A pilot study of an organised population-based testing programme for prostate cancer.

OBJECTIVE: To determine the feasibility of a digitally automated population-based programme for organised prostate cancer testing (OPT) in Southern Sweden. PATIENTS AND METHODS: A pilot project for a regional OPT was conducted between September 2020 and February 2021, inviting 999 randomly selected men aged 50, 56, or 62 years. Risk stratification was based on prostate-specific antigen (PSA) level, PSA density (PSAD), and bi-parametric prostate magnetic resonance imaging (MRI). Men with a PSA level of 3-99 ng/mL had an MRI, and men with elevated PSA level (≥3 ng/mL) had a urological check-up, including a digital rectal examination and transrectal ultrasonography (TRUS). Indications for targeted and/or systematic transrectal prostate biopsies were suspicious lesions on MRI (Prostate Imaging-Reporting and Data System [PI-RADS] 4-5) and/or PSAD > 0.15 ng/mL/mL. Additional indications for prostate biopsies were palpable tumours, PSA ratio < 0.1, or cancer suspicion on TRUS. Patient selection, mail correspondence, data collection, and algorithm processing were performed by an automated digital management system. Feasibility is reported descriptively. RESULTS: A total of 418 men had a PSA test (42%), with increasing participation rates by age (50 years, 38%; 56 years, 44%; and 62 years, 45%). Among these, 35 men (8%) had elevated PSA levels (≥3 ng/mL: one of 139, aged 50 years; 10/143, aged 56 years; and 24/146, aged 62 years). On MRI, 16 men (48%) had a negative scan (PI-RADS < 3), seven men (21%) had PI-RADS 3, nine men (27%) had PI-RADS 4, and one man (3%) had PI-RADS 5. All men with PI-RADS 4 or 5 underwent prostate biopsies, as well as two men with PI-RADS 3 due to PSAD > 0.15 ng/mL/mL or a suspicious finding on TRUS. Prostate cancer was diagnosed in 10 men. Six men underwent active treatment, whereas four men were assigned to active surveillance. CONCLUSION: Our OPT model is feasible from an operational point of view, but due to the limited scale of this study no conclusions can be made regarding the efficacy of the diagnostic model or outcome.

Population-based Organised Prostate Cancer Testing: Results from the First Invitation of 50-year-old Men.

BACKGROUND: The European Union recently recommended evaluation of the feasibility of organised prostate cancer screening. In Sweden, regional population-based organised prostate cancer testing (OPT) programmes were introduced in 2020. OBJECTIVE: To describe initial participation rates and diagnostic outcomes. DESIGN, SETTING, AND PARTICIPANTS: The three most populated Swedish regions invited all men aged 50 yr to OPT by a letter in 2020-2022. Men with prostate-specific antigen (PSA) ≥3 ng/ml were referred for prostate magnetic resonance imaging (MRI). PSA assays differed across regions. Men with Prostate Imaging Reporting and Data System (PI-RADS) 1-3 and PSA density ≥0.15 ng/ml/cm3 or PI-RADS 4-5 were referred for a biopsy. Data were obtained from the Swedish Register for Organised Prostate Cancer Testing. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall and regional participation rates, PSA distributions, PI-RADS score distributions, cancer detection, and treatment were evaluated. RESULTS AND LIMITATIONS: A total of 23 855 (35%) of 68 060 invited men participated; 696 (2.9%) had PSA ≥3 ng/ml, and of them, 306 (44%) had a biopsy indication and 221 (32%) had a biopsy. On biopsy, 93 (42%) had Gleason grade group ≥2 (0.39% of PSA-tested men) and 44 (20%) Gleason grade group 1 cancer. Most men with cancer had treatment with curative intent (70%) or were under active surveillance (28%). Across regions, proportions of men with PSA ≥3 ng/ml ranged from 2.3% to 4.0%, and those with PI-RADS score 4-5 ranged from 12% to 21%. A limitation is that results are applicable only to first testing of men in their early 50s. CONCLUSIONS: The OPT programmes are feasible with good compliance to the diagnostic pathway. The use of MRI and PSA density avoided a biopsy for over half of the men with PSA ≥3 ng/ml. Inter-regional differences in diagnostic outcomes show a need for standardisation of the diagnostic pathway's components. PATIENT SUMMARY: We report the diagnostic outcomes of inviting 68 000 50-yr-old men to organised prostate cancer testing.

