Long-term impact of commonly performed operations in pediatric urology on reproductive and sexual health.

Introduction: Sexual dysfunction is highly prevalent among men of reproductive age. Clinical practice guidelines have been established to assist providers in identification and education of patients who are at increased risk for infertility and sexual dysfunction with certain congenital and acquired urogenital disorders. The authors sought to review the reproductive and sexual health implications of treating common childhood urological conditions with commonly performed surgical procedures. Methods: To ensure the inclusion of influential and highly regarded research, we prioritized citations from the most-frequently cited articles on our respective review topics. Our inclusion criteria considered studies with substantial sample sizes and rigorously designed methodologies. Several topics were reviewed, including penile chordee, hypospadias, posterior urethral valves, varicoceles, undescended testicles, and testicular torsion. Results: For chordee, surgical plication or corporal grafting may be employed. Erectile function remains unaltered post-surgery, while penile length may decrease after repair, which may be avoided using dermal grafts. Hypospadias repair hinges on severity and availability of the urethral plate. Those who underwent hypospadias repair report decreased penile length, but sexual satisfaction, libido, and semen quality are comparable to controls. Posterior urethral valves are usually treated with valve ablation. While valve ablation and bladder neck incision have not been found to affect ejaculatory function, high degree of concurrent renal dysfunction related to nephrogenic and bladder dysfunction may impact semen parameters and erectile function. Regarding varicocele, earlier management has been associated with better long-term fertility outcomes, and surgical intervention is advisable if there is observable testicular atrophy. Earlier repair of undescended testicle with orchiopexy has been found to improve fertility rates as well as decrease malignancy rates. Unilateral orchiectomy for testicular torsion without the ability for salvage has been shown to have decreased semen parameters but unaffected fertility rates. Conclusion: Infertility and sexual dysfunction are multivariable entities, with etiologies both congenital and acquired. At the same time, many common pediatric urology surgeries are performed to correct anatomic pathology that may lead to reproductive dysfunction in adulthood. This review highlights the need for diagnosis and management of pediatric urologic conditions as these conditions may impact long-term sexual function post-operatively.

Long-term impact of commonly performed operations in pediatric urology on sexual health Many men of reproductive age face sexual health challenges, prompting the creation of guidelines for identifying and addressing issues related to urogenital disorders. This study explores the impacts of common surgical procedures on reproductive and sexual health in children with urological conditions. By reviewing extensive literature, the study focuses on the long-term effects of pediatric urologic surgeries, emphasizing influential and frequently cited research for a comprehensive understanding. For conditions like chordee, surgical options such as plication or grafting may be considered. While erectile function typically remains unchanged, there might be a decrease in penile length post-surgery, which can be addressed with specific techniques. Hypospadias repair varies based on severity, with those undergoing the procedure having shorter penises. However, their sexual satisfaction, libido, and semen quality are comparable to others. Treatment of posterior urethral valves (PUV) often involves valve ablation, however some studies have shown altered semen parameters following ablation. Managing varicocele early on leads to better outcomes, and surgery is recommended if testicular atrophy is observed. Orchiopexy and orchiectomy are procedures for undescended testis (UDT) and testicular torsion in children. Pediatric urologic diseases and their surgical interventions can significantly affect sexual function and fertility in adulthood due to their multifactorial nature. While some procedures aim to preserve or enhance sexual potential such as proper urethral development, others may inadvertently impact sexual health negatively, such as necrotic testes removal. This underscores the importance of thorough diagnosis and management of pediatric urologic conditions to safeguard long-term sexual function post-surgery.

Characterization and Impact of TERT Promoter Region Mutations on Clinical Outcome in Renal Cell Carcinoma.

