A Multipronged Intervention to Reduce Readmissions and Readmission Intensity After Radical Cystectomy.

OBJECTIVE: To develop a multipronged, evidence-based protocol to reduce readmission risk and readmission intensity, as represented by the duration of the index readmission, after radical cystectomy. MATERIALS AND METHODS: A per-protocol study was performed. The protocol included preoperative nutritional supplementation, early stent removal, and a follow-up phone call within 4-5days of discharge. The preprotocol period was from February 1, 2020 to July 31, 2021 and the postprotocol period was from December 1, 2020 to November 31, 2021. Using multivariate regression models, we compared outcomes among patients treated with radical cystectomy before and after protocol initiation. RESULTS: We identified 70 preprotocol patients and 126 postprotocol patients. After adjusting for age, sex, BMI, and frailty score, there was a significant reduction in 90-day readmission intensity (7 vs 5days; P = .048) among postprotocol patients. CONCLUSION: After implementation of an evidence-based protocol for patients undergoing radical 90-day readmission intensity decreased significantly. This protocol may move the needle forward on reducing readmissions, but a larger randomized trial is needed.

Factors Associated With Restarting Androgenic Anabolic Steroids After Cessation in Men With Infertility: A Retrospective Analysis.

Introduction The use of androgenic anabolic steroids (AAS) negatively affects male fertility by disrupting hormone release and reducing testosterone levels. Despite this, many men using steroids are unaware of fertility-related consequences. We aimed to determine the factors associated with AAS resumption during fertility treatment, specifically focusing on the duration, age, and dosage of AAS use prior to treatment. Our study, the first of its kind, investigated risk factors for resuming AAS following fertility assessment. Methods We conducted a retrospective review of adult men diagnosed with infertility due to chronic AAS use between 2012 and 2022 at the University of Miami. The study included men with azoospermia or severe oligospermia who were instructed to stop using AAS. Excluded were those who underwent orchiectomy for benign or malignant conditions. We collected data on demographic characteristics, AAS route details, fertility treatments, and AAS resumption. We hypothesized that risk factors for restarting AAS would include duration of AAS use, type of AAS, pre-treatment testosterone levels, and increased age. Results We identified 94 men with infertility caused by AAS use. Among them, 31 (33.0%) resumed AAS therapy within eight months after cessation. The median age of men who restarted AAS was 40 years. Those who resumed AAS had used it for a longer duration prior to fertility assessment compared to those who did not (60 months vs. 17 months, respectively). However, we found no statistically significant differences in age, duration of AAS use, AAS administration details, or serum testosterone levels at the time of initial assessment. Conclusion In conclusion, most men seeking fertility assessment due to AAS abuse did not resume testosterone therapy. However, those who did restart AAS had a longer history of AAS use. Future high-quality prospective studies are needed to better understand the risk factors associated with resuming AAS in male infertility caused by anabolic steroids.

Catheter Free Day of Surgery Discharge vs Overnight Observation Following Artificial Urinary Sphincter Placement.

Introduction To confirm the safety and examine outcomes of a day of surgery discharge following artificial urinary sphincter implantation in a population discharged without a catheter. Methods We retrospectively identified 110 patients, 31 of whom were discharged on the day of surgery, from a single surgeon following artificial urinary sphincter implantation. After institutional board review approval, patient charts were reviewed capturing demographics as well as three, thirty, and ninety-day outcomes. Further outcomes specific to urinary retention were obtained. Results Patients who were discharged the same day were older (71 vs. 68), had shorter operative times (92 minutes vs 109 minutes), and were less likely to have been smokers (6% vs 31%). There were no differences in the proportion of patients who underwent prior radiation or prior implant surgery. There was no significant difference in the number of patients who had emergency department visits, urinary retention, office calls, office visits, or unplanned office visits at all time points following surgery. There was no significant difference in overall urinary retention (15% vs 5%), retention presenting after the initial surgical event (6% vs 5%), or need for a suprapubic tube (0% vs 5%). Conclusions Day of surgery discharge is a safe discharge strategy for patients who have undergone artificial urinary sphincter placement. Furthermore, catheter-free days of discharge surgery did not have a significantly greater risk of urinary retention, office calls, emergency department (ED) visits, or office visits compared to our overnight observation population. This approach should be considered for all patients undergoing artificial urinary sphincter (AUS) implantation.

