Bioavailability of the tumor necrosis factor alpha/regulated on activation, normal T cell expressed and secreted (RANTES) biosystem inside the gestational sac during the pre-immune stages of embryo development.

OBJECTIVES: In-vivo studies of the bioavailability of major components of the tumor necrosis factor alpha (TNFα) biosystem inside the gestational sac during embryogenesis have not been reported. We sought to determine the concentration of TNFα, soluble (s) TNFα receptors (sTNFR1, sTNFR2), and RANTES in the primate extraembryonic celomic fluid (ECF). METHODS: A validated timed-pregnant baboon animal model (N: 10) for experimental research in pregnancy was used to collect paired maternal blood and ECF samples in ongoing pregnancies. The concentrations (pg/dL) of TNFα, sTNFR1, sTNFR2, and RANTES were then determined by ELISA immunoassays. RESULTS: All animals delivered at term healthy newborns. The differential concentration of TNFα, sTNFR1, sTNFR2, and RANTES between the maternal plasma and the ECF could be determined with ratios for TNFα (5.4), sTNFR2 (1.85) and RANTES (3.59) that contrasted with that of sTNFR1 (0.07), which favored the gestational sac compartment. No significant correlations were noted between maternal plasma and ECF TNFR1, sTNFR2 and RANTES. There was a trend for a correlation between TNFα in maternal plasma and ECF (R=0.74; p=0.07). CONCLUSIONS: We report the physiological concentrations of TNFα, sTNFR1, sTNFR2, and RANTES in extraembryonic celomic fluid during embryogenesis in primates.

Targeting receptor tyrosine kinases in ovarian cancer: Genomic dysregulation, clinical evaluation of inhibitors, and potential for combinatorial therapies.

Epithelial ovarian cancer (EOC) remains one of the leading causes of cancer-related deaths among women worldwide. Receptor tyrosine kinases (RTKs) have long been sought as therapeutic targets for EOC, as they are frequently hyperactivated in primary tumors and drive disease relapse, progression, and metastasis. More recently, these oncogenic drivers have been implicated in EOC response to poly(ADP-ribose) polymerase (PARP) inhibitors and epigenome-interfering agents. This evidence revives RTKs as promising targets for therapeutic intervention of EOC. This review summarizes recent studies on the role of RTKs in EOC malignancy and the use of their inhibitors for clinical treatment. Our focus is on the ERBB family, c-Met, and VEGFR, as they are linked to drug resistance and targetable using commercially available drugs. The importance of these RTKs and their inhibitors is highlighted by their impact on signal transduction and intratumoral heterogeneity in EOC and successful use as maintenance therapy in the clinic through suppression of the VEGF/VEGFR axis. Finally, the therapeutic potential of RTK inhibitors is discussed in the context of combinatorial targeting via co-inhibiting proliferative and anti-apoptotic pathways, epigenomic/transcriptional programs, and harnessing the efficacy of PARP inhibitors and programmed cell death 1/ligand 1 immune checkpoint therapies.

Mithplatins: Mithramycin SA-Pt(II) Complex Conjugates for the Treatment of Platinum-Resistant Ovarian Cancers.

DNA coordinating platinum (Pt) containing compounds cisplatin and carboplatin have been used for the treatment of ovarian cancer therapy for four decades. However, recurrent Pt-resistant cancers are a major cause of mortality. To combat Pt-resistant ovarian cancers, we designed and synthesized a conjugate of an anticancer drug mithramycin with a reactive Pt(II) bearing moiety, which we termed mithplatin. The conjugates displayed both the Mg2+ -dependent noncovalent DNA binding characteristic of mithramycin and the covalent crosslinking to DNA of the Pt. The conjugate was three times as potent as cisplatin against ovarian cancer cells. The DNA lesions caused by the conjugate led to the generation of DNA double-strand breaks, as also observed with cisplatin. Nevertheless, the conjugate was highly active against both Pt-sensitive and Pt-resistant ovarian cancer cells. This study paves the way to developing mithplatins to combat Pt-resistant ovarian cancers.

