Abstract Background Whether the commonly used bacillus Calmette-Guérin (BCG) strains Connaught and Tice confer different treatment responses in non–muscle-invasive bladder cancer (NMIBC) is unknown. ...Objectives To compare clinical efficacy, immunogenicity, and genetics of BCG Connaught and Tice. Design, setting, and participants A prospective randomized single-institution trial with treatment of 142 high-risk NMIBC patients with BCG Connaught or Tice. Intervention Patients were randomized to receive six instillations of BCG Connaught or Tice. For experimental studies, BCG strains were compared in C57Bl/6 mice. Bladders and lymphoid tissues were analyzed by cytometry and the latter cultivated to detect live BCG. BCG genomic DNA was sequenced and compared with reference genomes. Outcome measurements and statistical analysis Recurrence-free survival was the primary end point of the clinical study. The Kaplan-Meier estimator was used for estimating survival and time-to-event end points. Nonparametric tests served for the analysis of the in vivo results. Results and limitations Treatment with BCG Connaught conferred significantly greater 5-yr recurrence-free survival compared with treatment with BCG Tice ( p = 0.0108). Comparable numbers of patients experienced BCG therapy-related side effects in each treatment group ( p = 0.09). In mice, BCG Connaught induced stronger T-helper cell 1–biased responses, greater priming of BCG-specific CD8+ T cells, and more robust T-cell recruitment to the bladder than BCG Tice. Genome sequencing of the BCG strains revealed candidate genes potentially involved in the differential clinical responses. Conclusions BCG strain may have an impact on treatment outcome in NMIBC immunotherapy. Patient summary We compared the efficacy of two commonly used bacillus Calmette-Guérin (BCG) strains for the treatment of NMIBC and found that treatment with BCG Connaught prevented recurrences more efficiently than BCG Tice. Comparison of the immunogenicity of the two strains in mice indicated superior immunogenicity of BCG Connaught. We also identified genetic differences that may explain the differential efficacy of the Connaught and Tice BCG strains. Trial registration NCT00003779.
Abstract Background Conventional cross-sectional imaging with computed tomography and magnetic resonance imaging (MRI) has limited accuracy for lymph node (LN) staging in bladder and prostate cancer ...patients. Objective To prospectively assess the diagnostic accuracy of combined ultrasmall superparamagnetic particles of iron oxide (USPIO) MRI and diffusion-weighted (DW) MRI in staging of normal-sized pelvic LNs in bladder and/or prostate cancer patients. Design, setting, and participants Examinations with 3-Tesla MRI 24–36 h after administration of USPIO using conventional MRI sequences combined with DW-MRI (USPIO-DW-MRI) were performed in 75 patients with clinically localised bladder and/or prostate cancer staged previously as N0 by conventional cross-sectional imaging. Combined USPIO-DW-MRI findings were analysed by three independent readers and correlated with histopathologic LN findings after extended pelvic LN dissection (PLND) and resection of primary tumours. Outcome measurements and statistical analysis Sensitivity and specificity for LN status of combined USPIO-DW-MRI versus histopathologic findings were evaluated per patient (primary end point) and per pelvic side (secondary end point). Time required for combined USPIO-DW-MRI reading was assessed. Results and limitations At histopathologic analysis, 2993 LNs (median: 39 LNs; range: 17–68 LNs per patient) with 54 LN metastases (1.8%) were found in 20 of 75 (27%) patients. Per-patient sensitivity and specificity for detection of LN metastases by the three readers ranged from 65% to 75% and 93% to 96%, respectively; sensitivity and specificity per pelvic side ranged from 58% to 67% and 94% to 97%, respectively. Median reading time for the combined USPIO-DW-MRI images was 9 min (range: 3–26 min). A potential limitation is the absence of a node-to-node correlation of combined USPIO-DW-MRI and histopathologic analysis. Conclusions Combined USPIO-DW-MRI improves detection of metastases in normal-sized pelvic LNs of bladder and/or prostate cancer patients in a short reading time. This trial is registered with ClinicalTrials.gov (identifier NCT00622973 ).
