B. Van Rhijn

Standard lymph node dissection for bladder cancer: significant variability in the number of reported lymph nodes.

PURPOSE We compared the nodal yield after histopathological examination of extended bilateral pelvic lymph node dissection specimens for bladder cancer at 2 hospitals. Surgery at each hospital was done by the same 4 staff urologists using a standardized extended bilateral pelvic lymph node dissection template. MATERIALS AND METHODS All consecutive patients with bladder cancer who underwent extended bilateral pelvic lymph node dissection from January 1, 2007 to December 31, 2009 were included in this study. Specimens were sent for pathological evaluation in a minimum of 2 packages per side. At the 2 pathology departments specimens were processed according to institutional protocols. RESULTS A total of 174 patients with a mean age of 62.7 years were included in analysis. At hospital 1 a mean of 16 lymph nodes were found after dissection vs a mean of 28 reported at hospital 2 (p <0.001). No significant differences were found in the number of tumor positive lymph nodes (p = 0.65). Mean lymph node density at hospitals 1 and 2 was 9.3% and 3.9%, respectively (p = 0.056). CONCLUSIONS Despite equal anatomical clearance by the same experienced surgeons we report a statistically significant difference between 2 pathology departments where the number of lymph nodes was evaluated after extended bilateral pelvic lymph node dissection for bladder cancer. Unless standardized methods are agreed on by pathologists, the number of reported lymph nodes as an indicator of surgical quality and lymph node density as a prognostic factor should be used cautiously.

Response to induction chemotherapy and surgery in non-organ confined bladder cancer: A single institution experience

AIM To evaluate the outcome of patients with locally advanced muscle-invasive and/or lymph node positive bladder cancer treated with induction chemotherapy and additional surgery. METHODS All patients who were treated with induction chemotherapy in our institution between 1990 and 2010, were retrospectively evaluated using an institutional database. Induction chemotherapy consisted of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC), or a combination of gemcitabine with either cisplatin or carboplatin (GC). RESULTS In total 152 patients were identified, with a mean age of 59 years (range 31-76). One hundred and seven patients (70.4%) received MVAC, 35 patients received GC (23.0%) and 10 patients received GC after initial treatment with MVAC (6.6%). Median follow-up was 68 months (range 4-187 months). Overall 125 patients (82.2%) underwent cystectomy, whereas 12 patients (7.9%) received radiotherapy. Fifteen patients had no local treatment. Median overall survival was 18 months (95%CI 15-23 months). In 37.5% of patients with complete clinical response, residual disease was found at surgery (positive predictive value, PPV 62.5%). Complete pathological response was seen in 26.3% of patients, with a 5 year overall survival (OS) estimate of 54% (39%-74%). For patients with persisting node positive disease after induction chemotherapy and surgery OS was significantly worse (p < 0.0001). CONCLUSIONS Complete clinical and/or pathological response to induction chemotherapy results in a significant survival benefit. The accuracy of the current clinical response evaluation after induction chemotherapy is limited. Although surgery may be important for staging and prognostic purposes, its role is unclear in node positive disease after induction chemotherapy.

Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: implications for perioperative anti-FGFR3 treatment

BACKGROUND Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response. PATIENTS AND METHODS We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201). RESULTS We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type. CONCLUSIONS FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting.

Presence of carcinoma in situ and high 2c-deviation index are the best predictors of invasive transitional cell carcinoma of the bladder in patients with high-risk Quanticyt

OBJECTIVES Karyometric analysis (Quanticyt) has proved of value as a cytologic marker for bladder cancer. This study was conducted to identify diagnostic and prognostic factors in a high-risk Quanticyt population to predict the prognosis of transitional cell carcinoma (TCC) of the bladder. METHODS Quanticyt is a karyometric system for quantitative bladder wash cytologic findings based on two nuclear features: the 2c-deviation index (2cDI) and the mean of nuclear shape. Samples are scored as low, intermediate, or high risk. Before 1995, 109 patients with high-risk quantitative bladder wash cytologic findings were identified at our clinic. Four patients with previous invasive tumors were excluded. RESULTS Histologically proven malignancy was found in 54 of 105 patients at first high-risk quantitative bladder wash cytologic findings. Invasive TCC was found in 16 patients, and another 10 patients had progression during a median follow-up of 3.7 years. In univariate analysis, the presence of carcinoma in situ (CIS), highest tumor grade, 2cDI, and highest tumor stage were significant predictors of progression. The presence of CIS proved to be the only predictor of progression in the multivariate analysis. A 2cDI of 2.00 c(2) or higher was a significant predictor of CIS, invasive TCC, and progression. At follow-up analysis after negative cystoscopy, 2cDI showed a tendency toward predicting progression. CONCLUSIONS These data confirm earlier findings that CIS is an important marker of progression. 2cDI as assessed by quantitative cytology is a practical tool to predict CIS, invasive TCC, and subsequent progression. A 2cDI of 2. 00 c(2) can be used to further stratify high-risk quantitative bladder wash cytologic findings.

