Publications by authors named "Martin Eklund"

112 Publications

Artificial Intelligence for Diagnosis and Gleason Grading of Prostate Cancer in Biopsies-Current Status and Next Steps.

Eur Urol Focus 2021 Jul 12;7(4):687-691. Epub 2021 Aug 12.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Diagnosis and Gleason grading of prostate cancer in biopsies are critical for the clinical management of men with prostate cancer. Despite this, the high grading variability among pathologists leads to the potential for under- and overtreatment. Artificial intelligence (AI) systems have shown promise in assisting pathologists to perform Gleason grading, which could help address this problem. In this mini-review, we highlight studies reporting on the development of AI systems for cancer detection and Gleason grading, and discuss the progress needed for widespread clinical implementation, as well as anticipated future developments. PATIENT SUMMARY: This mini-review summarizes the evidence relating to the validation of artificial intelligence (AI)-assisted cancer detection and Gleason grading of prostate cancer in biopsies, and highlights the remaining steps required prior to its widespread clinical implementation. We found that, although there is strong evidence to show that AI is able to perform Gleason grading on par with experienced uropathologists, more work is needed to ensure the accuracy of results from AI systems in diverse settings across different patient populations, digitization platforms, and pathology laboratories.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.euf.2021.07.002DOI Listing
July 2021

Prostate cancer screening using a combination of risk-prediction, MRI, and targeted prostate biopsies (STHLM3-MRI): a prospective, population-based, randomised, open-label, non-inferiority trial.

Lancet Oncol 2021 09 13;22(9):1240-1249. Epub 2021 Aug 13.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Surgery, Capio St Göran's Hospital, Stockholm, Sweden.

Background: Screening for prostate cancer using prostate-specific antigen (PSA) reduces prostate cancer mortality but can lead to adverse outcomes. We aimed to compare a traditional screening approach with a diagnostic strategy of blood-based risk prediction combined with MRI-targeted biopsies.

Methods: We did a prospective, population-based, randomised, open-label, non-inferiority trial (STHLM3-MRI) in Stockholm county, Sweden. Men aged 50-74 years were randomly selected by Statistics Sweden and invited by mail to participate in screening; those with an elevated risk of prostate cancer, defined as either a PSA of 3 ng/mL or higher or a Stockholm3 score of 0·11 or higher were eligible for randomisation. Men with a previous prostate cancer diagnosis, who had undergone a prostate biopsy within 60 days before the invitation to participate, with a contraindication for MRI, or with severe illness were excluded. Eligible participants were randomly assigned (2:3) using computer-generated blocks of five, stratified by clinically significant prostate cancer risk, to receive either systematic prostate biopsies (standard group) or biparametric MRI followed by MRI-targeted and systematic biopsy in MRI-positive participants (experimental group). The primary outcome was the detection of clinically significant prostate cancer at prostate biopsy, defined as a Gleason score of 3 + 4 or higher. We used a margin of 0·78 to assess non-inferiority for the primary outcome. Key secondary outcome measures included the proportion of men with clinically insignificant prostate cancer (defined as a Gleason score of 3 + 3), and the number of any prostate MRI and biopsy procedures done. We did two comparisons: Stockholm3 (using scores of 0·11 and 0·15 as cutoffs) versus PSA in the experimental group (paired analyses) and PSA plus standard biopsy versus Stockholm3 plus MRI-targeted and systematic biopsy (unpaired, randomised analyses). All analyses were intention to treat. This study is registered with ClinicalTrials.gov, NCT03377881.

Findings: Between Feb 5, 2018, and March 4, 2020, 49 118 men were invited to participate, of whom 12 750 were enrolled and provided blood specimens, and 2293 with elevated risk were randomly assigned to the experimental group (n=1372) or the standard group (n=921). The area under the receiver-operating characteristic curve for detection of clinically significant prostate cancer was 0·76 (95% CI 0·72-0·80) for Stockholm3 and 0·60 (0·54-0·65) for PSA. In the experimental group, a Stockholm3 of 0·11 or higher was non-inferior to a PSA of 3 ng/mL or higher for detection of clinically significant prostate cancer (227 vs 192; relative proportion [RP] 1·18 [95% CI 1·09-1·28], p<0·0001 for non-inferiority), and also detected a similar number of low-grade prostate cancers (50 vs 41; 1·22 [0·96-1·55], p=0·053 for superiority) and was associated with more MRIs and biopsies. Compared with PSA of 3 ng/mL or higher, a Stockholm3 of 0·15 or higher provided identical sensitivity to detect clinically significant cancer, and led to fewer MRI procedures (545 vs 846; 0·64 [0·55-0·82]) and fewer biopsy procedures (311 vs 338; 0·92 (0·86-1·03). Compared with screening using PSA and systematic biopsies, a Stockholm3 of 0·11 or higher combined with MRI-targeted and systematic biopsies was associated with higher detection of clinically significant cancers (227 [3·0%] men tested vs 106 [2·1%] men tested; RP 1·44 [95% CI 1·15-1·81]), lower detection of low-grade cancers (50 [0·7%] vs 73 [1·4%]; 0·46 [0·32-0·66]), and led to fewer biopsy procedures. Patients randomly assigned to the experimental group had a lower incidence of prescription of antibiotics for infection (25 [1·8%] of 1372 vs 41 [4·4%] of 921; p=0·0002) and a lower incidence of admission to hospital (16 [1·2%] vs 31 [3·4%]; p=0·0003) than those in the standard group.

Interpretation: The Stockholm3 test can inform risk stratification before MRI and targeted biopsies in prostate cancer screening. Combining the Stockholm3 test with an MRI-targeted biopsy approach for prostate cancer screening decreases overdetection while maintaining the ability to detect clinically significant cancer.

Funding: The Swedish Cancer Society, the Swedish Research Council, and Stockholm City Council.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(21)00348-XDOI Listing
September 2021

OpenPhi: An interface to access Philips iSyntax whole slide images for computational pathology.

Bioinformatics 2021 Aug 6. Epub 2021 Aug 6.

Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Summary: Digital pathology enables applying computational methods, such as deep learning, in pathology for improved diagnostics and prognostics, but lack of interoperability between whole slide image formats of different scanner vendors is a challenge for algorithm developers. We present OpenPhi - Open PatHology Interface, an Application Programming Interface for seamless access to the iSyntax format used by the Philips Ultra Fast Scanner, the first digital pathology scanner approved by the United States Food and Drug Administration. OpenPhi is extensible and easily interfaced with existing vendor-neutral applications.

