Systemic and tumor-directed therapy for oligometastatic prostate cancer: study protocol for a phase II trial for veterans with de novo oligometastatic disease.

BACKGROUND: The treatment paradigm for metastatic hormone-sensitive prostate cancer (mHSPC) patients is evolving. PET/CT now offers improved sensitivity and accuracy in staging. Recent randomized trial data supports escalated hormone therapy, local primary tumor therapy, and metastasis-directed therapy. The impact of combining such therapies into a multimodal approach is unknown. This Phase II single-arm clinical trial sponsored and funded by Veterans Affairs combines local, metastasis-directed, and systemic therapies to durably render patients free of detectable disease off active therapy. METHODS: Patients with newly-diagnosed M1a/b prostate cancer (PSMA PET/CT staging is permitted) and 1-5 radiographically visible metastases (excluding pelvic lymph nodes) are undergoing local treatment with radical prostatectomy, limited duration systemic therapy for a total of six months (leuprolide, abiraterone acetate with prednisone, and apalutamide), metastasis-directed stereotactic body radiotherapy (SBRT), and post-operative fractionated radiotherapy if pT ≥ 3a, N1, or positive margins are present. The primary endpoint is the percent of patients achieving a serum PSA of < 0.05 ng/mL six months after recovery of serum testosterone ≥150 ng/dL. Secondary endpoints include time to biochemical progression, time to radiographic progression, time to initiation of alternative antineoplastic therapy, prostate cancer specific survival, health related quality-of-life, safety and tolerability. DISCUSSION: To our knowledge, this is the first trial that tests a comprehensive systemic and tumor directed therapeutic strategy for patients with newly diagnosed oligometastatic prostate cancer. This trial, and others like it, represent the critical first step towards curative intent therapy for a patient population where palliation has been the norm. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03298087 (registration date: September 29, 2017).

Distal urethral reconstruction with AlloDerm: a case report and review of the literature.

Reconstruction of large urethral defects is a complex problem for which no standardized surgical guidelines exist due to the lack of clinical trials demonstrating definitively the superiority of one technique over another. AlloDerm has been used in other surgical specialties with success, however, its utility in urologic surgery and, more specifically, for urethral reconstruction has been limited. In this case report, we demonstrate its application in a single-staged closure of a significant anterior urethral defect following distal penile necrosis secondary to an extruded penile prosthesis in a diabetic patient.

Eicosanoid-induced store-operated calcium entry in dendritic cells.

BACKGROUND: Eicosanoids are generally recognized to exert potent immunomodulatory properties, including effects on T cell, antigen-presenting cell (APC), and dendritic cell (DC) maturation and function. Since DC maturation and function may also be regulated by store-operated calcium entry (SOCE), we hypothesized that the effects of eicosanoids on DC function may in part be regulated through changes in intracellular calcium. METHODS: DC derived from the bone marrow of male Balb/ByJ mice cultured for 7 d in the presence of granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) were used to study the effects of eicosanoids on SOCE and the resulting Ca(2+) mobilization. RESULTS: The 5-lipoxygenase (5-LO) products leukotriene B(4) (LTB(4)) and LTD(4,) but not LTC(4), depleted Ca(2+) from DC endoplasmic reticulum stores. The specificity of LTB(4) and LTD(4) on Ca(2+) store-depletion was confirmed by the ability of the specific receptor antagonists, LY25583 and MK571, respectively, to abrogate Ca(2+) store depletion. RT-PCR demonstrated DC receptors for LTB(4) (BLT(1) and BLT(2)) and the cysteinyl-LTs (CysLT(1), CysLT(2), and GPR17). We also detected transient receptor potential canonical (TRPC) 1, 2, 4, and 6 and stromal interaction molecule 1 (STIM1) on CD11c(+) DCs, suggesting these proteins also participate in DC SOCE. In contrast, the cyclooxygenase (CO) metabolite PGE(2) had no effect on DC Ca(2+) mobilization. CONCLUSIONS: To our knowledge, these are the first observations of distinct effects of eicosanoids on DC Ca(2+) mobilization, which may have important implications for the regulation of DC maturation at sites of immune and non-immune inflammation.

Evaluation of Urology Residency Training and Perceived Resident Abilities in the United States.

