Indications and Outcomes for Deferred Cytoreductive Nephrectomy Following Immune Checkpoint Inhibitor Combination Therapy: Can Systemic Therapy be Withdrawn in Patients with No Evidence of Disease?

Background: Upfront cytoreductive nephrectomy (CN) is no longer the standard of care for patients with metastastic renal cell carcinoma (mRCC) with intermediate or poor prognosis according to the International mRCC Database Consortium categories. Objective: To investigate indications for CN following first-line ipilimumab-nivolumab, and assess management and outcomes for patients achieving no evidence of disease (NED) after CN. Design setting and participants: This was a retrospective cohort study among 125 patients with synchronous mRCC who received ipilimumab-nivolumab treatment between March 2019 and June 2022 at four European centres. At one of the four centres, nivolumab was stopped following NED. Outcome measurements and statistical analysis: We measured complete response of metastases (mCR) according to Response Evaluation Criteria in Solid Tumours 1.1; near-complete response of mestastases (mnCR) was defined as a >80% reduction in cumulative metastatic volume. Treatment-free survival (TFS), disease-free survival (DFS), progression-free survival (PFS), and cancer-specific survival (CSS) were determined. Results and limitations: At median follow-up of 25 mo, 23/125 patients (18%) had undergone deferred CN. Of 26 patients (21%) with mCR or mnCR, 19 (73%) underwent CN to achieve NED, of whom 11 (58%) discontinued nivolumab, with median TFS of 21 mo. For patients who continued (n = 8, 42%) versus discontinued nivolumab following NED, 2-yr DFS was 83% versus 60% (p = 0.675) and 3-yr CSS was 100% versus 70% (p = 0.325). Four patients underwent CN because of a dissociated response of the primary tumour and were still alive at median follow-up of 5 mo. Conclusions: CN can result in NED, durable DFS, and substantial time off systemic therapy. More collaborative data are required to ascertain the benefits of treatment discontinuation versus oncologic safety. Patient summary: In our study using real-world data, 18% of patients treated with immunotherapy underwent deferred kidney surgery. The majority were free of disease after 3 years. Half of the patients who stopped immunotherapy after surgery have been off therapy for 21 months or longer. Larger studies are needed to investigate the effect of kidney surgery and discontinuation of immunotherapy on survival.

Urothelial Carcinoma in Bladder Diverticula: A Multicenter Analysis of Characteristics and Clinical Outcomes.

BACKGROUND: Urothelial carcinoma arising in a bladder diverticulum (UCBD) is uncommon, and data on treatment and outcome are sparse. OBJECTIVE: To analyze clinicopathological characteristics of UCBD and to compare outcome after radical cystectomy (RC) and partial cystectomy (PC). DESIGN, SETTING, AND PARTICIPANTS: Data of 115 UCBD patients treated with RC (n=81) or PC (n=34) between 2000 and 2016 were collected from 11 institutional databases and were analyzed retrospectively. Median follow-up was 5.0yr (95% confidence interval [CI]: 4.0-6.2). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Upstaging of tumor stage at diagnostic transurethral resection (TUR) to the RC/PC specimen was investigated. Overall survival (OS) and metastasis-free survival (MFS) after RC and PC were analyzed using Kaplan-Meier estimates, and compared using the log-rank test. Intravesical recurrences after PC were reported. A multivariable Cox proportional-hazard model was used to identify factors associated with OS. RESULTS AND LIMITATIONS: There were no statistically significant differences in clinicopathological characteristics between RC and PC groups. Fifty-five percent of patients with cTa/is/1 at diagnostic TUR had ≥pT2 tumors at RC/PC. Five-year OS and MFS were, respectively, 62% and 66% for RC and 66% and 55% for PC (p=0.9 and p=0.6). Intravesical tumor recurrence was seen in six of 34 (18%) PC patients. In multivariable analysis, positive surgical margins and extravesical disease (≥pT2) were associated with worse OS, whereas treatment modality was not (RC: reference; PC: hazard ratio 0.94, [95% CI: 0.47-1.90], p=0.9). CONCLUSIONS: Upstaging of UCBD was frequent, indicating an inaccuracy in clinical staging. We found no differences in OS or MFS between PC and RC groups; therefore, PC may represent a feasible surgical alternative to RC in selected UCBD patients. PATIENT SUMMARY: In this report, we looked at the treatment of urothelial carcinoma arising in a bladder diverticulum (UCBD). We found that bladder-sparing treatment by partial cystectomy may be an alternative to radical cystectomy in carefully selected UCBD patients.

Results of the York Mason Procedure with and without Concomitant Graciloplasty to Treat Iatrogenic Rectourethral Fistulas.

