CD8+ T cell activation in cancer comprises an initial activation phase in lymph nodes followed by effector differentiation within the tumor.

Improvements in tumor immunotherapies depend on better understanding of the anti-tumor T cell response. By studying human tumor-draining lymph nodes (TDLNs), we found that activated CD8+ T cells in TDLNs shared functional, transcriptional, and epigenetic traits with TCF1+ stem-like cells in the tumor. The phenotype and TCR overlap suggested that these TDLN cells were precursors to tumor-resident stem-like CD8+ T cells. Murine tumor models revealed that tumor-specific CD8+ T cells were activated in TDLNs but lacked an effector phenotype. These stem-like cells migrated into the tumor, where additional co-stimulation from antigen-presenting cells drove effector differentiation. This model of CD8+ T cell activation in response to cancer is different from that of canonical CD8+ T cell activation to acute viruses, and it proposes two stages of tumor-specific CD8+ T cell activation: initial activation in TDLNs and subsequent effector program acquisition within the tumor after additional co-stimulation.

An intra-tumoral niche maintains and differentiates stem-like CD8 T cells.

Tumour-infiltrating lymphocytes are associated with a survival benefit in several tumour types and with the response to immunotherapy1-8. However, the reason some tumours have high CD8 T cell infiltration while others do not remains unclear. Here we investigate the requirements for maintaining a CD8 T cell response against human cancer. We find that CD8 T cells within tumours consist of distinct populations of terminally differentiated and stem-like cells. On proliferation, stem-like CD8 T cells give rise to more terminally differentiated, effector-molecule-expressing daughter cells. For many T cells to infiltrate the tumour, it is critical that this effector differentiation process occur. In addition, we show that these stem-like T cells reside in dense antigen-presenting-cell niches within the tumour, and that tumours that fail to form these structures are not extensively infiltrated by T cells. Patients with progressive disease lack these immune niches, suggesting that niche breakdown may be a key mechanism of immune escape.

Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin-Unresponsive Nonmuscle-Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial.

PURPOSE: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up. MATERIALS AND METHODS: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF). RESULTS: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease. CONCLUSIONS: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.

Utility of ultrasonography in preoperative assessment of tumor thrombi in kidney cancer.

INTRODUCTION: This study examined the clinical accuracy of ultrasonography compared to magnetic resonance imaging (MRI) and intraoperative findings for evaluation of tumor thrombi level in patients with renal cell carcinoma. MATERIALS AND METHODS: We retrospectively identified 38 patients at our institution who underwent both ultrasonography and MRI before undergoing open radical nephrectomy with tumor thrombectomy between 2010 and 2019. We compared tumor thrombus level findings of both ultrasonography and MRI, as well as the diagnostic accuracy of each to intraoperative findings. Agreement between ultrasonography, MRI, and surgery was tested with kappa. Logistic regression models identified factors that predict a mismatched thrombus level between an imaging modality and surgical findings. RESULTS AND CONCLUSIONS: Tumor thrombus levels determined by ultrasonography matched with MRI in 26 (68.4%) cases. Compared to operative findings, ultrasonography accurately identified the cephalad extent of thrombi in 30 (79.0%) cases, under-staged five (13.2%) cases, and over-staged three (7.9%). Magnetic resonance imaging agreed with operative findings in 30 (79.0%) cases, under-staged five (13.2%) and over-staged three (7.9%) cases. On univariable regression assessment, M1 stage was predictive of a mismatched result between MRI and surgery (OR: 6.0, 95% CI: 1.02-35.3, p = 0.047), but this association did not hold-up in a multivariable model. Ultrasonography and magnetic resonance imaging identified the preoperative tumor thrombus level at a rate of 79%. Ultrasonography is an effective preoperative imaging modality for evaluating tumor thrombi associated with kidney cancer, notably as an adjunct to magnetic resonance imaging.

Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.

BACKGROUND: BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer. METHODS: In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849. FINDINGS: Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths. INTERPRETATION: Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state. FUNDING: FKD Therapies Oy.

