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PURPOSE Neoadjuvant chemotherapy (NAC) has proven survival benefits for patients with invasive urothelial carcinoma of the bladder, yet its role for upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a multicenter, single-arm, phase II trial of NAC with gemcitabine and split-dose cisplatin (GC) for patients with high-risk UTUC before extirpative surgery to evaluate response, survival, and tolerability. METHODS Eligible patients with defined criteria for high-risk localized UTUC received four cycles of split-dose GC before surgical resection and lymph node dissection. The primary study end point was rate of pathologic response (defined as < ypT2N0). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS Among 57 patients evaluated, 36 (63%) demonstrated pathologic response (95% CI, 49 to 76). A complete pathologic response (ypT0N0) was noted in 11 patients (19%). Fifty-one patients (89%) tolerated at least three complete cycles of split-dose GC, 27 patients (47%) tolerated four complete cycles, and all patients proceeded to surgery. With a median follow up of 3.1 years, 2- and 5-year PFS rates were 89% (95% CI, 81 to 98) and 72% (95% CI, 59 to 87), while 2- and 5-year OS rates were 93% (95% CI, 86 to 100) and 79% (95% CI, 67 to 94), respectively. Pathologic complete and partial responses were associated with improved PFS and OS compared with nonresponders (≥ ypT2N any; 2-year PFS 100% and 95% v 76%, P < .001; 2-year OS 100% and 100% v 80%, P < .001). CONCLUSION NAC with split-dose GC for high-risk UTUC is a well-tolerated, effective therapy demonstrating evidence of pathologic response that is associated with favorable survival outcomes. Given that these survival outcomes are superior to historical series, these data support the use of NAC as a standard of care for high-risk UTUC, and split-dose GC is a viable option for NAC.

INTRODUCTION: Small cell carcinoma of the bladder (SCCB) is a rare variant of bladder cancer with poor outcomes. We evaluated long-term outcomes of nonmetastatic (M0) and metastatic (M1) SCCB and correlated pathologic response with genomic alterations of patients treated with neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: Clinical history and pathology samples from SCCB patients diagnosed at our institution were reviewed. RESULTS: One hundred and ninety-nine SCCB patients were identified. (M0: 147 [74%]; M1: 52 [26%]). Among M0 patients, 108 underwent radical cystectomy (RC) (NAC: 71; RC only: 23; adjuvant chemotherapy: 14); 14 received chemoradiotherapy; the rest received chemotherapy alone or no cancer-directed therapy. RC-only patients had a median follow-up of 9.1 years, and median disease-free survival (DFS) and overall survival (OS) were 1.1 and 1.2 years, respectively. NAC patients had pathologic response (

The NCCN Guidelines for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer and other urinary tract cancers (upper tract tumors, urothelial carcinoma of the prostate, primary carcinoma of the urethra). These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines regarding the treatment of non–muscle-invasive bladder cancer, including how to treat in the event of a bacillus Calmette-Guérin (BCG) shortage; new roles for immune checkpoint inhibitors in non–muscle invasive, muscle-invasive, and metastatic bladder cancer; and the addition of antibody–drug conjugates for metastatic bladder cancer.

To analyse the risk of uretero-enteric anastomotic stricture in patients randomised to open (ORC) or robot-assisted radical cystectomy (RARC) with extracorporeal urinary diversion.We included 118 patients randomised to RARC (n = 60) or ORC (n = 58) at a single, high-volume institution from March 2010 to April 2013. Urinary diversion was performed by experienced open surgeons. Stricture was defined as non-malignant obstruction on imaging, corroborated by clinical status, and requiring procedural intervention. The risk of stricture within 1 year was compared between groups using Fisher's exact test.In all, 58 and 60 patients were randomised to RARC and ORC, respectively. We identified five strictures, all in the ORC group. In patients with ≥1 year of follow-up, the increase in risk of stricture from open surgery was 9.3% (95% confidence interval 1.5%, 17%). Of the five strictures, three were managed endoscopically while two required open revision. There was no evidence that perioperative Grade 3-5 complications were associated with development of a stricture (P = 1) and no evidence of a difference in 24-month estimated glomerular filtration rate between arms (P = 0.15).In this study at a high-volume centre, RARC with extracorporeal urinary diversion achieved excellent ureteric anastomotic outcomes. Purported increased risk of stricture is not a reason to avoid RARC. Future research should examine the impact of different surgical techniques and operator experience on the risk of stricture, especially as more intracorporeal diversions are performed.

PURPOSE Neoadjuvant gemcitabine and cisplatin (GC) followed by radical cystectomy (RC) is standard for patients with muscle-invasive bladder cancer (MIBC). On the basis of the activity of atezolizumab (A) in metastatic BC, we tested neoadjuvant GC plus A for MIBC. METHODS Eligible patients with MIBC (cT2-T4aN0M0) received a dose of A, followed 2 weeks later by GC plus A every 21 days for four cycles followed 3 weeks later by a dose of A before RC. The primary end point was non–muscle-invasive downstaging to < pT2N0. RESULTS Of 44 enrolled patients, 39 were evaluable. The primary end point was met, with 27 of 39 patients (69%) < pT2N0, including 16 (41%) pT0N0. No patient with < pT2N0 relapsed and four (11%) with ≥ pT2N0 relapsed with a median follow-up of 16.5 months (range: 7.0-33.7 months). One patient refused RC and two developed metastatic disease before RC; all were considered nonresponders. The most common grade 3-4 adverse event (AE) was neutropenia (n = 16; 36%). Grade 3 immune-related AEs occurred in five (11%) patients with two (5%) requiring systemic steroids. The median time from last dose of chemotherapy to surgery was 7.8 weeks (range: 5.1-17 weeks), and no patient failed to undergo RC because of AEs. Four of 39 (10%) patients had programmed death-ligand 1 (PD-L1)–positive tumors and were all < pT2N0. Of the patients with PD-L1 low or negative tumors, 23 of 34 (68%) achieved < pT2N0 and 11 of 34 (32%) were ≥ pT2N0 ( P = .3 for association between PD-L1 and < pT2N0). CONCLUSION Neoadjuvant GC plus A is a promising regimen for MIBC and warrants further study. Patients with < pT2N0 experienced improved relapse-free survival. The PD-L1 positivity rate was low compared with published data, which limits conclusions regarding PD-L1 as a predictive biomarker.