BACKGROUND: Rectourethral fistulas (RUFs) are rare but devastating complications after surgery or radiation therapy to the urethra, prostate, or rectum. RUF repair is challenging, especially in irradiated patients. OBJECTIVE: To evaluate the efficacy of the York Mason (YM) procedure with or without concomitant gracilis muscle interposition (graciloplasty) for RUF repair. DESIGN, SETTING, AND PARTICIPANTS: Records of patients with an iatrogenic RUF who underwent the YM procedure between 2008 and 2018 in two university hospitals were reviewed. Data on etiology, diagnostic and operative procedures, urinary and fecal diversion, and postoperative follow-up were collected. INTERVENTION: Twenty-eight patients underwent 33 YM procedures. Concomitant graciloplasty was performed in four (14%) primary repairs and two (7%) repairs for recurrent RUFs. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was successful RUF repair, defined as absence of symptoms and no leakage on control urethrocystography. The secondary endpoint was colostomy reversal rate. RESULTS AND LIMITATIONS: Median follow-up was 24 mo. Ten patients (36%) were irradiated previously. The ultimate success rate was 75% after a maximum of three YM procedures. Success rates were 89% and 50% in patients with nonirradiated and irradiated fistulas, respectively. In irradiated patients, the success rates of the first YM procedure with and without graciloplasty were 100% and 29%, respectively. In recurrent cases, concomitant graciloplasty did not result in better outcomes. Colostomy reversal was possible in 15 patients after successful repair. In all patients, fecal continence was intact and no anal stenosis was reported. Limitations of the study include small sample size and the retrospective design. CONCLUSIONS: Combination of the YM procedure with graciloplasty resulted in higher success rates of RUF repair in patients with irradiated fistulas. Fecal continence was preserved, and colostomy reversal is feasible. PATIENT SUMMARY: We analyzed the outcomes, complications, and colostomy reversal rate of the York Mason procedure for the repair of rectourethral fistulas (RUFs). We found that concomitant graciloplasty increases success rates in case of prior radiation therapy. Colostomy reversal is feasible after RUF repair.

Concurrent Radiotherapy and Panitumumab after Lymph Node Dissection and Induction Chemotherapy for Invasive Bladder Cancer.

PURPOSE: In this prospective study we evaluated the safety and efficacy of concurrent radiotherapy and panitumumab following neoadjuvant/induction chemotherapy and pelvic lymph node dissection as a bladder preserving therapy for invasive bladder cancer. MATERIALS AND METHODS: Patients with cT1-4N0-2M0 bladder cancer were treated with pelvic lymph node dissection and 4 cycles of platinum based induction chemotherapy followed by a 6½-week schedule of weekly panitumumab (2.5 mg/kg) and concurrent radiotherapy to the bladder (33 × 2 Gy). As the primary objective we compared concurrent radiotherapy and panitumumab toxicity to a historical control toxicity rate of concurrent cisplatin/radiotherapy (less than 35% of patients with Grade 3-5 toxicity). A sample size of 31 patients was estimated. Secondary end points included complete remission at 3-month followup, the bladder preservation rate, EGFR (epidermal growth factor receptor) expression and RAS mutational status. RESULTS: Of the 38 cases initially included in this study 34 were staged cN0. After pelvic lymph node dissection 7 cases (21%) were up staged to pN+. Of the 38 patients 31 started concurrent radiotherapy and panitumumab. During concurrent radiotherapy and panitumumab 5 patients (16%, 95% CI 0-31) experienced systemic or local grade 3-4 toxicity. Four patients did not complete treatment due to adverse events. Complete remission was achieved in 29 of 31 patients (94%, 95% CI 83-100). At a median followup of 34 months 4 patients had local recurrence, for which 3 (10%) underwent salvage cystectomy. Two tumors showed EGFR or RAS mutation while 84% showed positive EGFR expression. CONCLUSIONS: Concurrent radiotherapy and panitumumab following induction chemotherapy and pelvic lymph node dissection has a safety profile that is noninferior to the historical profile of concurrent cisplatin/radiotherapy. The high complete remission and bladder preservation rates are promising and warrant further study.

Divergent Biological Response to Neoadjuvant Chemotherapy in Muscle-invasive Bladder Cancer.

