A comprehensive history of injection therapy for erectile dysfunction, 1982-2023.

INTRODUCTION: Although oral phosphodiesterase 5 inhibitors represent a first choice and long-term option for about half of all patients with erectile dysfunction (ED), self-injection therapy with vasoactive drugs remains a viable alternative for all those who are not reacting or cannot tolerate oral drug therapy. This current injection therapy has an interesting history beginning in 1982. OBJECTIVES: To provide a comprehensive history of self-injection therapy from the very beginnings in 1982 by contemporary witnesses and some members of the International Society for Sexual Medicine's History Committee, a complete history of injection therapy is prepared from eyewitness accounts and review of the published literature on the subject, as well as an update of the current status of self-injection therapy. METHODS: Published data on injection therapy, as a diagnostic and therapeutic tool for ED, were reviewed thoroughly by PubMed and Medline research from 1982 until June 2023. Early pioneers and witnesses added firsthand details to this historical review. Therapeutic reports of injection therapy were reviewed, and results of side effects and complications were thoroughly reviewed. RESULTS: The pioneers of the first hours were Ronal Virag (1982) for papaverine, Giles Brindley (1983) for cavernosal alpha-blockade (phentolamine and phenoxybenzamine), Adrian Zorgniotti (1985) for papaverine/phentolamine, and Ganesan Adaikan and N. Ishii (1986) for prostaglandin E1. Moxisylyte (thymoxamine) was originally marketed but later withdrawn. The most common side effect is priapism, with the greatest risk of this from papaverine, which has modified its use for therapy. Currently, prostaglandin E1 and trimixes continue to be the agents of choice for diagnostic and therapeutic use in ED. A recent agent is a mixture of a vasoactive intestinal polypeptide (aviptadil) and phentolamine. CONCLUSIONS: After 40 years, self-injection therapy represents the medication with the highest efficacy and reliability rates and remains a viable option for many couples with ED. The history of this therapy is rich.

Model definition for genetic evaluation of purebred and crossbred lambs including heterosis.

Crossbreeding is a common practice among commercial sheep producers to improve animal performance. However, genetic evaluation of U.S. sheep is performed within breed type (terminal sire, semi-prolific, and western range). While incorporating crossbred records may improve assessment of purebreds, it requires accounting for heterotic and breed effects in the evaluation. The objectives of this study were to: 1) describe the development of a paternal composite (PC) line, 2) determine the effect of direct and maternal heterosis on growth traits of crossbred lambs, 3) estimate (co)variance components for direct and maternal additive, and uncorrelated maternal environmental, effects, and 4) provide an interpretation of the estimates of random effects of genetic groups, and to use those solutions to compare the genetic merit of founding breed subpopulations. Data included purebred and crossbred records on birth weight (BN; n = 14,536), pre-weaning weight measured at 39 or 84 d (WN; n = 9,362) depending on year, weaning weight measured at 123 d (WW; n = 9,297), and post-weaning weight measured at 252 d (PW; n = 1,614). Mean (SD) body weights were 5.3 (1.1), 16.8 (3.9) and 28.0 (7.6), 39.1 (7.2), and 54.2 (8.7) kg for BN, WN (at the two ages), WW, and PW, respectively. In designed experiments, the Siremax, Suffolk, Texel, Polypay, Columbia, Rambouillet, and Targhee breeds were compared within the same environment. Estimates of heterotic effects and covariance components were obtained using a multiple trait animal model. Genetic effects based on founders' breeds were significant and included in the model. Percent estimates of direct heterosis were 2.89 ± 0.61, 2.60 ± 0.65, 4.24 ± 0.56, and 6.09 ± 0.86, and estimates of maternal heterosis were 1.92 ± 0.87, 4.64 ± 0.80, 3.95 ± 0.66, and 4.04 ± 0.91, for BN, WN, WW, and PW, respectively. Correspondingly, direct heritability estimates were 0.17 ± 0.02, 0.13 ± 0.02, 0.17 ± 0.02, and 0.46 ± 0.04 for BN, WN, WW, and PW. Additive maternal effects accounted for trivial variation in PW. For BN, WN, and WW, respectively, maternal heritability estimates were 0.16 ± 0.02, 0.10 ± 0.02, and 0.07 ± 0.01. Uncorrelated maternal environmental effects accounted for little variation in any trait. Direct and maternal heterosis had considerable impact on growth traits, emphasizing the value of crossbreeding and the need to account for heterosis, in addition to breed effects, if crossbred lamb information is included in genetic evaluation.

