The Good, the Bad and the Ugly of Testicular Immune Regulation: A Delicate Balance Between Immune Function and Immune Privilege.

The testis is one of several immune privilege sites. These sites are necessary to decrease inflammation and immune responses that could be damaging to the host. For example, inflammation in the brain, eye or placenta could result in loss of cognitive function, vision or rejection of the semi-allogeneic fetus, respectively. In the testis, immune privilege is "good" as it is necessary for protection of the developing auto-immunogenic germ cells. However, there is also a downside or "bad" part of immune privilege, where pathogens and cancers can take advantage of this privilege and persist in the testis as a sanctuary site. Even worse, the "ugly" of privilege is how re-emerging viruses, such as Ebola and Zika viruses, can establish persistence in the testes and be sexually transmitted even months after they have been cleared from the bloodstream. In this review, we will discuss the delicate balance within the testis that provides immune privilege to protect the germ cells while still allowing for immune function to fight off pathogens and tumors.

Moderate or severe LUTS is associated with increased recurrence of non - muscle - invasive urothelial carcinoma of the bladder.

PURPOSE: Non - muscle - invasive bladder cancer (NMIBC) can recur despite transurethral resection (TURBT) and adjuvant intravesical therapy. Tobacco products excreted in the urine are hypothesized to cause tumor - promoting effects on urothelial cells through direct contact. We determined if moderate or severe lower urinary tract symptoms (LUTS) (defined as International Prostate Symptom Score [IPSS] ≥ 8) was associated with increased tumor recurrence. MATERIALS AND METHODS: We retrospectively identified 70 consecutive men initially diagnosed with NMIBC at our institution from 2010 - 2016. Means were compared with independent T - test and proportions with chi - square analysis. Multivariate logistic regression was performed to determine independent predictors of recurrence. RESULTS: The majority of patients had Ta disease (58.6%) followed by T1 (28.6%) and Tis (12.9%). Forty - one (58.6%) patients had moderate or severe LUTS upon presentation within 30 days of initial TURBT with mean IPSS of 13.2 vs. 5.2 in the control group (p < 0.01). Biopsy - proven tumor recurrence occurred in 24 (34.3%) patients at mean follow-up of 31.7 months. Mean time to recurrence was 14.6 months. Moderate or severe LUTS was an independent predictor of tumor recurrence (odds ratio [OR]: 19.1, 95% confidence interval [CI]: 2.86 - 127; p = 0.002). Voiding or storage symptoms based on the IPSS did not independently correlate with tumor recurrence (p = 0.08 and p = 0.31, respectively) although total mean IPSS score did (OR: 1.26, 95% CI: 1.07 - 1.47, p = 0.005). CONCLUSIONS: The presence of moderate or severe LUTS may be an important prognostic factor in NMIBC. Patients with significant urinary symptoms could be monitored more aggressively due to higher recurrence risk.

PSA screening and deaths from prostate cancer after diagnosis--a population based analysis.

BACKGROUND: The United States Preventative Health Task Force recently recommended prostate specific antigen (PSA) screening be abandoned, believing the results of prior studies failed to show benefits that outweighed risks. Prior analyses did not include a complete 10 year follow-up in their analyses. METHODS: SEER rate sessions were used to obtain for U.S. White and Black men age-adjusted incidence rates for prostate cancer, in total and by loco-regional and distant (D2) spread for 1983-2009, as well as for prostate cancer diagnoses with associated prostate cancer deaths within 10 years of diagnosis (incidence based mortality rates) for 1983-1999. The SEER-Stat Program was used to tabulate rate estimates and calculate standard errors. The Joinpoint Regression Program was used to provide estimates and 95% confidence intervals (CI) of annual percent changes (APC) and times at which APC changed (joinpoints), as well as to test for parallelism to see if APC's differed between groups of rates. RESULTS: All analyses showed a 1991-1993 joinpoint, consistent with an impact of PSA screening. Between 1991 and 1999, incidence based mortality rates showed a decline for Whites of 10.9% (CI 9.2%-12.7%) and for Blacks of 11.6% (CI 9.7%-13.4%); incidence based mortality and D2 spread rate curves were similar (P > 0.05, test for parallelism). CONCLUSION: Incidence based mortality declined by about 10% per year between 1991 and 1999 in a fashion similar to that of D2 spread, but not loco-regional spread or overall, incidence.