PURPOSE: After cisplatin-based neoadjuvant chemotherapy (NAC), 60% of patients with muscle-invasive bladder cancer (MIBC) still have residual invasive disease at radical cystectomy. The NAC-induced biological alterations in these cisplatin-resistant tumors remain largely unstudied. EXPERIMENTAL DESIGN: Radical cystectomy samples were available for gene expression analysis from 133 patients with residual invasive disease after cisplatin-based NAC, of whom 116 had matched pre-NAC samples. Unsupervised consensus clustering (CC) was performed and the consensus clusters were investigated for their biological and clinical characteristics. Hematoxylin & Eosin and IHC on tissue microarrays were used to confirm tissue sampling and gene expression analysis. RESULTS: Established molecular subtyping models proved to be inconsistent in their classification of the post-NAC samples. Unsupervised CC revealed four distinct consensus clusters. The CC1-Basal and CC2-Luminal subtypes expressed genes consistent with a basal and a luminal phenotype, respectively, and were similar to the corresponding established pretreatment molecular subtypes. The CC3-Immune subtype had the highest immune activity, including T-cell infiltration and checkpoint molecule expression, but lacked both basal and luminal markers. The CC4-Scar-like subtype expressed genes associated with wound healing/scarring, although the proportion of tumor cell content in this subtype did not differ from the other subtypes. Patients with CC4-Scar-like tumors had the most favorable prognosis. CONCLUSIONS: This study expands our knowledge on MIBC not responding to cisplatin by suggesting molecular subtypes to understand the biology of these tumors. Although these molecular subtypes imply consequences for adjuvant treatments, this ultimately needs to be tested in clinical trials.

Prostate sparing cystectomy for bladder cancer: A two-center study.

PURPOSE: To assess long-term functional and oncologic outcomes of prostate sparing cystectomy (PSC) as a sexuality-preserving alternative to radical cystectomy in a selected group of bladder cancer (BC) patients. MATERIALS AND METHODS: Between 1995 and 2014, 185 BC patients underwent PSC according to one of two standardized procedures at two centers. All patients had received extensive evaluation to rule out prostate cancer and BC at the bladder neck and prostatic urethra (PU), including prostate specific antigen blood analysis, transrectal ultrasound and/or prostate biopsies, PU biopsies and/or PU frozen section analysis. All patients received an orthotopic ileal neobladder. Overall survival (OS) was assessed by Kaplan-Meier estimates. Cumulative incidence of cancer specific mortality, any recurrence and loco-regional recurrence were calculated using competing-risk methods. Finally, functional outcomes (voiding, continence and erectile function) were evaluated. RESULTS: 185 patients (cTa-3N0M0) with a mean age of 57 years (SD: 9) were included. Median follow-up was 7.5 years (IQR: 5.6-10.8). Five-year OS was 71% and 5-year cumulative incidence of recurrence was 31%. Twenty patients (10.8%) had a loco-regional recurrence, two recurrences were in the PU. During follow-up, prostate cancer was detected in six patients (3.2%). Erectile function was preserved in 86.1% of patients, complete daytime and nighttime continence in 95.6% and 70.2%, respectively. CONCLUSION: This two-center study shows that in men with BC in whom the prostate and PU were proven free of malignancy, PSC would represent a valid treatment option with excellent functional outcome. Oncologic outcomes were comparable to what is known from radical cystoprostatectomy series.

Metric substage according to micro and extensive lamina propria invasion improves prognostics in T1 bladder cancer.

BACKGROUND: Reliable prognosticators for T1 bladder cancer (T1BC) are urgently needed. OBJECTIVE: To compare the prognostic value of 2 substage systems for T1BC in patients treated by transurethral resection (TUR) and adjuvant bacillus Calmette-Guérin therapy. DESIGN, SETTING, AND PARTICIPANTS: The slides of 601 primary T1BCs from four institutes were reviewed by 2 uropathologists and substaged according to 2 classifications: metric substage according to T1 microinvasive (T1m-lamina propria invasion <0.5mm) and T1 extensive invasive (pT1e-invasion ≥ 0.5mm), and according to invasion of the muscularis mucosae (MM) (T1a-invasion above or into MM/T1b). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable analyses for progression-free (PFS) and cancer-specific survival (CSS) were performed including substage, size, multiplicity, carcinoma in situ, sex, age, WHO-grade 1973, and WHO-grade 2004 as variables. RESULTS: Median follow-up was 5.9 years (interquartile range: 3.3-9.0). Progression to T2BC was observed in 148 (25%) patients and 94 (16%) died of BC. The MM was not present at the invasion front in 135 (22%) of tumors. Slides were substaged as follows: 213 T1m and 388 T1e and 281 T1a and 320 T1b. On multivariable analysis, T1m/e substage and WHO 1973 grade were the strongest prognosticators for PFS (hazard ratio [HR] = 3.8 and HR = 1.8) and CSS (HR = 2.7 and HR = 2.6), respectively. Other prognostic factors for CSS were age (HR = 1.03), and tumor size (HR = 1.8). Substage according to MM-invasion was not significant. Our study was limited by its retrospective design and that standard re-TUR was not performed if TUR was macroscopically complete and muscularis propria was present in resected specimens. CONCLUSIONS: Metric substaging of T1BC was possible in all cases of 601 T1BC patients and it was a strong independent prognosticator of both PFS and CSS.

