Transdermal oestradiol and exercise in androgen deprivation therapy (ESTRACISE): protocol.

OBJECTIVE: To report the protocol of a study evaluating the efficacy of transdermal oestradiol (E2) gel in reducing the adverse effects of androgen deprivation therapy (ADT), specifically on sexual function, and to assess the utility of E2 in combination with supervised exercise. STUDY DESIGN AND METHODS: The primary endpoint of this open-label Phase IIA randomized controlled trial is the efficacy of transdermal E2 gel. Secondary endpoints include: (i) the occurrence of ADT-induced adverse effects; (ii) the safety and tolerability of E2; (iii) the impact of E2 with or without exercise on physical, physiological, muscle, and systemic biomarkers; and (iv) quality of life. The trial will recruit high-risk PCa patients (n = 310) undergoing external beam radiation therapy with adjuvant subcutaneous ADT. Participants will be stratified and randomized in a 1:1 ratio to either the E2 + ADT arm or the ADT-only control arm. Additionally, a subset of patients (n = 120) will be randomized into a supervised exercise programme. RESULTS: The primary outcome is assessed according to the efficacy of E2 in mitigating the deterioration of Expanded Prostate Cancer Index Composite sexual function domain scores. Secondary outcomes are assessed according to the occurrence of ADT-induced adverse effects, safety and tolerability of E2, impact of E2 with or without exercise on physical performance, body composition, bone mineral density, muscle size, systematic biomarkers, and quality of life. CONCLUSION: The ESTRACISE study's innovative design can offer novel insights about the benefits of E2 gel, and the substudy can reinforce the benefits resistance training and deliver valuable new novel insights into the synergistic benefits of E2 gel and exercise, which are currently unknown. TRIAL REGISTRATION: The protocol has been registered in euclinicaltrials.eu (2023-504704-28-00) and in clinicaltrials.gov (NCT06271551).

CD3+ and CD8+ T cell-based immune cell score as a prognostic factor in clear-cell renal cell carcinoma.

BACKGROUND AND PURPOSE: Immunoscore® is a prognostic parameter based on densities of lymphocyte populations in the tumor center and invasive margin. Immunoscore® is validated in colorectal cancer as a high Immunoscore® is associated with longer survival. Previous studies have suggested that Immunoscore® may also predict oncological outcomes in clear-cell renal cell carcinoma (ccRCC). This study aims to assess the prognostic role of immune cell score in ccRCC. MATERIAL AND METHODS: All patients with ccRCC undergoing surgery between 2007 and 2020 in Central Finland Central Hospital were retrospectively identified. CD3+ and CD8+ cell densities were calculated from tissue samples to determine the immune cell score using Immunoscore® principles. Receiver-operating characteristic analysis, Kaplan-Meier survival curve, and Cox regression were used to evaluate the association between immune cell score and survival. RESULTS: A total of 203 patients (mean age 66.5 years) were identified. The median follow-up time was 6.2 years. Based on the immune cell score, the patients were divided into three groups: low, intermediate, and high. In Cox regression analysis, adjusted with age, sex, and Charlson Comorbidity Index, no significant differences in disease-specific mortality were observed among the three groups. The hazard ratios (HRs) for disease-specific mortality were 0.93 (95% confidence interval [CI] 0.48-1.79) and 1.12 (0.52-2.37) for intermediate- and high-immune cell score groups when compared to low-immune cell score group, respectively. INTERPRETATION: This study found no association between immune cell score and survival. These results indicate that immune cell score may not serve as a prognostic tool in ccRCC.

Nationwide analysis of survival after radical cystectomy for bladder cancer in Finland.

