The role and participation of immune cells in the endometrial tumor microenvironment.

The tumor microenvironment is surrounded by blood vessels and consists of malignant, non-malignant, and immune cells, as well as signalling molecules, which primarily affect the therapeutic response and curative effects of drugs in clinical studies. Tumor-infiltrating immune cells participate in tumor progression, impact anticancer therapy, and eventually lead to the development of immune tolerance. Immunotherapy is evolving as a promising therapeutic intervention to stimulate and activate the immune system to suppress cancer cell growth. Endometrial cancer (EC) is an immunogenic disease, and in recent years, immunotherapy has shown benefit in the treatment of recurrent and advanced EC. This review discusses the key molecular pathways associated with the intra-tumoral immune response and the involvement of circulatory signalling molecules. Specific immunologic signatures in EC which offer targets for immunomodulating agents, are also discussed. We have summarized the available literature in support of using immunotherapy in EC. Lastly, we have also discussed ongoing clinical trials that may offer additional promising immunotherapy options in the future. The manuscript also explored innovative approaches for screening and identifying effective drugs, and to reduce the financial burdens for the development of personalized treatment strategies. Collectively, we aim to provide a comprehensive review of the role of immune cells and the tumor microenvironment in the development, progression, and treatment of EC.

Is there a role for secondary debulking in ovarian cancer? A review of the current literature.

PURPOSE OF REVIEW: Until recently, no data was available from randomized, controlled trials (RCT) to assess the role of secondary cytoreductive surgery (CRS) in the management of recurrent epithelial ovarian cancer. This review highlights results from the three completed RCTs, and other recent literature on this topic. RECENT FINDINGS: Both the AGO and iMODEL criteria predict high rates of complete gross resection at the time of secondary CRS. Overall survival (OS) was improved in the surgical arms in both DESKTOP 3 and SOC-1. In contrast, surgery did not improve OS in GOG 213, but greater than 80% of patients received bevacizumab with chemotherapy in GOG 213. SUMMARY: Secondary cytoreduction for recurrent ovarian cancer can be considered in patients who meet specific criteria. Available data supports improvement in OS for patients not receiving bevacizumab, who achieve complete gross resection. Surgery is harmful to patients with gross residual disease.

Comparison of equine synovial sepsis rate following intrasynovial injection in ambulatory versus hospital settings.

BACKGROUND: Frequency of synovial sepsis in horses following intrasynovial injection has been reported, but not compared with respect to the environment in which the injection was performed. OBJECTIVES: To describe occurrence of synovial sepsis following intrasynovial injections performed in ambulatory vs hospital settings. STUDY DESIGN: Retrospective cohort study. METHODS: Records from the Colorado State University were evaluated (2014-2018) and horses receiving intrasynovial injections were identified. Patients presenting for septic synovial structures were excluded. Patient signalment, primary supervising service, medications injected, location (field/hospital), whether synovial sepsis resulted, and at what time sepsis was recognised were recorded. Logistic regression was used to estimate the contributions of covariates to the occurrence of synovial sepsis following injection. RESULTS: During the study period, 3866 intrasynovial injections were performed in 1112 horses during 1623 sessions, with 643/1623 sessions performed in the field. The most frequently used medications were hyaluronate (846/1623, 52.1%), triamcinolone acetonide (780 /1623, 48.1%) and amikacin sulfate (684/1623, 42.1%). Four horses developed synovial sepsis (0.2% sessions, 0.1% synovial structures); 3/4 were injected in the field, 2/4 received antibiotics with the injection. The frequency of septic synovitis was 10.4 cases per 10 000 injections, or 1 in 967 injections. All horses recovered following synovial lavage and antibiotic therapy. Performing injections in the field (P = .2) or without antibiotics (P = .7) did not alter the risk of synovial sepsis. MAIN LIMITATIONS: Limitations include the retrospective nature of data collection and low rate of infection overall, which prohibited evaluation of individual medication regimes as factors associated with resultant infection. CONCLUSIONS: The frequency of synovial sepsis in this population of horses was not higher when injections were performed in the field or without concurrent antibiotic administration. These data may help to inform practitioners and clients regarding the relative potential risk of complications following intrasynovial medication in different environmental settings.

Intra-articular administration of antibiotics in horses: Justifications, risks, reconsideration of use and outcomes.

Antibiotics have been injected intra-articularly by equine veterinarians for decades, either prophylactically when other drugs are administered for osteoarthritis or therapeutically to treat septic arthritis. This route of administration has also more recently gained attention in human orthopaedic clinical practice, particularly as an alternative to systemic antibiotic administration to treat infections following prosthetic arthroplasty. While the rationale for injecting antibiotics intra-articularly has been largely focused on achieving high local drug concentrations, there has been relatively little focus on pharmacokinetic parameters of antibiotics administered by this route, or on the potential for local toxicity. The increasing incidence of antibiotic resistance in veterinary and human medicine prompts reconsideration of off-label antibiotic usage and evaluation of evidence-based dosing strategies. The purpose of this review was to summarise the current literature describing intra-articular antibiotic usage, including specific studies where pharmacokinetics, potential safety and toxicity have been evaluated. This review will advance practitioners' understanding of the use of intra-articularly administered antibiotics, including the overall pros and cons of the approach.

