Longitudinal GFR trends after neoadjuvant chemotherapy prior to nephroureterectomy for upper tract urothelial carcinoma.

PURPOSE: Renal function dictates sequencing and eligibility for definitive therapy in upper tract urothelial carcinoma. We investigated longitudinal glomerular filtration rate (GFR) changes after neoadjuvant chemotherapy (NAC) and nephroureterectomy (RNU). MATERIALS AND METHODS: Patients treated with ≥3 cycles of chemotherapy prior to RNU for UTUC from 2000 to 2019 were included. GFR was calculated by CKD-Epi before chemotherapy, before RNU, 1 to 3 months, and 12 months post-RNU. Pathologic stage and overall survival were compared in those with stable GFR (+/-10% of baseline) to the rest of the cohort. RESULTS: One hundred and fifty-two patients received ≥3 cycles of NAC, with 121 (79%) receiving at least 1 cycle of cisplatin. Renal function dropped by mean of 22.3 ml/min/1.73 m2 from the beginning of chemotherapy to 1-year post-surgery. In patients receiving cisplatin, a mean decline of 26.2 ml/min/1.73 m2 was observed vs. 8.8 ml/min/1.73 m2 without cisplatin-based NAC (P < 0.01). GFR after RNU was unchanged between 3 and 12 months postoperatively. At 1 to 3 months after RNU, 19% of patients had GFR<30 ml/min/1.73m2. Improvement in GFR during NAC was associated with invasive final pathologic stage (P = 0.018) and worse overall survival (P = 0.049). CONCLUSIONS: In patients managed with NAC prior to RNU, renal function stabilizes at 1 to 3 months post-operatively and remains clinically similar for cisplatin or non-cisplatin-based therapy. Improvement in GFR during NAC was associated with higher pathologic stage and poorer survival, especially in those receiving non-cisplatin-based therapy, an observation that requires further investigation.

Lentiviral interferon: A novel method for gene therapy in bladder cancer.

Interferon alpha (IFNα) gene therapy is emerging as a new treatment option for patients with non-muscle invasive bladder cancer (NMIBC). Adenoviral vectors expressing IFNα have shown clinical efficacy treating bacillus Calmette-Guerin (BCG)-unresponsive bladder cancer (BLCA). However, transient transgene expression and adenoviral immunogenicity may limit therapeutic activity. Lentiviral vectors can achieve stable transgene expression and are less immunogenic. In this study, we evaluated lentiviral vectors expressing murine IFNα (LV-IFNα) and demonstrate IFNα expression by transduced murine BLCA cell lines, bladder urothelium, and within the urine following intravesical instillation. Murine BLCA cell lines (MB49 and UPPL1541) were sensitive to IFN-mediated cell death after LV-IFNα, whereas BBN975 was inherently resistant. Upregulation of interleukin-6 (IL-6) predicted sensitivity to IFN-mediated cell death mediated by caspase signaling, which when inhibited abrogated IFN-mediated cell killing. Intravesical therapy with LV-IFNα/Syn3 in a syngeneic BLCA model significantly improved survival, and molecular analysis of treated tumors revealed upregulation of apoptotic and immune-cell-mediated death pathways. In particular, biomarker discovery analysis identified three clinically actionable targets, PD-L1, epidermal growth factor receptor (EGFR), and ALDHA1A, in murine tumors treated with LV-IFNα/Syn3. Our findings warrant the comparison of adenoviral and LV-IFNα and the study of novel combination strategies with IFNα gene therapy for the BLCA treatment.

Antiadenovirus Antibodies Predict Response Durability to Nadofaragene Firadenovec Therapy in BCG-unresponsive Non-muscle-invasive Bladder Cancer: Secondary Analysis of a Phase 3 Clinical Trial.

A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer >800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers >800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers >800 and peak antibody fold change >8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers >800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. PATIENT SUMMARY: This study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer. Prospective assessment of serum anti-human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec.