BACKGROUND: Population-based survival results after radical cystectomy (RC) are limited. Our objective was to report short and long-term survival results after RC for bladder cancer from Finland in a population-based setting. MATERIALS AND METHODS: The Finnish National Cystectomy Database containing retrospectively collected essential RC data covering the years 2005-2017 was combined with the survival data from the Finnish Cancer Registry. Kaplan-Meier plots were used to estimate survival and the survival graphs were illustrated according to the final pathological staging. Centers were divided according to operational volume, and the results were then compared using Pearsons's Chi-squared test. RESULTS: A total of 2047 patients were included in the study. 30-, and 90-day mortality was 1.3%, and 3.8%, respectively. The OS of the entire RC population at 5- and 10 years was 66% and 55%, and CSS was 74% and 72%, respectively. Center volume did not significantly associate with surgical mortality or long-term survival. The 5- and 10-year OS according to pT-category was 87% and 74% for pT0, 85% and 69% for pTa-pTis-pT1, 70% and 58% for pT2, 50% and 42% for pT3 and 41% and 30% for pT4. The corresponding 5- and 10-year CSS rates were 96% and 93% for pT0, 91% and 90% for pTa-pTis-pT1, 78% and 75% for pT2, 56% and 55% for pT3 and 47% and 44% for pT4. The 5- and 10-year OS rates in patients with no lymph node metastases (pN-) were 74% and 62%, and CSS 82% and 80%, respectively. If lymph nodes were positive (pN+), the corresponding OS rates were 44% and 34% and CSS 49% and 48%, respectively. CONCLUSION: RC survival results have improved in contemporary series and are associated with the pTNM-status. The nationwide results from Finland demonstrate outcome comparable to high volume single-center series.

Periodic trends in geographical variation of prostate cancer incidence and mortality in Finland between 1985 and 2019.

BACKGROUND: Evaluation of regional variation of prostate cancer (PCa) incidence and PCa-specific mortality is essential in the assessment of equity in a national healthcare system. We evaluated PCa incidence and PCa-specific mortality between different municipalities and hospital districts in Finland over 1985-2019. MATERIAL AND METHODS: Men diagnosed with PCa in Finland from 1985 through 2019 were retrieved from Finnish Cancer Registry. Age-standardized PCa incidence and mortality rates were estimated by municipality and hospital district as well as municipality urbanization, education, and income level using hierarchical Bayesian modeling. Standard deviations (SD) of the regional rates were compared between periods from 1985-1989 to 2015-2019. RESULTS: We identified 123,185 men diagnosed with any stage PCa between 1985 and 2019. SD of PCa incidence rate (per 100,000 person-years) showed that the total variation of PCa incidence between different municipalities was substantial and varied over time: from 22.2 (95% CI, 17.1-27.8) in 1985-1989 to 56.5 (95% CI, 49.8-64.5) in 2000-2004. The SD of PCa mortality rate between all municipalities was from 9.0 (95% CI, 6.6-11.8) in 2005-2009 to 2.4 (95% CI, 0.9-4.8) in 2015-2019. There was a trend toward a lower PCa-specific mortality rate in municipalities with higher education level. DISCUSSION: Regional variation in the incidence rate of PCa became more evident after initiation of PSA testing in Finland, which indicates that early diagnostic practice (PSA testing) of PCa has been different in different parts of the country. Variation in the national PCa mortality rate was indeed recognizable, however, this variation diminished at the same time as the mortality rate declined in Finland. It seems that after the initiation period of PSA testing, PSA has equalized PCa mortality outcomes in Finland.

Survival and mortality of elderly men with localized prostate cancer managed with primary androgen deprivation therapy or by primary observation.