Insurance Type and Area Deprivation Are Associated With Worse Overall Mortality for Patients With Muscle-invasive Bladder Cancer.

OBJECTIVE: To examine the association of area-level socioeconomic status, rural-urban residence, and type of insurance with overall and cancer-specific mortality among patients with muscle-invasive bladder cancer. METHODS: Using the Pennsylvania Cancer Registry, which collects demographic, insurance, and clinical information on every patient with cancer within the state, we identified all patients diagnosed with non-metastatic muscle-invasive bladder cancer between 2010 and 2016 based on clinical and pathologic staging. We used the Area Deprivation Index (ADI) as a surrogate for socioeconomic status and Rural-Urban Commuting Area codes to classify urban, large town, and rural communities. ADI was reported in quartiles, with 4 representing the lowest socioeconomic status. We fit multivariable logistic regression and Cox models to assess the relationship of these social determinants with overall and cancer-specific survival adjusting for age, sex, race, stage, treatment, rural-urban classification, insurance and ADI. RESULTS: We identified 2597 patients with non-metastatic muscle-invasive bladder cancer. On multivariable analysis, Medicare (hazards ratio [HR] 1.15), Medicaid (HR 1.38), ADI 3 (HR 1.16) and ADI 4 (HR 1.21) were independent predictors of greater overall mortality (all P < 0.05). Female sex and receipt of non-standard treatment were associated with increased overall mortality and bladder cancer-specific mortality. There was no significant difference in both overall and cancer-specific survival between patients who were non-Hispanic White compared to non-White or between those from urban areas, large towns, or rural locations. CONCLUSION: Lower socioeconomic status and Medicare and Medicaid insurance were associated with a greater risk of overall mortality while rural residence was not a significant factor. Implementation of public health programs may help reduce the gap in mortality for low SES at-risk populations.

Genomic Patterns of Malignant Peripheral Nerve Sheath Tumor (MPNST) Evolution Correlate with Clinical Outcome and Are Detectable in Cell-Free DNA.

Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome and multiregional exome sequencing, transcriptomic, and methylation profiling of 95 tumor samples revealed the order of genomic events in tumor evolution. Following biallelic inactivation of NF1, loss of CDKN2A or TP53 with or without inactivation of polycomb repressive complex 2 (PRC2) leads to extensive somatic copy-number aberrations (SCNA). Distinct pathways of tumor evolution are associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumors with H3K27me3 loss evolve through extensive chromosomal losses followed by whole-genome doubling and chromosome 8 amplification, and show lower levels of immune cell infiltration. Retention of H3K27me3 leads to extensive genomic instability, but an immune cell-rich phenotype. Specific SCNAs detected in both tumor samples and cell-free DNA (cfDNA) act as a surrogate for H3K27me3 loss and immune infiltration, and predict prognosis. SIGNIFICANCE: MPNST is the most common cause of death and morbidity for individuals with NF1, a relatively common tumor predisposition syndrome. Our results suggest that somatic copy-number and methylation profiling of tumor or cfDNA could serve as a biomarker for early diagnosis and to stratify patients into prognostic and treatment-related subgroups. This article is highlighted in the In This Issue feature, p. 517.

Mosaicism in Tumor Suppressor Gene Syndromes: Prevalence, Diagnostic Strategies, and Transmission Risk.