Abstract Aim Lymph node metastases influence prognosis and outcome in patients with bladder and prostate cancer. Cross sectional imaging criteria are limited in detecting metastases in normal sized ...lymph nodes. This prospective study assessed the diagnostic accuracy of ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) for the detection of metastases in normal sized lymph nodes using extended pelvic lymph node dissection (ePLND) and histopathology as the reference standard. Methods Seventy-five patients (bladder cancer, n = 19, prostate cancer n = 48, both, n = 8) were examined using 3T MR before and after USPIO-administration. A preoperative reading with two readers in consensus and a second postoperative reading with three independent blinded readers were performed. Results were correlated with histopathology and diagnostic accuracies were calculated for all readings. Results A total of 2993 lymph nodes were examined histopathologically. Fifty-four metastatic nodes were found in 20/75 patients (26.7%). The first reading had a sensitivity of 55.0%, specificity of 85.5%, positive predictive value (PPV) of 57.9%, negative predictive value (NPV) of 83.9%, and diagnostic accuracy (DA) of 77.3% on a per patient level. The second reading had a mean sensitivity of 58.3%, specificity of 83.0%, PPV of 58.0%, NPV of 84.4% and DA of 76.4% on a per patient level. The majority of missed metastases were smaller than 5 mm in short axis diameter. Conclusions USPIO-enhanced MRI in bladder and prostate cancer patients allows detection of metastases in normal sized lymph nodes and might guide the surgeon to remove suspicious lymph nodes not included in standard PLND.
Objective
To evaluate oncological outcome trends over the last three decades in patients after radical cystectomy (RC) and extended pelvic lymph node (LN) dissection.
Patients and Methods
...Retrospective analysis of the University of Southern California (USC) RC cohort of patients (1488 patients) operated with intent to cure from 1980 to 2005 for biopsy confirmed muscle‐invasive urothelial bladder cancer.
To focus on outcomes of unexpected (cN0M0) LN‐positive patients, the USC subset was extended with unexpected LN‐positive patients from the University of Berne (UB) (combined subgroup 521 patients).
Patients were grouped and compared according to decade of surgery (1980–1989/1990–1999/≥2000).
Survival probabilities were calculated with Kaplan–Meier plots, log‐rank tests compared outcomes according to decade of surgery, followed by multivariable verification.
Results
The 10‐year recurrence‐free survival was 78–80% in patients with organ‐confined, LN‐negative disease, 53–60% in patients with extravesical, yet LN‐negative disease and ≈30% in LN‐positive patients.
Although the number of patients receiving systemic chemotherapy increased, no survival improvement was noted in either the entire USC cohort, or in the combined LN‐positive USC‐UB cohort.
In contrast, patient age at surgery increased progressively, suggesting a relative survival benefit.
Conclusions
Radical surgery remains the mainstay of therapy for muscle‐invasive bladder cancer.
Yet, our study reveals predictable outcomes but no survival improvement in patients undergoing RC over the last three decades.
Any future survival improvements are likely to result from more effective systemic treatments and/or earlier detection of the disease.
Therapeutic intravesical instillation of bacillus Calmette-Guérin (BCG) is effective at triggering inflammation and eliciting successful tumor immunity in patients with non-muscle invasive bladder ...cancer, with 50 to 70% clinical response. Therapeutic success relies on repeated instillations of live BCG administered as adjuvant therapy shortly after tumor resection; however, the precise mechanisms remain unclear. Using an experimental model, we demonstrate that after a single instillation, BCG could disseminate to bladder draining lymph nodes and prime interferon-γ-producing T cells. Nonetheless, repeated instillations with live BCG were necessary for a robust T cell infiltration into the bladder. Parenteral exposure to BCG before instillation overcame this requirement; after the first intravesical instillation, BCG triggered a more robust acute inflammatory process and accelerated T cell entry into the bladder, as compared to the standard protocol. Moreover, parenteral exposure to BCG before intravesical treatment of an orthotopic tumor markedly improved response to therapy. Indeed, patients with sustained preexisting immunity to BCG showed a significant improvement in recurrence-free survival. Together, these data suggest that monitoring patients' response to purified protein derivative, and, in their absence, boosting BCG responses by parenteral exposure before intravesical treatment initiation, may be a safe and effective means of improving intravesical BCG-induced clinical responses.