PURPOSE: We compare health-related quality of life using a broad range of validated measures in patients randomized to robotic-assisted radical cystectomy vs open radical cystectomy. METHODS: We retrospectively analyzed patients that had enrolled in both a randomized controlled trial comparing robotic-assisted laparoscopic radical cystectomy vs open radical cystectomy and a separate prospective study of health-related quality of life. The prospective health-related quality of life study collected 14 patient-reported outcomes measures preoperatively and at 3, 6, 12, 18, and 24 months postoperatively. Linear mixed-effects models with an interaction term (study arm×time) were used to test for differences in mean domain scores and differing effects of approach over time, adjusting for baseline scores. RESULTS: A total of 72 patients were analyzed (n=32 robotic-assisted radical cystectomy, n=40 open radical cystectomy). From 3-24 months post-radical cystectomy, no significant differences in mean scores were detected. Mean differences were small in the following European Organization for Research and Treatment of Cancer QLQ-C30 (Core Quality of Life Questionnaire) domains: Global Quality of Life (−1.1; 95% CI −8.4, 6.2), Physical Functioning (−0.4; 95% CI −5.8, 5.0), Role Functioning (0.7; 95% CI −8.6, 10.0). Mean differences were also small in bladder cancer–specific domains (European Organization for Research and Treatment of Cancer QLQ-BLM30 [Muscle Invasive Bladder Cancer Quality of Life Questionnaire]): Body Image (2.9; 95% CI −7.2, 13.1), Urinary Symptoms (8.0; 95% CI −3.0, 19.0). In Urostomy Symptoms, there was a significant interaction term (P < .001) due to lower open radical cystectomy scores at 3 and 24 months. Other domains evaluating urinary, bowel, sexual, and psychosocial health-related quality of life were similar. CONCLUSIONS: Over a broad range of health-related quality of life domains comparing robotic-assisted radical cystectomy and open radical cystectomy, there are unlikely to be clinically relevant differences in the medium to long term, and therefore health-related quality of life over this time period should not be a consideration in choosing between approaches.

BACKGROUND: Radical cystectomy (RC) has the potential for profound changes to health-related quality of life (HRQOL). OBJECTIVE: To evaluate a broad range of HRQOL outcomes in a large RC cohort. DESIGN, SETTING, AND PARTICIPANTS: A single-center prospective study enrolled RC patients from 2008 to 2014. We collected 14 separate patient-reported outcome measures at the presurgical visit and at 3, 6, 12, 18, and 24 mo after RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: To visualize the patterns of recovery over time across domains, we used generalized estimating equations (GEEs) with nonlinear terms. Given substantial differences in patient selection for the type of urinary diversion, we separately modeled longitudinal HRQOL within conduit and continent diversion groups. The mean pre-RC scores were compared to illustrate the baseline HRQOL differences between diversion groups. RESULTS AND LIMITATIONS: The analyzed cohort included 411 patients (n = 205 ileal conduit, n = 206 continent diversion). At baseline, patients receiving continent diversion reported better mean physical (p < 0.001), urinary (p = 0.006), and sexual function (p < 0.001), but lower social function (p = 0.015). After RC, GEE modeling showed physical function scores decreasing 5/100 points by 6 mo, and subsequently stabilizing or returning to baseline. By 12 mo, social function improved by 10/100 points among continent diversions, while remaining stable among ileal conduits. Global quality of life exceeded baseline scores by 6 mo. Sexual function scores were low before RC, with limited recovery. Psychosocial domains were stable or improved, except for 10/100-point worsening of body image among ileal conduits. CONCLUSIONS: RC patients reported favorable HRQOL recovery within 24 mo in most areas other than body image (ileal conduits) and sexual function (both). Importantly, large measurable decreases in scores were not reported by 3 mo after RC. These contemporary outcomes and the excellent locoregional control provided by RC further support it as the gold standard therapy for high-risk bladder cancer. PATIENT SUMMARY: We review quality of life in the 24 mo following radical cystectomy. Large decreases in health-related quality of life were not reported, with most areas returning to, or exceeding, baseline, except for sexual function and body image.

Cigarette smoking is a risk factor for developing nonmuscle invasive bladder cancer, and continued smoking exposure after diagnosis may increase the likelihood of adverse clinical outcomes. We compare self-reported vs biochemically verified nicotine exposure to determine the accuracy of self-report among recently diagnosed nonmuscle invasive bladder cancer patients.This cross-sectional analysis consisted of 517 nonmuscle invasive bladder cancer patients who contributed a urine or saliva specimen the same day as self-reporting their smoking, use of e-cigarettes, nicotine replacement therapy and whether they lived with a smoker. Cotinine, the primary metabolite of nicotine, was used as an objective biomarker of recent nicotine exposure.The prevalence of high, low and no cotinine exposure was 13%, 54% and 33%, respectively. Overall, 7.3% of patients (38/517) reported being a current cigarette smoker, while 13% (65/517) had cotinine levels consistent with active smoking exposure. Of these 65 patients 27 denied current smoking, resulting in a sensitivity of self-reported current smoking of 58%. After considering other sources of nicotine exposure such as e-cigarettes, cigars, nicotine replacement therapy and living with a smoker, the sensitivity was higher, at 82%. Nearly all patients with low cotinine denied any smoking-related exposure.Our findings suggest either biochemical verification with cotinine or additional questions about other sources of nicotine are needed to accurately identify nonmuscle invasive bladder cancer patients who have smoking-related exposures. Accurate classification of active and passive smoking exposure is essential to allow clinicians to advise cessation and help researchers estimate the association between post-diagnosis smoking-related exposure and nonmuscle invasive bladder cancer recurrence risk.

