Urological outcomes in adult females born with anorectal malformation or Hirschsprung disease.

INTRODUCTION: Women born with anorectal malformation (ARM) or Hirschsprung disease (HD) may have impaired urologic function resulting in sequelae in adulthood. This study assessed and compared self-reported urinary outcomes in adult females born with ARM or HD to a reference population. METHODS: This was an IRB approved, cross-sectional study of female-born patients with ARM or HD, who completed surveys between November 2021 and August 2022. Female patients between the ages of 18 and 80 years were included. Lower Urinary Tract Symptom Questionnaires were administered through REDCap and the responses were compared to a reference population using Chi-squared or Fisher's exact tests. RESULTS: Sixty-six born female patients answered the questionnaires, two of them identified as non-binary. The response rate was 76%. Median age was 31.6 years. The majority were born with cloaca (56.3%), followed by other type of ARMs (28.1%), complex malformation (9.4%), and HD (6.3%). A history of bladder reconstruction was present for 26.6%. Catheterization through a channel or native urethra was present in 18.8%. Two had ureterostomies and were excluded from the analysis. Seven had chronic kidney disease or end-stage renal disease, three with a history of kidney transplantation. Patients with cloaca had significantly higher rates of urinary incontinence, urinary tract infection, and social problems due to impaired urological functioning, when compared to an age-matched reference population (Table 3). CONCLUSION: This study emphasizes the need for a multi-disciplinary team that includes urology and nephrology following patients with ARM long term, especially within the subgroup of cloaca. LEVEL OF EVIDENCE: III.

"Everyone screens to some extent": Barriers and facilitators of developmental screening among children with sickle cell disease: A mixed methods study.

BACKGROUND: Developmental delays are common among children with sickle cell disease (SCD). Existing guidelines support consistent screening to increase the identification of deficits and support referral to rehabilitative interventions, yet adherence remains variable. This study sought to assess current practices and identify barriers and facilitators to improve developmental screening for children 0-3 years with SCD. PROCEDURE: A mixed methods approach, guided by the Exploration and Preparation stages of the Exploration, Preparation, Implementation, and Sustainment (EPIS) framework, assessed developmental screening practices among primary care providers and hematologists. Phase 1 included the SCD Developmental Surveillance and Screening Guideline and Practice Survey. Phase 2 included the SCD Developmental Screening Organizational Survey alongside semi-structured interviews. Descriptive and qualitative methods summarized the findings. RESULTS: Thirty-three providers from general pediatrics and hematology completed phase 1. Use of standardized developmental screening measures was variable, with the most frequently used being the Modified Checklist for Autism in Toddlers (77%) and the Ages and Stages Questionnaire (55%). Fifteen providers participated in phase 2, and reported they were most likely to engage in changes to improve their practice (mean = 4.4/5) and least likely to support spiritual health and well-being (mean = 3.5/5). Three themes emerged:(i) developmental screening is not standardized or specific to SCD, (ii) children with SCD benefit from a multidisciplinary team, and (iii) healthcare system limitations are a barrier. CONCLUSIONS: Developmental screening is inconsistent and insufficient for young children with SCD. Providers are interested in supporting children with SCD, but report a lack of standardized measures and consistent guidance as barriers.

Endometriosis in a Prepubertal Patient with 46,XY Difference in Sex Development: A Case Report.

INTRODUCTION: Endometriosis typically presents in postmenarchal patients with cyclic and acyclic pelvic pain. However, there are reports of endometriosis in premenarchal patients. CASE: We report a 10-year-old individual with 46,XY difference of sex development who was found to have endometriosis at the time of laparoscopic gonadectomy for gonadoblastoma. CONCLUSIONS: Although rare, endometriosis can occur in 46,XY individuals prior to puberty, highlighting the complex origin of the disease.

Value of a multidisciplinary geriatric oncology committee on patient care in a community-based, academic cancer center.

