Bladder cancer can be classified histologically as urothelial or non-urothelial. Urothelial cancer has a propensity for divergent differentiation, which has increasingly been recognized in recent ...years due to heightened awareness and improved immunohistochemistry techniques. Furthermore, the recent World Health Organization classification of urothelial cancers improved clarity on this issue, with its listing of 13 histologic variants of urothelial cancer. The divergent differentiation patterns include, amongst others, squamous, glandular, micropapillary, nested, lymphepithelioma-like, plasmacytoid and sarcomatoid variants of urothelial cancer. Attempts to quantify the amount of divergent differentiation present, such as using the nonconventional differentiation number, have been made recently, which will improve the ability to compare publications from different centres. Genetic-based studies have indicated that the histologic variants of urothelial cancer arise from a common clonal precursor. Mostly, the current evidence suggests that urothelial cancer with divergent differentiation has a worse prognosis when compared with pure urothelial cancer. This article will review the current literature on variant histologies of urothelial cancer, and well as new developments in pure squamous cell carcinoma, small cell carcinoma and adenocarcinoma of the bladder.
The role of adjuvant chemotherapy for patients with high-risk urothelial carcinoma of the bladder (UCB) is not well defined. Here we address the value of adjuvant chemotherapy in patients undergoing ...radical cystectomy for UCB in an off-protocol routine clinical setting.
We collected and analyzed data from 11 centers contributing retrospective cohorts of patients with UCB treated with radical cystectomy without neoadjuvant chemotherapy. Patients were grouped into quintiles based on their risk of disease progression using estimates from a fitted multivariable Cox proportional hazards model. The association of adjuvant chemotherapy with survival was explored across separate quintiles.
The cohort consisted of 3,947 patients, 932 (23.6%) of whom received adjuvant chemotherapy. Adjuvant chemotherapy was independently associated with improved survival (hazard ratio, 0.83; 95% confidence interval, 0.72-0.97%, P = 0.017). However, the effect of adjuvant chemotherapy was significantly modified by the individual's risk of disease progression such that an increasing benefit from adjuvant chemotherapy was seen across higher-risk subgroups (P < 0.001). There was a significant improvement in survival between the treated and nontreated patients in the highest-risk quintile (hazard ratio, 0.75; 95% confidence interval, 0.62-0.90; P = 0.002). This group was characterized by an estimated 32.8% 5-year probability of cancer-specific survival, with 86.6% of patients having both advanced pathologic stage (> or =T(3)) and nodal involvement.
Adjuvant chemotherapy is associated with a significant improvement in survival for patients treated in an off-protocol clinical setting. Selective administration in patients at the highest risk for disease progression, such as those with advanced pathologic stage and nodal involvement, may optimize the therapeutic benefit of adjuvant chemotherapy.
Extracellular vesicles released by prostate cancer present in seminal fluid, urine, and blood may represent a non-invasive means to identify and prioritize patients with intermediate risk and high ...risk of prostate cancer. We hypothesize that enumeration of circulating prostate microparticles (PMPs), a type of extracellular vesicle (EV), can identify patients with Gleason Score≥4+4 prostate cancer (PCa) in a manner independent of PSA.
Plasmas from healthy volunteers, benign prostatic hyperplasia patients, and PCa patients with various Gleason score patterns were analyzed for PMPs. We used nanoscale flow cytometry to enumerate PMPs which were defined as submicron events (100-1000nm) immunoreactive to anti-PSMA mAb when compared to isotype control labeled samples. Levels of PMPs (counts/µL of plasma) were also compared to CellSearch CTC Subclasses in various PCa metastatic disease subtypes (treatment naïve, castration resistant prostate cancer) and in serially collected plasma sets from patients undergoing radical prostatectomy.
PMP levels in plasma as enumerated by nanoscale flow cytometry are effective in distinguishing PCa patients with Gleason Score≥8 disease, a high-risk prognostic factor, from patients with Gleason Score≤7 PCa, which carries an intermediate risk of PCa recurrence. PMP levels were independent of PSA and significantly decreased after surgical resection of the prostate, demonstrating its prognostic potential for clinical follow-up. CTC subclasses did not decrease after prostatectomy and were not effective in distinguishing localized PCa patients from metastatic PCa patients.
PMP enumeration was able to identify patients with Gleason Score ≥8 PCa but not patients with Gleason Score 4+3 PCa, but offers greater confidence than CTC counts in identifying patients with metastatic prostate cancer. CTC Subclass analysis was also not effective for post-prostatectomy follow up and for distinguishing metastatic PCa and localized PCa patients. Nanoscale flow cytometry of PMPs presents an emerging biomarker platform for various stages of prostate cancer.