Reproducibility and Prognostic Performance of the 1973 and 2004 World Health Organization Classifications for Grade in Non-muscle-invasive Bladder Cancer: A Multicenter Study in 328 Bladder Tumors.

BACKGROUND: Histologic grade is an important prognosticator in patients with non-muscle-invasive bladder cancer (NMIBC). Currently, 2 classifications for grade are widely used; the World Health Organization (WHO) 1973 and the WHO 2004. We compare inter-observer variability of both classifications and investigate which histologic criteria cause this variability. Furthermore, the prognostic value of both classifications was assessed. PATIENTS AND METHODS: Three pathologists reviewed 328 bladder tissue samples of 232 patients with NMIBC in a blinded manner. WHO 1973 grade, WHO 2004 grade, histologic criteria of both classifications, and T-category were evaluated. Reproducibility was analyzed using the weighted Fleiss κ, association between criteria scores and grade with the χ2 test, and time-to-recurrence and time-to-progression with the log-rank test and Cox regression. RESULTS: Reproducibility of both classifications was poor. The WHO 2004 showed better reproducibility (κ = 0.35; 95% confidence interval (CI), 0.29-0.42) compared with the WHO 1973 as a 3-tiered (κ = 0.24; 95% CI, 0.19-0.28), but not as a 2-tiered (G1 + G2 vs. G3) classification (κ = 0.36; 95% CI, 0.29-0.42). Reproducibility of individual criteria was poor (κ range, -0.05 to 0.25). All criteria were associated with grade (P < .05). After a median follow-up of 60 months, 33 of 232 and 112 of 232 patients developed progression and recurrence, respectively. In 1 out of the 3 pathologists, progression was predicted by both the WHO 1973 grade and the WHO 2004 grade in multivariable analysis. Recurrence was not predicted by grade (multivariable). CONCLUSIONS: Reproducibility of the WHO 2004 and WHO 1973 classification for grade are poor. Scoring of individual criteria is poorly reproducible, suggesting that descriptions of these criteria for grade are not specific. The prognostic value of both the WHO 1973 and the WHO 2004 differ per pathologist.

Endo-Urological Techniques for Benign Uretero-Ileal Strictures Have Poor Efficacy and Affect Renal Function.

INTRODUCTION: Uretero-ileal strictures (UES) following urinary diversion are therapeutically challenging. We compared the efficacy, safety and renal outcome following therapeutic endo-urological techniques (EUTs) and open surgical revision of the anastomosis (SRA) for UES. MATERIAL AND METHODS: We retrospectively analysed all EUTs and SRAs performed for UES in 2 hospitals between 1987 and 2015. Restenosis was defined as recurrent radiographically diagnosed hydronephrosis and re-intervention. Renal function (estimated glomerular filtration rate [eGFR]) decrease was correlated with the number of EUTs per patient. RESULTS: Eighty-five UES were treated with 105 EUTs and 31 open revisions. Due to total obstruction, 28 (27%) EUTs were aborted. During a median follow-up of 33 months, restenosis occurred following 53 out of 77 (69%) completed EUTs and 4 out of 31 (13%) SRAs (p < 0.001 on univariable and multivariable analyses). No serious (Clavien ≥3b) EUT-related complications occurred vs. 5 (19%) related to SRA (p < 0.001). The number of finalised EUTs was independently associated with eGFR loss (ß = 12.3 mL/min/1.73 m2 loss per EUT, p = 0.008), with a significant cutoff value of >1 EUTs. SRA did not affect renal function (ß = 6.8 mL/min/1.73 m2 loss, p = 0.276). CONCLUSIONS: Although EUTs are less invasive, they have an inferior efficacy to SRA. Our results suggest that a maximum of one EUT may be attempted without significantly compromising renal function.

Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy.

