Thromboprophylaxis during neoadjuvant chemotherapy for bladder cancer reduces thromboembolism and bleeding.

OBJECTIVES: To assess the risk of venous thromboembolic events (VTEs) and bleeding with or without thromboprophylaxis during neoadjuvant chemotherapy in bladder cancer patients scheduled for radical cystectomy. MATERIALS AND METHODS: We conducted a retrospective cohort study in 4886 patients with non-metastatic bladder cancer undergoing cystectomy across 28 centres in 13 countries between 1990 and 2021. Inverse probability weighting analyses were performed to estimate the effect of thromboprophylaxis on VTE and bleeding. RESULTS: In 147 patients (3%) VTEs were recorded within the first year. These occurred a median (interquartile range [IQR]) of 127 (82-198) days after bladder cancer diagnosis. Bleeding events occurred in 131 patients (3%) within the first year. These occurred a median (IQR) of 101 (83-171) days after cancer diagnosis. In inverse probability weighting analyses, compared to patients without thromboprophylaxis during chemotherapy, patients with thromboprophylaxis had not only a lower risk of VTE (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.12-0.81; P = 0.016) but also a lower bleeding risk (HR 0.03, 95% CI 0.09-0.12; P <0.0001). The retrospective nature of the study was its main limitation. CONCLUSIONS: In this retrospective analysis, the benefit of thromboprophylaxis during neoadjuvant chemotherapy before cystectomy is in line with data from randomised trials in other malignancies. Our data suggest thromboprophylaxis is protective against VTEs and should be the standard of care during neoadjuvant chemotherapy.

Carboplatin-based adjuvant chemotherapy versus observation after radical cystectomy in patients with pN1-3 urothelial bladder cancer.

PURPOSE: To test the impact of carboplatin-based ACT on overall survival (OS) in patients with pN1-3 cM0 BCa. METHODS: A retrospective analysis was conducted on 1057 patients with pTany pN1-3 cM0 urothelial BCa treated with or without carboplatin-based ACT after radical cystectomy and bilateral lymph-node dissection between 2002 and 2018 at 12 European and North-American hospitals. No patient received neoadjuvant chemotherapy or radiation therapy. Only patients with negative surgical margins at surgery were included. A 3:1 propensity score matching (PSM) was performed using logistic regression to adjust for baseline characteristics. Univariable and multivariable Cox regression analyses were used to predict the effect of carboplatin-based ACT on OS. The Kaplan-Meier method was used to display OS in the matched cohort. RESULTS: Of the 1057 patients included in the study, 69 (6.5%) received carboplatin-based ACT. After PSM, 244 total patients were identified in two cohorts that did not differ for baseline characteristics. Death was recorded in 114 (46.7%) patients over a median follow-up of 19 months. In the multivariable Cox regression analyses, increasing age at surgery (hazard ratio [HR] 1.02, 95% confidence interval [CI] 1.01-1.06, p < 0.001) and increasing number of positive lymph nodes (HR 1.06, 95% CI 1.01-1.07, p = 0.02) were independent predictors of worse OS. The delivery of carboplatin-based ACT was not predictive of improved OS (HR 0.67, 95% CI 0.43-1.04, p = 0.08). The main limitations of this study are its retrospective design and the relatively low number of patients involved. CONCLUSIONS: Carboplatin-based might not improve OS in patients with pN1-3 cM0 BCa. Our results underline the need for alternative therapies for cisplatin-ineligible patients.

Immediate radical cystectomy versus BCG immunotherapy for T1 high-grade non-muscle-invasive squamous bladder cancer: an international multi-centre collaboration.

PURPOSE: To compare cancer-specific mortality (CSM) and overall mortality (OM) between immediate radical cystectomy (RC) and Bacillus Calmette-Guérin (BCG) immunotherapy for T1 squamous bladder cancer (BCa). METHODS: We retrospectively analysed 188 T1 high-grade squamous BCa patients treated between 1998 and 2019 at fifteen tertiary referral centres. Median follow-up time was 36 months (interquartile range: 19-76). The cumulative incidence and Kaplan-Meier curves were applied for CSM and OM, respectively, and compared with the Pepe-Mori and log-rank tests. Multivariable Cox models, adjusted for pathological findings at initial transurethral resection of bladder (TURB) specimen, were adopted to predict tumour recurrence and tumour progression after BCG immunotherapy. RESULTS: Immediate RC and conservative management were performed in 20% and 80% of patients, respectively. 5-year CSM and OM did not significantly differ between the two therapeutic strategies (Pepe-Mori test p = 0.052 and log-rank test p = 0.2, respectively). At multivariable Cox analyses, pure squamous cell carcinoma (SqCC) was an independent predictor of tumour progression (p = 0.04), while concomitant lympho-vascular invasion (LVI) was an independent predictor of both tumour recurrence and progression (p = 0.04) after BCG. Patients with neither pure SqCC nor LVI showed a significant benefit in 3-year recurrence-free survival and progression-free survival compared to individuals with pure SqCC or LVI (60% vs. 44%, p = 0.04 and 80% vs. 68%, p = 0.004, respectively). CONCLUSION: BCG could represent an effective treatment for T1 squamous BCa patients with neither pure SqCC nor LVI, while immediate RC should be preferred among T1 squamous BCa patients with pure SqCC or LVI at initial TURB specimen.

