Meeting report on the NIDDK/AUA Workshop on Congenital Anomalies of External Genitalia: challenges and opportunities for translational research.

Congenital anomalies of the external genitalia (CAEG) are a prevalent and serious public health concern with lifelong impacts on the urinary function, sexual health, fertility, tumor development, and psychosocial wellbeing of affected individuals. Complications of treatment are frequent, and data reflecting long-term outcomes in adulthood are limited. To identify a path forward to improve treatments and realize the possibility of preventing CAEG, the National Institute of Diabetes and Digestive and Kidney Diseases and the American Urological Association convened researchers from a range of disciplines to coordinate research efforts to fully understand the different etiologies of these common conditions, subsequent variation in clinical phenotypes, and best practices for long term surgical success. Meeting participants concluded that a central data hub for clinical evaluations, including collection of DNA samples from patients and their parents, and short interviews to determine familial penetrance (small pedigrees), would accelerate research in this field. Such a centralized datahub will advance efforts to develop detailed multi-dimensional phenotyping and will enable access to genome sequence analyses and associated metadata to define the genetic bases for these conditions. Inclusion of tissue samples and integration of clinical studies with basic research using human cells and animal models will advance efforts to identify the developmental mechanisms that are disrupted during development and will add cellular and molecular granularity to phenotyping CAEG. While the discussion focuses heavily on hypospadias, this can be seen as a potential template for other conditions in the realm of CAEG, including cryptorchidism or the exstrophy-epispadias complex. Taken together with long-term clinical follow-up, these data could inform surgical choices and improve likelihood for long-term success.

Association of Long-Term Dynamics in Circulating Testosterone with Serum PSA in Prostate Cancer-Free Men with Initial-PSA < 4 ng/mL.

We previously reported that an accelerated decline in circulating testosterone level is associated with a higher risk of prostate cancer (PCa). This study is to examine whether testosterone change rate is related to serum prostate-specific antigen (PSA) concentration among PCa-free men. Longitudinal data were derived from electronic medical records at a tertiary hospital in the Southeastern USA. PCa-free men with initial-PSA < 4 ng/mL and ≥ 2 testosterone measurements were included (n = 632). Three PSA measures (peak, the most recent, and average PSA) during the study period (from first testosterone measurement to the most recent hospital visit) were examined using multivariable-adjusted geometric means and were compared across quintiles of testosterone change rate (ng/dL/month) and current testosterone level (cross-sectional). Mean (standard deviation, SD) age at baseline was 59.3 (10.5) years; mean study period was 93.0 (55.3) months. After adjusting for covariates including baseline testosterone, the three PSA measures all significantly increased across quintile of testosterone change rate from increase to decline (peak PSA: quint 1 = 1.09, quint 5 = 1.41; the most recent PSA: quint 1 = 0.85, quint 5 = 1.00; average PSA: quint 1 = 0.89, quint 5 = 1.02; all Ptrend < 0.001). But current testosterone level was not associated with PSA levels. Stratified analyses indicated men with higher adiposity (body mass index > 24.1 kg/m2) or lower baseline testosterone (≤ 296 ng/dL) were more sensitive to testosterone change in regard to PSA. Among PCa-free men, accelerated testosterone decline might correlate with higher serum PSA concentration. It will help to elucidate the mechanisms relating aging-accompanying testosterone dynamics to prostate carcinogenesis.

BMI trajectories and risk of overall and grade-specific prostate cancer: An observational cohort study among men seen for prostatic conditions.

BACKGROUND: Dynamic longitudinal patterns in body mass index (BMI) have been suggested to better predict health outcomes than static measures. Effects of BMI trajectories on prostate cancer (PCa) risk have not been thoroughly explored. METHODS: Cohort data were derived from electronic medical records of patients who were admitted to a tertiary-care hospital in the Southeastern USA during 1994-2016. Patients with a history of urologic clinic visit because of any prostatic condition and with repeatedly measured BMI (n = 4857) were included. BMI trajectories prior to PCa diagnosis were assessed using the developmental trajectory analysis method. Cox proportional hazards regression modeling was used to estimate adjusted hazard ratio (aHR) with 95% confidence intervals (CIs) for overall and grade-specific PCa. RESULTS: The median age (interquartile range, IQR) of the participants at baseline was 63 (54, 72) years. Over a median follow-up (IQR) of 8.0 (2.0, 13.0) years, 714 (14.7%, 714/4857) were diagnosed with PCa. Men with growing BMI trajectory progressing from normal weight to overweight/obese had a 76% increased PCa risk (aHR = 1.76; 95% CI: 1.25, 2.48), and men being obese and experiencing progressive weight gain had 3.72-fold increased PCa risk (aHR = 3.72; 95% CI: 1.60, 8.66), compared to men with persistently normal BMI. The associations were more pronounced for PCa with Gleason score ≥7. No significant association of decreasing BMI trajectory progressing from obese to normal BMI was found with PCa risk. CONCLUSIONS: Progressively body weight gain during middle-to-late adulthood was associated with increased PCa risk for both normal weight and overweight men. Further studies are warranted to confirm this finding.