[18F]Fluciclovine Positron Emission Tomography/Computerized Tomography for Preoperative Staging in Patients with Intermediate to High Risk Primary Prostate Cancer.

PURPOSE: Accurate preoperative staging of prostate cancer is essential for treatment planning. Conventional imaging is limited in detection of metastases. Our primary aim was to determine if [18F]fluciclovine positron emission tomography/computerized tomography is an early indicator of subclinical metastasis among patients with high risk prostate cancer. MATERIALS AND METHODS: A total of 68 patients with unfavorable intermediate to very high risk prostate cancer without systemic disease on conventional imaging were recruited before robotic radical prostatectomy with extended pelvic lymph node dissection. Diagnostic performance of [18F]fluciclovine positron emission tomography/computerized tomography and conventional imaging for detection of metastatic disease, and correlation of positivity to node and metastatic deposit size were determined. RESULTS: Overall 57 of 68 patients completed the protocol, of whom 31 had nodal metastasis on histology. [18F]Fluciclovine positron emission tomography/computerized tomography sensitivity and specificity in detecting nodal metastasis was 55.3% and 84.8% per patient, and 54.8% and 96.4% per region (right and left pelvis, presacral and nonregional), respectively. Compared with conventional imaging [18F]Fluciclovine positron emission tomography/computerized tomography had significantly higher sensitivity on patient based (55.3% vs 33.3%, p <0.01) and region based (54.8% vs 19.4%, p <0.01) analysis, detecting metastasis in 7 more patients and 22 more regions, with similar high specificity. Four additional patients had distant disease or other cancer detected on [18F] fluciclovine positron emission tomography/computerized tomography which precluded surgery. Detection of metastasis was related to size of metastatic deposits within lymph nodes and overall metastatic burden. CONCLUSIONS: [18F]Fluciclovine positron emission tomography/computerized tomography detects occult metastases not identified on conventional imaging and may help guide treatment decisions and lymph node dissection due to high specificity for metastatic disease.

Feasibility and Initial Results: Fluciclovine Positron Emission Tomography/Ultrasound Fusion Targeted Biopsy of Recurrent Prostate Cancer.

PURPOSE: We assessed the feasibility and cancer detection rate of fluciclovine (18F) positron emission tomography-ultrasound fusion targeted biopsy vs standard template biopsy in the same patient with biochemical failure after nonsurgical therapy for prostate cancer. MATERIALS AND METHODS: A total of 21 patients with a mean ± SD prostate specific antigen of 7.4 ± 6.8 ng/ml and biochemical failure after nonoperative prostate cancer treatment underwent fluciclovine (18F) positron emission tomography-computerized tomography (mean 364.1 ± 37.7 MBq) and planning transrectal prostate ultrasound with 3-dimensional image reconstruction. Focal prostatic activity on positron emission tomography was delineated and co-registered with planning ultrasound. During the subsequent biopsy session computer generated 12-core template biopsies were performed and then fluciclovine defined targets were revealed and biopsied. Histological analysis of template and targeted cores were completed. RESULTS: Template biopsy was positive for malignancy in 6 of 21 patients (28.6%), including 10 of 124 regions and 11 of 246 cores, vs targeted biopsy in 10 of 21 (47.6%), including 17 of 50 regions and 40 of 125 cores. Five of 21 patients had positive findings on targeted biopsy only and 1 of 21 had positive findings on template biopsy only. An additional case was upgraded from Grade Group 2 to 3 on targeted biopsy. Extraprostatic disease was detected in 8 of 21 men (38.1%) with histological confirmation in all 3 who underwent lesion biopsy. CONCLUSIONS: Fluciclovine positron emission tomography real-time ultrasound fusion guidance for biopsy is feasible in patients with biochemical failure after nonsurgical therapy for prostate cancer. It identifies more recurrent prostate cancer using fewer cores compared with template biopsy in the same patient. Further study is required to determine in what manner targeted biopsy may augment template biopsy of recurrent prostate cancer.