Oncologic Surveillance for Variant Histology Bladder Cancer after Radical Cystectomy.

PURPOSE: Presently, major guidelines do not provide specific recommendations on oncologic surveillance for patients who harbor variant histology (VH) bladder cancer (BCa) at radical cystectomy. We aimed to create a personalized followup scheme that dynamically weighs other cause mortality (OCM) vs the risk of recurrence for VH BCa, and to compare it with a similar one for pure urothelial carcinoma (pUC). MATERIALS AND METHODS: Within a multi-institutional registry, 528 and 1,894 patients with VH BCa and pUC, respectively, were identified. The Weibull regression was used to detect the time points after which the risk of OCM exceeded the risk of recurrence during followup. The risk of OCM over time was stratified based on age and comorbidities, and the risk of recurrence on pathological stage and recurrence site. RESULTS: Individuals with VH had a higher risk of recurrence (recurrence-free survival 30% vs 51% at 10 years, p <0.001) and shorter median time to recurrence (88 vs 123 months, p <0.01) relative to pUC. Among VH, micropapillary variant conferred the greatest risk of recurrence on the abdomen and lungs, and mixed variants carried the greatest risk of metastasizing to bones and other sites compared to pUC. Overall, surveillance should be continued for a longer time for individuals with VH BCa. Notably, patients younger than 60 years with VH and pT0/Ta/T1/N0 at radical cystectomy should continue oncologic surveillance after 10 years vs 6.5 years for pUC individuals. CONCLUSIONS: VH BCa is associated with greater recurrence risk than pUC. A followup scheme that is valid for pUC should not be applied to individuals with VH. Herein, we present a personalized approach for surveillance that may allow an improved shared decision.

Trends in risk-group distribution and Pentafecta outcomes in patients treated with nerve-sparing, robot-assisted radical prostatectomy: a 10-year low-intermediate volume single-center experience.

PURPOSE: To evaluate the trends in risk-group distribution and Pentafecta outcomes in patients treated with nerve-sparing (NS), robot-assisted radical prostatectomy (RARP) in a single low-intermediate volume prostate cancer (PCa) center over a 10-year period. MATERIALS AND METHODS: We queried a prospectively maintained database for patients who underwent NS RARP between 2009 and 2018 in a low-intermediate volume PCa center. Risk-groups were defined according to the D'Amico classification. Pentafecta outcomes referred to the postsurgical presence of potency and continence, and the absence of biochemical recurrence (BCR), positive surgical margins (PSM), and perioperative complications. The Kruskall-Wallis test, the t test and the Mann-Whitney tests were used when appropriate. RESULTS: 603 patients underwent NS RARP and 484 patients were evaluated for Pentafecta outcomes. Median postsurgical follow-up was 28 months. Overall, 137 (22.7%), 376 (62.3%), and 90 (15%) patients were diagnosed in the low-, intermediate-, and high-risk groups, respectively. Patients undergoing NS RARP shifted from 33 to 20% in the low-risk group, from 52 to 62% in the intermediate-risk group, and from 10 to 13% in the high-risk group. Patients reaching Pentafecta increased from 38 to 44%. No postoperative potency was the main reason for non-achieving Pentafecta (71%). BCR strongly limited Pentafecta achievement in the high-risk group (61%), but not in intermediate (24%) and low-risk (30%) groups. CONCLUSIONS: Low-intermediate volume PCa centers show similar trends to high-volume centers regarding risk group distributions over time in PCa patients undergoing NS RARP. We reported an increase in Pentafecta outcomes achievement over time even for experienced surgeons. Pentafecta outcomes achievement is risk-group dependent.

The impact of treatment modality on survival in patients with clinical node-positive bladder cancer: results from a multicenter collaboration.

