Autoimmune hypophysitis secondary to therapy with immune checkpoint inhibitors: Four cases describing the clinical heterogeneity of central endocrine dysfunction.

INTRODUCTION: Immune checkpoint inhibitors are becoming increasingly important in oncology. Immune-related adverse events, including autoimmune hypophysitis, have been reported before. CASE REPORT: We present a case series of three males and one female, suffering from either malignant melanoma or renal cell carcinoma, who developed hypophysitis under Nivolumab and/or Ipilimumab. A wide range of clinical manifestations from asymptomatic hypophysitis, headache, general weakness, loss of appetite, visual field impairment, and confusion to acute life-threatening Addison crisis was observed.Management and outcome: All patients received corticosteroids. Immune checkpoint inhibitors were discontinued in three cases until resolution of symptoms. DISCUSSION: The objective of our report is to raise the awareness of physicians, regarding this rare clinical entity, which may become life-threatening, if not promptly recognized and properly treated.

Preoperatively Dilated Ureters are a Specific Risk Factor for the Development of Ureteroenteric Strictures after Open Radical Cystectomy and Ileal Neobladder.

PURPOSE: We evaluated preoperative ureteral obstruction as a risk factor for benign ureteroenteric anastomosis strictures in patients who underwent open radical cystectomy and ileal neobladder diversion. MATERIALS AND METHODS: A total of 953 patients in whom bilateral ileoureterostomy was performed between January 1986 and March 2009 formed the study population. A nonrefluxing Le Duc technique was applied in 357 consecutive patients and a refluxing Wallace type technique was applied in 596. We defined ureteroenteric anastomosis stricture as the need for specific therapy (eg stenting, dilatation or reimplantation) or as proven loss of renal function. Kaplan-Meier analysis was done to calculate the likelihood of ureteroenteric anastomosis stricture development. RESULTS: Median followup in the study population was 65 months. Preoperatively 109 patients had unilateral or bilateral obstructed ureters. Unilateral or bilateral obstruction developed in 107 of the 953 patients (127 reno-ureteral units, including 63 on the right side and 64 on the left side). Of the reno-ureteral units 98 had benign and 29 had malignant ureteroenteric anastomosis strictures. The overall stricture rate due to any cause in preoperatively obstructed ureters was 19.3% at 10 years vs 6.4% in preoperatively undilated ureters. For the refluxing Wallace type technique the 10-year ureteroenteric anastomosis stricture rate was 2.4% for preoperatively undilated and 7.6% for preoperatively obstructed ureters. For the nonrefluxing technique the corresponding rates at 10 years were 14.2% and 35.54%, respectively. CONCLUSIONS: Preoperatively obstructed ureters are at significantly higher risk for benign ureteroenteric anastomosis strictures during the postoperative course after ileal neobladder diversion. Most such Le Duc strictures are bilateral and most such Wallace type strictures are unilateral. The risk of ureteroenteric anastomosis stricture after ureteroenterostomy using the nonrefluxing technique is threefold the risk of the refluxing technique. There was no preponderance of left ureteroenteric anastomosis strictures after each technique.

Urinary diversion: how experts divert.

OBJECTIVE: To determine the rates of the available urinary diversion options for patients treated with radical cystectomy for bladder cancer in different settings (pioneering institutions, leading urologic oncology centers, and population based). METHODS: Population-based data from the literature included all patients (n = 7608) treated in Sweden during the period 1964-2008, from Germany (n = 14,200) for the years 2008 and 2011, US patients (identified from National Inpatient Sample during 1998-2005, 35,370 patients and 2001-2008, 55,187 patients), and from Medicare (n = 22,600) for the years 1992, 1995, 1998, and 2001. After the International Consultation on Urologic Diseases-European Association of Urology International Consultation on Bladder Cancer 2012, the urinary diversion committee members disclosed data from their home institutions (n = 15,867), including the pioneering institutions and the leading urologic oncology centers. They are the coauthors of this report. RESULTS: The receipt of continent urinary diversion in Sweden and the United States is <15%, whereas in the German high-volume setting, 30% of patients receive a neobladder. At leading urologic oncology centers, this rate is also 30%. At pioneering institutions up to 75% of patients receive an orthotopic reconstruction. Anal diversion is <1%. Continent cutaneous diversion is the second choice. CONCLUSION: Enormous variations in urinary diversion exist for >2 decades. Increased attention in expanding the use of continent reconstruction may help to reduce these disparities for patients undergoing radical cystectomy for bladder cancer. Continent reconstruction should not be the exclusive domain of cystectomy centers. Efforts to increase rates of this complex reconstruction must concentrate on better definition of the quality-of-life impact, technique dissemination, and the centralization of radical cystectomy.