Availability And Implementation: OpenPhi is implemented in Python and is available as open-source under the MIT license at: https://gitlab.com/BioimageInformaticsGroup/openphi. The Philips Software Development Kit is required and available at: https://www.openpathology.philips.com.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bioinformatics/btab578DOI Listing
August 2021

The STHLM3-model, Risk-based Prostate Cancer Testing Identifies Men at High Risk Without Inducing Negative Psychosocial Effects.

Eur Urol Open Sci 2021 Feb 7;24:43-51. Epub 2021 Jan 7.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

Background: The new STHLM3 test, combining protein markers, genetic markers, and clinical data to assess a man's prostate cancer (PCa) risk, has been investigated in Sweden within the frame of the STHLM3 trial.

Objective: To assess whether the STHLM3 test influences men's worry level, PCa knowledge, attitude, and health-related quality of life (HRQoL).

Design Setting And Participants: Invitations with login to the web survey were mailed to 10 000 men, 50-69 yr of age, who were eligible for the STHLM3 trial. The survey was sent 3 mo invitation to the STHLM3 trial (baseline) and 5 mo STHLM3 (follow-up). At baseline, the men were unaware of the upcoming invitation to STHLM3. The survey covered the following: PCa-specific worry and perceived vulnerability, knowledge about PCa, attitude toward PCa testing and health behavior, and HRQoL.

Outcome Measurements And Statistical Analysis: Survey scores were compared between baseline and follow-up by using the nonparametric Wilcoxon-signed rank tests for paired samples. Analysis of covariance was performed for PCa risk group comparisons.

Results And Limitations: A total of 994 men (10%) responded to our survey at baseline and follow-up, and were assessed as follows: low risk: 421 men; intermediate risk: 421 men; and high risk:152, of whom 59 were diagnosed with PCa after further investigation. In men assessed as having low and intermediate risk, level of worrying decreased at follow-up ( <  0.001), whereas no changes were observed in men at high risk. Moreover, no HRQoL changes were observed over time. The low response rate is the main limitation.

Conclusions: We found that the STHLM3 model, a risk-based PCa test, showed no negative impact on the well-being of men.

Patient Summary: Since our results suggest that the risk-based screening as used in STHLM3 did not induce negative psychological effects on the participants, we can recommend this risk-based approach for population-based prostate cancer screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.euros.2020.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317863PMC
February 2021

Identifying Prostate Cancer Among Men with Lower Urinary Tract Symptoms.

Eur Urol Open Sci 2021 Feb 1;24:11-16. Epub 2021 Jan 1.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: In men aged above 50 yr, lower urinary tract symptoms (LUTS), benign prostate hyperplasia, and prostate cancer are common urological conditions. Current guidelines for general practitioners frequently recommend prostate-specific antigen (PSA) testing in patients with LUTS for the detection of prostate cancer.

Objective: To assess the performance of PSA, PSA density, and the Stockholm3 blood test for identification of prostate cancer among men with LUTS.

Design Setting And Participants: In this post hoc analysis of a population-based diagnostic trial (STHLM3,  = 58 588), 4588 men aged 50-69 yr, without previous prostate cancer, with International Prostate Symptom Score (IPSS) data, and having PSA ≥ 3 ng/mL were identified. Men with at least moderate LUTS, defined as an IPSS score of ≥8, were included. PSA density and Stockholm3 scores were calculated.

Intervention: Participants underwent 10-12-core systematic prostate biopsies.

Outcome Measurements And Statistical Analysis: The primary outcome was significant prostate cancer (sPCa) defined as International Society of Urological Pathology (ISUP) grade ≥2. Logistic regression analysis adjusted for age and previous biopsy status was performed. The area under the receiver operating characteristic curve (AUC) was calculated, and decision curve analysis was performed.

Results And Limitations: Out of 4588 men, 1544 (34%) reported at least moderate LUTS. The median age was 64 yr, and 11% had undergone a previous prostate biopsy. The Stockholm3 test showed superior discrimination for sPCa to PSA density, which in turn showed superior discrimination to PSA (AUC 0.77 vs 0.70 vs 0.61,  <  0.02). Calibration of the Stockholm3 test was adequate. Performing biopsy only in men with PSA ≥5 ng/mL saved 64% of biopsies, but resulted in missing 52% of detectable sPCa. Recommending biopsy for men with PSA density ≥0.07 resulted in sparing 26% of biopsy procedures and delaying the diagnosis of 12% of sPCa cases, with a 6.1% risk of sPCa among unbiopsied men. Recommending men with Stockholm3 ≥ 0.11 for biopsy resulted in sparing 53% of biopsy procedures and delaying the diagnosis of 20% of sPCa cases, with a 5.1% risk of finding sPCa in unbiopsied men.

Conclusions: PSA density and the Stockholm3 blood test were superior to PSA for the identification of prostate cancer among men with LUTS.

Patient Summary: In this analysis of a large Swedish study, we find that the use of prostate-specific antigen (PSA) density or the Stockholm3 blood test instead of only PSA might improve the detection of prostate cancer among men with lower urinary tract symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.euros.2020.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317798PMC
February 2021

Progression on active surveillance for prostate cancer in Black men: a systematic review and meta-analysis.

Prostate Cancer Prostatic Dis 2021 Jul 8. Epub 2021 Jul 8.

Department of Urology, University of Illinois at Chicago, Chicago, IL, USA.

Background: Several studies evaluated prostate cancer (PCa) outcomes in Black men on active surveillance (AS); most studies contained few Black men and results were conflicting. We performed a systematic review and meta-analyze of race and outcomes on AS.

Methods: A systematic search was performed for articles of men with Grade Group 1 or 2 (GG1 or GG2) PCa on AS. All studies required race-specific comparative progression data. Progression to treatment, PSA, or biopsy progression were considered and relative risk (RR) estimates of Black men progressing were extracted and pooled using random-effects models. Differences by study-level characteristics were evaluated using subgroup and a cumulative meta-analysis by time.