PURPOSE: To assess the impact of perioperative chemotherapy on survival in cN+ BCa patients and analyze it according to the pN status. METHODS: A retrospective analysis was conducted on 639 BCa patients with cTanyN1-3M0 BCa treated with radical cystectomy (RC) and bilateral lymph node dissection (LND) with or without perioperative chemotherapy in ten tertiary referral centers from 1990 to 2017. Selected cN+ patients received induction chemotherapy (IC), whereas adjuvant chemotherapy (ACT) was delivered to selected pN+ patients. Univariable and multivariable Cox regression analyses were used to predict overall mortality (OM) after surgery, adjusting for clinicopathological confounders. Kaplan-Meier analyses assessed OM according to the treatment modality. RESULTS: Overall, 356 (56%) patients were treated with surgery alone, 155 (24%) with IC followed by surgery, and 128 (20%) with ACT following surgery. Over a median follow-up of 25 months, 316 deaths were recorded. At univariable analysis, patients treated with IC and surgery had lower OM both considering cN+ [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.87, p = 0.004] and cN+pN- patients (HR 0.61, 95% CI 0.37-0.99, p = 0.05) compared to those treated with surgery alone. cN+pN+ patients treated with ACT experienced lower OM compared to those treated with IC or surgery alone at multivariable analysis (HR 0.40, 95% CI 0.22-0.74, p = 0.003). CONCLUSION: Patients with cTany cN+ cM0 BCa benefit more in terms of OS when treated with IC followed by RC + LND compared to RC + LND alone, regardless of LNMs at final histopathology examination. More data are needed to assess the role of ACT in the management of cN+ patients.

Adjuvant chemotherapy is ineffective in patients with bladder cancer and variant histology treated with radical cystectomy with curative intent.

OBJECTIVES: Adjuvant chemotherapy (ACT) is recommended for non-organ-confined bladder cancer (BCa) after radical cystectomy (RC) and pelvic lymph node dissection (PLND), but there are sparse data regarding its specific efficacy in patients with histological variants. The aim of our study was to evaluate the role of ACT on survival outcomes in patients with variant histology in a large multicenter cohort. MATERIALS AND METHODS: We retrospectively evaluated data of 3963 patients with BCa treated with RC and bilateral PLND with curative intent at several institutions between 1999 and 2018. The histological type was classified into six groups: pure urothelial carcinoma (PUC) or squamous, sarcomatoid, micropapillary, glandular and neuroendocrine differentiation. Multivariable competing risk analysis was applied to assess the role of ACT on recurrence and cancer-specific mortality (CSM) in each histological subtype. RESULTS: Of the 3963 patients included in the study, 23% had variant histology at RC specimen and 723 (18%) patients received ACT. ACT was found to be significantly associated with reduced risk of recurrence (sub-hazard ratio [SHR]: 0.55, confidence interval [CI] 0.42-0.71, p < 0.001) and CSM (SHR: 0.58, CI 0.44-0.78, p < 0.001) in the PUC only, while no histological subtype received a significant benefit on survival outcomes (all p > 0.05) from administration of ACT. The limitation of the study includes the retrospective design, the lack of a central pathology review and the number of ACT cycles. CONCLUSION: In our study, the administration of ACT was associated with improved survival outcomes in PUC only. No histological subtype found a benefit in overall recurrence and CSM from ACT.

Delaying BCG immunotherapy onset after transurethral resection of non-muscle-invasive bladder cancer is associated with adverse survival outcomes.

PURPOSE: This study was carried out to assess whether a prolonged time between primary transurethral resection of non-muscle-invasive bladder cancer (TURB) and implementation of bacillus Calmette-Guerin (BCG) immunotherapy (time to BCG; TTBCG) is associated with adverse oncological survival in patients with T1 high-grade (HG) non-muscle-invasive bladder cancer (NMIBC). MATERIALS AND METHODS: Data on 429 patients from 13 tertiary care centers with primary T1HG NMIBC treated with reTURB and maintenance BCG between 2001 and 2019 were retrospectively reviewed. Change-point regression was applied following Muggeo's approach. The population was divided into subgroups according to TTBCG, whereas the recurrence-free survival (RFS) and progression-free survival (PFS) were estimated with log-rank tests. Additionally, Cox regression analyses were performed. Due to differences in baseline patient characteristics, propensity-score-matched analysis (PSM) and inverse-probability weighting (IPW) were implemented. RESULTS: The median TTBCG was 95 days (interquartile range (IQR): 71-127). The change-point regression analysis revealed a gradually increasing risk of recurrence with growing TTBCG. The risk of tumor progression gradually increased until a TTBCG of approximately 18 weeks. When the study population was divided into two subgroups (time intervals: ≤ 101 and > 101 days), statistically significant differences were found for both RFS (p = 0.029) and PFS (p = 0.005). Furthermore, in patients with a viable tumor at reTURB, there were no differences in RFS and PFS. After both PSM and IPW, statistically significant differences were found for both RFS and PFS, with worse results for longer TTBCG. CONCLUSION: This study shows that delaying BCG immunotherapy after TURB of T1HG NMIBC is associated with an increased risk of tumor recurrence and progression.

A risk-group classification model in patients with bladder cancer under neoadjuvant cisplatin-based combination chemotherapy.

