Multiplex serum immune profiling reveals circulating LAG-3 is associated with improved patient survival in high grade serous ovarian cancer.

OBJECTIVE: High grade serous ovarian cancer (HGSOC) exhibits low response rates to clinically available immunotherapies. Nevertheless, emerging research has demonstrated that certain immune factors are predictive for HGSOC patient clinical outcomes, with our own groups previous work demonstrating that intratumoral levels of the immune checkpoint receptor LAG-3 is associated with improved patient survival. In this current study we sought to uncover non-invasive circulating immune prognostic and predictive signatures in HGSOC. METHODS: A multiplex approach was employed that examined circulating levels of immune checkpoint receptors LAG-3 and PD-1 along with 48 common cytokine and chemokines in a cohort of 75 HGSOC treatment naïve patient serum samples. RESULTS: Elevated serum LAG-3 was significantly associated with improved progression-free survival (PFS) and overall survival (OS) in HGSOC, while circulating PD-1 levels were largely unrelated with patient clinical outcomes. Cytokine and chemokine analysis revealed lower IL-15 expression correlated with improved PFS and OS, while increased IL-1α, IL-1Ra, IL-6, IL8 and VEGF were significantly associated with preoperative CA-125 levels. ROC analysis demonstrated that serum LAG-3 levels exhibited consistent reasonable predictability as a single agent. CONCLUSIONS: Serum-derived LAG-3 was identified out of a diverse array of chemokine and cytokines as the immune-based factor most significantly associated with improved HGSOC survival. These findings suggest that LAG-3 could be implemented as a non-invasive patient predictive marker for improved HGSOC clinical outcomes.

Adjuvant Therapy in Node-Positive Endometrial Cancer: A Focus on Chemotherapy.

PURPOSE OF REVIEW: In advanced-stage and high-risk endometrial cancer, adjuvant treatment is the standard of care and typically includes chemotherapy with or without radiotherapy. Debate continues over the optimal use of these two treatment modalities together or separately. This review covers the historical literature leading to the current recommendation for adjuvant chemotherapy, in addition to looking forward to the relatively new field of targeted molecular treatment. RECENT FINDINGS: The review covers recent phase III trials comparing chemotherapy to radiotherapy in high-risk endometrial cancer. Additionally, the era of genomic medicine has a new foothold in endometrial cancer, and the review covers new discoveries on molecular classification and prognostic implications. Fortunately, the majority of endometrial cancer has a good prognosis. For advanced-stage and high-risk histologies, the prognosis can be guarded, with adjuvant treatment improving outcomes. Gynecologic oncologists continue to debate the optimal treatment modality/modalities, a debate which will likely become more robust as the field of molecular treatment in endometrial cancer evolves.

Pubic Symphysis Separation and Regression in Vaginal versus Cesarean Delivery.

OBJECTIVE: To quantify the association of pubic symphysis separation with mode of delivery and follow the resolution of this physiologic separation in the postpartum period. METHODS: Prospective observational cohort study that recruited two cohorts of primiparous women: those undergoing vaginal and cesarean delivery (45 and 46 patients, respectively). Chart review collected intrapartum factors. Patients were followed with serial anterior-posterior radiographs within 48 hours of delivery and at 6, 12, and 24 weeks postpartum, to evaluate the extent of pubic symphysis separation. Differences between the two cohorts in intrapartum factors were assesses as was pubic symphysis separation at each time point. RESULTS: Mean age of women was 25.8 (SD 5.1) years, and 56% were White. Mean birth weight was 3.5 (SD 0.52) kg. Mean immediate postpartum pubic symphysis separation was 7.6 (SD 2.2) mm and did not differ between groups, at 7.18 mm for vaginal delivery versus 8.04 mm for cesarean delivery (CD; P = 0.08). Pubic symphysis separation was not significantly different for CD with and without labour. Black race and obesity were associated with increased pubic symphysis separation. No intrapartum events were related to extent of separation. Normalization of pregnancy pubic symphysis separation to 4-5 mm occurred by 6 weeks postpartum. Separation of >10mm and <15mm occurred in 10 of the 91 women and occurred after vaginal and cesarean delivery. The widest pubic symphysis separation was observed in 3 patients after vaginal delivery. CONCLUSION: Physiological pubic symphysis separation occursduring pregnancy and regresses postpartum with minimal effects from labour and delivery. Cesarean deliverydoes not prevent physiological pubic symphysis separation.

