Penis Transplantation: First US Experience.

OBJECTIVE: We describe the first successful penis transplant in the United States in a patient with a history of subtotal penectomy for penile cancer. BACKGROUND: Penis transplantation represents a new paradigm in restoring anatomic appearance, urine conduit, and sexual function after genitourinary tissue loss. To date, only 2 penis transplants have been performed worldwide. METHODS: After institutional review board approval, extensive medical, surgical, and radiological evaluations of the patient were performed. His candidacy was reviewed by a multidisciplinary team of surgeons, physicians, psychiatrists, social workers, and nurse coordinators. After appropriate donor identification and recipient induction with antithymocyte globulin, allograft procurement and recipient preparation took place concurrently. Anastomoses of the urethra, corpora, cavernosal and dorsal arteries, dorsal vein, and dorsal nerves were performed, and also inclusion of a donor skin pedicle as the composite allograft. Maintenance immunosuppression consisted of mycophenolate mofetil, tacrolimus, and methylprednisolone. RESULTS: Intraoperative, the allograft had excellent capillary refill and strong Doppler signals after revascularization. Operative reinterventions on postoperative days (PODs) 2 and 13 were required for hematoma evacuation and skin eschar debridement. At 3 weeks, no anastomotic leaks were detected on urethrogram, and the catheter was removed. Steroid resistant-rejection developed on POD 28 (Banff I), progressed by POD 32 (Banff III), and required a repeat course of methylprednisolone and antithymocyte globulin. At 7 months, the patient has recovered partial sensation of the penile shaft and has spontaneous penile tumescence. Our patient reports increased overall health satisfaction, dramatic improvement of self-image, and optimism for the future. CONCLUSIONS: We have shown that it is feasible to perform penile transplantation with excellent results. Furthermore, this experience demonstrates that penile transplantation can be successfully performed with conventional immunosuppression. We propose that our successful penile transplantation pilot experience represents a proof of concept for an evolution in reconstructive transplantation.

Patterns of Recurrence in Upper Tract Transitional Cell Carcinoma: Imaging Surveillance.

OBJECTIVE: The objective of our study was to evaluate recurrence patterns of upper tract transitional cell carcinomas (UT-TCCs) after radical nephroureterectomy (RNU). MATERIALS AND METHODS: Sixty-eight patients (mean age, 78 years; 34 men and 34 women) with UT-TCC after having undergone RNU from 2001 to 2008 were included in this study. Radiologic examinations and clinical notes were reviewed to record tumor location, tumor morphology, histologic T stages and grades, lymphovascular invasion (LVI) status, and surgical procedures. Five-year imaging and clinical follow-up (2001-2013) findings were noted at 3, 6, 12, 18, 24, 36, 48, 60, and more than 60 months after RNU for recurrence pattern and tumor-free survival. Kaplan-Meier survival curves and Cox regression models were used to assess tumor-free survival and to perform a multivariate analysis. RESULTS: Forty-one postoperative recurrences were noted in 20 patients. The mean time to relapse was 16 months, and time to relapse ranged from 1 to 66 months. Tumor site (multifocal lesions involving both renal collecting system and ureter), tumor morphology (mass), T stage (muscle invasion [T2-T4]), histologic grade (grade 3), and the presence of LVI were identified as risk factors for postoperative recurrence in UT-TCC. T stage was the only independent risk factor. CONCLUSION: Urinary tract, lymph node, liver, bone, and lung recurrences were common in patients with UT-TCC and were detected most frequently at 3-24 months. Tumor site, tumor morphology, T stage, grade, and LVI status were associated with recurrence after RNU. T stage was the only independent predictor of tumor-free survival. Close surveillance for extra-urinary tract recurrences in high-risk groups and a shorter-interval follow-up of the urinary tract in low-risk patients with adjuvant chemotherapy are recommended. Identifying recurrence patterns in UT-TCC can aid in planning an effective tailored imaging surveillance strategy.

Anatomical Location of the Vesical Branches of the Inferior Hypogastric Plexus in Human Cadavers.