OBJECTIVE: To identify differences and potential deficiencies in urology residency training programs in the United States as they are perceived by residents/recent graduates and program directors. MATERIALS AND METHODS: A 45-question and 38-question survey was sent to chief residents/recent graduates and program directors, respectively, at all 120 US urology programs regarding prior medical education, urologic training curricula, and perceived surgical proficiency, among other topics. RESULTS: Survey response rate was 58% and 52% for residents and program directors, respectively. Responses regarding program characteristics (e.g., salary, vacation) and research training were similar between program directors and residents. However, their responses regarding skills training and subspecialty training (e.g., robotics and pediatrics) differed substantially. Program directors reported the availability of advanced skills trainers (robot-88%, laparoscopic-86%), whereas fewer residents felt they were available (robot 54% and laparoscopic 72%). The same discrepancies persisted with questions about subspecialty exposure (e.g., program directors reported 48% renal transplant experience vs. 13% reported by residents). Most residents felt comfortable performing essential urology procedures (e.g., cystoscopy/ureteroscopy, open nephrectomy). In contrast, the majority expressed a lack of confidence in performing unsupervised advanced minimally invasive procedures (e.g., laparoscopic and robotic partial nephrectomy, endopyelotomy). Among the responding residents, 72% pursued fellowship training; nearly two-thirds of these residents chose to enter fellowship in order to overcome perceived training deficiencies. CONCLUSIONS: Program directors and residents have differing perceptions regarding the education and resources associated with US urology residency training programs. US graduates of urology residency programs express a perceived lack of confidence in several procedures that are commonly encountered in a general urologic practice.

Aquablation outcomes for the U.S. cohort of men with LUTS due to BPH in large prostates (80-150 cc).

Between September and December 2017, 82 men with moderate-to-severe lower urinary tract symptoms due to benign prostatic hyperplasia LUTS/BPH and prostate volume of 80-150 cc underwent Aquablation in a prospective multicenter clinical trial in the United States. Baseline patient and clinical demographics and standardized postoperative parameters were collected and tabulated in a central independently monitored database. Adverse events through 3 months were adjudicated by an independent clinical events committee. Mean pre-treatment prostate volume was 108 ± 21.1 cc. Mean operative time was 38.2 ± 14.4 min and mean Aquablation resection time was 7.7 ± 3.3 min. Additional electrocautery for hemostasis was not needed in any patient following Aquablation. The average length of stay following the procedure was 1.6 ± 1.0 days. Mean pre- and 3 months post-treatment IPSS scores were 23.7 ± 6.4 and 7.1 ± 5.1, -16.6, p < 0.01. Mean pre- and 3 months post-treatment Qmax were 9.2 ± 3.3 ml/s and 19.5 ± 13 ml/s, + 10.8 ml/s, p < 0.01. Mean pre- and 3 months post-treatment post-void residuals were 120.6 ± 119.1 cc and 50.6 ± 61.6 cc, -72.0 cc, p < 0.01. The observed Clavien-Dindo grade 2 or higher event rate at 3 months was 34.1%. Aquablation is a safe and effective treatment option for men with large prostates (80-150 cc) suffering from LUTS/BPH.

Pregnancy after kidney and kidney-pancreas transplantation under tacrolimus: a single center's experience.

BACKGROUND: Chronic renal failure leads to amenorrhea, and successful pregnancy is rare. The aim of the present report is to examine the outcome of pregnancies under tacrolimus after kidney transplantation (KTx) and simultaneous kidney-pancreas transplantation (SPKTx). METHOD: All pregnancies under tacrolimus after KTx or SPKTx from 1993 to April 2002 were retrospectively examined. Renal function and the mother's survival were followed until December 2002. RESULTS: Thirteen mothers after KTx delivered 19 babies, and 2 mothers after SPKTx delivered 3 babies. All mothers survived the pregnancy and retained allograft function. One mother had a stillborn baby from an unrecognized amniotic fluid leak and a small ischemic placenta. The mean gestational period was 34.4 +/- 5.1 weeks. Mean birth weight was 2373 +/- 1001 g. Birth-weight percentile to gestational period was 40 +/- 28. None of the mothers experienced rejection during the pregnancy. Three pregnancies in mothers with KTx experienced toxemia of pregnancy, and one mother with SPKTx developed pre-eclampsia during both pregnancies. Five mothers (6 deliveries, 27.3%) required caesarian section. During the follow-up period, one mother died from a cerebrovascular accident. Another five mothers returned to dialysis 55.6 +/- 32.4 months after the last delivery and 99.4+28.5 months after the last KTx. Both SPKTx mothers have maintained normal renal and pancreatic allograft function 42 and 62 months postdelivery. CONCLUSION: All mothers survived the pregnancy. One baby was stillborn. Forty-one percent of babies were either preterm or premature, and 27% of babies were delivered by caesarean section. Toxemia of pregnancy or pre-eclampsia was observed in 23% of pregnancies postKTx and SPKTx. None of the mothers experienced rejection during their pregnancy.