INTRODUCTION: The heterogeneity in health and functional ability among older patients makes the management of cancer a unique challenge. The Geriatric Oncology Program at the University of Maryland Baltimore Washington Medical Center (BWMC) was created to optimize cancer management for older patients. This study aimed to assess the benefits of the implementation of such a program at a community-based academic cancer center. MATERIALS AND METHODS: We analyzed patients aged ≥80 years presenting to the Geriatric Oncology Program between 2017 and 2022. A multidisciplinary team of specialists collectively reviewed each patient using geriatric-specific domains and stratified each patient into one of three management groups- Group 1: those deemed fit to receive standard oncologic care (SOC); Group 2: those recommended to receive optimization services prior to reassessment for SOC; and Group 3: those deemed to be best suited for supportive care and/or hospice care. RESULTS: The study cohort consisted of 233 patients, of which 76 (32.6%) received SOC, 43 (18.5%) were optimized, and 114 (49.0%) received supportive care or hospice referral. Among the optimized patients, 69.8% were deemed fit for SOC upon re-evaluation following their respective optimization services. The Canadian Study of Health and Aging-Clinical Frailty Scale (CSHA-CFS) score was implemented in 2019 (n = 90). Patients receiving supportive/hospice care only had an average score of 5.8, while the averages for those in the optimization and SOC groups were 4.6 and 4.1, respectively (p ≤0.001). Patients receiving SOC had the longest average survival of 2.71 years compared to the optimization (2.30 years) and supportive care groups (0.93 years) (p ≤0.001). For all patients that underwent surgical interventions post-operatively, 23 patients (85%) were discharged home and four (15%) were discharged to a rehabilitation facility. DISCUSSION: The present study demonstrates the profound impact that the complexities in health status and frailty among older individuals can have during cancer management. The Geriatric Oncology Program at BWMC maximized treatment outcomes for older adults through the provision of SOC therapies and optimization services, while also minimizing unnecessary interventions on an individual patient-centric level.

Acceleration of benzo(a)pyrene-induced colon carcinogenesis by Western diet in a rat model of colon cancer.

Colorectal cancer (CRC) is the third leading cause of cancer-related mortalities in the USA and around 52,550 people were expected to die from this disease by December 2023. The objective of this study was to investigate the effect of diet type on benzo(a)pyrene [B(a)P]-induced colon cancer in an adult male rat model, the Polyposis In the Rat Colon (PIRC) kindred type. Groups of PIRC rats (n = 10) were fed with AIN-76A regular diet (RD) or Western diet (WD) and received 25, 50 and 100 µg B(a)P/kg body wt. via oral gavage for 60 days. Rats fed diets alone, but no B(a)P, served as controls. After exposure, rats were euthanized; colon and liver samples were analyzed for activation of drug metabolizing enzymes (DMEs) CYP1A1, CYP1B1, SULT and GST. Plasma and tissue samples were analyzed by reverse phase-HPLC for B(a)P metabolites. In addition to these studies, DNA isolated from colon and liver tissues was analyzed for B(a)P-induced DNA adducts by the 32P-postlabeling method using a thin-layer chromatography system. Western diet consumption resulted in a marked increase in DME expression and B(a)P metabolite concentrations in rats that were administered 100 µg/kg B(a)P + WD (p < 0.05) compared to other treatment groups. Our findings demonstrate that WD accelerates the development of colon tumors induced by B(a)P through enhanced biotransformation, and the products of this process (metabolites) were found to bind with DNA and form B(a)P-DNA adducts, which may have given rise to colon polyps characterized by gain in tumor number, sizes, and dysplasia.

Effectiveness of Liposomal Bupivacaine With Bupivacaine Hydrochloride vs Bupivacaine Hydrochloride Alone as a Local Anesthetic for Children Undergoing Ambulatory Urologic Surgery: The Baby ORIOLES Randomized Clinical Trial.

