Puberty Blocker and Aging Impact on Testicular Cell States and Function.

Spermatogonial stem cell (SSC) acquisition of meiotogenetic state during puberty to produce genetically diverse gametes is blocked by drugs collectively referred as 'puberty blocker' (PB). Investigating the impact of PB on juvenile SSC state and function is challenging due to limited tissue access and clinical data. Herein, we report largest clinically annotated juvenile testicular biorepository with all children with gender dysphoria on chronic PB treatment highlighting shift in pediatric patient demography in US. At the tissue level, we report mild-to-severe sex gland atrophy in PB treated children. We developed most extensive integrated single-cell RNA dataset to date (>100K single cells; 25 patients), merging both public and novel (52 month PB-treated) datasets, alongside innovative computational approach tailed for germ cells and evaluated the impact of PB and aging on SSC. We report novel constitutional ranges for each testicular cell type across the entire age spectrum, distinct effects of treatments on prepubertal vs adult SSC, presence of spermatogenic epithelial cells exhibiting post-meiotic-state, irrespective of age, puberty status, or PB treatment. Further, we defined distinct effects of PB and aging on testicular cell lineage composition, and SSC meiotogenetic state and function. Using single cell data from prepubertal and young adult, we were able to accurately predict sexual maturity based both on overall cell type proportions, as well as on gene expression patterns within each major cell type. Applying these models to a PB-treated patient that they appeared pre-pubertal across the entire tissue. This combined with the noted gland atrophy and abnormalities from the histology data raise a potential concern regarding the complete 'reversibility' and reproductive fitness of SSC. The biorepository, data, and research approach presented in this study provide unique opportunity to explore the impact of PB on testicular reproductive health.

The prevalence of impostor phenomenon and its association with burnout amongst urologists.

OBJECTIVES: To characterise the prevalence of impostor phenomenon (IP; tendency for high-achieving individuals to perceive themselves as fraudulent in their successes) amongst attending staff in urology, to identify variables that predict more severe impostorism, and to study the association of IP with burnout. SUBJECTS AND METHODS: A survey composed of the Clance Impostor Phenomenon Scale (CIPS), demographic information, practice details, and burnout levels was e-mailed to urologists via urological subspecialty societies. Survey results were analysed to identify associations between IP severity, survey respondent characteristics, and symptoms of professional burnout. This study was conducted in the United States of America. RESULTS: A total of 614 survey responses were received (response rate 11.0%). In all, 40% (n = 213) of responders reported CIPS scores qualifying as either 'frequent' or 'intense' impostorism (i.e., scores of 61-100). On multivariable analysis, female gender, fewer years in practice (i.e., 0-2 years), and lower academic rank were all independently associated with higher CIPS scores (adjusted P < 0.05). Regarding burnout, 46% of responders reported burnout symptoms. On multivariable analysis, increase in CIPS score was independently associated with higher odds of burnout (odds ratio 1.06, 95% confidence interval 1.04-1.07; P < 0.001). CONCLUSION: Impostor phenomenon is prevalent in the urological community and is experienced more severely in younger and female urologists. IP is also independently associated with burnout. Increased female representation may improve IP amongst our female colleagues. More work is needed to determine strategies that are effective in mitigating feelings of IP and professional burnout amongst urologists, particularly those earlier in their careers.

Examination of nutritional factors associated with urolithiasis risk in plant based meat alternatives marketed to children and infants.

INTRODUCTION: The global prevalence of pediatric nephrolithiasis continues to rise amidst increased sodium and animal protein intake. Plant-based meat alternatives (PBMAs) have recently gained popularity due to health benefits, environmental sustainability, and increased retail availability. PBMAs have the potential to reduce the adverse metabolic impact of animal protein on kidney stone formation. We analyzed PBMAs targeted to children to characterize potential lithogenic risk vs animal protein. METHODS: We performed a dietary assessment using a sample of PBMAs marketed to or commonly consumed by children and commercially available at national retailers. Nutrient profiles for PBMAs were compiled from US Department of Agriculture databases and compared to animal protein sources using standardized serving sizes. We also analyzed nutrient profiles for plant-based infant formulas against typical dairy protein-based formulas. Primary protein sources were identified using verified ingredient lists. Oxalate content was extrapolated from dietary data sources. RESULTS: A total of 41 PBMAs were analyzed: chicken (N = 18), hot dogs (N = 3), meatballs (N = 5), fish (N = 10), and infant formula (N = 5). Most products (76%) contained a high-oxalate ingredient as the primary protein source (soy, wheat, or almond). Average oxalate content per serving was substantially higher in these products (soy 11.6 mg, wheat 3.8 mg, almond 10.2 mg) vs animal protein (negligible oxalate). PBMAs containing pea protein (24%) had lower average oxalate (0.11 mg). Most PBMAs averaged up to six times more calcium and three times more sodium per serving compared to their respective animal proteins. Protein content was similar for most categories. CONCLUSIONS: Three-quarters of the examined plant-based meat products for children and infants contain high-oxalate protein sources. Coupled with higher per-serving sodium and calcium amounts, our findings raise questions about possible lithogenic risk in some PBMAs, and further studies are needed to assess the relationship between PBMAs and nephrolithiasis.