Role of Lymphadenectomy during Radical Cystectomy for Nonmuscle-Invasive Bladder Cancer: Results from a Multi-Institutional Experience.

PURPOSE: While lymph node dissection (LND) at radical cystectomy (RC) for muscle-invasive bladder cancer has been studied extensively, the role of LND for nonmuscle-invasive bladder cancer (NMIBC) remains incompletely defined. Herein, we aim to assess the association between extent of LND during RC for NMIBC and local pelvic recurrence-free survival (LPRS), cancer-specific survival (CSS) and overall survival (OS). MATERIALS AND METHODS: A multi-institutional retrospective review was performed of patients with NMIBC undergoing RC at 3 large tertiary referral centers. To identify a threshold for lymph node yield (LNY) to optimize LPRS, CSS and OS, separate Cox regression models were developed for each possible LNY threshold. Model performance including Q-statistics and hazard ratios (HRs) were used to identify optimal LNY thresholds. RESULTS: A total of 1,647 patients underwent RC for NMIBC, with a median LNY of 15 (quartiles 9,23). Model performance curves suggested LNY of 10 and 20 to optimize LPRS and CSS/OS, respectively. On multivariable regression, LNY >10 was associated with lower risk of LPR compared to LNY ≤10 (HR 0.63, 95% CI 0.42-0.93, p=0.02). Similarly, LNY >20 was associated with improved CSS (HR 0.67, 95% CI 0.52-0.87, p=0.002) and OS (HR 0.75, 95% CI 0.64-0.88, p <0.001) compared to LNY ≤20. Similar results were observed in the cT1 and cTis subgroups. CONCLUSIONS: Greater extent of LND during RC for NMIBC is associated with improved LPRS, CSS and OS, supporting the inclusion of LND during RC for NMIBC, particularly among patients with cTis or cT1 disease. Future prospective studies are warranted to assess the ideal anatomical template of LND in NMIBC.

Progression of Disease after Bacillus Calmette-Guérin Therapy: Refining Patient Selection for Neoadjuvant Chemotherapy before Radical Cystectomy.

PURPOSE: Data from the pre-neoadjuvant chemotherapy (NAC) era suggests patients who progress on bacillus Calmette-Guérin (BCG) to muscle-invasive bladder cancer (P-MIBC) exhibit worse outcomes compared to de novo MIBC (D-MIBC). Herein, we investigate whether P-MIBC is an independent poor risk factor in the setting of contemporary NAC use. MATERIALS AND METHODS: A review of patients who underwent radical cystectomy (RC) for cT2-3 MIBC from 2005 to 2018 was performed. Patients were stratified into high risk (lymphovascular invasion, variant histology, hydronephrosis, cT3b) vs low risk (no risk factors) and P-MIBC (≤pT1 treated with at least induction BCG who progressed to ≥cT2) vs D-MIBC. RESULTS: Among 801 patients who underwent RC 20.3% had P-MIBC and 79.7% had D-MIBC. In low-risk patients treated without NAC, P-MIBC was associated with pathological upstaging (64.9% vs 42.7%, p=0.004) and worse overall (OS, p=0.006) and cancer-specific survival (CSS, p=0.001) compared to D-MIBC. P-MIBC status conferred uniformly poor survival outcomes to patients who did not receive NAC compared to D-MIBC without NAC (median OS 51.5 months [95% CI 40.0-81.0] vs 85.1 months [95% CI 62.8-96.0], p=0.040; median CSS not reached, p=0.014). However, P-MIBC status did not remain a negative prognostic factor in the setting of NAC (median OS 90.5 months [95% CI 34.0-not estimable] vs 87.8 months [95% CI 68.7-not estimable], p=0.606; median CSS not reached, p=0.448). CONCLUSIONS: P-MIBC confers a poor prognosis when managed with RC alone. Treatment with NAC results in equivalent pathological response and survival outcomes compared to D-MIBC. P-MIBC should be included in risk-stratified approaches to NAC selection.