Objective
To evaluate the effect of adjuvant chemotherapy (AC) on mortality after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) with positive lymph nodes (LNs) and to ...identify patient subgroups that are most likely to benefit from AC.
Patients and methods
We retrospectively analysed data of 263 patients with LN‐positive UTUC, who underwent full surgical resection. In all, 107 patients (41%) received three to six cycles of AC, while 156 (59.3%) were treated with RNU alone. UTUC‐related mortality was evaluated using competing‐risks regression models.
Results
In all patients (Tall N+), administration of AC had no significant impact on UTUC‐related mortality on univariable (P = 0.49) and multivariable (P = 0.11) analysis. Further stratified analyses showed that only N+ patients with pT3–4 disease benefited from AC. In this subgroup, AC reduced UTUC‐related mortality by 34% (P = 0.019). The absolute difference in mortality was 10% after the first year and increased to 23% after 5 years. On multivariable analysis, administration of AC was associated with significantly reduced UTUC‐related mortality (subhazard ratio 0.67, P = 0.022). Limitations of this study are the retrospective non‐randomised design, selection bias, absence of a central pathological review and different AC protocols.
Conclusions
AC seems to reduce mortality in patients with pT3–4 LN‐positive UTUC after RNU. This subgroup of LN‐positive patients could serve as target population for an AC prospective randomised trial.
Study Type – Prognosis (retrospective cohort) Level of Evidence 2b
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.
What's known on the subject? and What does the study add?
Little is known on the association between obesity and urothelial carcinoma of the bladder (UCB). Most studies have shown that higher body ...mass index (BMI) is associated with higher rates of perioperative complications. Only one study specifically investigated obesity and bladder cancer‐specific outcomes and reported no significant association between higher BMI and disease‐specific survival in patients with UCB treated with radical cystectomy. However, that study was limited by its small sample size and a high rate of preoperative therapies.
In contrast to the only previous study evaluating the association of BMI with oncological outcomes in UCB, we found that obesity (BMI ≥30 kg/m2) was associated with features of biologically aggressive UCB and clinical outcomes after radical cystectomy and, even when adjusting for the effects of standard clinicopathological features, obesity remained an independent predictor of cancer recurrence, cancer‐specific mortality and overall mortality.
Objective
To investigate the association between body mass index (BMI) and oncological outcomes in patients after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) in a large multi‐institutional series.
Patients and Methods
Data were collected from 4118 patients treated with RC and pelvic lymphadenectomy for UCB. Patients receiving preoperative chemotherapy or radiotherapy were excluded.
Univariable and multivariable models tested the effect of BMI on disease recurrence, cancer‐specific mortality and overall mortality.
BMI was analysed as a continuous and categorical variable (<25 vs 25–29 vs ≥30 kg/m2).
Results
Median BMI was 28.8 kg/m2 (interquartile range 7.9); 25.3% had a BMI <25 kg/m2, 32.5% had a BMI between 25 and 29.9 kg/m2, and 42.2% had a BMI ≥30 kg/m2.
Patients with a higher BMI were older (P < 0.001), had higher tumour grade (P < 0.001), and were more likely to have positive soft tissue surgical margins (P = 0.006) compared with patients with lower BMI.
In multivariable analyses that adjusted for the effects of standard clinicopathological features, BMI >30 was associated with higher risk of disease recurrence (hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.46–1.91, P < 0.001), cancer‐specific mortality (HR 1.43, 95% CI 1.24–1.66, P < 0.001), and overall mortality (HR 1.81, CI 1.60–2.05, P < 0.001). Themain limitation is the retrospective design of the study.
Conclusions
Obesity is associated with worse cancer‐specific outcomes in patients treated with RC for UCB.
Focusing on patient‐modifiable factors such as BMI may have significant individual and public health implications in patients with invasive UCB.
Prostate cancer risk calculators incorporate many factors to evaluate an individual's risk for prostate cancer. We validated two common North American-based, prostate cancer risk calculators.
We ...conducted a prospective, multi-institutional study of 2,130 patients who underwent a prostate biopsy for prostate cancer detection from five centers. We evaluated the performance of the Sunnybrook nomogram-based prostate cancer risk calculator (SRC) and the Prostate Cancer Prevention Trial (PCPT) -based risk calculator (PRC) to predict the presence of any cancer and high-grade cancer. We examined discrimination, calibration, and decision curve analysis techniques to evaluate the prediction models.