Results: In total, 12 studies were included (3137 Black and 12,206 non-Black men); eight prospective (27%, n = 4210) and four retrospectives (73%, n = 11,133) cohorts. The overall RR of progression for Black men was 1.62 (95%CI, 1.21-2.17), I = 64% (95% CI, 32-80%), (χ = 30.23; P = 0.001; τ = 0.16). Black men with GG1 PCa alone had a higher pooled progression: RR = 1.81 (95% CI, 1.23-2.68). Including only studies with clinical progression (excluding progression to treatment), potentiated results: RR = 1.82 (95%CI, 1.27-2.60). However, a cumulative meta-analysis demonstrated decreasing pooled effect over time, with contemporary studies after 2019 showing a tempered effect (RR: 1.29, 95% CI: 1.20-1.39).

Conclusions: Many studies attribute racial disparity in PCa to delayed presentation of disease, however, AS is unique since all AS eligible men have a low grade and stage PCa. Our findings suggest Black men may have an increased risk of progression during AS, but the association is not so strong that Black men should be discouraged from undergoing AS. Indeed, contemporary evidence suggests stricter inclusion, better confirmatory testing or better access to care may temper these findings. Importantly, these results utilize self-reported race, a social construct that has many limitations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41391-021-00425-1DOI Listing
July 2021

MRI-Targeted or Standard Biopsy in Prostate Cancer Screening.

N Engl J Med 2021 09 9;385(10):908-920. Epub 2021 Jul 9.

From the Departments of Medical Epidemiology and Biostatistics (M.E., A.D., M.B., H.G., T.N.) and Molecular Medicine and Surgery (F.J., M. Aly, S.C.), and the Department of Clinical Sciences at Danderyd Hospital (T.N.), Karolinska Institutet, the Department of Diagnostic Radiology (F.J.), the Department of Surgery (M.B., H.G.) and the Department of Clinical Pathology and Cytology, Unilabs (A.G.), Capio St. Göran's Hospital, C-Medical Urology Odenplan (M. Annerstedt), and the Department of Urology, Karolinska University Hospital Solna (M. Aly, S.C.) - all in Stockholm.

Background: High rates of overdiagnosis are a critical barrier to organized prostate cancer screening. Magnetic resonance imaging (MRI) with targeted biopsy has shown the potential to address this challenge, but the implications of its use in the context of organized prostate cancer screening are unknown.

Methods: We conducted a population-based noninferiority trial of prostate cancer screening in which men 50 to 74 years of age from the general population were invited by mail to participate; participants with prostate-specific antigen (PSA) levels of 3 ng per milliliter or higher were randomly assigned, in a 2:3 ratio, to undergo a standard biopsy (standard biopsy group) or to undergo MRI, with targeted and standard biopsy if the MRI results suggested prostate cancer (experimental biopsy group). The primary outcome was the proportion of men in the intention-to-treat population in whom clinically significant cancer (Gleason score ≥7) was diagnosed. A key secondary outcome was the detection of clinically insignificant cancers (Gleason score 6).

Results: Of 12,750 men enrolled, 1532 had PSA levels of 3 ng per milliliter or higher and were randomly assigned to undergo biopsy: 603 were assigned to the standard biopsy group and 929 to the experimental biopsy group. In the intention-to-treat analysis, clinically significant cancer was diagnosed in 192 men (21%) in the experimental biopsy group, as compared with 106 men (18%) in the standard biopsy group (difference, 3 percentage points; 95% confidence interval [CI], -1 to 7; P<0.001 for noninferiority). The percentage of clinically insignificant cancers was lower in the experimental biopsy group than in the standard biopsy group (4% [41 participants] vs. 12% [73 participants]; difference, -8 percentage points; 95% CI, -11 to -5).

Conclusions: MRI with targeted and standard biopsy in men with MRI results suggestive of prostate cancer was noninferior to standard biopsy for detecting clinically significant prostate cancer in a population-based screening-by-invitation trial and resulted in less detection of clinically insignificant cancer. (Funded by the Swedish Research Council and others; STHLM3-MRI ClinicalTrials.gov number, NCT03377881.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2100852DOI Listing
September 2021

The emerging role of artificial intelligence in the reporting of prostate pathology.

Pathology 2021 08 6;53(5):565-567. Epub 2021 Jun 6.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pathol.2021.04.002DOI Listing
August 2021

Real world treatment utilization patterns in patients with castration-resistant prostate cancer.

Scand J Urol 2021 Aug 7;55(4):299-306. Epub 2021 Jun 7.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: Studies describing treatment utilization for castration-resistant prostate cancer (CRPC) are limited. We aimed to describe the treatment utilization of a contemporary population-based CRPC cohort between 2006 and 2016.

Methods: We identified 1699 men with a PC diagnosis between 2005 and 2015, who developed CRPC between 2006 and 2015 in the Stockholm region of Sweden. Demographic information, stage and grade at PC diagnosis, stage at CRPC, prostate-specific antigen (PSA) nadir, PSA doubling time, treatment utilization rate within 1 year of CRPC diagnosis, reason for stopping therapy, treatment sequence trajectory, overall and PC specific survival was described.

Results: Treatment for men with de novo metastatic disease ( = 463) was 32%, treatment for men with progressive metastatic disease after PC diagnosis ( = 66) was 44%, treatment for men with nonmetastatic CRPC ( = 113) was 34% and treatment for those with an unknown stage at time of CRPC diagnosis ( = 857) was 12%. Docetaxel was used in 39%, abiraterone acetate plus prednisone in 15%, enzalutamide in 13%, cabazitaxel in 11% and radium-223 in 5% of treatments. Treatment increased from 22% in 2006-2009 for metastatic cancer to 50% in 2013-2015 ( < .001). Factors associated with treatment were an unknown stage at diagnosis (OR: 0.3, 95% CI: 0.2-0.4), age ≥75 years (OR: 0.2, 95% CI: 0.1 - 0.3), PSA doubling time >3 months (OR: 0.4, 95% CI: 0.3 - 0.6) and a diagnosis between 2013 and 2015 (OR: 3.4, 95% CI: 2.0 - 5.8).

Conclusions: Despite treatment availability, in this large real-world cohort we found treatment utilization to remain low.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21681805.2021.1936626DOI Listing
August 2021

Increased Pathway Complexity Is a Prognostic Biomarker in Metastatic Castration-Resistant Prostate Cancer.

Cancers (Basel) 2021 Mar 30;13(7). Epub 2021 Mar 30.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden.