The Impact of Upper Tract Urothelial Carcinoma Diagnostic Modality on Intravesical Recurrence after Radical Nephroureterectomy: A Single Institution Series and Updated Meta-Analysis.

PURPOSE: Diagnostic ureteroscopic biopsy for upper tract urothelial carcinoma (UTUC) has been hypothesized to increase intravesical recurrence of urothelial carcinoma after radical nephroureterectomy (RNU). Moreover, the impact of ureteroscopy without biopsy or percutaneous biopsy on intravesical recurrence remains unknown. Herein, we compared post-RNU intravesical recurrences across UTUC diagnostic modalities. MATERIALS AND METHODS: Patients undergoing RNU at our institution between 1995 and 2019 were categorized by UTUC diagnostic modality: 1) no ureteroscopy or percutaneous biopsy; 2) percutaneous biopsy; 3) ureteroscopy without biopsy; 4) ureteroscopic biopsy. Intravesical recurrences were compared using Kaplan-Meier analyses and Cox-proportional hazard models. Results of group 4 vs 1 were pooled with the literature using a fixed effects meta-analysis. RESULTS: In a cohort of 834 RNU patients, 210 (25.2%) had undergone no ureteroscopy, 57 (6.6%) percutaneous biopsy, 125 (15.0%) ureteroscopy without biopsy, and 442 (53.0%) ureteroscopic biopsy. Two-year intravesical recurrence rates were 15.0%, 12.7%, 18.4%, and 21.9% for groups 1 through 4, respectively (p=0.09). Multivariable analysis found that group 4 had increased intravesical recurrences (HR 1.40, p=0.04) relative to group 1 while group 2 (HR 1.07, p=0.87) and group 3 (HR 1.15, p=0.54) did not. Group 4 remained associated with intravesical recurrence on subset analyses accounting for post-RNU surveillance cystoscopy frequency. On meta-analysis including 11 other series, ureteroscopic biopsy was associated with intravesical recurrence (HR 1.47, p <0.01). CONCLUSIONS: Ureteroscopic biopsy before RNU, but not percutaneous biopsy or ureteroscopy without biopsy, was associated with increased intravesical recurrence. Clinical trials of intravesical chemotherapy after ureteroscopic biopsy are warranted to reduce intravesical recurrences.

Incidence and predictors of occult preoperative deep vein thrombosis at radical cystectomy for urothelial carcinoma.

INTRODUCTION: Patients undergoing radical cystectomy are at high perioperative risk for deep vein thrombosis due to age, malignancy, recent transurethral resection, and neoadjuvant chemotherapy. We, therefore, evaluated the incidence and predictors of occult preoperative deep vein thrombosis prior to radical cystectomy for urothelial carcinoma. METHODS: We prospectively screened 52 asymptomatic patients with urothelial carcinoma undergoing radical cystectomy at our institution with lower extremity ultrasound and D-dimer assay within two weeks prior to surgery. Patients with a prior history of deep vein thrombosis and those on systemic anticoagulation were excluded. RESULTS: We identified 4/52 patients (7.7%) with preoperative asymptomatic deep vein thrombosis prior to radical cystectomy. Median D-dimer for patients with and without preoperative deep vein thrombosis was 787 ng/ml (interquartile range [IQR] 365-1257) and 260 ng/ml (IQR 158-498), respectively. A D-dimer threshold of >250 ng/ml had a sensitivity of 100% and specificity of 50%, resulting in a negative predictive value of 100% and positive predictive value of 14.8% for preoperative deep vein thrombosis. Increasing the D-dimer threshold to >1000 ng/ml created a sensitivity of 50% and specificity of 85%, resulting in a negative predictive value of 92% and positive predictive value of 33%. D-dimer values did not significantly vary with neoadjuvant chemotherapy or days since transurethral resection. CONCLUSIONS: Approximately 8% of patients had an occult deep vein thrombosis prior to radical cystectomy. D-dimer can provide sensitive diagnostic utility for deep vein thrombosis in the pre-radical cystectomy setting and could help guide use of preoperative lower extremity ultrasound in this high-risk patient population.

