Prostate Cancer Screening With PSA, Kallikrein Panel, and MRI: The ProScreen Randomized Trial.

Importance: Prostate-specific antigen (PSA) screening has potential to reduce prostate cancer mortality but frequently detects prostate cancer that is not clinically important. Objective: To describe rates of low-grade (grade group 1) and high-grade (grade groups 2-5) prostate cancer identified among men invited to participate in a prostate cancer screening protocol consisting of a PSA test, a 4-kallikrein panel, and a magnetic resonance imaging (MRI) scan. Design, Setting, and Participants: The ProScreen trial is a clinical trial conducted in Helsinki and Tampere, Finland, that randomized 61 193 men aged 50 through 63 years who were free of prostate cancer in a 1:3 ratio to either be invited or not be invited to undergo screening for prostate cancer between February 2018 and July 2020. Interventions: Participating men randomized to the intervention underwent PSA testing. Those with a PSA level of 3.0 ng/mL or higher underwent additional testing for high-grade prostate cancer with a 4-kallikrein panel risk score. Those with a kallikrein panel score of 7.5% or higher underwent an MRI of the prostate gland, followed by targeted biopsies for those with abnormal prostate gland MRI findings. Final data collection occurred through June 31, 2023. Main Outcomes and Measures: In descriptive exploratory analyses, the cumulative incidence of low-grade and high-grade prostate cancer after the first screening round were compared between the group invited to undergo prostate cancer screening and the control group. Results: Of 60 745 eligible men (mean [SD] age, 57.2 [4.0] years), 15 201 were randomized to be invited and 45 544 were randomized not to be invited to undergo prostate cancer screening. Of 15 201 eligible males invited to undergo screening, 7744 (51%) participated. Among them, 32 low-grade prostate cancers (cumulative incidence, 0.41%) and 128 high-grade prostate cancers (cumulative incidence, 1.65%) were detected, with 1 cancer grade group result missing. Among the 7457 invited men (49%) who refused participation, 7 low-grade prostate cancers (cumulative incidence, 0.1%) and 44 high-grade prostate cancers (cumulative incidence, 0.6%) were detected, with 7 cancer grade groups missing. For the entire invited screening group, 39 low-grade prostate cancers (cumulative incidence, 0.26%) and 172 high-grade prostate cancers (cumulative incidence, 1.13%) were detected. During a median follow-up of 3.2 years, in the group not invited to undergo screening, 65 low-grade prostate cancers (cumulative incidence, 0.14%) and 282 high-grade prostate cancers (cumulative incidence, 0.62%) were detected. The risk difference for the entire group randomized to the screening invitation vs the control group was 0.11% (95% CI, 0.03%-0.20%) for low-grade and 0.51% (95% CI, 0.33%-0.70%) for high-grade cancer. Conclusions and Relevance: In this preliminary descriptive report from an ongoing randomized clinical trial, 1 additional high-grade cancer per 196 men and 1 low-grade cancer per 909 men were detected among those randomized to be invited to undergo a single prostate cancer screening intervention compared with those not invited to undergo screening. These preliminary findings from a single round of screening should be interpreted cautiously, pending results of the study's primary mortality outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT03423303.

Risk of Clinically Significant Prostate Cancer after a Nonsuspicious Prostate MRI-A Comparison with the General Population.

