Assessment of PSA responses and changes in the rate of tumor growth (g-rate) with immune checkpoint inhibitors in US Veterans with prostate cancer.

We examined data from US Veterans with prostate cancer (PC) to assess disease response to immune checkpoint inhibitors (ICI) as monotherapy or combined with abiraterone or enzalutamide to assess ICI efficacy in the real-world. We queried the VA corporate data warehouse (CDW) to identify Veterans with a diagnosis of PC who received ICI for any malignancy and had ≥1 PSA measurement while receiving ICI. To evaluate ICI monotherapy, we restricted analysis to Veterans who had not received LHRH agonists/antagonists, PC-directed medical therapy, or radiation/extirpative surgery of the bladder/prostate within and preceding the duration of ICI administration. For ICI combination analysis, we identified Veterans who received abiraterone or enzalutamide for PC while on ICI. We calculated rates of tumor (PSA) growth (g-rates), comparing them to a 1:2 matched reference cohort. We identified 787 Veterans with PC and ≥1 PSA measurement while receiving an ICI. Median duration of ICI therapy was 155 days. 223 Veterans received ICI monotherapy, with only 17(8%) having a reduction in PSA (median decline = 43%). 12 (5%) had PSA declines >30% (PSA30) which included 6 (3%) who had PSA reductions greater than 50% (PSA50). Median g-rates for ICI plus abiraterone (n = 20) or enzalutamide (n = 31) were 0.000689/d-1 and 0.002819/d-1, respectively, and were statistically insignificant compared to g-rates of matched cohorts receiving abiraterone (g = 0.000925/d-1, P = 0.73) or enzalutamide (g = 0.001929/d-1, P = 0.58) alone. Our data align with clinical trial data in PC, demonstrating limited benefit from ICI monotherapy and predicting no survival benefit from simultaneous abiraterone or enzalutamide with an ICI using g-rate.

Atypical Presentation Delays Treatment of Pediatric Testicular Torsion.

OBJECTIVE: The aim of the study is to identify patient- and care-related factors associated with time to treatment for acute testicular torsion and the likelihood of testicular loss. METHODS: Data were retrospectively collected for patients 18 years and younger who had surgery for acute testicular torsion between April 1, 2005, and September 1, 2021. Atypical symptoms and history were defined as having abdominal, leg, or flank pain, dysuria, urinary frequency, local trauma, or not having testicular pain. The primary outcome was testicular loss. The primary process measure was time from emergency department (ED) triage to surgery. RESULTS: One hundred eleven patients were included in descriptive analysis. The rate of testicular loss was 35%. Forty-one percent of all patients reported atypical symptoms or history. Eighty-four patients had adequate data to calculate time from symptom onset to surgery and time from triage to surgery and were included in analyses of factors affecting risk of testicular loss. Sixty-eight patients had adequate data to evaluate all care-related time points and were included in analyses to determine factors affecting time from ED triage to surgery. On multivariable regression analyses, increased risk of testicular loss was associated with younger age and longer time from symptom onset to ED triage, while longer time from triage to surgery was associated with reporting atypical symptoms or history.The most frequently reported atypical symptom was abdominal pain, in 26% of patients. These patients were more likely to have nausea and/or vomiting and abdominal tenderness but equally likely to report testicular pain and swelling and have testicular findings on examination. CONCLUSIONS: Patients presenting to the ED with acute testicular torsion reporting atypical symptoms or history experience slower transit from arrival in the ED to operative management and may be at greater risk of testicular loss. Increased awareness of atypical presentations of pediatric acute testicular torsion may improve time to treatment.

Virilization of a 46,XX Fetus Following Aromatase Inhibitor Treatment of Breast Cancer.

Virilization of the 46,XX infant may be attributed to maternal or fetoplacental origin. Maternal sources may be endogenous, as with an androgen-producing tumor, or drug-related. Iatrogenic virilization by maternal drug exposure is rarely reported, with individual case reports and case series demonstrating the effects of progesterone and other medications affecting the pituitary-ovarian axis.1-3 The class of medications known as aromatase inhibitors are recognized as effective in treating hormone receptor-positive breast cancer by preventing the conversion of androgens into estrogens by aromatase. In fetal development, placental aromatase plays a critical role in preventing virilization of the XX fetus by maternal and fetal androgens during development. In the setting of placental aromatase deficiency, the XX fetus may be virilized. It is conceivable, therefore, that maternal exposure to aromatase inhibitors early in gestation may lead to in utero virilization, though there have been no known reports of this phenomenon to date. We present a case of virilization of a 46,XX infant attributed to pharmacologic aromatase inhibition. The infant's parents provided informed consent for the reporting of this case.

