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Background: Immune checkpoint inhibitors (ICIs) are an important therapeutic pillar in metastatic urothelial carcinoma (mUC). The occurrence of immune-related adverse events (irAEs) appears to be associated with improved outcomes in observational studies. However, these associations are likely affected by immortal time bias and do not represent causal effects. The aim of this study was to assess the effect of irAEs on outcomes while correcting for immortal time bias, using target trial emulation (TTE). Methods: TTE was contrasted to adjusted naïve and time-updated Cox models. We performed a multi-institutional retrospective study involving mUC patients under ICI. The primary objective was to assess the impact of irAEs on progression-free survival (PFS) and overall survival (OS). Secondary endpoints included the influence of irAEs on objective response rates (ORRs) to ICI and the influence of systemic corticosteroids on outcomes. Results: Among 335 patients (median age: 69 yrs), 69.6% received ICI in the second line or further lines. During a median follow-up of 21.1 months, 122 (36.4%) patients developed irAEs of any grade (grade ≥ 3: 14.9%). Hazard ratios (HRs) for PFS ranged from 0.37 for naïve adjusted Cox model to 0.88 (95% confidence interval (CI), 0.59–1.30) with time-updated covariates, and from 0.41 to 1.10 (95% CI, 0.69–1.75) for OS. TTE accounting for immortal time bias yielded a HR of 1.02 (95% CI, 0.72–1.44) for PFS, and 0.90 (95% CI, 0.62–1.30) for OS. In contrast to the naïve Cox model (HR = 2.26, 95% CI 1.26–4.05), the presence of irAEs was no longer a predictive factor for improved ORR in time-updated Cox models (HR = 1.27, 95% CI 0.68–2.36) and TTE (HR = 1.43, 95% CI 0.89–2.29). In patients with irAEs, systemic corticosteroids did not negatively impact survival. Conclusion: Using TTE, we were able to show that the occurrence of irAEs is no longer associated with better survival or improved response rates to ICI in mUC patients, in contrast to the naïve analysis. These findings demonstrate that TTE is a suitable formal framework to avoid immortal time bias in studies with time-dependent non-interventional exposures. [ABSTRACT FROM AUTHOR]

In the last decades the survival of metastatic gastrointestinal (GI) cancer patients could have been significantly extended due to the introduction of targeted- and immunotherapy. However, only the minority of patients will experience long-lasting survival. Hence, novel therapeutics are clearly necessary for GI cancer patients. Molecular high-throughput profiling techniques have revealed potential novel targetable molecular alterations, emphasizing the necessity for tailored therapeutic approaches. Nuclear export proteins, particularly Exportin-1 (XPO1), have emerged as promising targets in cancer therapy due to their crucial role in cellular homeostasis and regulation of key cellular functions. Dysregulation of XPO1-mediated nuclear export leads to the functional loss of tumor suppressors and pro-apoptotic factors, facilitating cancer progression. Selinexor, a XPO1 inhibitor, has shown promising activity in preclinical and clinical studies, particularly in hematological malignancies. However, its efficacy in GI cancers remains underexplored. This review aims to elucidate the functional and pathophysiological role of XPO1 in GI cancers. Despite the potential of XPO1 inhibitors in suppressing cell proliferation and inducing apoptosis, comprehensive molecular landscape data and validation of selective inhibitors in GI cancers are lacking. Targeting XPO1 presents a significant therapeutic potential for the treatment of GI cancer patients. Further research is necessary to fully elucidate the molecular landscape according to XPO1 expression in GI tumors and to validate the efficacy of selective XPO1 inhibitors. These efforts are expected to contribute to the development of more effective and personalized therapeutic strategies for GI cancer patients. [ABSTRACT FROM AUTHOR]

Purpose: There is lack of evidence regarding the indication for re-transurethral resection of bladder tumor (reTURBT) for Ta high grade (HG) non-muscle invasive bladder cancer (NMIBC). This study aims to evaluate the oncological outcomes of patients with TaHG NMIBC to determine the benefit from performing reTURBT. Methods: We relied on a multicenter cohort of 317 TaHG NMIBC from 12 centers who underwent TURBT and a subsequent complete Bacillus Calmette-Guérin induction from 2009 to 2021. Kaplan Meier analyses estimated recurrence free survival (RFS) and progression free survival (PFS) according to reTURBT. Sub-analyses evaluated PFS in patients with multiple risk factors indicating necessity for reTURBT according to international guidelines (multifocality, size > 3 cm, recurrent cancer, carcinoma in situ, lymph vascular invasion, histological variant, incomplete and absence of muscle layer at index TURBT). Multivariable cox-regression analysis predicted recurrence and progression. Results: Of the 317 patients, 123 (39%) underwent reTURBT, while 194 (61%) did not. Residual disease was detected in 46% of cases, with a 3.2% upstaging rate. Median follow-up was 30 months. The 3-year RFS was higher in patients who underwent reTURBT (79% vs. 58%, p < 0.001), but no significant difference was observed in PFS. ReTURBT reduced the risk of recurrence [multivariable hazard ratio: 0.45, 95% Confidence interval (CI) 0.29–0.71]. Among patients who did not undergo reTURBT, those with ≥ 2 risk factors had lower 3-year PFS (73% vs. 92%, p < 0.001) than those with 0–1 risk factor, whereas no difference in 3-year PFS was observed in patients who underwent reTURBT regardless of the number of risk factors (85% vs. 87%, p = 0.8). Conclusion: ReTURBT demonstrated efficacy in reducing recurrence among patients with TaHG NMIBC, yet its impact on progression remained uncertain. Our study underscores the importance of adhering to current international guidelines, particularly for patients with multiple risk factors indicating necessity for reTURBT. [ABSTRACT FROM AUTHOR]