We have demonstrated in canines that somatic nerve transfer to vesical branches of the inferior hypogastric plexus (IHP) can be used for bladder reinnervation after spinal root injury. Yet, the complex anatomy of the IHP hinders the clinical application of this repair strategy. Here, using human cadavers, we clarify the spatial relationships of the vesical branches of the IHP and nearby pelvic ganglia, with the ureteral orifice of the bladder. Forty-four pelvic regions were examined in 30 human cadavers. Gross post-mortem and intra-operative approaches (open anterior abdominal, manual laparoscopic, and robot-assisted) were used. Nerve branch distances and diameters were measured after thorough visual inspection and gentle dissection, so as to not distort tissue. The IHP had between 1 to 4 vesical branches (2.33 ± 0.72, mean ± SD) with average diameters of 0.51 ± 0.06 mm. Vesical branches from the IHP arose from a grossly visible pelvic ganglion in 93% of cases (confirmed histologically). The pelvic ganglion was typically located 7.11 ± 6.11 mm posterolateral to the ureteral orifice in 69% of specimens. With this in-depth characterization, vesical branches from the IHP can be safely located both posterolateral to the ureteral orifice and emanating from a more proximal ganglionic enlargement during surgical procedures.

An electroencephalogram biomarker of fentanyl drug effects.

Opioid drugs influence multiple brain circuits in parallel to produce analgesia as well as side effects, including respiratory depression. At present, we do not have real-time clinical biomarkers of these brain effects. Here, we describe the results of an experiment to characterize the electroencephalographic signatures of fentanyl in humans. We find that increasing concentrations of fentanyl induce a frontal theta band (4 to 8 Hz) signature distinct from slow-delta oscillations related to sleep and sedation. We also report that respiratory depression, quantified by decline in an index of instantaneous minute ventilation, occurs at ≈1700-fold lower concentrations than those that produce sedation as measured by reaction time. The electroencephalogram biomarker we describe could facilitate real-time monitoring of opioid drug effects and enable more precise and personalized opioid administration.

A prospective study of symptom distress and return to baseline function after open versus laparoscopic radical prostatectomy.

PURPOSE: We assessed and compared outcomes following open and laparoscopic radical prostatectomy. MATERIALS AND METHODS: Patients who were scheduled to undergo open or laparoscopic radical prostatectomy were enrolled in the study and followed prospectively. Before surgery the patients were administered a multi-item validated questionnaire, and were followed by telephone and with mail questionnaires periodically for 12 months. Complications were recorded from chart review and compared. Symptom distress and return to baseline for various parameters were compared between the 2 groups. RESULTS: Of the patients 102 who underwent open prostatectomy and 104 treated with laparoscopic prostatectomy were enrolled in the study. At 1 year 90% in the open and 91% in the laparoscopic group returned the questionnaire. Symptom distress between the 2 groups did not differ at any time during followup. There was no significant difference in return to baseline at 1 year for continence, erectile function or physical function. Of the patients 95% had a return to baseline physical function, approximately 90% do not wear a pad and approximately 50% returned to baseline erectile function with or without phosphodiesterase type 5 inhibitors at 1 year. Although complications were few there was a significant difference in the number for laparoscopic vs open prostatectomy with a slightly higher rate of hematuria and lymphocele formation in the laparoscopic group. Cancer control at 1 year was excellent in both groups. CONCLUSIONS: Radical prostatectomy is an effective form of therapy for patients with clinically localized cancer of the prostate. The open and laparoscopic techniques have similar functional outcomes, and these data provide patients a realistic view of what to expect following these 2 methods of radical prostatectomy.

Epidural Anesthesia to Facilitate Organ Blood Flow During the First Penile Transplantation in the United States: A Case Report.

Regional anesthesia has been used to help create local sympathectomy and improve blood flow in plastic surgery procedures involving tissue grafts and flaps. However, anesthetic techniques that reduce systemic vascular resistance must be used with caution in patients with aortic stenosis (AS). Combined neuraxial and general anesthesia with careful titration of the local anesthetic dose can be a safe approach for patients with AS undergoing microvascular procedures. We present the anesthetic management of the first North American penile transplant, on an obese patient with moderate AS.

An RNA-Based Digital Circulating Tumor Cell Signature Is Predictive of Drug Response and Early Dissemination in Prostate Cancer.