BACKGROUND: We compare the risk of clinically significant (csPCa; ISUP Grade Group ≥ 2) and insignificant prostate cancer (isPCa; ISUP Grade Group 1) in men with a nonsuspicious prostate MRI (nMRI; PI-RADS ≤ 2) with the general population, and assess the value of PSA density (PSAD) in stratification. METHODS: In this retrospective population-based cohort study we identified 1,682 50-79-year-old men, who underwent nMRI at HUS (2016-2019). We compared their age-standardized incidence rates (IR) of csPCa and the odds of isPCa to a local age- and sex-matched general population (n = 230,458) during a six-year follow-up. Comparisons were performed by calculating incidence rate ratios (IRR) and ORs with 95% confidence intervals (CI). We repeated the comparison for the 920 men with nMRI and PSAD < 0.15 ng/mL/cm3. RESULTS: Compared with the general population, the IR of csPCa was significantly higher after nMRI [1,852 vs. 552 per 100,000 person-years; IRR 3.4 (95% CI, 2.8-4.1)]. However, the IR was substantially lower if PSAD was low [778 per 100,000 person-years; IRR 1.4 (95% CI, 0.9-2.0)]. ORs for isPCa were 2.4 (95% CI, 1.7-3.5) for all men with nMRI and 5.0 (95% CI, 2.8-9.1) if PSAD was low. CONCLUSIONS: Compared with the general population, the risk of csPCa is not negligible after nMRI. However, men with nMRI and PSAD <0.15 ng/mL/cm3 have worse harm-benefit balance than men in the general population. IMPACT: Prostate biopsies for men with nMRI should be reserved for cases indicated by additional risk stratification. See related In the Spotlight, p. 641.

Histomic and transcriptomic features of MRI-visible and invisible clinically significant prostate cancers are associated with prognosis.

Magnetic resonance imaging (MRI) is increasingly used to triage patients for prostate biopsy. However, 9% to 24% of clinically significant (cs) prostate cancers (PCas) are not visible in MRI. We aimed to identify histomic and transcriptomic determinants of MRI visibility and their association to metastasis, and PCa-specific death (PCSD). We studied 45 radical prostatectomy-treated patients with csPCa (grade group [GG]2-3), including 30 with MRI-visible and 15 with MRI-invisible lesions, and 18 men without PCa. First, histological composition was quantified. Next, transcriptomic profiling was performed using NanoString technology. MRI visibility-associated differentially expressed genes (DEGs) and Reactome pathways were identified. MRI visibility was classified using publicly available genes in MSK-IMPACT and Decipher, Oncotype DX, and Prolaris. Finally, DEGs and clinical parameters were used to classify metastasis and PCSD in an external cohort, which included 76 patients with metastatic GG2-4 PCa, and 84 baseline-matched controls without progression. Luminal area was lower in MRI-visible than invisible lesions and low luminal area was associated with short metastasis-free and PCa-specific survival. We identified 67 DEGs, eight of which were associated with survival. Cell division, inflammation and transcriptional regulation pathways were upregulated in MRI-visible csPCas. Genes in Decipher, Oncotype DX and MSK-IMPACT performed well in classifying MRI visibility (AUC = 0.86-0.94). DEGs improved classification of metastasis (AUC = 0.69) and PCSD (AUC = 0.68) over clinical parameters. Our data reveals that MRI-visible csPCas harbor more aggressive histomic and transcriptomic features than MRI-invisible csPCas. Thus, targeted biopsy of visible lesions may be sufficient for risk stratification in patients with a positive MRI.

Population-based randomized trial of screening for clinically significant prostate cancer ProScreen: a pilot study.

OBJECTIVES: To evaluate the feasibility of a population-based screening trial using prostate-specific antigen (PSA), a kallikrein panel and multiparametric magnetic resonance imaging (MRI) aimed at minimizing overdiagnosis, while retaining mortality benefit. PATIENTS AND METHODS: Feasibility of the screening algorithm was evaluated in terms of participation, screening test results and cancer detection. A random sample of 400 men aged 65 years was identified from the population registry and invited for screening with three stepwise tests (PSA, kallikrein panel and MRI). Men with PSA levels ≥3 ng/mL were further tested with the kallikrein panel, and those with positive findings (risk >7.5%) were referred for prostate MRI. Men with positive MRI (Prostate Imaging Reporting and Data System [PI-RADS] score 3-5) had targeted biopsies only. Men with negative MRI, but PSA density ≥0.15 underwent systematic biopsies. RESULTS: Of the 399 men invited, 158 (40%) participated and 27 had PSA levels ≥3 ng/mL (7% of the invited and 17% of the participants). Of these, 22 had a positive kallikrein panel (6% of the invited and 81% of the PSA-positive men). Finally, 10 men (3% of the invited and 45% of 4Kscore [kallikrein panel]-positive) had a suspicious MRI finding (PI-RADS score ≥3) and five were diagnosed with a clinically significant prostate cancer (Gleason Grade Group [GG] ≥2) at fusion biopsy (3% of the participants), with two GG 1 cases (1%). Additional testing (kallikrein panel and MRI) after PSA reduced biopsies by 56%. CONCLUSION: The findings constitute proof of principle for our screening protocol, as we achieved a substantial detection rate for clinically significant cancer with few clinically insignificant cases. Participation, however, was suboptimal.