Crossbreeding is common in commercial sheep enterprises. It allows breeds with different attributes to be combined to generate crossbred progeny tailored to production environments and customer preferences. Additionally, crossbreds often benefit from heterosis, performing at levels above the average of their parental breeds. Over two decades, body weights were collected at birth and at pre-weaning, weaning, and post-weaning ages on purebred and crossbred lambs from semi-prolific (Polypay), western range (Columbia, Rambouillet, Targhee), and terminal sire (Siremax, Suffolk, Texel) breeds at the U.S. Sheep Experiment Station. When combined, the value of direct heterosis­that due to a lamb being crossbred­and maternal heterosis­that due to the lamb's dam being crossbred­increased birth (5%) and post-natal (up to 10%) weights in crossbred lambs. This highlights the value of crossbreeding to the U.S. sheep industry, especially in western range production systems. Genetic variation between and within breeds also was detected for the purebred parental breeds. Such heterotic and breed effects must be accounted for if crossbred performance is to be incorporated in genetic evaluation of purebreds. Therefore, these results provide the foundation for utilizing crossbred information in the evaluation and selection of purebred sheep in the United States.

Interobserver and Intraobserver Agreement are Unsatisfactory When Determining Abstract Study Design and Level of Evidence.

BACKGROUND: Understanding differences between types of study design (SD) and level of evidence (LOE) are important when selecting research for presentation or publication and determining its potential clinical impact. The purpose of this study was to evaluate interobserver and intraobserver reliability when assigning LOE and SD as well as quantify the impact of a commonly used reference aid on these assessments. METHODS: Thirty-six accepted abstracts from the Pediatric Orthopaedic Society of North America (POSNA) 2021 annual meeting were selected for this study. Thirteen reviewers from the POSNA Evidence-Based Practice Committee were asked to determine LOE and SD for each abstract, first without any assistance or resources. Four weeks later, abstracts were reviewed again with the guidance of the Journal of Bone and Joint Surgery (JBJS) LOE chart, which is adapted from the Oxford Centre for Evidence-Based Medicine. Interobserver and intraobserver reliability were calculated using Fleiss' kappa statistic (k). χ2 analysis was used to compare the rate of SD-LOE mismatch between the first and second round of reviews. RESULTS: Interobserver reliability for LOE improved slightly from fair (k=0.28) to moderate (k=0.43) with use of the JBJS chart. There was better agreement with increasing LOE, with the most frequent disagreement between levels 3 and 4. Interobserver reliability for SD was fair for both rounds 1 (k=0.29) and 2 (k=0.37). Similar to LOE, there was better agreement with stronger SD. Intraobserver reliability was widely variable for both LOE and SD (k=0.10 to 0.92 for both). When matching a selected SD to its associated LOE, the overall rate of correct concordance was 82% in round 1 and 92% in round 2 (P<0.001). CONCLUSION: Interobserver reliability for LOE and SD was fair to moderate at best, even among experienced reviewers. Use of the JBJS/Oxford chart mildly improved agreement on LOE and resulted in less SD-LOE mismatch, but did not affect agreement on SD. LEVEL OF EVIDENCE: Level II.

Evaluation and Management of Testosterone Deficiency: AUA Guideline.