Men's Perception of Being Invited for Prostate Cancer Testing and the Information About Its Pros and Cons-A Survey from Two Population-based Testing Programmes.

Background: There is no national screening programme for prostate cancer in Sweden. Instead, population-based organised prostate cancer testing (OPT) projects are introduced to make information and testing more equal and effective. Objective: To evaluate men's perception of being invited to OPT and of the information in the invitation letter, and whether their perception is influenced by educational level. Design setting and participants: A questionnaire was sent out to men invited to OPT in 2020: 600 50-yr-old men in Region Västra Götaland and 1000 50-, 56-, and 62-yr-old men in Region Skåne. Outcome measurements and statistical analysis: Responses were evaluated on a Likert scale. The chi-square test was used to compare proportions. Results and limitations: A total of 534 men (34%) responded. Almost all considered the OPT concept as very good (84%) or good (13%). Among men not previously undergone a prostate-specific antigen (PSA) test, a larger proportion with nonacademic (53%) than with academic education (41%) responded that the text about disadvantages was very clear (p = 0.03). A similar difference was observed for the text about advantages (68% vs 58%, p = 0.09). There was no association between education and searching for more information elsewhere. The low response rate is the main limitation. Conclusions: Almost all responding men evaluating the invitation letter for OPT were positive about making a personal decision regarding whether or not to have a PSA test. Most were content with the brief information. Men with academic education were somewhat less likely to find the information very clear. This shows a need for further research about how best to describe the advantages and disadvantages of prostate cancer testing. Patient summary: Almost all men who responded to a questionnaire to evaluate the invitation letter for organised prostate cancer testing were positive about the opportunity to make a personal decision regarding whether or not to have a prostate-specific antigen test.

Implementation of the measure of case discussion complexity to guide selection of prostate cancer patients for multidisciplinary team meetings.

BACKGROUND: Multidisciplinary team meetings (MDTMs) provide an integrated team approach to ensure individualized and evidence-based treatment recommendations and best expert advice in cancer care. A growing number of patients and more complex treatment options challenge MDTM resources and evoke needs for case prioritization. In this process, decision aids could provide streamlining and standardize evaluation of case complexity. We applied the recently developed Measure of Case Discussion Complexity, MeDiC, instrument with the aim to validate its performance in another healthcare setting and diagnostic area as a means to provide cases for full MDTM discussions. METHODS: The 26-item MeDiC instrument evaluates case complexity and was applied to 364 men with newly diagnosed prostate cancer in Sweden. MeDiC scores were generated from individual-level health data and were correlated with clinicopathological parameters, healthcare setting, and the observed clinical case selection for MDTMs. RESULTS: Application of the MeDiC instrument was feasible with rapid scoring based on available clinical data. Patients with high-risk prostate cancers had significantly higher MeDiC scores than patients with low or intermediate-risk cancers. In the total study, population affected lymph nodes and metastatic disease significantly influenced MDTM referral, whereas comorbidities and age did not predict MDTM referral. When individual patient MeDiC scores were compared to the clinical MDTM case selection, advanced stage, T3/T4 tumors, involved lymph nodes, presence of metastases and significant physical comorbidity were identified as key MDTM predictive factors. CONCLUSIONS: Application of the MeDiC instrument in prostate cancer may be used to streamline case selection for MDTMs in cancer care and may complement clinical case selection.

Designing and Implementing a Population-based Organised Prostate Cancer Testing Programme.