BACKGROUND: Mutations in the promoter region of the TERT gene have been detected in a variety of cancers. These mutations can potentially lead to unlimited cell divisions and result in poor clinical prognosis. OBJECTIVE: To determine the role and relevance of TERT promoter region mutations in both clear cell (ccRCC) and non-clear cell (nccRCC) renal cell carcinoma using ultra-deep and whole-genome sequencing methods on primary tumor samples. DESIGN, SETTING, AND PARTICIPANTS: DNA from 281 kidney tumors (147 ccRCC and 134 nccRCC) was sequenced between 2013 and 2015, and clinical outcomes for these patients from a single institution were retrospectively analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Differences in patient characteristics and mutational status were tested using Fisher's exact test for categorical variables and the Wilcoxon rank sum test for continuous variables. Survival times were estimated using the Kaplan-Meier method and differences were tested using the log-rank test. RESULTS AND LIMITATIONS: TERT mutations occurred in 12.2% of ccRCC and 10.4% of nccRCC cases. In >80% of the cases, mutations were located at C228T and were found to co-occur only rarely with other relevant RCC driver genes. The median follow-up among survivors overall was 2.5 yr (range 0.1-18.3). TERT promoter mutations were significantly associated with cancer-specific survival in ccRCC (hazard ratio 2.68, 95% confidence interval 1.19-6.01; p=0.013). In nccRCC, TERT mutations were significantly associated with larger tumors and metastatic development. Assessment of further relevant clinical associations was precluded in the nccRCC group by the heterogeneous and small sample size. CONCLUSIONS: Our data suggests that TERT mutational status reflects a distinct pathogenesis with an aggressive disease course in RCC. Stratifying patients with this unique tumorigenesis that leads to poor clinical outcomes could be a putative target for novel therapeutics. PATIENT SUMMARY: We show a previously unrecognized frequency of TERT promoter mutations in both clear cell and non-clear cell renal cell carcinoma. TERT promoter mutations were associated with some worse outcomes in patients with clear cell renal cell carcinoma.

Comparative Genomic Profiling of Matched Primary and Metastatic Tumors in Renal Cell Carcinoma.

BACKGROUND: Next-generation sequencing (NGS) studies of matched pairs of primary and metastatic tumors in renal cell carcinoma (RCC) have been limited to small cohorts. OBJECTIVE: To evaluate the discordance in somatic mutations between matched primary and metastatic RCC tumors. DESIGN, SETTING, AND PARTICIPANTS: Primary tumor (P), metastasis (M), and germline DNA from 60 patients with RCC was subjected to NGS with a targeted exon capture-based assay of 341 cancer-associated genes. Somatic mutations were called using a validated pipeline. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Mutations were classified as shared (S) or private (Pr) in relation to each other within individual P-M pairs. The concordance score was calculated as (S-Pr)/(S+Pr). To calculate enrichment of Pr/S mutations for a particular gene, we calculated a two-sided p value from a binomial model for each gene with at least ten somatic mutation events, and also implemented a separate permutation test procedure. We adjusted p values for multiple hypothesis testing using the Benjamini-Hochberg procedure. The mutation discordance was calculated using Mann-Whitney U tests according to gene mutations or metastatic sites. RESULTS AND LIMITATIONS: Twenty-one pairs (35%) showed Pr mutations in both P and M samples. Of the remaining 39 pairs (65%), 14 (23%) had Pr mutations specific to P samples, 12 (20%) had Pr mutations to M samples, and 13 (22%) had identical somatic mutations. No individual gene mutation was preferentially enriched in either P or M samples. P-M pairs with SETD2 mutations demonstrated higher discordance than pairs with wild-type SETD2. We observed that patients who received therapy before sampling of the P or M tissue had higher concordance of mutations for P-M pairs than patients who did not (Mann-Whitney p=0.088). CONCLUSIONS: Our data show mutation discordance within matched P-M RCC tumor pairs. As most contemporary precision medicine trials do not differentiate mutations detected in P and M tumors, the prognostic and predictive value of mutations in P versus M tumors warrants further investigation. PATIENT SUMMARY: In this study we evaluated the concordance of mutations between matched primary and metastatic tumors for 60 kidney cancer patients using a panel of 341 cancer genes. Forty-seven patients carried nonidentical cancer gene mutations within their matched primary-metastatic pair. The mutation profile of the primary tumor alone could compromise precision in selecting effective targeted therapies and result in suboptimal clinical outcomes.