Stromal FAP Expression is Associated with MRI Visibility and Patient Survival in Prostate Cancer.

Some clinically significant prostate cancers are missed by MRI. We asked whether the tumor stroma in surgically treated localized prostate cancer lesions positive or negative with MRI are different in their cellular and molecular properties, and whether the differences are reflected to the clinical course of the disease. We profiled the stromal and immune cell composition of MRI-classified tumor lesions by applying multiplexed fluorescence IHC (mfIHC) and automated image analysis in a clinical cohort of 343 patients (cohort I). We compared stromal variables between MRI-visible lesions, invisible lesions, and benign tissue and assessed the predictive significance for biochemical recurrence (BCR) and disease-specific survival (DSS) using Cox regression and log-rank analysis. Subsequently, we carried out a prognostic validation of the identified biomarkers in a population-based cohort of 319 patients (cohort II). MRI true-positive lesions are different from benign tissue and MRI false-negative lesions in their stromal composition. CD163+ cells (macrophages) and fibroblast activation protein (FAP)+ cells were more abundant in MRI true-positive than in MRI false-negative lesions or benign areas. In MRI true-visible lesions, a high proportion of stromal FAP+ cells was associated with PTEN status and increased immune infiltration (CD8+, CD163+), and predicted elevated risk for BCR. High FAP phenotype was confirmed to be a strong indicator of poor prognosis in two independent patient cohorts using also conventional IHC. The molecular composition of the tumor stroma may determine whether early prostate lesions are detectable by MRI and associates with survival after surgical treatment. Significance: These findings may have a significant impact on clinical decision making as more radical treatments may be recommended for men with a combination of MRI-visible primary tumors and FAP+ tumor stroma.

Associations of PTEN and ERG with Magnetic Resonance Imaging Visibility and Assessment of Non-organ-confined Pathology and Biochemical Recurrence After Radical Prostatectomy.

BACKGROUND: Diagnosing clinically significant prostate cancer (PCa) is challenging, but may be facilitated by biomarkers and multiparametric magnetic resonance imaging (MRI). OBJECTIVE: To determine the association between biomarkers phosphatase and tensin homolog (PTEN) and ETS-related gene (ERG) with visible and invisible PCa lesions in MRI, and to predict biochemical recurrence (BCR) and non-organ-confined (non-OC) PCa by integrating clinical, MRI, and biomarker-related data. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis of a population-based cohort of men with PCa, who underwent preoperative MRI followed by radical prostatectomy (RP) during 2014-2015 in Helsinki University Hospital (n = 346), was conducted. A tissue microarray corresponding to the MRI-visible and MRI-invisible lesions in RP specimens was constructed and stained for PTEN and ERG. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations of PTEN and ERG with MRI-visible and MRI-invisible lesions were examined (Pearson's χ2 test), and predictions of non-OC disease together with clinical and MRI parameters were determined (area under the receiver operating characteristic curve and logistic regression analyses). BCR prediction was analyzed by Kaplan-Meier and Cox proportional hazard analyses. RESULTS AND LIMITATIONS: Patients with MRI-invisible lesions (n = 35) had less PTEN loss and ERG-positive expression compared with patients (n = 90) with MRI-visible lesions (17.2% vs 43.3% [p = 0.006]; 8.6% vs 20.0% [p = 0.125]). Patients with invisible lesions had better, but not statistically significantly improved, BCR-free survival probability in Kaplan-Meier analyses (p = 0.055). Rates of BCR (5.7% vs 21.1%; p = 0.039), extraprostatic extension (11.4% vs 44.6%; p < 0.001), seminal vesicle invasion (0% vs 21.1%; p = 0.003), and lymph node metastasis (0% vs 12.2%; p = 0.033) differed between the groups in favor of patients with MRI-invisible lesions. Biomarkers had no independent role in predicting non-OC disease or BCR. The short follow-up period was a limitation. CONCLUSIONS: PTEN loss, BCR, and non-OC RP findings were more often encountered with MRI-visible lesions. PATIENT SUMMARY: Magnetic resonance imaging (MRI) of the prostate misses some cancer lesions. MRI-invisible lesions seem to be less aggressive than MRI-visible lesions.