Consecutive quantitative cytology in bladder cancer

OBJECTIVES Quantitative cytology (Quanticyt) provides an objective reproducible alternative for routine cytology. To increase the sensitivity of cytology, we studied the application of consecutive cytology in patients in follow-up for superficial bladder cancer. METHODS Between 1991 and 1998, a set of five or more bladder wash samples was obtained from 614 patients. These patients were retrospectively studied for follow-up data. Each sample was scored according to the Quanticyt risk score. RESULTS In 614 patients (508 men, 106 women), 5832 bladder wash samples were taken. The mean interval between the first and fifth sample per patient was 21.5 months (SD 13.8 months). The mean number of tumor recurrences per patient was 2.17 (SD 1.82). The risk score of the first sample was not predictive of recurrence. Invasive disease was found in 0%, 0%, and 0.8% of patients with one low, intermediate, and high-risk sample, respectively. After five samples, the corresponding rate was 0%, 0%, and 10%. A comparison of visual cytology and quantitative cytology revealed that the false-negative rate was significantly different (17% versus 3.8%). The positive predictive value was highest for visual cytology (17% versus 9.2%). CONCLUSIONS Adding consecutive quantitative cytology to urine cytopathologic evaluation improves the detection rate of high-grade lesions. Combining quantitative cytology and visual cytology provided a more accurate prediction of tumor stage.

1001 The impact of re-TUR on clinical outcomes in a large cohort of t1g3 patients treated with BCG

INTRODUCTION AND OBJECTIVES: Low risk non-muscle invasive bladder cancer (NMIBC) is an heterogeneous neoplasm, characterized by a high percentage of recurrences but a low tendency of progression. In this group of patients, overtreatment posts and impact in the quality of life and it implies high significant economical costs and an important deterioration of the quality of life, without evidence of improving their survival. Therefore, it seems reasonable to develop a program based on surveillance and monitoring of new recurrences. Our aim is to report our experience with low-risk bladder cancer patients under an active surveillance program after cancer recurrence, and to analyse which variables might help to predict progression. METHODS: From 2006 we have offered the option of active surveillance to all low risk tumours at time of recurrence. Follow-up included flexible cystoscopy and cytology every six months. TUR was performed when tumour size or number of lesions increased, at high grade cytology, when hematuria, tumour aspect worsened or patients’ choice. RESULTS: 68 patients were included. Mean age at recurrence was 71.5 years. Only 13,2% were female. Almost all patients received immediate postoperative mytomicin C (96%). Histological initial features were stage pTa in 48.5%, stage pT1a in 25%, pTx in 7.4% and PUNLMP in 17.6%; all were low grade. Mean time between TUR and recurrence was 33 months. The mean follow-up was 25,8 months. 32 (47%) patients underwent TUR after recurrence (mean time 20 months). Main cause of TUR (50%) was the increase of the number of lesions and tumor size, 18% due to hematuria, 6% to positive citology. Concerning recurrence features, 80% were single tumors and size was 5 mm in 60%. Seven patients (21.87%) progressed in stage (pTa to pT1a) (4) or grade (3). All patients with progression, tumor size was 5 mm or had positive cytology. None of our patients progressed to muscle invasive bladder cancer. CONCLUSIONS: Patients with recurrent, small, non muscleinvasive bladder tumours can be safely offered monitoring under an active surveillance protocol. Active surveillance can be safely considered in patients with less than 5mm recurrence or negative cytology.

Prognostic factors and risk groups in T1G3 patients initially treated with BCG: Results of a multicenter retrospective series in 1743 patients

Prognostic Factors And Risk Groups In T1g3 Patients Initially Treated With Bcg : Results Of A Multicenter Retrospective Series In 1743 Patients

Concomitant CIS on TURBT does not impact oncological outcomes in patients treated with neoadjuvant or induction chemotherapy followed by radical cystectomy

BackgroundCisplatin-based neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer improves all-cause and cancer specific survival. We aimed to evaluate whether the detection of carcinoma in situ (CIS) at the time of initial transurethral resection of bladder tumor (TURBT) has an oncological impact on the response to NAC prior to radical cystectomy.Patients and methodsPatients were identified retrospectively from 19 centers who received at least three cycles of NAC or induction chemotherapy for cT2-T4aN0-3M0 urothelial carcinoma of the bladder followed by radical cystectomy between 2000 and 2013. The primary and secondary outcomes were pathological response and overall survival, respectively. Multivariable analysis was performed to determine the independent predictive value of CIS on these outcomes.ResultsOf 1213 patients included in the analysis, 21.8% had concomitant CIS. Baseline clinical and pathologic characteristics of the ‘CIS’ versus ‘no-CIS’ groups were similar. The pathological response did not differ between the two arms when response was defined as pT0N0 (17.9% with CIS vs 21.9% without CIS; p = 0.16) which may indicate that patients with CIS may be less sensitive to NAC or ≤ pT1N0 (42.8% with CIS vs 37.8% without CIS; p = 0.15). On Cox regression model for overall survival for the cN0 cohort, the presence of CIS was not associated with survival (HR 0.86 (95% CI 0.63–1.18; p = 0.35). The presence of LVI (HR 1.41, 95% CI 1.01–1.96; p = 0.04), hydronephrosis (HR 1.63, 95% CI 1.23–2.16; p = 0.001) and use of chemotherapy other than ddMVAC (HR 0.57, 95% CI 0.34–0.94; p = 0.03) were associated with shorter overall survival. For the whole cohort, the presence of CIS was also not associated with survival (HR 1.05 (95% CI 0.82–1.35; p = 0.70).ConclusionIn this multicenter, real-world cohort, CIS status at TURBT did not affect pathologic response to neoadjuvant or induction chemotherapy. This study is limited by its retrospective nature as well as variability in chemotherapy regimens and surveillance regimens.