A randomized, controlled trial for transurethral treatment of bladder tumors using PlasmaButton vaporization electrode or monopolar loop electrocautery.

INTRODUCTION: The use of an electrocautery device (monopolar loop) for patients undergoing transurethral resection of bladder tumors (TURBT) is standard of care. The aim of this study is to establish non-inferiority of complication rates for a bipolar energy device, the PK PlasmaButton (PK Button), when compared to the monopolar loop. MATERIALS AND METHODS: Seventy-eight subjects (41 monopolar loop and 37 PK Button), were enrolled in a single-center, prospective, randomized study with cystoscopically detected bladder tumors that were judged endoscopically resectable with only one trip into the operating room. Intra and postoperative data on complication rates, operative time, catheterization time and disease recurrence rates at 3 month follow up were collected. RESULTS: Overall complication rates after TURBT with the monopolar loop or PK Button were similar, (56% versus 38% respectively, p = 0.107), however there were more bladder perforations in the monopolar loop arm compared to the PK Button arm (12.2% versus 0%, respectively, p = 0.028). There was no difference in overall operative time (p = 0.170), catheterization time (p = 0.709) and disease recurrence (p = 0.199). CONCLUSION: The results of this study demonstrated no difference between the monopolar loop and PK Button in regard to overall complications; however, there was a higher rate of bladder perforation with monopolar TURBT. PK Button vaporization for bladder tumors represents a promising alternative to traditional monopolar TURBT without compromising short term (3 month) cancer recurrence rates.

The role of adjuvant radiotherapy in pathologically lymph node-positive prostate cancer.

BACKGROUND: Postoperative management of prostate cancer with lymph node involvement (LNI) is controversial. Retrospective evidence supports the selective use of radiotherapy (RT) after extended pelvic lymph node dissection. It is unclear whether this is generalizable to practice in the United States, where extended dissection is uncommon. The authors identified patients with LNI who potentially could derive a survival benefit with adjuvant RT plus androgen-deprivation therapy (ADT). METHODS: Patients with N1M0 prostate adenocarcinoma who underwent radical prostatectomy (RP) and subsequently received ADT from 2003 through 2011 were identified from the National Cancer Database. Kaplan-Meier analyses, log-rank tests, and multivariable Cox proportional hazards regression were performed using overall survival (OS) as the primary outcome. RESULTS: In total, 906 of 2569 eligible patients (35.3%) received RT, and RT was more frequently received by patients who were diagnosed in later years, had fewer positive lymph nodes, had involved surgical margins, and were aged <65 years (all P < .05). The 5-year OS rate was 87% versus 82% in those who received RT versus those who did not (P = .007). After propensity score matching, 826 patients remained in each cohort. RT retained an association with OS (5-year OS: 88% vs 81%; P = .009; hazard ratio, 1.43; 95% confidence interval, 1.10-1.86; P = .008). No interaction was identified between the effect of RT on OS across tested strata of total lymph nodes examined, lymph node ratio, total number of positive lymph nodes, margin status, Gleason score, and prostate-specific antigen. CONCLUSIONS: RT plus ADT was associated with improved OS after RP in patients with LNI. These results may help guide therapy in the absence of randomized evidence. Cancer 2017;123:512-520. © 2016 American Cancer Society.

Update of the ICUD-SIU consultation on upper tract urothelial carcinoma 2016: treatment of localized high-risk disease.