Expected impact of MRI-related interreader variability on ProScreen prostate cancer screening trial: a pre-trial validation study.

BACKGROUND: The aim of this study is to investigate the potential impact of prostate magnetic resonance imaging (MRI) -related interreader variability on a population-based randomized prostate cancer screening trial (ProScreen). METHODS: From January 2014 to January 2018, 100 men aged 50-63 years with clinical suspicion of prostate cancer (PCa) in Helsinki University Hospital underwent MRI. Nine radiologists individually reviewed the pseudonymized MRI scans of all 100 men in two ProScreen trial centers. All 100 men were biopsied according to a histological composite variable comprising radical prostatectomy histology (N = 38) or biopsy result within 1 year from the imaging (N = 62). Fleiss' kappa (κ) was used to estimate the combined agreement between all individual radiologists. Sample data were subsequently extrapolated to 1000-men subgroups of the ProScreen cohort. RESULTS: Altogether 89% men of the 100-men sample were diagnosed with PCa within a median of 2.4 years of follow-up. Clinically significant PCa (csPCa) was identified in 76% men. For all PCa, mean sensitivity was 79% (SD ±10%, range 62-96%), and mean specificity 60% (SD ±22%, range 27-82%). For csPCa (Gleason Grade 2-5) MRI was equally sensitive (mean 82%, SD ±9%, range 67-97%) but less specific (mean 47%, SD ±20%, range 21-75%). Interreader agreement for any lesion was fair (κ 0.40) and for PI-RADS 4-5 lesions it was moderate (κ 0.60). Upon extrapolating these data, the average sensitivity and specificity to a screening positive subgroup of 1000 men from ProScreen with a 30% prevalence of csPCa, 639 would be biopsied. Of these, 244 men would be true positive, and 395 false positive. Moreover, 361 men would not be referred to biopsy and among these, 56 csPCas would be missed. The variation among the radiologists was broad as the least sensitive radiologist would have twice as many men biopsied and almost three times more men would undergo unnecessary biopsies. Although the most sensitive radiologist would miss only 2.6% of csPCa (false negatives), the least sensitive radiologist would miss every third. CONCLUSIONS: Interreader agreement was fair to moderate. The role of MRI in the ongoing ProScreen trial is crucial and has a substantial impact on the screening process.

Prostate MRI added to CAPRA, MSKCC and Partin cancer nomograms significantly enhances the prediction of adverse findings and biochemical recurrence after radical prostatectomy.

BACKGROUND: To determine the added value of preoperative prostate multiparametric MRI (mpMRI) supplementary to clinical variables and their role in predicting post prostatectomy adverse findings and biochemically recurrent cancer (BCR). METHODS: All consecutive patients treated at HUS Helsinki University Hospital with robot assisted radical prostatectomy (RALP) between 2014 and 2015 were included in the analysis. The mpMRI data, clinical variables, histopathological characteristics, and follow-up information were collected. Study end-points were adverse RALP findings: extraprostatic extension, seminal vesicle invasion, lymph node involvement, and BCR. The Memorial Sloan Kettering Cancer Center (MSKCC) nomogram, Cancer of the Prostate Risk Assessment (CAPRA) score and the Partin score were combined with any adverse findings at mpMRI. Predictive accuracy for adverse RALP findings by the regression models was estimated before and after the addition of MRI results. Logistic regression, area under curve (AUC), decision curve analyses, Kaplan-Meier survival curves and Cox proportional hazard models were used. RESULTS: Preoperative mpMRI data from 387 patients were available for analysis. Clinical variables alone, MSKCC nomogram or Partin tables were outperformed by models with mpMRI for the prediction of any adverse finding at RP. AUC for clinical parameters versus clinical parameters and mpMRI variables were 0.77 versus 0.82 for any adverse finding. For MSKCC nomogram versus MSKCC nomogram and mpMRI variables the AUCs were 0.71 and 0.78 for any adverse finding. For Partin tables versus Partin tables and mpMRI variables the AUCs were 0.62 and 0.73 for any adverse finding. In survival analysis, mpMRI-projected adverse RP findings stratify CAPRA and MSKCC high-risk patients into groups with distinct probability for BCR. CONCLUSIONS: Preoperative mpMRI improves the predictive value of commonly used clinical variables for pathological stage at RP and time to BCR. mpMRI is available for risk stratification prebiopsy, and should be considered as additional source of information to the standard predictive nomograms.