Abstract Background There is paucity of data on bacillus Calmette-Guérin (BCG) perfusion in patients with non–muscle-invasive urothelial carcinoma (NMIUC) of the upper urinary tract (UUT). Objective ...To assess the long-term results of BCG perfusion in patients with UUT NMIUC in terms of efficacy and tolerability. Design, setting, and participants Retrospective analysis of 55 consecutive patients (64 renal units RUs) with UUT NMIUC prospectively followed according to a standardised protocol for a median of 42 mo (range: 2–237 mo). Our series includes negatively selected patients, most of whom were not eligible for radical surgery, with additional invasive urothelial carcinoma of the urinary tract in roughly one-third of the cases. Intervention Antegrade BCG perfusion of the UUT was performed either with curative intent for carcinoma in situ (Tis; 42 RUs) or with adjuvant intent after ablation of Ta/T1 tumours (22 RUs). Measurements Primary outcome measures were recurrence-free, progression-free, and nephroureterectomy-free survival. The secondary outcome measure was treatment tolerability. Results and limitations Recurrence occurred in 30 of 64 RUs (47%), 17 of 42 (40%) with Tis and 13 of 22 (59%) with Ta/T1 tumours. Progression occurred in 11 of 64 RUs (17%), 2 of 42 (5%) with Tis and 9 of 22 (41%) with Ta/T1 tumours. Nephroureterectomy was eventually performed in 7 of 64 RUs (11%), 2 of 42 (5%) with Tis and 5 of 22 (23%) with Ta/T1 tumours. Patients treated with curative intent for Tis tended to have better recurrence-free survival ( p = 0.42) and significantly better progression-free survival ( p < 0.01) and nephroureterectomy-free survival ( p = 0.05) compared with those treated with adjuvant intent after ablation of Ta/T1 tumours. Adverse events, mostly minor, occurred in a total of 11 patients (20%), with one case of fatal Escherichia coli septicaemia. Conclusions In our patients with UUT NMIUC, antegrade BCG perfusion resulted in a high kidney-preservation rate. Patients treated with curative intent for Tis apparently benefited in terms of local disease control more than those treated with adjuvant intent after ablation of Ta/T1 tumours. Treatment tolerability was good.
Abstract Background After radical cystectomy, patients are in a catabolic state because of postoperative stress response, extensive wound healing, and ileus. Objective To evaluate whether recovery ...can be improved with total parenteral nutrition (TPN) in patients following extended pelvic lymph node dissection (ePLND), cystectomy, and urinary diversion (UD). Design, setting, and participants We conducted a prospective, randomised, single-centre study of 157 consecutive cystectomy patients. Intervention Seventy-four patients (group A) received TPN during the first 5 postoperative days, with additional oral intake ad libitum. Eighty-three patients (group B) received oral nutrition alone. Outcome measurements and statistical analysis The primary outcome was the occurrence of postoperative complications. Secondary outcomes were time to recovery of bowel function, biochemical nutritional (serum albumin, serum prealbumin, serum total protein) and inflammatory (C-reactive protein) parameters, length of hospital stay, and costs attributed to the TPN. The Pearson χ2 test was used for dichotomous variables; the Wilcoxon rank sum test was used for continuous variables. Results and limitations Postoperative complications occurred in 51 patients (69%) in group A and in 41 patients (49%) in group B ( p = 0.013), a difference resulting from group A having more infectious complications than group B (32% vs 11%; p = 0.001). Serum prealbumin and serum total protein were significantly lower in group B on postoperative day 7 but not on postoperative day 12. Time to gastrointestinal recovery and length of hospital stay did not differ between the two groups. The costs for TPN were €614 per patient. A potential limitation is the use of a glucose-based parenteral nutrition without lipids. Conclusions Postoperative TPN is associated with a higher incidence of complications, mainly infections, and higher costs following ePLND, cystectomy, and UD versus oral nutrition alone.