Background: Enfortumab vedotin (EV) has been approved for the treatment of patients with locally advanced/metastatic urothelial carcinoma (la/mUC) who previously received platinum-based chemotherapy followed by immune checkpoint inhibitors. However, the pivotal clinical trials did not include patients previously treated with avelumab maintenance therapy. Objective: The aim of the present retrospective analysis was to assess the effectiveness of EV following avelumab in patients with mUC enrolled in the ARON-2EV study. Patients and Methods: The study included 182 patients with mUC treated with EV following avelumab maintenance. The primary objective was to assess clinical outcomes, including progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and duration of response (DoR). Statistical analysis involved Fisher exact test, Kaplan–Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models. Results: Median OS and PFS were 12.7 (95% CI 10.2–14.1) and 7.9 (95% CI 6.4–9.9) months, respectively. Complete response (CR) was achieved in 5% and partial response (PR) in 34% of patients, with an ORR of 39%. The DoR in patients who achieved CR/PR was 10.9 months (95% CI 8.1–11.4). The incidence of grade ≥ 3 peripheral neuropathy and skin rash was 9%, followed by 8% of grade ≥ 3 diarrhea and 4% of grade ≥ 3 hyperglycemia. Conclusions: The results of our large international retrospective study confirm the effectiveness of EV and endorse its use in the population of patients with mUC treated with EV following the frontline platinum-based chemotherapy and subsequent maintenance treatment with avelumab. [ABSTRACT FROM AUTHOR]

Sarcopenia, defined as age-associated loss of skeletal muscle function and muscle mass, is a negative prognostic marker for survival in several tumor entities. However, data evaluating the impact of sarcopenia and fat distribution on penile cancer are rarely described. We performed a retrospective study including 38 patients who were diagnosed with squamous cell carcinoma of the penis. By measuring skeletal muscle mass and fat distribution at axial abdominal computed tomography images at the third lumbar vertebra several body composition parameters including skeletal muscle index (SMI), psoas muscle index (PMI), visceral obesity and visceral-to-subcutaneous fat ratio were determined. Among 38 patients, 26% (n = 10) of the patients with penile cancer were identified as sarcopenic. SMI, age, lymph node metastases, distant metastases and penile cancer of the shaft were identified as significant risk factors for overall survival. PMI and distant metastases were significantly associated with cancer specific survival. None of the analysed adipose tissue parameters could be identified as risk factors for survival in this study. We showed that sarcopenia occurs in a relevant part of patients with penile cancer and is a significant risk factor for overall survival (p = 0.032) and cancer specific survival (p = 0.034) for patients with penile cancer. Regarding fat distribution further studies are needed to evaluate its impact on sarcopenia and survival. [ABSTRACT FROM AUTHOR]

Upper tract urothelial carcinoma (UTUC) accounts for the 5–10% of all urothelial carcinomas (UCs). In this analysis, we reported the real-world data from the ARON-2 study (NCT05290038) on the efficacy of pembrolizumab in patients with UTUC who recurred or progressed after platinum-based chemotherapy. Medical records of patients with metastatic UTUC treated with pembrolizumab as second-line therapy were reviewed from 34 institutions in 14 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Univariate and multivariate analyses were used to explore the association of variables of interest with OS and PFS. 235 patients were included in our analysis. Median OS was 8.6 months (95% CI 6.6–12.1), the 1 year OS rate was 43% while the 2 years OS rate 29%. The median PFS was 5.1 months (95% CI 3.9–6.9); 46% of patients were alive at 6 months, 34% at 12 months and 25% at 24 months. According to RECIST 1.1, 18 patients (8%) experienced complete response (CR), 57 (24%) partial response (PR), 44 (19%) stable disease (SD), and 116 (49%) progressive disease (PD), with an ORR of 32%. Our study confirms the effectiveness of pembrolizumab in patients pretreated with a platinum-based combination, irrespective of their sensitivity to the first-line treatment and of their histology. In addition, we emphasized the limited benefit of the treatment with pembrolizumab in patients with hepatic metastases and poor ECOG performance status. [ABSTRACT FROM AUTHOR]

Background: The benefit of immune checkpoint inhibitors (ICIs) for poor performance status patients with advanced urothelial carcinoma (UC) remains unknown. Objective: In the present sub-analysis of the ARON-2 study, we investigated the role of pembrolizumab for advanced UC patients with ECOG (Eastern Cooperative Oncology Group) performance status (ECOG-PS) 2. Patients and Methods: Patients aged ≥ 18 years with a cytologically and/or histologically confirmed diagnosis of advanced UC progressing or recurring after platinum-based therapy and treated with pembrolizumab between 1 January 2016 to 1 April 2024 were included. In this sub-analysis we focused on patients with ECOG-PS 2. Results: We included 1,040 patients from the ARON-2 dataset; of these, 167 patients (16%) presented an ECOG-PS 2. The median overall survival (OS) was 14.8 months (95% confidence interval (CI) 12.5–16.1) in the overall study population, 18.2 months (95% CI 15.8–22.2) in patients with ECOG-PS 0–1, and 3.7 months (95% CI 3.2–5.2) in subjects with ECOG-PS 2 (p < 0.001). The median progression-free survival (PFS) in the overall study population was 5.3 months (95% CI 4.3–97.1), 6.2 months (95% CI 5.5–97.1) in patients with ECOG-PS 0–1, and 2.8 months (95% CI 2.1–3.4) in patients with ECOG-PS 2. Among the latter, liver metastases and progressive disease during first-line therapy were significant predictors of OS at both univariate and multivariate analyses. For PFS, univariate and multivariate analyses showed a prognostic role for lung metastases, liver metastases, and progressive disease during first-line therapy. Conclusions: This large real–world evidence study suggests the effectiveness of second-line pembrolizumab for mUC patients with poor performance status. The presence of liver metastases and progressive disease during first-line therapy is associated with worse clinical outcomes and, thus, should be taken into account when making treatment decisions in clinical practice. [ABSTRACT FROM AUTHOR]

