Brant A. Inman

A Population-Based, Longitudinal Study of Erectile Dysfunction and Future Coronary Artery Disease

OBJECTIVE To assess the association between erectile dysfunction (ED) and the long-term risk of coronary artery disease (CAD) and the role of age as a modifier of this association. PARTICIPANTS AND METHODS From January 1, 1996, to December 31, 2005, we biennially screened a random sample of 1402 community-dwelling men with regular sexual partners and without known CAD for the presence of ED. Incidence densities of CAD were calculated after age stratification and adjusted for potential confounders by time-dependent Cox proportional hazards models. RESULTS The prevalence of ED was 2% for men aged 40 to 49 years, 6% for men aged 50 to 59 years, 17% for men aged 60 to 69 years, and 39% for men aged 70 years or older. The CAD incidence densities per 1000 person-years for men without ED in each age group were 0.94 (40-49 years), 5.09 (50-59 years), 10.72 (60-69 years), and 23.30 (> or =70 years). For men with ED, the incidence densities of CAD for each age group were 48.52 (40-49 years), 27.15 (50-59 years), 23.97 (60-69 years), and 29.63 (> or =70 years). CONCLUSION ED and CAD may be differing manifestations of a common underlying vascular pathology. When ED occurs in a younger man, it is associated with a marked increase in the risk of future cardiac events, whereas in older men, ED appears to be of little prognostic importance. Young men with ED may be ideal candidates for cardiovascular risk factor screening and medical intervention.

PD-L1 (B7-h1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: Associations with localized stage progression

PD‐L1 (programmed death ligand 1, B7‐H1) is a cell surface glycoprotein that can impair T‐cell function. PD‐L1 is aberrantly expressed by multiple human malignancies and has been shown to carry a highly unfavorable prognosis in patients with kidney cancer. The role of PD‐L1 was evaluated as a mechanism for local stage progression in urothelial carcinoma (UC) of the bladder.

B7-H3 Ligand Expression by Prostate Cancer: A Novel Marker of Prognosis and Potential Target for Therapy

B7 coregulatory ligands can be aberrantly expressed in human disease. In the context of cancer, these ligands may act as antigen-specific inhibitors of T-cell-mediated antitumoral immunity. We recently reported that B7-H1 expression by carcinomas of the kidney and bladder portends aggressive disease and diminished survival. The expression of these proteins in prostate cancer, however, has not been investigated. We evaluated B7-H3 and B7-H1 protein expression in the pathologic specimens of 338 men treated for clinically localized prostate cancer between 1995 and 1998 with radical retropubic prostatectomy. Expression levels of B7-H3 in prostate cancer were correlated with pathologic indicators of aggressive cancer as well as clinical outcome. We report that B7-H3 is uniformly and aberrantly expressed by adenocarcinomas of the prostate, high-grade prostatic intraepithelial neoplasia, and four prostate cancer cell lines, whereas B7-H1 is rarely expressed. B7-H3 is expressed by benign prostatic epithelia, although at a more reduced level relative to neoplastic tissue. Increasing levels of B7-H3 intensity correlate with worsening clinicopathologic features of prostate cancer. Marked B7-H3 intensity, present in 67 (19.8%) specimens, confers a >4-fold increased risk of cancer progression after surgery (risk ratio, 4.42; P < 0.001). A survey of normal tissues revealed that B7-H3 is expressed within the liver, urothelium, and fetal kidney. In summary, B7-H3 is aberrantly expressed in all prostate cancers and represents an independent predictor of cancer progression following surgery. Moreover, B7-H3 encompasses a novel diagnostic and potential therapeutic target for the clinical management of prostate cancer and, perhaps, other malignancies as well.

Urachal carcinoma: Clinicopathologic features and long-term outcomes of an aggressive malignancy

Urachal carcinoma (UrC) is a rare malignancy, and patients with this disease have a poor prognosis. In this article, the authors report 50 years of experience with this tumor at the Mayo Clinic.