Superior efficacy of neoadjuvant chemotherapy and radical cystectomy in cT3-4aN0M0 compared to cT2N0M0 bladder cancer: Superior efficacy of neoadjuvant chemotherapy and radical cystectomy

In this study, we compared complete pathological downstaging (pCD, ≤(y)pT1N0) and overall survival (OS) in patients with cT2 versus cT3–4aN0M0 UC of the bladder undergoing radical cystectomy (RC) with or without neoadjuvant chemo‐ (NAC) or radiotherapy (NAR). A population‐based sample of 5,517 patients, who underwent upfront RC versus NAC + RC or NAR + RC for cT2‐4aN0M0 UC between 1995–2013, was identified from the Netherlands Cancer Registry. Data were retrieved from individual patient files and pathology reports. pCD‐rates were compared using Chi‐square tests and OS was estimated by Kaplan–Meier analyses. Multivariable analyses were conducted to determine odds (OR) and hazard ratios (HR) for pCD‐status and OS, respectively. We included 4,504 (82%) patients with cT2 and 1,013 (18%) with cT3–4a UC. Median follow‐up was 9.2 years. In cT2 UC, pCD‐rate was 25% after upfront RC versus 43% (p < 0.001) and 33% (p = 0.130) after NAC + RC and NAR + RC, respectively. In cT3–4a UC, pCD‐rate was 8% after upfront RC versus 37% (p < 0.001) and 16% (p = 0.281) after NAC + RC and NAR + RC, respectively. In cT2 UC, 5‐year OS was 57% and 51% for NAC + RC and upfront RC, respectively (p = 0.135), whereas in cT3–4a UC, 5‐year OS was 55% for NAC + RC versus 36% for upfront RC (p < 0.001). In multivariable analysis for OS, NAC was beneficial in cT3–4a UC (HR: 0.67, 95%CI 0.51–0.89) but not in cT2 UC (HR: 0.91, 95%CI 0.72–1.15). NAR did not influence OS. In conclusion, NAC + RC was associated with superior pCD compared to RC alone and NAR + RC. Superior OS for NAC + RC compared to RC alone was especially evident in cT3–4a disease.

Recurrence and progression according to stage at re-TUR in t1g3 bladder cancer patients treated with BCG: Not as bad as previously thought

INTRODUCTION AND OBJECTIVES: Intravesical induction immunotherapy with Bacille Calmette-Guerin (BCG) is the standard of care treatment for high risk non-muscle invasive bladder cancer (NMIBC). Despite this, rates of recurrence and progression to muscleinvasion remain unacceptably high. We sought to optimize immunologic response to intravesical induction immunotherapy with standardized BCG intradermal vaccination prior to induction, and herein report our two year outcomes. METHODS: BCG-naive patients with high-risk NMIBC who were candidates for BCG therapy were prospectively enrolled from 2014-2015. Patients who were PPD-negative were subsequently vaccinated with BCG in standard intradermal fashion, and 3 weeks later, standard induction immunotherapy with Tice BCG was performed. Urinary cytokines, BCG-specific T and mononuclear cells, and clinical outcomes were analyzed. RESULTS: 15 patients were enrolled and 13 completed the study; 5 controls were also enrolled. The median follow-up was 20.4 months (range: 28.1 to 14.8m). No patient experienced dose-limiting toxicity or a Grade 3+ adverse event. No patients progressed to muscleinvasive disease. 9 patients successfully converted PPD. 9 of 13 patients recurred in the lower tract (69.2%) and all were successfully salvaged. Immunologically, BCG-specific T cell lymphoproliferation was increased, as was IFN-g secretion, IFN-g ELISPOT response, and direct ex vivo IFN-g response. Flow cytometry demonstrated that BCG significantly enhanced CD4+ and CD8+ T cells in most patients. Compared to controls, primed patients exhibited an increase in IFN-g release in response to BCG ex vivo at both 3 months and 6 months after therapy. Priming resulted in an earlier and more robust increase in urinary IL-2, IL-17, and IL-8 compared to control patients suggesting a potential benefit from earlier and higher activation of local immune response. CONCLUSIONS: Vaccination with BCG prior to induction immunotherapy results in improved immunologic measurements and increased urinary cytokines associated with control of high-risk NMIBC. Priming may represent a method to increase the efficacy of BCG immunotherapy for high-risk NMIBC. Further study with dedicated multicenter clinical trials and long term follow-up is warranted.