Immune Modeling Analysis Reveals Immunologic Signatures Associated With Improved Outcomes in High Grade Serous Ovarian Cancer.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy worldwide, as patients are typically diagnosed at a late stage and eventually develop chemoresistant disease following front-line platinum-taxane based therapy. Only modest results have been achieved with PD-1 based immunotherapy in ovarian cancer patients, despite the fact that immunological responses are observed in EOC patients. Therefore, the goal of this present study was to identify novel immune response genes and cell subsets significantly associated with improved high grade serous ovarian cancer (HGSOC) patient prognosis. A transcriptomic-based immune modeling analysis was employed to determine levels of 8 immune cell subsets, 10 immune escape genes, and 22 co-inhibitory/co-stimulatory molecules in 26 HGSOC tumors. Multidimensional immune profiling analysis revealed CTLA-4, LAG-3, and Tregs as predictive for improved progression-free survival (PFS). Furthermore, the co-stimulatory receptor ICOS was also found to be significantly increased in patients with a longer PFS and positively correlated with levels of CTLA-4, PD-1, and infiltration of immune cell subsets. Both ICOS and LAG-3 were found to be significantly associated with improved overall survival in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. Finally, PVRL2 was identified as the most highly expressed transcript in our analysis, with immunohistochemistry results confirming its overexpression in HGSOC samples compared to normal/benign. Results were corroborated by parallel analyses of TCGA data. Overall, this multidimensional immune modeling analysis uncovers important prognostic immune factors that improve our understanding of the unique immune microenvironment of ovarian cancer.

Chronic venous ulcer: minimally invasive treatment of superficial axial and perforator vein reflux speeds healing and reduces recurrence.

BACKGROUND: Chronic venous ulcer (CVU) is common and is responsible for significant health care expenditures worldwide. Compression is the mainstay of treatment, but long-term compliance with this therapy is often inconsistent, particularly in the elderly and infirm. Surgical ablation of axial and perforator reflux has been used as an adjunct to compression to reduce recurrence rates and assist healing. These surgical techniques are being replaced by minimally invasive procedures, such as thermal ablation and foam sclerotherapy, in the treatment of uncomplicated venous disease. The role for these techniques in the treatment of CVU is just beginning to be defined. METHODS: Eighty-six patients with CVU with 95 active ulcers (Clinical, Etiology, Anatomy, Physiology-CEAP clinical class 6) presenting to a multispecialty wound clinic were retrospectively reviewed and analyzed by leg. All patients underwent duplex scanning for venous insufficiency. Ulcer dimensions at each visit were recorded and used to calculate healing rates. Presence or absence of ulcer recurrence at 1-year follow-up was recorded. Ulcers treated with compression alone ("compression group") were compared with those treated with compression and minimally invasive interventions, such as thermal ablation of superficial axial reflux and ultrasound-guided foam sclerotherapy (UGFS) of incompetent perforating veins and varicosities ("intervention group"). RESULTS: The average age in the intervention and compression groups was 67 and 71 years, respectively (P = not significant [NS]). Body mass index was 32.4 ± 9.5 and 33.6 ± 11.8 kg/m(2), in the compression and intervention groups, respectively (P = not significant [NS]). Ulcers were recurrent in 42% of the intervention group and 26% of the compression group (P = NS). In the intervention group, 33% had radiofrequency ablation of axial reflux, 31% had UGFS of perforators, and 29% had both treatments. The only complication of intervention was a single case of cellulitis requiring hospitalization. Compared with the compression group, the ulcers in the intervention group healed faster (9.7% vs. 4.2% per week; P = 0.001) and showed fewer recurrences at 1-year follow-up (27.1% vs. 48.9 %; P < 0.015). Multivariate analysis showed use of intervention was the strongest determinant of healing with a coefficient of variation of 7.432, SE 2.406, P = 0.003. Analysis of just the intervention group before and after intervention using matched pairs showed acceleration of healing after intervention from ranging from a median of 1.2% (interquartile range [IQR], 14.3) to 9.7% (IQR, 11.3) per week (P ≤ 0.001). CONCLUSIONS: Minimally invasive ablation of superficial axial and perforator vein reflux in patients with active CVU is safe and leads to faster healing and decreased ulcer recurrence when combined with compression alone in the treatment of CVU.