PURPOSE: To provide a comprehensive overview and update of the joint consultation of the International Consultation on Urological Diseases (ICUD) and Société Internationale d'Urologie for the treatment of localized high-risk upper tract urothelial carcinoma (UTUC). METHODS: A detailed analysis of the literature was conducted reporting on treatment modalities and outcomes in localized high-risk UTUC. An international, multidisciplinary expert committee evaluated and graded the data according to the Oxford System of Evidence-based Medicine modified by the ICUD. RESULTS: Radical nephroureterectomy (RNU) is the standard of treatment for high-grade or clinically infiltrating UTUC and includes the removal of the entire kidney, ureter and ipsilateral bladder cuff. The distal ureter can be managed either by extravesical or transvesical approach, whereas endoscopically assisted procedures are associated with decreased intravesical recurrence-free survival. Post-operative intravesical chemotherapy decreases the risk of subsequent bladder tumour recurrence. Regional lymph node dissection is of prognostic importance in infiltrative UTUC, but its extent has not been standardized. Renal-sparing surgery is an option for manageable, high-grade tumours of any part of the upper tract, especially of the distal ureter, as an alternative to RNU. Endoscopy-based renal-sparing procedures are associated with a higher risk of recurrence and progression. CONCLUSIONS: A multimodal approach should be considered in localized high-risk UTUC to improve outcomes. RNU is the standard of treatment in high-risk disease. Renal-sparing approaches may be oncologically equivalent alternatives to RNU in well-selected patients, especially in those with distal ureteric tumours.

The importance of surgical margins in renal cell and urothelial carcinomas.

This chapter reviews the prevalence, outcomes, and management of positive surgical margins for patients with either renal cell or urothelial carcinomas. Though renal cell carcinoma tends to be resistant to conventional radio- or chemotherapy, kidney cancer patients with positive surgical margins can often be managed with close surveillance with acceptable outcomes. On the other hand, urothelial tumors tend to be more aggressive, and positive surgical margins after radical cystectomy often requires adjuvant therapy.

Extended lymph node dissection in robotic radical prostatectomy: Current status.

INTRODUCTION: The role and extent of extended pelvic lymph node dissection (ePLND) during radical prostatectomy (RP) for prostate cancer patients remains unclear. MATERIALS AND METHODS: A PubMed literature search was performed for studies reporting on treatment regimens and outcomes in patients with prostate cancer treated by RP and extended lymph node dissection between 1999 and 2013. RESULTS: Studies have shown that RP can improve progression-free and overall survival in patients with lymph node-positive prostate cancer. While this finding requires further validation, it does allow urologists to question the former treatment paradigm of aborting surgery when lymph node invasion from prostate cancer occurred, especially in patients with limited lymph node tumor infiltration. Studies show that intermediate- and high-risk patients should undergo ePLND up to the common iliac arteries in order to improve nodal staging. CONCLUSIONS: Evidence from the literature suggests that RP with ePLND improves survival in lymph node-positive prostate cancer. While studies have shown promising results, further improvements and understanding of the surgical technique and post-operative treatment are required to improve treatment for prostate cancer patients with lymph node involvement.

Robotic partial nephrectomy versus laparoscopic partial nephrectomy: a single laparoscopic trained surgeon's experience in the development of a robotic partial nephrectomy program.

OBJECTIVES: We evaluated whether the surgical approach during the implementation of a robotic kidney surgery program influenced perioperative and oncologic outcomes. METHODS: We prospectively evaluated a single institution experience with minimally invasive partial nephrectomy between 2006 and 2010. The study cohort comprised 86 consecutively treated patients who underwent laparoscopic partial nephrectomy (LPN, N = 59) or robotic-assisted (RPN, N = 27) partial nephrectomy by a single surgeon. RESULTS: There was no difference between the LPN and RPN cohort in terms of gender, age, operative side, American Society of Anesthesiology score, or preoperative estimated glomerular filtration rate (eGFR). An early unclamping technique was used for 22 (82%) patients in the RPN cohort and 6 (10%) patients in the LPN cohort. (P < 0.001). Warm ischemia time was lower in the RPN cohort (mean 18.5 vs. 28.0 min, P = <0.001) as result of majority undergoing early unclamping. There was no difference in operative time, estimated blood loss, length of stay, transfusion rate, positive surgical margin, or postoperative decrease in eGFR. There was no difference in mean eGFR decrease after early unclamping (16%) versus traditional clamping (22%); however, 11 (29%) patients had greater than 50% decrease in eGFR after traditional clamping versus 0 patients after early unclamping (P = 0.014). CONCLUSION: Patients undergoing RPN during implementation of a robotic kidney surgery program when compared with LPN appear to have equivalent perioperative outcomes and oncologic efficacy. RPN patients had surgery later in our minimally invasive partial nephrectomy experience, and these results may not be generalizable to laparoscopic and/or robotic naïve surgeons.