PURPOSE: There has been a marked increase in testosterone prescriptions in the past decade resulting in a growing need to give practicing clinicians proper guidance on the evaluation and management of the testosterone deficient patient. MATERIALS AND METHODS: A systematic review utilized research from the Mayo Clinic Evidence Based Practice Center and additional supplementation by the authors. Evidence-based statements were based on body of evidence strength Grade A, B, or C and were designated as Strong, Moderate, and Conditional Recommendations with additional statements presented in the form of Clinical Principles or Expert Opinions (table 1 in supplementary unabridged guideline, http://jurology.com/). RESULTS: This guideline was developed by a multi-disciplinary panel to inform clinicians on the proper assessment of patients with testosterone deficiency and the safe and effective management of men on testosterone therapy. Additional statements were developed to guide the clinician on the appropriate care of patients who are at risk for or have cardiovascular disease or prostate cancer as well as patients who are interested in preserving fertility. CONCLUSIONS: The care of testosterone deficient patients should focus on accurate assessment of total testosterone levels, symptoms, and signs as well as proper on-treatment monitoring to ensure therapeutic testosterone levels are reached and symptoms are ameliorated. Future longitudinal observational studies and clinical trials of significant duration in this space will improve diagnostic techniques and treatment of men with testosterone deficiency as well as provide more data on the adverse events that may be associated with testosterone therapy.

Decreasing suicide risk among patients with prostate cancer: Implications for depression, erectile dysfunction, and suicidal ideation screening.

OBJECTIVE: Prostate cancer is the most common malignancy among males, accounting for 19% of cancers, and the third most common cancer-related cause of death. Suicide rates in the United States have increased among males over the last decade. Further, suicide rates are higher in oncology patients, including patients with prostate cancer, compared to the general population. The objective of this article is to review the current literature and address the relationship between prostate cancer, depression, erectile dysfunction, and suicidal ideation. MATERIALS AND METHODS: We reviewed the current literature pertaining to prostate cancer and depression, and prostate cancer and suicide. Furthermore, associations were made between erectile dysfunction and depression. RESULTS: Men with prostate cancer at increased risk for suicidal death are White, unmarried, elderly, and men with distant disease. Time since diagnosis is also an important factor, since men are at risk of suicide>15 years after diagnosis. Approximately 60% of men with prostate cancer experience mental health distress, with 10%-40% having clinically significant depression. Additionally, patients that received androgen deprivation therapy (ADT) are 23% more likely to develop depression compared to those without ADT. Longitudinal studies of prostate cancer patients suggest that erectile dysfunction after curative treatment may have a significant psychological effect leading to depression. Herein, a newly proposed screening algorithm suggests for an evaluation with the expanded prostate cancer index composite-clinical practice, patient health questionnaire-9, and an 8-question suicidal ideation questionnaire to assess for health-related quality of life, depression, and suicidal ideation. CONCLUSION: The burden of screening for erectile dysfunction, depression and suicidal ideation lies with the entire health care team, as there appears to be an association between these diagnoses, that is, compounded in patients with prostate cancer. The screening algorithm should assist with guiding timely and appropriate psychiatric referral to optimize outcomes in these high-risk patients.

Plication procedures-excisional and incisional corporoplasty and imbrication for Peyronie's disease.

Plication procedures for the correction of Peyronie's disease (PD) curvature are management options for PD patients. There are basically three types of procedures: excisional corporoplasty, incisional corporoplasty, and plication-only. This review is a compilation of English literature, peer-reviewed, published articles addressing these types of operations for Peyronie's curvature correction, not congenital curvature. According to the urology literature, this surgical type was initially used for correction of curvature associated with hypospadias repair or congenital penile curvature. The procedures also, for the most part, historically became an alternative for plaque excision and graft repair, because of the difficulty with such repairs and the often-resultant erectile dysfunction (ED). A brief section traces some of the origins of these various repairs, followed by a brief section on the selection criteria for these types of surgery for the patient with PD penile curvature. We also review the significant articles in which the three types were presented with modifications. Finally, several articles that compare the various surgical repairs are summarized in the order that they appear in the literature. These types of surgery have become a mainstay for the surgical correction of penile curvature due to PD.

Factors associated with suicide in patients with genitourinary malignancies.