The objective of the current research was to explore the potential prognostic value of readily available clinical and pathologic variables in bladder cancer. The novel association found between cholesterol levels and prognosis may provide the rationale for exploring novel treatments. Patients included had histologically confirmed urothelial bladder cancer and were treated with at least 3 cycles of cisplatin-based neoadjuvant chemotherapy before radical cystectomy with lymphadenectomy. A total of 245 patients at low, intermediate and high risk, presenting with 0-1, 2 or 3-4 risk factors, including positive lymph nodes, Hb <12.8, NLR ≥2.7 and cholesterol levels ≥199, were included. Five-year cancer-specific survival rate was 0.67, 0.78 and 0.94 at high, intermediate and low risk, respectively. Total cholesterol levels at the time of cystectomy may represent a commonly assessable prognostic factor and may be incorporated in a clinically meaningful risk-group classification model.

Lay abstract This present study assessed a large group of patients with urothelial bladder cancer treated with chemotherapy followed by radical cystectomy, to capture the predictive power of commonly collected clinical, pathological and biochemical factors. The design of the study highlighted that higher cholesterol levels at the time of cystectomy were associated with shorter cancer-specific survival. This finding suggests that high blood-cholesterol levels truly have a negative influence on surviving cancer. In conclusion, total cholesterol levels at the time of cystectomy may represent a commonly assessable prognostic factor and could be incorporated into a clinically meaningful and valuable risk-group classification model.

How to improve patient selection for neoadjuvant chemotherapy in bladder cancer patients candidate for radical cystectomy and pelvic lymph node dissection.

PURPOSE: To improve patient selection for neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) in bladder cancer patients (BCa). METHODS: Retrospective evaluation of 1057 patients with cT2-4N0M0 BCa treated with RC and pelvic lymph node dissection between 1990 and 2018 at 3 referral centers. Adverse pathologic features (APF) were defined as pT3-pT4/pN + disease at RC. A regression tree model (CART) was used to assess preoperative risk group classes. A multivariable logistic regression (MVA) was performed to identify predictors of APF at RC. RESULTS: Median age was 70 years and most of the patients were men (83%). Of the 1057 patients included in our study, 688 (65%) had APF. CART analysis was able to stratify patients into 3 risk groups: low (cT2 and single disease, odds ratio [OR] 0.62), intermediate (cT2 and multiple disease, OR 1.08), and high (cT3-cT4, OR 1.28). On MVA APF were associated with variant histology (odds ratio [OR] 3.97, 95% confidence interval [CI] 1.46-10.83, p = 0.007), multifocality at TUR (OR 2.56, CI 1.27-5.17, p = 0.09), completeness of resection (OR 0.47, CI 0.23-0.96, p = 0.04) and clinical extravesical disease (OR 3.42, CI 1.63-7.14, p = 0.001). CONCLUSION: We defined three pre-operative risk classes. Our results indicate that patients with a cT3-T4 disease are those who might benefit more from NAC whereas those with T2 single disease should be those to whom NAC probably shouldn't be proposed. Given the high rate of understaging in BCa patients, NAC can be proposed in selected cases of cT2/multifocal disease.

Incidence and survival outcomes in patients with upper urinary tract urothelial carcinoma diagnosed with variant histology and treated with nephroureterectomy.

OBJECTIVE: To evaluate the incidence and survival outcomes of histological variants of upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). MATERIALS AND METHODS: We retrospectively analysed data from 1610 patients treated with RNU for clinically non-metastatic UTUC between 1990 and 2016 in several centres participating in the UTUC Collaboration. Histological variants were classified as micropapillary, squamous, sarcomatoid and other, including other rare variants (<10 cases for each). Multivariable competing risk analyses were conducted to assess the effect of variant histology on overall recurrence and cancer-specific mortality (CSM). RESULTS: Overall, 1460 patients (91%) had pure urothelial carcinoma (PUC), whereas 150 (9%) were diagnosed with a variant histology, including 89 (5.0%), 41 (2.0%), 10 (1.0%) and 10 (1.0%) cases of micropapillary, squamous, sarcomatoid and other tumours, respectively. Variant histology was associated with the presence of adverse pathological features compared with PUC, including non-organ-confined disease (59% vs 38%; P < 0.001), lymph node invasion (28% vs 24%; P = 0.02), high-grade disease (88% vs 71%; P < 0.001), tumour necrosis (28% vs 16%; P = 0.001) and positive surgical margins (15% vs 8%; P = 0.01). In competing risk analysis, micropapillary variant was the only factor associated with worse recurrence (sub-hazard ratio [SHR] 2.27, 95% confidence interval [CI] 1.25-4.79; P = 0.02) whereas sarcomatoid variant was associated with worse CSM (SHR 16.8, 95% CI 6.86-41.17; P < 0.001). CONCLUSION: We found that one out of 10 patients with UTUC treated with RNU had variant histology. Only micropapillary and sarcomatoid variants were associated with poorer oncological outcomes after adjusting for available confounding factors.

Differences in trends in the use of robot-assisted and open radical cystectomy and changes over time in peri-operative outcomes among selected centres in North America and Europe: an international multicentre collaboration.