Long-term results of pediatric renal transplantation into a dysfunctional lower urinary tract.

BACKGROUND: The authors reviewed their long-term experience with pediatric renal transplantation into a dysfunctional lower urinary tract to evaluate the results of contemporary lower urinary tract evaluation and management on graft survival and function. METHODS: Between 1990 and 1996, 21 renal transplants were performed in 20 children with dysfunctional lower urinary tracts and 61 transplants were performed in 61 patients with normal lower urinary tracts. The minimum follow-up was 36 months (mean, 62.0 +/- 19.6 months). The cause of lower urinary tract dysfunction included posterior urethral valves (n=13), prune belly syndrome (n=4), meningomyelocele (n=2), and urogenital sinus abnormality (n=1). Urodynamics were performed on all children with dysfunctional lower urinary tracts. Using these perioperative assessments, lower tract management strategies were devised, including timed voiding alone (n=6), clean intermittent catheterization (n=8), bladder augmentation (n=4), and supravesical urinary diversion (n=2). RESULTS: Overall 5-year actuarial patient and graft survival rates were 100% versus 95% (P=not significant [NS]) and 83% versus 69% in the dysfunctional and normal urinary tract groups (P=NS), respectively. Mean serum creatinine levels in dysfunctional and normal urinary tract patients with functioning grafts at 3 years were 1.3 +/- 0.5 and 1.3 +/- 0.7 mg/dL, respectively (P=NS). However, 35% of patients with a dysfunctional lower urinary tract experienced urologic complications. CONCLUSIONS: Pediatric renal transplantation into a dysfunctional lower urinary tract yields outcomes comparable to transplantation into the normal lower urinary tract. Because of the high urologic complication rates, careful surveillance of lower urinary tract function by urodynamic evaluation is essential to optimize these outcomes.

Cadaveric renal transplantation using kidneys from donors greater than 60 years old.

Transplantation of kidneys from donors over the age of 60 yr is controversial. However, as the demand for cadaveric kidneys far exceeds the supply, exploration of the usefulness of kidneys outside the currently accepted donor pool is necessary. Between January 1987 and July 1989, 31 (5.5%) of the 558 cadaveric renal transplants performed at the University of Pittsburgh utilized organs from donors older than 60 yr. Median recipient age was 41 yr (range 24-71 yr); 4 recipients were diabetic and 6 had panel-reactive antibody levels greater than 20% at the time of transplant. All recipients were treated with cyclosporine, prednisone and azathioprine. The 1-yr allograft survival was 65% which was less than but not statistically different from the graft survival of 80% in a retrospective selected control group who received grafts from younger donors aged 11 to 50 yr. However, the 1-yr graft survival of older donor kidneys with cold ischemia time greater than 48 hours was 38%, which was significantly poorer than the 78% 1-yr graft survival seen with cold ischemia times less than 48 h (p=0.04 Breslow). The mean serum creatinine was significantly higher in the older donor kidneys at 1, 3, and 12 months post-transplant than in the control kidneys even when kidneys with greater than 48 h of cold ischemia time were excluded. In summary, transplantation of cadaver kidneys from donors older than 60 yr results in acceptable graft survival rates. These kidneys are more susceptible to cold ischemic injury and function with a higher serum creatinine than kidneys from younger donors. Expansion of the donor pool by the use of older donor kidneys in selected recipients could have an impact on alleviating the chronic national cadaver kidney shortage.

Hemorrhagic complications of enoxaparin and aspirin in patients with kidney transplants.

STUDY OBJECTIVE: To evaluate the frequency of early posttransplant hemorrhagic complications in patients with kidney and kidney-pancreas transplants who received thromboprophylaxis with enoxaparin and aspirin. DESIGN: Retrospective chart review. SETTING: University-based tertiary care center. PATIENTS: Thirteen patients who had received enoxaparin within 10 days of kidney or kidney-pancreas transplantation. INTERVENTION: Medical records were reviewed, and data from patients who had received low-dose aspirin 81 mg once/day and enoxaparin within 10 days of transplantation were collected. MEASUREMENTS AND MAIN RESULTS: Major bleeding events were defined as intracranial or retroperitoneal bleeding, or a decrease in hemoglobin of greater than 2 g/dl that was confirmed on repeat evaluation. Nine (69%) of the 13 patients had confirmed major bleeding events and required blood transfusions. Six of the nine patients had elevated serum creatinine levels. CONCLUSION: The combination of enoxaparin and low-dose aspirin early after kidney or kidney-pancreas transplantation was associated with a high frequency of hemorrhagic events. Further evaluation is needed to determine the safety of enoxaparin in combination with aspirin after transplantation.