Vitrification versus slow freezing of human ovarian tissue: a systematic review and meta-analysis of histological outcomes.

A systematic review and meta-analysis of pertinent literature published from 2006 to January 2022 were conducted to study and compare vitrification and slow freezing, the two prominent methods of ovarian tissue cryopreservation. The primary outcome measures for this study were (1) proportion of intact primordial follicles, (2) proportion of intact stromal cells, (3) proportion of DNA fragmentation in primordial follicles, and (4) mean primordial follicle density. This meta-analysis of 19 studies revealed a significantly greater proportion of intact stromal cells in vitrified tissue versus slow-frozen tissue. No significant differences upon pooled analyses were observed between the two cryopreservation methods with respect to the proportion of intact primordial follicles, proportion of DNA fragmentation, or mean primordial follicle density. Due to differences seen in stromal cell viability, vitrification may be a preferred option to preserve histology of tissue. However, more work should be done to compare the two freezing techniques with less heterogeneity caused by patients, samples, and protocols.

Path to Parity: Trends in Female Representation Among Physicians, Trainees, and Applicants in Urology and Surgical Specialties.

OBJECTIVE: To characterize recent trends among practicing female surgeons, surgical trainees, and surgical residency applicants to assess potential progress toward gender parity. METHODS: Workforce statistics on U.S. practicing surgeons, trainees, and applicants among 9 surgical specialties were obtained from the Association of American Medical Colleges and Electronic Residency Application Service public databases. Physician and trainee data during 2007-2019 and residency applicant data during 2016-2020 were analyzed by surgical specialty. We used Cochrane Armitage trend tests to assess changes over time. RESULTS: Female practicing urologists increased 104% during the study period, the third-largest increase among 9 surgical specialties (range 36%-114%, all P < .01), representing continued growth in the prevalence and proportion of women among surgical trainees in all surgical disciplines. In contrast, the overall change for female urology residents (28%) lagged significantly, ranking eighth among the 9 specialties (range 9%-149%, all P < .01), suggesting slowing growth in the training pipeline. Finally, while the proportional change in urology applicants has been significant (33%, P < .01), growth rates have markedly slowed in the past 5 years compared to women in practice and training since 2007. CONCLUSION: While female representation among practicing urologists has improved relative to other surgical disciplines, declining rates of women entering and applying to urology residency suggest a longer trajectory toward gender parity.

Local treatment of rhabdomyosarcoma of the female genital tract: Expert consensus from the Children's Oncology Group, the European Soft-Tissue Sarcoma Group, and the Cooperative Weichteilsarkom Studiengruppe.

The International Soft-Tissue Sarcoma Consortium (INSTRuCT) was founded as an international collaboration between different pediatric soft-tissue sarcoma cooperative groups (Children's Oncology Group, European Pediatric Soft-Tissue Sarcoma Group, and Cooperative Weichteilsarkom Studiengruppe). Besides other tasks, a major goal of INSTRuCT is to develop consensus expert opinions for best clinical treatment. This consensus paper for patients with rhabdomyosarcoma of the female genital tract (FGU-RMS) provides treatment recommendations for local treatment, long-term follow-up, and fertility preservation. Therefore, a review of the current literature was combined with recommendations of the treatment protocols of the appropriate clinical trials. Additionally, opinions of international FGU-RMS experts were incorporated into recommendations. Results were that the prognosis of FGU-RMS is favorable with an excellent response to chemotherapy. Initial complete surgical resection is not indicated, but diagnosis should be established properly. In patients with tumors localized at the vagina or cervix demonstrating incomplete response after induction chemotherapy, local radiotherapy (brachytherapy) should be carried out. In patients with persistent tumors at the corpus uteri, hysterectomy should be performed. Fertility preservation should be considered in all patients. In conclusion, for the first time, an international consensus for the treatment of FGU-RMS patients could be achieved, which will help to harmonize the treatment of these patients in different study groups.