BACKGROUND: An early report on the molecular subtyping of muscle-invasive bladder cancer (MIBC) by gene expression suggested that response to neoadjuvant chemotherapy (NAC) varies by subtype. OBJECTIVE: To investigate the ability of molecular subtypes to predict pathological downstaging and survival after NAC. DESIGN, SETTING, AND PARTICIPANTS: Whole transcriptome profiling was performed on pre-NAC transurethral resection specimens from 343 patients with MIBC. Samples were classified according to four published molecular subtyping methods. We developed a single-sample genomic subtyping classifier (GSC) to predict consensus subtypes (claudin-low, basal, luminal-infiltrated and luminal) with highest clinical impact in the context of NAC. Overall survival (OS) according to subtype was analyzed and compared with OS in 476 non-NAC cases (published datasets). INTERVENTION: Gene expression analysis was used to assign subtypes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Receiver-operating characteristics were used to determine the accuracy of GSC. The effect of GSC on survival was estimated by Cox proportional hazard regression models. RESULTS AND LIMITATIONS: The models generated subtype calls in expected ratios with high concordance across subtyping methods. GSC was able to predict four consensus molecular subtypes with high accuracy (73%), and clinical significance of the predicted consensus subtypes could be validated in independent NAC and non-NAC datasets. Luminal tumors had the best OS with and without NAC. Claudin-low tumors were associated with poor OS irrespective of treatment regimen. Basal tumors showed the most improvement in OS with NAC compared with surgery alone. The main limitations of our study are its retrospective design and comparison across datasets. CONCLUSIONS: Molecular subtyping may have an impact on patient benefit to NAC. If validated in additional studies, our results suggest that patients with basal tumors should be prioritized for NAC. We discovered the first single-sample classifier to subtype MIBC, which may be suitable for integration into routine clinical practice. PATIENT SUMMARY: Different molecular subtypes can be identified in muscle-invasive bladder cancer. Although cisplatin-based neoadjuvant chemotherapy improves patient outcomes, we identified that the benefit is highest in patients with basal tumors. Our newly discovered classifier can identify these molecular subtypes in a single patient and could be integrated into routine clinical practice after further validation.

Pathological downstaging and survival after induction chemotherapy and radical cystectomy for clinically node-positive bladder cancer-Results of a nationwide population-based study.

BACKGROUND: Induction chemotherapy (IC) for clinically node-positive bladder cancer is applied without clinical evidence of improved outcome. Our objective was to compare complete pathological downstaging (pCD) and overall survival (OS) for IC versus upfront radical cystectomy (RC) in cT1-4aN1-3M0 urothelial carcinoma (UC). METHODS: This population-based study included 659 cN+ patients treated with RC between 1995 and 2013. IC was applied in 212 (32%) patients. We defined pCD as ≤(y)pT1N0 at RC. Multivariable analyses were preformed to identify independent predictors of pCD and OS. RESULTS: In cN1 and cN2-3 patients, 31% and 19% of patients proved to be pN0 at upfront RC. In cN1, pCD was achieved in 39% following IC versus 5% for upfront RC (P < 0.001). In cN2-3 UC, rates were 27% versus 3% (P < 0.001). Three-year OS for pCD and ypCD were 81% and 84%, respectively. Three-year OS rates were 66% versus 37% (cN1) and 43% versus 22% (cN2-3), again in favour of IC (P < 0.001). In multivariable analyses, IC was associated with pCD (Odds ratio, 14; 95% confidence interval [CI], 7.4-25) and a 53% decreased risk of death (Hazard ratio [HR], 0.47; 95% CI, 0.36-0.61). Indication bias and unequal distributions of factors associated with OS (e.g. patients proceeding to RC) limit interpretation of our results. CONCLUSIONS: Patients with clinical nodal involvement should not be neglected. Up to 1/4 of patients with cN+ disease had pN0 at upfront RC. Moreover, IC followed by RC for clinically node-positive UC was associated with improved pathological downstaging compared with RC alone. A potential OS benefit for IC needs to be validated in a randomised trial. TAKE HOME MESSAGE: IC followed by RC for clinically node-positive UC is associated with improved pathological downstaging compared with RC alone. A potential OS benefit for IC needs to be validated in a randomised trial.

Elevated Derived Neutrophil-to-Lymphocyte Ratio Corresponds With Poor Outcome in Patients Undergoing Pre-Operative Chemotherapy in Muscle-Invasive Bladder Cancer.