BACKGROUND: Approximately 70% of all suicides in patients aged >60 years are attributed to physical illness, with higher rates noted in patients with cancer. The purpose of the current study was to characterize suicide rates among patients with genitourinary cancers and identify factors associated with suicide in this specific cohort. METHODS: Patients with prostate, bladder, kidney, testis, and penile cancer were identified in the Surveillance, Epidemiology, and End Results database (1988-2010). Standardized mortality ratios (SMRs) and 95% confidence intervals (95% CIs) were calculated for each anatomic site. Multivariable logistic regression models generated odds ratios (ORs) for the identification of factors associated with suicide for each malignancy. RESULTS: There were 2268 suicides identified among 1,239,522 individuals with genitourinary malignancies observed for 7,307,377 person-years. The SMRs for patients with cancer were 1.37 for prostate cancer (95% CI, 0.99-1.86), 2.71 for bladder cancer (95% CI, 2.02-3.62), 1.86 for kidney cancer (95% CI, 1.32-2.62), 1.23 for testis cancer (95% CI, 0.88-1.73), and 0.95 for penile cancer (95% CI, 0.65-1.35). On multivariable analysis, male sex was found to be associated with odds of suicide among patients with bladder cancer (OR, 6.63) and kidney cancer (OR, 4.98). Increasing age was associated with suicide for patients with prostate, bladder, and testis cancer (OR range, 1.03-1.06). Distant disease was associated with suicide in patients with prostate, bladder, and kidney cancer (OR range, 2.82-5.43). Among patients with prostate, bladder, and kidney cancer, African American patients were less likely to commit suicide compared with white individuals (OR range, 0.26-0.46). CONCLUSIONS: Suicide in patients with genitourinary malignancies poses a public health dilemma, especially among men, the elderly, and those with aggressive disease. Clinicians should be aware of risk factors for suicide in these patients.

A phase II, single-blind, randomized, crossover evaluation of the safety and efficacy of avanafil using visual sexual stimulation in patients with mild to moderate erectile dysfunction.

OBJECTIVE: To evaluate the safety, efficacy and time course of three doses of avanafil (50 mg, 100 mg and 200 mg) compared with sildenafil 50 mg or placebo, given in conjunction with visual sexual stimulation (VSS) videos in men with mild to moderate erectile dysfunction (ED). PATIENTS AND METHODS: Male patients, 35-70 years of age, with mild to moderate ED of ≥6 months duration, were included in the study. During the course of the study, each patient received placebo, active control (sildenafil 50 mg), and one dose of avanafil (50 mg, 100 mg or 200 mg), all administered in random order at least 72 h apart. RigiScan® (Dacomed Corp., Minneapolis, MN, USA) monitoring was used in conjunction with 20-min VSS videos (20, 60, and 100 min after dosing) to determine the duration of and time to ≥60% penile rigidity, maximum rigidity, tumescent activity units (TAUs), rigidity activity units (RAUs), and responses to the five-point Erection Assessment Scale. Safety assessments included adverse events (AEs), vital sign changes in response to dosing, laboratory results (complete blood counts, chemistry panel, prostate-specific antigen, serum testosterone, prothrombin time and urine analysis) and physical examination findings. RESULTS: Eighty-three patients were randomized and received at least one dose of study medication; 82 patients completed the study. Peak response to avanafil occurred in the early interval (20-40 min after dosing), while peak response to sildenafil occurred either in the middle (60-80 min) or late (100-120 min) intervals after dosing. Results were qualitatively similar for all other efficacy endpoints. During the 20-40-min interval, the majority of values for TAUs and RAUs with the avanafil 50-mg, 100-mg and 200-mg treatments were significantly superior to placebo (P < 0.05). Avanafil treatment was generally well tolerated; facial flushing (7-15%) was the most commonly observed AE, and no visual disturbances were reported. CONCLUSION: A favourable safety profile and improvement in sexual function, coupled with rapid onset of action and durability of effect, make avanafil an attractive option for males with ED, especially in the setting of on-demand treatment.

Retrospective study of multidisciplinary rounding on a thoracic surgical oncology unit

Multidisciplinary rounding (MDR) reduces medical errors and improves the quality of care for hospitalized patients. The purpose of this study was to evaluate hospital length of stay, patient satisfaction, admission to a skilled care facility, and the use of home health care or hospice in patients who received MDR compared to those who did not. This retrospective study included the records of 3,077 thoracic surgical patients with cancer who were admitted to a midwestern National Cancer Institute-designated comprehensive cancer center from January 1, 2006, through July 1, 2011. Overall mean length of stay was 5.3 days in the MDR group compared to 6.5 days in the no MDR group. The MDR group also had significantly shorter mean length of stay compared to the no MDR group among patients who were discharged home from the hospital, admitted to hospice following a hospital discharge, discharged to a skilled care facility, or admitted to home healthcare services. No significant differences in satisfaction scores were reported in patients who received MDR compared to those who did not. MDR is an important aspect of inpatient oncology care, and staff should be identified to participate who have expertise relevant to patients' needs.