BACKGROUND: European guidelines recommend that well-informed men at elevated risk of having prostate cancer (PCa) should be offered prostate-specific antigen (PSA) testing with risk-stratified follow-up. The Swedish National Board of Health and Welfare recommends against screening for PCa but supports regional implementation of organised prostate cancer testing (OPT). OBJECTIVE: To report the process for designing and implementing OPT programmes. DESIGN, SETTING, AND PARTICIPANTS: Population-based OPT programmes in two Swedish regions, designed to include men aged between 50 and 74 yr, launched in September 2020 for 50-yr-old men. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The number of men invited, the participation rate, and the numbers of magnetic resonance imaging (MRI) scans, urological visits, and biopsies from September 2020 to June 2021 were recorded. RESULTS AND LIMITATIONS: Two Swedish regions co-designed an OPT programme with a risk-stratified diagnostic algorithm based on prostate-specific antigen (PSA), PSA density, MRI findings, and age. An automated administrative system was developed on a nationwide web-based platform. Invitation letters and test results are automatically generated and sent out by post. Men with PSA ≥3ng/ml, a suspicious MRI lesion, and/or PSA density ≥0.15 ng/ml/cm3 are referred for a prostate biopsy. Test results are registered for quality control and research. By June 2021, a total of 16 515 men were invited, of whom 6309 (38%) participated; 147 had an MRI scan and 39 underwent prostate biopsy. The OPT framework, algorithm, and diagnostic pathways have been working well. CONCLUSIONS: We designed and implemented a framework for OPT with a high grade of automation. The framework and organisational experiences may be of value for others who plan a programme for early detection of PCa. PATIENT SUMMARY: We describe the implementation of an organised testing programme for early detection of prostate cancer in two Swedish regions. This model is the first of its kind and may serve as a template for similar programmes.

A retrospective study assessing the accuracy of [18F]-fluorocholine PET/CT for primary staging of lymph node metastases in intermediate and high-risk prostate cancer patients undergoing robotic-assisted laparoscopic prostatectomy with extended lymph node dissection.

BACKGROUND: Previous studies have investigated [18F]-fluorocholine (FCH) positron emission tomography with computed tomography (PET/CT) in primary staging of men with intermediate or high-risk prostate cancer and have generally shown high specificity and poor sensitivity. FCH PET/CT is not recommended for the primary staging of metastases in the European guidelines for prostate cancer. However, it has been an option in the Swedish recommendations. Our aim was to assess PET/CT for primary staging of lymph node metastases before robotic-assisted laparoscopic prostatectomy (RALP) with extended pelvic lymph node dissection (ePLND) in patients with intermediate or high-risk prostate cancer. METHOD: We identified all men with prostate cancer undergoing FCH PET/CT for initial staging followed by RALP and ePLND at Skåne University Hospital between 2015 and 2018. The result from PET/CT scan was compared with pathology report as the reference method for calculation of sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS: In total, 252 patients were included in the final analysis. Among 85 patients with a suspicion of regional lymph node metastases on FCH PET/CT only 31 had pathology-proven metastases. The sensitivity was 43% (95% CI 0.32-0.55) and the specificity 70% (95% CI 0.63-0.76) for PET/CT to predict lymph node metastases. PPV was 36% and NPV was 75%. Risk group analyses showed similar results. CONCLUSION: Our study emphasizes the poor performance of FCH PET/CT to predict lymph node metastasis in intermediate and high-risk prostate cancer. The method should be replaced with newer radiopharmaceuticals, such as prostate-specific membrane antigen ligands.

Degree of preservation of the neurovascular bundles during radical prostatectomy and urinary continence 1 year after surgery.