Integrated Genomic Analysis of Primary Prostate Tumor Foci and Corresponding Lymph Node Metastases Identifies Mutations and Pathways Associated with Metastasis.

Prostate cancer is a highly heterogeneous disease and mortality is mainly due to metastases but the initial steps of metastasis have not been well characterized. We have performed integrative whole exome sequencing and transcriptome analysis of primary prostate tumor foci and corresponding lymph node metastases (LNM) from 43 patients enrolled in clinical trial. We present evidence that, while there are some cases of clonally independent primary tumor foci, 87% of primary tumor foci and metastases are descended from a common ancestor. We demonstrate that genes related to oxidative phosphorylation are upregulated in LNM and in African-American patients relative to White patients. We further show that mutations in TP53, FLT4, EYA1, NCOR2, CSMD3, and PCDH15 are enriched in prostate cancer metastases. These findings were validated in a meta-analysis of 3929 primary tumors and 2721 metastases and reveal a pattern of molecular alterations underlying the pathology of metastatic prostate cancer. We show that LNM contain multiple subclones that are already present in primary tumor foci. We observed enrichment of mutations in several genes including understudied genes such as EYA1, CSMD3, FLT4, NCOR2, and PCDH15 and found that mutations in EYA1 and CSMD3 are associated with a poor outcome in prostate cancer.

Surgery in Early Metastatic Seminoma: A Phase II Trial of Retroperitoneal Lymph Node Dissection for Testicular Seminoma With Limited Retroperitoneal Lymphadenopathy.

PURPOSE: The long-term toxicities of chemotherapy and radiotherapy can represent a significant burden to testicular cancer survivors. Retroperitoneal lymph node dissection (RPLND) is an established treatment for testicular germ cell tumors with minimal late morbidity although little data exist on its efficacy in early metastatic seminoma. Surgery in early metastatic seminoma is a prospective phase II single-arm, multi-institutional trial of RPLND as first-line treatment for testicular seminoma with clinically low-volume retroperitoneal lymphadenopathy. PATIENTS AND METHODS: Twelve sites in the United States and Canada prospectively enrolled adult patients with testicular seminoma and isolated retroperitoneal lymphadenopathy (1-3 cm). Open RPLND was performed by certified surgeons with a primary end point of 2-year recurrence-free survival (RFS). Complication rates, pathologic up/downstaging, recurrence patterns, adjuvant therapies, and treatment-free survival were assessed. RESULTS: A total of 55 patients were enrolled, with a median (IQR) largest clinical lymph node size of 1.6 cm (1.3-1.9). RPLND pathology demonstrated a median (IQR) largest lymph node size of 2.3 cm (0.9-3.5); nine patients (16%) were pN0, 12 (22%) pN1, 31 (56%) pN2, and 3 (5%) pN3. One patient received adjuvant chemotherapy. With a median (IQR) follow-up of 33 months (12.0-61.6), 12 patients experienced recurrence, with a 2-year RFS of 81% and a recurrence rate of 22%. Of the patients who experienced recurrence, 10 were treated with chemotherapy and two underwent additional surgery. At last follow-up, all patients who experienced a recurrence were disease-free and the 2-year overall survival was 100%. Four patients (7%) experienced short-term complications, and four patients experienced long-term complications including incisional hernia (1) and anejaculation (3). CONCLUSION: RPLND is a treatment option for testicular seminoma with clinically low-volume retroperitoneal lymphadenopathy and is associated with low long-term morbidity.