Development of a personalized diagnostic model for kidney stone disease tailored to acute care by integrating large clinical, demographics and laboratory data: the diagnostic acute care algorithm - kidney stones (DACA-KS).

BACKGROUND: Kidney stone (KS) disease has high, increasing prevalence in the United States and poses a massive economic burden. Diagnostics algorithms of KS only use a few variables with a limited sensitivity and specificity. In this study, we tested a big data approach to infer and validate a 'multi-domain' personalized diagnostic acute care algorithm for KS (DACA-KS), merging demographic, vital signs, clinical, and laboratory information. METHODS: We utilized a large, single-center database of patients admitted to acute care units in a large tertiary care hospital. Patients diagnosed with KS were compared to groups of patients with acute abdominal/flank/groin pain, genitourinary diseases, and other conditions. We analyzed multiple information domains (several thousands of variables) using a collection of statistical and machine learning models with feature selectors. We compared sensitivity, specificity and area under the receiver operating characteristic (AUROC) of our approach with the STONE score, using cross-validation. RESULTS: Thirty eight thousand five hundred and ninety-seven distinct adult patients were admitted to critical care between 2001 and 2012, of which 217 were diagnosed with KS, and 7446 with acute pain (non-KS). The multi-domain approach using logistic regression yielded an AUROC of 0.86 and a sensitivity/specificity of 0.81/0.82 in cross-validation. Increase in performance was obtained by fitting a super-learner, at the price of lower interpretability. We discussed in detail comorbidity and lab marker variables independently associated with KS (e.g. blood chloride, candidiasis, sleep disorders). CONCLUSIONS: Although external validation is warranted, DACA-KS could be integrated into electronic health systems; the algorithm has the potential used as an effective tool to help nurses and healthcare personnel during triage or clinicians making a diagnosis, streamlining patients' management in acute care.

Association between age-related reductions in testosterone and risk of prostate cancer-An analysis of patients' data with prostatic diseases.

The relationship between serum total testosterone and prostate cancer (PCa) risk is controversial. The hypothesis that faster age-related reduction in testosterone is linked with increased PCa risk remains untested. We conducted our study at a tertiary-level hospital in southeast of the USA, and derived data from the Medical Registry Database of individuals that were diagnosed of any prostate-related disease from 2001 to 2015. Cases were those diagnosed of PCa and had one or more measurements of testosterone prior to PCa diagnosis. Controls were those without PCa and had one or more testosterone measurements. Multivariable logistic regression models for PCa risk of absolute levels (one-time measure and 5-year average) and annual change in testosterone were respectively constructed. Among a total of 1,559 patients, 217 were PCa cases, and neither one-time measure nor 5-year average of testosterone was found to be significantly associated with PCa risk. Among the 379 patients with two or more testosterone measurements, 27 were PCa cases. For every 10 ng/dL increment in annual reduction of testosterone, the risk of PCa would increase by 14% [adjusted odds ratio, 1.14; 95% confidence interval (CI), 1.03-1.25]. Compared to patients with a relatively stable testosterone, patients with an annual testosterone reduction of more than 30 ng/dL had 5.03 [95% CI: 1.53, 16.55] fold increase in PCa risk. This implies a faster age-related reduction in, but not absolute level of serum total testosterone as a risk factor for PCa. Further longitudinal studies are needed to confirm this finding.

Pseudomonas aeruginosa as an Etiologic Agent of Nephrolithiasis in Deep Water Divers.

Background: A number of occupations and professions may be associated with unique hazards relevant to urologic care. Case Presentation: We relate the presentation, care, and the occupational hazard of urinary tract infection (UTI), presenting as cystitis and pyelonephritis, with stone formation in a scuba diver. The patient voiced concern that his diving suit malfunction was related to his UTI and stone disease. We review the risk of UTI in the diving environment. We also report the development of infection-related stone in this case. Our evaluation included consultation with an expert in diving and associated equipment. Conclusion: Careful installation of P-valves in dry suits, proper maintenance, and monitoring for leakage improved post-dive hygiene, and proper maintenance of P-valve tubing and diving equipment may decrease the incidence of these complications described. Urologists treating UTI and stone disease should be aware of this occupation-related hazard.

How do stones form? Is unification of theories on stone formation possible?