The difficulty in selecting patients for cytoreductive nephrectomy: An evaluation of previously described predictive models.

PURPOSE: To externally evaluate a preoperative points system and a preoperative nomogram, both created to assess time to death after cytoreductive nephrectomy (CN). MATERIALS AND METHODS: We identified 298 patients who underwent CN at our institution, a tertiary cancer center, between 1989 and 2015. To validate the points system, we compared reported overall survival (OS) for each criterion to observed OS in our cohort. To evaluate the nomogram, we prognosticated risk of death at 6 months after surgery for 280 patients with sufficient follow-up in our cohort and evaluated discrimination using area under the curve (AUC) and calibration. Decision curve analysis was performed to assess clinical utility of the nomogram. RESULTS: Significant differences in OS were observed between patients with and without 5 of 7 criteria on univariate analysis: low albumin (P<0.0001), high lactate dehydrogenase (P = 0.002), liver metastasis (P = 0.004), retroperitoneal lymphadenopathy (P = 0.002), and supradiaphragmatic lymphadenopathy (P = 0.019). Discrimination from the preoperative model, predicting death within 6 months of surgery was lower in our cohort (AUC = 0.65, 95% CI: 0.52-0.79) than the original publication (AUC = 0.76). Decision curve analysis demonstrated little benefit for applicability. CONCLUSIONS: Five previously defined risk factors are predictive of decreased OS after CN in our cohort. We found lower discrimination using the preoperative model and minimal clinical utility according to decision analysis in our study cohort. These findings suggest the need for improved models to aid patient stratification and consequent treatment choice.

Genomic alterations as predictors of survival among patients within a combined cohort with clear cell renal cell carcinoma undergoing cytoreductive nephrectomy.

PURPOSE: To establish prognostic genomic biomarkers for patients with metastatic clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: We identified 60 patients who presented with metastatic ccRCC at our institution between 2001 and 2015 and had genomic sequencing on their primary tumor. We pooled these patients with 107 other patients with the same inclusion criteria from three well-known public databases. Five commonly mutated genes were chosen for analysis: VHL, PBRM1, BAP1, SETD2, and KDM5C. Overall survival (OS) was estimated using the Kaplan-Meier method and the log-rank test was used for comparisons between groups. RESULTS: Median OS in the cohort was 2.5 years. Higher Fuhrman grade was associated with decreased median OS (P<0.001). Mutations in SETD2 (P = 0.027) and KDM5C (P = 0.019) were associated with reduced risk of death (hazard ratio [HR] = 0.58 [95% CI: 0.35-0.94] and HR = 0.43 [95% CI: 0.22-0.85], respectively). BAP1 mutations (P = 0.008) were associated with increased risk of death (HR = 1.81 [95% CI: 1.16-2.83]). There were significantly more female patients with a BAP1 mutation than females in the overall cohort (P = 0.001). CONCLUSIONS: Mutations in BAP1 negatively affected OS, whereas SETD2 and KDM5C mutations were associated with prolonged OS in our pooled cohort of 167 patients with metastatic ccRCC. Our results expand upon efforts at understanding genomic biomarkers in localized disease. Those efforts set the stage for our novel investigation examining associations of select recurrent somatic mutations in stage IV patients with ccRCC.

Integration of Recurrent Somatic Mutations with Clinical Outcomes: A Pooled Analysis of 1049 Patients with Clear Cell Renal Cell Carcinoma.