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease, characterized by common and rare driver gene alterations that provide a selective growth advantage for progressing tumour cells. We hypothesized that the number of distinct gene driver alteration-affected pathways or gene classes was associated with poor prognosis in patients initiating androgen receptor signalling inhibitors (ARSi). We performed a post hoc analysis of an amalgamated baseline circulating tumour DNA (ctDNA) mutational landscape dataset of ARSi-treated men with mCRPC ( = 342). We associated the detected hotspot, pathogenic, and/or high impact protein function-affecting perturbations in 39 genes into 13 pathways. Progression-free (PFS) and overall survival (OS) were analysed using Kaplan-Meier curves and multivariate Cox regression models. Driver gene alterations were detected in 192/342 (56.1%) evaluable patients. An increased number of affected pathways, coined pathway complexity index (PCI), resulted in a decremental PFS and OS, and was independently associated with prognosis once ≥3 pathway or gene classes were affected (PFS HR (95%CI): 1.7 (1.02-2.84), = 0.04, and OS HR (95%CI): 2.5 (1.06-5.71), = 0.04). Additionally, visceral disease and baseline PSA and plasma ctDNA levels were independently associated with poor prognosis. Elevated PCI is associated with poor ARSi outcome and supports comprehensive genomic profiling to better infer mCRPC prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13071588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037684PMC
March 2021

Artificial Intelligence in Magnetic Resonance Imaging-based Prostate Cancer Diagnosis: Where Do We Stand in 2021?

Eur Urol Focus 2021 Mar 24. Epub 2021 Mar 24.

Department of Urology, Faculty of Medicine, University of Freiburg Medical Centre, Freiburg, Germany.

Context: Men suspected of harboring prostate cancer (PCa) increasingly undergo multiparametric magnetic resonance imaging (mpMRI) and mpMRI-guided biopsy. The potential of mpMRI coupled to artificial intelligence (AI) methods to detect and classify PCa before decision-making requires investigation.

Objective: To review the literature for studies addressing the diagnostic performance of combined mpMRI and AI approaches to detect and classify PCa, and to provide selection criteria for relevant articles having clinical significance.

Evidence Acquisition: We performed a nonsystematic search of the English language literature using the PubMed-MEDLINE database up to October 30, 2020. We included all original studies addressing the diagnostic accuracy of mpMRI and AI to detect and classify PCa with histopathological analysis as a reference standard.

Evidence Synthesis: Eleven studies assessed AI and mpMRI approaches for PCa detection and classification based on a ground truth that referred to the entire prostate either with radical prostatectomy specimens (RPS) or relocalization of positive systematic and/or targeted biopsy. Seven studies retrospectively annotated cancerous lesions onto mpMRI identified in whole-mount sections from RPS, three studies used a backward projection of histological prostate biopsy information, and one study used a combined cohort of both approaches. All studies cross-validated their data sets; only four used a test set and one a multisite validation scheme. Performance metrics for lesion detection ranged from 87.9% to 92% at a threshold specificity of 50%. The lesion classification accuracy of the algorithms was comparable to that of the Prostate Imaging-Reporting and Data System.

Conclusions: For an algorithm to be implemented into radiological workflows and to be clinically applicable, it must be trained with a ground truth labeling that reflects histopathological information for the entire prostate and it must be externally validated. Lesion detection and classification performance metrics are promising but require prospective implementation and external validation for clinical significance.

Patient Summary: We reviewed the literature for studies on prostate cancer detection and classification using magnetic resonance imaging (MRI) and artificial intelligence algorithms. The main application is in supporting radiologists in interpreting MRI scans and improving the diagnostic performance, so that fewer unnecessary biopsies are carried out.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.euf.2021.03.020DOI Listing
March 2021

Low-Dose Tamoxifen for Mammographic Density Reduction: A Randomized Controlled Trial.

J Clin Oncol 2021 Jun 18;39(17):1899-1908. Epub 2021 Mar 18.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Purpose: Tamoxifen prevents breast cancer in high-risk women and reduces mortality in the adjuvant setting. Mammographic density change is a proxy for tamoxifen therapy response. We tested whether lower doses of tamoxifen were noninferior to reduce mammographic density and associated with fewer symptoms.

Patients And Methods: Women, 40-74 years of age, participating in the Swedish mammography screening program were invited to the 6-month double-blind six-arm randomized placebo-controlled noninferiority dose-determination KARISMA phase II trial stratified by menopausal status (EudraCT 2016-000882-22). In all, 1,439 women were accrued with 1,230 participants accessible for intention-to-treat analysis. The primary outcome was proportion of women treated with placebo, 1, 2.5, 5, and 10 mg whose mammographic density decreased at least as much as the median reduction in the 20 mg arm. The noninferior margin was 17%. Secondary outcome was reduction of symptoms. Post hoc analyses were performed by menopausal status. Per-protocol population and full population were analyzed in sensitivity analysis.

Results: The 1,439 participants, 566 and 873 pre- and postmenopausal women, respectively, were recruited between October 1, 2016, and September 30, 2019. The participants had noninferior mammographic density reduction following 2.5, 5, and 10 mg tamoxifen compared with the median 10.1% decrease observed in the 20 mg group, a reduction confined to premenopausal women. Severe vasomotor symptoms (hot flashes, cold sweats, and night sweats) were reduced by approximately 50% in the 2.5, 5, and 10 mg groups compared with the 20 mg group.

Conclusion: Premenopausal women showed noninferior magnitude of breast density decrease at 2.5 mg of tamoxifen, but fewer side effects compared with the standard dose of 20 mg. Future studies should test whether 2.5 mg of tamoxifen reduces the risk of primary breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.02598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189632PMC
June 2021

Interobserver reproducibility of perineural invasion of prostatic adenocarcinoma in needle biopsies.

Virchows Arch 2021 Jun 3;478(6):1109-1116. Epub 2021 Feb 3.

Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Numerous studies have shown a correlation between perineural invasion (PNI) in prostate biopsies and outcome. The reporting of PNI varies widely in the literature. While the interobserver variability of prostate cancer grading has been studied extensively, less is known regarding the reproducibility of PNI. A total of 212 biopsy cores from a population-based screening trial were included in this study (106 with and 106 without PNI according to the original pathology reports). The glass slides were scanned and circulated among four pathologists with a special interest in urological pathology for assessment of PNI. Discordant cases were stained by immunohistochemistry for S-100 protein. PNI was diagnosed by all four observers in 34.0% of cases, while 41.5% were considered to be negative for PNI. In 24.5% of cases, there was a disagreement between the observers. The kappa for interobserver variability was 0.67-0.75 (mean 0.73). The observations from one participant were compared with data from the original reports, and a kappa for intraobserver variability of 0.87 was achieved. Based on immunohistochemical findings among discordant cases, 88.6% had PNI while 11.4% did not. The most common diagnostic pitfall was the presence of bundles of stroma or smooth muscle. It was noted in a few cases that collagenous micronodules could be mistaken for a nerve. The distance between cancer and nerve was another cause of disagreement. Although the results suggest that the reproducibility of PNI may be greater than that of prostate cancer grading, there is still a need for improvement and standardization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00428-021-03039-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203540PMC
June 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
January 2021

Effect of artificial intelligence-based triaging of breast cancer screening mammograms on cancer detection and radiologist workload: a retrospective simulation study.