Stepwise description and outcomes of bladder neck sparing during robot-assisted laparoscopic radical prostatectomy.

PURPOSE: While bladder neck sparing may improve post-prostatectomy urinary continence, there is concern that it may lead to more positive surgical margins and compromise cancer control. We compared the continence and cancer control outcomes of bladder neck sparing vs nonsparing techniques during robot-assisted laparoscopic radical prostatectomy. MATERIALS AND METHODS: Data were prospectively collected on 1,067 robot-assisted laparoscopic radical prostatectomies done from September 2005 through October 2011. We compared the procedures according to bladder neck sparing (791) and nonsparing (276). Continence was defined by zero pad responses on the EPIC (Expanded Prostate Cancer Index) item quantifying daily use. Biochemical recurrence was defined as prostate specific antigen 0.1 ng/ml or greater. Cox regression was performed to assess factors associated with post-prostatectomy continence and biochemical recurrence-free survival. RESULTS: Median followup for bladder neck sparing vs nonsparing was 25.8 vs 51.7 months. Men treated with bladder neck sparing were more likely to have clinical T1c tumors (p <0.001) and less likely to have biopsy Gleason grade 6 or less disease (p = 0.023). They experienced fewer urinary leaks (p = 0.009) and shorter length of stay (p = 0.006). Regarding cancer control outcomes, there was no difference in bladder neck sparing vs nonsparing base (1.2% vs 2.6%, p = 0.146) and overall surgical margin positivity (each 13.8%, p = 0.985). On adjusted analyses bladder neck sparing vs nonsparing was associated with better continence (HR 1.69, 95% CI 1.43-1.99) and similar biochemical recurrence-free survival (HR 1.20, 95% CI 0.62-2.31, p = 0.596). CONCLUSIONS: Bladder neck sparing is associated with fewer urinary leak complications, shorter hospitalization and better post-prostatectomy continence without compromising cancer control compared to bladder neck nonsparing.

Robotic Repair of Ureteroenteric Stricture Following Radical Cystectomy: A Multi-Institutional Experience.

OBJECTIVE: To examine the safety, feasibility and durability of robotic reimplantation of ureteroenteric stricture after radical cystectomy. MATERIALS AND METHODS: A retrospective multi-institutional review was performed for all patients undergoing robotic repair of ureteroenteric stricture from January 2010 to January 2019. Functional outcomes and complications were followed and data were analyzed with SPSS statistical software. RESULTS: A total of 46 patients and 58 renal units were identified, of which 15 had right sided, 19 left sided and 12 patients had bilateral strictures. Presentation of stricture was asymptomatic in 14 (30.4%) patients. Symptomatic presentations included infection in 22 (47.8%), worsening renal function in 11 (23.9%) and pain in 3 (6.5%) patients. Median time from cystectomy to diagnosis of stricture was 5 months (1-40). Median stricture length was 1.5 cm (range 0.5-10). All strictures were of benign etiology except for 4 (6.9%), which were due to malignancy. Overall, 49 (84.5%) ureters underwent primary re-implantation, while 9 (15.5%) required Boari-like advancement flaps prior to re-implantation. Median operative time was 190 min (range 45-540) with median estimated blood loss of 50 mL (range 25-2000) and median length of stay of 2 days (range 1-33, IQR 2-4). Seven (15.2%) patients experienced complications; 3 (6.5%) were low grade and 4 (8.7%) high grade. With median follow up of 18 months (range 1-51) the stricture recurrence rate was 8.6%. CONCLUSION: Robotic reimplantation of ureteroenteric strictures following radical cystectomy is safe and feasible in experienced centers with high success rates.

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.

Prediction of erectile function following treatment for prostate cancer.