Repeat multiparametric MRI in prostate cancer patients on active surveillance.

INTRODUCTION: This study was conducted to describe the changes in repeat multiparametric MRI (mpMRI) occurring in prostate cancer (PCa) patients during active surveillance (AS), and to study possible associations between mpMRI-related parameters in predicting prostate biopsy (Bx) Gleason score (GS) upgrading >3+3 and protocol-based treatment change (TC). MATERIALS AND METHODS: The study cohort consisted of 76 AS patients with GS 3+3 PCa and at least two consecutive mpMRIs of the prostate performed between 2006-2015. Patients were followed according to the Prostate Cancer Research International Active Surveillance (PRIAS) protocol and an additional mpMRI. The primary end points were GS upgrading (GU) (>3+3) in protocol-based Bxs and protocol-based TC. RESULTS: Out of 76 patients, 53 (69%) had progression (PIRADS upgrade, size increase or new lesion[s]), while 18 (24%) had radiologically stable disease, and 5 (7%) had regression (PIRADS or size decrease, disappearance of lesion[s]) in repeat mpMRIs during AS. PIRADS scores of 4-5 in the initial mpMRI were associated with GU (p = 0.008) and protocol-based TC (p = 0.009). Tumour progression on repeat mpMRIs was associated with TC (p = 0.045) but not with GU (p = 1.00). PIRADS scores of 4-5 predict GU (sensitivity 0.80 [95% confidence interval (CI); 0.51-0.95, specificity 0.62 [95% CI; 0.52-0.77]) with PPV and NPV values of 0.34 (95% CI; 0.21-0.55) and 0.93 (95% CI; 0.80-0.98), respectively. CONCLUSION: mpMRI is a useful tool not only to select but also to monitor PCa patients on AS.

A randomized trial of early detection of clinically significant prostate cancer (ProScreen): study design and rationale.

The current evidence of PSA-based prostate cancer screening shows a reduction in cause-specific mortality, but with substantial overdiagnosis. Recently, new developments in detection of clinically relevant prostate cancer include multiple kallikreins as biomarkers besides PSA, and multiparametric magnetic resonance imaging (mpMRI) for biopsy decision. They offer opportunities for improving the outcomes in screening, particularly reduction in overdiagnosis and higher specificity for potentially lethal cancer. A population-based randomized screening trial will be started, with 67,000 men aged 55-67 years at entry. A quarter of the men will be allocated to the intervention arm, and invited to screening. The control arm will receive no intervention. All men in the screening arm will be offered a serum PSA determination. Those with PSA of 3 ng/ml or higher will have an additional multi-kallikrein panel and those with indications of increased risk of clinically relevant prostate cancer will undergo mpMRI. Men with a malignancy-suspect finding in MRI are referred to targeted biopsies. Screening interval is 6 years for men with baseline PSA < 1.5 ng/ml, 4 years with PSA 1.5-3.0 and 2 years if initial PSA > 3. The main outcome of the trial is prostate cancer mortality, with analysis at 10 and 15 years. The statistical power is sufficient for detecting a 28% reduction at 10 years and 22% at 15 years. The proposed study has the potential to provide the evidence to justify screening as a public health policy if mortality benefit can be sustained with substantially reduced overdiagnosis.