Lancet Digit Health 2020 09;2(9):e468-e474

Department of Pathology and Oncology, Karolinska Institute, Stockholm, Sweden; Breast Radiology, Karolinska University Hospital, Stockholm, Sweden.

Background: We examined the potential change in cancer detection when using an artificial intelligence (AI) cancer-detection software to triage certain screening examinations into a no radiologist work stream, and then after regular radiologist assessment of the remainder, triage certain screening examinations into an enhanced assessment work stream. The purpose of enhanced assessment was to simulate selection of women for more sensitive screening promoting early detection of cancers that would otherwise be diagnosed as interval cancers or as next-round screen-detected cancers. The aim of the study was to examine how AI could reduce radiologist workload and increase cancer detection.

Methods: In this retrospective simulation study, all women diagnosed with breast cancer who attended two consecutive screening rounds were included. Healthy women were randomly sampled from the same cohort; their observations were given elevated weight to mimic a frequency of 0·7% incident cancer per screening interval. Based on the prediction score from a commercially available AI cancer detector, various cutoff points for the decision to channel women to the two new work streams were examined in terms of missed and additionally detected cancer.

Findings: 7364 women were included in the study sample: 547 were diagnosed with breast cancer and 6817 were healthy controls. When including 60%, 70%, or 80% of women with the lowest AI scores in the no radiologist stream, the proportion of screen-detected cancers that would have been missed were 0, 0·3% (95% CI 0·0-4·3), or 2·6% (1·1-5·4), respectively. When including 1% or 5% of women with the highest AI scores in the enhanced assessment stream, the potential additional cancer detection was 24 (12%) or 53 (27%) of 200 subsequent interval cancers, respectively, and 48 (14%) or 121 (35%) of 347 next-round screen-detected cancers, respectively.

Interpretation: Using a commercial AI cancer detector to triage mammograms into no radiologist assessment and enhanced assessment could potentially reduce radiologist workload by more than half, and pre-emptively detect a substantial proportion of cancers otherwise diagnosed later.

Funding: Stockholm City Council.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2589-7500(20)30185-0DOI Listing
September 2020

Biomarker discrimination and calibration with MRI-targeted biopsies: an analysis with the Stockholm3 test.

Prostate Cancer Prostatic Dis 2021 06 9;24(2):457-464. Epub 2020 Nov 9.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: The validated Stockholm3 test is used to improve PC detection. Stockholm3, however, was developed using systematic biopsies. We aimed to assess Stockholm3 operating performance when using MRI-targeted biopsies for PC detection.

Methods: A prospective cohort of 532 men was considered for prostate biopsy during 2016-2017. All men underwent Stockholm3 testing and MRI before biopsy. All PIRADs ≥3 lesion underwent targeted biopsy; all men underwent systematic biopsy. The primary outcome was ISUP Grade Group ≥2 (GG ≥ 2) PC. Detection strategies included: (1) systematic biopsies alone, (2) targeted biopsies alone, (3) targeted with associated systematic biopsies for MRI+, and (4) all biopsies in all men. For each strategy, the Stockholm3 operating characteristics were assessed with discrimination, calibration, and decision curve analysis (DCA).

Results: Median age was 65 years, median PSA was 6.2 ng/mL, median Stockholm3 score was 16.5%, and overall detection of GG ≥ 2 PC was 36% (193/532). Stockholm3 showed accurate discrimination for separating GG ≥ 2 cancer from benign and GG1, with an area under the curve of 0.84-0.86 depending on the biopsy strategy. Calibration analysis showed that Stockholm3 underestimated risks for GG ≥ 2 PC risk using MRI-targeted biopsies: there was a net benefit over biopsies in all men for Stockholm3 at risk thresholds varying from >3% in systematic biopsies to >15% in targeted with systematic biopsies in MRI+ men. When using a Stockholm3 score of >10% cutoff, a range of 32-38% of biopsies could be avoided while missing 5-11% of GG ≥ 2 PC and 0-3% of GG ≥ 3 PC.

Conclusions: Stockholm3 shows high discriminatory performance in an MRI-targeted biopsy setting, however risks are underpredicted due to MRI-targeted biopsies being more sensitive than the systematic biopsies for which Stockholm3 was developed. Stockholm3, along with any risk prediction model developed for systematic prostate biopsy decisions, will need recalibration for optimal use in an MRI-driven biopsy setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41391-020-00297-xDOI Listing
June 2021

Factors contributing to healthcare professional burnout during the COVID-19 pandemic: A rapid turnaround global survey.

PLoS One 2020 3;15(9):e0238217. Epub 2020 Sep 3.

Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America.

Background: Healthcare professionals (HCPs) on the front lines against COVID-19 may face increased workload and stress. Understanding HCPs' risk for burnout is critical to supporting HCPs and maintaining the quality of healthcare during the pandemic.

Methods: To assess exposure, perceptions, workload, and possible burnout of HCPs during the COVID-19 pandemic we conducted a cross-sectional survey. The main outcomes and measures were HCPs' self-assessment of burnout, indicated by a single item measure of emotional exhaustion, and other experiences and attitudes associated with working during the COVID-19 pandemic.

Findings: A total of 2,707 HCPs from 60 countries participated in this study. Fifty-one percent of HCPs reported burnout. Burnout was associated with work impacting household activities (RR = 1·57, 95% CI = 1·39-1·78, P<0·001), feeling pushed beyond training (RR = 1·32, 95% CI = 1·20-1·47, P<0·001), exposure to COVID-19 patients (RR = 1·18, 95% CI = 1·05-1·32, P = 0·005), and making life prioritizing decisions (RR = 1·16, 95% CI = 1·02-1·31, P = 0·03). Adequate personal protective equipment (PPE) was protective against burnout (RR = 0·88, 95% CI = 0·79-0·97, P = 0·01). Burnout was higher in high-income countries (HICs) compared to low- and middle-income countries (LMICs) (RR = 1·18; 95% CI = 1·02-1·36, P = 0·018).