Background: There is an ongoing debate as to whether sex could be associated with immune checkpoint inhibitor (ICI) benefit. Existing literature data reveal contradictory results, and data on first-line immune combinations are lacking. Method: This was a real-world, multicenter, international, observational study to determine the sex effects on the clinical outcomes in metastatic renal cell carcinoma (mRCC) patients treated with immuno-oncology combinations as first-line therapy. Results: A total of 1827 mRCC patients from 71 cancer centers in 21 countries were included. The median OS was 38.7 months (95% CI 32.7–44.2) in the overall study population: 40.0 months (95% CI 32.7–51.6) in males and 38.7 months (95% CI 26.4–41.0) in females (p = 0.202). The median OS was higher in males vs. females in patients aged 18-49y (36.9 months, 95% CI 29.0–51.6, vs. 24.8 months, 95% CI 16.8–40.4, p = 0.426, with + 19% of 2y-OS rate, 72% vs. 53%, p = 0.006), in the clear cell histology subgroup (44.2 months, 95% CI 35.8–55.7, vs. 38.7 months, 95% CI 26.0–41.0, p = 0.047), and in patients with sarcomatoid differentiation (34.4 months, 95% CI 26.4–59.0, vs. 15.3 months, 95% CI 8.9–41.0, p < 0.001). Sex female was an independent negative prognostic factor in the sarcomatoid population (HR 1.72, 95% CI 1.15 − 2.57, p = 0.008). Conclusions: Although the female's innate and adaptive immunity has been observed to be more active than the male's, women in the subgroup of clear cell histology, sarcomatoid differentiation, and those under 50 years of age showed shorter OS than males. [ABSTRACT FROM AUTHOR]

Background: About 20% of patients with renal cell carcinoma present with non-clear cell histology (nccRCC), encompassing various histological types. While surgery remains pivotal for localized-stage nccRCC, the role of cytoreductive nephrectomy (CN) in metastatic nccRCC is contentious. Limited data exist on the role of CN in metastatic nccRCC under current standard of care. Objective: This retrospective study focused on the impact of upfront CN on metastatic nccRCC outcomes with first-line immune checkpoint inhibitor (IO) combinations or tyrosine kinase inhibitor (TKI) monotherapy. Methods: The study included 221 patients with nccRCC and synchronous metastatic disease, treated with IO combinations or TKI monotherapy in the first line. Baseline clinical characteristics, systemic therapy, and treatment outcomes were analyzed. The primary objective was to assess clinical outcomes, including progression-free survival (PFS) and overall survival (OS). Statistical analysis involved the Fisher exact test, Pearson's correlation coefficient, analysis of variance, Kaplan–Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models. Results: Median OS for patients undergoing upfront CN was 36.8 (95% confidence interval [CI] 24.9–71.3) versus 20.8 (95% CI 12.6–24.8) months for those without CN (p = 0.005). Upfront CN was significantly associated with OS in the multivariate Cox regression analysis (hazard ratio 0.47 [95% CI 0.31−0.72], p < 0.001). In patients without CN, the median OS and PFS was 24.5 (95% CI 18.1–40.5) and 13.0 months (95% CI 6.6–23.5) for patients treated with IO+TKI versus 7.5 (95% CI 4.3–22.4) and 4.9 months (95% CI 3.0–8.1) for those receiving the IO+IO combination (p = 0.059 and p = 0.032, respectively). Conclusions: Our study demonstrates the survival benefits of upfront CN compared with systemic therapy without CN. The study suggests that the use of IO+TKI combination or, eventually, TKI monotherapy might be a better choice than IO+IO combination for patients who are not candidates for CN regardless of IO eligibility. Prospective trials are needed to validate these findings and refine the role of CN in current mRCC management. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors have changed previous treatment paradigm of advanced urothelial carcinoma (UC). The ARON-2 study (NCT05290038) aimed to assess the real-world effectiveness of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy. Patients and Methods: Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were retrospectively collected from 88 institutions in 23 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Cox proportional hazards models were adopted to explore the presence of prognostic factors. Results: In total, 836 patients were included: 544 patients (65%) received pembrolizumab after progression to first-line platinum-based chemotherapy in the metastatic setting (cohort A) and 292 (35%) after recurring within < 12 months since the completion of adjuvant or neoadjuvant chemotherapy (cohort B). The median follow-up time was 15.3 months. The median OS and the ORR were 10.5 months and 31% in the overall study population, 9.1 months and 29% in cohort A and 14.6 months and 37% in cohort B. At multivariate analysis, ECOG-PS ≥ 2, bone metastases, liver metastases and pembrolizumab setting (cohort A vs B) proved to be significantly associated with worst OS and PFS. Stratified by the presence of 0, 1–2 or 3–4 prognostic factors, the median OS was 29.4, 12.5 and 4.1 months (p < 0.001), while the median PFS was 12.2, 6.4 and 2.8 months, respectively (p < 0.001). Conclusions: Our study confirms that pembrolizumab is effective in the advanced UC real-world context, showing outcome differences between patients recurred or progressed after platinum-based chemotherapy. [ABSTRACT FROM AUTHOR]