BACKGROUND: Androgen deprivation therapy (ADT) remains a primary treatment for localized prostate cancer (PCa) even though there is no evidence that its use is beneficial in the absence of curative treatment. METHODS: Men aged ≥70 years (n = 16,534) diagnosed with localized PCa from 1985 to 2014 and managed either with primary observation or ADT in the absence of curative treatment were included. The cases were identified from the population-based Finnish Cancer Registry. We estimated the standardized mortality ratios (SMR) for overall mortality by treatment group. We determined the relative risk (RR) of PCa-specific mortality (PCSM) and other-cause mortality between the two treatment groups. Survival was determined using the life table method. Two age groups (70-79 years and ≥ 80 years) and three calendar time cohorts (1985-1994, 1995-2004, and 2005-2014) were compared following adjustment of propensity score matching between the treatment groups with four covariates (age, year of diagnosis, educational level, and hospital district). Follow-up continued until death or until December 31, 2015. RESULTS: Patients in the observation group had lower overall SMRs than those in the ADT group in both age cohorts over the entire study period. PCSM was higher in men aged 70-79 years undergoing primary ADT compared to those managed by observation only (RR: 1.70, 95% confidence interval [CI]: 1.29-2.23 [1985-1994]; RR 1.55, 95% CI: 1.35-1.84 [1995-2004]; and RR 2.71, 95% CI: 2.08-3.53 [2005-2014]); p = 0.005 for periodic trend. A similar trend over time was also observed in men aged > 80 years; (p for age-period interaction = 0.237). Overall survival was also higher among men in their 70's managed by observation compared to those undergoing ADT. CONCLUSIONS: Primary ADT within four months period from diagnosis is not associated with improved long-term overall survival or decreased PCSM compared to primary conservative management for men with localized PCa. However, this observational study's conclusions should be weighted with confounding factors related to cancer aggressiveness and comorbidities.

The impact of socioeconomic status on stage specific prostate cancer survival and mortality before and after introduction of PSA test in Finland.

Socioeconomic status (SES) has an impact on prostate cancer (PCa) outcomes. Men with high SES have higher incidence and lower mortality of PCa versus lower SES males. PCa cases diagnosed in Finland in 1985-2014 (N = 95,076) were identified from the Finnish Cancer Registry. Information on education level (EL) was obtained from Statistics Finland. EL was assessed with three-tiered scale: basic, upper secondary and higher education. PCa stage at diagnosis was defined as localized, metastatic or unknown. Years of diagnosis 1985-1994 were defined as pre-PSA period and thereafter as post-PSA period. We report PCa-specific survival (PCSS) and relative risks (RR) for PCa specific mortality (PCSM) among cancer cases in Finland, where healthcare is 100% publicly reimbursed and inequality in healthcare services low. Men with higher EL had markedly better 10-year PCSS: 68 versus 63% in 1985-1994 and 90 versus 85% in 1995-2004 compared to basic EL in localized PCa. The RR for PCSM among men with localized PCa and higher EL compared to basic EL was 0.76(95%confidence interval (CI) 0.66-0.88) in 1985-1994 and 0.61(95%CI 0.53-0.70) in 1995-2004. Variation in PCSS and PCSM between EL categories was evident in metastatic PCa, too. The difference in PCSM between EL categories was larger in the first 10-year post-PSA period than before that but decreased thereafter in localized PCa, suggesting PSA testing became earlier popular among men with high EL. In summary, higher SES/EL benefit PCa survival both in local and disseminated disease and the effect of EL was more pronounced in early post-PSA period.

Stage-specific mortality and survival trends of prostate cancer patients in Finland before and after introduction of PSA.