Survival outcomes in patients with muscle invasive bladder cancer undergoing radical vs. partial cystectomy.

PURPOSE: While radical cystectomy (RC) is the standard of care for muscle invasive bladder cancer (MIBC), partial cystectomy (PC) is an effective alternative in select patients. We sought to examine differences in survival for RC and PC in a hospital-based registry. MATERIAL AND METHODS: We identified patients diagnosed with cT2-4 bladder cancer who underwent RC or PC from 2003 to 2015 in the National Cancer Database (NCDB). Using inverse probability treatment weighting (IPTW) to control for known confounders, we compared the primary outcome of overall survival (OS) in patients who underwent RC vs. PC. Kaplan-Meier survival analysis, univariable and multivariable Cox proportional hazards modeling were used. We performed a secondary survival analysis for a subcohort of patients with cT2, cN0, tumor size ≤5 cm, and no concurrent carcinoma in situ (CIS), who may be optimal candidates for PC. RESULTS: A total of 22,534 patients met inclusion criteria, of which 6.9% (1,457) underwent PC. RC had longer median OS than PC (67.8 vs. 54.1 months) and on Cox regression analysis (HR 0.88, 95% CI, 0.80-0.95, P = 0.002). However, in our subcohort, there was no difference in OS between RC and PC (HR 1.02, 95% CI, 0.9-1.2, P = 0.74). PC was associated with increased time from surgery to any systemic therapy or death in the subcohort. CONCLUSIONS: Among patients with clinically organ-confined MIBC, PC appears to afford similar survival outcomes to RC in a large national data set. The safety and tolerability of PC may warrant consideration in highly selected patients.

Urodynamic findings in female patients with nocturia: An age-matched case-control study.

INTRODUCTION: Nocturia negatively impacts the quality of life and is associated with poor general health, but our understanding of its etiologies is incomplete. Urodynamic studies (UDS) findings in patients with nocturia are not well described and may help guide management. Our objective was to compare UDS findings with age-matched patients with and without nocturia. MATERIALS AND METHODS: We retrospectively reviewed UDS findings of 1124 patients (2010-2017). A total of 484 (43%) presented with nocturia and 821 (73%) were female. Female patients were separated into age-matched groups with and without nocturia. Urinary symptoms, past medical diagnoses, demographic information, and UDS findings were compared. RESULTS: A total of 596 female patients were included, 298 (50%) with nocturia and 298 without. Past medical history, including diabetes mellitus and cardiovascular disease, did not differ between groups. Patients with nocturia were more likely to have pelvic pain (p = 0.0014) and other daytime symptoms (frequency, urgency, and urgency incontinence). On UDS, patients with nocturia were more likely to have bladder outlet obstruction (BOO) (p = 0.025) and dysfunctional voiding (DV) (p < 0.0001). There was no difference in the frequency of detrusor overactivity (DO). Bladder capacity and postvoid residual volumes were lower, though not significantly, in the nocturia group. CONCLUSIONS: When comparing UDS findings in contemporary, age-matched groups of female patients with and without nocturia, we found only BOO and DV to be associated with nocturia. While the treatment of nocturia is often aimed at managing DO, our data suggest that this may not be the primary urodynamic correlation with nocturia. Further studies are needed to assess whether successful treatment of BOO and DV can improve nocturia.

Rare case of an isolated scaphoid congenital megalourethra: before and after reconstruction.

Congenital megalourethra, first described in 1955, is a rare urethral anomaly resulting from dysgenesis of the penile corpus spongiosum, with or without corpus cavernosum involvement, leading to dilatation of the penile urethra. Presentations come in two forms, scaphoid and fusiform, with the former being more common and resulting from deficient or absent corpus spongiosum. Fusiform types are much rarer, and consist of absence of both the corpus spongiosum and cavernosum.3 Here, we present a case involving the surgical correction of an isolated scaphoid-type congenital megalourethra with significantly improved postoperative cosmetic and functional outcomes.

Heterogeneity in the pharmacological management of radiation-induced hemorrhagic cystitis.