The ARON-2 study (NCT05290038) aimed to assess the real-world efficacy of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy. This retrospective analysis reports the outcomes of urothelial carcinoma (UC) patients with bone metastases (BM). Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were reviewed from60 institutions in 20 countries. Patients were assessed for Overall Response Rate (ORR), Progression-Free Survival (PFS), and Overall Survival (OS). Univariate and multivariate analyses were used to explore the association of variables of interest with OS and PFS. 881 patients were included; of them, 263 (30%) presented BM. Median follow-up time was 22.7 months. Patients with BM showed both shorter median OS (5.9 months vs 13.1 months, p < 0.001) and PFS (3.5 months, vs 7.3 months, p < 0.001) compared to patients without BM. Patients who received bone targeted agents (BTAs) showed a significantly longer median OS (8.5 months vs 4.6 months, p = 0.003) and PFS (6.1 months vs 3.2 months, p = 0.003), while no survival benefits were observed among patients who received radiation therapy for BM during pembrolizumab treatment compared to those who did not. In multivariate analysis, performance status, concomitant liver metastases, and the lack of use of BTAs were significantly associated with worse OS and PFS. Bone involvement in UC patients treated with pembrolizumab predicts inferior survival. Poor performance status and liver metastases may further worsen outcomes, while the use of BTAs is associated with improved outcomes. [ABSTRACT FROM AUTHOR]

Background: Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab. Methods: We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model. Results: A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months, p = 0.002) and OS (8.7 vs. 14.1 months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival. Conclusions: Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation. [ABSTRACT FROM AUTHOR]

Preoperative homeostasis of sex hormones in testicular germ cell tumor (TGCT) patients is scarcely characterized. We aimed to explore regulation of sex hormones and their implications for histopathological parameters and prognosis in TGCT using a data-driven explorative approach. Pre-surgery serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), estradiol (E2) and prolactin were measured in a retrospective multicenter TGCT cohort (n = 518). Clusters of patients were defined by latent class analysis. Clinical, pathologic and survival parameters were compared between the clusters by statistical hypothesis testing, Random Forest modeling and Peto-Peto test. Cancer tissue expression of sex hormone-related genes was explored in the publicly available TCGA cohort (n = 149). We included 354 patients with pure seminoma and 164 patients with non-seminomatous germ cell tumors (NSGCT), with a median age of 36 years. Three hormonal clusters were defined: 'neutral' (n = 228) with normal sex hormone homeostasis, 'testicle' (n = 91) with elevated T and E2, low pituitary hormones, and finally 'pituitary' subset (n = 103) with increased FSH and LH paralleled by low-to-normal levels of the gonadal hormones. Relapse-free survival in the hormonal subsets was comparable (p = 0.64). Cancer tissue expression of luteinizing hormone- and follicle-stimulating hormone-coding genes was significantly higher in seminomas, while genes of T and E2 biosynthesis enzymes were strongly upregulated in NSGCT. Substantial percentages of TGCT patients are at increased risk of sex hormone dysfunction at primary diagnosis before orchiectomy. TGCT may directly influence systemic hormonal homeostasis by in-situ synthesis of sex hormones. [ABSTRACT FROM AUTHOR]

Background: The advent of immune-checkpoint inhibitors has challenged previous treatment paradigms for advanced urothelial carcinoma (UC) in the post-platinum setting as well as in the first-line setting for cisplatin-ineligible patients. In this study, we investigated the effectiveness of pembrolizumab as first-line treatment for cisplatin-ineligible UC. Methods: Data from patients aged ≥ 18 years with cisplatin-ineligible UC and receiving first-line pembrolizumab from January 1st 2017 to September 1st 2022 were collected. Cisplatin ineligibility was defined according to the Galsky criteria. Thirty-three Institutions from 18 countries were involved in the ARON-2 study. Results: Our analysis included 162 patients. The median follow-up time was 18.9 months (95%CI 15.3–76.9). In the overall study population, the median OS was 15.8 months (95%CI 11.3–32.4). The median OS was significantly longer in males versus females while no statistically significant differences were observed between patients aged < 65y versus ≥ 65y and between smokers and non-smokers. According to Recist 1.1 criteria, 26 patients (16%) experienced CR, 32 (20%) PR, 39 (24%) SD and 55 (34%) PD. Conclusions: Our data confirm the role of pembrolizumab as first-line therapy for cisplatin-unfit patients. Further studies investigating the biological and immunological characteristics of UC patients are warranted in order to optimize the outcome of patients receiving immunotherapy in this setting. [ABSTRACT FROM AUTHOR]