BACKGROUND: The early diagnosis and right treatment strategy of localized prostate cancer (PCa) remains problematic. In order to characterize the survival of PCa patients, we compared patients' all-cause and cancer-specific mortalities between pre- and post-PSA periods by stage in Finland. MATERIAL AND METHODS: All PCa cases diagnosed in Finland between 1985 and 2013 (N = 91,329) were identified from the Finnish Cancer Registry (FCR). PCa stage at diagnosis was defined as localized, local node positive or metastasized. Standardized mortality ratios (SMRs), and relative and cause-specific survival were assessed by stage and introduction of PSA testing. The main limitation was the high proportion of men with unknown stage (28%). RESULTS: A clear decreasing trend in the SMR of PCa patients was evident when pre- and post-PSA eras were compared: for localized PCa, the SMR was 1.43 (95%CI 1.38-1.48) in 1985-1989 and 0.98 (95%CI 0.95-1.01) in 2000-2004, and for metastasized PCa, the SMRs were 4.51 (95%CI 4.30-4.72) and 3.01 (95%CI 2.89-3.12), respectively. Difference between cause-specific and relative survival was pronounced in localized PCa in post-PSA period: 10-year relative survival was 94.6% (95%CI 91.4-97.8) and cause-specific 84.2% (95%CI 82.9-85.5%). In metastasized PCa the difference was not that significant. CONCLUSIONS: From 1985 to 2009, the SMR among men diagnosed with PCa decreased significantly in Finland. Among men with localized PCa, the SMR decreased even below that of the Finnish male population. This and the increased difference between relative and cause-specific survival reflects most likely selection of men to opportunistic PSA testing. The results highlight the importance of caution in the use of PSA testing in healthy men.

Increased expression of fibroblast growth factor 13 in prostate cancer is associated with shortened time to biochemical recurrence after radical prostatectomy.

Fibroblast growth factor homologous factors (FHFs) belong to the fibroblast growth factor (FGF) superfamily, which plays an important role in prostate cancer (PCa). Mining of public database suggests that FGF13 (FHF2) mRNA expression is altered in over 30% of PCa cases. This study examined the FGF13 expression pattern in human PCa specimens and evaluated its potential as a biomarker for patient outcome after radical prostatectomy (RP). Immunohistochemistry (IHC) showed that FGF13 was detectable in the majority of human PCa samples, and FGF13 IHC scores were higher in high-grade prostatic intraepithelial neoplasia, in primary PCa and in metastatic PCa than in benign prostatic tissue. There was a significant association between high cytoplasmic FGF13 staining and a risk of biochemical recurrence (BCR) after RP. This was also evident in the intermediate to high-risk patient groups. In contrast, positive nuclear FGF13 staining along with low cytoplasmic FGF13 group showed a decreased BCR risk. Multivariate regression analysis indicated that high cytoplasmic FGF13 staining was associated with BCR and that this could serve as an independent prognostic marker in PCa. Several PCa cell lines showed increased FGF13 expression at the mRNA and protein levels compared to the immortalized prostate epithelial cell line PNT1a. Analysis of co-labeled cells suggested a possible interaction of FGF13 with α-tubulin and the voltage-gated sodium channel proteins (Na(V)s/VGSCs). Our data indicate that, for PCa patients after RP, FGF13 serves as a potential novel prognostic marker that improves prediction of BCR-free survival, in particular if combined with other clinical parameters.

Loss of PTEN expression in ERG-negative prostate cancer predicts secondary therapies and leads to shorter disease-specific survival time after radical prostatectomy.

The clinical course of prostate cancer is highly variable. Current prognostic variables, stage, and Gleason score have limitations in assessing treatment regimens for individual patients, especially in the intermediate-risk group of Gleason score 7. ERG:TMPRSS2 fusion and loss of PTEN are some of the most common genetic alterations in prostate cancer. Immunohistochemistry of PTEN and ERG has generated interest as a promising method for more precise outcome prediction but requires further validation in population-based cohorts. We studied the predictive value of ERG and PTEN expression by immunohistochemistry in two large radical prostatectomy cohorts comprising 815 patients with extensive follow-up information. Clinical end points were initiation of secondary therapy, overall survival, and disease-specific survival. Predictions of clinical outcomes were also assessed according to androgen receptor (AR) activity. PTEN loss, especially in ERG-negative cancers, predicted initiation of secondary treatments and shortened disease-specific survival time, as well as stratifying Gleason score 7 patients into different prognostic groups with regard to secondary treatments and disease-specific survival. High AR immunoreactivity in ERG-negative cancers with PTEN loss predicted worse disease-specific survival. We also observed that in Gleason score 7 ERG-negative cases with PTEN loss and high AR expression have significantly shorter disease-specific survival time compared with ERG-positive cases. Our conclusion is that loss of PTEN is a strong determining factor for shorter disease-specific survival time and initiation of secondary therapies after radical prostatectomy. The predictive value of PTEN immunoreactivity is further accentuated in ERG-negative cancers with high AR expression. Negative PTEN expression, accompanied by ERG status, can be used to stratify patients with Gleason score 7 into different survival groups. Assessment of PTEN and ERG status could provide an additional tool for initial diagnostics when determining the prognosis and subsequent follow-up regimen for patients treated by radical prostatectomy.