Female gender is associated with a worse survival after radical cystectomy for urothelial carcinoma of the bladder: a competing risk analysis.

OBJECTIVE: To determine the association of gender with outcome after radical cystectomy for patients with bladder cancer. METHODS: An observational cohort study was conducted using retrospectively collected data from 11 centers on patients with advanced bladder cancer treated with radical cystectomy. The association of gender with disease recurrence and cancer-specific mortality was examined using a competing risk analysis. RESULTS: The study comprised 4296 patients, including 890 women (21%). The median follow-up duration was 31.5 months for all patients. Disease recurred in 1430 patients (33.9%) (36.8% of women and 33.1% of men) at a median of 11 months after surgery. Death from any cause was observed in 46.0% of men and 50.1% of women. Cancer-specific death was observed in 33.0% of women and 27.2% of men. Multivariable regression with competing risk found that female gender was associated with an increased risk for disease recurrence and cancer-specific mortality (hazard ratio, 1.27; 95% confidence interval, 1.108-1.465; P = .007) compared with male gender. Important limitations include the inability to account for additional potential confounders, such as differences in environmental exposures, treatment selection, and histologic subtypes between men and women. CONCLUSION: Our analysis identified female gender as a poor-risk feature for patients undergoing radical cystectomy. This adverse prognostic factor was independent of standard clinical and pathologic features and competing risk from non-cancer-related death.

ICUD-EAU International Consultation on Bladder Cancer 2012: Urinary diversion.

CONTEXT: A summary of the 2nd International Consultation on Bladder Cancer recommendations on the reconstructive options after radical cystectomy (RC), their outcomes, and their complications. OBJECTIVE: To review the literature regarding indications, surgical details, postoperative care, complications, functional outcomes, as well as quality-of-life measures of patients with different forms of urinary diversion (UD). EVIDENCE ACQUISITION: An English-language literature review of data published between 1970 and 2012 on patients with UD following RC for bladder cancer was undertaken. No randomized controlled studies comparing conduit diversion with neobladder or continent cutaneous diversion have been performed. Consequently, almost all studies used in this report are of level 3 evidence. Therefore, the recommendations given here are grade C only, meaning expert opinion delivered without a formal analysis. EVIDENCE SYNTHESIS: Indications and patient selection criteria have significantly changed over the past 2 decades. Renal function impairment is primarily caused by obstruction. Complications such as stone formation, urine outflow, and obstruction at any level must be recognized early and treated. In patients with orthotopic bladder substitution, daytime and nocturnal continence is achieved in 85-90% and 60-80%, respectively. Continence is inferior in elderly patients with orthotopic reconstruction. Urinary retention remains significant in female patients, ranging from 7% to 50%. CONCLUSIONS: RC and subsequent UD have been assessed as the most difficult surgical procedure in urology. Significant disparity on how the surgical complications were reported makes it impossible to compare postoperative morbidity results. Complications rates overall following RC and UD are significant, and when strict reporting criteria are incorporated, they are much higher than previously published. Fortunately, most complications are minor (Clavien grade 1 or 2). Complications can occur up to 20 yr after surgery, emphasizing the need for lifelong monitoring. Evidence suggests an association between surgical volume and outcome in RC; the challenge of optimum care for elderly patients with comorbidities is best mastered at high-volume hospitals by high-volume surgeons. Preoperative patient information, patient selection, surgical techniques, and careful postoperative follow-up are the cornerstones to achieve good long-term results.

Extranodal extension is a powerful prognostic factor in bladder cancer patients with lymph node metastasis.

BACKGROUND: Lymph node metastasis (LNM) is the most powerful pathologic predictor of disease recurrence after radical cystectomy (RC). However, the outcomes of patients with LNM are highly variable. OBJECTIVE: To assess the prognostic value of extranodal extension (ENE) and other lymph node (LN) parameters. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis of 748 patients with urothelial carcinoma of the bladder and LNM treated with RC and lymphadenectomy without neoadjuvant therapy at 10 European and North American centers (median follow-up: 27 mo). INTERVENTION: All subjects underwent RC and bilateral pelvic lymphadenectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Each LNM was microscopically evaluated for the presence of ENE. The number of LNs removed, number of positive LNs, and LN density were recorded and calculated. Univariable and multivariable analyses addressed time to disease recurrence and cancer-specific mortality after RC. RESULTS AND LIMITATIONS: A total of 375 patients (50.1%) had ENE. The median number of LNs removed, number of positive LNs, and LN density were 15, 2, and 15, respectively. The rate of ENE increased with advancing pT stage (p<0.001). In multivariable Cox regression analyses that adjusted for the effects of established clinicopathologic features and LN parameters, ENE was associated with disease recurrence (hazard ratio [HR]: 1.89; 95% confidence interval [CI], 1.55-2.31; p<0.001) and cancer-specific mortality (HR: 1.90; 95% CI, 1.52-2.37; p<0.001). The addition of ENE to a multivariable model that included pT stage, tumor grade, age, gender, lymphovascular invasion, surgical margin status, LN density, number of LNs removed, number of positive LNs, and adjuvant chemotherapy improved predictive accuracy for disease recurrence and cancer-specific mortality from 70.3% to 77.8% (p<0.001) and from 71.8% to 77.8% (p=0.007), respectively. The main limitation of the study is its retrospective nature. CONCLUSIONS: ENE is an independent predictor of both cancer recurrence and cancer-specific mortality in RC patients with LNM. Knowledge of ENE status could help with patient counseling, clinical decision making regarding inclusion in clinical trials of adjuvant therapy, and tailored follow-up scheduling after RC.

Does increasing the nodal yield improve outcomes in patients without nodal metastasis at radical cystectomy?

PURPOSE: To determine whether the number of lymph nodes (LNs) examined is associated with outcomes in patients without nodal metastasis after radical cystectomy (RC). PATIENTS AND METHODS: We retrospectively analyzed data from 4,188 patients treated at 12 centers with RC and pelvic lymphadenectomy without neo-adjuvant chemotherapy for urothelial carcinoma of the bladder (UCB). Outcomes of patients without LN metastasis (n = 3,088) were examined according to the LN yield analyzed as continuous variable, tertiles, and using the cutoffs of ≥ 9 and ≥ 20. RESULTS: The median nodal yield was 18 (range 1-123; IQR:20). A total of 2591 (84 %) and 1445 (47 %) patients had a LN yield ≥ 9 and ≥ 20, respectively. Median follow-up was 47 months (IQR:70). In multivariable analyses that adjusted for the standard clinicopathologic factors, higher LN yield was associated with a decreased risk of disease recurrence (continuous: HR = 0.996, p = 0.05; 3rd vs 1st tertile: HR = 0.853, p = 0.048; cutoff ≥ 20: HR = 0.851, p = 0.032). In the subgroups of patients with muscle-invasive UCB or those with ≥ 9 LN removed, LN yield was not associated with outcomes (p values >0.05). CONCLUSIONS: In this large multicenter cohort of patients with node-negative UCB, higher nodal yield improved recurrence-free survival when all patients were analyzed. Patients with a high LN yield (≥ 20 LN removed or 3rd tertile) had the largest benefit. The lack of prognostic significance of LN yield in patients with muscle-invasive UCB or those stratified by 9 LNs removed suggests that this effect is weak. Further prospective studies are needed to help identify preoperatively the optimal template for each patient.

Radical cystectomy for urothelial carcinoma of the bladder without neoadjuvant or adjuvant therapy: long-term results in 1100 patients.

BACKGROUND: The optimal treatment strategy for muscle-invasive bladder cancer (BCa) remains controversial. OBJECTIVE: Better define the long-term outcomes of radical cystectomy (RC) alone for BCa and determine the impact of pathologic downstaging after transurethral resection in a large and homogeneous single-center series. DESIGN, SETTING, AND PARTICIPANTS: A cohort of 1100 patients undergoing RC with pelvic lymph node dissection (PLND) without neoadjuvant therapy for urothelial carcinoma of the bladder between January 1, 1986, and December 2009 was evaluated. Patients with other than metastases to the pelvic lymph nodes were excluded. Median age was 65 yr. Clinical course, pathologic characteristics, and long-term outcomes were evaluated. Follow-up was obtained until December 2009 with a median of 38 mo and a completeness of 96.5%. INTERVENTION: RC with PLND; urinary diversion with ileal neobladder whenever possible. MEASUREMENTS: Primary end points were disease-specific survival (DSS), recurrence-free survival (RFS), and overall survival (OS) according to the tumor stage of the RC specimen versus the maximum tumor stage. The log-rank test was used to compare subgroups. RESULTS AND LIMITATIONS: The 30-d (90-d) mortality rate was 3.2% (5.2%). The 10-yr OS, DSS, and RFS rates were 44.3%, 66.8%, and 65.5%, respectively. Based on the tumor stage of the RC specimen, the 10-yr DSS rate was pT0/a/is/1 pN0: 90.5%, pT2a/b pN0: 66.8%, pT3a/b pN0: 59.7%, pT4a/b pN0: 36.6%, and pTall pN+: 16.7%. Downstaging by transurethral resection of the prostate was observed in 382 patients. Patients with maximum tumor stage pT2a/b pN0 had distinctly better 10-yr DSS rates than those with pT2a/b pN0 in the RC specimen: pT2a pN0: 92.2% versus 73.8%; pT2b: 75.0% versus 62.0%. A total of 49% female and 80% male patients received an ileal neobladder. CONCLUSIONS: This contemporary and homogeneous single-center series found acceptable OS, DFS, and RFS for patients undergoing RC. Pathologic downstaging had a significant impact on survival.

Multicenter validation of the prognostic value of patient age in patients treated with radical cystectomy.

PURPOSE: Small studies have suggested that older patients have worse outcomes following radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). We evaluated the association of patient age with clinical outcomes in a large multi-institutional RC series. METHODS: Data were collected from 4,429 patients treated with RC and lymphadenectomy for UCB without neoadjuvant chemotherapy. Age at RC was analyzed both as a continuous and categorical variable. RESULTS: Higher age at RC, analyzed as a continuous or categorical variable, was associated with advanced pathologic stage (P < 0.001), higher tumor grade (P = 0.045), presence of lymphovascular invasion (P = 0.018), and positive soft-tissue surgical margin status (P = 0.004). Elderly patients were less likely to receive postoperative chemotherapy (P < 0.001). In multivariable analyses, higher age was associated with disease recurrence, cancer-specific, and overall mortality (P < 0.001). Patients ≥ 80 years had a significantly greater risk of cancer-specific mortality than patients <50 years (HR 1.763, P < 0.001). Age minimally improved the accuracy of a base model that included standard pathologic features for prediction of disease recurrence (+0.2-0.3%) and cancer-specific survival (+0.3%). Conversely, age improved the predictive accuracy for overall survival by a sizeable margin (+4.2-4.5%). CONCLUSIONS: This large external validation study confirms that advanced patient age is minimally but significantly associated with worse prognosis after RC. Nevertheless, a large proportion of elderly patients benefitted from RC with curative intent. We need to improve our understanding of the reasons for the worse UCB outcomes in this growing segment of the population and to develop strategies to improve cancer care in the elderly.

25 years of experience with 1,000 neobladders: long-term complications.

PURPOSE: We analyzed the long-term complications (greater than 90 days postoperatively) in a large, single center series of patients who underwent cystectomy and substitution with an ileal neobladder. MATERIALS AND METHODS: A total of 1,540 radical cystectomies were performed at our center between January 1986 and September 2008. Of the patients 1,013 received an ileal neobladder. Only the 923 patients with followup longer than 90 days (median 72 months, range 3 to 267) were included in analysis. All long-term complications were identified. The complication rate was calculated using the Kaplan-Meier method. RESULTS: The overall survival rate was 65.5%, 49.8% and 28.3% at 5, 10 and 20 years, respectively. The overall long-term complication rate was 40.8% with 3 neobladder related deaths. Hydronephrosis, incisional hernia, ileus or small bowel obstruction and feverish urinary tract infection were observed in 16.9%, 6.4%, 3.6% and 5.7% of patients, respectively, 20 years postoperatively. Subneovesical obstruction in 3.1% of cases was due to local tumor recurrence in 1.1%, neovesicourethral anastomotic stricture in 1.2% and urethral stricture in 0.9%. Chronic diarrhea was noted in 9 patients. Vitamin B12 was substituted in 2 patients. Episodes of severe metabolic acidosis occurred in 11 patients and 307 of 923 required long-term bicarbonate substitution. Rare complications included cutaneous neobladder fistulas in 2 cases, and intestinal neobladder fistulas, iatrogenic neobladder perforation, spontaneous perforation and necrotizing pyocystis in 1 each. CONCLUSIONS: Even in experienced hands the long-term complication rate of radical cystectomy and neobladder formation are not negligible. Most complications are diversion related. The challenge of optimum care for these elderly patients with comorbidities is best mastered at high volume hospitals by high volume surgeons.

Discrepancy between clinical and pathological stage: external validation of the impact on prognosis in an international radical cystectomy cohort.

OBJECTIVE: • To compare the clinical and pathologic stage among a large, multi-institutional series of patients undergoing radical and to determine the effect of stage discrepancy on outcomes. PATIENTS AND METHODS: • Data was collected from nine centers and 3,393 patients with urothelial carcinoma of the bladder (UCB) treated with radical cystectomy and pelvic lymphadenectomy without neo-adjuvant chemotherapy. • A retrospective cohort design was used to assess the percentage of patients experiencing stage discrepancy and the impact of stage discrepancy on time to disease relapse and time to death from UCB. RESULTS: • Clinical under staging occurred in 50% of patients and pathologic down staging occurred in 18% of patients. • Up staging to muscle invasive disease occurred in 45.9% (n = 592) of 1,291 patients with clinical ≤T1, including 30.6% of patients with Tis only at transurethral resection. • Of the 3,166 patients with clinically organ confined (OC) tumor stage, 1,357 (42.9%) were up staged to non-organ confined pathologic tumor stage. • Within each clinical stage stratum, patients who were clinically under staged had a higher probability of disease relapse or death from UCB compared to those who were same staged or down staged on pathologic examination (P < 0.05). CONCLUSIONS: • We identified clinical under staging in half of the patients undergoing radical cystectomy for UCB. • Up staging resulted in a higher likelihood of disease progression and eventual death from UCB. • These findings should be considered when utilizing pre-operative risk-adapted strategies for selecting candidates for neoadjuvant chemotherapy.

Lessons learned from 1,000 neobladders: the 90-day complication rate.

PURPOSE: We report the 90-day morbidity of the ileal neobladder in a large, contemporary, homogenous series of patients who underwent radical cystectomy at a tertiary academic referral center using a standard approach. MATERIALS AND METHODS: Between January 1986 and September 2008 we performed 1,540 radical cystectomies. A total of 281 patients had an absolute contraindication for orthotopic reconstruction. The remaining 1,259 patients were candidates for a neobladder. Of these patients 1,013 (66%) finally received a neobladder and form the basis of this report. All patients had a thorough followup until December 2008 or until death. All complications within 90 days of surgery were defined, categorized and classified by an established 5 grade and 11 domain modification of the original Clavien system. RESULTS: Of 1,013 patients 587 (58%) experienced at least 1 complication within 90 days of surgery. Infectious complications were most common (24%) followed by genitourinary (17%), gastrointestinal (15%) and wound related complications (9%). The 90-day mortality rate was 2.3%. Of the patients 36% had minor (grade 1 to 2) and 22% had major (grade 3 to 5) complications. On univariate analysis the incidence and severity of the 90-day complications rate correlate highly significantly with age, tumor stage, American Society of Anesthesiologists score and preoperative comorbidity. CONCLUSIONS: Radical cystectomy and ileal neobladder formation represent a major surgery with potential relevant early complications even in the most experienced hands. The rate of severe and lethal complications is acceptably low.

Soft tissue surgical margin status is a powerful predictor of outcomes after radical cystectomy: a multicenter study of more than 4,400 patients.

PURPOSE: We evaluated the association of soft tissue surgical margins with characteristics and outcomes of patients treated with radical cystectomy for urothelial carcinoma of the bladder. MATERIALS AND METHODS: We retrospectively collected the data of 4,410 patients treated with radical cystectomy and pelvic lymphadenectomy without neoadjuvant chemotherapy at 12 academic centers in the United States, Canada and Europe. A positive soft tissue surgical margin was defined as presence of tumor at inked areas of soft tissue on the radical cystectomy specimen. RESULTS: Positive soft tissue surgical margins were identified in 278 patients (6.3%). On univariate analysis positive soft tissue surgical margin was significantly associated with advanced pT stage, higher tumor grade, lymphovascular invasion and lymph node metastasis (p <0.001). Actuarial 5-year recurrence-free and cancer specific survival probabilities were 62.8% +/- 0.8% and 69% +/- 0.8% for patients without soft tissue surgical margins vs 21.6% +/- 3.1% and 26.4% +/- 3.3% for those with positive soft tissue surgical margins (p <0.001). On multivariable analyses adjusting for the effect of standard clinicopathological features and adjuvant chemotherapy positive soft tissue surgical margin was an independent predictor of disease recurrence and cancer specific mortality (HR 1.52 and HR 1.51, p <0.001, respectively). Soft tissue surgical margin retained independent predictive value in subgroups with advanced disease such as pT3Nany, pT4Nany or Npositive. CONCLUSIONS: Positive soft tissue surgical margin is a strong predictor of recurrence and eventual death from urothelial carcinoma of the bladder. Soft tissue surgical margin status should always be reported in the pathological reports after radical cystectomy. Due to uniformly poor outcomes patients with positive soft tissue surgical margins should be considered for studies on adjuvant local and/or systemic therapy.

International validation of the prognostic value of lymphovascular invasion in patients treated with radical cystectomy.

OBJECTIVE: To externally validate the prognostic value of lymphovascular invasion (LVI) in a large international cohort of patients treated with radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). PATIENTS AND METHODS: We collected data from 4257 patients treated with RC and pelvic lymphadenectomy for UCB, without neoadjuvant chemotherapy, at 12 centres. LVI was defined as presence of nests of tumour cells within an endothelium-lined space. RESULTS: LVI was detected in 1407 patients (33.1%); the proportion of LVI increased with advancing stage, higher grade, soft-tissue surgical margin involvement, and lymph node metastasis (P < 0.001 for all). In standard multivariate models, LVI was associated with both disease recurrence (hazard ratio 1.43, P < 0.001) and cancer-specific mortality (1.45, P < 0.001). In the entire cohort, adding LVI to a base model that included standard features improved only minimally its predictive accuracy for both recurrence and cancer-specific mortality (by 1.1% and 1.2%, respectively). In 3122 patients with negative lymph nodes, LVI remained independently associated with and improved the predictive accuracy of the standard predictors for recurrence (hazard ratio 1.68, P < 0.001; +2.3%) and cancer-specific mortality (1.70, P < 0.001; +2.4%). By contrast, in 1071 node-positive patients, LVI only marginally improved the prediction of cancer-specific recurrence (hazard ratio 1.20, P < 0.001; +0.2%) and survival (1.23, P < 0.001; +0.5%). CONCLUSIONS: LVI is strongly associated with clinical outcome in node-negative patients treated with RC. The assessment of LVI might help to identify patients who could benefit from adjuvant therapy after RC. After confirmation in different populations, LVI should be included in the staging of UCB.

Characteristics and outcomes of patients with clinical T1 grade 3 urothelial carcinoma treated with radical cystectomy: results from an international cohort.

BACKGROUND: Management of T1 grade 3 (T1G3) urothelial carcinoma of the bladder (UCB), with its variable behaviour, represents one of the most difficult challenges for urologists and patients alike. OBJECTIVE: To evaluate the characteristics and long-term outcome of patients with clinical T1G3 UCB treated with radical cystectomy (RC). DESIGN, SETTING, AND PARTICIPANTS: Data from 1136 patients treated with RC for clinical T1G3 UCB without neoadjuvant chemotherapy were collected at 12 centres located in Europe, the United States, and Canada. Median age was 67 yr (range: 29-94), with a male-to-female ratio of 4:1. MEASUREMENTS: Patients' characteristics and outcome are evaluated. RESULTS AND LIMITATIONS: Of the 1136 patients, 33.4% had non-organ-confined stage at cystectomy, and 16.2% had lymph node (LN) metastasis; 49.7% were upstaged after RC to muscle-invasive disease, while 21.4% were downstaged to lower than T1G3. Within a median follow-up of 48 mo, 35.5% of patients died of metastatic UCB. CONCLUSIONS: Approximately half of the patients treated with RC without neoadjuvant chemotherapy for clinical T1G3 UCB are upstaged to muscle-invasive UCB. These rates support the inadequacy of clinical decision making based on current treatment paradigms and staging tools. Therefore, identification of patients with clinical T1G3 disease at high risk of disease progression is of the utmost importance, as these patients are likely to benefit from early RC.

Upper urinary tract recurrence after radical cystectomy for bladder cancer--who is at risk?

PURPOSE: Patients who underwent radical cystectomy for bladder cancer are at risk for upper urinary tract recurrence. We identified subgroups of patients at increased risk for upper urinary tract recurrence. MATERIALS AND METHODS: All 1,420 patients who underwent radical cystectomy for bladder cancer at our center between January 1986 and October 2008 were included in the study. Negative frozen sections of the ureteral margins were obtained from all patients. Data analysis included preoperative tumor history, pathological findings of the cystectomy specimen and complete followup. Survival was calculated using the Kaplan-Meier method. RESULTS: Until October 2008, 25 cases of upper urinary tract recurrence were observed. The overall rate of upper urinary tract recurrence at 5, 10 and 15 years was 2.4%, 3.9% and 4.9%, respectively. Of the patients 3 had superficial tumors of the renal pelvis and 22 had invasive upper tract transitional cell carcinoma. Upper urinary tract recurrence did not develop in any patients with nontransitional cell carcinoma. Four risk factors for upper urinary tract recurrence were identified including history of carcinoma in situ (RR 2.3), history of recurrent bladder cancer (RR 2.6), cystectomy for nonmuscle invasive bladder cancer (RR 3.8) and tumor involvement of the distal ureter in the cystectomy specimen (RR 2.7). Patients with transitional cell carcinoma who had none of these risk factors had an upper urinary tract recurrence rate of only 0.8% at 15 years. This rate increased with the number of positive risk factors, ie 8.4% in patients with 1 to 2 risk factors and 13.5% in those with 3 to 4 risk factors. CONCLUSIONS: Patients who underwent cystectomy for transitional cell carcinoma and with at least 1 risk factor for upper urinary tract recurrence should have closer followup regimens than those with nontransitional cell carcinoma or without any of these risk factors.

Quantification of the survival benefit of early versus deferred cystectomy in high-risk non-muscle invasive bladder cancer (T1 G3).

OBJECTIVES: To review understaging and survival of patients who underwent early versus deferred radical cystectomy (RCX) for high-risk non-muscle invasive bladder cancer (NMIBC; T1 G3). METHODS: The results of 1,521 RCXs including 1,420 for bladder cancer were reviewed: (1) A total of 114 patients with high-risk NMIBC underwent a single TUR-BT followed by immediate RCX to estimate the understaging rate. (2) As much as 260 patients with NMIBC had long-term follow-up before RCX to determine the upgrading and upstaging over time. (3) We compared survival in patients with initial T1 G3 bladder cancer (BC) treated with early RCX (n = 175) versus deferred RCX (n = 99) for recurrent T1 G3. RESULTS: (1) Our understaging rate was 20.2%. (2) Allowing NMIBC to upgrade portents a 19% survival disadvantage. (3) The 10 years cancer-specific survival rate was 78.7% in early and 64.5% in deferred RCX. CONCLUSIONS: Early, as compared to deferred RCX, has a distinct survival advantage for high-risk NMIBC. Patients should be counselled accordingly.

Oncological followup after radical cystectomy for bladder cancer-is there any benefit?

PURPOSE: Tumor recurrence after radical cystectomy for bladder cancer can be detected in an asymptomatic patient by regular followup or in a symptomatic patient by symptom guided examination. To our knowledge it is still unknown whether detecting tumor recurrence at an asymptomatic stage offers a better survival rate. MATERIALS AND METHODS: A total of 1,270 radical cystectomies for bladder cancer were performed at a single institution between January 1, 1986 and December 2006. All patients had regular followup examinations with chest x-ray and abdominal ultrasound every 3 months, computerized tomography of the abdomen every 6 months, and bone scan and excretory urography every 12 months. Additional examinations were required for symptomatic disease. We analyzed the first site and date of tumor recurrence. Survival was compared using the log rank test. RESULTS: The 20-year recurrence rate was 48.6% in the complete series. Tumor recurrence developed in 444 patients, including 154 asymptomatic and 290 symptomatic patients, with a mean time after radical cystectomy of 20 and 17.5 months, respectively. The most frequent symptoms were pain, ileus, acute urinary retention, hydronephrosis with flank pain, hematuria, neurological symptoms and a palpable mass. Of the 444 patients 182 (41%) had local recurrence and 324 (73%) had distant failure at the time of first recurrence. The overall survival rate 1, 2 and 5 years after first recurrence was 22.5%, 10.1% and 5.5% in asymptomatic patients, and 18.9%, 8.2% and 2.9% in symptomatic patients, respectively (log rank not significant). CONCLUSIONS: This study fails to demonstrate a survival benefit for detecting tumor recurrence early at an asymptomatic stage by regular followup examinations. These data show that symptom guided followup examinations may provide similar results at lower cost.

Neobladder formation after pelvic irradiation.

OBJECTIVE: To assess the results of the use of the ileal neobladder in patients with previous pelvic irradiation. METHODS: Between January 1986 and July 2008, 1,570 radical cystectomies and 1,002 ileal neobladders were performed at a single institution. From this series, 94 patients (6%) with prior pelvic irradiation were retrospectively identified. In 25 of these irradiated patients, an ileal neobladder was done. All complications within 90 days of surgery were defined and graded using a five-grade modification of the original Clavien system and stratified into 11 categories. Functional outcome data and late complications were reported. RESULTS: Seventy-six percent of the neobladder patients versus 52% of the non-neobladder patients developed complications occurring within 90 days of surgery. However, grade 3-5 complications were less frequent in the neobladder group. Unusual and serious late complications have been observed. Nineteen out of 25 neobladder patients enjoy perfect night and day time continence. Three out of seven female and 1/18 male patients suffer from treatment refractory severe stress incontinence. One male and one female patients are primarily hypercontinent. CONCLUSIONS: Salvage surgery (cystoprostatectomy, anterior exenteration) followed by orthotopic lower urinary tract reconstruction can be a safe, effective procedure that can provide a well functioning lower urinary tract in properly selected patients with defunctionalized bladder, tumor recurrence or de novo bladder cancer after definitive radiation therapy. Prerequisits for the neobladder as procedure of choice are good renal function, perfect preoperative continence, no recurrent gastrointestinal or gynecologic tumor, no fistula formation, and no severe damage of the small bowel.