BACKGROUND: Radiation-induced hemorrhagic cystitis is a complication of pelvic radiotherapy, with an incidence of up to 5%. The resultant hematuria may be severe and refractory to conservative measures. Our objective was to describe the pattern of inpatient treatments among a cohort of patients with radiation-induced hemorrhagic cystitis requiring pharmacological management. METHODS: We conducted a retrospective case series to identify all inpatient admissions at a single institution during which patients with radiation cystitis underwent pharmacological intervention for refractory hematuria between 2004 and 2019. Patient demographics, medical history, details of radiation therapy, and relevant admission data were collected. Details of treatment, including the use of pharmacotherapy and surgical treatment, were reviewed and summarized. RESULTS: We identified 21 patients who were treated during 26 admissions. Most were male (91%) with a history of external beam radiation therapy (86%), primarily for prostate cancer (85%), and a median age of 73 (IQR: 67-85). Most patients received continuous bladder irrigation as the first intervention during their admission (65%), for a median duration of 40 hours (IQR: 25-59). Eleven separate pharmacologic agents were used, with variations in initial pharmacotherapy utilization over time. Most patients were treated with a combination of surgical and pharmacological interventions (85%). The median length of stay was 9 days (IQR: 5-17) and the 90-day readmission rate was 35%. CONCLUSIONS: Pharmacologic treatment for refractory radiation-induced hemorrhagic cystitis is inconsistent and lacks evidence to support treatment strategies. Further work is needed to determine the optimal management for this morbid complication.

Partial cystectomy: Review of a single center experience from 2004 to 2019.

PURPOSE: Partial cystectomy (PC) is a bladder sparing option to treat bladder cancer in a carefully selected group of patients. We sought to analyze outcomes of partial cystectomy (PC) in a contemporary cohort of patients at a single institution. MATERIAL AND METHODS: Records were reviewed for 43 patients with a primary urothelial carcinoma (UC) who had a partial cystectomy with curative intent at Columbia University Medical Center from 2004 to 2019. Endpoints of interest were noninvasive recurrence (defined as any recurrent nonmuscle invasive disease), advanced recurrence (defined as a muscle invasive recurrence or metastasis), and death. We used unadjusted Cox proportional hazards regressions and log rank tests to estimate the association between clinical characteristics and endpoints of interest. RESULTS: Among 43 patients with bladder cancer treated with partial cystectomy, median patient age was 73 years (interquartile range 67-77.5) and 86% were male. Twenty-three percent of patients received preoperative neoadjuvant chemotherapy (NAC) and 49% of patients were given perioperative intravesical chemotherapy at the time of PC. Pathologic stage was

Biologic adjuvant urethral coverings for single-stage primary hypospadias repairs: A systematic review and pooled proportional meta-analysis of postoperative urethrocutaneous fistulas.

BACKGROUND: The use of barrier layers between the neourethra and skin is associated with lower rates of post-operative urethrocutaneous fistula (UCF) following hypospadias surgery. Recent studies have evaluated the ability of biologic adjuvant urethral coverings (BAUCs) - namely acellular matrix (AM), tissue adhesives (TAs), and autologous platelet-rich plasma or fibrin (PRP/PRF) - to prevent wound complications following hypospadias surgery. In general, however, these studies are small and conducted at single institutions. OBJECTIVE: To assess the effect of BAUCs on the rate of UCF following single-stage primary hypospadias repair. METHODS: We conducted a systematic review of studies reporting the rate of postoperative UCF in pediatric patients undergoing single-stage, primary hypospadias repairs using either AM, TA, or PRP/PRF as a layer interposed between the neourethra and skin. We then performed a pooled proportional meta-analysis of post-operative UCF. Patients within each study who underwent comparable surgery but did not receive a BAUC were used as controls. RESULTS: 10 studies were included in our review. The meta-analysis included 280 patients from 7 studies who underwent hypospadias repairs with BAUCs. The pooled incidence of UCF was 10% (95% CI 6-14%). Mean follow-up ranged 5-23.5 months in the 5/7 studies reporting specific durations, and ≥6 month and 14-30 months, respectively, in the other two studies. Patients in whom a BAUC was used had significantly lower odds of UCF than control patients (OR 0.39, 95% CI 0.24-0.64, p = 0.0002). In subgroup analyses, significant superiority held for AM and TA; proximal or penoscrotal cases; transverse preputial island flap (TPIF) technique; when both cases and controls had local flaps; and when neither cases nor controls had flaps. DISCUSSION: The use of BAUCs was associated with decreased rates of post-operative UCF in single-stage primary hypospadias repairs and may be most beneficial in more severe cases and when used in addition to local flaps or when using a flap is not possible. In 2/3 studies of PRP/PRF and 2/4 studies of tubularized incised plate (TIP) technique, dartos flaps were used in controls but not BAUC patients, which may explain the lack of benefit demonstrated for these subgroups. This meta-analysis is limited by the quality of evidence in the included studies, which are not uniformly randomized. Furthermore, the follow-up durations and methods for assessing complications are not standardized between included studies. CONCLUSION: The meta-analysis herein suggests that using BAUCs may reduce UCF rates following hypospadias surgery. Rigorous prospective evaluation is needed to validate this benefit.