OBJECTIVES: To compare trends in the use of robot-assisted radical cystectomy (RARC) and changes over time in peri-operative outcomes in selected North American and European centres. MATERIALS AND METHODS: We conducted a retrospective evaluation of 2401 patients treated with open radical cystectomy (ORC) or RARC for bladder cancer at 12 centres in North America and Europe between 2006 and 2018. We used the Kruskal-Wallis and chi-squared test to evaluate differences between continuous and categorical variables. RESULTS: Overall, 49.5% of patients underwent RARC and 51.5% ORC. RARC became the most commonly performed procedure in contemporary patients, with an increase from 29% in 2006-2008 to 54% in 2015-2018 (P < 0.001). In the North American centres the use of RARC was higher than that of ORC from 2006, and remained stable over time, whereas in the European centres its use increased exponentially from 2% to 50%. In both groups patients who underwent RARC had less advanced T stages (P < 0.001), lower American Society of Anesthesiologists scores (P < 0.05), lower blood loss (P = 0.001) and shorter length of hospital stay (P < 0.05). No differences were found in early complications. Early readmission and re-operation rates were worse for patients treated with RARC in the European centres; however, when contemporary patients only were considered, the statistical significance was lost. CONCLUSION: The present study shows that the use of RARC has constantly increased since its introduction, overtaking ORC in the most contemporary series. While RARC was more frequently performed than ORC since its introduction in the North American centres and its use remained substantially stable over time, its use increased exponentially in the European centres. The different trends in use of RARC/ORC and changes over time in peri-operative outcomes between the North American and European centres can be attributed to the earlier introduction and spread of RARC in the former compared with the latter.

The impact of completeness of last transurethral resection of bladder tumors on the outcomes of radical cystectomy.

PURPOSE: To evaluate the role of a complete transurethral resection of bladder tumors (c-TURBT) on oncological outcomes after radical cystectomy (RC) and its relationship with adverse pathological features. METHODS: We retrospectively analyzed data of 727 patients treated with RC and bilateral pelvic lymph node dissection at three tertiary referral centers. Possible c-TURBT was reported by the treating surgeon. Multivariable Cox regression analyses were used to assess the relationship of c-TURBT and survival outcomes after surgery in 1:1 propensity score-matched cohort adjusted for age and gender. Moreover, multivariable logistic regression (MVA) was built to predict the relationship between c-TURBT and pT3-T4 stages at RC, lymph node invasion (LNI) and positive soft tissue surgical margin (STSM). RESULTS: A total of 433 (60%) patients received a c-TURBT. 3.0% of patients with a c-TURBT achieved a pT0-pTa-pTis status vs. 2.0% of patients with incomplete TURBT. At multivariable Cox regression analyses, c-TURBT was not associated with survival outcomes. At MVA, incompleteness of TURBT was significantly associated with a pT3-T4 stage [odds ratio (OR) 8.04, 95% confidence interval (CI) 2.33-27.67, p = 0.001]. No significant association was found between c-TURBT, LNI and STSM. CONCLUSION: We found a low rate of achievement of pT0 stage at RC. An incomplete TURBT before RC represented a predictor of pT3-T4 stages, but no effect of a c-TURBT was shown on survival outcomes. Given the current inadequacy of clinical staging strategies with more than 50% of extravesical disease being under-staged, our results could improve patients selection for NAC, driving the decision-making in doubtful cases.

Radical Cystectomy in Pathological T4a and T4b Bladder Cancer Patients: Is There Any Space for Sub Stratification?

INTRODUCTION: According to TNM staging, pathological T4ab are comprehensive of the invasion of prostate, seminal vesicles, uterus or vagina and pelvic or abdominal wall. However, few data are available on the perioperative and oncological outcomes of specific organ invasion. MATERIALS AND METHODS: A total of 917 consecutive bladder cancer (BCa) patients treated with radical cystectomy (RC) at a single institution between 1990 and 2015 were studies. Cox regression analyses were used to stratify pT4ab according to the site of invasion and survival. RESULTS: Overall, 176 (19.2%) and 40 (4.4%) patients harbored pT4a or pT4b disease. Specifically, 84 (9.2%) patients reported prostate and/or SVI invasion, 62 (6.8%) prostate only, 16 (1.7%) uterus, 14 (1.5%) vaginal, 24 (2.6%) pelvic wall, and 16 (1.7%) abdominal wall invasion. The median follow-up in pT4 patients was 48 months. The 1-year cancer-specific mortality (CSM) rates were 71, 65, 24, 50, 50, and 72%, for vaginal, uterus, prostate only, prostate and/or seminal vesicles, pelvic wall, and abdominal wall invasions, respectively. At multivariable Cox regression, the invasion of prostate only (hazard ratio [HR] 3.53), prostate and/or SVI (HR 4.98), uterus (HR 7.16), vagina (HR 6.12), pelvic (HR 11.81), abdominal (8.36) were associated with adverse CSM. CONCLUSIONS: Our study described the differences in survival related to invasion site in pT4 patients, confirming poor survival expectancies in this subgroup. Patients with prostate invasion only seem to be associated with better survival than those affected by concomitant invasion of seminal vesicles. Uterus and vaginal invasions were associated with poor survival outcomes. Patients Summary: In this study, we looked at the outcome of locally advanced invasive BCa (stage pT4) in patients treated with RC at a tertiary referral hospital. We analyzed the differences in survival related to the specific organ invasion. We confirmed poor survival in this subgroup of patients. Only patients who had prostate invasion only seem to have a better survival.