CONTEXT: Sexual function is the health-related quality of life (HRQOL) domain most commonly impaired after prostate cancer treatment; however, validated tools to enable personalized prediction of erectile dysfunction after prostate cancer treatment are lacking. OBJECTIVE: To predict long-term erectile function following prostate cancer treatment based on individual patient and treatment characteristics. DESIGN: Pretreatment patient characteristics, sexual HRQOL, and treatment details measured in a longitudinal academic multicenter cohort (Prostate Cancer Outcomes and Satisfaction With Treatment Quality Assessment; enrolled from 2003 through 2006), were used to develop models predicting erectile function 2 years after treatment. A community-based cohort (community-based Cancer of the Prostate Strategic Urologic Research Endeavor [CaPSURE]; enrolled 1995 through 2007) externally validated model performance. Patients in US academic and community-based practices whose HRQOL was measured pretreatment (N = 1201) underwent follow-up after prostatectomy, external radiotherapy, or brachytherapy for prostate cancer. Sexual outcomes among men completing 2 years' follow-up (n = 1027) were used to develop models predicting erectile function that were externally validated among 1913 patients in a community-based cohort. MAIN OUTCOME MEASURES: Patient-reported functional erections suitable for intercourse 2 years following prostate cancer treatment. RESULTS: Two years after prostate cancer treatment, 368 (37% [95% CI, 34%-40%]) of all patients and 335 (48% [95% CI, 45%-52%]) of those with functional erections prior to treatment reported functional erections; 531 (53% [95% CI, 50%-56%]) of patients without penile prostheses reported use of medications or other devices for erectile dysfunction. Pretreatment sexual HRQOL score, age, serum prostate-specific antigen level, race/ethnicity, body mass index, and intended treatment details were associated with functional erections 2 years after treatment. Multivariable logistic regression models predicting erectile function estimated 2-year function probabilities from as low as 10% or less to as high as 70% or greater depending on the individual's pretreatment patient characteristics and treatment details. The models performed well in predicting erections in external validation among CaPSURE cohort patients (areas under the receiver operating characteristic curve, 0.77 [95% CI, 0.74-0.80] for prostatectomy; 0.87 [95% CI, 0.80-0.94] for external radiotherapy; and 0.90 [95% CI, 0.85-0.95] for brachytherapy). CONCLUSION: Stratification by pretreatment patient characteristics and treatment details enables prediction of erectile function 2 years after prostatectomy, external radiotherapy, or brachytherapy for prostate cancer.

Surgical Pathology Findings in Patients Who Have Undergone Radical Cystectomy/Cystoprostatectomy With Extended Versus Standard Lymph Node Dissection for Urothelial Carcinoma of the Bladder: A Contemporary Analysis.

Radical cystectomy/cystoprostatectomy with pelvic lymph node dissection (with or without neoadjuvant chemotherapy) is the gold standard in the management of patients with urothelial carcinoma (UCa) with muscularis propria (detrusor muscle) invasion. However, it remains controversial how extensive the lymph node dissection should be. In this article, we analyzed the clinicopathologic findings in patients who had radical cystectomy/cystoprostatectomy with extended versus standard lymph node dissection. A search was made through our Urologic Pathology files for radical cystectomy/cystoprostatectomy cases with extended and standard lymph node dissection for UCa. A total of 264 cases were included in the study (218 cystoprostatectomy and 46 cystectomy specimens). Mean patients age was 68 years (range = 32-92 years). Patients in all stage categories had more extended lymph node dissection performed compared with standard lymph node dissection: pT0 (20 vs 7), pTis (40 vs 12), pTa (8 vs 4), pT1 (27 vs 5), pT2 (39 vs 8), pT3 (51 vs 17), and pT4 (18 vs 8). In cases with neoadjuvant therapy there was a 19% lymph node positivity rate compared with a 24% positivity rate in those with no presurgical therapy. The only cases categorized as pT2 and below with positive lymph node metastasis were those that had extended lymph node dissection performed. Positive lymph nodes were more frequently detected in cases that had extended lymph node dissection. More than 35% of the positive lymph nodes were in nonregional distribution. Extended lymph node dissection should be considered in patients with UCa even in the low stage or post-neoadjuvant chemotherapy setting.