A mosaic state arises when pathogenic variants are acquired in certain cell lineages during postzygotic development, and mosaic individuals may present with a generalized or localized phenotype. Here, we review the current state of knowledge regarding mosaicism for eight common tumor suppressor genes-NF1, NF2, TSC1, TSC2, PTEN, VHL, RB1, and TP53-and their related genetic syndromes/entities. We compare and discuss approaches for comprehensive diagnostic genetic testing, the spectrum of variant allele frequency, and disease severity. We also review affected individuals who have no mutation identified after conventional genetic analysis, as well as genotype-phenotype correlations and transmission risk for each tumor suppressor gene in full heterozygous and mosaic patients. This review provides new insight into similarities as well as marked differences regarding the appreciation of mosaicism in these tumor suppressor syndromes.

The ClinGen Brain Malformation Variant Curation Expert Panel: Rules for somatic variants in AKT3, MTOR, PIK3CA, and PIK3R2.

PURPOSE: Postzygotic (somatic) variants in the mTOR pathway genes cause a spectrum of distinct developmental abnormalities. Accurate classification of somatic variants in this group of disorders is crucial for affected individuals and their families. METHODS: The ClinGen Brain Malformation Variant Curation Expert Panel was formed to curate somatic variants associated with developmental brain malformations. We selected the genes AKT3, MTOR, PIK3CA, and PIK3R2 as the first set of genes to provide additional specifications to the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) sequence variant interpretation guidelines, which currently focus solely on germline variants. RESULTS: A total of 24 of the original 28 ACMG/AMP criteria required modification. Several modifications used could be applied to other genes and disorders in which somatic variants play a role: 1) using variant allele fraction differences as evidence that somatic mutagenesis occurred as a proxy for de novo variation, 2) incorporating both somatic and germline evidence, and 3) delineating phenotype on the basis of variable tissue expression. CONCLUSION: We have established a framework for rigorous interpretation of somatic mosaic variants, addressing issues unique to somatic variants that will be applicable to many genes and conditions.

Safety During Ureteroscopy: Radiation, Eyes, and Ergonomics.

It is known that urologic surgeons are at risk of work-place injury due to the physical requirements of operating and exposure to hazards. These hazards include radiation, exposure to body fluids, use of laser energy, and orthopedic injury due to the physical nature of operating. The risks that these hazards present can be mitigated by implementing several evidence-based safety measures. The methods to protect against radiation exposure include keeping radiation usage in the operating room as low as reasonably achievable, donning lead aprons, and wearing protective glasses. Additionally, protective glasses decrease the risk of eye injury from laser injury and exposure to body fluids. Finally, practicing sound surgical ergonomics is essential to minimize the risk of orthopedic injury and promote career longevity. The interventions discussed herein are simple and easy to implement in one's daily practice of urology.

Chromosomal microarray analysis, including constitutional and neoplastic disease applications, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).

Chromosomal microarray technologies, including array comparative genomic hybridization and single-nucleotide polymorphism array, are widely applied in the diagnostic evaluation for both constitutional and neoplastic disorders. In a constitutional setting, this technology is accepted as the first-tier test for the evaluation of chromosomal imbalances associated with intellectual disability, autism, and/or multiple congenital anomalies. Furthermore, chromosomal microarray analysis is recommended for patients undergoing invasive prenatal diagnosis with one or more major fetal structural abnormalities identified by ultrasonographic examination, and in the evaluation of intrauterine fetal demise or stillbirth when further cytogenetic analysis is desired. This technology also provides important genomic data in the diagnosis, prognosis, and therapy of neoplastic disorders, including both hematologic malignancies and solid tumors. To assist clinical laboratories in the validation of chromosomal microarray methodologies for constitutional and neoplastic applications, the American College of Medical Genetics and Genomics (ACMG) Laboratory Quality Assurance Committee has developed these updated technical laboratory standards, which replace the ACMG technical standards and guidelines for microarray analysis in constitutional and neoplastic disorders previously published in 2013.