Purpose: Upper tract urothelial carcinoma (UTUC) represents an often aggressive malignancy associated with poor prognosis. Therefore, finding reliable prognostic biomarkers in patients undergoing curative surgery for improved risk stratification is crucial. We evaluated the prognostic value of the Fibrinogen/C-reactive protein (FC)-score in a cohort of surgically treated UTUC patients. Methods: 170 patients with radiologically and histologically verified UTUC who underwent radical curative surgery between 1990 and 2020, were included. The FC-score was calculated for each patient, with patients receiving 1 point each if Fibrinogen and/or CRP levels were elevated above the 25th or 75th percentile, respectively. Patients were divided into three subgroups according to their FC-score of 0, 1 or 2 point(s). Kaplan–Meier analysis, uni- and multivariable Cox proportional hazard models were implemented. We determined cancer-specific survival (CSS) as primary endpoint, whereas overall survival (OS) and recurrence-free survival (RFS) were considered secondary endpoints. Results: High FC-score (2 points) was significantly associated with adverse histological features such as vascular invasion (OR = 4.08, 95%CI 1.18–14.15, p =.0027) and tumour necrosis (OR = 6.67, 95%CI 1.35–32.96, p = 0.020). Both, uni- and multivariable Cox proportional hazard models showed the FC-score as a significant predictor for CSS (univariable analysis: FC-score = 1: HR = 1.90, 95%CI 0.92–3.93, p = 0.085 | FC-score = 2: HR = 2.86, 95%CI 1.22–6.72, p = 0.016). Furthermore, in univariable analysis, patients with higher FC-score had significantly shorter OS (FC-score = 1: HR = 1.32, 95%CI 0.70–2.49, p = 0.387 | FC-score = 2: HR = 2.19, 95%CI 1.02–4.67, p = 0.043). However, this did not prevail in multivariable analysis. Conclusion: The FC-score represents a novel potential biomarker in patients with UTUC undergoing radical curative surgery. [ABSTRACT FROM AUTHOR]

Purpose: Risk calculators (RC) aim to improve prebiopsy risk stratification. Their latest versions now include multiparametric magnetic resonance imaging (mpMRI) findings. For their implementation into clinical practice, critical external validations are needed. Methods: We retrospectively analyzed the patient data of 554 men who underwent ultrasound-guided targeted and systematic prostate biopsies at 2 centers. We validated the mpMRI-RCs of Radtke et al. (RC-R) and Alberts et al. (RC-A), previously shown to predict prostate cancer (PCa) and clinically significant PCa (csPCa). We assessed these RCs' prediction accuracy by analyzing the receiver-operating characteristics (ROC) curve and evaluated their clinical utility using Decision Curve Analysis (DCA), including Net-Benefit and Net-Reduction curves. Results: We found that the Area Under the ROC Curve (AUC) for predicting PCa was 0.681 [confidence interval (CI) 95% 0.635–0.727] for RC-A. The AUCs for predicting csPCa were 0.635 (CI 95% 0.583–0.686) for RC-A and 0.676 (CI 95% 0.627–0.725) for RC-R. For example, at a risk threshold of 12%, RC-A needs to assess 334 and RC-R 500 patients to detect one additional true positive PCa or csPCa patient, respectively. At the same risk threshold of 12%, RC-A only needs to assess 6 and RC-R 16 patients to detect one additional true negative PCa or csPCa patient. Conclusion: The mpMRI-RCs, RC-R and RC-A, are robust and valuable tools for patient counseling. Although they do not improve PCa and csPCa detection rates by a clinically meaningful margin, they aid in avoiding unnecessary prostate biopsies. Their implementation could reduce overdiagnosis and reduce PCa screening morbidity. [ABSTRACT FROM AUTHOR]

Purpose: Lymphovascular invasion (LV1) and presence of > 50% embryonal carcinoma (> 50% EC) represent risk factors for progression in patients with clinical stage 1 (CS1) nonseminomatous (NS) testicular germ cell tumours. As serum levels of microRNA-371a-3p (M371) are capable of detecting small amounts of GCT, we evaluated if LV1 and > 50% EC are associated with M371 levels. Methods: M371 serum levels were measured postoperatively in 153 NS CS1 patients and both pre- and postoperatively in 131 patients. We registered the following factors: age, tumour size, LV status, > 50% EC, teratoma in primary, preoperative elevation of classical tumour markers. M371 expression was compared among subgroups. The ability of M371 to predict LV1 was calculated by receiver operating characteristics (ROC) curves. Multiple regression analysis was used to look for associations of M371 levels with other factors. Results: Postoperatively elevated M371 levels were found in 29.4% of the patients, but were neither associated with LV status nor with > 50% EC. Likewise, relative decrease of M371 was not associated. ROC analysis of postoperative M371 levels revealed an AUC of 0.5 for the ability to predict LV1 while preoperative M371 had an AUC of 0.732. Multiple regression analysis revealed significant associations of preoperative M371 levels with LV status (p = 0.003), tumour size (p = 0.001), > 50% EC (p = 0.004), and teratoma component (p = 0.045). Conclusion: Postoperatively elevated M371 levels are not associated with risk factors for progression in NS CS1 patients. However, the significant association of preoperative M371 expression with LV1 deserves further evaluation. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is a highly vascularized and immunogenic tumor, being an ideal candidate for checkpoint blockade-based immunotherapy. Accordingly, checkpoint inhibitors have demonstrated clinical efficacy in patients with metastatic RCC (mRCC). Sex-specific differences in cancer immunotherapy may be explained by the interaction of sex hormone signaling, genetic and environmental factors, affecting the innate and adaptive immune response in men and women in different ways. The aim of this prospective study was to monitor for the first time changes in sex hormones including luteinizing hormone (LH), follicle-stimulating hormone (FSH), LH/FSH ratio and 17-ß-estradiol (E2) in 22 mRCC patients (12 male and 10 female) receiving nivolumab therapy. In contrast to female patients, male patients showed a significant increase in E2 (p = 0.006) and LH/FSH ratio (p = 0.013) from the beginning of nivolumab therapy to week 12 of follow-up. Moreover, survival analysis revealed a significant negative association between LH/FSH ratio and progression-free survival (PFS) (p = 0.022) as well as between therapy response (p = 0.009) in males compared to females at interim evaluation (week 6/8). Our findings may therefore be the first reference to sex hormone changes during immunotherapy. [ABSTRACT FROM AUTHOR]