The Role of a Combined Regimen With Intravesical Chemotherapy and Hyperthermia in the Management of Non-muscle-invasive Bladder Cancer: A Systematic Review

CONTEXT Due to the suboptimal clinical outcomes of current therapies for non-muscle-invasive bladder cancer (NMIBC), the search for better therapeutic options continues. One option is chemohyperthermia (C-HT): microwave-induced hyperthermia (HT) with intravesical chemotherapy, typically mitomycin C (MMC). During the last 15 yr, the combined regimen has been tested in different clinical settings. OBJECTIVE To perform a systematic review to evaluate the efficacy of C-HT as a treatment for NMIBC. EVIDENCE ACQUISITION The review process followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. An electronic search of the Medline, Embase, Cochrane Library, CancerLit, and ClinicalTrials.gov databases was undertaken. Relevant conference abstracts and urology journals were also searched manually. Two reviewers independently reviewed candidate studies for eligibility and abstracted data from studies that met inclusion criteria. The primary end point was time to recurrence. Secondary end points included time to progression, bladder preservation rate, and adverse event (AE) rate. EVIDENCE SYNTHESIS A total of 22 studies met inclusion criteria and underwent data extraction. When possible, data were combined using random effects meta-analytic techniques. Recurrence was seen 59% less after C-HT than after MMC alone. Due to short follow-up, no conclusions can be drawn about time to recurrence and progression. The overall bladder preservation rate after C-HT was 87.6%. This rate appeared higher than after MMC alone, but valid comparison studies were lacking. AEs were higher with C-HT than with MMC alone, but this difference was not statistically significant. CONCLUSIONS Published data suggest a 59% relative reduction in NMIBC recurrence when C-HT is compared with MMC alone. C-HT also appears to improve bladder preservation rate. However, due to a limited number of randomized trials and to heterogeneity in study design, definitive conclusions cannot be drawn. In the future, C-HT may become standard therapy for high-risk patients with recurrent tumors, for patients who are unsuitable for radical cystectomy, and in cases for which bacillus Calmette-Guérin treatment is contraindicated.

IDENTIFICATION OF A SOLUBLE FORM OF B7-H1 THAT RETAINS IMMUNOSUPPRESSIVE ACTIVITY AND IS ASSOCIATED WITH AGGRESSIVE RENAL CELL CARCINOMA

Purpose: Release of inhibitory coregulatory proteins into the circulation may represent one mechanism by which tumors thwart immune responses. Our objective was to determine whether soluble B7-H1 (sB7-H1) levels in patients with clear cell renal cell carcinoma (ccRCC) are associated with pathologic features and patient outcome. Experimental Design: We developed an ELISA for quantification of sB7-H1 in biological fluids. Biochemical confirmation of the measured analyte as sB7-H1 was done by protein microsequencing using supernates from tumor cell lines. Biological activity of sB7-H1 was assessed in vitro utilizing T-cell apoptosis assays. We tested sB7-H1 levels in the sera from 172 ccRCC patients and correlated sB7-H1 levels with pathologic features and patient outcome. Results: sB7-H1 was detected in the cell supernatants of some B7-H1–positive tumor cell lines. Protein sequencing established that the measured sB7-H1 retained its receptor-binding domain and could deliver proapoptotic signals to T cells. Higher preoperative sB7-H1 levels were associated with larger tumors (P < 0.001), tumors of advanced stage (P = 0.017) and grade (P = 0.044), and tumors with necrosis (P = 0.003). A doubling of sB7-H1 levels was associated with a 41% increased risk of death (P = 0.010). Conclusion: Our observations suggest that sB7-H1 may be detected in the sera of ccRCC patients and that sB7-H1 may systemically impair host immunity, thereby fostering cancer progression and subsequent poor clinical outcome. Clin Cancer Res; 17(7); 1915–23. ©2011 AACR.

Costimulation, Coinhibition and Cancer

The immune system is an important defense mechanism against cancer and is often dysfunctional in patients with malignancies. The central regulator of the anti-cancer adaptive immune response is the T lymphocyte. T lymphocyte activation requires the completion of a carefully orchestrated series of specific steps that can be preempted or disrupted by any number of critical events. Particularly important is the provision of a costimulatory signal, the binding of accessory molecules on the antigen presenting cell to receptors on the T lymphocyte. Though costimulatory signals were traditionally envisioned as T lymphocyte-activating events, recent discoveries have highlighted their duality: they can be either stimulatory (costimulation) or inhibitory (coinhibition). In this article we review costimulation and coinhibition as potential targets for cancer therapy. We begin by presenting a general framework for thinking about the immune system in the context of cancer. Our discussion then bridges the various aspects of immune dysfunction seen in cancer with the presence of coinhibitory (ex: PD-1, PD-L1, CTLA-4, BTLA) and costimulatory (ex: CD28, ICOS, 4-1BB, CD40, OX40, CD27) signaling. Lastly, we develop a model of cancer-related immune dysfunction that parallels the concept of immunoediting. Throughout the article we emphasize clinically relevant research often applicable-but not limited-to the example of renal cell carcinoma.