[PSA and blood test diagnostics of prostate cancer]. / PSA ja eturauhassyövän verinäytediagnostiikka.

Gleason grading of tumor biopses is the only method to distinguish clinically significant prostate cancer. Local cancer is usually symptomless, and men would benefit from functional screening. The aim of improving blood test diagnostics is to find those for whom it is profitable on the basis of blood test to proceed to biopsies. Overdiagnosis would be simultaneously avoided. In blood test diagnostics, established use is made only of the levels of prostate-specific antigen (PSA) and free PSA. New methods for blood test diagnosis are "Prostate Health Index" and the four-kallikrein panel.

Optimal Strategies for Managing Prostate-specific Antigen Recurrence After Primary Radiotherapy in Prostate Cancer: The Finnish Perspective.

Biochemical recurrence after radiotherapy for prostate cancer is a clinical dilemma. Patients at low risk of disease progression can be safely monitored. In Finland, options for those with reasonable life expectancy include salvage high-dose-rate brachytherapy and transurethral ultrasound ablation under magnetic resonance imaging guidance.

3D laparoscopic prostatectomy: results of multicentre study.

INTRODUCTION: Three-dimensional laparoscopic prostatectomy (3D LRP) is a potentially cost-effective option for robot-assisted laparoscopic prostatectomy (RALP). Results for two-dimensional LRP and RALP are well documented; however, little has been published on the outcomes of 3D LRP. Our objective was to report the perioperative and short-term results of 3D LRP in a multicentre study. MATERIALS AND METHODS: In total, 496 unselected men with prostate cancer underwent 3D LRP by three surgeons between December 2013 and December 2018. Median age was 64 (43-76) years. Median prostate-specific antigen (PSA) was 7.9 (0.7-148) ng/ml. Preoperative and perioperative data and complications according to the Clavien-Dindo classification were collected. PSA and continence results were reported at 3 and 12 months postoperatively. Data were analysed with IBM SPSS statistics (25). RESULTS: Pathological Gleason score was 6 in 29%, 7 in 55.4%, 8 in 9.1%, 9 in 5.2% and 10 in 1.2% of patients. Pathological tumour classification was T2c in 59.5%, T3a in 19.5% and T3b in 10.9% of cases. Positive surgical margins occurred in 27.2%. Lymphadenectomy was performed in 36.3%, with positive lymph nodes in 11.8%. Median operative time was 137 (78-334) min and median blood loss 200 (10-1100) ml. Clavien-Dindo IIIa and IIIb complications occurred in 6.9% and 1.6%, respectively. At 3 and 12 months postoperatively, 90.2% and 91.4% of patients, respectively, had PSA <0.2 ng/ml, while 77.1% and 87.7% of patients were completely dry or using a maximum of one pad daily. CONCLUSIONS: 3D LRP shows promising results, comparable to similar studies published on RALP.

Intraoperative complications in kidney tumor surgery: critical grading for the European Association of Urology intraoperative adverse incident classification.