Relationship between circulating FSH levels and body composition and bone health in patients with prostate cancer who undergo androgen deprivation therapy: The BLADE study.

Background: Among its extragonadal effects, follicle-stimulating hormone (FSH) has an impact on body composition and bone metabolism. Since androgen deprivation therapy (ADT) has a profound impact on circulating FSH concentrations, this hormone could potentially be implicated in the changes of fat body mass (FBM), lean body mass (LBM), and bone fragility induced by ADT. The objective of this study is to correlate FSH serum levels with body composition parameters, bone mineral density (BMD), and bone turnover markers at baseline conditions and after 12 months of ADT. Methods: Twenty-nine consecutive non-metastatic prostate cancer (PC) patients were enrolled from 2017 to 2019 in a phase IV study. All patients underwent administration of the luteinizing hormone-releasing hormone antagonist degarelix. FBM, LBM, and BMD were evaluated by dual-energy x-ray absorptiometry at baseline and after 12 months of ADT. FSH, alkaline phosphatase, and C-terminal telopeptide of type I collagen were assessed at baseline and after 6 and 12 months. For outcome measurements and statistical analysis, t-test or sign test and Pearson or Spearman tests for continuous variables were used when indicated. Results: At baseline conditions, a weak, non-significant, direct relationship was found between FSH serum levels and FBM at arms (r = 0.36) and legs (r = 0.33). Conversely, a stronger correlation was observed between FSH and total FBM (r = 0.52, p = 0.006), fat mass at arms (r = 0.54, p = 0.004), and fat mass at trunk (r = 0.45, p = 0.018) assessed after 12 months. On the other hand, an inverse relationship between serum FSH and appendicular lean mass index/FBM ratio was observed (r = -0.64, p = 0.001). This is an ancillary study of a prospective trial and this is the main limitation. Conclusions: FSH serum levels after ADT could have an impact on body composition, in particular on FBM. Therefore, FSH could be a promising marker to monitor the risk of sarcopenic obesity and to guide the clinicians in the tailored evaluation of body composition in PC patients undergoing ADT. Funding: This research was partially funded by Ferring Pharmaceuticals. The funder had no role in design and conduct of the study, collection, management, analysis, and interpretation of the data and in preparation, review, or approval of the manuscript. Clinical trial number: clinicalTrials.gov NCT03202381, EudraCT Number 2016-004210-10.

Treatments given to cancer patients can cause negative side effects. For example, a treatment known as androgen deprivation therapy ­ which is used to reduce male sex hormone levels in prostate cancer patients ­ can lead to increased body fat percentage and decreased bone density. These adverse effects can have further negative impacts on patient health, such as increasing the risk of cardiovascular disease and fractures from falls from standing height or less, respectively. Understanding how androgen deprivation therapy contributes to these negative side effects may help clinicians better manage care and outcomes for patients with prostate cancer. Follicle stimulating hormone (or FSH for short) has roles in male and female reproduction but has also been linked to changes in body composition. For example, elevated FSH levels are associated with higher total fat body mass in post-menopausal women. While androgen deprivation therapy is known to alter FSH blood levels, the impact of this change in prostate cancer patients was not well understood. To investigate the effect of androgen deprivation therapy on FSH levels and body composition, Bergamini et al. used X-ray technology to measure total fat body mass in prostate cancer patients before and after undergoing 12 months of androgen deprivation therapy. The findings showed that patient FSH blood levels significantly decreased after 12 months of treatment. Higher FSH blood levels strongly correlated with increased total fat body mass after 12 months of treatment. The findings of this clinical trial suggest that FSH blood levels impact the body composition of patients undergoing androgen deprivation therapy. As a result, FSH blood levels may be a suitable biomarker for identifying patients that are more likely to develop obesity and are therefore at greater risk of complications such as cardiovascular disease.

Metastasis Within Three Years from Radical Nephroureterectomy as a Potential Surrogate for Overall Survival.