Blood-based biomarkers are critical in metastatic prostate cancer, where characteristic bone metastases are not readily sampled, and they may enable risk stratification in localized disease. We established a sensitive and high-throughput strategy for analyzing prostate circulating tumor cells (CTC) using microfluidic cell enrichment followed by digital quantitation of prostate-derived transcripts. In a prospective study of 27 patients with metastatic castration-resistant prostate cancer treated with first-line abiraterone, pretreatment elevation of the digital CTCM score identifies a high-risk population with poor overall survival (HR = 6.0; P = 0.01) and short radiographic progression-free survival (HR = 3.2; P = 0.046). Expression of HOXB13 in CTCs identifies 6 of 6 patients with ≤12-month survival, with a subset also expressing the ARV7 splice variant. In a second cohort of 34 men with localized prostate cancer, an elevated preoperative CTCL score predicts microscopic dissemination to seminal vesicles and/or lymph nodes (P < 0.001). Thus, digital quantitation of CTC-specific transcripts enables noninvasive monitoring that may guide treatment selection in both metastatic and localized prostate cancer.Significance: There is an unmet need for biomarkers to guide prostate cancer therapies, for curative treatment of localized cancer and for application of molecularly targeted agents in metastatic disease. Digital quantitation of prostate CTC-derived transcripts in blood specimens is predictive of abiraterone response in metastatic cancer and of early dissemination in localized cancer. Cancer Discov; 8(3); 288-303. ©2018 AACR.See related commentary by Heitzer and Speicher, p. 269This article is highlighted in the In This Issue feature, p. 253.

Risk Factors for Disease Progression After Postprostatectomy Salvage Radiation: Long-term Results of a Single-institution Experience.

BACKGROUND: Salvage radiotherapy (SRT) has been successfully used for recurrent prostate cancer after radical prostatectomy; however, the optimal timing of SRT remains controversial. Our objective was to identify the risk factors for disease progression after SRT, with a focus on the pre-SRT prostate-specific antigen (PSA) levels in the modern era of PSA testing. PATIENTS AND METHODS: We performed a retrospective review of 551 consecutive patients who had undergone postradical prostatectomy SRT for recurrent prostate cancer from 2000 to 2013. The exclusion criteria were hormonal therapy before or concurrent with SRT, adjuvant RT, distant metastases, and missing data. Disease progression was defined as a repeat PSA level of ≥ 0.2 ng/mL greater than the post-SRT nadir, a continued increase in the PSA level despite SRT, initiation of systemic therapy, local recurrence, nodal failure, and/or distant metastases. Univariate and multivariable Cox regression analysis were performed to identify the predictors of disease progression. Secondarily, PSA kinetics were evaluated in the model and compared using the Akaike information criterion. RESULTS: Of the 551 patients, 307 underwent SRT, of whom 134 experienced subsequent disease progression. The median interval to recurrence was 6.03 years (95% confidence interval, 3.74-8.36 years). On multivariable analysis, Gleason score, T stage, positive surgical margins, and pre-SRT PSA level were associated with progression; PSA kinetics did not independently predict for progression. When the pre-SRT PSA level was stratified (≤ 0.30, 0.31-0.50, 0.51-1.00, and > 1 ng/mL), incremental elevations were associated with an increased risk of disease progression. CONCLUSION: Multiple factors predict for progression after SRT. These risk factors could help identify those who would derive the greatest benefit from additional systemic treatment. The findings of the present study also support initiation of early SRT, irrespective of the PSA kinetics.

Long-term results of adjuvant versus early salvage postprostatectomy radiation: A large single-institutional experience.