Imaging of pre- and post-cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for pediatric intraperitoneal malignancy.

Although rare, pediatric peritoneal carcinomatosis does occur in primary abdominopelvic tumors. Additionally, peritoneal carcinomatosis has been described to occur as metastatic disease where the primary tumor is outside the abdominopelvic cavity. Where amenable, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) can be beneficial in disease management. However, favorable outcomes are predicated on specific tumor histology as well as proper patient selection, which significantly relies on preoperative imaging. This review gives a comprehensive, up-to-date summary on pediatric peritoneal carcinomatosis pre-surgical evaluation; where imaging is beneficial and limited; pediatric radiologists' role in helping to quantify disease; and how we, as pediatric radiologists, can help the surgeons and oncologists in the selection of patients for cytoreductive surgery and HIPEC.

Spinal anesthesia in infants undergoing urologic surgery duration greater than 60 minutes.

INTRODUCTION: Spinal anesthesia (SA) has been safely utilized in infants. There are limited data regarding the safety and efficacy of SA in pediatric urologic surgery lasting ≥60 min. We outlined the perioperative course for infants undergoing single-injection 0.5% plain bupivacaine SA-only for urologic procedures lasting ≥60 min. OBJECTIVE: To characterize the safety and efficacy of SA for urologic surgery in infants lasting ≥60 min. METHODS: We reviewed our prospectively maintained database of infants undergoing SA for urologic procedures lasting ≥60 min from May 2018 to March 2021. Patients received preoperative intranasal dexmedetomidine, some received intranasal fentanyl, and all patients received lidocaine cream applied preoperatively over the lumbar spine. Oral sucrose on a pacifier was provided as needed, and the patient's arms were swaddled for the procedure. Success was defined as no conversion to general anesthesia. Time points for start/end of spinal injection, procedure duration, wheels in/out of operating room (OR), and discharge were collected. RESULTS: Of 245 cases conducted with SA during the study period, 76 (31%) infants underwent surgery lasting ≥60 min. Of these, 73 (96%) were successfully completed with SA alone. In the 3 cases converted to general anesthesia, 2 (67%) required mask anesthesia after 96 and 169 min (for the last <10 min of surgery), and one was converted to intubation before start of surgery. Median patient age was 6 (IQR 5-7) months, and median procedure length was 95 (IQR 75-120) minutes. Following initial preoperative intranasal dexmedetomidine ± fentanyl, at least one additional dose of IV sedative was given in 27 (36%) cases at a median time of 90 (IQR 60-120) minutes into surgery. Following closure, patients exited the OR after a median 10 (IQR 8-12) minutes and subsequently discharged after spending a median of 73 (IQR 61-96) minutes in recovery. DISCUSSION: We describe pediatric urologic surgical cases lasting ≥60 min that employed single-injection intrathecal bupivacaine alone without adjunct intrathecal agents. In this report, SA was safely utilized in infants undergoing urologic procedures lasting at least 60 min, with about 40% of patients receiving additional IV dexmedetomidine and fentanyl. Non-medication measures (swaddling, oral sucrose) were important for maximizing patient comfort. Communication between surgeon and anesthesia as cases progress is key to maintaining adequate anesthesia. CONCLUSION: A single-injection bupivacaine-only spinal anesthesia approach for urologic surgery lasting over an hour and up to 3 h is safe and effective in infants. Selecting appropriate candidates for SA should be a joint decision between the surgeon and the anesthesiologist.

Primary Hyperoxaluria Type 3 Can Also Result in Kidney Failure: A Case Report.