PURPOSE: We sought to determine if the addition of liposomal bupivacaine to bupivacaine hydrochloride improves opioid-free rate and postoperative pain scores among children undergoing ambulatory urologic surgery. MATERIALS AND METHODS: A prospective, phase 3, single-blinded, single-center randomized trial with superiority design was conducted in children 6 to 18 years undergoing ambulatory urologic procedures between October 2021 and April 2023. Patients were randomized 1:1 to receive dorsal penile nerve block (penile procedures) or incisional infiltration with spermatic cord block (inguinal/scrotal procedures) with weight-based liposomal bupivacaine plus bupivacaine hydrochloride or bupivacaine hydrochloride alone. The primary outcome was opioid-free rate at 48 hours. Secondary outcomes included parents' postoperative pain measure scores, numerical pain scale scores, and weight-based opioid utilization at 48 hours and 10 to 14 days. RESULTS: We randomized 104 participants, with > 98% (102/104) with complete follow-up data at 48 hours and 10 to 14 days. At interim analysis, there was no significant difference in opioid-free rate at 48 hours between arms (60% in the intervention vs 62% in the control group; estimated difference in proportion -1.9% [95% CI, -20%-16%]; P = .8). We observed no increased odds of patients being opioid-free at 48 hours with the intervention compared to the control group (OR 0.96 [95% CI 0.41-2.3]; P = .9). The trial met the predetermined futility threshold for early stopping. There was no difference in parents' postoperative pain measure scores, numerical pain scale scores, or opioid utilization at 48 hours or 10 to 14 days. No difference in adverse events was observed. CONCLUSIONS: The addition of liposomal bupivacaine to bupivacaine hydrochloride did not significantly improve opioid-sparing effect or postoperative pain compared with bupivacaine hydrochloride alone among children ≥ 6 years undergoing ambulatory urologic surgery.

Achieving goal capacity for continence surgery: A cumulative event analysis of bladder exstrophy patients.

BACKGROUND: Following successful closure of patients with classic bladder exstrophy (CBE), the next major milestone is the establishment of urinary continence. Prior to determining the most appropriate continence surgery, it is imperative to reach an adequate bladder capacity minimum of 100 cc in order to make the decision between bladder neck reconstruction (BNR) or continent stoma, with or without augmentation cystoplasty (AC). OBJECTIVE: To examine the timing of when patients achieve threshold bladder capacity for BNR eligibility. We hypothesize most patients will achieve an adequate bladder capacity (100 cc) by 7 years old when continence surgeries will begin to be considered. STUDY DESIGN: An institutional database of 1388 exstrophy patients was retrospectively reviewed for CBE patients after successful primary bladder closure. Bladder capacities were measured via gravity cystography and data presented as descriptive statistics. The cohort was stratified by location, neonatal (≤28 days) or delayed closure period and osteotomy status. The bladder capacities were categorized to either reaching goal or not and a cumulative event analysis was performed. The event being reaching 100 cc capacity or greater and time being the number of years between bladder closure and attainment of goal capacity. RESULTS: 253 patients met inclusion criteria between 1982 and 2019. The majority were of male gender (72.9%), had their closure performed at the authors' institution (52.5%), within the neonatal period (80.7%), and without an osteotomy (51.7%). 64.9% of patients reached goal bladder capacity. There were no significant differences in those who did or did not achieve goal except for clinical follow up. Cumulative event analysis demonstrated a median time of 5.73 years (95% CI 5.2-6.20) corresponded with a 50% event probability of reaching goal capacity. Cox-proportional hazards showed location of closure was significantly associated with hazards of reaching goal bladder capacity (HR = 0.58, CI 0.40-0.85, p = 0.005). Based on this model, the median time to event would be 5.20 years (95% CI 4.76-5.80) for cases done at the authors' hospital and 6.26 years for those performed at an outside hospital (95% CI 5.77-7.24). CONCLUSIONS: These findings help surgeons counsel families appropriately on the odds of attaining goal capacity at various ages. For those who do not reach 100 cc by five years of age, it helps further characterize the odds of requiring a continent stoma with bladder augmentation and the best timing for reconstructive surgery in order to safely gain urinary continence. Families may also be assured that most patients would have the breadth of surgical options when it comes to continence as more than half of patients reached the bladder capacity threshold.

Safety and Efficacy of Long-Acting Liposomal Bupivacaine Plus Bupivacaine Hydrochloride for Dorsal Penile Block During Ambulatory Pediatric Urologic Surgery.