The effect of tumor grade heterogeneity on recurrence in non-muscle invasive bladder cancer.

OBJECTIVE: To investigate the outcomes of mixed-grade non-muscle invasive bladder cancer (NMIBC) based on the degree of high-grade predominance. METHODS: We identified patients in our institutional database who had a transurethral resection of bladder tumor(s) for NMIBC. Tumors with mixed-grade features on pathology report were reanalyzed, assigned the percentage high-grade component, and stratified into ≤ 5% high-grade and > 5% high-grade groups. All others were classified as low-grade or high-grade NMIBC. Differences in recurrence-free survival were assessed by log-rank test. A multivariable Cox regression model was used to evaluate the impact of tumor grade on recurrence, controlling for tumor stage, size, multifocality, and intravesical therapy. RESULTS: Two hundred and twenty patients were followed for a median of 2 years; 127 (58%) had low-grade NMIBC, 66 (30%) had high-grade NMIBC, and 27 (12%) had mixed-grade NMIBC. Of the mixed-grade patients, 14 had a ≤ 5% high-grade component, and 13 had a > 5% high-grade component. Recurrence rates across all groups ranged from 42% to 79%. There was no significant difference in intravesical recurrence-free survival among the grade categories as assessed by log-rank test. On multivariable Cox regression analysis, grade category was not significantly associated with likelihood of recurrence. CONCLUSIONS: The prognosis of mixed-grade histology in NMIBC has not previously been well defined. Although grade category was not found to be an independent significant predictor of recurrence, the recurrence rate for mixed-grade tumors was quite high overall. Further studies are required to better understand appropriate risk stratification and treatment of mixed-grade NMIBC.

The Management of Newly-Diagnosed Non-muscle Invasive Bladder Cancer in Veterans Integrated Services Network 02 of the Veterans Health Administration.

INTRODUCTION: Over 1,500 bladder cancers were diagnosed among US Veterans in 2010, the majority of which were non-muscle invasive bladder cancer (NMIBC). Little is known about NMIBC treatment within the Veterans Health Administration. The objective of the study was to assess the quality of care for Veterans with newly-diagnosed NMIBC within Veterans Integrated Service Network (VISN) 02. MATERIALS AND METHODS: We used ICD-9 and ICD-10 codes to identify patients with newly-diagnosed bladder cancer from 1/2016-8/2017. We risk-stratified the patients into low, intermediate, and high-risk based on the 2016 American Urological Association Guidelines on NMIBC. Our primary objectives were percentages of transurethral resection of bladder tumors (TURBTs) with detrusor, repeat TURBT in high-risk and T1 disease, high-risk NMIBC treated with induction intravesical therapy (IVT), and responders treated with maintenance IVT. We performed logistic regression for association between distance to diagnosing hospital and receipt of induction IVT in high-risk patients. RESULTS: There were 121 newly-diagnosed NMIBC patients; 16% low-risk, 28% intermediate-risk, and 56% high-risk. Detrusor was present in 80% of all initial TURBTs and 84% of high-risk patients. Repeat TURBT was performed in 56% of high-risk NMIBC and 60% of T1. Induction IVT was given to 66% of high-risk patients and maintenance IVT was given to 59% of responders. On multivariate logistic regression, distance to medical center was not associated with receipt of induction IVT (OR = 0.99, 95% CI [0.97,1.01], p = 0.52). CONCLUSIONS: We observed high rates of sampling of detrusor in the first TURBT specimen, utilization of repeat TURBT, and administration of induction and maintenance intravesical BCG for high-risk patients among a regional cohort of US Veterans with NMIBC. While not a comparative study, our findings suggest high quality NMIBC care in VA VISN 02.

Conservative Management Following Complete Clinical Response to Neoadjuvant Chemotherapy of Muscle Invasive Bladder Cancer: Contemporary Outcomes of a Multi-Institutional Cohort Study.

