Pim kinase isoforms: devils defending cancer cells from therapeutic and immune attacks.

Pim kinases are being implicated in oncogenic process in various human cancers. Pim kinases primarily deal with three broad categories of functions such as tumorigenesis, protecting cells from apoptotic signals and evading immune attacks. Here in this review, we discuss the regulation of Pim kinases and their expression, and how these kinases defend cancer cells from therapeutic and immune attacks with special emphasis on how Pim kinases maintain their own expression during apoptosis and cellular transformation, defend mitochondria during apoptosis, defend cancer cells from immune attack, defend cancer cells from therapeutic attack, choose localization, self-regulation, activation of oncogenic transcription, metabolic regulation and so on. In addition, we also discuss how Pim kinases contribute to tumorigenesis by regulating cellular transformation and glycolysis to reinforce the importance of Pim kinases in cancer and cancer stem cells.

Percutaneous BCG enhances innate effector antitumor cytotoxicity during treatment of bladder cancer: a translational clinical trial.

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.

Survival differences among patients with bladder cancer according to sex: Critical evaluation of radical cystectomy use and delay to treatment.

OBJECTIVE: Sex differences in bladder cancer survival are well known. However, the effect of type of treatment, timing to surgery when rendered, and survival outcomes according to sex have not been extensively examined. Given the relatively low incidence of bladder cancer in females, large multicenter and population-based studies are required to elucidate sex differences in survival. In this study, we sought to characterize the effect of use and timing of radical cystectomy (RC) according to sex and survival outcomes. METHODS: A total of 9,907 patients aged 66 years or older diagnosed with clinical stage II to IV N0M0 bladder cancer from January 1, 2001 to December 31, 2011 from Surveillance, Epidemiology, and End Results-Medicare data were analyzed. We used multivariable regression analyses to identify factors predicting the use and delay of RC. Cox proportional hazards models were used to analyze survival outcomes. RESULTS: Of the 9,907 patients diagnosed with bladder cancer, 3,256 (32.9%) were females. Women were significantly more likely to undergo RC across all stages compared to their male counterparts (stage II: relative risk [RR] = 1.48, 95% CI: 1.33-1.65, P<0.001; stage III: RR = 1.24, 95% CI: 1.13-1.37, P<0.001; and stage IV: RR = 1.33, 95% CI: 1.19-1.49, P<0.001). Moreover, there was no significant difference in delay to RC according to sex across all clinical stages. Using propensity score matching, women had worse overall (hazard ratio = 1.07; CI: 1.01-1.14; P = 0.024), and worse cancer-specific survival (hazard ratio = 1.26; CI: 1.17-1.36, P<0.001) than men. CONCLUSION: 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.

Finasteride Reduces Risk of Bladder Cancer in a Large Prospective Screening Study.

UNLABELLED: The androgen receptor has been implicated in the development and progression of bladder cancer (BCa), largely based on studies of animal models. We investigated whether finasteride was associated with a reduced incidence of BCa as observed by self-report in the Prostate, Lung, Colorectal, and Ovarian cancer screening trial. Cox proportional hazard regression analysis was performed to determine the association of finasteride use with time to diagnosis of BCa, controlling for age and tobacco use. Of the 72,370 male participants who met inclusion criteria, 6069 (8.4%) had reported the use of finasteride. BCa was diagnosed in 1.07% (65 of 6069) of those who reported finasteride compared with 1.46% (966 of 66,301) of those who reported no use during the trial. In a multiple Cox regression analysis, self-reported use of finasteride was associated with a decreased risk of development of BCa (hazard ratio: 0.634; 95% confidence interval, 0.493-0.816; p=0.0004), controlling for age and smoking. Limitations of this study include that it is observational and not randomized, that many of the confounding variables for BCa, such as alcohol use, were not available for use in the analysis, and that finasteride use was by annual self-report, which is subject to missing values and error. PATIENT SUMMARY: Finasteride is a common medication used to reduce the size of the prostate and to promote hair growth by manipulating testosterone in men. Men are more likely than women to develop bladder cancer (BCa), but our study noted that men using finasteride were less likely to have a BCa diagnosis.

Sequential intravesical mitomycin plus Bacillus Calmette-Guérin for non-muscle-invasive urothelial bladder carcinoma: translational and phase I clinical trial.

PURPOSE: To determine the safety and toxicities of sequential MMC (mitomycin C) + BCG (bacillus Calmette-Guérin) 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 with 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 posttreatment urine concentrations of IL2, IL8, IL10, and TNFα increased over the 6-week treatment period. A greater increase in posttreatment urinary IL8 during the 6-week period was observed in patients receiving MMC + BCG compared with patients receiving BCG monotherapy. In mice, intravesical MMC + BCG skewed tumor-associated macrophages (TAM) toward a beneficial M1 phenotype. CONCLUSIONS: Instillation of sequential MMC + BCG is safe 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.

Use of medical comorbidities to predict complications after hip fracture surgery in the elderly.

BACKGROUND: Comorbidities before and complications following hip fracture surgery can impact the return of function. We hypothesized that the American Society of Anesthesiologists (ASA) classification of medical comorbidities is a useful surrogate variable for the patient's general medical condition and would be a strong predictor of perioperative medical complications following hip fracture surgery. METHODS: A retrospective review of the cases of 197 elderly patients who had undergone operative management of a hip fracture was performed. The ASA class, data regarding perioperative medical and surgical complications, and demographic data were obtained. Medical complications were defined as those requiring intervention by an internist or medical specialist. Differences in complication rates among the ASA classes were determined. RESULTS: Medical complications were more common in patients in ASA class 3 (p < 0.001) and those in class 4 (p = 0.001) than in those in class 2. Patients in ASA class 3 had a 3.78 times greater chance of having a medical complication than did those in class 2 (p < 0.001). Patients in ASA class 4 had a 7.39 times greater chance of having medical complications than did those in class 2 (p = 0.001). No significant relationship was identified between the ASA class and surgical complications. CONCLUSIONS: 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.