This study evaluates the tolerability and efficacy of preoperative dorsal penile nerve block with Exparel plus bupivacaine hydrochloride in children>6 years old undergoing ambulatory urologic surgery. We demonstrate that the drug combination is well-tolerated, with appropriate analgesic efficacy in the recovery room as well as at 48-hour and 10-14 day follow-up periods. These preliminary data justify the need to perform a prospective, randomized trial comparing Exparel plus bupivacaine hydrochloride to other common local anesthetic regimens used in pediatric urologic surgery.

The exstrophy experience: A national survey assessing urinary continence, bladder management, and oncologic outcomes in adults.

INTRODUCTION AND OBJECTIVE: The bladder exstrophy-epispadias complex (BEEC) is a rare spectrum of congenital genitourinary malformations with an incidence of 1:10,000 to 1:50,000. Advances in reconstructive surgical techniques have improved clinical outcomes, but there is a paucity in data about disease sequela in adulthood. This is the largest survey to date in the United States exploring the urinary continence, bladder management, and oncologic outcomes in adults with BEEC. METHODS: Respondents were over the age of 18 with a diagnosis of bladder exstrophy, cloacal exstrophy, or epispadias. They were treated at the authors' institution, included in the Association for the Bladder Exstrophy Community (A-BE-C) mailing list, and/or engaged in A-BE-C social media. A survey was created using uniquely designed questions and questionnaires. Survey responses between May 2020 and July 2020 were processed using Research Electronic Data Capture (REDCap). Quantitative and qualitative statistics were used to analyze the data with significance at p < 0.05. RESULTS: A total of 165 patients completed the survey. The median age was 31.5 years (IQR 25.9-45.9). Many patients considered themselves continent of urine, with a median satisfaction score of 74 (IQR 50-97) on a scale from 0 (consider themselves to be completely incontinent) to 100 (consider themselves to be completely continent). There was less leakage among those with a continent urinary diversion compared to those who void or catheterize per urethra (p = 0.003). Patients with intestinal-urinary tract reconstruction, such as augmentation cystoplasty or neobladder creation, were more likely to perform bladder irrigations (p = 0.03). Patients with continent channels were more likely to report UTI than all other forms of bladder management (89.0% vs. 66.2%, p = 0.003). Three (1.9%) patients were diagnosed with bladder cancer. A small portion of patients (27.2%) were given bladder cancer surveillance recommendations by a physician. DISCUSSION: Most patients achieved a satisfactory level of urinary continence, with the highest continence rates in those with a continent urinary diversion. Those with intestinal-urinary tract reconstruction were more likely to perform bladder irrigations, perhaps to avoid complications from intestinal mucous production. The rates of self-reported UTI and were higher in patients with continent channels, but recurrent UTIs were not affected by the type of genitourinary reconstruction. Bladder cancer exists in this population, highlighting the need for long-term follow-up. CONCLUSION: Most BEEC patients achieve a satisfactory level of urinary continence, with the best outcomes in those with a continent urinary diversion. This population requires long-term follow-up with a transitional urologist to ensure adequate oncologic care.

Adrenal pheochromocytoma in a patient with Lynch Syndrome.

Lynch Syndrome (LS), or hereditary non-polyposis colorectal cancer, is the most common cause of hereditary colorectal cancer. There are well described extra-colonic manifestations of LS, including gynecologic and upper urinary tract malignancies. Other extra-colonic manifestations of LS are less understood. Here we present an unusual case of a functional adrenal pheochromocytoma in a 31-year old man with LS.

Patient and in-hospital predictors of post-discharge opioid utilization: Individualizing prescribing after radical prostatectomy based on the ORIOLES initiative.