PURPOSE: The purpose of this study was to evaluate freedom from biochemical failure (FFBF), freedom from androgen deprivation therapy (FFADT), freedom from distant metastases (FFDM), and overall survival (OS) after adjuvant radiation therapy (ART) versus early salvage radiation therapy (ESRT) in men with prostate cancer and adverse pathologic features (pT3 and/or positive surgical margins). METHODS AND MATERIALS: Of 718 patients consecutively treated with postoperative radiation therapy (RT) for prostate cancer between 1992 and 2013, we retrospectively identified 171 men receiving ART and 230 receiving ESRT (RT delivered at a prostate-specific antigen level ≤0.5 ng/mL) who had adverse pathologic features. Postirradiation FFBF (BF was defined as prostate-specific antigen level rise to ≥0.2 ng/mL), FFADT, FFDM, and OS were compared using Kaplan-Meier and Cox regression methods. Propensity score (PS)-matching was performed to estimate treatment effects while accounting for covariates predicting treatment allocation. RESULTS: Median follow-up was 7.4 and 8.0 years for patients treated with ART and ESRT, respectively. Ten-year FFBF (69% vs 56%, P = .003) and 10-year FFADT (88% vs 81%, P = .046) rates were higher after ART; however, FFDM and OS did not significantly differ. After PS-matching, ART was associated with improved FFBF (P < .0001), FFADT (P = .0001), and FFDM (P = .02). Findings were confirmed in multivariable analyses in unmatched and PS-matched cohorts. Sensitivity analyses showed that FFBF benefit associated with ART lost statistical significance only after 38% of ART patients were assumed to have been cured by surgery and excluded from the model. This corresponds to the upper bound of patients with adverse pathologic features who did not recur after observation in prior randomized trials. CONCLUSIONS: Postoperative RT confers excellent long-term cancer control. These results suggest ART may be associated with improved FFBF, FFADT, and FFDM, but comparable OS. Given the retrospective study design, these findings should be interpreted with caution. Optimal timing of postoperative RT further awaits results of ongoing trials.

Patient-reported Functional Outcomes Following Open, Laparoscopic, and Robotic Assisted Radical Prostatectomy Performed by High-volume Surgeons at High-volume Hospitals.

BACKGROUND: Functional outcomes following radical prostatectomy (RP) have received increased focus with dissemination of minimally invasive approaches. OBJECTIVE: To examine contemporary patient-reported functional outcomes following open RP. (ORP), laparoscopic RP, (LRP), and robotic assisted RP (RARP) performed by high-volume surgeons at high-volume hospitals. DESIGN, SETTINGS, AND PARTICIPANTS: This was a retrospective cohort study of 1686 men with cT1-cT2 prostate cancer treated with ORP (n=441), LRP (n=156), or RARP (n=1089) by high-volume surgeons (annual volume ≥25 cases) at two academic centers from 2009 to 2012. Surveys containing the Expanded Prostate Cancer Index Composite urinary and sexual domains were administered at a median of 30.5 mo postoperatively. INTERVENTIONS: ORP, LRP, and RARP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Bother with overall urinary and sexual function was examined and stratified by surgical technique. Logistic regression models evaluated the associations of clinicopathologic features with survey responses. RESULTS AND LIMITATIONS: In total, 6.4% of men reported a moderate or big problem with overall urinary function (ORP 5.8%, LRP 5.1%, RARP 6.8%; p=0.62), whereas 37.3% reported a moderate or big problem with overall sexual function (ORP 37.2%, LRP 36.1%, RARP 37.5%; p=0.95). On multivariable analysis, older age at surgery (odds ratio [OR]: 1.08; p<0.0001) was associated with overall urinary bother, whereas older age at surgery (OR: 1.03; p=0.005), preoperative erectile dysfunction treatment (OR: 2.22; p<0.0001), greater prostate volume (OR: 1.01; p=0.02), and RP Gleason score (7 vs 6: OR: 0.96; p=0.004; 8-10 vs 6: OR: 2.25; p=0.0006) were associated with overall sexual bother. Surgical technique was not associated with either functional outcome. Limitations included selection bias and a retrospective design. CONCLUSIONS: In this study of high-volume surgeons at high-volume hospitals, patients reported excellent functional outcomes independent of surgical technique. These results have implications for patient counseling. PATIENT SUMMARY: In this study of high-volume surgeons at high-volume hospitals, patients reported excellent outcomes for urinary and sexual function following radical prostatectomy regardless of surgical technique.

Bicalutamide monotherapy versus leuprolide monotherapy for prostate cancer: effects on bone mineral density and body composition.