INTRODUCTION: The European Association of Urology committee in 2020 suggested a new classification, intraoperative adverse incident classification (EAUiaiC), to grade intraoperative adverse events (IAE) in urology. AIMS: We applied and validated EAUiaiC, for kidney tumor surgery. PATIENTS AND METHODS: A retrospective multicenter study was conducted based on chart review. The study group comprised 749 radical nephrectomies (RN) and 531 partial nephrectomies (PN) performed in 12 hospitals in Finland during 2016-2017. All IAEs were centrally graded for EAUiaiC. The classification was adapted to kidney tumor surgery by the inclusion of global bleeding as a transfusion of ≥3 units of blood (Grade 2) or as ≥5 units (Grade 3), and also by the exclusion of preemptive conversions. RESULTS: A total of 110 IAEs were recorded in 13.8% of patients undergoing RN, and 40 IAEs in 6.4% of patients with PN. Overall, bleeding injuries in major vessels, unspecified origin and parenchymal organs accounted for 29.3, 24.0, and 16.0% of all IEAs, respectively. Bowel (n = 10) and ureter (n = 3) injuries were rare. There was no intraoperative mortality. IAEs were associated with increased tumor size, tumor extent, age, comorbidity scores, surgical approach and indication, postoperative Clavien-Dindo (CD) complications and longer stay in hospital. 48% of conversions were reactive with more CD-complications after reactive than preemptive conversion (43 vs. 25%). CONCLUSIONS: The associations between IAEs and preoperative variables and postoperative outcome indicate good construct validity for EAUiaiC. Bleeding is the most important IAE in kidney tumor surgery and the inclusion of transfusions could provide increased objectivity.

Randomised double-blind phase 3 clinical study testing impact of atorvastatin on prostate cancer progression after initiation of androgen deprivation therapy: study protocol.

INTRODUCTION: Blood cholesterol is likely a risk factor for prostate cancer prognosis and use of statins is associated with lowered risk of prostate cancer recurrence and progression. Furthermore, use of statins has been associated with prolonged time before development of castration resistance (CR) during androgen deprivation therapy (ADT) for prostate cancer. However, the efficacy of statins on delaying castration-resistance has not been tested in a randomised placebo-controlled setting.This study aims to test statins' efficacy compared to placebo in delaying development of CR during ADT treatment for primary metastatic or recurrent prostate cancer. Secondary aim is to explore effect of statin intervention on prostate cancer mortality and lipid metabolism during ADT. METHODS AND ANALYSIS: In this randomised placebo-controlled trial, a total of 400 men with de novo metastatic prostate cancer or recurrent disease after primary treatment and starting ADT will be recruited and randomised 1:1 to use daily 80 mg of atorvastatin or placebo. All researchers, study nurses and patients will be blinded throughout the trial. Patients are followed until disease recurrence or death. Primary outcome is time to formation of CR after initiation of ADT. Serum lipid levels (total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and trigyserides) are analysed to test whether changes in serum cholesterol parameters during ADT predict length of treatment response. Furthermore, the trial will compare quality of life, cardiovascular morbidity, changes in blood glucose and circulating cell-free DNA, and urine lipidome during trial. ETHICS AND DISSEMINATION: This study is approved by the Regional ethics committees of the Pirkanmaa Hospital District, Science centre, Tampere, Finland (R18065M) and Tarto University Hospital, Tarto, Estonia (319/T-6). All participants read and sign informed consent form before study entry. After publication of results for the primary endpoints, anonymised summary metadata and statistical code will be made openly available. The data will not include any information that could make it possible to identify a given participant. TRIAL REGISTRATION NUMBER: Clinicaltrial.gov: NCT04026230, Eudra-CT: 2016-004774-17, protocol code: ESTO2, protocol date 10 September 2020 and version 6.

Individualised non-contrast MRI-based risk estimation and shared decision-making in men with a suspicion of prostate cancer: protocol for multicentre randomised controlled trial (multi-IMPROD V.2.0).

