, with minimal morbidity. For patients with SN macrometastasis, radiotherapy with a total dose of 50 Gy resulted in more isolated groin recurrences compared with IFL.

Objective: Patients with advanced ovarian cancer face a range of treatment options, and there is unwarranted variation in treatment decision-making between UK providers. Decision support tools that produce data on treatment outcomes as a function of individual patient characteristics, would help both patients and clinicians to make informed, preference- and values-based choices. However, data on treatment outcomes to include in such tools are lacking. Methods: Following a literature review, a questionnaire was designed for use in a Delphi process to establish which treatment outcomes are important to both patients and clinicians in decision-making for treatment for advanced ovarian cancer. Patient and clinician panels were established. Results: Following 2 Delphi rounds, consensus was achieved for 7/11 items in the patient panel and 8/11 items in the clinician panel. Consensus across both panels was achieved for inclusion of both overall survival and progression free survival as important items in the decision-making process, although there remained differences of opinion as to whether these should be presented as relative or absolute values. Conclusion: Information needs for treatment decision-making in ovarian cancer differ between and within patient and clinician groups. Whilst overall survival and progression free survival are universally accepted as important data items, decision support tools will need to be nuanced to allow presentation of a range of outcomes and associated probabilities, and in a range of formats, that can be tailored to the preferences of clinician and patients. [ABSTRACT FROM AUTHOR]

Background Women testing positive for BRCA1/2 pathogenic variants have high lifetime risks of breast cancer (BC) and ovarian cancer. The effectiveness of risk reducing surgery (RRS) has been demonstrated in numerous previous studies. We evaluated long-term uptake, timing and effectiveness of risk reducing mastectomy (RRM) and bilateral salpingo-oophorectomy (RRSO) in healthy BRCA1/2 carriers. Methods Women were prospectively followed up from positive genetic test (GT) result to censor date. 1² testing compared categorical variables; Cox regression model estimated HRs and 95% CI for BC/ovarian cancer cases associated with RRS, and impact on all-cause mortality; Kaplan-Meier curves estimated cumulative RRS uptake. The annual cancer incidence was estimated by women-years at risk. Results In total, 887 women were included in this analysis. Mean follow-up was 6.26 years (range=0.01-24.3; total=4685.4 women-years). RRS was performed in 512 women, 73 before GT. Overall RRM uptake was 57.9% and RRSO uptake was 78.6%. The median time from GT to RRM was 18.4 months, and from GT to RRSO-10.0 months. Annual BC incidence in the study population was 1.28%. Relative BC risk reduction (RRM versus non-RRM) was 94%. Risk reduction of ovarian cancer (RRSO versus non-RRSO) was 100%. Conclusion Over a 24-year period, we observed an increasing number of women opting for RRS. We showed that the timing of RRS remains suboptimal, especially in women undergoing RRSO. Both RRM and RRSO showed a significant effect on relevant cancer risk reduction. However, there was no statistically significant RRSO protective effect on BC. [ABSTRACT FROM AUTHOR]

Abstract Fenofibrate, an agonist of PPAR-alpha, in doses above 25 μM, inhibits proliferation and induces apoptosis in Ishikawa endometrial cancer cells. We show that these effects are potentiated by retinoic acid, an agonist of the retinoid-X-receptor. DNA content analysis shows that G1/S phase progression through the cell cycle is inhibited. Independent Component Analysis of gene microarray experiments demonstrated downregulation of Cyclin D1 (CCND1) and associated changes in cell cycle gene expression. Expression of PPAR-alpha mRNA was reduced by >75% using RNA-interference but this resulted in only minor changes in biological effects. A nude mouse model of endometrial carcinoma was used to investigate the effect of fenofibrate in vivo but failed to show consistent inhibition of tumour growth. Conclusion The combination of fenofibrate and retinoic acid is a potent inhibitor of Ishikawa endometrial cancer cell growth in vitro.

