The ASA class is strongly associated with medical problems in the perioperative period following hip fracture surgery in the elderly. Patients identified as being at higher risk (in ASA class 3 or 4) preoperatively should be closely managed medically so that perioperative medical complications can be managed and evolving medical issues can be addressed in a timely fashion.

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Purpose To determine the safety and toxicities of sequential MMC + BCG in patients with non-muscle invasive bladder cancer (NMIBC) and explore evidence for potentiation of BCG activity by MMC. Experimental Design A 3+3 phase I dose-escalation trial of six weekly treatments was conducted in patients with NMIBC. MMC (10, 20 or 40 mg) was instilled intravesically for 30 minutes, followed by a 10-minute washout with gentle saline irrigation and then instillation of BCG (half or full strength) for 2 hours. Urine cytokines were monitored and compared to levels in a control cohort receiving BCG only. Murine experiments were carried out as described previously. Results Twelve patients completed therapy including 3 patients receiving full doses. The regimen was well tolerated with no treatment-related dose limiting toxicities. Urinary frequency and urgency, and fatigue were common. Eleven (91.7%) patients were free of disease at a mean (range) follow-up of 21.4 (8.4-27.0) months. Median post-treatment urine concentrations of IL-2, IL-8, IL-10 and TNF-α increased over the 6-week treatment period. A greater increase in post-treatment urinary IL-8 during the 6-week period was observed in patients receiving MMC + BCG compared to patients receiving BCG monotherapy. In mice, intravesical MMC + BCG skewed tumor-associated macrophages (TAMs) towards a beneficial M1 phenotype. Conclusions Instillation of sequential MMC + BCG is safe and tolerable up to 40 mg MMC plus full strength BCG. This approach could provide improved antitumor activity over BCG monotherapy by augmenting beneficial M1 TAMs.

Background: Intravesical bacillus Calmette-Guérin (BCG) is the gold standard immunologic agent for treating patients with high-grade non-muscle invasive bladder cancer (NMIBC). Nevertheless, relapse rates remain high and BCG unresponsive NMIBC often requires bladder removal. Preclinical data suggest that priming with percutaneous BCG vaccine could improve response to intravesical BCG. Methods: A single-arm trial (NCT02326168) was performed to study the safety, immunogenicity, and preliminary efficacy of priming. Percutaneous BCG was given 21 days prior to intravesical BCG instillation in patients (n = 13) with high-risk NMIBC. Immune responses were monitored and compared to a sequentially enrolled cohort of nine control patients receiving only intravesical BCG. The effect of BCG on natural killer (NK) and γδ T cell in vitro cytotoxicity was tested. γδ T cell subsets were determined by T cell receptor gene expression with NanoString. Results: Priming was well tolerated and caused no grade ≥3 adverse events. The 3-month disease-free rate for prime patients was 85% (target goal ≥ 75%). Priming boosted BCG-specific immunity at 3 months and increased the activation status of in vitro expanded circulating NK and γδ T cells and their cytotoxicity against bladder cancer cells through receptor NKG2D. BCG enhanced the cytotoxicity of NK and γδ T cells against K562, RT4, and UM-UC6 but not against T24, UM-UC-3, or UM-UC-14 cells. Infiltrating γδ T cell subsets identified in the bladder includes γ9δ2 and γ8δ2. Conclusions: BCG priming is safe and tolerable. Poor sensitivity to NK and γδ T cell cytotoxicity by some bladder tumors represents a potential BCG-resistance mechanism.

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Sex differences persist with women who are significantly more likely to undergo RC independent of clinical stage. However, women have significantly worse survival than men. Delay from diagnosis to surgery did not account for this decreased survival among women.