PURPOSE To compare oncologic outcomes and genomic alteration profiles in patients with bladder and urachal adenocarcinoma, urothelial carcinoma (UC) with glandular differentiation, and UC, not otherwise specified (NOS) undergoing surgical resection, with emphasis on response to systemic therapy. METHODS We identified patients with bladder cancer with glandular variants who underwent surgical resection at Memorial Sloan Kettering from 1995 to 2018 (surgical cohort) and/or patients who had tumor sequencing using a targeted next-generation sequencing platform (genomics cohort). Pathologic complete and partial response rates to neoadjuvant chemotherapy (NAC) and recurrence-free and cancer-specific survival were measured. Alteration frequencies between histologic subtypes were compared. RESULTS Thirty-seven patients with bladder adenocarcinoma, 46 with urachal adenocarcinoma, 84 with UC with glandular differentiation, and 1,049 with UC, NOS comprised the surgical cohort. Despite more advanced disease in patients with bladder and urachal adenocarcinoma, no significant differences in recurrence or cancer-specific survival by histology were observed after adjusting for stage. In patients with UC with glandular differentiation, NAC resulted in partial (≤ pT1N0) and complete (pT0N0) responses in 28% and 17%, respectively. Bladder and urachal adenocarcinoma genomic profiles resembled colorectal adenocarcinoma with frequent TP53, KRAS, and PIK3CA alterations while the genomic profile of UC with glandular differentiation more closely resembled UC, NOS. Limitations include retrospective nature of analysis and small numbers of nonurothelial histology specimens. CONCLUSION The genomic profile of bladder adenocarcinomas resembled colorectal adenocarcinomas, whereas UC with glandular differentiation more closely resembled UC, NOS. Differences in outcomes among patients with glandular bladder cancer variants undergoing surgical resection were largely driven by differences in stage. Cisplatin-based NAC demonstrated activity in UC with glandular differentiation, suggesting NAC should be considered for this histologic variant.

PURPOSE: Frailty is associated with adverse outcomes following radical cystectomy. Prospective tools to identify factors affecting outcomes are needed. We describe a novel electronic rapid fitness assessment to evaluate geriatric patients undergoing radical cystectomy. MATERIALS AND METHODS: Prior to undergoing radical cystectomy between February 2015 and February 2018, 80 patients over the age of 75 completed the electronic rapid fitness assessment and were perioperatively comanaged by the Geriatrics Service. Physical and cognitive function over 12 domains were evaluated and an accumulated geriatric deficit score compiled. Hospital length of stay, discharge disposition, unplanned intensive care unit admissions, urgent care visits, readmissions, complications, and deaths were assessed. RESULTS: Sixty-five patients who underwent radical cystectomy for bladder cancer without concomitant procedures completed the assessment. Median age was 80 (77, 84), and 52 (80%) were male. A higher proportion of patients with intensive care unit admission, urgent care visit, and major complications had impairments identified within electronic rapid fitness assessment domains, including Timed Up and Go. Readmission rates were similar between patients with or without deficits identified. Higher accumulated geriatric deficit score was significantly associated with intensive care unit admission (p=0.035), death within 90 days (p=0.037), and discharge to other than home (p=0.0002). CONCLUSIONS: We demonstrated the feasibility of assessing fitness in patients over 75 undergoing radical cystectomy using a novel electronic fitness tool. Physical limitations and overall impairment corresponded to higher intensive care unit admission rates and adverse postoperative outcomes. Larger studies in less resourced environments are required to validate these findings.

Background Plasmacytoid urothelial carcinoma (PUC) is a rare, aggressive histologic variant of urothelial cancer characterised by a diffuse growth pattern and CDH1 mutation. We studied the efficacy of preoperative platinum-based chemotherapy in nonmetastatic PUC and immune checkpoint inhibitors (ICIs) in advanced PUC. Methods Cases of nonmetastatic PUC and advanced PUC treated with ICIs at our institution were identified. Outcomes were compared to those of a published cohort of patients with urothelial carcinoma not otherwise specified. Results We identified 81 patients with nonmetastatic PUC. Of the patients with localised disease who underwent neoadjuvant chemotherapy, pathologic complete response and downstaging rates were 12 and 21%, respectively. Pathologic downstaging was not associated with significant improvement in clinical outcomes. Up to 18% of localised disease and 28% of locally advanced cases had unresectable disease at the time of surgery. ICI-treated advanced PUC (N = 21) had progression-free and overall survival of 4.5 and 10.5 months, respectively, and a 38% response rate. FGFR3 and DNA damage response gene alterations were observed in 3 and 15% of cases, respectively. Conclusions PUC is associated with high disease burden and poor chemosensitivity. Increased awareness and recognition of this disease variant will allow for new treatment strategies.

OBJECTIVE: To determine predictors of symptomatic uretero-enteric anastomotic strictures (UAS) formation following radical cystectomy (RC) and urinary diversion (UD). MATERIALS AND METHODS: 2,888 consecutive patients who underwent open RC at our institution from 1995–2014 were included for analysis. Data was collected from institutional databases and individual medical records. Symptomatic benign UAS was defined as percutaneous nephrostomy tube insertion for rising creatinine or unilateral hydronephrosis comparing pre- and post-operative imaging. Univariate and multivariable Cox proportional hazards models were utilized to identify features associated with UAS formation. RESULTS: UAS developed in 123/2,888 patients following RC. There were 94 symptomatic and 29 asymptomatic strictures. Median follow-up was 32 months (IQR 12, 72) for patients without stricture. Higher BMI (p=0.002), ASA score >2 (p2, lymph node involvement, grade III/IV complications within 30 days, male sex, and a history of PAS. We conclude that while surveillance is important for patients who undergo cystectomy for malignancy, it may be beneficial for patients with history of PAS undergo more intensive follow-up compared to those patients without history of PAS.