INTRODUCTION: European Association of Urology and UK National Institute for Health and Care Excellence guidelines recommend that all men with suspicions of prostate cancer should undergo prebiopsy contrast enhanced, that is, multiparametric prostate MRI. Subsequent prostate biopsies should also be performed if MRI is positive, that is, Prostate Imaging-Reporting and Data System (PI-RADS) scores 3-5. However, several retrospective post hoc analyses have shown that this approach still leads to many unnecessary biopsy procedures. For example, 88%-96% of men with PI-RADS, three findings are still diagnosed with clinically non-significant prostate cancer or no cancer at all. METHODS AND ANALYSIS: This is a prospective, randomised, controlled, multicentre trial, being conducted in Finland, to demonstrate non-inferiority in clinically significant cancer detection rates among men undergoing prostate biopsies post-MRI and men undergoing prostate biopsies post-MRI only after a shared decision based on individualised risk estimation. Men without previous diagnosis of prostate cancer and with abnormal digital rectal examination findings and/or prostate-specific antigen between 2.5 ug/L and 20.0 ug/L are included. We aim to recruit 830 men who are randomised at a 1:1 ratio into control (all undergo biopsies after MRI) and intervention arms (the decision to perform biopsies is based on risk estimation and shared decision-making). The primary outcome of the study is the proportion of men with clinically significant prostate cancer (Gleason 4+3 prostate cancer or higher). We will also compare the overall biopsy rate, benign biopsy rate and the detection of non-significant prostate cancer between the two study groups. ETHICS AND DISSEMINATION: The study (protocol V.2.0, 4 January 2021) was approved by the Ethics Committee of the Hospital District of Southwest Finland (IORG number: 0001744, IBR number: 00002216; trial number: 99/1801/2019). Participants are required to provide written informed consent. Full reports of this study will be submitted to peer-reviewed journals, mainly urology and radiology. TRIAL REGISTRATION NUMBER: NCT04287088; the study is registered at ClinicalTrials.gov.

Increased Expression and Altered Cellular Localization of Fibroblast Growth Factor Receptor-Like 1 (FGFRL1) Are Associated with Prostate Cancer Progression.

Fibroblast growth factor receptors (FGFRs) 1-4 are involved in prostate cancer (PCa) regulation, but the role of FGFR-like 1 (FGFRL1) in PCa is unclear. FGFRL1 expression was studied by qRT-PCR and immunohistochemistry of patient tissue microarrays (TMAs) and correlated with clinical patient data. The effects of FGFRL1 knockdown (KD) in PC3M were studied in in vitro culture models and in mouse xenograft tumors. Our results showed that FGFRL1 was significantly upregulated in PCa. The level of membranous FGFRL1 was negatively associated with high Gleason scores (GSs) and Ki67, while increased cytoplasmic and nuclear FGFRL1 showed a positive correlation. Cox regression analysis indicated that nuclear FGFRL1 was an independent prognostic marker for biochemical recurrence after radical prostatectomy. Functional studies indicated that FGFRL1-KD in PC3M cells increases FGFR signaling, whereas FGFRL1 overexpression attenuates it, supporting decoy receptor actions of membrane-localized FGFRL1. In accordance with clinical data, FGFRL1-KD markedly suppressed PC3M xenograft growth. Transcriptomics of FGFRL1-KD cells and xenografts revealed major changes in genes regulating differentiation, ECM turnover, and tumor-stromal interactions associated with decreased growth in FGFRL1-KD xenografts. Our results suggest that FGFRL1 upregulation and altered cellular compartmentalization contribute to PCa progression. The nuclear FGFRL1 could serve as a prognostic marker for PCa patients.

Visual MRI T-category versus VI-RADS evaluation from multiparametric MRI in the detection of muscle-invasion in patients with suspected bladder cancer: single centre registered clinical trial (MIB-trial).