Retrospective evaluation of association between perioperative antimicrobial protocol and complications following elective equine synovial endoscopy.

BACKGROUND: Prophylactic perioperative antimicrobial protocols in equine synovial endoscopy have been described but not compared with respect to post-operative outcomes and complications. Increasing antimicrobial resistance in equine practice and interest in promoting judicious use of antimicrobials has prompted reevaluation of drug selection and dosing strategies. OBJECTIVES: To determine the frequency of and compare post-operative complications following elective synovial endoscopy between horses receiving different perioperative antimicrobial protocols. METHODS: Records from the Colorado State University Veterinary Teaching Hospital were evaluated (2014-2018) and equine patients undergoing elective synovial endoscopy were identified. Patients undergoing endoscopy for sepsis or internal fixation were excluded. Patient signalment, clinician, joint and limb involved, perioperative antimicrobial regimen, number endoscopic portals and closure technique, and post-operative complications including incidence of joint infection were recorded. Generalized linear models were used to estimate the odds of post-operative complications. RESULTS: Elective synovial endoscopies of 516 horses in 537 procedures evaluating 761 synovial structures were performed. No horses developed post-operative septic synovitis. Administration of post-operative antimicrobials, type used and patient sex were all significantly associated with increased risk of complications, which were predominantly gastrointestinal-related. Complication rates in horses receiving a single preoperative dose of cefazolin were lower than in horses receiving potassium penicillin, gentamicin or multiple doses. Complication rates were lower in females compared to castrated or intact males. Other factors evaluated (breed, age, surgeon, anaesthesia duration or hospitalization, joint/limb operated, number endoscopic portals) were not associated with increased risk of complications post-operatively in this case population. CONCLUSIONS: Prophylactic perioperative antimicrobial protocols in equine practice deserve periodic reconsideration due to increased antimicrobial resistance. Prolonged antimicrobial usage beyond the time of surgery was unnecessary to prevent septic synovitis following synovial endoscopy in this case population and was furthermore associated with an increased risk of gastrointestinal complications.

Adjuvant Human Papillomavirus Vaccine to Reduce Recurrent Cervical Dysplasia in Unvaccinated Women: A Systematic Review and Meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis evaluating the efficacy of adjuvant human papillomavirus (HPV) vaccination in preventing recurrent cervical intraepithelial neoplasia (CIN) 2 or greater after surgical excision. DATA SOURCES: Electronic databases (Cochrane, PubMed, EMBASE, MEDLINE, Scopus, and ClinicalTrials.gov) were searched for studies comparing surgical excision alone to surgical excision with adjuvant HPV vaccination for CIN 2 or greater. Studies published from January 1990 to January 2019 were included. METHODS: A total of 5,901 studies were reviewed. The primary outcomes evaluated included: recurrence of CIN 2 or greater, CIN 1 or greater, and HPV 16,18 associated CIN within 6-48 months. We used Covidence software to assist with screening, and meta-analysis was performed using Review Manager. TABULATION, INTEGRATION, AND RESULTS: Six studies met inclusion criteria and were included in the final analysis. In total 2,984 women were included; 1,360 (45.6%) received adjuvant HPV vaccination after surgical excision, and 1,624 (54.4%) received either placebo or surgical management alone for CIN 2 or greater. Recurrence of CIN 2 or greater occurred within 6-48 months in 115 women (3.9%) overall; however, recurrence was significantly lower for vaccinated women: 26 of 1,360 women (1.9%) vs 89 of 1,624 unvaccinated women (5.9%) (relative risk [RR] 0.36 95% CI 0.23-0.55). The risk of CIN 1 or greater was also significantly lower with adjuvant HPV vaccination, occurring in 86 of 1,360 vaccinated women (6.3%) vs 157 of 1,624 unvaccinated women (9.7%) (RR 0.67 95% CI 0.52-0.85). Thirty-five women developed recurrent CIN 2 or greater lesions specific to HPV 16,18; nine received adjuvant vaccination (0.9%) vs 26 who were unvaccinated (2.0%) (RR 0.41 95% CI 0.20-0.85). CONCLUSION: Adjuvant HPV vaccination in the setting of surgical excision for CIN 2 or greater is associated with a reduced risk of recurrent cervical dysplasia overall and a reduction in the risk of recurrent lesions caused by the most oncogenic strains (HPV 16,18). Human papillomavirus vaccination should therefore be considered for adjuvant treatment in patients undergoing surgical excision for CIN 2 or greater. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42019123786.

A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis.

The search for effective treatments for obesity and its comorbidities is of prime importance. We previously identified IKK-ε and TBK1 as promising therapeutic targets for the treatment of obesity and associated insulin resistance. Here we show that acute inhibition of IKK-ε and TBK1 with amlexanox treatment increases cAMP levels in subcutaneous adipose depots of obese mice, promoting the synthesis and secretion of the cytokine IL-6 from adipocytes and preadipocytes, but not from macrophages. IL-6, in turn, stimulates the phosphorylation of hepatic Stat3 to suppress expression of genes involved in gluconeogenesis, in the process improving glucose handling in obese mice. Preliminary data in a small cohort of obese patients show a similar association. These data support an important role for a subcutaneous adipose tissue-liver axis in mediating the acute metabolic benefits of amlexanox on glucose metabolism, and point to a new therapeutic pathway for type 2 diabetes.