Objectives To evaluate treatment patterns and associated outcomes of patients with urethral cancer. Patients and methods After obtaining institutional review board approval we identified 165 patients treated for primary urethral cancer between 1956 and 2017. Treatment included monotherapy (surgery or radiation), dual therapy (surgery+radiation, surgery+chemotherapy, or chemotherapy+radiation) or triple therapy (surgery+radiation+chemotherapy). Rates of different treatments were described by treatment year. The association between treatment type and outcomes was evaluated with multivariable Cox regression models, adjusting for disease characteristics. Results The study cohort included 74 men and 91 women, with a median age of 61 years. Common histologies were squamous cell (36%), urothelial (27%) and adenocarcinoma (25%). At presentation, 72% of patients had invasive disease, 24% had nodal involvement, and 5% had metastases. Treatment included monotherapy (57%), dual therapy (21%), and triple therapy (10%). The use of monotherapy decreased over time, while rates of dual therapy remained consistent, and rates of triple therapy increased. The median follow-up was 4.7 years. Estimated 5-year local recurrence-free, disease-specific and overall survival were 51%, 48% and 41%, respectively. Monotherapy was associated with decreased local recurrence-free survival after adjusting for stage, histology, sex and year of treatment (P = 0.017). There was no evidence that treatment type was associated with distant recurrence, cancer-specific or overall survival. Conclusions We found preliminary evidence that multimodal therapy, more commonly used in recent years, was of benefit in patients with primary urethral cancer. This finding should be confirmed in further studies involving multiple centres because of the low incidence of the disease.

Background Postoperative ileus is a common complication of intraabdominal surgeries, including radical cystectomy with reported rates as high as 32%. Perioperative fluid administration has been associated with improvement in postoperative ileus rates, but it is difficult to generalize because earlier studies lacked standardized definitions of postoperative ileus and other relevant outcomes. The hypothesis was that targeted individualized perioperative fluid management would improve postoperative ileus in patients receiving radical cystectomy. Methods This is a parallel-arm, double-blinded, single-center randomized trial of goal-directed fluid therapy versus standard fluid therapy for patients undergoing open radical cystectomy. The primary outcome was postoperative ileus, and the secondary outcome was complications within 30 days post-surgery. Participants were at least 21 yr old, had a maximum body mass index of 45 kg/m2 and no active atrial fibrillation. The intervention in the goal-directed therapy arm combined preoperative and postoperative stroke volume optimization and intraoperative stroke volume variation minimization to guide fluid administration, using advanced hemodynamic monitoring. Results Between August 2014 and April 2018, 283 radical cystectomy patients (142 goal-directed fluid therapy and 141 standard fluid therapy) were included in the analysis. Postoperative ileus occurred in 25% (36 of 142) of patients in the goal-directed fluid therapy arm and 21% (30 of 141) of patients in the standard arm (difference in proportions, 4.1%; 95% CI, −5.8 to 13.9; P = 0.418). There was no difference in incidence of high-grade complications between the two arms (20 of 142 [14%] vs. 23 of 141 [16%]; difference in proportions, −2.2%; 95% CI, −10.6 to 6.1; P = 0.602), with the exception of acute kidney injury, which was more frequent in the goal-directed fluid therapy arm (56% [80 of 142] vs. 40% [56 of 141] in the standard arm; difference in proportions, 16.6%; 95% CI, 5.1 to 28.1; P = 0.005; P = 0.170 after adjustment for multiple testing). Conclusions Goal-directed fluid therapy may not be an effective strategy for lowering the risk of postoperative ileus in patients undergoing open radical cystectomy. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. Background: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. Objective: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. Design: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference. Setting: Online Delphi survey and consensus conference. Participants: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. Outcome measurements and statistical analysis: Statements were ranked by experts according to their level of agreement: 1–3 (disagree), 4–6 (equivocal), 7–9 (agree). A priori (level 1) consensus was defined as 70% agreement and 15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). Results and limitations: Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease. Conclusions: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach, The authors would like to thank Peter E. Clark from Atrium Health, Levine Cancer Institute, Charlotte, NC, USA, for his contribution to the Delphi survey. Angela Corstorphine of Kstorfin Medical Communications Ltd provided medical writing support with the preparation of this manuscript; this support was funded jointly by EAU and ESMO.

INTRODUCTION AND OBJECTIVE:Radical cystectomy (RC) with urinary diversion is the gold standard therapy for high risk invasive bladder cancer, however the procedure affects multiple organ systems wi...

Objective To test whether 2 sequential BCG-induction courses improve the response of high-risk non–muscle invasive bladder cancer. Achieving a complete response (CR) to BCG is critical to disease-free survival. Patients with preexisting BCG-specific immunity owing to prior exposure to BCG have longer disease-free survival than BCG-naive patients likely due to heterologous immunity from the initial priming of the immune system. We evaluated this hypothesis in a phase II prospective clinical trial. Methods From 2015 to 2018, we recruited patients with primary or recurrent NMIBC (high-grade Ta, T1 tumors, with or without CIS) to receive 2-induction courses (12 intra-vesical instillations) of BCG. The primary aim of the study was CR rate 6 months after start of the first BCG induction. CR was defined as no tumor at cystoscopy or TURB biopsy. No maintenance BCG was given. We targeted at least 75 evaluable patients, and a CR of 80% or better was deemed significant. Results Eighty-one patients agreed to participate. Five withdrew before starting BCG, leaving 76 evaluable patients. Sixty-three patients (83%) completed the 12 instillations on schedule. Of these, 62 patients (91%) had a CR at 6 months. None of the patients had tumor progression. Serious adverse event was seen in 1 patient (1%). Recurrence-free survival at 2 years after complete response was 85% (95% CI 77%, 95%). Conclusion The high response rate in patients with high-risk non–muscle-invasive bladder cancer justifies 2 BCG induction cycles in current practice.