INTRODUCTION: The only phase III trial that evaluated the role of adjuvant chemotherapy following radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) was terminated early. Thus, eventual overall survival (OS) surrogacy, as per Prentice, cannot be assessed in this setting. We aimed to identify an intermediate clinical endpoint (ICE) that could serve as an OS surrogate after RNU for UTUC. PATIENTS AND METHODS: We retrospectively analyzed 823 high-grade UTUC patients treated with RNU at 8 tertiary referral centers. We explored the role of any recurrence (aR), defined as recurrence in the urinary tract or in the resection bed as well the presence of distant metastasis (DM), defined as metastatic disease outside the urinary tract and regional lymph nodes, on OS through a time-varying Cox regression analyses fitted at the landmark points of 1, 2, 3, and 4 years from RNU. Models' discrimination was assessed using Harrell's c index, after internal validation. RESULTS: Median follow-up for survivors was 5.6 years (interquartile range: 2.0-8.8). Overall, 391 and 212 patients experienced aR and DM, respectively. In a time-varying model, aR and DM were predictors of OS: hazard ratio [HR]:1.20, 95% confidence interval [CI]: 1.13-1.28 (P < .001) and HR:1.26, 95% CI: 1.18-1.34 (P < .001), respectively. Progression to DM within 3 years from RNU was the most informative ICE for predicting OS (c index: 0.81; HR: 4.40; 95%CI: 2.45-7.92; P < .001), compared to DM within 1, 2, and 4 years (c indexes: 0.74, 0.76, and 0.78, respectively). Progression to DM within 3 years from RNU was further found superior for predicting OS compared to aR at any landmark points. CONCLUSIONS: Progression to DM within 3 years represents a potential OS surrogate for surgically-treated UTUC. This information could help in patient counseling, future study design and expedite results release of ongoing randomized controlled trials.

Effect of Degarelix Administration on Bone Health in Prostate Cancer Patients Without Bone Metastases. The Blade Study.

CONTEXT: As patients are now living with prostate cancer for longer, the long-term impact of hormonal treatment on bone health is an increasingly debated subject. OBJECTIVE: To characterize the changes in bone mineral density (BMD) and bone turnover markers after degarelix administration in prostate cancer patients without bone metastases. To explore the predictive role of body composition on treatment induced bone loss. METHODS: BMD and body composition (lean body mass, fat body mass, and appendicular mass index [ALMI]) were assessed by dual X-ray absorptiometry on study entry and after 12 months of degarelix therapy. Alkaline phosphate (ALP) and C-terminal telopeptide of type I collagen (CTX) were assessed at baseline, and 6 and 12 months. RESULTS: Twenty-nine patients entered the study. Degarelix administration was associated with a significant decrease in BMD after 12 months (2.4% reduction from baseline at lumbar spine). Serum CTX and ALP increased significantly (median increase from baseline 99% and 19.3%, respectively). An inverse correlation was observed between ALMI and CTX, but not ALP, at both baseline (Pearson r = -0.62, P < .0001) and month 12 (Pearson r = -0.41, P = .032). Moreover, a significant inverse correlation between changes in ALMI and CTX at 12 months (Pearson r = -0.43, P = .019) and a direct relationship between changes of ALMI and ALP (Pearson r = 0.44, P = .016) during degarelix therapy were observed. CONCLUSION: Degarelix administration is associated with a significant decrease in BMD and increase in bone turnover markers. ALMI is a promising predictor of bone loss in prostate cancer patients receiving androgen deprivation therapy, and ALMI changes during therapy are associated with bone turnover derangement favoring bone quality alterations.

Oncologic Surveillance After Radical Nephroureterectomy for High-risk Upper Tract Urothelial Carcinoma.

BACKGROUND: The appropriate surveillance protocol after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) is still poorly addressed. OBJECTIVE: To evaluate the appropriate intensity and duration of oncologic surveillance following RNU, according to a prior history of bladder cancer (BCa). DESIGN, SETTING, AND PARTICIPANTS: We identified 1378 high-risk UTUC patients, according to the European Association of Urology (EAU) guidelines, from a prospectively maintained database involving eight European referral centers. Surveillance protocol was based on cystoscopies and cross-sectional imaging, as per the EAU guidelines. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: First, we evaluated the noncumulative risk of bladder and other-site recurrences (including distant metastasis and locoregional relapse) against the follow-up time points, as suggested by the current EAU guidelines. Second, in an effort to identify the time points when the risk of other-cause mortality (OCM) exceeded that of recurrence and follow-up might be discontinued, we relied on adjusted Weibull regression. RESULTS AND LIMITATIONS: The median follow-up was 4 yr. A total of 427 and 951 patients with and without a prior BCa history, respectively, were considered. At 5-yr, the time point after which cystoscopies should be performed semiannually, the bladder recurrence risk was 10%; at 4 yr, the bladder recurrence risk was 13%. At 2 yr, the time point after which imaging should be obtained semiannually, the nonbladder recurrence risk was 42% in case of nonprior BCa and 47% in case of prior BCa; at 4 yr, the nonbladder recurrence risk was 23%. Among patients without a prior BCa history, individuals younger than 60 yr should continue both cystoscopies and imaging beyond 10 yr from RNU, 70-79-yr-old patients should continue only imaging beyond 10 yr, while patients older than 80 yr might discontinue oncologic surveillance because of an increased risk of OCM. Limitations include the fact that patients were treated and surveilled over a relatively long period of time. CONCLUSIONS: We suggest intensifying the frequency of imaging to semiannual till the 4th year after RNU, the time point after which the risk of recurrence was almost halved. Cystoscopies could be obtained annually from the 4th year given a similar risk of recurrence at 4 and 5 yr after RNU. Oncologic surveillance could be discontinued in some cases in the absence of a prior BCa history. PATIENT SUMMARY: In this study, we propose a revision of the current guidelines regarding surveillance protocols following radical nephroureterectomy. We also evaluated whether oncologic surveillance for high-risk upper tract urothelial carcinoma could be discontinued and, if so, in what circumstances.