Novel role of androgens in mitochondrial fission and apoptosis.

Androgen and androgen receptors (AR) play critical roles in the proliferation of prostate cancer through transcriptional regulation of target genes. Here, we found that androgens upregulated the expression of dynamin-related protein 1 (Drp1), which is involved in the induction of mitochondrial fission, a common event in mitosis and apoptosis. Clinical tissue samples and various prostate cancer cell lines revealed a positive correlation between Drp1 and AR levels. Treatment of androgen-sensitive cells with an AR agonist, R1881, and antagonist, bicalutamide, showed that Drp1 is transcriptionally regulated by androgens, as confirmed by an AR ChIP-seq assay. Live imaging experiments using pAcGFP1-Mito stably transfected LNCaP (mito-green) cells revealed that androgen did not induce significant mitochondrial fission by itself, although Drp1 was upregulated. However, when treated with CGP37157 (CGP), an inhibitor of mitochondrial Ca²âº efflux, these cells exhibited mitochondrial fission, which was further enhanced by pretreatment with R1881, suggesting that androgen-induced Drp1 expression facilitated CGP-induced mitochondrial fission. This enhanced mitochondrial fission was correlated with increased apoptosis. Transfection with dominant-negative (DN-Drp1, K38A) rescued cells from increased apoptosis, confirming the role of androgen-induced Drp1 in the observed apoptosis with combination treatment. Furthermore, we found that CGP reduced the expression of Mfn1, a protein that promotes mitochondrial fusion, a process which opposes fission. We suggest that androgen-increased Drp1 enhanced mitochondrial fission leading to apoptosis. The present study shows a novel role for androgens in the regulation of mitochondrial morphology that could potentially be utilized in prostate cancer therapy.

Summary of the recommendations on sexual dysfunctions in men.

INTRODUCTION: Sexual health is an integral part of overall health. Sexual dysfunction can have a major impact on quality of life and psychosocial and emotional well-being. AIM: To provide evidence-based, expert-opinion consensus guidelines for clinical management of sexual dysfunction in men. METHODS: An international consultation collaborating with major urologic and sexual medicine societies convened in Paris, July 2009. More than 190 multidisciplinary experts from 33 countries were assembled into 25 consultation committees. Committee members established scope and objectives for each chapter. Following an exhaustive review of available data and publications, committees developed evidence-based guidelines in each area. Main Outcome Measures. New algorithms and guidelines for assessment and treatment of sexual dysfunctions were developed based on work of previous consultations and evidence from scientific literature published from 2003 to 2009. The Oxford system of evidence-based review was systematically applied. Expert opinion was based on systematic grading of medical literature, and cultural and ethical considerations. RESULTS: Algorithms, recommendations, and guidelines for sexual dysfunction in men are presented. These guidelines were developed in an evidence-based, patient-centered, multidisciplinary manner. It was felt that all sexual dysfunctions should be evaluated and managed following a uniform strategy, thus the International Consultation of Sexual Medicine (ICSM-5) developed a stepwise diagnostic and treatment algorithm for sexual dysfunction. The main goal of ICSM-5 is to unmask the underlying etiology and/or indicate appropriate treatment options according to men's and women's individual needs (patient-centered medicine) using the best available data from population-based research (evidence-based medicine). Specific evaluation, treatment guidelines, and algorithms were developed for every sexual dysfunction in men, including erectile dysfunction; disorders of libido, orgasm, and ejaculation; Peyronie's disease; and priapism. CONCLUSIONS: Sexual dysfunction in men represents a group of common medical conditions that need to be managed from a multidisciplinary perspective.

High yield of saturation prostate biopsy for patients with previous negative biopsies and small prostates.