Antibiotic prophylaxis is not associated with reduced urinary tract infection-related complications after cystectomy and ileal conduit.

OBJECTIVES: Majority of complications after ileal conduit urinary diversion with cystectomy are related to urinary tract infections (UTIs). Controversy exists regarding use of prophylactic antibiotics after surgery. We determined if prophylactic antibiotic use during ureteral stent placement after ileal conduit urinary diversion decreased incidence of UTI-related complications. METHODS: We retrospectively identified 75 consecutive patients who underwent ileal conduit urinary diversion with cystectomy at our institution from 2010 to 2016. Patients were stratified based on presence or absence of a UTI-related complication in the 90-day postoperative period. Means were compared with independent t-test and proportions with chi-square analysis. Multivariate logistic regression was performed to determine independent predictors of UTI-related complications. RESULTS: Forty-five patients (60%) were prescribed prophylactic antibiotics after surgery. Mean duration of antibiotic use was 15 d, and mean duration of ureteral stenting was 25 d. Most common antibiotics used included fluoroquinolones (n = 23, 30.7%) followed by sulfamethoxazole-trimethoprim (n = 14, 18.7%). Rate of 90-day UTI-related complications was 36% (n = 27), and 90-day UTI-related readmission rate was 14.7% (n = 11). On bivariate and multivariate analysis, prophylactic antibiotic use was not associated with reduced 90-day UTI-related complications (P > 0.05). Patients prescribed prophylactic antibiotics had increased incidence of Clostridium difficile infections in the 90-day postoperative period compared to controls (20% vs. 3.3%; P = 0.038). CONCLUSIONS: Prophylactic antibiotic use after ileal conduit urinary diversion with cystectomy was not associated with reduced UTI-related complications, and rate of Clostridium difficile infections was higher in this patient cohort. The effect of early removal of ureteral stents on UTI risk still has to be elucidated.

Interactions between benign prostatic hyperplasia (BPH) and prostate cancer in large prostates: a retrospective data review.

PURPOSE: To study the interaction between benign prostatic hyperplasia (BPH) and prostate cancer (PCa). METHODS: In this study, we performed a chart review of a cohort of 448 biopsy naive men. These men received a multi-core biopsy at our institution due to increased prostate-specific antigen (PSA) serum levels (>4 ng/ml) and/or suspicious findings on digital rectal examination in the years between 2008 and 2013. Utilizing PSA and transrectal ultrasound (TRUS) prostate volume, we obtained the PSA density (PSAD) for each individual. PSAD was calculated by dividing serum PSA concentration by TRUS prostate volume. RESULTS: Large prostates >65 g may secrete enough PSA to have a PSAD above the suggested cutoff of 0.15, yet 50 % patients have no histologic evidence of PCa, whereas prostates <35 g and an elevated PSAD of above 0.15 will have histologic evidence of PCa 70 % of the time. CONCLUSIONS: These results suggest that BPH in large prostates may be protective of PCa. The interaction of the different prostate zones, in particular the transition zone and peripheral zone, may play a significant role in the phenomenon observed in this study. However, sampling error may introduce bias that 12-16 core biopsies in larger prostates may be more likely missing the cancer lesion.

Implications on clinical management of the small renal mass in patients 80 years of age and older based on a retrospective review of the SEER database.