BACKGROUND: Analyses of associations between clinicopathologic outcomes and recurrent somatic mutations in clear cell renal cell carcinoma (ccRCC) have been limited to individual cohorts. OBJECTIVE: To define clinicopathologic associations between specific mutations and ccRCC disease characteristics. DESIGN, SETTING, AND PARTICIPANTS: DNA sequencing data were pooled from three collaborative genomic cohorts (n=754) and our institutional database (n=295). All patients had clinical data and identification of somatic mutations from their primary tumors. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Analysis of gene mutations for associations with maximal tumor size (linear regression) and pathologic stage (logistic regression). Cancer-specific survival (CSS) and recurrence-free survival (RFS) were calculated using competing risks methods. Analyses were adjusted for cohort site, and results were adjusted for multiple testing (q value). Relevant genes were used in multivariable models that included confounding variables and the validated Mayo Clinic Stage, Size, Grade, and Necrosis (SSIGN) score. RESULTS AND LIMITATIONS: Association with tumor size was found for mutations in BAP1 (q=0.013). No mutations were found to be associated with stage after adjusted analysis. Mutations in BAP1 (q=0.004) and TP53 (q=0.001) were associated with decreased CSS in a multivariable model; only TP53 (q=0.005) remained significant when SSIGN score was included. SETD2 mutations (q=0.047) were associated with decreased RFS in multivariable models, including models with SSIGN score. CONCLUSIONS: In >1000 patients with ccRCC, pooled analysis and multivariable modeling demonstrated that three mutated genes have statistically significant associations with poor clinical outcomes. This included the more commonly mutated BAP1 and SETD2 and the less frequently mutated TP53. After adjustment for clinical confounders, mutations of TP53 and SETD2 were associated with decreased CSS and RFS, respectively. PATIENT SUMMARY: Using rigorous statistical methods, this study affirmed that certain mutations in clear cell renal cell carcinoma may portend inferior survival and an increased risk of recurrence.

Tumor Xenografts of Human Clear Cell Renal Cell Carcinoma But Not Corresponding Cell Lines Recapitulate Clinical Response to Sunitinib: Feasibility of Using Biopsy Samples.

BACKGROUND: Parallel development of preclinical models that recapitulate treatment response observed in patients is central to the advancement of personalized medicine. OBJECTIVE: To evaluate the use of biopsy specimens to develop patient-derived xenografts and the use of corresponding cell lines from renal cell carcinoma (RCC) tumors for the assessment of histopathology, genomics, and treatment response. DESIGN, SETTING, AND PARTICIPANTS: A total of 74 tumor specimens from 66 patients with RCC were implanted into immunocompromised NOD-SCID IL2Rg-/- mice. Four cell lines generated from patients' specimens with clear cell pathology were used for comparative studies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Preclinical models were established and assessed. Engraftment rates were analyzed using chi-square testing. Analysis of variance (two-way analysis of variance) was conducted to assess tumor growth. RESULTS AND LIMITATIONS: Overall, 33 RCC mouse xenograft models were generated with an overall engraftment rate of 45% (33 of 74). Tumor biopsies engrafted comparably with surgically resected tumors (58% vs 41%; p=0.3). Xenograft tumors and their original tumors showed high fidelity in regard to histology, mutation status, copy number change, and targeted therapy response. Engraftment rates from metastatic tumors were higher but not more significant than primary tumors (54% vs 34%; p=0.091). Our engraftment rate using metastases or biopsies was comparable with recent reports using resected primary tumors. In stark contrast to corresponding cell lines, all tested xenografts recapitulated patients' clinical response to sunitinib. CONCLUSIONS: Patient-derived xenograft models can be effectively established from tumor biopsies. Preclinical xenograft models but not matched cell lines reflected clinical responses to sunitinib. PATIENT SUMMARY: Matched patient-derived clear cell renal cell carcinoma xenografts and cell lines from responsive and refractory patients treated with sunitinib were established and evaluated for pharmacologic response to anti-vascular endothelial growth factor treatment. Both models accurately reflected the genetic characteristics of original tumors, but only xenografts recapitulated drug responses observed in patients. These models could serve as a powerful platform for precision medicine.