BACKGROUND: Multiparametric Magnetic Resonance Imaging (mpMRI) has been proposed to add value in the diagnostic pathway of bladder cancer (BC). We wanted to evaluate the performance of mpMRI for muscle-invasion detection in BC patients using a subjective MRI visual T-category and the Vesical Imaging-Reporting and Data System (VI-RADS) score. METHODS: This single centre clinical trial included 45 patients with suspected BC (ClinicalTrials.gov Identifier: NCT02662166). All patients had mpMRI prior to transurethral resection of bladder tumour (TUR-BT). The imaging was correlated to histopathological findings. Two individual radiologists evaluated all the mpMRI images. A binary cut-off point for the detection of muscle-invasion in the MRI visual T-category was defined between T1 and T2 and the VI-RADS cut-off score was 3. Cohen's Kappa values were used to evaluate the agreement between the two radiologists. Sensitivity, Specificity, Area Under Receiver Operator Characteristics Curve (AUC), Positive Predictive Value (PPV) and Negative Predictive Value (NPV) were calculated to evaluate the performance of both radiologists separately. RESULTS: AUC values for reader A and B using the MRI visual T-category were 0.76 and 0.56, while the corresponding values for VI-RADS were 0.63 and 0.57, respectively. There was no statistically significant difference between the radiologists nor the reporting systems (p > .05) in the detection of muscle-invasion. The inter-reader agreement was substantial (0.61-0.80). CONCLUSION: Both the subjective MRI visual T-category and VI-RADS score had only a low to moderate accuracy for the detection of muscle-invasion in BC with no statistically significant difference between the reporting systems.

Does every Clavien-Dindo complication matter? A national multi-center study in kidney cancer surgery.

BACKGROUND: There is huge variation in Clavien-Dindo (CD) complication rates in urology. We sought to optimize the use of the CD system in kidney tumor surgery. METHODS: We retrospectively analyzed 1,286 patients undergoing kidney tumor operations in 12 Finnish hospitals during 2016-2017. Primary CD assignments were made by site urologists. Data were centrally reviewed by two authors in consensus meetings. Consistency of the primary assignments was assessed by the number of cases requiring correction. Complication load was compared as different outcome rates between five university hospital regions. RESULTS: The overall complication rate in primary data was 40% (517/1286) and varied significantly from 32 to 62% (p < 0.001) between the regions. The need for corrections in central review was significantly greater for CD1 (54%) compared to CD2 (16%, p < 0.001) and CD3-5 (11%, p < 0.001) categories. The final data comprised 500 CD complications after 390 surgeries. The most frequent pathologies were bleeding (8.4%), urological complications (5.9%) and postoperative fever (4.7%). The overall CD2 complications rate was statistically (p < 0.001) higher in region D and that of CD3-5 was higher (p = 0.007) in region B. In multivariable analysis, university hospital region, male sex, BMI ≥ 27, ECOG ≥ 1, partial nephrectomy type and open surgery significantly increased the risk of complications. CONCLUSIONS: Comparative use of CD1 complications may be too inconsistent and only CD2-5 complications should be reported. Central review of the primary data and detailed guidelines are necessary.

Familial aggregation of testicular cancer among early-onset cancer survivors. A prospective observational cohort data from Finland.

Testicular cancer (TC) is the most common form of cancer in men aged 15-35 years. Familial risk for TC is among highest of all cancers. MATERIAL AND METHODS: A prospective observational cohort of 9111 relatives in 2,188 families of early-onset TC patients, called probands, diagnosed at age ≤40 years in Finland between 1970 and 2012. Standardized incidence ratios (SIR) were used as measures of familial aggregation for early-onset (≤40 years) TC. Follow-up ended at diagnosis of TC, death or 31 December 2014 whichever earliest. RESULTS: Among first-degree relatives of early-onset TCs, in all 12 early-onset TC cases (0.24%) were diagnosed over the follow-up; the SIR for any first-degree relative was 4.59 (95% confidence interval (CI): 2.37-8.01) and for brothers the SIR was 6.51 (95% CI 3.12-11.96). DISCUSSION: Familial aggregation of TC shows substantial risk for early-onset TC among first-degree relatives of early-onset TC patients in Finland. This is important to acknowledge to avoid diagnostic delay especially of TC.