Intravesical capsaicin for the treatment of interstitial cystitis: a pilot study.

OBJECTIVES: To study the safety and efficacy of intravesically administered capsaicin, a C-fiber afferent neurotoxin, in patients with interstitial cystitis (IC). METHODS: A pilot study of intravesical capsaicin therapy was performed on 5 female patients diagnosed with IC using NIDDK criteria. Patients were evaluated with cystoscopy and CMG on initial presentation. Bladder capacity, urinary histamine, PGE2 and substance P were measured before and after treatment. A symptom score, visual analogue pain score and frequency/nocturia charts were completed before treatment and weekly thereafter by each patient. Topical anesthesia (30 mls of 0.5% bupivacaine) was instilled intravesically for 30 minutes prior to each treatment with capsaicin. The initial instillation consisted of vehicle (1% ethanol in normal saline) and subsequent weekly instillations of capsaicin in increasing concentrations (10, 50, 100, and 250 uM solutions in 1% ethanol) were given as tolerated by the patient. RESULTS: Four out of 5 of the patients experienced subjective improvement in both symptom and pain score. Bladder capacity improved in 1 patient and symptoms of frequency and nocturia improved in 2 patients. Urinary histamine and PGE2 revealed no trend between before and after treatment; however, 3 out of 5 of the patients did have a trend to decreased substance P. No complications were noted during the course of this study. CONCLUSIONS: Intravesical capsaicin is a safe and promising treatment for interstitial cystitis. A potential mechanism of action is desensitization of bladder C-fiber afferents which presumably initiate painful sensations in IC patients. Low dose intravesical capsaicin therapy represents a potential treatment option for interstitial cystitis.

Significance of divergent expression of prostaglandin EP4 and EP3 receptors in human prostate cancer.

PGE2 has been implicated in prostate cancer tumorigenesis. We hypothesized that abnormal prostaglandin receptor (EPR) expression may contribute to prostate cancer growth. Twenty-six archived radical prostatectomy specimens were evaluated by immunohistochemistry (IHC) and Western blotting for the expression of EP1, EP2, EP3, and EP4. As a corollary, EPR expression in one normal (PZ-HPV7) and four prostate cancer cell lines (CA-HPV10, LNCaP, PC3, and Du145) were assessed by Western blotting. Prostate cancer and normal cell growth were compared in vitro after EPR blockade, siRNA EPR knockdown, or overexpression. EP1, EP2, EP3, and EP4 receptors were detected by IHC in all areas of benign tissue within the clinical prostate cancer specimens. In areas of prostate cancer, EP4 and EP2 were overexpressed in 85% (22 of 26) and 75% (18 of 24) and EP3 expression was reduced in all (26 of 26, 100%) specimens (P < 0.05 vs. benign tissue). EP1 showed no specific differential expression pattern. Increased EP4 and reduced EP3 was confirmed by Western blotting in fresh clinical specimens and in prostate cancer cell lines (CA-HPV10, LNCaP, PC3, and Du145) compared with the normal prostate cell line (PZ-HPV7). EP2 and EP4 siRNA knockdown resulted in reduced in vitro growth and metastasis-related gene expression (MMP9 and Runx2) of prostate cancer lines, and in vitro migration was inhibited by EP4 antagonists. As a corollary, EP3-overexpressing PC3 cells displayed impaired growth in vitro. Human prostate cancer is associated with EP4 and EP2 overexpression and reduced EP3 expression. These data suggest that targeting specific EPR may represent a novel therapeutic approach for prostate cancer.

Thyroid hormone in the treatment of post-transplant acute tubular necrosis (ATN).

Delayed graft function (DGF) in cadaver kidney transplants is a common problem and is often due to acute tubular necrosis (ATN). DGF in transplants may have a deleterious effect on long-term graft survival. Since thyroid hormone has been shown to hasten recovery from ATN in experimental models, we designed a trial to determine if a defined course of triiodothyronine (T3) would improve the short- or long-term outcome of patients with DGF in cadaveric transplants. A prospective, randomized, placebo controlled, double blind trial of T3 was carried out in patients with DGF in cadaveric renal transplants. End-points were percentage requiring dialysis, percentage recovering function, time to recovery and length of hospital stay. Long-term outcomes were percentage grafts functioning at 1 year and mean serum creatinine at 1 year. Forty-four patients were randomized to receive either T3 or placebo. Three patients were dropped from each group when early biopsies disclosed that DGF was due to rejection. The groups were well matched by age, cold ischemia time of the graft, and percentage reactivity to a random panel of antigens. Baseline thyroid function studies, including T3, reverse T3 (rT3), and thyroid stimulating hormone (TSH) levels, were similar between the two groups and typical of 'euthyroid-sick syndrome'. T3 had no effect on percentage requiring dialysis, time to recovery, percentage recovering function, or length of stay. At 1 year follow-up, graft function was similar in both groups and significantly lower than that seen in patients with good initial function. Thyroid hormone, given early in the course of DGF in cadaver kidney recipients, had no effect on the course of DGF. Long-term graft function is impaired in patients who experience post-transplant DGF compared to those who have good initial function.