Tumor-Associated Macrophages and Ovarian Cancer: Implications for Therapy.

The tumor microenvironment (TME) has been implicated to play an important role in the progression of ovarian cancer. One of the most important components of the TME is tumor associated macrophages (TAMs). Phenotypically, macrophages are broadly categorized as M1 pro-inflammatory or M2 anti-inflammatory, based on the cytokines and chemokines that they secrete. The tumor microenvironment is associated with macrophages of an M2 phenotype which suppress the surrounding immune environment, assist tumor cells in evading immune targeting, and support tumor growth and metastasis. Contrarily, M1 macrophages help mount an immune response against tumors, and are associated with a more favorable prognosis in solid tumors. One of the characteristic indicators of a poor prognosis in ovarian cancer is the overrepresentation of M2-type TAMs. As such, therapeutic modalities targeting TME and TAMs are of increasing interest. Pharmacological approaches to eliminate TAMs, include decreasing macrophage survival and recruitment and increasing phagocytosis, have been underwhelming. Clinical strategies targeting these macrophage subtypes via repolarization to an M1 antitumoral state deserve increasing attention, and may serve as a new modality for immunotherapy.

Human macrophage-engineered vesicles for utilization in ovarian cancer treatment.

Background: Ovarian cancer is a deadly female malignancy with a high rate of recurrent and chemotherapy-resistant disease. Tumor-associated macrophages (TAMs) are a significant component of the tumor microenvironment and include high levels of M2-protumor macrophages that promote chemoresistance and metastatic spread. M2 macrophages can be converted to M1 anti-tumor macrophages, representing a novel therapeutic approach. Vesicles engineered from M1 macrophages (MEVs) are a novel method for converting M2 macrophages to M1 phenotype-like macrophages. Methods: Macrophages were isolated and cultured from human peripheral blood mononuclear cells. Macrophages were stimulated to M1 or M2 phenotypes utilizing LPS/IFN-γ and IL-4/IL-13, respectively. M1 MEVs were generated with nitrogen cavitation and ultracentrifugation. Co-culture of ovarian cancer cells with macrophages and M1 MEVs was followed by cytokine, PCR, and cell viability analysis. Murine macrophage cell line, RAW264.7 cells were cultured and used to generate M1 MEVs for use in ovarian cancer xenograft models. Results: M1 MEVs can effectively convert M2 macrophages to an M1-like state both in isolation and when co-cultured with ovarian cancer cells in vitro, resulting in a reduced ovarian cancer cell viability. Additionally, RAW264.7 M1 MEVs can localize to ovarian cancer tumor xenografts in mice. Conclusion: Human M1 MEVs can repolarize M2 macrophages to a M1 state and have anti-cancer activity against ovarian cancer cell lines. RAW264.7 M1 MEVs localize to tumor xenografts in vivo murine models.

Mithramycin and Analogs for Overcoming Cisplatin Resistance in Ovarian Cancer.

Ovarian cancer is a highly deadly malignancy in which recurrence is considered incurable. Resistance to platinum-based chemotherapy bodes a particularly abysmal prognosis, underscoring the need for novel therapeutic agents and strategies. The use of mithramycin, an antineoplastic antibiotic, has been previously limited by its narrow therapeutic window. Recent advances in semisynthetic methods have led to mithramycin analogs with improved pharmacological profiles. Mithramycin inhibits the activity of the transcription factor Sp1, which is closely linked with ovarian tumorigenesis and platinum-resistance. This article summarizes recent clinical developments related to mithramycin and postulates a role for the use of mithramycin, or its analog, in the treatment of platinum-resistant ovarian cancer.

Incidence of venous thromboembolism after robotic-assisted hysterectomy in obese patients with endometrial cancer: do we need extended prophylaxis?