Interpretation: Burnout is present at higher than previously reported rates among HCPs working during the COVID-19 pandemic and is related to high workload, job stress, and time pressure, and limited organizational support. Current and future burnout among HCPs could be mitigated by actions from healthcare institutions and other governmental and non-governmental stakeholders aimed at potentially modifiable factors, including providing additional training, organizational support, and support for family, PPE, and mental health resources.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238217PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470306PMC
September 2020

Incorporating Magnetic Resonance Imaging and Biomarkers in Active Surveillance Protocols - Results From the Prospective Stockholm3 Active Surveillance Trial (STHLM3AS).

J Natl Cancer Inst 2021 May;113(5):632-640

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: Active surveillance (AS) for men with low-risk prostate cancer (PC) can lead to patient morbidity and healthcare overutilization. The aim of this study was to evaluate an AS protocol using the Stockholm3 test and magnetic resonance imaging (MRI) to reduce biopsy intensity.

Methods: We conducted a prospective multicenter study of 280 invited men from a contemporary screening study (STHLM3), with Gleason Score (GS) 3 + 3 PC on a current AS protocol. Patients underwent prostate-MRI and blood sampling for analysis of the Stockholm3 test including protein biomarkers, genetic variants, and clinical variables to predict risk of GS ≥3 + 4 PC followed by systematic biopsies and targeted biopsies (for Prostate Imaging Reporting and Data System version 2 ≥3 lesions) in all men. Primary outcomes were reclassification to GS ≥3 + 4 PC and clinically significant PC (csPCa), including unfavorable intermediate risk PC or higher based on National Comprehensive Cancer Network guidelines.

Results: Adding MRI-targeted biopsies to systematic biopsies increased sensitivity of GS ≥3 + 4 PC compared with systematic biopsies alone (relative sensitivity [RS] = 1.52, 95% confidence interval [CI] = 1.28 to 1.85). Performing biopsies in only MRI positive increased sensitivity of GS ≥3 + 4 PC (RS = 1.30, 95% CI = 1.04 to 1.67) and reduced number of biopsy procedures by 49.3% while missing 7.2% GS ≥3 + 4 PC and 1.4% csPCa. Excluding men with negative Stockholm3 test reduced the number of MRI investigations at follow-up by 22.5% and biopsies by 56.8% while missing 6.9% GS ≥3 + 4 PC and 1.3% csPCa.

Conclusion: Including MRI and targeted/systematic biopsies in the follow-up for men on AS increased sensitivity of PC reclassification. Incorporation of risk prediction models including biomarkers may reduce the need for MRI use in men with low-risk PC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djaa131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096373PMC
May 2021

External Evaluation of 3 Commercial Artificial Intelligence Algorithms for Independent Assessment of Screening Mammograms.

JAMA Oncol 2020 10;6(10):1581-1588

Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.

Importance: A computer algorithm that performs at or above the level of radiologists in mammography screening assessment could improve the effectiveness of breast cancer screening.

Objective: To perform an external evaluation of 3 commercially available artificial intelligence (AI) computer-aided detection algorithms as independent mammography readers and to assess the screening performance when combined with radiologists.

Design, Setting, And Participants: This retrospective case-control study was based on a double-reader population-based mammography screening cohort of women screened at an academic hospital in Stockholm, Sweden, from 2008 to 2015. The study included 8805 women aged 40 to 74 years who underwent mammography screening and who did not have implants or prior breast cancer. The study sample included 739 women who were diagnosed as having breast cancer (positive) and a random sample of 8066 healthy controls (negative for breast cancer).

Main Outcomes And Measures: Positive follow-up findings were determined by pathology-verified diagnosis at screening or within 12 months thereafter. Negative follow-up findings were determined by a 2-year cancer-free follow-up. Three AI computer-aided detection algorithms (AI-1, AI-2, and AI-3), sourced from different vendors, yielded a continuous score for the suspicion of cancer in each mammography examination. For a decision of normal or abnormal, the cut point was defined by the mean specificity of the first-reader radiologists (96.6%).

Results: The median age of study participants was 60 years (interquartile range, 50-66 years) for 739 women who received a diagnosis of breast cancer and 54 years (interquartile range, 47-63 years) for 8066 healthy controls. The cases positive for cancer comprised 618 (84%) screen detected and 121 (16%) clinically detected within 12 months of the screening examination. The area under the receiver operating curve for cancer detection was 0.956 (95% CI, 0.948-0.965) for AI-1, 0.922 (95% CI, 0.910-0.934) for AI-2, and 0.920 (95% CI, 0.909-0.931) for AI-3. At the specificity of the radiologists, the sensitivities were 81.9% for AI-1, 67.0% for AI-2, 67.4% for AI-3, 77.4% for first-reader radiologist, and 80.1% for second-reader radiologist. Combining AI-1 with first-reader radiologists achieved 88.6% sensitivity at 93.0% specificity (abnormal defined by either of the 2 making an abnormal assessment). No other examined combination of AI algorithms and radiologists surpassed this sensitivity level.

Conclusions And Relevance: To our knowledge, this study is the first independent evaluation of several AI computer-aided detection algorithms for screening mammography. The results of this study indicated that a commercially available AI computer-aided detection algorithm can assess screening mammograms with a sufficient diagnostic performance to be further evaluated as an independent reader in prospective clinical trials. Combining the first readers with the best algorithm identified more cases positive for cancer than combining the first readers with second readers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2020.3321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453345PMC
October 2020

Artificial intelligence assistance significantly improves Gleason grading of prostate biopsies by pathologists.

Mod Pathol 2021 03 5;34(3):660-671. Epub 2020 Aug 5.