Background: Platinum-based pre-operative chemotherapy (POC) for muscle-invasive bladder cancer (MIBC) increases the complete pathological response rate at cystectomy and improves overall survival. However, 60% of MIBC patients still has muscle-invasive disease at cystectomy despite POC. Therefore, accurate prediction of response to POC is an important clinical need. We hypothesized that an elevated neutrophil-to-lymphocyte ratio (NLR) corresponds with adverse outcome in patients undergoing POC and radical cystectomy. Objective: To explore the correlation between the NLR and outcome in MIBC patients treated by POC and radical cystectomy. Methods: In 123 MIBC patients (urothelial carcinoma) who were treated by platinum-based POC and radical cystectomy, the derived NLR (dNLR) was retrospectively calculated by dividing the neutrophil count by the difference between leukocytes and neutrophil counts, prior to the start of chemotherapy. The correlation of the dNLR with pathological response at cystectomy and survival was analyzed by logistic regression analysis or the Kaplan-Meier method. Results: The complete pathological response (ypT0N0Mx) rate was 28.5%, 8.9% obtained a partial response (ypTa/T1/TisN0Mx), and 62.6% were non-responders (stage ≥ ypT2 and/or N+). An elevated dNLR (>2.21) correlated with non-response to POC (OR 2.70, 95% confidence interval: 1.15-6.38, p = 0.02) but this effect was nullified when corrected for clinically node-positive disease and clinical T stage. Patients with an elevated dNLR had shorter progression-free and overall survival albeit non-significant (p = 0.42, and p = 0.45, respectively). Conclusions: An elevated dNLR corresponded with poor outcome in terms of survival and non-response to POC in MIBC patients undergoing radical surgery. However, after correction for well-known prognostic factors, such as positive lymph node status at diagnostic imaging and clinical T stage, the correlation for the dNLR was nullified. Therefore, we conclude that the dNLR is insufficient to predict response to POC in this heterogeneous patient population.

Incidence, Characteristics and Implications of Thromboembolic Events in Patients with Muscle Invasive Urothelial Carcinoma of the Bladder Undergoing Neoadjuvant Chemotherapy.

PURPOSE: Neoadjuvant chemotherapy and pelvic surgery are significant risk factors for thromboembolic events. Our study objectives were to investigate the timing, incidence and characteristics of thromboembolic events during and after neoadjuvant chemotherapy and subsequent radical cystectomy in patients with muscle invasive bladder cancer. MATERIALS AND METHODS: We performed a multi-institutional retrospective analysis of 761 patients who underwent neoadjuvant chemotherapy and radical cystectomy for muscle invasive bladder cancer from 2002 to 2014. Median followup from diagnosis was 21.4 months (range 3 to 272). Patient characteristics included the Khorana score, and the incidence and timing of thromboembolic events (before vs after radical cystectomy). Survival was calculated using the Kaplan-Meier method. The log rank test and multivariable Cox proportional hazards regression were used to compare survival between patients with vs without thromboembolic events. RESULTS: The Khorana score indicated an intermediate thromboembolic event risk in 88% of patients. The overall incidence of thromboembolic events in patients undergoing neoadjuvant chemotherapy was 14% with a wide variation of 5% to 32% among institutions. Patients with thromboembolic events were older (67.6 vs 64.6 years, p = 0.02) and received a longer neoadjuvant chemotherapy course (10.9 vs 9.7 weeks, p = 0.01) compared to patients without a thromboembolic event. Of the thromboembolic events 58% developed preoperatively and 72% were symptomatic. On multivariable regression analysis the development of a thromboembolic event was not significantly associated with decreased overall survival. However, pathological stage and a high Khorana score were adverse risk factors for overall survival. CONCLUSIONS: Thromboembolic events are common in patients with muscle invasive bladder cancer who undergo neoadjuvant chemotherapy before and after radical cystectomy. Our results suggest that a prospective trial of thromboembolic event prophylaxis during neoadjuvant chemotherapy is warranted.

Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer: A Systematic Review and Two-Step Meta-Analysis.

BACKGROUND: Platinum-based neoadjuvant chemotherapy has been shown to improve survival outcomes in muscle-invasive bladder cancer patients. We performed a systematic review and meta-analysis to provide updated results of previous findings. We also summarized published data to compare clinical outcomes of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) versus gemcitabine and cisplatin/carboplatin (GC) in the neoadjuvant setting. METHODS: A meta-analysis of 15 randomized clinical trials was performed to compare neoadjuvant chemotherapy plus local treatment with the same local treatment alone. Because no randomized trials have investigated MVAC versus GC in the neoadjuvant setting, a meta-analysis of 13 retrospective studies was performed to compare MVAC with GC. RESULTS: A total of 3,285 patients were included in 15 randomized clinical trials. There was a significant overall survival (OS) benefit associated with cisplatin-based neoadjuvant chemotherapy (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79-0.96). A total of 1,766 patients were included in 13 retrospective studies. There was no significant difference in pathological complete response between MVAC and GC. However, GC was associated with a significantly reduced overall survival (HR, 1.26; 95% CI, 1.01-1.57). After excluding carboplatin data, GC still seemed to be inferior to MVAC in OS (HR, 1.31; 95% CI, 0.99-1.74), but the difference was no longer statistically significant. CONCLUSION: These results support the use of cisplatin-based combination neoadjuvant chemotherapy in muscle-invasive bladder cancer. Although GC and MVAC had similar treatment response rates, the different survival outcome observed in this study requires further investigation. IMPLICATIONS FOR PRACTICE: Platinum-based neoadjuvant chemotherapy (NCT) has been shown to improve survival outcomes in muscle-invasive bladder cancer (MIBC) patients, but the optimal neoadjuvant regimen has not been established. Methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) and gemcitabine and cisplatin/carboplatin (GC) are two of the most commonly used chemotherapy regimens in modern oncology. In this two-step meta-analysis, an updated and more precise estimate of the survival benefit of cisplatin-based NCT in MIBC is provided. This study also demonstrated that MVAC might have superior overall survival compared with GC (with or without carboplatin data) in the neoadjuvant setting. The findings suggest that NCT should be standard care in MIBC, and MVAC could be the preferred neoadjuvant regimen.