Of the 2,130 patients, 867 men (40.7%) were found to have cancer, and 1,263 (59.3%) did not have cancer. Of the patients with cancer, 403 (46.5%) had a Gleason score of 7 or more. The area under the concentration-time curve (AUC) for the SRC was 0.67 (95% CI, 0.65 to 0.69); the AUC for the PRC was 0.61 (95% CI, 0.59 to 0.64). The AUC was higher for predicting aggressive disease from the SRC (0.72; 95% CI, 0.70 to 0.75) compared with that from the PRC (0.67; 95% CI, 0.64 to 0.70). Decision curve analyses showed that the SRC performed better than the PRC for risk thresholds of more than 30% for any cancer and more than 15% for aggressive cancer.
The SRC performed better than the PRC, but neither one added clinical benefit for risk thresholds of less than 30%. Further research is needed to improve the AUCs of the risk calculators, particularly for higher-grade cancer.
A novel TRIM family member, TRIM59 gene was characterized to be upregulated in SV40 Tag oncogene-directed transgenic and knockout mouse prostate cancer models as a signaling pathway effector. We ...identified two phosphorylated forms of TRIM59 (p53 and p55) and characterized them using purified TRIM59 proteins from mouse prostate cancer models at different stages with wild-type mice and NIH3T3 cells as controls. p53/p55-TRIM59 proteins possibly represent Ser/Thr and Tyr phosphorylation modifications, respectively. Quantitative measurements by ELISA showed that the p-Ser/Thr TRIM59 correlated with tumorigenesis, whereas the p-Tyr-TRIM59 protein correlated with advanced cancer of the prostate (CaP). The function of TRIM59 was elucidated using short hairpin RNA (shRNA)-mediated knockdown of the gene in human CaP cells, which caused S-phase cell-cycle arrest and cell growth retardation. A hit-and-run effect of TRIM59 shRNA knockdown was observed 24 hours posttransfection. Differential cDNA microarrray analysis was conducted, which showed that the initial and rapid knockdown occurred early in the Ras signaling pathway. To confirm the proto-oncogenic function of TRIM59 in the Ras signaling pathway, we generated a transgenic mouse model using a prostate tissue-specific gene (PSP94) to direct the upregulation of the TRIM59 gene. Restricted TRIM59 gene upregulation in the prostate revealed the full potential for inducing tumorigenesis, similar to the expression of SV40 Tag, and coincided with the upregulation of genes specific to the Ras signaling pathway and bridging genes for SV40 Tag-mediated oncogenesis. The finding of a possible novel oncogene in animal models will implicate a novel strategy for diagnosis, prognosis, and therapy for cancer.
Purpose The conventional primary end point in trials of perioperative systemic therapy for muscle invasive bladder cancer is 5-year overall survival. We identified an association between disease-free ...survival at 2 to 3 years and 5-year overall survival. Materials and Methods We retrospectively analyzed a multicenter database containing records of 2,724 patients treated with radical cystectomy for muscle invasive bladder cancer with negative margins. Of these patients 844 had received adjuvant chemotherapy. We evaluated the association of disease-free survival at 2 and 3 years with overall survival at 5 years using Cox proportional hazards modeling and the kappa statistic. Results Overall 2-year/3-year disease-free survival was 0.63/0.57 and 5-year overall survival was 0.47. The overall agreement between 2-year disease-free survival and 5-year overall survival was 79%, and between 3-year disease-free survival and 5-year overall survival was 81%. Agreements were similar when analyzed within pathological substages, radical cystectomy decades and adjuvant chemotherapy subgroups. The kappa statistic was 0.57 (95% CI 0.53–0.60) for 2-year disease-free survival/5-year overall survival and 0.61 (95% CI 0.58–0.64) for 3-year disease-free survival/5-year overall survival, indicating moderate agreement. The hazard ratio for disease-free survival as a time dependent variable was 12.7 (95% CI 11.60–13.90), indicating a strong relationship between disease-free and overall survival. Conclusions Disease-free survival rates at 2 and 3 years correlate with and are potential intermediate surrogates for 5-year overall survival in patients treated with radical cystectomy for muscle invasive bladder cancer regardless of adjuvant chemotherapy. These data warrant external validation and may expedite the development of adjuvant systemic therapy. In addition, they may be applicable to the neoadjuvant setting.
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