There are two basic pathways for formation of calcium based kidney stones. Most idiopathic calcium oxalate (CaOx) stones are formed in association with sub-epithelial plaques of calcium phosphate (CaP), known as Randall's plaques, on renal papillary surfaces. Crystal formation and retention within the terminal collecting ducts, the ducts of Bellini, leading to the formation of Randall's plugs, is the other pathway. Both pathways require supersaturation leading to crystallization, regulated by various crystallization modulators produced in response to changing urinary conditions. High supersaturation, as a result of a variety of genetic and environmental factors, leads to crystallization in the terminal collecting ducts, eventually plugging their openings into the renal pelvis. Stasis behind the plugs may lead to the formation of attached or unattached stones in the tubular lumen. Deposition of crystals on the plug surface facing the pelvic or tubular urine may result in stone formation on the Randall's plugs. Kidneys of idiopathic stone formers may be subjected to oxidative stress as a result of increased urinary excretion of calcium/oxalate/phosphate and/or decrease in the production of functional crystallization inhibitors or in relation to co-morbidities such as hypertension, atherosclerosis, or acute kidney injury. We have proposed that production of reactive oxygen species (ROS) causes dedifferentiation of epithelial/endothelial cells into osteoblast type cells and deposition of CaP in the basement membrane of renal tubules or vessels. Growth, aggregation and melding of CaP crystals leads to the formation of plaque which grows by further calcification of interstitial collagen and membranous vesicles. Plaque becomes exposed to pelvic urine once the covering papillary epithelium is breached. Surface layers of CaP are replaced by CaOx through direct transformation or demineralization of CaP and mineralization of CaOx. Alternatively, or in addition, CaOx crystals nucleate directly on the plaque surface. Stone growth may also depend upon supersaturation in the pelvic urine, triggering further nucleation, growth and aggregation.

Management of renal masses with laparoscopic-guided radiofrequency ablation versus laparoscopic partial nephrectomy.

BACKGROUND AND PURPOSE: Laparoscopic-guided radiofrequency ablation (LRFA) has been introduced as a minimally invasive nephron-sparing management option for renal tumors. Many patients who desire treatment present with multiple comorbidities, which poses a therapeutic challenge. Our purpose is to determine if multipass LRFA is comparable, in terms of surgical risk and immediate postoperative outcomes, to laparoscopic partial nephrectomy (LPN). PATIENTS AND METHODS: A retrospective study identified 36 and 33 patients who underwent LRFA and LPN, respectively. Perioperative demographic data, tumor characteristics, and follow-up data were evaluated. Statistical analysis was performed using the Student t test and chi-square analysis. RESULTS: Age, American Society of Anesthesiology score, and Charlson Comorbidity Index were significantly higher in the LRFA group than the LPN group (P < 0.001). Average tumor size was 2.8 cm and 3.1 cm for the LRFA and LPN groups, respectively. There were no significant differences in change between the preoperative and postoperative creatinine/glomerular filtration rate values or perioperative complication rates for the groups. Estimated blood loss and length of stay were significantly lower for the LRFA group than the LPN group (P < 0.05). Follow-up ranged 6 to 23 months and 6 to 58 months for the LRFA and the LPN groups, respectively. There has been no evidence of tumor recurrence in the follow-up period. CONCLUSIONS: We present our initial report comparing patients undergoing LRFA v LPN for the management of renal tumors. Our preliminary results with our experience with multipass laparoscopic-guided RFA demonstrate that this technique can be safely used in an elderly, higher risk population. Long-term follow-up is needed to determine oncologic efficacy.

Comparison of the incidence of latent prostate cancer detected at autopsy before and after the prostate specific antigen era.

PURPOSE: Most data regarding the prevalence of latent prostate cancer found only at autopsy are from old reports. To determine if significant differences exist in the prevalence of latent prostate cancer between periods before and after the advent of screening for prostate cancer, we compared 2 groups of men undergoing autopsy during the 2 periods. MATERIALS AND METHODS: Our institutional autopsy record database was searched to identify all men found to have prostate cancer before or after death between 1955 and 1960 (total 3,307 men and 1,578 men older than 40 years), and between 1991 and 2001 (total 2,938 men, 1,380 men older than 40 years). We calculated the age based incidence of latent prostate cancer detected only at autopsy in an at risk population of men (older than 40 years). We also compared Gleason grade distribution and proportion of stage cT3 or greater cancers between the 2 periods. RESULTS: Between 1955 and 1960 the prevalence of latent prostate cancer detected only at autopsy in men older than 40 years was 4.8% compared to 1.2% (p < 0.0001) between 1991 and 2001. A significant decrease in the prevalence of latent, autopsy detected cancers was observed in men 70 to 89 years old at death. Autopsy detected cancers were found to be grossly invading adjacent structures (stage cT3 or greater) in 17 of 76 (22%) cancers discovered between 1955 and 1960, while none of the latent prostate cancers found in the 1991 to 2001 period were found to extend grossly beyond the prostate. CONCLUSIONS: Autopsy rates are decreasing at our institution. With the more widespread use of screening, the prevalence of latent prostate cancer has decreased 3-fold. The decrease in the prevalence of latent prostate cancer is especially dramatic in men older than 70 years. Further study will determine the significance of many of the tumors currently detected clinically, which may have been latent and found at autopsy if not for screening.