BACKGROUND: Many elderly or impotent men with prostate cancer may not receive a bundle-preserving radical prostatectomy as a result of uncertainty regarding the effect on urinary incontinence. OBJECTIVE: We searched for predictors of urinary incontinence 1 yr after surgery among surgical steps during radical prostatectomy. DESIGN, SETTING, AND PARTICIPANTS: More than 100 surgeons in 14 centers prospectively collected data on surgical steps during an open or robot-assisted laparoscopic radical prostatectomy. At 1 yr after surgery, a neutral third-party secretariat collected patient-reported information on urinary incontinence. After excluding men with preoperative urinary incontinence or postoperative irradiation, data were available for 3379 men. INTERVENTION: Surgical steps during radical prostatectomy, including dissection plane as a measure of the degree of preservation of the two neurovascular bundles. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Urinary incontinence 1 yr after surgery was measured as patient-reported use of pads. In different categories of surgical steps, we calculated the percentage of men changing pads "about once per 24 h" or more often. Relative risks were calculated as percentage ratios between categories. RESULTS AND LIMITATIONS: A strong association was found between the degree of bundle preservation and urinary incontinence 1 yr after surgery. We set the highest degree of bundle preservation (bilateral intrafascial dissection) as the reference category (relative risk = 1.0). For the men in the remaining six groups, ordered according to the degree of preservation, we obtained the following relative risks (95% confidence interval [CI]): 1.07 (0.63-1.83), 1.19 (0.77-1.85), 1.56 (0.99-2.45), 1.78 (1.13-2.81), 2.27 (1.45-3.53), and 2.37 (1.52-3.69). In the latter group, no preservation of any of the bundles was performed. The pattern was similar for preoperatively impotent men and for elderly men. Limitations of this analysis include the fact that noise influences the relative risks, due to variations between surgeons in the use of undocumented surgical steps of the procedure, variations in surgical experience and in how the surgical steps are reported, as well as variations in the metrics of patient-reported use of pads. CONCLUSIONS: We found that the degree of preservation of the two neurovascular bundles during radical prostatectomy predicts the rate of urinary incontinence 1 yr after the operation. According to our findings, preservation of both neurovascular bundles to avoid urinary incontinence is also meaningful for elderly and impotent men. PATIENT SUMMARY: We studied the degree of preservation of the two neurovascular bundles during radical prostatectomy and found that the risk of incontinence decreases if the surgeon preserves two bundles instead of one, and if the surgeon preserves some part of a bundle rather than not doing so.

Interobserver variability in the pathological assessment of radical prostatectomy specimens: findings of the Laparoscopic Prostatectomy Robot Open (LAPPRO) study.

OBJECTIVE: The aim of this study was to strengthen the validity of future findings in the Laparoscopic Prostatectomy Robot Open (LAPPRO) study by investigating the extent of interobserver variability between local pathologists and re-evaluating reference pathologists. MATERIAL AND METHODS: LAPPRO is a Swedish prospective study comparing robot-assisted laparoscopic prostatectomy to open retropubic radical prostatectomy. Patients were recruited from 2008 to 2011. A random selection of 289 prostatectomy specimens was re-evaluated, in a blind fashion, by two reference pathologists from a University Hospital in Denmark and compared with original reports from local pathologists. RESULTS: The exact concordance rate of Gleason score (GS) between local and reference pathologists was 56% (Spearman correlation coefficient 0.54). Exact concordance rates (κ value) for pathological tumour stage (pT), extraprostatic extension (EPE), surgical margin status (SMS) and seminal vesicle invasion (SVI) were 87% (0.63), 86% (0.59), 92% (0.76) and 98% (0.82), respectively. In subanalyses for surgical technique, exact concordance rates of GS, pT, EPE, SMS and SVI were 58%, 83%, 84%, 90% and 97%, respectively, for surgical technique 1 (ST1), compared to 55%, 88%, 87%, 93% and 98%, for surgical technique 2 (ST2). In ST1 specimens undergrading of GS by the local pathologists compared to central review was more common than overgrading (26% vs 16%). The inverse relationship was seen in ST2 specimens (14% vs 32%). CONCLUSION: Re-evaluation of randomly selected prostatectomy specimens in the LAPPRO cohort showed comparable results compared to previous studies of this kind. A systematic variation in the assessment of GS exists, attributable to individual differences in judgement between pathologists. Dichotomising GS (≤ 7 vs ≥ 8) overcomes the systematic variation.

The learning curve for laparoscopic radical prostatectomy: an international multicenter study.