PURPOSE: To evaluate patient-reported outcomes (PROs) for bladder cancer patients undergoing neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) using longitudinal data and propensity-matched scoring analyses. METHODS: 155 patients with muscle-invasive bladder cancer scheduled for RC completed the European Organization for Research and Treatment of Cancer questionnaires, EORTC QLQ-C30, EORTC QLQ-BLM30, Fear of Recurrence Scale, Mental Health Inventory and Satisfaction with Life Scale within 4 weeks of surgery. A propensity-matched analysis was performed comparing pre-surgery PROs among 101 patients who completed NAC versus 54 patients who did not receive NAC. We also compared PROs pre- and post-chemotherapy for 16 patients who had data available for both time points. RESULTS: In propensity-matched analysis, NAC-treated patients reported better emotional and sexual function, mental health, urinary function and fewer financial concerns compared to those that did not receive NAC. Longitudinal analysis showed increases in fatigue, nausea and appetite loss following chemotherapy. CONCLUSION: Propensity-matched analysis did not demonstrate a negative effect of NAC on PRO. Several positive associations of NAC were found in the propensity-matched analysis, possibly due to other confounding differences between the two groups or actual clinical benefit. Longitudinal analysis of a small number of patients found small to modest detrimental effects from NAC similar to toxicities previously reported. Our preliminary findings, along with known survival and toxicity data, should be considered in decision-making for NAC.

Purpose While a definitive cure can be achieved by radical cystectomy and pelvic lymph node dissection in select patients with regional lymphadenopathy, the benefit remains uncertain in patients who present with non-regional metastases. We analyzed the survival outcomes of post-chemotherapy retroperitoneal lymph node dissection. Materials and methods We reviewed our institutional database and identified 13 patients with radiographically evident or biopsy proven retroperitoneal nodal metastases with a significant response to chemotherapy. These patients underwent consolidative surgery with concomitant or delayed retroperitoneal lymph node dissection. The primary endpoints were progression-free survival and disease-specific survival from the time of retroperitoneal lymph node dissection. Results All patients had primary urothelial cell carcinoma. Twelve patients underwent concomitant radical cystectomy, pelvic and retroperitoneal lymph node dissection. Seven patients (54%) had residual disease in the retroperitoneum and the median number of retroperitoneal nodes containing metastases was 4 (IQR 2-6). Six (86%) developed disease recurrences within 2 years of surgery and 5 (71%) died of cancer. Of the 6 patients without residual disease in the retroperitoneum, 2 (33%) developed recurrences and died of disease progression. The 2-year disease-specific survival was worse for patients with residual disease in the retroperitoneum than those without residual retroperitoneal disease (34%, 95% CI 5-68 vs 50%, 95% CI 6-85). Conclusions The presence of retroperitoneal nodal metastases at post-chemotherapy retroperitoneal lymph node dissection is a poor prognosticator. Consolidative surgery with retroperitoneal lymph node dissection provides important prognostic information and may be therapeutic in a very small subset of these patients.

Background The clinical significance of the plasmacytoid variant (PCV) in urothelial carcinoma (UC) is currently lacking. Objective To compare clinical outcomes of patients with any PCV with that of patients with pure UC treated with radical cystectomy (RC). Design, setting, and participants We identified 98 patients who had pathologically confirmed PCV UC and 1312 patients with pure UC and no variant history who underwent RC at our institution between 1995 and 2014. Outcome measurements and statistical analysis Univariable and multivariable Cox regression and Cox proportional hazards regression to determine if PCV was associated with overall survival (OS). Results and limitations Patients with PCV UC were more likely to have advanced tumor stage ( p =0.001), positive lymph nodes ( p =0.038), and receive neoadjuvant chemotherapy than those with pure UC (46% vs 22%, p 0.0001). The rate of positive soft tissue surgical margins was over five times greater in the PCV UC group compared with the pure UC group (21% vs 4.1%, respectively, p 0.0001). Median OS for the pure UC versus the PCV patients were 8 yr and 3.8 yr, respectively. On univariable analysis, PCV was associated with an increased risk of overall mortality (hazard ratio=1.34, 95% confidence interval: 1.02–1.78, p =0.039). However, on multivariable analysis adjusted for age, sex, neoadjuvant chemotherapy received, lymph node status, pathologic stage, and soft margin status, the association between PCV and OS was no longer significant (hazard ratio=1.06, 95% confidence interval: 0.78, 1.43, p =0.7). This retrospective study is limited by the lack of pathological reanalysis, and the impact of other concurrent mixed histology cannot be determined in this study. Conclusions Patients with PCV features have a higher disease burden at RC compared with those with pure UC. However, PCV was not an independent predictor of survival after RC on multivariable analysis, suggesting that PCV histology should not be used as an independent prognostic factor. Patient summary Plasmacytoid urothelial carcinoma is a rare and aggressive form of bladder cancer. Patients with plasmacytoid urothelial carcinoma had worse adverse pathologic features, but this was not associated with worse overall mortality when compared with patients with pure urothelial carcinoma.