PURPOSE: Gonadotropin-releasing hormone agonists decrease bone mineral density, lean mass, and muscle size and increase fat mass in men with prostate cancer. Less is known about the effects of bicalutamide monotherapy on bone mineral density and body composition. PATIENTS AND METHODS: In a 12-month, open-label study, we randomly assigned 52 men with prostate cancer and no bone metastases to receive either leuprolide or bicalutamide (150 mg by mouth daily). Bone mineral density and body composition were measured by dual energy x-ray absorptiometry and quantitative computed tomography. RESULTS: Mean (+/- standard error) bone mineral density of the posterior-anterior lumbar spine decreased by 2.5% +/- 0.5% in the leuprolide group and increased by 2.5 +/- 0.5 in the bicalutamide group from baseline to 12 months (P <.001). Mean changes in bone mineral density of the total body, total hip, femoral neck, and trabecular bone of the lumbar spine also differed significantly between groups (P < or =.003 for each comparison). Fat mass increased by 11.1% +/- 1.3% in the leuprolide group and by 6.4% +/- 1.1% in the bicalutamide group (P =.01). Changes in lean mass, muscle size, and muscle strength were similar between the groups. Breast tenderness and enlargement were more common in the bicalutamide group than in the leuprolide group. Fatigue, loss of sexual interest, and vasomotor flushing were less common in the bicalutamide group than in the leuprolide group. CONCLUSION: In men with prostate cancer, bicalutamide monotherapy increases bone mineral density, lessens fat accumulation, and has fewer bothersome side effects than treatment with a gonadotropin-releasing hormone agonist.

Prostato-symphyseal fistula after photoselective vaporization of the prostate: case series and literature review of a rare complication.

OBJECTIVE: To report our experience with the management of prostato-symphyseal fistula (PSF) after photoselective vaporization (PVP) or transurethral resection of the prostate (TURP) and review cases of this complication in published reports. MATERIALS AND METHODS: We report the management of 3 patients with PSF after PVP at our institution. A total of 5 published cases of PSF after PVP or TURP were identified from the National Library of Medicine MEDLINE database. A total of 8 patients were reviewed. RESULTS: Overall, the mean age was 71 years (range, 50-83 years), and average follow-up was 4.3 months (range, 1-7 months). Mean prostate volume was 32 mL (range, 16-38 mL). Five patients developed PSF after PVP and 3 patients after TURP. The most common postoperative symptoms included difficulty ambulating (100%) and pelvic, groin, and/or lower abdominal pain (85%). Associated diagnoses included osteitis pubis (38%) and urinoma (50%). Infectious complications were urinary tract infection (25%), osteomyelitis (38%), and infected urinoma (38%). Average time to diagnosis of PSF was 3.5 months (range, 0.5-11 months). Operative intervention was necessary in 75% of patients. CONCLUSION: This is the first reported case series on the management of PSF after PVP or TURP. This complication can be difficult to diagnose, manage, and may cause significant patient morbidity. Management requires a multidisciplinary approach. Patients commonly present with non-urologic symptoms leading to a delay in diagnosis. Further studies are needed to assess the incidence and optimal management of this complication.

Changes in body composition during androgen deprivation therapy for prostate cancer.

The aim of this study was to determine the effects of initial treatment with a GnRH agonist on body composition in asymptomatic men with nonmetastatic prostate cancer. Forty men with locally advanced, node-positive or biochemically recurrent prostate cancer, no radiographic evidence of metastases, and no prior androgen deprivation therapy were treated with leuprolide 3-month depot 22.5 mg im every 12 wk for 48 wk. The main outcome measures were percentage changes in weight, percentage fat body mass, percentage lean body mass, fat distribution, and muscle size after 48 wk. Thirty-two subjects were evaluable. Serum T concentrations decreased by 96.3% plus or minus 0.4% (P < 0.001). Weight increased by 2.4% plus or minus 0.8% (P = 0.005). Percentage fat body mass increased by 9.4% plus or minus 1.7% (P < 0.001), and percentage lean body mass decreased by 2.7% plus or minus 0.5% (P < 0.001). Cross-sectional areas of the abdomen and abdominal sc fat increased by 3.9% plus or minus 1.2% (P = 0.003) and 11.1% plus or minus 3.4% (P = 0.003), respectively. In contrast, the cross-sectional area of intraabdominal fat did not change significantly (P = 0.94). Cross-sectional paraspinal muscle area decreased by 3.2% plus or minus 1.3% (P = 0.02). GnRH agonists increase weight and percentage fat body mass and decrease percentage lean body mass and muscle size in men with nonmetastatic prostate cancer. Increased fatness resulted primarily from accumulation of sc rather than intraabdominal adipose tissue.

Prognostic significance of indeterminate lung nodules in renal cell carcinoma.