Summary: The aim of this short review is to summarize "clinical practice changing" abstracts about genitourinary cancers from this year's ASCO Annual Meeting. The phase 3 JAVELIN Bladder 100 trial showed astonishing overall survival (OS) data up to 22 months in metastatic urothelial carcinoma (mUC), using a novel gold standard in the first-line setting of mUC—immunotherapy maintenance with avelumab after response to platinum-based chemotherapy. In the first-line treatment of metastatic RCC (mRCC), two phase 2 trials (OMNIVORE and HCRN GU16-260) evaluated the efficacy of a novel sequential strategy, nivolumab monotherapy followed by ipilimumab rescue if nonresponse to nivolumab, confirming that this therapeutic concept is less effective as upfront combination treatment. Finally, updated 24-month progression-free survival (PFS) and OS rates of the KEYNOTE-426 are presented, showing efficacy most in intermediate- and poor-risk patients for the combination pembrolizumab plus axitinib compared with sunitinib. According to the impressive data from the HERO trial, the US Food and Drug Administration granted relugolix priority review as the first oral GNRH receptor antagonist in advanced prostate cancer. Moreover, 18F‑DCFPyL-PET/CT is a promising diagnostic tool for biochemical recurrence as the CONDOR trial confirmed diagnostic superiority of PyL-PET/CT compared with conventional imaging in detecting occult metastasis even in low PSA values. In nonmetastatic castration-resistant prostate cancer (nmCRPC), final OS data of ARAMIS, PROSPER and SPARTAN evaluating efficacy and safety of second-generation antiandrogens versus placebo were presented. In patients with mCRPC progressing after docetaxel, 177Lu-PSMA-617 demonstrated improved rates of 50% reduction in PSA relative to cabazitaxel (TheraP study). [ABSTRACT FROM AUTHOR]

Purpose: To report on the oncological outcome of organ-sparing surgery (OSS) compared to (total or partial) penectomy regarding recurrence patterns and survival in squamous cell carcinoma (SCC) of the penis. Methods: This was a retrospective study of all patients with penile SCC and eligible follow-up data of at least 2 years at our institution. Patients with tumors staged ≥ pT1G2 underwent invasive lymph node (LN) staging by dynamic sentinel-node biopsy or modified inguinal lymphadenectomy. Radical inguinal lymphadenectomy was performed when LNs were palpable at diagnosis and in those with a positive LN status after invasive nodal staging. Follow-up visits were assessed, and local, regional and distant recurrences were defined and analyzed. Results: 55 patients were identified with a mean follow-up of 63.7 months. Surgical management was OSS in 26 patients (47.2%) and partial or total penectomy in 29 cases (52.8%). Histopathological staging was: pTis (12.7%), pTa (16.3%), pT1a (18.2%), pT1b (5.5%), pT2 (29.1%) and pT3 (18.2%), respectively. Patients in the penectomy group were significantly older (mean 68 vs. 62 years; p = 0.026) with a higher rate of advanced tumor stage (≥ pT2: 44.8% vs. 11.5%; p = 0.002). The local recurrence rate was 42.3% (n = 11) following OSS compared to 10.3% (n = 3) after penectomy (p = 0.007). Kaplan–Meier curves showed no significant differences between the two groups regarding metastasis-free and overall survival. Conclusions: OSS is associated with a higher local recurrence rate compared to penectomy, yet it has no negative impact on overall and metastasis-free survival. [ABSTRACT FROM AUTHOR]

Prostate cancer and urothelial carcinoma are the two most common urological cancers. The aim of this short review is to highlight abstracts from this year's ASCO Annual Meeting. The phase III SPCG-13 trial showed no difference in biochemical disease-free survival by the addition of docetaxel after primary radiation therapy of localized high-risk prostate cancer. In bone dominant metastatic castration resistant prostate cancer, the phase II radium-223 dose escalation study concluded that the currently used dose with 6 cycles of 55 kBq/kg remains the standard of care. The PARP inhibitor olaparib plus abiraterone provided a significant benefit in radiological progression-free survival compared with abiraterone alone, independent of homologous recombination repair (HRR) mutation status. In localized muscle-invasive urothelial carcinoma, two phase II trials (ABACUS and PURE-01) exploring the pathological complete remission rate of atezolizumab and pembrolizumab prior to cystectomy in cisplatin-unfit or cisplatin-fit patients are presented. Novel targeted therapies such as fibroblast growth factor receptor (FGFR) inhibitors or monoclonal antibodies against nectin-4 confirmed astonishing objective response rates in heavily pretreated metastatic urothelial carcinoma (mUC) patients, resulting in a median overall survival (OS) up to 13.8 months. Finally, updated 1‑year and 2‑year OS survival rates of pembrolizumab and atezolizumab in the first line setting of mUC are presented. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging (MRI) of the prostate has become the gold standard for visualization of prostate cancer. Prostate MRI is usually performed as multiparametric MRI (mpMRI). Since mpMRI has several drawbacks, a biparametric MRI (bpMRI) of the prostate has been proposed. Many studies have been published on mpMRI and bpMRI in recent years. This short review offers an overview of the latest developments in this rapidly evolving field of research. [ABSTRACT FROM AUTHOR]