Sacral Neuromodulation for the Dysfunctional Elimination Syndrome: A Single Center Experience With 20 Children

PURPOSE Recent advances in neuromodulation have demonstrated promise in treating children with the dysfunctional elimination syndrome refractory to medical management. Sacral nerve stimulation with the InterStim implantable device has been used in adults for management of chronic urinary complaints. However, there are few data regarding the usefulness of sacral nerve stimulation in children. We report our experience with sacral nerve stimulation for severe dysfunctional elimination syndrome. MATERIALS AND METHODS A total of 20 patients 8 to 17 years old with the dysfunctional elimination syndrome refractory to maximum medical treatment underwent sacral nerve stimulation at our institution. Patients were followed prospectively for a median of 27 months after the procedure. RESULTS Urinary incontinence, urgency and frequency, nocturnal enuresis and constipation were improved or resolved in 88% (14 of 16), 69% (9 of 13), 89% (8 of 9), 69% (11 of 16) and 71% (12 of 17) of the patients, respectively. Urinary retention requiring intermittent catheterization persisted in 75% of the patients (3 of 4) despite sacral nerve stimulation. Complications requiring operative treatment occurred in 20% of the patients (4 of 20). Following marked symptomatic improvement 2 devices were explanted at 20 and 19 months following placement, and both patients have remained symptom-free. CONCLUSIONS Sacral nerve stimulation is effective in the majority of our patients, and should be considered in children with severe dysfunctional elimination syndrome refractory to maximum medical treatment.

Targeting Molecular and Cellular Inhibitory Mechanisms for Improvement of Antitumor Memory Responses Reactivated by Tumor Cell Vaccine

Development of effective vaccination approaches to treat established tumors represents a focus of intensive research because such approaches offer the promise of enhancing immune system priming against tumor Ags via restimulation of pre-existing (memory) antitumoral helper and effector immune cells. However, inhibitory mechanisms, which function to limit the recall responses of tumor-specific immunity, remain poorly understood and interfere with therapies anticipated to induce protective immunity. The mouse renal cell carcinoma (RENCA) tumor model was used to investigate variables affecting vaccination outcomes. We demonstrate that although a whole cell irradiated tumor cell vaccine can trigger a functional antitumor memory response in the bone marrows of mice with established tumors, these responses do not culminate in the regression of established tumors. In addition, a CD103+ regulatory T (Treg) cell subset accumulates within the draining lymph nodes of tumor-bearing mice. We also show that B7-H1 (CD274, PD-L1), a negative costimulatory ligand, and CD4+ Treg cells collaborate to impair the recall responses of tumor-specific memory T cells. Specifically, mice bearing large established RENCA tumors were treated with tumor cell vaccination in combination with B7-H1 blockade and CD4+ T cell depletion (triple therapy treatment) and monitored for tumor growth and survival. Triple treatment therapy induced complete regression of large established RENCA tumors and raised long-lasting protective immunity. These results have implications for developing clinical antitumoral vaccination regimens in the setting in which tumors express elevated levels of B7-H1 in the presence of abundant Treg cells.

Timing of Androgen Deprivation Therapy and its Impact on Survival After Radical Prostatectomy: A Matched Cohort Study

PURPOSE We assessed the impact of the timing of androgen deprivation on disease progression after radical prostatectomy for patients with localized prostate cancer. MATERIALS AND METHODS We evaluated all patients who underwent radical prostatectomy between 1990 and 1999. Patients with pathological lymph node negative disease who received androgen deprivation therapy were then separated into 5 groups for analysis based on the time of hormone therapy initiation: 1--adjuvant androgen deprivation, 2--androgen deprivation therapy started at a postoperative prostate specific antigen of 0.4 ng/ml or greater, 3--at prostate specific antigen 1.0 or greater, 4--at prostate specific antigen 2.0 or greater and 5--at systemic progression. The first 4 groups were matched by clinical and pathological features to control groups who did not receive androgen deprivation after surgery using a nested, matched cohort design. Median followup for the entire cohort was 10 years. Clinical end points included systemic progression-free survival and cancer specific survival. RESULTS After matching clinicopathological variables adjuvant androgen deprivation therapy was associated with improved 10-year systemic progression-free survival (95% vs 90%, p <0.001) and 10-year cancer specific survival (98% vs 95%, p = 0.009), although overall survival for these patients remained unchanged (84% vs 83%, p = 0.427). In contrast, we found that men who started hormonal therapy at a postoperative prostate specific antigen of 0.4 or greater, 1.0 or 2.0 did not have improved systemic progression-free or cancer specific survival. CONCLUSIONS Adjuvant hormonal therapy modestly improves cancer specific survival and systemic progression-free survival after prostatectomy. The benefit of hormone therapy is lost when androgen deprivation is delivered at the time of prostate specific antigen recurrence or systemic progression.