OBJECTIVES: Men with previously negative prostate biopsies but continued suspicion for carcinoma present a diagnostic dilemma often managed by saturation prostate biopsy (SPB). We sought to determine the patient characteristics for which repeat biopsy by SPB provides the greatest utility for prostate cancer detection. METHODS: The records of the men at the state hospital and affiliated Veterans Affairs Medical Center with previously negative prostate biopsy findings who had then undergone SPB were reviewed. The predictors of cancer were analyzed, and those that were significant were included in a multivariate logistic regression model. RESULTS: A total of 82 men underwent SPB from November 2001 to March 2006. Their mean age was 61 years (range 43 to 76), and 44 (54%) were white, 37 (45%) were African American, and 1 (1%) was Asian. The mean prostate-specific antigen level at SPB was 9.1 ng/mL (range 1.0 to 34). The number of prior biopsies was one in 43 patients (52%) and two or more in 39 patients (47%). The prostate volume averaged 53 cm(3) (range 12 to 200). SPB included a median of 24 cores (range 24 to 40). Of the 82 patients, 16 (19.5%) were diagnosed with cancer, of whom 10 (63%) elected to undergo radical prostatectomy. The only significant predictors of prostate cancer were the prostate-specific antigen level (P = 0.009) and prostate volume. The cancer detection rate was 57% for patients with a prostate volume less than 37 cm(3) and 7% for those with larger glands, and the difference was significant on multivariate analysis (odds ratio 31, 95% confidence interval 6 to 158, P <0.0001). CONCLUSIONS: The results of our study have shown that SPB is an effective diagnostic tool with a high yield for men with persistent suspicion for prostate cancer, prior negative biopsy findings, and a prostate volume less than 37 cm(3).

The use of multiple anchors for the treatment of idiopathic scoliosis.

STUDY DESIGN: Retrospective study. OBJECTIVE: The purpose of this study was to determine the effectiveness of concave collar-button wires used as anchors to correct and maintain spinal alignment in adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Correction of idiopathic scoliotic deformity has been reported with various systems. We have added concave collar-button wires to a multihook, dual-rod system as an adjunct to translation and stabilization of the spine during correction of AIS. METHODS: Sixty-seven patients failing brace treatment or with curve patterns >45 degrees underwent spinal correction. Evaluation was obtained with preoperative standing posteroanterior, lateral, and recumbent right and left bending radiographs using the Cobb method. The initial postoperative films and latest radiographs were measured also. A dual-rod multihook construct with a derotation maneuver was used in all cases. Collar-button wire implants were placed from the convex side of the deformity toward the concave rod through the base of the spinous processes within the construct to achieve and augment correction and stability. Twenty-four patients underwent prior anterior release and fusion by video assisted thoracoscopic surgery. RESULTS: Sixty-seven patients in total underwent this procedure. We achieved a 72.2% mean correction of thoracic curves and 63.2% mean correction of lumbar curves. There was a mean loss of correction of 2 degrees in the thoracic area and 2.2 degrees in the lumbar area after 2 years. Sagittal curve was unchanged after surgery. All patients demonstrated a solid fusion with no evidence of pseudarthrosis or junctional deformities. There were no cases of clinically significant wire breakage or hook pullout. Three delayed infections were noted. CONCLUSION: The use of multiple concave collar-button wires as anchors is a safe, easy, and reliable method of spinal stabilization in the coronal and sagittal planes. There is minimal loss of correction at long-term follow-up.

A multi-institution, minimally invasive urological oncology fellowship: a critical assessment of the clinical training and academic benefits.