440 Background: Neoadjuvant chemotherapy (NAC) has proven survival benefits for invasive urothelial carcinoma of the bladder, yet its role in upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a phase II multicenter trial of NAC with gemcitabine and cisplatin (GC) in patients with high-risk UTUC prior to extirpative surgery to evaluate major outcomes of response, survival, and tolerability. Methods: Eligible patients with defined criteria for high-risk localized UTUC received four cycles of GC prior to surgical resection and lymph node dissection. The primary study endpoint was pathologic response rate (defined as < pT2N0). Patients with progressive disease prior or unable to proceed to surgery were considered treatment failures. Secondary endpoints included time to disease progression (PFS), overall survival (OS), and safety and tolerability. Results: Among 57 patients evaluated, 36 (63%) demonstrated pathologic response, meeting the primary endpoint of the study. A complete response was noted in 11 patients (19%), defined as pT0N0. Forty patients (70%) tolerated all four cycles of GC, and all patients proceeded to surgery. The 90-day ≥ grade 3 surgical complication rate was 7.0%. With a median follow up of 42.3 months among survivors, six patients succumbed to disease. Two and five-year PFS were 76% (95% CI 66, 89) and 61% (95% CI 47, 78). Two and five-year OS were 93% (95% CI 86, 100) and 79% (95% CI 67, 94). Patients demonstrating pathologic response had improved PFS and OS compared to those who did not (two-year PFS 91% vs 52%, log-rank p < 0.001, two-year OS 100% vs 80%, log-rank p < 0.001). Conclusions: NAC for high-risk UTUC demonstrates outcomes of favorable pathologic response, is well tolerated requiring minimal delay to surgery without significant perioperative complication risk, and thus should be considered a new standard of care option for patients with high-risk UTUC. Better survival outcomes in patients with favorable pathologic features after NAC indicate a potential clinical benefit to this approach. Clinical trial information: NCT01261728.

OBJECTIVES: To evaluate treatment patterns and associated outcomes of patients with urethral cancer. PATIENTS AND METHODS: After obtaining IRB approval we identified 165 patients treated for primary urethral cancer between 1956–2017. Treatment included monotherapy (surgery or radiation), dual-therapy (surgery+radiation, surgery+chemotherapy, or chemotherapy+radiation) or triple-therapy (surgery+radiation+chemotherapy). Rates of different treatments were described by treatment year. The association between treatment type and outcomes was evaluated with multivariate Cox-regression models adjusting for disease characteristics. RESULTS: The study cohort included 74 males and 91 females with a median age of 61 years. Common histologies were squamous-cell (36%), urothelial (27%) and adenocarcinoma (25%). At presentation, 72% of patients had invasive disease, 24% had nodal involvement, and 5% had metastases. Treatment included monotherapy (57%), dual-therapy (21%), and triple-therapy (10%). The use of monotherapy decreased over time, while rates of dual-therapy remained consistent, and rates of triple-therapy increased. Median followup was 4.7 years. Estimated five-year local recurrence-free, disease-specific and overall survival were 51%, 48% and 41%, respectively. Monotherapy was associated with decreased local recurrence-free survival after adjusting for stage, histology, sex and year of treatment (p=0.017). There was no evidence that treatment type was associated with distant recurrence, cancer-specific and overall survival. CONCLUSIONS: We found preliminary evidence that multimodal therapy, more commonly used in recent years, was of benefit in patients with primary urethral cancer. This finding should be confirmed in further studies involving multiple centers due to the low incidence of the disease.

PURPOSE: To evaluate trends in oncologic characteristics and outcomes, as well as perioperative management, among patients undergoing radical cystectomy at Memorial Sloan Kettering from 1995 to 2015. MATERIALS AND METHODS: We retrospectively reviewed our institutional database to analyze changes in disease recurrence probability, cancer-specific and all-cause mortality, incidence of muscle-invasive bladder cancer, use of perioperative chemotherapy, rate of positive soft-tissue surgical margins, and lymph node yield. RESULTS: In 2,740 patients with non-metastatic urothelial carcinoma undergoing radical cystectomy from 1995 to 2015, the 5-year probability of disease recurrence decreased from a peak of 42% in 1997 to 34% in 2013 (p=0.045), while 5-year probability of cancer-specific mortality likewise declined from 36% in 1997 to 24% in 2013 (p=0.009). Incidence of non-muscle-invasive disease before radical cystectomy did not change, comprising 30%–35% of patients across the study period. Use of neoadjuvant chemotherapy rose significantly: 57% of patients with muscle-invasive bladder cancer from 2010 to 2015 received it. We observed a corresponding rise in complete pathologic response (pT0) at radical cystectomy, as well as decreasing positive soft-tissue surgical margins (10% to 2.5%) and rising lymph node yield (7 to 24) from 1995 to 2015. CONCLUSIONS: Over a 21-year period, outcomes after radical cystectomy at our institution improved significantly, as probability of recurrence and cancer-specific mortality decreased. Increasing utilization of neoadjuvant chemotherapy, rising pT0 rates, decreased positive soft-tissue surgical margins, and increasing lymph node yields likely contributed, suggesting that optimized surgical and perioperative care led to improved cancer outcomes in patients undergoing radical cystectomy.

INTRODUCTION AND OBJECTIVE:Postoperative ileus (POI) is a common complication of intra-abdominal surgeries, including radical cystectomy (RC) with reported POI rates as high as 32%. Targeted indivi...

INTRODUCTION AND OBJECTIVE:Neoadjuvant chemotherapy (NAC) has established survival benefits prior to cystectomy for bladder cancer, yet its role in upper tract urothelial carcinoma (UTUC) prior to ...

INTRODUCTION AND OBJECTIVE:Upper tract urothelial carcinoma (UTUC) is a rare disease associated with poor prognosis. Increasing recent attention has been paid to surgical care and multidisciplinary...

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on the clinical presentation and workup of suspected bladder cancer, treatment of non–muscle-invasive urothelial bladder cancer, and treatment of metastatic urothelial bladder cancer because important updates have recently been made to these sections. Some important updates include recommendations for optimal treatment of non–muscle-invasive bladder cancer in the event of a bacillus Calmette-Guérin (BCG) shortage and details about biomarker testing for advanced or metastatic disease. The systemic therapy recommendations for second-line or subsequent therapies have also been revised. Treatment and management of muscle-invasive, nonmetastatic disease is covered in the complete version of the NCCN Guidelines for Bladder Cancer available at NCCN.org. Additional topics covered in the complete version include treatment of nonurothelial histologies and recommendations for nonbladder urinary tract cancers such as upper tract urothelial carcinoma, urothelial carcinoma of the prostate, and primary carcinoma of the urethra.