Robotic surgery for gynecologic malignancy is associated with a lower rate of venous thromboembolism (VTE) than laparotomy. Obese patients represent a particularly high-risk group for VTE, but prior studies tend to focus on patients with a much lower BMI and without extended VTE prophylaxis. Our objective was to examine the role of extended thromboprophylaxis in obese patients who underwent robotic-assisted surgery for endometrial cancer. We conducted a retrospective cohort study of obese patients (BMI ≥ 35 kg/m2) who underwent robotic surgery for newly diagnosed endometrial cancer. The primary outcome measured was the occurrence of a VTE event within the 30-day postoperative period. The Farrington-Manning score test was used for equivalence analysis with a 5% margin. Secondary outcomes were perioperative complications. One hundred thirty-two robotic cases for endometrial cancer met our criteria. One hundred twenty-one (92%) received preoperative pharmacologic thromboprophylaxis, and 100% used pneumatic compression devices. Ninety-three percent and 90% received preoperative pharmacologic prophylaxis in the extended and no extended group, respectively (p-value = 0.7). Seventy patients (54%) received 4-week extended prophylaxis. Estimated blood loss was similar in both groups (75 mL vs 60 mL, p-value = 0.6). Perioperative complications and readmissions were similar between the two groups. There were no VTE events during hospital stay. One patient in the group that did not receive extended prophylaxis developed a VTE in the 30-day postoperative period (1.6%), versus 0% in the group that did receive extended prophylaxis (p-value = 0.1). The risk of VTE was low. The absence of extended VTE prophylaxis did not significantly increase the risk for VTE in obese patients with newly diagnosed endometrial cancer who underwent robotic-assisted surgery.

Robotic-assisted interval cytoreductive surgery in ovarian cancer: a feasibility study.

OBJECTIVE: The primary objective was to assess the feasibility of robotic-assisted interval cytoreductive surgery for achieving complete cytoreduction for patients with advanced-stage ovarian cancer. The secondary objective was to examine the perioperative outcomes. METHODS: A retrospective study of 12 patients with stage IIIC or IV ovarian, fallopian tube, and primary peritoneal carcinoma who underwent interval cytoreductive surgery after neo-adjuvant chemotherapy. RESULTS: Optimal cytoreduction was achieved in 100% of selected patients. Complete cytoreductive surgery was achieved in 75% of patients. The estimated mean blood loss was 100 mL. The median length of hospital stay was 2 days. Perioperative complication and 30-day readmission rates were 8.3% (1 patient). The median follow-up time was 9.5 months. CONCLUSION: Robotic-assisted interval cytoreductive surgery in ovarian cancer is safe and feasible and may be an alternative to standard laparotomy in selected patients.

Evaluating Blood Loss and the Effect of Antiplatelet Treatment in Foot and Ankle Amputations.

The interrelationship between diabetes mellitus and cardiovascular disease is well-documented, and, secondary to the latter, is the use of antiplatelet therapy. Although diabetes and the associated vascular manifestations are driving forces behind lower extremity amputations, few data are available on the risks of perioperative antiplatelet therapy with foot and ankle amputations. The goal of the present study was to address the surgical effect of continuing or discontinuing antiplatelet therapy before foot and/or ankle amputation. The following data were retrospectively collected: blood loss, pre- and postoperative hematocrit and hemoglobin, operative time, amputation type, age, diabetic status, antiplatelet treatment, and number of transfusions during the perioperative period. Perioperative antiplatelet therapy was defined as exposure to aspirin or clopidogrel within 3 days before surgery. To compare the outcomes between groups, the following factors were analyzed using bivariate analyses and then multivariate regression models: (1) the need for transfusions, (2) high blood loss (>20 mL), (3) volume of blood loss, and (4) operative time. The noninferiority of continued antiplatelet use was assessed in terms of operative time and blood loss, using a noninferiority margin of 10 minutes or 10 mL, respectively. Antiplatelet therapy was not a statistically significant risk factor for any of the studied outcomes on multivariate analysis. Equivalence testing revealed that continuing antiplatelet therapy is not inferior to discontinuing perioperative therapy in terms of blood loss and operative time. Multivariate analysis of the data suggested that antiplatelet therapy has no statistically significant impact on blood loss, transfusion rate, or operative time.