PURPOSE: Incidental detection of small renal masses has increased in recent years with increased use of various imaging modalities, and a substantial number of diagnoses are made in the elderly population. Minimally invasive surgical procedures have previously been established as options with excellent long-term oncological results, but surveillance strategies have more recently been introduced as alternatives for surgical intervention. This study reviews the outcomes for elderly patients treated with observation or surgery for small renal masses in order to better elucidate optimal management strategies. METHODS: A total of 4647 patients from the SEER database met criteria for inclusion in this study. Cumulative incidences of RCC-specific mortality and non-RCC-related mortality were estimated, and frequency distributions by tumor size and surgical status were calculated. RESULTS: No difference in RCC-related mortality was observed among all treatment groups, including surveillance, for tumors 1-30 mm in size. RCC-related mortality was significantly lower for surgically treated patients for all other tumor size groups. Mortality unrelated to RCC was significantly higher in patients undergoing surveillance compared to those undergoing surgical intervention for tumor sizes 1-30 or 1-40 mm. CONCLUSIONS: A small renal mass in patients of 80+ years of age is best defined as up to 3 cm in size. For these patients, observation appears be a valid, if not preferential strategy. Patients 80+ years of age with renal masses greater than 3 cm still appear to benefit from surgical intervention.

Moderate or severe LUTS is associated with increased recurrence of non - muscle - invasive urothelial carcinoma of the bladder

ABSTRACT Purpose: Non - muscle - invasive bladder cancer (NMIBC) can recur despite transurethral resection (TURBT) and adjuvant intravesical therapy. Tobacco products excreted in the urine are hypothesized to cause tumor - promoting effects on urothelial cells through direct contact. We determined if moderate or severe lower urinary tract symptoms (LUTS) (defined as International Prostate Symptom Score [IPSS] ≥ 8) was associated with increased tumor recurrence. Materials and Methods: We retrospectively identified 70 consecutive men initially diagnosed with NMIBC at our institution from 2010 - 2016. Means were compared with independent T - test and proportions with chi - square analysis. Multivariate logistic regression was performed to determine independent predictors of recurrence. Results: The majority of patients had Ta disease (58.6%) followed by T1 (28.6%) and Tis (12.9%). Forty - one (58.6%) patients had moderate or severe LUTS upon presentation within 30 days of initial TURBT with mean IPSS of 13.2 vs. 5.2 in the control group (p < 0.01). Biopsy - proven tumor recurrence occurred in 24 (34.3%) patients at mean follow-up of 31.7 months. Mean time to recurrence was 14.6 months. Moderate or severe LUTS was an independent predictor of tumor recurrence (odds ratio [OR]: 19.1, 95% confidence interval [CI]: 2.86 - 127; p = 0.002). Voiding or storage symptoms based on the IPSS did not independently correlate with tumor recurrence (p = 0.08 and p = 0.31, respectively) although total mean IPSS score did (OR: 1.26, 95% CI: 1.07 - 1.47, p = 0.005). Conclusions: The presence of moderate or severe LUTS may be an important prognostic factor in NMIBC. Patients with significant urinary symptoms could be monitored more aggressively due to higher recurrence risk.

Clinical outcome of patients with docetaxel-resistant hormone-refractory prostate cancer treated with second-line cyclophosphamide-based metronomic chemotherapy.

For patients with docetaxel-resistant hormone-refractory prostate cancer (HRPC) no standard chemotherapeutic treatment exists. In this study, we evaluate the efficacy of cyclophosphamide (CP)-based metronomic chemotherapy in this patient population. Patients with metastatic HRPC with disease progression under docetaxel-based chemotherapy were eligible. The primary endpoint was prostate-specific antigen (PSA) response. Secondary endpoints were survival and toxicity. Low-dose CP (50 mg/d) and dexamethasone (1 mg/d) were administered orally in a metronomic manner. Treatment was continued until disease progression or intolerable side effects occurred. Seventeen patients were enrolled in this study. The median follow-up was 12 weeks (range: 4-60). Median age was 68 years (range: 42-85). Median PSA at study entry was 134 ng/ml (range: 46.0-6554). Nine patients had a PSA response (median 44.4%), four patients >or=50% and five patients <50%. Eight patients had a PSA progression. Overall survival was 24 months. Five patients reported a decrease in bone pain after 4 weeks' treatment. No grade 3 and 4 toxicities were noted. In this study, low-dose metronomically administered CP demonstrated efficacy as a second-line treatment in patients with docetaxel-resistant HRPC. The treatment was well tolerated and almost without toxicity. Further advantages of low-dose CP were its convenient oral administration, dosing schedule, low cost, and low-toxicity profile. These attributes in combination with immunoregulatory and antiangiogenic potentials make CP also a prime candidate for combination with other treatment regimens.