Does Ureteral Stent Drainage Prior to Cystectomy Increase the Risk of Subsequent Upper Tract Urothelial Carcinoma and Ureteral Complications?

OBJECTIVE: To guide management of preoperative hydronephrosis prior to radical cystectomy (RC), we compared post-RC risks of upper tract urothelial carcinoma (UTUC) and ureteroenteric anastomotic complications between ureteral stent and percutaneous nephrostomy tube drainage. METHODS: Patients who underwent RC for urothelial carcinoma without a prior diagnosis of UTUC at our institution between 2000 and 2015 were included and divided into 4 patient groups: (1) no hydronephrosis (75%, N = 787); (2) hydronephrosis without preoperative upper tract drainage (13%, N = 132); (3) hydronephrosis treated with nephrostomy tube (3%, N = 36); (4) hydronephrosis treated with ureteral stent (9%, N = 94). The incidence of post-RC UTUC and ureteral complications was compared using Kaplan-Meier analyses and multivariable Cox proportional hazard modeling. RESULTS: We identified a total of 1049 patients who underwent RC (median postoperative follow-up 4.3 years). Five-year post-RC UTUC incidence was 6.6%, 10.2%, 17%, 18.7% for groups 1-4, respectively (P= .13). On multivariable analysis, nephrostomy tube drainage (hazard ratio [HR] 4.10, P = .02) and preoperative ureteral stenting (HR 2.35, P = .04) were both associated with UTUC after RC, but ureteral stenting did not have a significantly higher association with UTUC than nephrostomy tube drainage. Severe hydronephrosis was also associated with development of UTUC (HR 4.03, P = .02). The incidence of ureteroenteric anastomotic complications did not vary by drainage modality. CONCLUSION: Preoperative hydronephrosis was associated with UTUC after RC, but ureteral stent placement did not increase the risk of UTUC or ureteral complications relative to nephrostomy tube placement. The choice of hydronephrosis drainage pre-RC should not be guided by concern for UTUC risk.

Timing and distribution of early renal cell carcinoma recurrences stratified by pathological nodal status in M0 patients at the time of nephrectomy.

OBJECTIVES: To evaluate the timing and distribution of first renal cell carcinoma metastasis after nephrectomy stratified by nodal status. METHODS: We evaluated patients treated with nephrectomy for sporadic, unilateral renal cell carcinoma between 1970 and 2011 who subsequently developed distant metastasis to three or fewer sites. Site-specific metastases-free 2-year survival rates were estimated using the Kaplan-Meier method. Associations of nodal status with time to metastasis were evaluated using multivariable Cox regression models. RESULTS: A total of 1049 patients met the inclusion criteria (135 pN1, 914 pN0/x patients). The median time to identification of first distant metastasis for pN1 patients was 0.4 years (interquartile range 0.2-1.1 years) versus 2.2 years (interquartile range 0.6-6.0 years) in pN0/x patients. The most common site of metastasis was to the lung, but this occurred earlier in pN1 patients (median 0.3 years vs 2.0 years). pN1 was associated with significantly lower site-specific 2-year metastases-free survival when compared with pN0/x for lung (37% vs 70%, P < 0.001), bone (63% vs 87%, P < 0.001), non-regional lymph nodes (60% vs 96%, P < 0.001) and liver metastases (79% vs 91%, P < 0.001). On multivariable analysis, pN1 status remained significantly associated with lung, bone, and non-regional lymph node (all P < 0.001) metastases, but it was no longer associated with liver metastases (P = 0.3). CONCLUSIONS: pN1 nodal status in M0 patients treated with nephrectomy for renal cell carcinoma is associated with more frequent early metastasis to sites conferring poor prognosis when compared with pN0/x. Our findings highlight the importance of rigorous, early surveillance though the multimodal use of a comprehensive history, physical, laboratory and radiological studies, as outlined in societal guidelines.