Risk‐reducing bilateral salpingo‐oophorectomy (RRBSO) is highly effective for the prevention of high‐grade serous ovarian cancer (HGSOC) in BRCA1/2 pathogenic variant carriers (PVCs), but does not completely eliminate future risk of primary peritoneal cancer (PPC). The requirement to completely remove fallopian tubes at RRBSO and carefully exclude occult cancer/serous tubal intraepithelial carcinoma (STIC) lesions may not have been appreciated historically. We calculated rates of HGSOC and PPC in confirmed BRCA1/2 PVCs registered on the regional database in those who did (cases) and did not (controls) undergo RRBSO after genetic testing. Expected annual rates of ovarian/peritoneal cancer were 1% for BRCA1 ≥ 35 years and 0.5% for BRCA2 ≥ 45 years. Follow‐up before 35/45 years was "risk free" and lead time excluded RRBSO <35 years and <45 years for BRCA1 and BRCA2, respectively. Women were followed from personal mutation report (controls) or RRBSO (cases) to death, ovarian/peritoneal cancer or last follow‐up, whichever was sooner. In total, 891 cases (BRCA1 = 468, BRCA2 = 423) and 1302 controls had follow‐up ≥35 years (BRCA1 = 736) and ≥45 years (BRCA2 = 566), respectively, over a total of 7261.1 risk eligible years (mean = 8.15 years). Twenty‐one occult ovarian cancers were found at RRBSO (2.4%), 16 at stage 1. Post RRBSO, 56.97 ovarian/peritoneal cancers were expected but only 3 were observed (HR = 0.053; 95% CI = 0.013‐0.14), with combined Kaplan‐Meier analysis HR = 0.029 (95% CI = 0.009‐0.100, P <.001). Risk reduction was greater in specialist (HR = 0.03; 95% CI = 0.001‐0.13) compared to non‐specialist centres (HR = 0.11; 95% CI = 0.02‐0.37) (P =.07). In controls, 23.35 ovarian/peritoneal cancers were expected with 32 observed (HR = 1.37; 95% CI = 0.95‐1.91). RRBSO <35/<45 years reduces the risk of ovarian/peritoneal cancer by 95% in BRCA1/2 PVCs and may be greater in specialist centres. What's new? Women who carry genetic variants in BRCA1/2 that are linked to high‐grade serous ovarian cancer are advised to undergo risk‐reducing prophylactic bilateral salpingo‐oophorectomy (RRBSO). RRBSO, however, is associated with a significant residual risk of primary peritoneal cancer (PPC). Here, the rate of PPC following prophylactic surgery for high‐grade serous ovarian cancer was investigated among 2,193 BRCA1/2 mutation carriers who had undergone RRBSO. Estimates indicate that prophylactic surgery reduced the overall risk of PPC by 95 percent, a far greater reduction than previously described. Residual risk was lowest when RRBSO was carried out at specialist centers compared to non‐specialist centers. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Treg) are a sub-population of T cells that suppress self-reactivity and are implicated in immune tolerance towards malignant cells. Circulating Treg cells are increased in several cancers. In endometrial cancer Treg cells have been investigated only in tumour tissues and, in contrast to some other tumours, fewer Treg cells were reported in endometrial cancer compared with benign controls. Flow cytometry was used to determine the frequency of circulating Treg cells in women undergoing hysterectomy for either endometrial cancer (n = 24) or non- cancer-related conditions (n = 21). Circulating Treg cells were more abundant in women with cancer compared to those without (4.68% vs. 3.66%, p = 0.05, Mann-Whitney test). This relationship disappeared, however, when only data from post-menopausal women were included in the analysis. Mean Treg cell frequency was 4.65% in postmenopausal women with cancer (n = 23) and 4.73% in postmenopausal controls (n = 5) ( p = 0.9). In women without cancer we found that mean Treg cell frequency was higher in postmenopausal women (4.73%, n = 5) in comparison to premenopausal controls (3.33%, n = 16) ( p = 0.02). These results suggest that the increased proportion of Treg cells seen in endometrial cancer patients might be, at least in part, attributed to their postmenopausal status or age. [ABSTRACT FROM AUTHOR]

In this article, the authors describe modern surgical approaches for the treatment of endometrial cancer. It begins with the standard surgical approaches that include abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and para-aortic lymphadenectomy. It then discusses the application of laparoscopic surgery in the management of both benign and malignant gynecological diseases. In addition, the article suggests the use of robotic hysterectomy in the treatment of cancer.

Purpose: To evaluate the prognostic value of vascular endothelial growth factor (VEGF)-D and VEGF receptor (VEGFR)-3 in endometrial carcinoma., Experimental Design: We assessed the levels of immunoreactivity for VEGF-D and VEGFR-3 in 71 endometrial carcinomas, 14 complex atypical endometrial hyperplasias, and 16 normal endometria by immunohistochemistry., Results: VEGF-D was stained in both tumor cells and adjacent stromal cells. VEGFR-3 was stained in both tumor cells and adjacent endothelial cells. Immunoreactivity for VEGF-D in tumor cells and adjacent stromal cells became significantly stronger as lesions progressed from normal endometrium to advanced carcinoma. Similarly, immunoreactivity for VEGFR-3 in tumor cells and adjacent endothelial cells was significantly greater as lesions progressed from normal endometrium to advanced carcinoma. A strong correlation was found between high levels of VEGF-D immunoreactivity in carcinoma cells and VEGFR-3 in both carcinoma cells and adjacent endothelial cells. Similarly, high levels of VEGF-D immunoreactivity in stromal cells were significantly correlated with those of VEGFR-3 in both carcinoma cells and endothelial cells. High levels of VEGF-D in carcinoma cells and stromal cells, as well as those of VEGFR-3 in carcinoma cells and endothelial cells, were significantly related to myometrial invasion and lymph node metastasis. A strong correlation was found between poor survival and high levels of VEGF-D in both carcinoma cells and stromal cells and between poor survival and high levels of VEGFR-3 in carcinoma cells. Moreover, the high levels of VEGF-D in stromal cells and VEGFR-3 in carcinoma cells were independent prognostic factors in endometrial carcinoma., Conclusions: The presence of VEGF-D and VEGFR-3 in endometrial carcinoma may predict myometrial invasion and lymph node metastasis and may prospectively identify patients who are at increased risk for poor outcome. In addition, VEGF-D and VEGFR-3 may be promising targets for new therapeutic strategies in endometrial carcinoma.