Department of Pathology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

The Gleason score is the most important prognostic marker for prostate cancer patients, but it suffers from significant observer variability. Artificial intelligence (AI) systems based on deep learning can achieve pathologist-level performance at Gleason grading. However, the performance of such systems can degrade in the presence of artifacts, foreign tissue, or other anomalies. Pathologists integrating their expertise with feedback from an AI system could result in a synergy that outperforms both the individual pathologist and the system. Despite the hype around AI assistance, existing literature on this topic within the pathology domain is limited. We investigated the value of AI assistance for grading prostate biopsies. A panel of 14 observers graded 160 biopsies with and without AI assistance. Using AI, the agreement of the panel with an expert reference standard increased significantly (quadratically weighted Cohen's kappa, 0.799 vs. 0.872; p = 0.019). On an external validation set of 87 cases, the panel showed a significant increase in agreement with a panel of international experts in prostate pathology (quadratically weighted Cohen's kappa, 0.733 vs. 0.786; p = 0.003). In both experiments, on a group-level, AI-assisted pathologists outperformed the unassisted pathologists and the standalone AI system. Our results show the potential of AI systems for Gleason grading, but more importantly, show the benefits of pathologist-AI synergy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-020-0640-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897578PMC
March 2021

Predictors of adverse pathology on radical prostatectomy specimen in men initially enrolled in active surveillance for low-risk prostate cancer.

World J Urol 2021 Jun 30;39(6):1797-1804. Epub 2020 Jul 30.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.

Purpose: To evaluate clinical variables, including magnetic resonance imaging (MRI) predictive of adverse pathology (AP) at radical prostatectomy (RP) in men initially enrolled in active surveillance (AS).

Methods: A population-based cohort study of men diagnosed with low-risk prostate cancer (PCa), in Stockholm County, Sweden, during 2008-2017 enrolled in AS their intended primary treatment followed by RP. AP was defined as ISUP grade group  ≥ 3 and/or pT-stage ≥ T3. Association between clinical variables at diagnosis and time to AP was evaluated using Cox regression and multivariate logistic regression to evaluate the association between AP and clinical variables at last biopsy before RP.

Results: In a cohort of 6021 patients with low-risk PCa, 3116 were selected for AS and 216 underwent RP. Follow-up was 10 years, with a median time on AS of 23 months. 37.7% of patients had AP at RP. Clinical T-stage [Hazard ratio (HR): 1.81, 95% confidence interval (CI) 1.04-3.18] and PSA (HR: 1.31, 95% CI 1.17-1.46) at diagnosis and age [Odds Ratio (OR): 1.09, 95% CI 1.02-1.18), PSA (OR: 1.22, 95% CI 1.07-1.41), and PI-RADS (OR 1.66, 95% CI 1.11-2.55)] at last re-biopsy were significantly associated with AP.

Conclusion: PI-RADS score is significantly associated with AP at RP and support current guidelines recommending MRI before enrollment in AS. Furthermore, age, cT-stage, and PSA are significantly associated with AP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00345-020-03394-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217019PMC
June 2021

Range of Radiologist Performance in a Population-based Screening Cohort of 1 Million Digital Mammography Examinations.

Radiology 2020 10 28;297(1):33-39. Epub 2020 Jul 28.

From the Departments of Pathology and Oncology (M.S., F.S.), Physiology and Pharmacology (K.D., P.L.), and Medical Epidemiology and Biostatistics (M.E.), Karolinska Institute, Stockholm, Sweden; Department of Radiology (M.S.) and Breast Radiology (F.S.), Karolinska University Hospital, Dalagatan 90, 113 43 Stockholm, Sweden; and the Department of Radiology, Capio Sankt Görans Hospital, Stockholm, Sweden (K.D.).

Background There is great interest in developing artificial intelligence (AI)-based computer-aided detection (CAD) systems for use in screening mammography. Comparative performance benchmarks from true screening cohorts are needed. Purpose To determine the range of human first-reader performance measures within a population-based screening cohort of 1 million screening mammograms to gauge the performance of emerging AI CAD systems. Materials and Methods This retrospective study consisted of all screening mammograms in women aged 40-74 years in Stockholm County, Sweden, who underwent screening with full-field digital mammography between 2008 and 2015. There were 110 interpreting radiologists, of whom 24 were defined as high-volume readers (ie, those who interpreted more than 5000 annual screening mammograms). A true-positive finding was defined as the presence of a pathology-confirmed cancer within 12 months. Performance benchmarks included sensitivity and specificity, examined per quartile of radiologists' performance. First-reader sensitivity was determined for each tumor subgroup, overall and by quartile of high-volume reader sensitivity. Screening outcomes were examined based on the first reader's sensitivity quartile with 10 000 screening mammograms per quartile. Linear regression models were fitted to test for a linear trend across quartiles of performance. Results A total of 418 041 women (mean age, 54 years ± 10 [standard deviation]) were included, and 1 186 045 digital mammograms were evaluated, with 972 899 assessed by high-volume readers. Overall sensitivity was 73% (95% confidence interval [CI]: 69%, 77%), and overall specificity was 96% (95% CI: 95%, 97%). The mean values per quartile of high-volume reader performance ranged from 63% to 84% for sensitivity and from 95% to 98% for specificity. The sensitivity difference was very large for basal cancers, with the least sensitive and most sensitive high-volume readers detecting 53% and 89% of cancers, respectively ( < .001). Conclusion Benchmarks showed a wide range of performance differences between high-volume readers. Sensitivity varied by tumor characteristics. © RSNA, 2020
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1148/radiol.2020192212DOI Listing
October 2020

Ethnic variation in prostate cancer detection: a feasibility study for use of the Stockholm3 test in a multiethnic U.S. cohort.

Prostate Cancer Prostatic Dis 2021 03 8;24(1):120-127. Epub 2020 Jul 8.

Department of Urology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60607, USA.

Background: The Stockholm3 test improves Gleason Grade Group ≥2 (GG ≥ 2) prostate cancer (PC) detection, however it has not been evaluated in an American cohort where clinical practice patterns and ethnicity differ. We aimed to identify subgroups within a Stockholm population with PC risk profiles matching American ethnicity-specific subgroups and compare the detection of PC and describe Stockholm3 performance within these subgroups.

Methods: All men age 49-70 years presenting for prostate biopsies were evaluated at UIC from 2016 to 2019, as well as men in Stockholm from 2012 to 2014 in the STHLM3 study. Propensity scores (PS) were estimated for each person using logistic regression for age, PSA, prostate volume, family history of PC, 5-alpha reductase inhibitor use, and prior biopsy. 3:1 PS matching was performed for Stockholm to Chicago ethnicity-specific cohorts and odds ratios (OR) were computed to compare detection of GG ≥ 2 PC between groups.