The aim of this study was to determine drug delivery/toxicity, and pathologic/surgical outcomes of patients with muscle-invasive bladder cancer (MIBC) receiving neoadjuvant gemcitabine-cisplatin (GC) plus radical cystectomy-pelvic lymph node dissection (RC-PLND).Chemotherapy and surgical/pathologic outcomes were retrospectively analyzed with 5-year survival follow-up at a referral center. Post-neoadjuvant chemotherapy (NAC) pathologic endpoints included complete response (pT0N0), residual non-MIBC (pTa/Tis/T1N0), and ≥ MIBC (≥ pT2 and/or N+). Associations of pathologic/surgical findings with overall survival (OS), disease-free survival (DFS), and surgical management with RC-PLND were analyzed (Cox regression).Clinical T2a-T4aN0M0 MIBC patients (n = 154) from January 2000-October 2012 received GC plus RC-PLND. Patients (n = 117; 76%) received GC × 4 and 136 (88%) GC × 3. Five-year OS was 61% (95% confidence interval [CI], 53-71). Median number of resected lymph nodes (LNs) was 19. Down-staging was observed as follows: pT0N0: 21%; pTa/Tis/T1N0: 25%, with similar 5-year OS (85% and 89%, respectively). Five-year OS for pT2 versus ≥ pT2 residual disease was 87% (95% CI, 78%-98%) versus 38% (95% CI, 27%-53%); P .001. Post-NAC stage ≥ pT2 (HR, 6.79; 95% CI, 2.63-17.53; P .001), positive LN (HR, 3.64; 95% CI, 1.84-7.19; P .001), and positive margins (HR, 4.15; 95% CI, 1.68-10.25; P = .002) were associated with increased risk of all-cause death (multivariable analysis). An HR of 0.97 (95% CI, 0.94-1.00) was observed for each additional node removed, but this effect was not statistically significant (P = .056).Neoadjuvant GC achieves meaningful pathologic responses. Patients with ≥ pT2 residual disease, positive margins, or positive LN post-chemotherapy have inferior survival.

The authors regret that a co-author was mistakenly missed from the authorship. The following co-author should have been included in the authorship: Peter-Paul M. Willemse Department of Oncological Urology, University Medical Center, Utrecht Cancer Center, Utrecht, The Netherlands

Micropapillary urothelial carcinoma (MPUC) is a rare but an aggressive variant of urothelial carcinoma. MPUC has been shown to commonly exhibit ERBB2 amplification and HER2 protein overexpression, but the frequency and distribution of these findings within micropapillary (MP) and not otherwise specified (NOS) components of tumors with mixed histology have not been addressed. Therefore, we evaluated ERBB2 amplification and HER2 expression in 43 MPUC cases by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Of the 35 tumors containing both MP and NOS components, ERBB2 amplification was present in both the MP and NOS components of 12 tumors (34.3%), in only the MP component of 11 tumors (31.4%), and exclusively in the NOS component of 4 tumors (11.4%). HER2 protein overexpression was significantly more commonly present in the MP component compared to the NOS component within the same tumor (68.6% versus 34.3%, P = .012). Overall, there was a moderately positive correlation between HER2 protein expression and ERBB2 amplification in both MP (ρ = 0.59, P < .001) and NOS (ρ = 0.70, P < .001) components. All MP/NOS areas with IHC score 3+ and none of MP/NOS areas with IHC score 0 were associated with ERBB2 amplification. We conclude that ERBB2 amplification and HER2 overexpression are preferentially but not exclusively identified in the MP component compared to the NOS component within the same tumor. Our findings identify the presence of intratumoral heterogeneity of ERBB2 amplification and HER2 expression in MPUC and provide grounds for further investigation into the mechanisms underlying the development of MPUC.

OBJECTIVE To determine the initial response to intravesical bacillus Calmette-Guerin and the 3-year recurrence rate of high-risk non-muscle-invasive bladder cancer in patients who have asymptomatic bacteriuria. METHODS Response and recurrence rates were investigated in 505 patients with high-risk non-muscle-invasive bladder cancer after treatment with induction bacillus Calmette-Guerin (TICE strain) therapy. Initial response was determined after 3 months and patients were followed every 3-6 months for 3 years. Before bacillus Calmette-Guerin and each follow-up cystoscopy, urine cultures were obtained, stratified as no growth, 104 or >105 colony-forming unit/mL. Any degree of bacteriuria on culture was classified as asymptomatic bacteriuria. RESULTS Of the 505 cases, 270 (53%) had asymptomatic bacteriuria. A total of 89% of patients with asymptomatic bacteriuria showed a complete response to bacillus Calmette-Guerin versus 76% of uninfected patients (P = 0.001), and 75% of bacteriuric patients survived tumor-free for 3 years versus 65% of uninfected patients. CONCLUSIONS Chronic bacteriuria might enhance the response of high-risk non-muscle-invasive bladder cancer to intravesical bacillus Calmette-Guerin and result in longer tumor-free survival than uninfected patients.

BackgroundAlthough guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.ObjectiveTo bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management.DesignA steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference.SettingOnline Delphi survey and consensus conference.ParticipantsThe European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management.Outcome measurements and statistical analysisStatements were ranked by experts according to their level of agreement: 1–3 (disagree), 4–6 (equivocal), and 7–9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus).Results and limitationsOverall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease.ConclusionsThese consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach.Patient summaryThis report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available.

INTRODUCTION AND OBJECTIVES:Neoadjuvant chemotherapy (NAC) has established survival benefits prior to radical cystectomy for invasive urothelial carcinoma, yet its role in managing high risk upper ...

