The role of lymph node density in bladder cancer prognostication

Pelvic lymph node metastases from bladder cancer occur in about 25% of patients undergoing radical cystectomy. While the majority of patients with lymph node metastases will develop progressive disease, some patients do exhibit long-term survival with and without adjuvant chemotherapy. The concept of lymph node density has been proposed as a means to stratify patient prognosis since it takes into account two important factors—the number of positive nodes (tumor burden) and the total number of nodes removed/examined (extent of dissection). Due to the lack of agreement on the extent of lymphadenectomy, lymph node density facilitates standardization of lymph node staging, thus allowing for adjuvant therapies and clinical trials to be more uniformly applied. Whether lymph node density provides improved prognostication over the standard nodal staging or absolute number of positive lymph nodes remains controversial. We review the literature regarding the role of lymph node density in the prognostic stratification of node-positive bladder cancer.     

Combination of BCG and interferon intravesical immunotherapy: an update

Objective

To provide an update on the use of interferon (IFN) in the treatment of non-muscle invasive bladder cancer (NMIBC).

Methods

A literature review of intravesical IFN was performed.

Results

In vitro evidence suggested that IFN combined with BCG may have a synergistic effect on the immune response, and treatment regimens with IFN have used reduced BCG dosage in an attempt to reduce toxicity. IFN combined with BCG may salvage some patients, single-course BCG failures or late relapsers, while those that relapse quickly may be destined to failure. However, based on the results of a recently reported randomized trial, the addition of IFN may not improve efficacy in BCG naïve patients.

Conclusions

BCG plus IFN remains an alternative in selected patients with NMIBC who fail intravesical BCG.

     

Two-year follow-up of the phase II marker lesion study of intravesical apaziquone for patients with non-muscle invasive bladder cancer

Objectives  To study the time-to-recurrence and duration of response in non-muscle invasive bladder cancer (NMIBC) patients, with a complete ablative response after intravesical apaziquone instillations. Methods  Transurethral resection of bladder tumour(s) (TURBT) was performed in patients with multiple pTa-T1 G1-2 urothelial cell carcinoma (UCC) of the bladder, with the exception of one marker lesion of 0.5–1.0 cm. Intravesical apaziquone was administered at weekly intervals for six consecutive weeks, without maintenance instillations. A histological confirmed response was obtained 2–4 weeks after the last instillation. Routine follow-up (FU) was carried out at 6, 9, 12, 18 and 24 months from the first apaziquone instillation. Results  At 3 months FU 31 of 46 patients (67.4%) had a complete response (CR) to ablative treatment. Side-effects on the long-term were only mild. Two CR patients dropped out during FU. On intention-to-treat (ITT) analysis 49.5% of the CR patients were recurrence-free at 24 months FU, with a median duration of response of 18 months. Of 15 no response (NR) patients, only two received additional prophylactic instillations after TURBT. On ITT-analysis 26.7% of the NR patients were recurrence-free (log rank test, P = 0.155). The overall recurrence-free survival was 39% (18 of 46 patients) at 24 months FU. Conclusions  The CR of the marker lesion in 67% of patients was followed by a recurrence-free rate of 56.5% at 1-year FU, and 49.5% at 2-year FU. These long-term results are good in comparison with the results of other ablative studies.     

Prognostic significance of non-papillary tumor morphology as a predictor of cancer progression and survival in patients with primary T1G3 bladder cancer

Objective  To investigate the prognostic significance of tumor morphology in relation to progression and survival in patients with primary T1G3 bladder cancer (BC) Methods  After review of pathology, 194 patients who were diagnosed with primary T1G3 BC after clinically complete transurethral resection between 1989 and 2005 were seen. Of these patients, 144 underwent surveillance and 50 underwent immediate cystectomy. Tumor morphology (gross and microscopic) in addition to other clinicopathological factors such as tumor size, multifocality, lymphovascular invasion (LVI), carcinoma-in-situ (CIS), intravesical therapy, and the absence of proper muscle were evaluated with regard to recurrence, progression, upstaging, and survival. In addition, correlations between tumor morphology and other factors were analyzed. Results  Median follow-up was 52.5 months. Five-year cancer-specific survival rates were 92.1% for entire cohort, 95.6% for surveillance group, and 84.0% for immediate cystectomy group, respectively. During surveillance, recurrence and progression were noted in 43.1, 13.2%, respectively. Of the potential prognostic factors analyzed, non-papillary morphology (both gross and microscopic) was a significant parameter of progression and intravesical therapy was significantly predictive of recurrence. After immediate cystectomy, 34% were upstaged. Non-papillary morphology and the absence of proper muscle were related to upstaging. For entire patients, non-papillary morphology and the absence of proper muscle were also significant predictors of patient’s survival (P = 0.048, HR = 4.826, and P = 0.007, HR = 5.663, respectively). Non-papillary tumors were significantly related to the presence of LVI and CIS compared to papillary tumors. Conclusions  Non-papillary tumor morphology was a predictor of cancer progression and survival in patients with primary T1G3 BC.     