Accuracy of Transurethral Resection of the Bladder in Detecting Variant Histology of Bladder Cancer Compared with Radical Cystectomy.

BACKGROUND: Correct identification of variant histologies (VHs) of bladder cancer (BCa) at transurethral resection of the bladder (TURB) could drive the subsequent treatment. OBJECTIVE: To evaluate the concordance in detecting VHs between TURB and radical cystectomy (RC) specimens in BCa patients. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively analyzed 1881 BCa patients who underwent TURB and subsequent RC at seven tertiary care centers between 1980 and 2018. VHs were classified as sarcomatoid, lymphoepithelioma-like, neuroendocrine, squamous, micropapillary, glandular, adenocarcinoma, nested, and other variants. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Concordance between TURB and RC was defined as the ability to achieve histological subtypes at TURB confirmed at RC specimen, and was expressed according to Cohen's kappa coefficient. RESULTS AND LIMITATIONS: Of the patients, 14.6% and 21% were diagnosed with VH at TURB and RC specimens, respectively. The most common VHs at TURB were squamous, neuroendocrine, and micropapillary carcinoma (5.2%, 1.5%, and 1.5%, respectively). At RC, the most frequent VHs were squamous, micropapillary, and sarcomatoid carcinoma (7.2%, 3.0%, and 2.7%, respectively). The overall concordance in detecting VH was defined as slight concordance (coefficient: 0.18). Moderate concordance was found for neuroendocrine, adenocarcinoma, and squamous carcinoma (coefficient: 0.49, 0.47, and 0.41, respectively). Micropapillary, glandular, and other variants showed slight concordance (coefficient: 0.05, 0.17, and 0.12, respectively), while nested and sarcomatoid carcinoma showed fair concordance (coefficient: 0.32 and 0.26, respectively). Results may be limited by the absence of centralized pathological analysis. CONCLUSIONS: A non-negligible percentage of patients were diagnosed with VH at both TURB and RC. TURB showed relatively low accuracy, ranging from poor to moderate, in detecting VHs. Our study underlines the need of additional diagnostic tools in order to identify VHs properly at precystectomy time and to improve patient survival outcomes. PATIENT SUMMARY: In this report, we underlined the low accuracy of transurethral resection of the bladder in detecting variant histologies and the need for additional diagnostic tools.

Bladder perforation during transurethral resection of the bladder: a comprehensive algorithm for diagnosis, management and follow-up.

INTRODUCTION: Despite bladder perforation (BP) is a frequent complication during transurethral resection of bladder (TURB) for bladder cancer (BCa), literature lacks systematic reviews focusing on this issue. We aimed to investigate incidence, diagnosis, therapy, and prognosis after BP during TURB for BCa; therapy was distinguished between conservative (without the need for bladder repair) and surgical management (requiring bladder wall closure). EVIDENCE ACQUISITION: A systematic search was conducted up to April 2021 using PubMed, Scopus, Cochrane Database of Systematic Reviews, and Web of Science to identify articles focusing on incidence, detection, management, or survival outcomes after iatrogenic BP. The selection of articles followed the preferred reporting items for systematic review and meta-analyses process. EVIDENCE SYNTHESIS: We included 41 studies, involving 21,174 patients. Overall, 521 patients experienced BP during TURB for BCa, with a mean incidence of 2.4%, up to 58.3% when postoperative cystography is routinely performed after all TURB procedures. Risk factors were low body mass index (BMI) (P=0.01), resection depth (P=0.006 and P=0.03), and low surgical experience (P=0.006). Extraperitoneal BP (68.5%) were treated conservatively in 97.5% of patients; intraperitoneal BP were managed with surgical bladder closure in 56% of cases. Overall, three immediate BP-related deaths were recorded due to septic complications. Extravesical tumor seeding was observed after 6 intraperitoneal and 1 extraperitoneal BP (median time: 6.2 months). Intraperitoneal BP (P=0.0003) and bladder closure (P<0.001) were found as independent predictors of extravesical tumor recurrence. CONCLUSIONS: BP is more frequent than expected when proper diagnosis is routinely performed after all TURB procedures. Risk factors include low BMI, resection depth, and unexperienced surgeon. The risk of sepsis after BP suggests empirical antibiotic prophylaxis after BP.