INTRODUCTION AND OBJECTIVES:Mucosal melanoma of the urethra is a rare disease with distinct clinical and pathological characteristics and poor outcomes compared to cutaneous melanoma. We describe t...

TPS509 Background: Intravesical BCG is the most effective treatment for high-grade non-muscle invasive bladder cancer (NMIBC), yet recurrences are common. Patients with BCG-relapsing NMIBC are often re-treated with BCG or BCG with interferon (IFN) with an expected response rate of only 40–60%. Several studies show that a major mechanism of resistance to BCG is high levels of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in the pretreatment tumor microenvironment. Gemcitabine is a commonly used intravesical treatment for NMIBC that, in addition to direct anti-tumor cytotoxic effects, may also reduce MDSCs and Tregs. Prior trials combining BCG with intravesical mitomycin C have shown improved efficacy over BCG alone but with higher toxicity. While gemcitabine has been shown to be better tolerated than mitomycin as an intravesical treatment, no study has looked at combined BCG and intravesical gemcitabine. We hypothesize that combining BCG and intravesical gemcitabine will be well tolerated and result in higher response rates by reducing levels of MDSCs and Tregs. A novel aspect of our trial design is the use of a modified continual reassessment method to more accurately identify the maximum tolerated dose instead of the traditional 3 + 3 design used in most NMIBC phase I trials. Methods: This is an investigator-initiated phase I trial (NCT04179162) that will study the safety of alternating intravesical gemcitabine and BCG. Inclusion and exclusion criteria are designed so most patients who would ordinarily be re-treated with BCG or BCG/IFN would be eligible. Patients must have recurrent high-grade NMIBC within 24 months of their last BCG treatment without meeting the criteria for BCG-unresponsive NMIBC. Intravesical gemcitabine is given twice a week on weeks 1, 4, 7, and 10, for a total of 8 doses. BCG (50 mg) is given once a week on weeks 2, 3, 5, 6, 8, and 9, for a total of 6 doses. The trial is monitored using a modified continual reassessment method with increasing dose levels of gemcitabine (500 mg, 1,000 mg, 1,500 mg, and 2,000 mg) being evaluated. Adverse events are assessed using the Common Terminology Criteria for Adverse Events version 5.0. The primary objective is to determine the maximum tolerated dose of this combination to inform our planned phase II trial. Correlative studies will look at the immunomodulating effects of gemcitabine by evaluating changes in immune cell populations in serial blood and urine specimens. Tissue and urine will also be evaluated for molecular determinants of response and resistance to the combination. The trial is open to enrollment with 10 of 25 planned patients accrued to date. Clinical trial information: NCT04179162.

Previous studies have demonstrated significant variation in recurrence rates after transurethral resection of bladder tumor, likely due to differences in surgical quality. We sought to create a framework to define, measure and improve the quality of transurethral resection of bladder tumor using a surgical checklist.We formed a multi-institutional group of urologists with expertise with bladder cancer and identified 10 critical items that should be performed during every high quality transurethral bladder tumor resection. We prospectively implemented a 10-item checklist into practice and reviewed the operative reports of such resections performed before and after implementation. Results at all institutions were combined in a meta-analysis to estimate the overall change in the mean number of items documented.The operative notes for 325 transurethral bladder tumor resections during checklist use were compared to those for 428 performed before checklist implementation. Checklist use increased the mean number of items reported from 4.8 to 8.0 per resection, resulting in a mean increase of 3.3 items (95% CI 1.9-4.7) on meta-analysis. With the checklist the percentage of reports that included all 10 items increased from 0.5% to 27% (p0.0001). Surgeons who reported more checklist items tended to have a slightly higher proportion of biopsies containing muscle, although not at conventional significance (p = 0.062).The use of a 10-item checklist during transurethral resection of bladder tumor improved the reporting of critical procedural elements. Although there was no clear impact on the inclusion of muscle in the specimen, checklist use may enhance surgeon attention to important aspects of the procedure and be a lever for quality improvement.

These NCCN Guidelines Insights discuss the major recent updates to the NCCN Guidelines for Bladder Cancer based on the review of the evidence in conjunction with the expert opinion of the panel. Recent updates include (1) refining the recommendation of intravesical bacillus Calmette-Guérin, (2) strengthening the recommendations for perioperative systemic chemotherapy, and (3) incorporating immunotherapy into second-line therapy for locally advanced or metastatic disease. These NCCN Guidelines Insights further discuss factors that affect integration of these recommendations into clinical practice.

Background We sought to determine if idiographic, or self-defined, measures added to our understanding of patients with bladder cancer's quality of life (QOL) prior to radical cystectomy (RC). We tested whether idiographic measures increased prediction of global QOL beyond standard (nomothetic) measures of QOL components. Methods We administered the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (QLQ)-C30 and QLQ-BLM30, and our own idiographic Quality of Life Appraisal Profile prior to RC. Idiographic measures included number of goal statements, distance from goal attainment, and ability to complete goal attainment activities. Multivariate linear regression was used to predict measures of global QOL and related constructs of life satisfaction and mental health. Results Two hundred fiftheen patients reported a median of 8 (interquartile range [IQR] 6, 11) goals and half had an average goal attainment rating above 6.9 out of 10 (IQR 5.5, 8.2). On multivariable analysis, QLQ-C30 role functioning and QLQ-BLM30 future perspective explained 15.7% of the variability in preoperative global QOL. Including goal attainment and activity difficulty explained an additional 12% of global QOL variance. Smaller gains were seen on measures of global health, life satisfaction, mental health, and activity, suggesting that idiographic measures capture aspects of QOL distinct from health and functional status defined by nomothetic scales. Conclusions Idiographic assessment of QOL added to prediction of global QOL above and beyond health-related components measured using nomothetic instruments. This self-defined information may be valuable in communicating with cancer patients about their QOL. Copyright © 2015 John Wiley & Sons, Ltd.