Experimental rat bladder urothelial cell carcinoma models

Bladder cancer is a major public health problem. Currently available therapeutic options seem to be unable to prevent bladder cancer recurrence and progression. To enable preclinical testing of new intravesical therapeutic agents, a suitable bladder tumor model that resembles human disease is highly desirable. The aim of this topic paper was to discuss the problems associated with current in vivo animal bladder tumor models, focusing on the orthotopic syngeneic rat bladder tumor model. In the second part of the paper the development of a potential new orthotopic rat bladder tumor model is described.     

Quantitative risk stratification and individual comprehensive therapy for invasive bladder cancers in China

Background  To evaluate the risk factors for invasive bladder cancer and to develop a predictive model for the improvement of individual comprehensive therapy for invasive bladder cancers. Materials and methods  The records of 356 patients with invasive bladder cancer, operated on at three Chinese medical institutes, were reviewed. The Cox proportional hazards regression model was used to assess the clinical and pathological variables affecting disease-free survival (DFS). The regression coefficients determined by Cox regression analysis were used to construct a predictive index (PI). PI was used to categorize the patients into different risk groups. Kaplan–Meier survival curves followed with log-rank test were plotted to compare the difference. Results  Tumor configuration (RR = 1.60, P = 0.01), multiplicity (RR = 1.41, P = 0.04), histological subtype (RR = 2.13, P < 0.01), tumor stage (RR = 2.50, P < 0.01), tumor grade (RR = 2.35, P < 0.01), node status (RR = 2.48, P < 0.01), and neoadjuvant chemotherapy (RR = 0.46, P = 0.02), had independent prognostic significance for DFS. PI = 0.47 × (configuration) + 0.34 × (multiplicity) + 0.76 × (tumor histological subtype) + 0.92 × (stage) + 0.86 × (grade) + 0.91 × (node status) − 0.79 × (neoadjuvant chemotherapy). The range of PI was −0.32 to 6.52, which was equally divided into three risk groups with significant differences on Kaplan–Meier curves and a log-rank test (P < 0.01). Meanwhile, the patient’s probability of survival could be calculated by PI. Conclusions  Seven factors (tumor configuration, multiplicity, histological subtype, tumor stage, tumor grade, node status, neoadjuvant chemotherapy) affect the prognosis after radical cystectomy (RC) for invasive bladder cancer. PI can be used to optimize the individual comprehensive therapy. Given fewer perioperative complications, fast recovery from surgery and relatively satisfactory quality of life, ureterocutaneostomy, and ileal conduit are suitable for the patients with short expected life spans. An erratum to this article can be found at     

FGFR3 mutations indicate better survival in invasive upper urinary tract and bladder tumours

Background

Promoter hypermethylation and microsatellite instability are frequent in tumours of the upper urinary tract (UTT) and infrequent in bladder tumours. FGFR3 mutations are common findings in bladder tumours and are associated with a good prognosis.

Objective

To investigate the occurrence of FGFR3 mutations in UTT and determine the prognostic effect of these genetic changes.

Design, setting, and participants

Tissue from the initial tumour was obtained from 280 patients (117 bladder tumours and 163 UTT). Patients were selected from pathologic archives to represent the disease spectrum of UCC throughout the urinary tract. Following UCC excision, patients underwent surveillance for a median of 56 mo (range 1–216 mo) or until death.

Measurements

FGFR3 mutation analysis was successfully performed on 252 of the 280 primary tumours using the SNaPshot method. Two-tailed statistical analyses were done using the χ², Fisher exact tests, and log rank tests. Cox proportional hazard ratios were estimated to obtain risks of recurrence, progression, and death, and to find independent prognostic factors in a multivariate model.