The era of antiangiogenic drugs targeting the vascular endothelial growth factor (VEGF) signaling pathway has become a mainstay in the treatment of metastatic renal cell carcinoma (mRCC), showing primary responses in 65-70% of patients. Nevertheless, most of those patients progress to angiogenesis inhibitors over time due to different modes of resistance (adaptive and intrinsic). Both in vitro and in vivo analyses provided evidence that PD-L1 upregulation in hypoxia conditions is dependent on hypoxia-inducible factor (HIF)-2alpha and is associated with an overexpression of VEGF. Thus, additional blockade of PD-L1 along with inhibition of angiogenesis pathways seems to represent a novel and innovative treatment concept in mRCC. In this short review, we provide an overview on ongoing phase III trials combining antiangiogenic therapies with checkpoint inhibitors in the first-line setting. Moreover, we critically analyze the impact of recently approved therapeutic antiangiogenic agents and checkpoint inhibitors after progression to first-generation tyrosine kinase inhibitors and their mode of action. In addition, response and resistance hypotheses and biomarkers to antiangiogenic therapy in clinical practice are critically discussed. [ABSTRACT FROM AUTHOR]

Th1-type immunity is considered to be required for efficient response to BCG in bladder cancer, although Th2 predisposition of BCG responders has recently been reported. The aim was to evaluate the relationship of Th1 and Th2 components in 23 patients undergoing BCG treatment. Peripheral blood, serum and urine samples were prospectively collected at baseline, during and after BCG. Th1 (neopterin, tryptophan, kynurenine, kynurenine-to-tryptophan ratio (KTR), IL-12, IFN-γ, soluble TNF-R75 and IL-2Rα) and Th2 (IL-4, IL-10) biomarkers as well as CD4 expression in T helper (Th), effector and regulatory T cells were determined. Local immune cell subsets were measured on formalin-fixed, paraffin-embedded cancer tissue by immunohistochemistry to examine expression of transcription factors that control Th1 (T-bet) and Th2-type (GATA3) immunity. We confirmed a Th2 predisposition with a mean GATA3/T-bet ratio of 5.51. BCG responders showed significantly higher levels of urinary ( p = 0.003) and serum neopterin ( p = 0.012), kynurenine ( p = 0.015), KTR ( p = 0.005), IFN-γ ( p = 0.005) and IL-12 ( p = 0.003) during therapy, whereas levels of IL-10 decreased significantly ( p < 0.001) compared to non-responders. GATA3/T-bet ratio correlated positively with serum neopterin ( p = 0.008), IFN-γ ( p = 0.013) and KTR ( p = 0.018) after the first BCG instillation. We observed a significant increase in CD4 expression in the Th cell population ( p < 0.05), with only a modest tendency toward higher frequency in responders compared to non-responders ( p = 0.303). The combined assessment of GATA3/T-bet ratio, neopterin and KTR may be a useful biomarker in predicting BCG response. Th2-promoting factors such as GATA3 may trigger Th1-type immune responses and thus contribute to the BCG success. [ABSTRACT FROM AUTHOR]

Purpose: To clarify the role of human papillomavirus (HPV) in non-muscle invasive bladder cancer, HPV-DNA was scrutinized in formalin-fixed, paraffin-embedded (FFPE) bladder cancer tissue using single-step PCR (HPV L1) for HPV detection, followed by reverse line blot (RLB) for genotyping. Methods: A total of 186 patients who underwent transurethral resection of the bladder due to primary, non-muscle invasive bladder cancer from 2006 to 2009 were reviewed. A positive control group of 22 cervical tissues with cervical carcinoma was included. Results: Histology confirmed urothelial carcinoma in all patients: primary CIS, pTa, pT1 and pTa + pT1 in 14 (7.5 %), 134 (72 %), 36 (19.4 %) and two (1.1 %) patients, respectively. A total of 119 (63.9 %) of them were classified as low-risk, while 67 (36.1 %) were high-risk cancers. Tumor recurrence and progression (≥pT2) were seen in 79 and 11 patients (mean follow-up 45 months). The presence of HPV-DNA by single-step PCR was detected in four (2.2 %) patients. HPV 16 and HPV 6 were positive in two (1.1 %) and one (0.6 %) patient, respectively In one case, no HPV genotype listed on the RLB assay could be identified. In the control group, the HPV infection rate was 100 %: HPV 16 in 12 (54.6 %) patients, HPV 16/18 in four (18.3 %) patients, HPV 18 in two (9.1 %) patients, HPV 16/45 in one patient (4.5 %), HPV 18/33 in one (4.5 %) patient, HPV 16/33 in one (4.5 %) patient and HPV 33 in one (4.5 %) patient. Conclusions: Our study demonstrates low prevalence of HPV infection in FFPE bladder cancer tissue, arguing against the etiological role of HPV in non-muscle urothelial carcinogenesis. [ABSTRACT FROM AUTHOR]