Minimizing radiation dose in management of stone disease: how to achieve 'ALARA'.

PURPOSE OF REVIEW: Exposure to radiation is known to have adverse effects such as secondary malignancies. Patients with nephrolithiasis are exposed to radiation in the workup and treatment of their condition. Furthermore, exposure to radiation is often repeated due to the high recurrence rate of nephrolithiasis. RECENT FINDINGS: We discuss practices inside and outside of the operating room to strive to keep radiation exposure as low as reasonably achievable (ALARA) for patients being treated for nephrolithiasis. These efforts include reduced dose computed tomography scans, fluoroless surgical techniques and new alternative technologies. SUMMARY: Maintaining radiation exposure ALARA for our patients is increasingly practical. The urologist must make every effort to adhere to ALARA principles to protect patients from the stochastic effects of radiation.

Novel Creation of a Noneverted Stoma During Ileal Conduit Urinary Diversion: Technique and Short-term Outcomes.

OBJECTIVE: To report our experience with a noneverted stoma technique used in ileal conduit urinary diversion. We successfully utilize this technique in patients when traditional everted stoma maturation is difficult due to a thick abdominal wall, bulky mesentery, and poor bowel compliance. METHODS: We retrospectively reviewed all patients who underwent surgical creation of ileal conduit using a noneverted stoma technique between 2009 and 2018. We recorded demographic and perioperative information, including 30-day postoperative complications, and stoma appearance at last follow-up visit. Using R software, chi-square testing of the distribution of stoma outcomes for obese and nonobese patients was performed. RESULTS: There were a total of 42 patients who underwent noneverted stoma maturation technique by a single surgeon. Our cohort meets obese criteria with a mean body mass index (BMI) of 30.2. Mean length of follow-up was 16.6 months (1-62). On follow-up, 35 (83.3%) of stomas were pink and everted appearing, 4 (9.5%) were flush, small, or noneverted, 1 (2.3%) had an eschar or area of granulation tissue around the stoma, and 2 (4.7%) did not have a stoma description documented. There were 9 (21%) stoma-related complications in our cohort. There was no statistical difference in stoma outcomes between obese (BMI > 30) and nonobese (BMI < 30) patients (P= .65). CONCLUSION: Ileal conduit creation with a noneverted stoma provides good stoma protuberance in patients with a thick abdominal wall, bulky mesentery, and poor bowel compliance. This technique is safe and should be considered in patients in whom stoma maturation is difficult.

Genetics of human malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNSTs) are heterogeneous, highly aggressive tumors with no widely effective treatment other than surgery. Genomic architecture of MPNST is similar to other soft tissue sarcomas, with a relatively modest burden of single nucleotide variants and an elevated frequency of copy-number alterations. Recent advances in genomic studies identified previously unrecognized critical involvement of polycomb repressor complex 2 (PRC2) core components SUZ12 and EED in transition to malignancy. Notably, somatic changes in NF1, CDKN2A/B, and PRC2 are found in most MPNST regardless of their etiology (e.g. neurofibromatosis type 1-associated vs. sporadic vs. radiation-induced), indicating that similar molecular mechanisms impact pathogenesis in these neoplasms. The timing and specific order of genetic or epigenetic changes may, however, explain the typically poorer prognosis of NF1-associated MPNSTs. Studies that reveal genes and regulatory pathways uniquely altered in malignancies are essential to development of targeted tumor therapies. Characterization of MPNST molecular profiles may also contribute to tools for earlier detection, and prediction of prognosis or drug response. Here we review the genetic discoveries and their implications in understanding MPNST biology.

Unconventional Use of the Lithoclast to Aid in the Treatment of Large Distal Ureteral Stone Burden in a Patient With a Ureterocele.