Results and limitations

FGFR3 mutations occurred with the same frequency in bladder and upper tract tumours. Mutations were associated with low-stage tumours and a milder disease course in bladder, ureter, and renal pelvis tumours. Strikingly, our data suggest that these mutations indicate a better survival in patients with invasive tumours from the bladder and upper urinary tract.

Conclusions

FGFR3 mutation status might be used to select patients with invasive UCC who have a lower risk of death.     

Initial Experimental Evaluation of Wireless Capsule Endoscopes in the Bladder: Implications for Capsule Cystoscopy

Background

Cystoscopy remains one of the most important diagnostic procedures for the lower urinary tract. Wireless capsule endoscopy was introduced in the 1990s but use to date is limited to gastroenterology.

Objective

We evaluated the feasibility in the pig model of using wireless capsule endoscopes (WCEs) for cystoscopy.

Design, setting, and participants

Experimental evaluation of capsule cystoscopy was performed in a 50-kg farm pig. The capsule was deployed into the bladder through a custom access sheath. Images were continuously transmitted at a rate of four frames per second to a laptop computer and processed using proprietary software. Manipulation of the WCE within the bladder was performed using a set protocol. The animal was then euthanized and gross inspection was performed.

Measurements

We measured the ability to deploy and manipulate the capsule within the bladder. Feasibility of capturing and retrieving images in real time was also assessed.

Results and limitations

The WCE was efficiently deployed and manipulated within the bladder passively and with the use of external magnets. The entire bladder mucosa was visualized. Real-time image transmission and capture were successful. No complications were seen during capsule cystoscopy. Minor urethral bleeding was observed after the experiment, likely related to placement of the access sheath required for deployment of the WCE. Limitations are that the evaluation of WCE was performed in the pig model, in only one female animal, using a nonsurvival approach. Furthermore, the study was not designed to differentiate normal from abnormal mucosal findings and focused solely on inspection of the bladder.

Conclusions

This report suggests that cystoscopy with a WCE is feasible. With this device, all aspects of the bladder mucosa could be visualized, and ongoing technologic and procedural developments are warranted for this new approach.     

Neoadjuvant and adjuvant chemotherapy in muscle-invasive bladder cancer

Context

The use of neoadjuvant and adjuvant chemotherapy in the treatment of muscle-invasive bladder cancer is still controversial.

Objective

To determine the optimal use of chemotherapy in the neoadjuvant and adjuvant settings in patients with advanced urothelial cell carcinoma. Bladder preservation is also discussed.

Evidence acquisition

A critical review of the published literature on chemotherapy for patients with locally advanced bladder cancer was performed.

Evidence synthesis

The presence of occult micrometastases at the time of radical cystectomy leads to both distant and local failure in patients with locally advanced transitional cell carcinoma of the bladder. Both neoadjuvant and adjuvant therapies have been evaluated in patients with locally advanced bladder cancer. Studies evaluating adjuvant chemotherapy have been limited by inadequate statistical power to detect meaningful clinical answers as well as by experimental arms utilizing inadequate chemotherapy.

Conclusions

The aggregate of available evidence suggests that neoadjuvant cisplatin-based combination chemotherapy should be considered as a standard of care for patients with muscle-invasive or locally advanced operable bladder cancer. In patients who are either unfit for or refuse radical cystectomy, neoadjuvant chemotherapy with or without radiation can render bladder preservation possible for patients who attain an excellent clinical response. With the introduction of new cytotoxic drugs, there is a need for well-designed studies to address the optimal utility of perioperative therapy in high-risk patients with bladder cancer.     

膀胱尿路上皮癌患者外周血T淋巴细胞凋亡蛋白Fas的表达

Objective To investigate the relationship between the Fas expression in peripheral blood T cells and bladder transitional cell carcinoma (TCC). Methods The Fas expression in peripheral blood T cells of 52 patients with TCC and 37 healthy people was detected by flowcytometry. The Fas-posi-tive rate was compared by t test between two designed groups. Results The Fas expression in CD4+ [(20.74±9.02)%] and CD8+[ (7.51±5.93 )% ] was increased in TCC patients as compared with controls ( P < 0. 01 ). Fas-positive CD8+ ceils were reduced in invasive TCC as compared with superficial TCC [ ( 5. 83±3.95 ) % vs ( 5. 83±3.95 ) %, P < 0.05 ], but there was no difference between primary and recurrent cases ( P > 0.05 ). Conclusion The abnormal Fas expression in peripheral blood T cells may play an important role in the development and progression of TCC.