Objective: To investigate the prevalence of human papillomavirus (HPV) in prepuces of asymptomatic boys and men, the present study was designed. Methods: Two hundred and fifty male prepuce specimens who underwent circumcision due to phimosis were collected. Samples were subdivided into groups regarding their age: children (group I, 0-10 years), adolescents (group II, 11-20 years) and adults (group III, >20 years). HPV High Screen Real-TM Quant 2x kit detecting HPV 6 and 11 (low risk) as well as another kit for identification of HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59 (high risk) were used. Additionally, a Taq Man assay has been designed targeting the L1 gene of HPV 6, 11, 16 and 18. Results: Evaluating the number of low-risk HPV subtypes, we found HPV 6 and 11 in 5.3 % of samples ( n = 12/226). Concerning high-risk HPV, we found a positivity in 4 % of samples ( n = 9/224). In contrast to low-risk data where no age distribution was observed, we found an age-specific accumulation of high-risk HPV subtypes in the children group ( n = 6/9). A second independent assay (Taq Man PCR assay) measuring HPV 6, 11, 16 and 18 of all positive samples confirmed only the high-risk HPV subtypes of the Real-TM Quant 2x assay. Conclusions: Our study provides evidence that qPCR estimation for HPV infection obviously underestimates the incidence rate of infected prepuces in boys and men with phimosis. Contrary, an overestimation of the HPV infection rate with the in situ hybridization method of phimotic prepuces cannot be excluded. [ABSTRACT FROM AUTHOR]

Purpose: Ablation of the testis has been the reference standard for malignant and benign testicular tumors in the past. Nowadays, an organ-sparing surgery (OSS) can be attempted in special cases. Removal of a testis for a benign lesion should be avoided. In this retrospective survey, we analyze the results and long-term follow-up of OSS in benign testicular tumors. Methods: Charts of all patients that underwent OSS because of a benign testicular tumor between 1999 and 2011 at our department were searched and the data from patients were collected. Before surgery, all patients underwent ultrasound (US) and complete staging. Surgery was performed under US or palpation guidance. Frozen-section examination of the tumor and tumor bed biopsies was obtained. All patients underwent postoperative follow-up. We retrospectively reviewed surgical technique, histology, epidemiology, and outcome in all patients. Results: In the study period, 40 benign testicular tumors were surgically removed in 37 consecutive patients. Definitive histology did not report of any malignant histopathologic features in all patients. All patients are free of disease after a mean follow-up of 63 months (range 10-120). During this period, two patients developed a second leydig cell tumor (LCT) on the contralateral side; another patient had a second LCT within the same testicle, but on the opposite pole. All patients underwent a subsequent organ-sparing tumor resection. Conclusions: An overtreatment for benign testicular tumors should be avoided. Our initial results indicate that OSS in benign tumors is a safe, feasible treatment for patients. [ABSTRACT FROM AUTHOR]

Objective: To investigate the prevalence of high-risk (HR) and low-risk (LR) human papillomavirus (HPV) in prepuces of boys and men without any HPV related lesions. Patients and methods: Between 2009 and 2011, a total collective of 250 boys and men were investigated in this prospective study. The samples were subdivided into 3 groups regarding their age, consisting of 125 (50 %) children (0–10 years), 38 (15.2 %) adolescents (11–20 years) and 87 (34.8 %) adults (>20 years). In situ hybridization (ISH) was performed to detect HR and LR virus types within the epithelium, followed by microscopic interpretation and determination between episomal and integrative signal pattern. Results: Our results revealed high levels of HPV concentration (HR and LR) in all age groups: HR versus LR positivity was seen in 45.5 versus 35 % (children), 60.6 versus 63.6 % (adolescents) and 58.3 versus 48.6 % (adults). The topmost rate of HR (59.8 %)- and LR (50.6 %)-positive probes was found in the group with high estimated sexual activity (>14 years). Conclusion: Concerning the high prevalence of male HPV infection even in children, indicating non-sexual transmission pathways, inclusion of boys in the vaccination program seems to be required reducing their burden of HPV related disease. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the cellular survival of donor fibroblasts after transplantation at the vesico-ureteral junction (VUJ) and to analyse their potential for reconstructive cell replacement in an animal model as autologous fibroblasts have been used as soft tissue augmentation material for scared and damaged tissue. Methods: Muscles biopsies were procured from the lower limb muscles of 4 pigs; cytoplasm of fibroblasts was labelled with nano-sized iron oxide particles. Six weeks after taking of the muscle biopsies, fibroblast transplantation was performed, 3 × 10 cells suspended in transplantation medium (in 1-ml syringes) were injected at the VUJ using the modified STING technique. Animals were killed 8 weeks later; seeded fibroblasts were identified using prussian blue staining protocol; histological evaluation and morphological analysis were performed by light microscopy (Mayer's haematoxylin-eosin staining); and bladders were scanned by MRI for visualization and localization of the iron-labelled donor cells. Results: Donor fibroblast cell colonization and cellular viability at the VUJ was demonstrated by MRI and histochemically indicating cellular uptake of iron particles at the VUJ. It was also evident that transplanted fibroblasts integrate into the extracellular matrix of the distal ureter augmenting ureteral host tissue. Conclusions: Labelled implanted autologous fibroblasts were visualized by staining procedure as well as MRI scan demonstrating persistence at the VUJ, suggesting that in vitro expanded fibroblasts survived in vivo after transplantation. [ABSTRACT FROM AUTHOR]