OBJECTIVES: Many patients with renal cell carcinoma (RCC) are found to have lung nodules at the time of diagnosis. The significance of these nodules is unclear. This study sought to determine whether the presence of indeterminate lung nodules affects survival for patients with early-stage RCC. METHODS AND MATERIALS: A retrospective review was performed of patients with stages I to III RCC at an academic hospital who underwent nephrectomy between 2001 and 2006 and had baseline imaging available for review. Presence of lung nodule(s) was determined, along with patient and disease characteristics. The time from diagnosis to last known follow-up, metastasis, and death were determined. The study follow-up period extended to July 2012. Univariate and multivariate Cox proportional hazards models assessed disease-free and overall survival. RESULTS: Of 548 patients, 240 met the inclusion criteria. Lung nodules were absent in 148 and present in 92 cases. Disease-free survival was associated with the presence of nodules (hazard ratio [HR] = 1.90; 95% CI: 1.04-3.46; P = 0.0362), tumor stage (stage II-HR = 5.61; 95% CI: 2.69-11.72; P<0.001 and stage III-HR = 2.49; 95% CI: 1.21-5.10; P = 0.0129) and tumor grade (HR = 2.43 for grades 3 or 4; 95% CI: 1.31-4.53; P = 0.005). The number and size of nodules were not associated with survival. Overall survival was associated with Charlson comorbidity score (HR = 1.30; 95% CI: 1.15-1.47; P<0.0001) and primary tumor size (HR = 1.29; 95% CI: 1.14-1.46; P<0.0001) but not the presence of lung nodules (HR = 1.73; 95% CI: 0.83-3.60; P = 0.1454). CONCLUSIONS: The presence of indeterminate lung nodules had a negative effect on disease-free survival. Stage and grade were also significant. These findings underscore the importance of baseline imaging and vigilant surveillance of patients in whom nodules are identified.

Long-term oncologic outcomes after radiofrequency ablation for T1 renal cell carcinoma.

BACKGROUND: Radiofrequency ablation (RFA) of renal cell carcinoma (RCC) is used to obtain local control of small renal masses. However, available long-term oncologic outcomes for RFA of RCC are limited by small numbers, short follow-up, and lack of pathologic diagnoses. OBJECTIVE: To assess the oncologic effectiveness of RFA for the treatment of biopsy-proven RCC. DESIGN, SETTING, AND PARTICIPANTS: Exclusion criteria included prior RCC or metastatic RCC, familial syndromes, or T2 RCC. We retrospectively reviewed long-term oncologic outcomes for 185 patients with sporadic T1 RCC. Median follow-up was 6.43 yr (interquartile range [IQR]: 5.3-7.7). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The chi-square test and Wilcoxon rank-sum tests were used to compare proportions and medians, respectively. Disease-specific survival and overall survival (OS) were calculated using Kaplan-Meier analysis, then stratified by tumor stage, and comparisons were made using log-rank analysis. The 5-yr disease-free survival (DFS) and OS rates are reported. A p value <0.05 was considered statistically significant. RESULTS AND LIMITATIONS: Median tumor size was 3 cm (IQR: 2.1-3.9 cm). Tumor stage was T1a: 143 (77.3%) or T1b: 42 (22.7%). Twenty-four patients (13%) were retreated for residual disease. There were 12 local recurrences (6.5%), 6 recurrences in T1a disease (4.2%) and 6 in T1b disease (14.3%) (p=0.0196). Median time to recurrence was 2.5 yr. Local salvage RFA was performed in six patients, of whom five remain disease free at 3.8-yr median follow-up. Tumor stage was the only significant predictor of DFS on multivariate analysis. At last follow-up, 164 patients (88.6%) were disease free (T1a: n=132 [92.3%]; T1b: n=32 [76.2%]; p=0.0038). OS was similar regardless of stage (p=0.06). Five patients developed metachronous renal tumors (2.7%). Four patients developed extrarenal metastases (2.2%), three of whom died of metastatic RCC (1.6%). CONCLUSIONS: In poor surgical candidates, RFA results in durable local control and low risk of recurrence in T1a RCC. Higher stage correlates with a decreased disease-free survival. Long-term surveillance is necessary following RFA. Patient selection based on tumor characteristics, comorbid disease, and life expectancy is of paramount importance.