OBJECTIVE: Judicious opioid stewardship would match each patient's prescription to their true medical necessity. However, most prescribing paradigms apply preset quantities and clinical judgment without objective data to predict individual use. We evaluated individual patient and in-hospital parameters as predictors of post-discharge opioid utilization after radical prostatectomy (RP) to provide evidence-based guidance for individualized prescribing. METHODS: A prospective cohort of patients who underwent open or robotic RP were followed in the Opioid Reduction Intervention for Open, Laparoscopic, and Endoscopic Surgery (ORIOLES) initiative. Baseline demographics, in-hospital parameters, and inpatient and post-discharge pain medication utilization were tabulated. Opioid medications were converted to oral morphine equivalents (OMEQ). Predictive factors for post-discharge opioid utilization were analyzed by univariable and multivariable linear regression, adjusting for opioid reduction interventions performed in ORIOLES. RESULTS: Of 443 patients, 102 underwent open and 341 underwent robotic RP. The factors most strongly associated with post-discharge opioid utilization included inpatient opioid utilization in the final 12 hours before discharge (+39.6 post-discharge OMEQ if inpatient OMEQ was >15 vs. 0), maximum patient-reported pain score (range 0-10) in the 12 hours before discharge (+27.6 OMEQ for pain score ≥6 vs. ≤1), preoperative opioid use (+76.2 OMEQ), and body mass index (BMI; +1.4 OMEQ per 1 kg/m2). A final predictive calculator to guide post-discharge opioid prescribing was constructed. CONCLUSIONS: Following RP, inpatient opioid use, patient-reported pain scores, prior opioid use, and BMI are correlated with post-discharge opioid utilization. These data can help guide individualized opioid prescribing to reduce risks of both overprescribing and underprescribing.

Assessment of Clonal Expansion Using CarcSeq Measurement of Lung Cancer Driver Mutations and Correlation With Mouse Strain- and Sex-Related Incidence of Spontaneous Lung Neoplasia.

Quantification of variation in levels of spontaneously occurring cancer driver mutations (CDMs) was developed to assess clonal expansion and predict future risk of neoplasm development. Specifically, an error-corrected next-generation sequencing method, CarcSeq, and a mouse CarcSeq panel (analogous to human and rat panels) were developed and used to quantify low-frequency mutations in a panel of amplicons enriched in hotspot CDMs. Mutations in a subset of panel amplicons, Braf, Egfr, Kras, Stk11, and Tp53, were related to incidence of lung neoplasms at 2 years. This was achieved by correlating median absolute deviation (MAD) from the overall median mutant fraction (MF) measured in the lung DNA of 16-week-old male and female, B6C3F1 and CD-1 mice (10 mice/sex/strain) with percentages of spontaneous alveolar/bronchioloalveolar adenomas and carcinomas reported in bioassay control groups. A total of 1586 mouse lung mutants with MFs >1 × 10-4 were recovered. The ratio of nonsynonymous to synonymous mutations was used to assess the proportion of recovered mutations conferring a positive selective advantage. The greatest ratio was observed in what is considered the most lung tumor-sensitive model examined, male B6C3F1 mice. Of the recurrent, nonsynonymous mouse mutations recovered, 55.5% have been reported in human tumors, with many located in or around the mouse equivalent of human cancer hotspot codons. MAD for the same subset of amplicons measured in normal human lung DNA samples showed a correlation of moderate strength and borderline significance with age (a cancer risk factor), as well as age-related cumulative lung cancer risk, suggesting MAD may inform species extrapolation.

CarcSeq Measurement of Rat Mammary Cancer Driver Mutations and Relation to Spontaneous Mammary Neoplasia.

The ability to deduce carcinogenic potential from subchronic, repeat dose rodent studies would constitute a major advance in chemical safety assessment and drug development. This study investigated an error-corrected NGS method (CarcSeq) for quantifying cancer driver mutations (CDMs) and deriving a metric of clonal expansion predictive of future neoplastic potential. CarcSeq was designed to interrogate subsets of amplicons encompassing hotspot CDMs applicable to a variety of cancers. Previously, normal human breast DNA was analyzed by CarcSeq and metrics based on mammary-specific CDMs were correlated with tissue donor age, a surrogate of breast cancer risk. Here we report development of parallel methodologies for rat. The utility of the rat CarcSeq method for predicting neoplastic potential was investigated by analyzing mammary tissue of 16-week-old untreated rats with known differences in spontaneous mammary neoplasia (Fischer 344, Wistar Han, and Sprague Dawley). Hundreds of mutants with mutant fractions ≥ 10-4 were quantified in each strain, most were recurrent mutations, and 42.5% of the nonsynonymous mutations have human homologs. Mutants in the mammary-specific target of the most tumor-sensitive strain (Sprague Dawley) showed the greatest nonsynonymous/synonymous mutation ratio, indicative of positive selection consistent with clonal expansion. For the mammary-specific target (Hras, Pik3ca, and Tp53 amplicons), median absolute deviation correlated with percentages of rats that develop spontaneous mammary neoplasia at 104 weeks (Pearson r = 1.0000, 1-tailed p = .0010). Therefore, this study produced evidence CarcSeq analysis of spontaneously occurring CDMs can be used to derive an early metric of clonal expansion relatable to long-term neoplastic outcome.