Primary hyperoxaluria (PH) is a group of genetic disorders that result in an increased hepatic production of oxalate. PH type 3 (PH3) is the most recently identified subtype and results from mutations in the mitochondrial 4-hydroxy-2-oxoglutarate aldolase gene (HOGA1). To date, there have been 2 cases of kidney failure reported in PH3 patients. We present a case of a young man with a history of recurrent urinary tract infections and voiding dysfunction who developed kidney failure at 33 years of age. He developed a bladder stone and bilateral staghorn calculi at 12 years of age. Initial metabolic evaluation revealed hyperoxaluria with very low urinary citrate excretion on multiple measurements for which he was placed on oral citrate supplements. Further investigation of the hyperoxaluria was not completed as the patient was lost to follow-up observation until he presented at 29 years of age with chronic kidney disease stage 4 (estimated glomerular filtration rate 24mL/min/1.73m2). Hemodialysis 3 times a week was started at 33 years of age, and subsequent genetic testing revealed a homozygous HOGA1 mutation (C.973G>A p.Gly325Ser) diagnostic of PH3. The patient is currently being evaluated for all treatment options including possible liver/kidney transplantation. All cases of a childhood history of recurrent urinary stone disease with marked hyperoxaluria should prompt genetic testing for the 3 known PH types. Hyperhydration and crystallization inhibitors (citrate) are standard of care, but the role of RNA interference agents for all 3 forms of PH is also under active study.

Surfaceome Profiling of Rhabdomyosarcoma Reveals B7-H3 as a Mediator of Immune Evasion.

Novel therapeutic strategies are needed for the treatment of rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children. By using a combination of cell surface proteomics and transcriptomic profiling of RMS and normal muscle, we generated a catalog of targetable cell surface proteins enriched in RMS tumors. Among the top candidates, we identified B7-H3 as the major immunoregulatory molecule expressed by RMS tumors. By using a large cohort of tissue specimens, we demonstrated that B7-H3 is expressed in a majority of RMS tumors while not detected in normal human tissues. Through a deconvolution analysis of the RMS tumor RNA-seq data, we showed that B7-H3-rich tumors are enriched in macrophages M1, NK cells, and depleted in CD8+-T cells. Furthermore, in vitro functional assays showed that B7-H3 knockout in RMS tumor cells increases T-cell mediated cytotoxicity. Altogether, our study uncovers new potential targets for the treatment of RMS and provides the first biological insights into the role of B7-H3 in RMS biology, paving the way for the development of next-generation immunotherapies.

Establishment of a Pediatric Ovarian and Testicular Cryopreservation Program for Malignant and Non-Malignant Conditions: The Mayo Clinic Experience.

STUDY OBJECTIVES: To describe the structure of a pediatric fertility preservation (FP) program and to share safety and patient satisfaction data. DESIGN: The FP program operates under prospective research protocols approved by the Mayo Clinic Institutional Review Board (IRB). SETTING: The FP program is a multidisciplinary effort between pediatric gynecology, reproductive endocrinology, pediatric urology, pediatric surgery, and laboratory medicine. PARTICIPANTS: The FP program enrolls patients between 0-17 years of age who have been diagnosed with a fertility-threatening condition and/or are scheduled to undergo gonadotoxic treatment. INTERVENTIONS: FP is offered in the form of ovarian tissue cryopreservation (OTC) and testicular (TTC) tissue cryopreservation. MAIN OUTCOME MEASURES: The outcome measures are the safety of the procedure and results of patient surveys conducted by phone using a standard list of questions to assess attitudes towards FP. RESULTS: To date, we have enrolled 38 OTC and 37 TTC patients. The median age (range) of OTC and TTC patients was 11 years (0.83-17 years) and 10 years (0.92-17 years) at the time of enrollment, respectively. Childhood cancers currently represent 88% of the fertility-threatening diagnoses. Meanwhile, patients with non-malignant conditions include those with gender dysphoria, aplastic anemia, and Turner's syndrome. To date, no serious adverse events (SAEs) have been reported following surgery. According to n = 34 one-year follow-ups, 100% of parents felt that FP was a good decision. CONCLUSION: Consistent with the literature, our data suggests FP is safe and improves the quality of care provided to pediatric patients for their fertility-threatening diagnoses and/or treatments. TRIAL REGISTRATION: NCT02872532, NCT02646384.

Feasibility Study of Vascularized Composite Urinary Bladder Allograft Transplantation in a Cadaver Model.