Protamine sulfate reduces the susceptibility of thermally injured mice to Pseudomonas aeruginosa infection.

BACKGROUND: In this study, we investigated the ability of protamine sulfate, at sub-bactericidal dosing, to interfere with the in vivo virulence of Pseudomonas aeruginosa (PAO1) during burn wound infection. MATERIALS AND METHODS: The study was conducted using the murine model of thermal injury. Preliminary experiments determined a protocol for administration of protamine sulfate that had no in vivo bactericidal effects. Based on this, the effect of local injection of protamine sulfate on the in vivo virulence of PAO1 was assessed using these parameters: (1) the percent mortality among PAO1-infected, thermally injured mice; (2) the local proliferation and spread of PAO1 within the infected burned tissue; (3) the systemic spread of PAO1 within thermally injured/infected mice; and (4) the local cytokine response elicited by PAO1 thermally injured/infected mice. RESULTS: Injection of protamine sulfate into the thermally injured tissue of PAO1-infected/thermally injured mice significantly decreased the percent mortality and inhibited the systemic dissemination of PAO1 microorganisms to the liver and spleen. It had no effect, however, on the ability of the bacteria to proliferate and spread within the thermally injured tissue. It also was determined that protamine sulfate was ineffective at preventing mouse death at the dose administered if injected intramuscularly instead of directly into burned tissue. Protamine sulfate reduced the expression of the proinflammatory cytokines IL-6 and LIF in the injured/infected tissue. Heparan sulfate given in conjunction with protamine sulfate returned mortality levels to those of untreated mice. CONCLUSIONS: Our results suggest that: (1) local injection of sub-bactericidal doses of protamine sulfate reduces the virulence of P. aeruginosa; (2) this effect is due to interference with the systemic rather than local spread of P. aeruginosa; and (3) local application of protamine sulfate may have potential as supportive therapy for prevention of systemic P. aeruginosa infection in severely burned patients.

Syndecan 1 shedding contributes to Pseudomonas aeruginosa sepsis.

The innate immune system is comprised of many components that function coordinately to prevent bacterial sepsis. However, thermal injury suppresses many of these factors, and the opportunistic pathogen Pseudomonas aeruginosa takes advantage of this condition, making it one of the leading causes of morbidity and mortality in the setting of thermal injury. P. aeruginosa is extremely efficient at colonizing burn wounds, spreading systemically, and causing sepsis, which often results in a systemic inflammatory response, multiple-organ failure, and death. The pathogenicity of P. aeruginosa is due to the arsenal of virulence factors produced by the pathogen and the immunocompromised state of the host. Syndecan 1 is a major heparan sulfate proteoglycan present on many host cells involved in thermal injury. Syndecan 1 anchored to the cell surface can be cleaved in a process termed ectodomain shedding. Syndecan 1 shedding results in the release of intact, soluble proteoglycan ectodomains that have diverse roles in innate immunity. Here we show for the first time that thermal injury results in shedding of syndecan 1 from host tissue. Our data show that syndecan 1 null mice are significantly less susceptible to P. aeruginosa infection than their wild-type counterparts, as demonstrated by (i) significantly lower mortality; (ii) absence of systemic spread of P. aeruginosa; and (iii) significant reductions in some proinflammatory cytokines. These results suggest that shed syndecan 1 plays an important role in the pathogenesis of P. aeruginosa infection of thermal injury and that syndecan 1-neutralizing agents may be effective supplements to current P. aeruginosa treatments.