Benzo(a)pyrene-induced cytotoxicity, cell proliferation, DNA damage, and altered gene expression profiles in HT-29 human colon cancer cells.

In the US alone, around 60,000 lives/year are lost to colon cancer. In order to study the mechanisms of colon carcinogenesis, in vitro model systems are required in addition to in vivo models. Towards this end, we have used the HT-29 colon cancer cells, cultured in Dulbecco's Modified Eagle Medium (DMEM), which were exposed to benzo(a)pyrene (BaP), a ubiquitous and prototypical environmental and dietary toxicant at 1, 10, 100 nM and 1, 5, 10, and 25 µM concentrations for 96 h. Post-BaP exposure, growth, cytotoxicity, apoptosis, and cell cycle changes were determined. The BaP metabolite concentrations in colon cells were identified and measured. Furthermore, the BaP biotransformation enzymes were studied at the protein and mRNA levels. The BaP exposure-induced damage to DNA was assessed by measuring the oxidative damage to DNA and the concentrations of BaP-DNA adducts. To determine the whole repertoire of genes that are up- or downregulated by BaP exposure, mRNA transcriptome analysis was conducted. There was a BaP exposure concentration (dose)-dependent decrease in cell growth, cytotoxicity, and modulation of the cell cycle in the treatment groups compared to untreated or dimethylsulfoxide (DMSO: vehicle for BaP)-treated categories. The phase I biotransformation enzymes, CYP1A1 and 1B1, showed BaP concentration-dependent expression. On the other hand, phase II enzymes did not exhibit any marked variation. Consistent with the expression of phase I enzymes, elevated concentrations of BaP metabolites were generated, contributing to the formation of DNA lesions and stable DNA adducts, which were also BaP concentration-dependent. In summary, our studies established that biotransformation of BaP contributes to cytotoxicity, proliferation of tumor cells, and alteration of gene expression by BaP. • Benzo(a)pyrene (BaP) is an environmental and dietary toxicant. • BaP causes cytotoxicity in cultured HT-29 colon cancer cells. • mRNA transcriptome analyses revealed that BaP impacts cell growth, cell cycle, biotransformation, and DNA damage.

Contemporary Assessment of the Most Cited Clinical, Basic Science, and Guidelines Papers in Urology: A Reference for Urology Journal Club.

OBJECTIVE: To perform bibliometric analysis of the top cited articles in urology as a guide for journal club article selection. METHODS: Bibliometric citation analysis was performed using Scopus. Tables illustrating the top cited clinical, basic science, and guidelines/position statements papers were constructed. Linear regression was used to determine association between h-index and number of citations. RESULTS: A total of 3,188,861 publications from 1788 to 2020 were analyzed. The top 100 cited clinical papers from 1788 to 2020, top 100 cited contemporary clinical papers from 2000 to 2020, top 25 cited basic science papers, and the top 25 cited guidelines/position statement papers were reported. Median number of citations in the top 100 cited clinical papers was 1463 (interquartile range 1186-1821). Memorial Sloan Kettering Cancer Center (12), Johns Hopkins University (6), and Harvard University (6) contributed the most top cited clinical papers in urology. Urologic oncology was the most represented subspecialty in both clinical (75%) and basic science (96%) papers. First author and last author h-index were found to correlate with the number paper citations in the top 100 cited clinical papers from 1788 to 2020 (first author ß:5.3, P= .003, last author ß:4.5, P= .03). Only 7% of the most cited clinical papers in urology were from female first authors, which was not statistically significantly different from those reported in prior publications published in 2009 and 2013. CONCLUSION: Contemporary citation analysis of indexed manuscripts in urology may serve as a valuable educational tool for urologists and trainees.