INTRODUCTION: Large ureteral stone burden can present significant challenges for the urologist to treat. Here we present the retrograde use of the Lithoclast Select, in a dilated distal ureter after incision of a ureterocele. METHODS: The patient is a 64 year-old female with large distal ureteral stone burden, with approximately 15 1-2 cm stones. She presented with significant right flank pain, urinary urgency, frequency, dysuria, and recurrent urinary tract infections. RESULTS: A 22-French rigid cystoscope was inserted into the bladder. Urethral outlet was normal. Patient was noted to have 2 right-sided ureteral orifices, consistent with a completely duplex system. At the medial right ureteral orifice a very large ureterocele was noted. The lower pole system was scoped and stone free. The ureter to the upper pole moiety was scoped and a large stone burden within the distal ureter was visualized. The Plasmacise Gyrus was used to incise the anterior part of the ureter by inserting the Plasmacise into the ureteral orifice and tenting it anteriorly. The 24-French nephroscope was then inserted into the distal ureter. Graspers were used to extract many fragments however several were unable to be extracted from the distal ureter due to their size and thus were fragmented and evacuated with the ultrasonic lithoclast within the distal ureter. A 365-µ laser fiber was also used to fragment some of the stones. There were no complications. CT Scan 4 months post operatively was negative for stone recurrence. Last follow up was 15 months postprocedure where the patient was doing well. CONCLUSIONS: Utilization of the rigid nephroscope and ultrasonic lithotripter in a female patient with a dilated distal ureter with a capacious or incised ureterocele is safe and effective, allowing for treatment of greater than 15 cm total distal ureteral stone burden.

Genomics of MPNST (GeM) Consortium: Rationale and Study Design for Multi-Omic Characterization of NF1-Associated and Sporadic MPNSTs.

The Genomics of Malignant Peripheral Nerve Sheath Tumor (GeM) Consortium is an international collaboration focusing on multi-omic analysis of malignant peripheral nerve sheath tumors (MPNSTs), the most aggressive tumor associated with neurofibromatosis type 1 (NF1). Here we present a summary of current knowledge gaps, a description of our consortium and the cohort we have assembled, and an overview of our plans for multi-omic analysis of these tumors. We propose that our analysis will lead to a better understanding of the order and timing of genetic events related to MPNST initiation and progression. Our ten institutions have assembled 96 fresh frozen NF1-related (63%) and sporadic MPNST specimens from 86 subjects with corresponding clinical and pathological data. Clinical data have been collected as part of the International MPNST Registry. We will characterize these tumors with bulk whole genome sequencing, RNAseq, and DNA methylation profiling. In addition, we will perform multiregional analysis and temporal sampling, with the same methodologies, on a subset of nine subjects with NF1-related MPNSTs to assess tumor heterogeneity and cancer evolution. Subsequent multi-omic analyses of additional archival specimens will include deep exome sequencing (500×) and high density copy number arrays for both validation of results based on fresh frozen tumors, and to assess further tumor heterogeneity and evolution. Digital pathology images are being collected in a cloud-based platform for consensus review. The result of these efforts will be the largest MPNST multi-omic dataset with correlated clinical and pathological information ever assembled.

Health Supervision for Children With Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a multisystem disorder that primarily involves the skin and peripheral nervous system. Its population prevalence is approximately 1 in 3000. The condition is usually recognized in early childhood, when pigmentary manifestations emerge. Although NF1 is associated with marked clinical variability, most children affected follow patterns of growth and development within the normal range. Some features of NF1 can be present at birth, but most manifestations emerge with age, necessitating periodic monitoring to address ongoing health and developmental needs and minimize the risk of serious medical complications. In this report, we provide a review of the clinical criteria needed to establish a diagnosis, the inheritance pattern of NF1, its major clinical and developmental manifestations, and guidelines for monitoring and providing intervention to maximize the health and quality of life of a child affected.

Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.

PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. METHODS: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. RESULTS: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. CONCLUSION: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.

Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-848.

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons-Leu844, Cys845, Ala846, Leu847, and Gly848-located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals.