Nomogram Predicting Bladder Cancer-specific Mortality After Neoadjuvant Chemotherapy and Radical Cystectomy for Muscle-invasive Bladder Cancer: Results of an International Consortium.

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) is associated with improved overall and cancer-specific survival. The post-NAC pathological stage has previously been reported to be a major determinant of outcome. OBJECTIVE: To develop a postoperative nomogram for survival based on pathological and clinical parameters from an international consortium. DESIGN, SETTING, AND PARTICIPANTS: Between 2000 and 2015, 1866 patients with MIBC were treated at 19 institutions in the USA, Canada, and Europe. Analysis was limited to 640 patients with adequate follow-up who had received three or more cycles of NAC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A nomogram for bladder cancer-specific mortality (BCSM) was developed by multivariable Cox regression analysis. Decision curve analysis was used to assess the model's clinical utility. RESULTS AND LIMITATIONS: A total of 640 patients were identified. Downstaging to non-MIBC (ypT1, ypTa, and ypTis) occurred in 271 patients (42 %), and 113 (17 %) achieved a complete response (ypT0N0). The 5-yr BCSM was 47.2 % (95 % confidence interval [CI]: 41.2-52.6 %). On multivariable analysis, covariates with a statistically significant association with BCSM were lymph node metastasis (hazard ratio [HR] 1.90 [95% CI: 1.4-2.6]; p < 0.001), positive surgical margins (HR 2.01 [95 % CI: 1.3-2.9]; p < 0.001), and pathological stage (with ypT0/Tis/Ta/T1 as reference: ypT2 [HR 2.77 {95 % CI: 1.7-4.6}; p < 0.001] and ypT3-4 [HR 5.9 {95 % CI: 3.8-9.3}; p < 0.001]). The area under the curve of the model predicting 5-yr BCSM after cross validation with 300 bootstraps was 75.4 % (95 % CI: 68.1-82.6 %). Decision curve analyses showed a modest net benefit for the use of the BCSM nomogram in the current cohort compared with the use of American Joint Committee on Cancer staging alone. Limitations include the retrospective study design and the lack of central pathology. CONCLUSIONS: We have developed and internally validated a nomogram predicting BCSM after NAC and radical cystectomy for MIBC. The nomogram will be useful for patient counseling and in the identification of patients at high risk for BCSM suitable for enrollment in clinical trials of adjuvant therapy. PATIENT SUMMARY: In this report, we looked at the outcomes of patients with muscle-invasive bladder cancer in a large multi-institutional population. We found that we can accurately predict death after radical surgical treatment in patients treated with chemotherapy before surgery. We conclude that the pathological report provides key factors for determining survival probability.

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

BACKGROUND: Cisplatin-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 METHODS: Patients 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. RESULTS: Of 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). CONCLUSION: In 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.

Treatment patterns and trends in patients dying of prostate cancer in Quebec: a population-based study.

INTRODUCTION: Since just after the year 2000 in Quebec, the management of metastatic castration-resistant prostate cancer (mcrpc) has evolved considerably, with the inclusion of docetaxel-based chemotherapy, bone-targeted therapies (zoledronic acid and denosumab), and more recently, abiraterone, enzalutamide, and cabazitaxel for docetaxel-refractory patients. In the present study, we aimed to analyze contemporary mcrpc management patterns and therapy utilization trends in Quebec. METHODS: The study cohort consisted of patients dying of prostate cancer (pca) between January 2001 and December 2013, selected from Quebec public health care insurance databases. Patient selection was based on death from a pca-related cause or therapy used according to the Canadian Urological Association guidelines on mcrpc management. Treatments included chemotherapy (mitoxantrone before 2005 and docetaxel after 2005), abiraterone, bone-targeted therapy (zoledronic acid or denosumab, or both), and palliative radiation therapy (rt). During the study period, neither enzalutamide nor cabazitaxel was publicly reimbursed in Quebec, and as a result, no capture of their use was possible for this study. Multivariate logistic regression was used to identify factors associated with the probability of receiving chemotherapy, bone-targeted therapies, and palliative rt before death from pca. RESULTS: Overall, the database search identified 3106 patients who died of pca between January 2001 and December 2013. Median age of death was 78 years. Of those 3106 patients, just 2568 (83%) received mcrpc-specific treatments: chemotherapy, abiraterone, palliative rt, or bone-targeted therapy; the other 17% of the patients were managed solely with maximum androgen blockade (androgen deprivation therapy plus anti-androgens) despite a record of pca-related death. Logistic regression analyses indicate that patients dying after 2005 were more likely to have received chemotherapy [odds ratio (or): 1.51; 95% ci: 1.22 to 1.85] and bone-targeted therapy (or: 1.97; 95% ci: 1.64 to 2.37). Age was a significant predictor for the use of chemotherapy, bone-targeted therapy, and palliative rt (ors in the range 0.96-0.98, p < 0.05). CONCLUSIONS: Patient age seems to be a strong determinant in the of selection mcrpc therapy, affecting the probability of the use of chemotherapy, bone-targeted therapy, or palliative rt. Although chemotherapy is still used only in a small percentage of patients, the introduction of new therapies-such as bone-targeted therapy, docetaxel, and abiraterone-affected treatment selection over time. The availability of enzalutamide since February 2014 will likely produce additional changes in mcrpc management.

Urologist referral delay and its impact on survival after radical cystectomy for bladder cancer.

BACKGROUND: Evidence shows that wait times before bladder cancer surgery have been increasing, and wait time can negatively affect survival. We aimed to determine if a long delay caused by an indirect referral before a first urologist visit affects the survival of patients undergoing radical cystectomy for bladder cancer. METHODS: We analyzed data from 1271 patients who underwent surgery for bladder cancer during the decade 2000-2009. The cohort was obtained by linking two administrative databases in the province of Quebec. Patients were considered to have been directly referred to a urologist if they had 5 or fewer visits with a general practitioner before their first urologist visit; otherwise, they were considered to have been indirectly referred. The effect on survival after surgery of a longer delay before a first urologist visit was assessed using Cox regression models. RESULTS: Median referral delay for the study population was 30 days (56 days for women, 23 days for men; p < 0.0001). Indirect referral was observed for 49% of women and 33% of men. Compared with patients who were directly referred, those who were indirectly referred after first symptoms of bladder cancer experienced poorer survival (hazard ratio: 1.29; 95% confidence interval: 1.10 to 1.52). Women who were indirectly referred had a significant 47% greater risk of death after radical cystectomy. Men who were indirectly referred also experienced decreased survival (adjusted hazard ratio: 1.25; 95% confidence interval: 1.03 to 1.51). CONCLUSIONS: Patients indirectly referred to a urologist had an increased risk of mortality after surgery. Compared with men, women had longer wait times and poorer survival.

Risk stratification of pT1-3N0 patients after radical cystectomy for adjuvant chemotherapy counselling.

BACKGROUND: In pT1-T3N0 urothelial carcinoma of the bladder (UCB) patients, multi-modal therapy is inconsistently recommended. The aim of the study was to develop a prognostic tool to help decision-making regarding adjuvant therapy. METHODS: We included 2145 patients with pT1-3N0 UCB after radical cystectomy (RC), naive of neoadjuvant or adjuvant therapy. The cohort was randomly split into development cohort based on the US patients (n=1067) and validation cohort based on the Europe patients (n=1078). Predictive accuracy was quantified using the concordance index. RESULTS: With a median follow-up of 45 months, 5-year recurrence-free and cancer-specific survival estimates were 68% and 73%, respectively. pT-stage, ge, lymphovascular invasion, and positive margin were significantly associated with both disease recurrence and cancer-specific mortality (P-values ≤ 0.005). The accuracies of the multivariable models at 2, 5, and 7 years for predicting disease recurrence were 67.4%, 65%, and 64.4%, respectively. Accuracies at 2, 5, and 7 years for predicting cancer-specific mortality were 69.3%, 66.4%, and 65.5%, respectively. We developed competing-risk, conditional probability nomograms. External validation revealed minor overestimation. CONCLUSION: Despite RC, a significant number of patients with pT1-3N0 UCB experience disease recurrence and ultimately die of UCB. We developed and externally validated competing-risk, conditional probability post-RC nomograms for prediction of disease recurrence and cancer-specific mortality.

First- and second-line therapy for metastatic urothelial carcinoma of the bladder.

Urothelial cancer of the bladder is the 4th most common malignancy in American men and the 9th most common in women. Although it is a chemosensitive disease, advanced bladder cancer seems to have reached a plateau with regard to median survival of patients. Standard first-line therapy remains gemcitabine plus cisplatin (gc) or methotrexate, vinblastine, doxorubicin, and cisplatin (mvac). In patients deemed unfit to receive cisplatin, gemcitabine plus carboplatin or gemcitabine plus paclitaxel can be considered. To date, no standard therapy has been established for patients who recur or are refractory to first-line therapy. Second-line vinflunine, by way of superiority over best supportive care, has shown promise in a phase iii trial. Cisplatin-based therapy (mvac or gc) can also be offered to patients previously treated with cisplatin, especially if they responded previously and are considered platinum-sensitive. Novel targeted therapies are sorely needed to further improve the delivery and efficacy of chemotherapy.

Relationship between initial PSA density with future PSA kinetics and repeat biopsies in men with prostate cancer on active surveillance.

The objective of our study is to examine the correlation between PSA density (PSAd) at the time of diagnosis with PSA velocity (PSAV), PSA doubling time and tumour progression, on repeat biopsy, in men with prostate cancer on active surveillance. Data from 102 patients with clinically localized prostate cancer on active surveillance in the period between 1992 and 2007, who had the necessary parameters available, were collected. PSAd was calculated and correlated with PSAV, PSA doubling time (PSADT), Gleason score at diagnosis and local progression on repeated biopsies. PSAV was 0.64 and 1.31 ng ml(-1) per year (P = 0.02), PSADT of 192 and 113 months (P = 0.4) for PSAd below and above 0.15, respectively. The rate of detecting high Gleason score (≥ 7) at diagnosis was 6 and 23% for PSAd below and above 0.15, respectively. A total of 101 patients underwent at least a second biopsy and the incidence of upgrading was 10 and 31% for PSAd below and above 0.15, respectively (P = 0.001). Although low PSAd is an accepted measure for suggesting insignificant prostate cancer, our study expands its role to indicate that PSAd < 0.15 may be an additional clinical parameter that may suggest indolent disease, as measured by future PSAV and repeat biopsy over time.

Outcome of surgical treatment of patients with upper versus lower urinary tract urothelial carcinoma: stage-by-stage comparison.

OBJECTIVES: It remains controversial whether we can apply similar principles in the management of upper urinary tract urothelial carcinoma (UUT-UC) based on the behavior of bladder urothelial carcinoma (B-UC). We sought to assess whether UUT-UC and B-UC have similar biology and performed a stage-by-stage comparative analysis of outcome between the 2 groups. METHODS: A retrospective review was performed on patients who underwent nephroureterectomy for UUT-UC and radical cystectomy for B-UC from 1991 to 2006. Standard variables were collected and recurrence-free and overall survival (OS) rates were calculated. RESULTS: 280 patients with a median age of 69 years were included (99 UUT-UC treated via nephroureterectomy and 181 B-UC treated via radical cystectomy). Median follow-up was 29 months. None received neoadjuvant chemotherapy. Patients with UUT-UC presented less commonly with invasive disease compared to those with B-UC (44 vs. 77% were >pT2). Overall, 5-year OS for the B-UC group was significantly lower than for the UUT-UC group (60.8 vs. 74.5%, p = 0.02). However, when patients were stratified by stage (>pT2), patients with B-UC had similar OS compared to those with UUT-UC (54.6 vs. 60.8%, p = 0.74). CONCLUSION: Invasive UUT-UC appears to have similar tumor biology compared to B-UC. Whether we can safely extrapolate on the benefit of neoadjuvant and adjuvant strategies to patients with UUT-UC requires further investigation.

Whole-mount prostate sections reveal differential endoglin expression in stromal, epithelial, and endothelial cells with the development of prostate cancer.

Endoglin is a nonsignaling receptor for transforming growth factor that contributes to the action of this growth factor in diverse cell types. It may also exhibit a function of its own. Endoglin levels vary with disease states and is a marker of new blood vessels. We studied endoglin expression in whole-mount prostate sections from 64 patients with localized prostate cancer, assessing reactivity in the epithelium, the stroma, and blood vessels. Cells in normal/benign acini were negative but significantly immunoreactive (P<0.001) in both prostatic intraepithelial neoplasia (PIN; 52% of cases) and malignant areas (77% of cases). In tumors, this involved less than 25% of malignant cells in 59% of specimens. The endoglin-stained stroma was detected mainly in areas surrounding PIN acini and tumors. Endoglin antibodies detected more microvessels than von Willebrand Factor antibodies in all prostatic areas (P<0.01). In addition, the number of microvessels increased with the development of cancer and correlated with Gleason score (P<0.01). Changes in endoglin expression in PIN and malignant cells, the surrounding stroma, and related blood vessels, suggest that endoglin function may be altered in prostate cancer.

Natural history of renal masses followed expectantly.

PURPOSE: An increasing number of incidental renal masses have been detected with increasing use of ultrasonography, computerized tomography and magnetic resonance imaging. We investigated the natural history of incidentally detected renal masses. MATERIALS AND METHODS: A total of 24 patients were included in this retrospective analysis. Average patient age was 68.3 years (range 29 to 83). The 16 males and 8 females were followed with abdominal imaging for a mean and median followup of 31.6 and 24 months, respectively (range 8 to 86). Patients elected to be observed because of age, poor medical condition or the presence of a mass in a solitary kidney. The majority of patients (22 of 24) were asymptomatic at diagnosis. Two patients were followed with bilateral renal masses, and 2 with T3b tumors. Of the 20 patients with incidental solitary renal masses, 6 were at the upper pole, 9 were mid polar and 5 lower pole. Mean maximum diameter of lesions was 3.3 cm (median 2.7, range 0.9 to 10). Growth rate was calculated based on diameter and tumor volume. RESULTS: Of the 24 patients only 5 demonstrated tumor growth during the surveillance period. No metastasis developed in any patients. Mean tumor growth rate observed in the 5 patients was 0.49 cm per year or 7.3 cc per year. Of the 24 patients 4 underwent surgery after surveillance because of apparent tumor growth or per patient request. Pathology revealed renal cell carcinoma in all 4. CONCLUSIONS: Tumor growth of renal masses is often limited. Most of our patients did not demonstrate significant growth when followed expectantly. Without tumor growth the risk of metastasis seems limited.

Bellini duct carcinoma with ovarian metastasis.

We report a case of collecting duct carcinoma presenting as pyelonephritis with hypercalcemia and metastasis to the ovary. Case management and literature review being presented.

A comparison of the International Index of Erectile Function and erectile dysfunction studies.

OBJECTIVE: To evaluate the ability of the five-item version of the International Index of Erectile Function (IIEF-5) to diagnose the vascular aetiology and severity of erectile dysfunction (ED), and to compare it with pharmacological testing and duplex Doppler ultrasonography, as such questionnaires are widely used by the pharmaceutical industry to categorize the severity of ED and to assess the efficacy of drug therapy. PATIENTS AND METHODS: In all, 80 patients (mean age 45.2 years, sd 14.0; mean duration of ED 3.5 years) were reviewed by an examiner unaware of their IIEF scores during testing. Penile blood flow was assessed in each patient after an intracavernosal injection with prostaglandin-E1 (10 micro g), with self-stimulation in privacy. The peak systolic velocity, end diastolic velocity and resistive index were measured for the vascular diagnosis. Visual ratings of erectile responses were also used for analysis. RESULTS: Of the 80 patients, 30 had a normal vascular response, 38 arterial insufficiency and 12 were diagnosed with venous leakage. There was no significant difference in the IIEF scores among patients with a normal vascular response, arterial insufficiency or venous leakage. Analysis of visual ratings of erections showed no difference in IIEF scores among the different groups of patients. CONCLUSION: The IIEF was designed and developed specifically for assessing and evaluating sexual function in clinical trials. However, as shown here, the IIEF cannot and should not be used as a tool to diagnose or compare specific vascular causes of ED.

Collagen injection for treatment of urinary incontinence in children.

PURPOSE: We assess the success rate of periurethral collagen injection in children with neurogenic bladder dysfunction secondary to myelomeningocele. MATERIALS AND METHODS: From 1992 to 1998, 15 male and 5 female patients with spina bifida (age 13.3 +/- 3.8 years) underwent endoscopic collagen injection for the treatment of urinary incontinence secondary to sphincter deficiency. Mean followup was 4.2 years. Pretreatment urodynamic study showed a stable compliant bladder with an average leak point pressure of 52 cm. H2O (range 23 to 100). Concurrent medical management included anticholinergics in 15 cases, agonists in 3, and clean intermittent catheterization in 16. Five patients had undergone previous ileocystoplasty. RESULTS: Collagen injections were given with the patient under general anesthesia. The number of injections was 1 in 5 cases, 2 in 11, 3 in 3, and 4 in 1. Average collagen volume injected per treatment was 6.6 cc (range 2 to 13). All patients were evaluated on a subjective continence scale of no change (wet), improved or completely dry at the time of assessment. Of the 20 patients, 16 had no change, 3 showed improvement and 1 was dry. Initial improvement in the first 2 months after injection deteriorated thereafter in 16 cases. CONCLUSIONS: The previously reported high success rate of collagen injection is not supported by this study. With long-term followup collagen injection is rarely effective for treating urinary incontinence in children with neurogenic sphincter deficiency.

Altered reactivity of pulmonary vessels in postobstructive pulmonary vasculopathy.

Chronic ligation of one pulmonary artery results in pulmonary vascular remodeling and bronchial angiogenesis, collectively known as postobstructive pulmonary vasculopathy (POPV). To investigate pulmonary vascular reactivity in POPV, we ligated the left main pulmonary artery of guinea pigs and, after 1-10 mo, prepared explants by inflating lungs with agarose and sectioning them into approximately 1-mm-thick slices; we measured areas of pulmonary vessels and determined contractile responses to histamine and serotonin (5-HT) and relaxant responses to ACh and sodium nitroprusside. We found maximal contractions of arteries to 5-HT (24. 4 +/- 2.6%) and of veins to histamine (53.9 +/- 4.7%) were significantly increased in POPV of 3-mo duration compared with those of controls (16.8 +/- 1.5 and 40.8 +/- 5.0%, respectively). Relaxation of arteries with ACh was enhanced at 10 mo but not at 1 mo after ligation. Relaxation with sodium nitroprusside was increased in veins at 1 mo after ligation but was not altered in arteries. Morphometry revealed reduced diameters of arteries and veins without increased medial thickness. Our data suggest that the enhanced contractile responses of pulmonary vessels to histamine and 5-HT in POPV were not a result of endothelial dysfunction or of structural alterations but might be caused by as-yet-undiscovered mechanisms.