Clinical Restaging and Tumor Sequencing are Inaccurate Indicators of Response to Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer.

BACKGROUND: Standard of care for patients with muscle-invasive bladder cancer (MIBC) includes neoadjuvant cisplatin-based chemotherapy (NAC) followed by consolidative therapy with either chemoradiation or radical cystectomy (RC). Some patients experience robust pathologic responses to NAC, and these have been reported to associate with somatic mutations in specific gene pathways including DNA damage response genes. OBJECTIVE: To evaluate the ability of post-NAC clinical restaging, with or without tumor sequencing, to predict final RC pathologic staging. DESIGN, SETTING, AND PARTICIPANTS: We reviewed our institutional review board-approved institutional database to identify patients with MIBC who underwent NAC followed by RC from 2003 to 2016. Following NAC prior to RC, cystoscopy was performed routinely, with resection of residual visible tumor and/or tumor base (transurethral resection [TUR]). For patients with pre-NAC tumor tissue available, tumor sequencing was performed. Outcome measurements and statistical analysis: Clinical restaging and tumor sequencing were evaluated for their ability to predict the final pathologic stage accurately at RC using chi-square or Fisher's exact test. RESULTS AND LIMITATIONS: A total of 114 patients underwent restaging TUR following NAC and prior to RC. The diagnostic accuracy of post-NAC clinical restaging including TUR was poor, with 32% of patients being downstaged falsely when compared with their final RC pathology. Forty-nine patients had sequencing of pre-NAC tumor tissue, of whom 32 showed at least one mutation of interest. However, NAC responses and rates of false downstaging did not differ significantly according to tumor mutation status. CONCLUSIONS: This study highlights the inaccuracy of post-NAC clinical restaging TUR with or without adjunctive tumor mutation analysis, to assess pathologic residual disease accurately. Caution must be taken when performing post-NAC restaging, especially when considering conservative management strategies such as active surveillance on this basis. Patient summary: Several groups are evaluating whether certain patients, whose bladder cancer responds well to upfront chemotherapy, may be able to forego cystectomy safely. We demonstrate that currently available staging tools and tumor DNA sequencing cannot identify such patients reliably and accurately.

Delaying primary closure of classic bladder exstrophy: When is it too late?

INTRODUCTION: With current trends towards delaying the closure of classic bladder exstrophy (CBE), bladder growth rate or ultimate capacity may be impacted. OBJECTIVE: To examine consecutive bladder capacities in CBE patients who had primary closures at differing ages and determine whether there is an optimal age for closure, with reference to bladder capacity. STUDY DESIGN: A retrospective review was performed using an institutional database. INCLUSION CRITERIA: CBE, successful neonatal (i.e. ≤28 days old) or delayed (i.e. >28 days old) primary closure, at least three consecutive bladder capacities or two measures taken 18 months apart, and first bladder capacity measured ≥3 months after closure. Only capacities prior to continence surgery and before 14 years of age were considered. Two cohorts were created: neonatal and delayed closure. To account for repeated measurements per patient, a linear mixed model evaluated effects of age and length of delay on bladder capacity based on closure cohort. Individuals in the delayed closure group were further stratified into quartiles to assess for detriment to the bladder based on length of delay. RESULTS: The cohort included 128 neonatal and 38 delayed patients. Median age at closure for the delayed group was 193 days (IQR 128-299). Based on univariate analysis, for the first three capacity measurements, the delayed group had significantly lower capacities despite having a similar median age when the measurements were taken. Linear mixed effects model showed significantly decreased total bladder capacity in delayed closure compared to neonates. The 2nd and 4th quartile groups had the most significant decreases in capacity. DISCUSSION: Time points for the most significant decline appear after the 2nd and 4th quartiles, representing 4-6 months and beyond 9 months, respectively. From this, the authors theorize that the appropriate time to close an exstrophy patient is as early as possible (1st quartile), or, if a delay is needed for growth of a bladder template, then between 6 and 9 months (3rd quartile). There may be a detriment to growth rate, however, statistical power may be lacking to discern this. Study limitations include the single-centered, retrospective design. However, results described here fill an important deficit in the knowledge of managing CBE. CONCLUSIONS: All patients in the delayed bladder closure group demonstrated a decline in bladder capacity compared to the control neonatal closure group, with significant differences in the 2nd and 4th quartiles. Thus, closing the bladder prior to nine months of age is recommended.