Clinical Relevance of Incidental Prostatic Lesions on FDG-Positron Emission Tomography/Computerized Tomography-Should Patients Receive Further Evaluation?

PURPOSE: FDG ((18)F-fluoro-2-deoxy-D-glucose)-PET/CT (positron emission tomography)/(computerized tomography) is a widely used diagnostic tool for whole body imaging. Incidental prostatic uptake is often found on FDG-PET/CT. The objective of this study was to determine the clinical relevance of incidental prostatic uptake on FDG-PET/CT. MATERIALS AND METHODS: We analyzed 108 consecutive male patients with bladder cancer who underwent FDG-PET/CT and subsequently radical cystoprostatectomy between May 2009 and November 2014. PET/CT scans were blindly reviewed by a dedicated nuclear medicine physician for incidental prostatic FDG uptake. If present, the maximum standardized uptake value was determined. Subsequently incidental prostatic uptake was categorized as suspect, indeterminate or nonsuspect for prostate cancer. RESULTS: Incidental prostatic uptake was present in 43 of 108 patients (40%). Of these 43 patients 13 (30%) had occult prostate cancer in cystoprostatectomy specimens. Overall prostate cancer was found in 25 of 108 specimens (23%). If all incidental prostatic uptake was regarded as prostate cancer, the sensitivity and specificity of FDG-PET/CT for prostate cancer detection were 52% and 64%, respectively. Positive and negative predictive values were 30% and 82%, respectively. If only lesions labeled suspect or indeterminate were regarded as prostate cancer, sensitivity, specificity, and positive and negative predictive values were 32%, 76%, 29% and 79%, respectively. Categorizing indeterminate lesions as nonprostate cancer did not improve diagnostic accuracy. Gleason score did not correlate with maximum standardized uptake value or serum prostate specific antigen. CONCLUSIONS: Incidental prostatic uptake on FDG-PET/CT has a low positive predictive value for prostate cancer. An attempt to classify lesions as suspect or nonsuspect did not increase diagnostic accuracy. Based on these results physicians should be cautious about applying invasive diagnostic methods to detect prostate cancer in case of incidental prostatic uptake on FDG-PET/CT.

ERBB2 Mutations Characterize a Subgroup of Muscle-invasive Bladder Cancers with Excellent Response to Neoadjuvant Chemotherapy.

UNLABELLED: A pathologic complete response to neoadjuvant chemotherapy (NAC) containing platinum is a strong prognostic determinant for patients with muscle-invasive bladder cancer (MIBC). Despite comprehensive molecular characterization of bladder cancer, associations of molecular alterations with treatment response are still largely unknown. We selected pathologic complete responders (ypT0N0; n=38) and nonresponders (higher than ypT2; n=33) from a cohort of high-grade MIBC patients treated with NAC. DNA was isolated from prechemotherapy tumor tissue and used for next-generation sequencing of 178 cancer-associated genes (discovery cohort) or targeted sequencing (validation cohort). We found that 9 of 38 complete responders had erb-b2 receptor tyrosine kinase 2 (ERBB2) missense mutations, whereas none of 33 nonresponders had ERBB2 mutations (p=0.003). ERBB2 missense mutations in complete responders were mostly confirmed activating mutations. ERCC2 missense mutations, recently found associated with response to NAC, were more common in complete responders; however, this association did not reach statistical significance in our cohort. We conclude that ERBB2 missense mutations characterize a subgroup of MIBC patients with an excellent response to NAC. PATIENT SUMMARY: In this report we looked for genetic alterations that can predict the response to neoadjuvant chemotherapy (NAC) in bladder cancer. We found that mutations in the gene ERBB2 are exclusively present in patients responding to NAC.

Perioperative treatment and radical cystectomy for bladder cancer--a population based trend analysis of 10,338 patients in the Netherlands.