PURPOSE: We report the outcomes in patients with muscle invasive bladder cancer from 2 institutions who experienced a clinically complete response to neoadjuvant platinum based chemotherapy and elected active surveillance. It was unknown whether conservative treatment could be safely implemented in these patients. MATERIALS AND METHODS: We retrospectively reviewed the records of patients with muscle invasive bladder cancer at our institutions who elected surveillance following a clinically complete response to transurethral resection of bladder tumors and neoadjuvant chemotherapy from 2001 to 2017. A clinically complete response was defined as absent tumor on post-chemotherapy transurethral resection of bladder tumor, negative cytology and normal cross-sectional imaging. RESULTS: In the 148 patients followed a median of 55 months (range 5 to 145) the 5-year disease specific, overall, cystectomy-free and recurrence-free survival rates were 90%, 86%, 76% and 64%, respectively. Of the patients 71 (48%) experienced recurrence in the bladder, including 16 (11%) with muscle invasive disease and 55 (37%) with noninvasive disease. Salvage radical cystectomy prevented cancer specific death in 9 of 12 patients (75%) who underwent cystectomy after muscle invasive relapse and in 13 of 14 (93%) after noninvasive relapse. CONCLUSIONS: We observed high rates of overall and disease specific survival with bladder preservation in patients who achieved a clinically complete response to neoadjuvant chemotherapy. These outcomes support the safety of active surveillance in carefully selected, closely monitored patients with muscle invasive bladder cancer. Future studies should aim to improve patient selection by identifying biomarkers predicting invasive relapse and developing novel imaging methods of early detection.

Systematic Review and Meta-Analysis on the Efficacy of Chemotherapy with Transurethral Resection of Bladder Tumors as Definitive Therapy for Muscle Invasive Bladder Cancer.

BACKGROUND: Bladder-sparing treatment of muscle invasive bladder cancer (MIBC) with systemic chemotherapy plus transurethral resection of bladder tumors (TURBT) is increasingly seen in the literature -both in case series and subanalyses of patients who opt out of or are unfit for radical cystectomy (RC). Survival outcomes among these patients are often impressive, but these are typically small retrospective studies from single institutions and therefore of limited clinical value. OBJECTIVES: Our aim is to summarize the literature regarding definitive treatment of MIBC with systemic chemotherapy plus TURBT and provide a meta-analysis of survival outcomes for patients who received this treatment. METHODS: A systematic literature search was performed consistent with the Prisma statement to identify publications reporting the outcomes of patients treated with TURBT and systemic chemotherapy as definitive treatment for locally confined MIBC. Identified studies were screened in a two-stage process: first by title and abstract; then by full-text reading. 18 publications (518 patients) were included in the qualitative systematic review and 10 publications (266 patients) were included in the meta-analysis. The primary objective was overall survival (OS). RESULTS: Overall survival ranged from 20% to 87.5% across studies at median follow-up ranging 4 to 120 months. 5-year survival rate for all patients included in the meta-analysis was estimated to be 72% [95% CI: 64%, 82%]. CONCLUSIONS: Definitive treatment with systemic chemotherapy plus TURBT can lead to favorable survival outcomes in select patients. Further study to improve patient selection for this method of treatment is needed.

Pitavastatin Differentially Modulates MicroRNA-Associated Cholesterol Transport Proteins in Macrophages.

There is emerging evidence identifying microRNAs (miRNAs) as mediators of statin-induced cholesterol efflux, notably through the ATP-binding cassette transporter A1 (ABCA1) in macrophages. The objective of this study was to assess the impact of an HMG-CoA reductase inhibitor, pitavastatin, on macrophage miRNAs in the presence and absence of oxidized-LDL, a hallmark of a pro-atherogenic milieu. Treatment of human THP-1 cells with pitavastatin prevented the oxLDL-mediated suppression of miR-33a, -33b and -758 mRNA in these cells, an effect which was not uniquely attributable to induction of SREBP2. Induction of ABCA1 mRNA and protein by oxLDL was inhibited (30%) by pitavastatin, while oxLDL or pitavastatin alone significantly induced and repressed ABCA1 expression, respectively. These findings are consistent with previous reports in macrophages. miRNA profiling was also performed using a miRNA array. We identified specific miRNAs which were up-regulated (122) and down-regulated (107) in THP-1 cells treated with oxLDL plus pitavastatin versus oxLDL alone, indicating distinct regulatory networks in these cells. Moreover, several of the differentially expressed miRNAs identified are functionally associated with cholesterol trafficking (six miRNAs in cells treated with oxLDL versus oxLDL plus pitavastatin). Our findings indicate that pitavastatin can differentially modulate miRNA in the presence of oxLDL; and, our results provide evidence that the net effect on cholesterol homeostasis is mediated by a network of miRNAs.

Platelet-rich plasma and other cellular strategies in orthopedic surgery.

The use of biologics in the treatment of musculoskeletal disease has become increasingly more common as research studies continue to provide further elucidation of their mechanisms in healing. Platelet-rich plasma, patches, growth factors, and stem cells are among the many biologics under active investigation and have varying levels of success in augmenting surgical or nonoperative interventions. However, the limitations of these treatments exist, and clear guidelines for their indications and application have yet to be established. Well-designed clinical trials will help determine the appropriate future use of biologics to ensure consistent outcomes.