Tolerogenic immunosuppression for organ transplantation.

BACKGROUND: Insight into the mechanisms of organ engraftment and acquired tolerance has made it possible to facilitate these mechanisms, by tailoring the timing and dosage of immunosuppression in accordance with two therapeutic principles: recipient pretreatment, and minimum use of post-transplant immunosuppression. We aimed to apply these principles in recipients of renal and extrarenal organ transplants. METHODS: 82 patients awaiting kidney, liver, pancreas, or intestinal transplantation were pretreated with about 5 mg/kg of a broadly reacting rabbit antithymocyte globulin during several hours. Post-transplant immunosuppression was restricted to tacrolimus unless additional drugs were needed to treat breakthrough rejection. After 4 months, patients on tacrolimus monotherapy were considered for dose-spacing to every other day or longer intervals. FINDINGS: We frequently saw evidence of immune activation in graft biopsy samples, but unless this was associated with graft dysfunction or serious immune destruction, treatment usually was not intensified. Immunosuppression-related morbidity was virtually eliminated. 78 (95%) of 82 patients survived at 1 year and at 13-18 months. Graft survival was 73 (89%) of 82 at 1 year and 72 (88%) of 82 at 13-18 months. Of the 72 recipients with surviving grafts, 43 are on spaced doses of tacrolimus monotherapy: every other day (n=6), three times per week (11), twice per week (15), or once per week (11). INTERPRETATION: The striking ability to wean immunosuppression in these recipients indicates variable induction of tolerance. The simple therapeutic principles are neither drug-specific nor organ-specific. Systematic application of these principles should allow improvements in quality of life and long-term survival after organ transplantation.

Kidney transplantation under a tolerogenic regimen of recipient pretreatment and low-dose postoperative immunosuppression with subsequent weaning.

OBJECTIVE: The purpose of this work was to perform kidney transplantation under a regimen of immunosuppression that facilitates rather than interferes with the recently defined mechanisms of alloengraftment and acquired tolerance. SUMMARY BACKGROUND DATA: In almost all centers, multiple immunosuppressive agents are given in large doses after kidney transplantation in an attempt to reduce the incidence of acute rejection to near zero. With the elucidation of the mechanisms of alloengraftment and acquired tolerance, it was realized that such heavy prophylactic immunosuppression could systematically subvert the clonal exhaustion-deletion that is the seminal mechanism of tolerance. In addition, it has been established that the rejection response can be made more readily treatable by pretransplant immunosuppression. Consequently, we conducted kidney transplantation in compliance with 2 therapeutic principles: recipient pretreatment and the least possible use of posttransplant immunosuppression. METHODS: One-hundred fifty unselected renal transplant recipients with a mean age of 51 +/- 15 years and multiple risk factors had pretreatment with approximately 5 mg/kg of rabbit antithymocyte globulin (Thymoglobulin) in the hours before transplantation, under covering bolus doses of prednisone to prevent cytokine reactions. Minimal posttransplant immunosuppression was with tacrolimus monotherapy to which steroids or other agents were added only for the treatment of rejection. At or after 4 months after transplant, spaced-dose weaning from tacrolimus monotherapy was begun in patients who had exhibited a satisfactory course. RESULTS: One-year actuarial patient and graft survival was 97% and 92%, respectively. Although the incidence of early acute rejection was 37%, only 7% required prolonged treatment with any agent other than tacrolimus. After a follow-up of 6 to 21 months, the mean serum creatinine in patients with functioning grafts is 1.8 +/- 1.0 mg/dL. Seventy-three percent of the patients met the criteria for spaced weaning. Although rejection episodes occasionally required restoration of daily treatment, 94 (63%) of the 150 patients currently receive tacrolimus in spaced doses ranging from every other day to once a week. CONCLUSIONS: With this approach to immunosuppression, it has been possible to avoid early posttransplant overimmunosuppression and thereby to promote the evolution of a degree of partial tolerance sufficient to undertake substantial dose reduction. The strategy, which is applicable for all organ grafts, constitutes a paradigm shift in transplant management at our center.