Purpose We determined the necessary extent of pelvic lymph node dissection in patients with strictly unilateral bladder cancer. Materials and Methods A total of 40 patients with cystectomy and ...unilateral bladder cancer preoperatively underwent flexible cystoscopy guided injection of radioactive technetium into the contralateral bladder wall. Preoperatively single photon emission computerized tomography was done in all cases to detect and localize radioactive lymph nodes. Radioactive lymph nodes were confirmed intraoperatively by a γ probe and removed separately. Backup extended pelvic lymph node dissection and ex vivo examination of the whole specimen with a γ camera were done to preclude missed radioactive lymph nodes. Single photon emission computerized tomography and intraoperative findings were used to generate a 3-dimensional projection model of each lymph node site. Results A total of 228 radioactive lymph nodes (median 6, range 1 to 17) were detected, including 193 (85%) on the ipsilateral side of injection and 35 (15%) on the contralateral side. Of the contralateral lymph nodes 6%, 5% and 4% were in the external iliac, obturator fossa and common iliac region, respectively, but none were in the contralateral internal iliac region. At least 1 radioactive lymph node per patient was detected on the ipsilateral side. Additional lymphatic drainage to the contralateral side was found in 40% of patients. Conclusions Crossover lymphatic drainage is a common phenomenon and unilateral pelvic lymph node dissection would have missed radioactive lymph nodes in 40% of patients. However, we noted no lymphatic drainage to the contralateral internal iliac region. Thus, when bladder tumors are strictly unilateral, contralateral pelvic lymph node dissection can be limited to the obturator fossa, and the external and common iliac regions. Consequently preserving the contralateral autonomic nerves situated close to the internal iliac vessels does not compromise surgical radicality.
Objective
To analyse the long‐term outcomes of patients with lymph node (LN)‐positive bladder cancer, who did not receive any adjuvant therapy after radical cystectomy (RC) and extended pelvic lymph ...node dissection (ePLND).
Patients and Methods
We conducted a retrospective, combined cohort analysis based on two prospectively maintained cystectomy databases from the University of Southern California and the University of Bern.
Eligible patients underwent RC with ePLND for cN0M0 disease but were found to have LN‐positive disease.
No patient had neoadjuvant therapy, and all had negative surgical margins.
Kaplan–Meier plots were used to estimate recurrence‐free survival (RFS) and overall survival (OS). Subgroup comparisons were performed using log‐rank tests, and multivariable analysis was based on Cox proportional hazard models.
Results
Of 521 patients with LN‐positive disease, 251 (48%) never received adjuvant therapy. Although the pathological stage distribution was similar, the 251 patients who did not receive adjuvant therapy were older and had both fewer total and positive LNs than those who underwent adjuvant therapy.
The median RFS for patients treated with RC alone was 1.6 years.
Recurrences mainly occurred <2 years after RC, resulting in 5‐ and 10‐year RFS rates of 32 and 26%, respectively.
Pathological T stage, the total number of LNs and the number of positive LNs detected were independent predictors of RFS and OS.
Conclusions
In this study, 25% of patients with documented LN metastases who did not receive adjuvant therapy were cured with RC and ePLND; however, a few relapses may occur later than 3 years.
Predictors of survival were pathological T stage, the number of total LNs and the number of positive LNs identified.
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