PURPOSE: We evaluated the clinical training and academic productivity of a unique minimally invasive urological oncology fellowship performed in 3-month rotations at 4 institutions. MATERIAL AND METHODS: With Georgia Cancer Coalition grant funding and institutional support a faculty urologist (JAB) completed 3-month fellowships at Thomas Jefferson University, Philadelphia in 2002, Indiana University, Indianapolis in 2003, Massachusetts General Hospital, Boston in 2003 and Henry Ford Hospital, Detroit in 2004. RESULTS: The trainee operated under the direction of 8 surgeons and assisted/observed another 5. Total operative experience was 355 cases, including 53 standard laparoscopic radical prostatectomies, 100 robotic assisted laparoscopic radical prostatectomies, 30 standard (including 13 donor) and 22 hand assisted laparoscopic nephrectomies, 6 nephroureterectomies, 14 partial nephrectomies, 3 renal cyst decortications, 12 pyeloplasties, 5 adrenalectomies, 2 hand assisted laparoscopic ureterolysis procedures, 1 laparoscopic partial and 1 radical cystectomy, hand assisted laparoscopic cystectomy, robotic cystectomy, 26 open and 2 laparoscopic retroperitoneal lymph node dissections, 5 complex open bladder surgeries, 6 complex open renal surgeries and approximately 24 endoscopic laser upper tract tumor cases. Post-fellowship sequential initiation of laparoscopic renal cancer (April 2002), prostatectomy (July 2003) and donor nephrectomy (November 2003) programs was accomplished at the home institution. Academic projects were completed during each fellowship phase with 43 presented abstracts and 2 book chapters, 2 non-peer reviewed articles and 12 peer reviewed articles published to date. CONCLUSIONS: A multi-institution fellowship allows serial acquisition and incorporation of a wide variety of cutting edge, minimally invasive and oncological procedures into an academic practice. It allows greater exposure to more high volume experts in varying oncological subspecialties. Clinical research and academic productivity are possible.

Assessment of patient concern and adequacy of informed consent regarding infertility resulting from prostate cancer treatment.

OBJECTIVES: To address in a questionnaire-based study the frequency at which fertility is a concern for men when they consider their prostate cancer treatment options. A secondary aim was to assess the rate at which men were informed of the fertility implications of prostate cancer treatment by their physician before their selection of a treatment option. METHODS: Two questionnaires were used. One questionnaire was distributed to men with localized prostate cancer who had undergone treatment within the past year. These questions addressed whether continence, erectile function, and fertility were discussed with them by their physician during the prostate cancer treatment selection process. The second questionnaire was distributed to men with newly diagnosed prostate cancer and queried their level of concern about the effects of prostate cancer treatment on sexual function, urinary function, and fertility. RESULTS: All patients receiving the first questionnaire stated that they were informed of the incontinence and impotence side effects of prostate cancer treatments, but only 8.7% stated that they were informed of the effect that prostate cancer treatments would have on their future fertility. Of the patients completing the second questionnaire, 53.7% responded that incontinence was the side effect of prostate cancer treatment that caused them the most concern, 42.6% stated that erectile dysfunction was the most concerning, and 3.7% listed fertility as the major concern. CONCLUSIONS: Urologists should consider approaching the topic of infertility when discussing the pros and cons of various prostate cancer therapies with their younger patients.

Therapeutic advantage of combining calcium channel blockers and TRAIL in prostate cancer.

Disruption of intracellular calcium initiates multiple cell-damaging processes, such as apoptosis. In normal cells, the levels of Ca(2+) are low in the mitochondria, whereas in apoptotic cells, Ca(2+) increases. Mitochondria uptake Ca(2+) via an inner membrane channel called the uniporter and extrude it into the cytoplasm through a Na(+)/Ca(2+) exchanger. Overload of Ca(2+) in the mitochondria in CGP-treated cells leads to its damage, thus affecting cellular function and survival. The goal of these experiments was to determine the importance of mitochondrial calcium ([Ca(2+)](m)) in apoptosis of prostate cancer cells. Furthermore, we have examined the advantages of increasing the [Ca(2+)](m) and treating the cells with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a potent apoptotic agent. Our results show that, under these treatment conditions, inhibiting the Na(+)/Ca(2+) exchanger using benzothiazepin CGP-37157 (CGP) did not induce apoptosis. However, combination of CGP and TRAIL increased the apoptotic response approximately 25-fold compared with control. Increase in apoptosis followed enhanced levels of [Ca(2+)](m) and was accompanied by pronounced mitochondrial changes characteristic of mitochondria-mediated apoptosis. Experiments with calcium ionophores showed that mere increase in cytosolic and/or mitochondrial Ca(2+) was not sufficient to induce apoptosis. These results have therapeutic implications as inhibitors of Na(+)/Ca(2+) exchanger are being used for treating some neurologic and cardiologic ailments, and TRAIL induces apoptosis preferentially in cancer cells. Furthermore, this system provides an excellent model to investigate the role of [Ca(2+)](m) in apoptosis.