Percutaneous Image-guided Core Needle Biopsy for Upper Tract Urothelial Carcinoma.

OBJECTIVE: To better understand the safety and diagnostic yield of percutaneous core-needle biopsy (PCNB) for upper tract urothelial carcinoma (UTUC). METHODS: Of 444 patients undergoing radical nephroureterectomy (RNU) for UTUC between 2009 and 2017 at our institution, 42 who had PCNB prior to RNU were identified for analysis. Endpoints included safety, diagnostic yield, and concordance with RNU pathology. PCNB specimens were deemed histologically concordant with RNU specimens for cases when cytologic evaluation of biopsy specimen and corresponding pathologic evaluation of RNU specimen both made a histologic diagnosis of urothelial carcinoma. RESULTS: Median tumor size was 3.8 cm (1.2-10.2 cm). All lesions arose from the pelvicalyceal system. CT-guidance was utilized in 52% (n = 22), and ultrasound-guidance in 48% (n = 20). Relative to RNU pathology, 95% of PCNBs demonstrated histologic concordance. Histologic grade was provided in 69% (n = 29) of PCNBs, with a 90% (n = 26) concordance with surgical pathology. Grades 1-2 and 3 complications occurred in 14.3% (n = 6) and 2.4% (n = 1), respectively. At a median follow-up of 28.2 months (range, 1.2-97.1 months) after biopsy, no cases of radiographic tract seeding were identified. CONCLUSION: In our cohort of 42 patients undergoing RNU for UTUC, PCNB appeared a safe diagnostic tool with high histologic yield and grade concordance. With greater than 2 years of follow-up, no cases of tract seeding were identified.

Oncolytic Measles Virotherapy and Opposition to Measles Vaccination.

Recent measles epidemics in US and European cities where vaccination coverage has declined are providing a harsh reminder for the need to maintain protective levels of immunity across the entire population. Vaccine uptake rates have been declining in large part because of public misinformation regarding a possible association between measles vaccination and autism for which there is no scientific basis. The purpose of this article is to address a new misinformed antivaccination argument-that measles immunity is undesirable because measles virus is protective against cancer. Having worked for many years to develop engineered measles viruses as anticancer therapies, we have concluded (1) that measles is not protective against cancer and (2) that its potential utility as a cancer therapy will be enhanced, not diminished, by prior vaccination.

Impact of anabolic androgenic steroids on sexual function.

BACKGROUND: To describe the impact of supra-physiologic anabolic-androgenic steroid (AAS) use, including agent, dosage, and duration of therapy, on sexual function. METHODS: We reviewed data from an online survey of AAS users to evaluate their sexual function on and off AAS. The online survey consisted of questions addressing demographics, anabolic steroid use and patterns, ancillary medications, testosterone (T)-related symptoms while on and off of therapy, as well as sexual function which was assessed using the 5-item, International Index of Erectile Function (IIEF-5). RESULTS: A total of 321 men responded to the survey, of which 90 failed to meet inclusion criteria, for a final cohort of 231 AAS users. The majority of men were Caucasian (85%), employed (62%), and younger than 35 years (58%), while an equal mix were single (47%) or married (46%). The mean IIEF-5 was 22.5, with higher scores associated with increased T dosages (>600 mg/week), use of 17-alpha alkylated hormones and anti-estrogens, and absence of concurrent medical conditions. Lower mean IIEF scores were associated with current and pre-AAS low T symptoms, self-reported angry or violent tendencies, self-reported erectile dysfunction (ED), decreased libido, decreased energy, and depression. After controlling for age, low T symptoms and decreased energy remained significantly associated with lower IIEF scores. Among 127 men reporting de novo decreased libido when not taking AAS, several factors were significantly associated including frequency and duration of T and use of adjunctive therapies, while post-cycle therapies were protective. Men who reported any other de novo symptom (decreased energy, libido, muscle mass or depression) after discontinuing T were also more likely to report de novo ED, as well as those using >10 years or for >40 weeks per year. CONCLUSIONS: The long-term impact of high dose AAS use on sexual function remains poorly defined. Although high T dosages appeared to be protective of erectile function during use, de novo symptoms such as decreased libido and ED occurred more frequently after discontinuing T, particularly among those using more frequently and for longer durations. Given the importance of these findings, long-term studies evaluating the impacts of discontinuing T on sexual dysfunction are indicated.