BACKGROUND: In Europe, population-based data concerning perioperative treatment (PT) and radical cystectomy (RC) are lacking. We assessed temporal trends in PT (neoadjuvant chemotherapy [NAC], neoadjuvant radiotherapy [NAR], adjuvant chemotherapy [AC], adjuvant radiotherapy [AR]) and RC in the Netherlands and identified patients' and hospital characteristics associated with PT. METHODS: This nationwide, retrospective, population-based study included cTa/is, T1-4, N0-3, M0-1 bladder cancer patients from the Netherlands Cancer Registry who underwent RC with curative intent between 1995 and 2013. PT-administration over time was compared with chi-square tests. Multivariable logistic regression analyses were performed to identify characteristics associated with PT usage. The sub-groups cT2-4N0M0 and cT2-4, N0 or NX, M0 or MX were separately analysed. RESULTS: In total, 10,338 patients met inclusion criteria. Eighty-six percent did not receive PT, 7.0% received NAC (or induction chemotherapy [IC]), 3.2% NAR, 1.8% AC, and 2.1% AR. NAC usage increased from 0.6% in 1995 to 21% in 2013 (p < 0.001), application of NAR decreased from 15% to 0.4% (p < 0.001). Usage of AC and AR in 2013 was <1.5%. Comparable temporal trends were found in 6032 patients staged cT2-4N0M0. Multivariable logistic regression analysis revealed that younger age, ≥ cT3, ≥ cN1 and treatment in academic/teaching hospitals were associated with NAC or IC (all p < 0.05). CONCLUSIONS: The increase in NAC administration in the Netherlands reflects a slow but steady adoption of evidence-based guidelines over the last two decades. Considerable variability in patients' and hospital characteristics in the likelihood of receiving NAC exists. Conversely, NAR, AR and AC are hardly administered anymore.

Lymph node count at radical cystectomy does not influence long-term survival if surgeons adhere to a standardized template.

INTRODUCTION: Multiple bladder cancer studies report that the number of removed lymph nodes (lymph node count [LNC]) at radical cystectomy (RC) is positively associated with survival. Although these reports suggest that LNC can be used as a proxy for surgical quality, all studies used variable or inconsistent pelvic lymph node dissection (PLND) templates. We therefore wished to establish whether LNC at RC influences survival if surgeons adhere to a standardized PLND template. MATERIALS AND METHODS: We included 274 patients who underwent RC from January 2005 until December 2012. All RCs were performed in either one of 2 hospitals (hospital A or B) by the same 4 urologists (all from hospital A) and a standardized PLND template was applied. PLND specimens were processed by 2 independent pathology departments (hospital A and B). We used Cox regression analysis to investigate the prognostic value of LNC adjusted for patient characteristics. We also compared LNC between hospitals and surgeons and investigated the effect of both the variables on overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS). RESULTS: Median LNC was 17 (interquartile range = 12). At a median follow-up of 64.3 months, there was no association between LNC and OS (P = 0.328), CSS (P = 0.645), or DFS (P = 0.450). Median LNC was higher in hospital B than in hospital A (20.0 vs. 16.0, P = 0.003). Median LNC varied significantly among surgeons (12-20, P<0.001). Neither the hospital of surgery nor the surgeon performing PLND influenced OS (P = 0.771 and P = 0.982, respectively), CSS (P = 0.310 and P = 0.691, respectively), or DFS (P = 0.256 and P = 0.296, respectively). CONCLUSION: If surgeons adhere to a standardized template, LNC at RC does not affect long-term survival.

Prognostic significance of substage and WHO classification systems in T1 urothelial carcinoma of the bladder.

PURPOSE OF REVIEW: Treatment of T1 urothelial bladder cancer (T1-BC) is challenging as risk assessment criteria for progression are lacking. Histological grade and T1 substage have been identified as important prognostic factors. Currently, no consensus exists regarding the optimal sub-staging and grading systems for T1-BC. We reviewed recent advances in the various grading and sub-staging systems and their clinical applicability. RECENT FINDINGS: Stratification by muscularis mucosae invasion is the most explored sub-staging system. Its prognostic value was established by 12/23 (52%) available studies. Importantly, muscularis mucosae identification varied substantially among pathologists. Sub-staging based on diameter of invasive carcinoma [T1 microinvasive and T1 extensive-invasive (T1m/e)] proved a more reproducible system with at least equal prognostic value. However, more study is needed to investigate interobserver variation. For nonmuscle-invasive bladder cancer grading, the 1973 and 2004 WHO classifications both provide independent prognostic information. However, remarkably few studies have investigated their applicability in T1-BC only. The available reports suggest that the 1973 WHO classification is superior to WHO 2004. SUMMARY: If multicenter studies confirm the promising results of T1m/e sub-staging, it may be incorporated in the Internation Union Against Cancer TNM classification system for urinary bladder cancer. More studies are warranted to define the optimal classification system for grade in T1-BC.