Quantification of cancer driver mutations in human breast and lung DNA using targeted, error-corrected CarcSeq.

There is a need for scientifically-sound, practical approaches to improve carcinogenicity testing. Advances in DNA sequencing technology and knowledge of events underlying cancer development have created an opportunity for progress in this area. The long-term goal of this work is to develop variation in cancer driver mutation (CDM) levels as a metric of clonal expansion of cells carrying CDMs because these important early events could inform carcinogenicity testing. The first step toward this goal was to develop and validate an error-corrected next-generation sequencing method to analyze panels of hotspot cancer driver mutations (hCDMs). The "CarcSeq" method that was developed uses unique molecular identifier sequences to construct single-strand consensus sequences for error correction. CarcSeq was used for mutational analysis of 13 amplicons encompassing >20 hotspot CDMs in normal breast, normal lung, ductal carcinomas, and lung adenocarcinomas. The approach was validated by detecting expected differences related to tissue type (normal vs. tumor and breast vs. lung) and mutation spectra. CarcSeq mutant fractions (MFs) correlated strongly with previously obtained ACB-PCR mutant fraction (MF) measurements from the same samples. A reconstruction experiment, in conjunction with other analyses, showed CarcSeq accurately quantifies MFs ≥10-4 . CarcSeq MF measurements were correlated with tissue donor age and breast cancer risk. CarcSeq MF measurements were correlated with deviation from median MFs analyzed to assess clonal expansion. Thus, CarcSeq is a promising approach to advance cancer risk assessment and carcinogenicity testing practices. Paradigms that should be investigated to advance this strategy for carcinogenicity testing are proposed.

Outcomes of inflatable penile prosthesis insertion using a neotunica allograft in neophalluses of patients on the bladder exstrophy-epispadias complex spectrum.

BACKGROUND: Men born on the bladder exstrophy-epispadias complex (BEEC) spectrum may undergo neophallus reconstruction with a variety of free flaps, most commonly radial forearm. In order to achieve erectile function, a penile prosthesis may be inserted following neophallus construction. OBJECTIVE: In this study, we sought to describe the perioperative and clinical outcomes of inflatable penile prosthesis (IPP) insertion into neophalluses of patients along the BEEC spectrum. STUDY DESIGN: Using a prospectively maintained institutional BEEC database, patients who had undergone both neophallus creation and IPP placement were identified for this study. Surgery was performed by two surgeons with expertise in IPP implantation. Operative details and postoperative outcomes and complications were collected with review of the medical record. RESULTS: Overall, there were a total of 13 men who underwent neophallus reconstruction with subsequent IPP placement. Of these men, 76.9% (10/13) had experienced successful primary closure in childhood. One patient had corporal loss secondary to complete primary repair of exstrophy (CPRE) following a failed primary attempt. The average age at IPP placement was 23.2 years (SD ± 5.06). Mean OR time (n = 11) was 244.8 min (SD ± 46.2). 76.9% (10/13) of the cases used AlloDerm™ as a neotunica albuginea for support of the IPP. Three patients (23.1%) experienced complications all of which required revision surgery. Two of these complications were erosions in patients for whom AlloDerm™ was not used in the initial IPP placement. DISCUSSION: The results of this study suggest that IPP placement in neophalluses of males on the BEEC spectrum have low perioperative and postoperative morbidity with successful outcomes. While the rate of complications is notably higher in this group compared to the native penis IPP literature, the use of AlloDerm™ or other allograft materials may help to narrow this gap. CONCLUSIONS: IPP placement in neophalluses of men on the BEEC spectrum is successful in the majority of cases. Complications may be reduced with the use of AlloDerm™ in initial placement.