Medication patterns and fertility rates in a cohort of anabolic steroid users.

BACKGROUND: To describe self-reported medication patterns and fertility rates in a population of anabolic steroid (AS) users. METHODS: We reviewed data from an online survey of AS users and identified a sub-group who had attempted to achieve a pregnancy with their partners while using AS. The online survey consisted of questions addressing demographics, AS use, ancillary medications, and fertility outcomes. RESULTS: A total of 97 men (of 231 total respondents) had attempted to achieve a pregnancy while taking AS and comprise the current cohort. The majority of men were 25-44 years old (63.9%), married (75.5%) and Caucasian (88.7%). Ancillary drug use was common with only 5.2% denying drug use other than ASs. The most common reported ancillary drugs were antiestrogens (89.7%) and sexual enhancement medications (SEMs) (68%). The fertility rate was 92.8%, with 82.4% achieving pregnancy within one year. Interestingly, only 13.5% sought fertility evaluation with treatment required in 8.3%. Age at initiation of AS use, maximum dosage utilized, yearly duration of supplementation, and number of years using steroids were not associated with a prolonged duration to pregnancy or decreased rate of pregnancy. CONCLUSIONS: Despite continued use of ASs, this cohort's self-reported fertility rates are unexpectedly high. This is presumably related to cycling of therapy and concomitant use of fertility preserving medications.

Pediatric Robotic Prostatectomy and Pelvic Lymphadenectomy for Embryonal Rhabdomyosarcoma.

We present the first published case of a pediatric robot-assisted prostatectomy and pelvic lymphadenectomy for refractory prostatic embryonal rhabdomyosarcoma. The patient is a 7-year-old male who had been treated with 3 cycles of chemotherapy and radiation, who underwent prostatectomy and lymphadenectomy for a recurrent mass. Surgery was uncomplicated and yielded negative surgical margins. We highlight the surgical technique and feasibility of utilizing robotic surgery for pediatric prostatectomy.

Surgical patient selection and counseling.

The objectives of patient selection and counseling are ultimately to enhance successful outcomes. However, the definition for success is often narrowly defined in published literature (ability to complete surgery, complications, satisfaction) and fails to account for patient desires and expectations, temporal changes, natural history of underlying diseases, or independent validation. Factors associated with satisfaction and dissatisfaction are often surgery-specific, although correlation with pre-operative expectations, revisions, and complications are common with most procedures. The process of appropriate patient selection is determined by the integration of patient and surgeon factors, including psychological capacity to handle unsatisfactory results, baseline expectations, complexity of case, and surgeon volume and experience. Using this model, a high-risk scenario includes one in which a low-volume surgeon performs a complex case in a patient with limited psychological capacity and high expectations. In contrast, a high-volume surgeon performing a routine case in a male with low expectations and abundant psychiatric reserve is more likely to achieve a successful outcome. To further help identify patients who are at high risk for dissatisfaction, a previously published mnemonic is recommended: CURSED Patient (compulsive/obsessive, unrealistic, revision, surgeon shopping, entitled, denial, and psychiatric). Appropriate patient counseling includes setting appropriate expectations, reviewing the potential and anticipated risks of surgery, post-operative instruction to limit complications, and long-term follow-up. As thorough counseling is often a time-consuming endeavor, busy practices may elect to utilize various resources including educational materials, advanced practice providers, or group visits, among others. The consequences for poor patient selection and counseling may range from poor surgical outcomes and patient dissatisfaction to lawsuits, loss of credibility, or even significant patient or personal harm.