SAHA-sensitized prostate cancer cells to TNFalpha-related apoptosis-inducing ligand (TRAIL): mechanisms leading to synergistic apoptosis.

Treatment of cancer cells with histone deacetylase inhibitors (HDACi) such as suberolylanilide hydroxamic acid (SAHA) activates genes that promote apoptosis. To enhance proapoptotic efficiency, SAHA has been used in combination with radiation, kinase inhibitors and cytotoxic drugs. Although several prostate cells respond to TNFalpha-Related Apoptosis-Inducing Ligand (TRAIL), LNCaP are resistant. This model system was utilized to examine the advantages of combined treatment with SAHA and TRAIL. In LNCaP cells, TRAIL induced synergistic apoptosis when combined even with the lowest dose of SAHA. Treatment with caspase inhibitor confirmed that SAHA-induced apoptosis was mediated through caspases. In addition to induction of apoptosis, SAHA and TRAIL decreased the levels of proapoptotic proteins IKKalpha, IKKbeta and IKKgamma, suggesting that SAHA treatment may reduce the activity of NFkappaB. However, assay for NFkappaB luciferase reporter activity showed highly significant increase in SAHA-treated cells, supporting earlier suggestions that HDACi promotes NFkappaB transcriptional activity. Further analyses to determine the mechanisms by which the combination of SAHA and TRAIL led to synergistic apoptosis indicated that the apoptotic response of LNCaP is due to a complex regulation of death receptor pathway and alterations of NFkappaB activity at several regulatory steps.

Sensitization of TRAIL-resistant cells by inhibition of heat shock protein 90 with low-dose geldanamycin.

Due to its specificity and effectiveness, tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) is being tested for cancer therapy. Inhibition of the function of heat shock protein 90 (HSP90) is under clinical trials for cancer therapy. However, some cancer cells are resistant to TRAIL, and at the dose required for inducing apoptosis, geldanamycin, a drug that inhibits HSP90 function, has shown adverse effects. Therefore, our working plan was to identify a sublethal dose of geldanamycin and combine it with TRAIL to induce apoptosis in TRAIL-resistant prostate cancer cells. Treatment of LNCaP with 250 nmol/L geldanamycin inhibited HSP90 function but did not induce significant apoptosis. However, combination of geldanamycin and TRAIL induced highly significant apoptosis in TRAIL-resistant LNCaP cells. In addition to inducing caspase activity and apoptosis, treatment with geldanamycin and TRAIL decreased inhibitor of kappaB (IkappaB) kinase (IKK) complex proteins, IKKalpha, IKKbeta, and IKKgamma. The loss of IKK affected IkappaBalpha/nuclear factor-kappaB (NF-kappaB) interaction and reduced nuclear transport of NF-kappaB, resulting in reduced NF-kappaB activity. Our data show increase in apoptosis using low, suboptimal dose of geldanamycin when used with TRAIL. These results provide a means to alleviate two problems: resistance to TRAIL and adverse effects of high-dose geldanamycin.

Combination of proteasomal inhibitors lactacystin and MG132 induced synergistic apoptosis in prostate cancer cells.

The proteasome inhibitor Velcade (bortezomib/PS-341) has been shown to block the targeted proteolytic degradation of short-lived proteins that are involved in cell maintenance, growth, division, and death, advocating the use of proteasomal inhibitors as therapeutic agents. Although many studies focused on the use of one proteasomal inhibitor for therapy, we hypothesized that the combination of proteasome inhibitors Lactacystin (AG Scientific, Inc., San Diego CA) and MG132 (Biomol International, Plymouth Meeting, PA) may be more effective in inducing apoptosis. Additionally, this regimen would enable the use of sublethal doses of individual drugs, thus reducing adverse effects. Results indicate a significant increase in apoptosis when LNCaP prostate cancer cells were treated with increasing levels of Lactacystin, MG132, or a combination of sublethal doses of these two inhibitors. Furthermore, induction in apoptosis coincided with a significant loss of IKKalpha, IKKbeta, and IKKgamma proteins and NFkappaB activity. In addition to describing effective therapeutic agents, we provide a model system to facilitate the investigation of the mechanism of action of these drugs and their effects on the IKK-NFkappaB axis.