Problems related to levodopa-carbidopa intestinal gel treatment in advanced Parkinson's disease.

BACKGROUND: Continuous levodopa-carbidopa intestinal gel (LCIG) diminishes daily "off" time and dyskinesia in patients with advanced Parkinson's disease (PD). Complications are common with percutaneous endoscopic gastrostomy with a jejunal extension tube (PEG-J). AIM OF THE STUDY: To report the clinical outcome of LCIG in patients with advanced PD in the years 2006-2014 at Helsinki University Hospital. PATIENTS AND METHODS: Levodopa-carbidopa intestinal gel treatment started following PEG-J placement in patients with advanced PD after successful in-hospital LCIG trial with a nasojejunal tube. Demographics, PEG-J procedures, discontinuation of LCIG, complications and mortality were retrospectively analyzed. RESULTS MEAN SD: Sixty patients with advanced PD [age 68(7) years; duration of PD: 11(4) years] had LCIG treatment for 26(23) months. The majority of patients with advanced PD were satisfied with the LCIG treatment. For 51 patients (85%), the pump was on for 16 hr a day, and for nine patients (15%) it was on for 24 hr a day. After 6 months, the levodopa-equivalent daily dose (LEDD) had increased by 30% compared to pre-LCIG LEDD. Sixty patients underwent a total of 156 PEG-J procedures, and 48 patients (80%) had a total of 143 complications. Forty-six patients (77%) had 119 PEG-J or peristomal complications, and 22 patients (37%) had a total of 25 other complications. The most common complications were accidental removal of the J-tube in 23 patients (38%) and ≥5% weight loss in 18 patients (30%). Fifteen patients discontinued the LCIG after 21 (21) months. At the end of the follow-up period of 33(27) months, 38 patients were still on LCIG and nine (15%) had died. CONCLUSION: Most patients were satisfied with LCIG treatment. A few patients lost weight whereas the majority had complications with PEG-J. When LCIG treatment is carried out, neurological and endoscopic units must be prepared for multiple endoscopic procedures.

The diagnostics of prostate cancer is changing.

The alternative to immediate radical treatment of prostate cancer is active surveillance, to which an estimated 30% of new patients with prostate cancer could be directed on the basis of risk classification. Active surveillance is based on repeated PSA measurements, digital rectal examination, repeat biopsies, and increasingly also on MRI. The most important prognostic factor in prostate cancer is still the Gleason score, forming the basis for the new grade group classification with the purpose of rendering active surveillance of prostate cancer a form of treatment that is more easily acceptable for the patients. MRI enables a more reliable selection of low-risk prostate cancer patients for active surveillance. The significance of MRI as a surveillance tool remains unclear.

[Magnetic resonance imaging of prostate cancer]. / Eturauhassyövän magneettikuvaus.

Prostate cancer has varying prognoses.The extremes of the disease spectrum involve well-differentiated prostate cancer that can be considered almost normal ageing without any significant effect on the patient's prognosis, and poorly differentiated, invasive carcinoma that requires active treatment. The selection of an appropriate line of treatment for each patient requires reliable assessment of the extent, aggressiveness and risk of recurrence of the disease. Multiparametric magnetic resonance imaging has improved the detection of prostate cancer and the assessment of its aggressiveness and local extent. Magnetic resonance imaging enables the detection of the most suspicious target for taking a biopsy specimen.

Death in sauna.

Bathing in sauna is common in Finland, where there are approximately 2 million saunas among the population of 5.2 million. In this paper, deaths occurring while in a sauna in 1990-2002 in Finland were studied by analyzing police and forensic autopsy reports, death certificates, and toxicological results. The annual rate of death occurring while in a sauna was less than 2 per 100,000 inhabitants. Close to half (51%) of the cases were determined to be natural deaths and exposure to heat was the cause of death in 25%. Overall, 50% of all cases were under the influence of alcohol. The main conclusion is that death in the sauna is a rare event even in Finland where the frequency of sauna bathing is high. The role of alcohol as a risk factor has grown. The prevention of these deaths should focus on less drinking of alcohol and avoid leaving a drunken bather alone in the sauna.