PURPOSE: It is not yet possible to estimate the number of cases required for a beginner to become expert in laparoscopic radical prostatectomy. We estimated the learning curve of laparoscopic radical prostatectomy for positive surgical margins compared to a published learning curve for open radical prostatectomy. MATERIALS AND METHODS: We reviewed records from 8,544 consecutive patients with prostate cancer treated laparoscopically by 51 surgeons at 14 academic institutions in Europe and the United States. The probability of a positive surgical margin was calculated as a function of surgeon experience with adjustment for pathological stage, Gleason score and prostate specific antigen. A second model incorporated prior experience with open radical prostatectomy and surgeon generation. RESULTS: Positive surgical margins occurred in 1,862 patients (22%). There was an apparent improvement in surgical margin rates up to a plateau at 200 to 250 surgeries. Changes in margin rates once this plateau was reached were relatively minimal relative to the CIs. The absolute risk difference for 10 vs 250 prior surgeries was 4.8% (95% CI 1.5, 8.5). Neither surgeon generation nor prior open radical prostatectomy experience was statistically significant when added to the model. The rate of decrease in positive surgical margins was more rapid in the open vs laparoscopic learning curve. CONCLUSIONS: The learning curve for surgical margins after laparoscopic radical prostatectomy plateaus at approximately 200 to 250 cases. Prior open experience and surgeon generation do not improve the margin rate, suggesting that the rate is primarily a function of specifically laparoscopic training and experience.

Cystatin C is downregulated in prostate cancer and modulates invasion of prostate cancer cells via MAPK/Erk and androgen receptor pathways.

Cystatin C is believed to prevent tumor progression by inhibiting the activities of a family of lysosomal cysteine proteases. However, little is known about the precise mechanism of cystatin C function in prostate cancer. In the present study, we examined the expression of cystatin C and its association with matrix metalloproteinases 2 (MMP2) and androgen receptor (AR) in a tissue microarray comparing benign and malignant specimens from 448 patients who underwent radical prostatectomy for localized prostate cancer. Cystatin C expression was significantly lower in cancer specimens than in benign tissues (p<0.001) and there was a statistically significant inverse correlation between expression of cystatin C and MMP2 (r(s) (2) = -0.056, p = 0.05). There was a clear trend that patients with decreased level of cystatin C had lower overall survival. Targeted inhibition of cystatin C using specific siRNA resulted in an increased invasiveness of PC3 cells, whereas induction of cystatin C overexpression greatly reduced invasion rate of PC3 in vitro. The effect of cystatin C on modulating the PC3 cell invasion was provoked by Erk2 inhibitor that specifically inhibited MAPK/Erk2 activity. This suggests that cystatin C may mediate tumor cell invasion by modulating the activity of MAPK/Erk cascades. Consistent with our immunohistochemical findings that patients with low expression of cystatin C and high expression of androgen receptor (AR) tend to have worse overall survival than patients with high expression of cystatin C and high AR expression, induced overexpression of AR in PC3 cells expressing cystatin C siRNA greatly enhanced the invasiveness of PC3 cells. This suggests that there may be a crosstalk between cystatin C and AR-mediated pathways. Our study uncovers a novel role for cystatin C and its associated cellular pathways in prostate cancer invasion and metastasis.

Multi-institutional study of symptomatic deep venous thrombosis and pulmonary embolism in prostate cancer patients undergoing laparoscopic or robot-assisted laparoscopic radical prostatectomy.

OBJECTIVES: The true incidence of symptomatic deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing laparoscopic radical prostatectomy is unknown. Our aim was to determine the incidence of symptomatic DVT and PE and the risk factors for these complications. METHODS: Fourteen surgeons from 13 referral institutions from both Europe and the United States provided retrospective data for all 5951 patients treated with laparoscopic radical prostatectomy (LRP), with or without robotic assistance, since the start of their institution's experience. Symptomatic DVT and PE within 90 d of surgery were regarded as venous thromboembolism (VTE). DVT was diagnosed mostly by Doppler ultrasound or contrast venography and PE by lung ventilation/perfusion scan or chest computed tomography or both. Statistical analysis included evaluation of incidence of symptomatic DVT and PE and risk factors as determined by exact methods and logistic regression. RESULTS: Of 5951 patients in the study, 31 developed symptomatic VTE (0.5%; 95% confidence interval [CI], 0.4%, 0.7%). Among patients with an event, 22 (71%) had DVT only, 4 had PE without identified DVT, and 5 had both. Two patients died of PE. Prior DVT (odds ratio [OR]=13.5; 95%CI, 1.4, 61.3), current tobacco smoking (OR=2.8; 95%CI, 1.0, 7.3), larger prostate volume (OR=1.18; 95%CI, 1.09, 1.28), patient re-exploration (OR=20.6; 95%CI, 6.6, 54.0), longer operative time (OR=1.05; 95%CI, 1.02, 1.09), and longer hospital stay (OR=1.05; 95%CI, 1.01, 1.09) were associated with VTE in univariate analysis. Neoadjuvant therapy, body mass index, surgical experience, surgical approach, pathologic stage, perioperative transfusion, and heparin administration were not significant predictors. CONCLUSIONS: The incidence of symptomatic VTE after LRP is low. These data do not support the administration of prophylactic heparin to all patients undergoing LRP, especially those without risk factors for VTE.