PURPOSE: The purpose of this study was to establish the feasibility of performing a urinary bladder vascularized composite allograft transplantation for either bladder augmentation or neobladder creation. MATERIALS AND METHODS: Six adult cadavers were studied. Cadavers were excluded for any previous pelvic surgery, radiation, vascular surgery or history of pelvic malignancy. An intravascular colored silicone and barium mixture was injected and both computerized tomography scans and gross dissections were performed. Contrast enhanced computerized tomography imaging was used to delineate urinary bladder vascular anatomy variability. Bladders were explanted en bloc from 2 cadavers with bilateral vascular pedicles based on the external iliac vessels and "transplanted" to replicate a bladder transplant. RESULTS: Contrast enhanced 3-D-computerized tomography reconstructions and cadaver dissections revealed distal vascular variability with proximal blood supply based primarily on the internal iliac artery. Urinary bladder vascularized composite allograft transplantation was successfully performed during 2 mock transplants with the vascular anastomosis done to the recipient external iliac artery and vein. CONCLUSIONS: Urinary bladder vascularized composite allograft transplantation is technically and anatomically feasible. This procedure may obviate the use of intestinal segments for bladder reconstruction in select patients. A phase 1 clinical trial is in progress.

Bladder hemangioma: An arduous diagnosis of hematuria.

Urinary bladder hemangiomas are a rare cause of gross hematuria in young patients. Multimodality imaging with ultrasound, computed tomography, and magnetic resonance imaging help define the site and extent of hemangioma. We describe a case of an otherwise healthy 9-year-old male presenting with recurrent gross hematuria. The initial US did not demonstrate a bladder mass, but subsequent cystoscopies showed progressive enlargement of an extensive sessile and partially pedunculated vascular mass. Imaging with ultrasound, computed tomography, and magnetic resonance imaging persistently demonstrated a hypervascular bladder mass without extravesical extension. Ultimately, biopsy of the mass made the diagnosis of bladder hemangioma.

Consult and procedure incidence outcomes following establishment of a fertility preservation program for children with cancer.

PURPOSE: Fertility is a quality of life outcome adversely affected by cancer therapy. Many childhood cancer patients, however, are not offered options to preserve their fertility. Providers acknowledge difficulty discussing impaired fertility to patients due to lack of knowledge of available options. Our objective was to review the impact of a pediatric multidisciplinary fertility preservation program on providers' fertility preservation counseling and discussion of options. METHODS: A retrospective medical chart review was conducted for pediatric cancer patients prior to and following program establishment. Fertility preservation discussions, consults, and incidence were noted. Following filtering and stratification, 198 and 237 patients were seen prior to and following program establishment, respectively. RESULTS: Following program establishment, provider-patient discussions of impaired fertility (p = 0.007), fertility preservation consults (p = 0.01), and incidence of fertility preservation procedures (p < 0.001) increased among patients. Furthermore, the number of patients who received fertility preservation consults after receiving gonadotoxic treatment decreased (p < 0.001). This trend was particularly noted in pre-pubertal and female patients, for whom fertility preservation options are limited without an established program. CONCLUSION: The establishment of a formal program greatly improved access to fertility preservation consults and procedures in children with cancer.

Robot-Assisted Laparoscopic Urachal Excision Using Hidden Incision Endoscopic Surgery Technique in Pediatric Patients.

Introduction: Although laparoscopic urachal excision in children has been well reported, there are limited data on a robot-assisted surgery (RAS) approach. The hidden incision endoscopic surgery (HIdES) technique is an established method of eliminating visible scars following a number of RAS urologic procedures. We report our experience of using a robotic approach to treat urachal anomalies in children, and we present the first description of utilizing the HIdES port configuration for this procedure. Materials and Methods: We retrospectively reviewed pediatric patients who underwent resection of a urachal remnant at our institution from 2013 to 2018. Surgical techniques were either the traditional open approach (OA) or RAS. HIdES trocar placement configuration was employed in all robotic cases. Patient demographics, perioperative data, pathology reports, and outcomes were abstracted and compared. Results: Twenty-three patients underwent a urachal remnant resection in the study period (RAS: 14 patients vs OA: 9 patients). RAS patients were older (8.5 vs 2.0 years, p = 0.031) and weighed more than OA patients (36.1 vs 13.9 kg, p = 0.063). Median operative time for RAS was longer than OA operative time (136 vs 33 minutes, p < 0.01). Fewer RAS patients were outpatient compared with OA (7.1% vs 66.7%, p < 0.01), but with a median length of stay of 1 day (0-1 day). Two patients (14.3%) in the RAS group experienced postoperative complications within 1 week of the procedure compared with 1 (11.1%) in the OA group. There was no significant difference in blood loss, postoperative narcotic requirements, or duration of follow-up between both groups. Conclusion: RAS is a safe and feasible alternative to open surgery for urachal anomalies. Complete excision can be achieved by using HIdES port configuration, allowing for excellent cosmetic outcomes that are superior to traditional surgical scars without limitation to essential surgical ergonomics.