Aberrant expression of cystatin C in prostate cancer is associated with neuroendocrine differentiation.

OBJECTIVE: To investigate the expression of cystatin C and the relationship with neuroendocrine differentiation and proliferation in benign and malignant prostatic tissues, as cystatin C, the most important inhibitor of human lysosomal cysteine proteases, is considered to be a major regulator of pathological protein degradation in inflammatory and neoplastic diseases. MATERIALS AND METHODS: Immunoreactivity for cystatin C, prostate-specific antigen, Ki-67 and the neuroendocrine marker chromogranin A was examined in whole-mount radical prostatectomy specimens and using tissue microarrays. Cystatin C in tissue homogenates was analysed by Western blotting and enzyme-linked immunosorbent assay (ELISA). The expression and relative levels of cystatin C mRNA were assessed by in situ hybridization and quantitative real-time polymerase chain reaction (QRT-PCR). RESULTS: The intensity of cystatin C immunostaining in Gleason grade 2 and 3 prostate cancer was significantly higher than in benign prostatic tissues, but decreased significantly with increasing Gleason grades. There was strong expression of cystatin C in neuroendocrine-like cells, which increased significantly with increasing Gleason grades. The Ki-67 immunoreactivity also increased significantly during de-differentiation. In situ hybridization showed staining patterns in concordance with the immunohistochemical results. ELISA showed high concentrations of cystatin C in benign and malignant tissue extracts and QRT-PCR further corroborated that the cystatin C gene is highly expressed in both benign and malignant prostatic tissues. CONCLUSIONS: There was a significant decrease in the immunohistochemical expression of cystatin C in non-neuroendocrine prostate cancer cells, concomitant with increasing Gleason grades. That there were more strongly cystatin C-positive neuroendocrine-like cells in prostate cancer than in benign prostatic tissue suggests a connection between cystatin C and neuroendocrine differentiation in prostate cancer progression.

Cystatin C is highly expressed in the human male reproductive system.

Cystatin C displays the strongest inhibitory activity of all cystatins toward lysosomal cysteine proteases in general and has a widespread distribution in human tissues and body fluids, including seminal plasma. The aim of this study was to investigate the distribution of cystatin C in the male reproductive system. Immunohistochemistry revealed a widespread distribution of cystatin C in normal tissues from the testis, epididymis, vas deferens, seminal vesicle, and prostate gland. Immunoreactive cystatin C was localized in basal and secretory epithelial cells, but also in neuroendocrine cells in the prostate, identified by immunostaining for chromogranin A. On adjacent tissue sections, we demonstrated local production of cystatin C utilizing nonradioactive in situ hybridization with a 201-base-long digoxigenin-labeled antisense RNA probe specific for the cystatin C transcript. Staining patterns obtained by immunohistochemistry and in situ hybridization correlated well. Enzyme-linked immunosorbent assay for quantitative analysis of cystatin C demonstrated that cystatin C was present at high concentrations in tissue homogenates from all locations investigated, compared to liver, muscle, spleen, and other general tissues. Western blotting of tissue homogenates revealed a predominant 15-kd cystatin C immunoreactive component in accordance with previous findings in other organs. Quantitative real-time polymerase chain reaction analysis to determine messenger RNA levels in whole tissue extracts showed that the cystatin C gene is highly expressed in the seminal vesicles and the prostate gland, indicating that the major amount of cystatin C in the male reproductive organs and seminal plasma is produced by cells in these 2 tissues. It is concluded that cystatin C is highly expressed and widely distributed throughout the male genital tract, suggesting that cystatin C is an important regulator for normal and pathological proteolysis in the male reproductive system.