Results: 504 Chicago men and 6980 Stockholm men were included. In African American (AA) men, 51% had GG ≥ 2 PC detected, while in risk-matched Stockholm men, 34% had GG ≥ 2 PC detected (OR: 2.1, p < 0.001). There was no statistical difference in GG ≥ 2 PC detected when matching Stockholm men to non-Hispanic Caucasian men (31% vs. 24%, OR: 0.7, p = 0.30) or Hispanic Caucasian men (31% vs. 27%, OR: 1.2, p = 0.42). The AUC for the Stockholm3 test of the matched Stockholm cohorts for AA, non-Hispanic Caucasian, and Hispanic Caucasian men was 0.85, 0.89, and 0.90, respectively.

Conclusions: Using statistical techniques to simulate a multi-ethnic Chicago cohort within the STHLM3 population, we found an excess risk of GG ≥ 2 PC among AA men. Our hypothesis that the Stockholm3 may have good predictive value in a multiethnic cohort is strengthened, and that recalibration to at least AA men seems likely to be needed to obtain well-calibrated predictions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41391-020-0250-2DOI Listing
March 2021

The ProBio trial: molecular biomarkers for advancing personalized treatment decision in patients with metastatic castration-resistant prostate cancer.

Trials 2020 Jun 26;21(1):579. Epub 2020 Jun 26.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: Multiple therapies exist for patients with metastatic castration-resistant prostate cancer (mCRPC). However, their improvement on progression-free survival (PFS) remains modest, potentially explained by tumor molecular heterogeneity. Several prognostic molecular biomarkers have been identified for mCRPC that may have predictive potential to guide treatment selection and prolong PFS. We designed a platform trial to test this hypothesis.

Methods: The Prostate-Biomarker (ProBio) study is a multi-center, outcome-adaptive, multi-arm, biomarker-driven platform trial for tailoring treatment decisions for men with mCRPC. Treatment decisions in the experimental arms are based on biomarker signatures defined as mutations in certain genes/pathways suggested in the scientific literature to be important for treatment response in mCRPC. The biomarker signatures are determined by targeted sequencing of circulating tumor and germline DNA using a panel specifically designed for mCRPC.

Discussion: Patients are stratified based on the sequencing results and randomized to either current clinical practice (control), where the treating physician decides treatment, or to molecularly driven treatment selection based on the biomarker profile. Outcome-adaptive randomization is implemented to early identify promising treatments for a biomarker signature. Biomarker signature-treatment combinations graduate from the platform when they demonstrate 85% probability of improving PFS compared to the control arm. Graduated combinations are further evaluated in a seamless confirmatory trial with fixed randomization. The platform design allows for new drugs and biomarkers to be introduced in the study.

Conclusions: The ProBio design allows promising treatment-biomarker combinations to quickly graduate from the platform and be confirmed for rapid implementation in clinical care.

Trial Registration: ClinicalTrials.gov Identifier NCT03903835. Date of registration: April 4, 2019. Status: Recruiting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-020-04515-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318749PMC
June 2020

Identification of areas of grading difficulties in prostate cancer and comparison with artificial intelligence assisted grading.

Virchows Arch 2020 Dec 15;477(6):777-786. Epub 2020 Jun 15.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

The International Society of Urological Pathology (ISUP) hosts a reference image database supervised by experts with the purpose of establishing an international standard in prostate cancer grading. Here, we aimed to identify areas of grading difficulties and compare the results with those obtained from an artificial intelligence system trained in grading. In a series of 87 needle biopsies of cancers selected to include problematic cases, experts failed to reach a 2/3 consensus in 41.4% (36/87). Among consensus and non-consensus cases, the weighted kappa was 0.77 (range 0.68-0.84) and 0.50 (range 0.40-0.57), respectively. Among the non-consensus cases, four main causes of disagreement were identified: the distinction between Gleason score 3 + 3 with tangential cutting artifacts vs. Gleason score 3 + 4 with poorly formed or fused glands (13 cases), Gleason score 3 + 4 vs. 4 + 3 (7 cases), Gleason score 4 + 3 vs. 4 + 4 (8 cases) and the identification of a small component of Gleason pattern 5 (6 cases). The AI system obtained a weighted kappa value of 0.53 among the non-consensus cases, placing it as the observer with the sixth best reproducibility out of a total of 24. AI may serve as a decision support and decrease inter-observer variability by its ability to make consistent decisions. The grading of these cancer patterns that best predicts outcome and guides treatment warrants further clinical and genetic studies. Results of such investigations should be used to improve calibration of AI systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00428-020-02858-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683442PMC
December 2020

Factors Contributing to Healthcare Professional Burnout During the COVID-19 Pandemic: A Rapid Turnaround Global Survey.

medRxiv 2020 May 22. Epub 2020 May 22.

Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States.

Background: Healthcare professionals (HCPs) on the front lines against COVID-19 may face increased workload, and stress. Understanding HCPs risk for burnout is critical to supporting HCPs and maintaining the quality of healthcare during the pandemic.

Methods: To assess exposure, perceptions, workload, and possible burnout of HCPs during the COVID-19 pandemic we conducted a cross-sectional survey. The main outcomes and measures were HCPs self-assessment of burnout and other experiences and attitudes associated with working during the COVID-19 pandemic.

Findings: A total of 2,707 HCPs from 60 countries participated in this study. Fifty-one percent of HCPs reported burnout. Burnout was associated with work impacting household activities (RR=1.57, 95% CI=1.39-1.78, P<0.001), feeling pushed beyond training (RR=1.32, 95% CI=1.20-1.47, P<0.001), exposure to COVID-19 patients (RR=1.18, 95% CI=1.05-1.32, P=0.005), making life prioritizing decisions (RR=1.16, 95% CI=1.02-1.31, P=0.03). Adequate personal protective equipment (PPE) was protective against burnout (RR=0.88, 95% CI=0.79-0.97, P=0.01). Burnout was higher in high-income countries (HICs) compared to low- and middle-income countries (LMICs) (RR=1.18; 95% CI=1.02-1.36, P=0.018).

Interpretation: Burnout is prevalent at higher than previously reported rates among HCPs working during the COVID-19 pandemic and is related to high workload, job stress, and time pressure, and limited organizational support. Current and future burnout among HCPs could be mitigated by actions from healthcare institutions and other governmental and non-governmental stakeholders aimed at potentially modifiable factors, including providing additional training, organizational support, support for family, PPE, and mental health resources.

Funding: N/A.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.05.17.20101915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273269PMC
May 2020

Head-to-head Comparison of Conventional, and Image- and Biomarker-based Prostate Cancer Risk Calculators.

Eur Urol Focus 2021 May 22;7(3):546-553. Epub 2020 May 22.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden.

Background: A new generation of risk calculators (RCs) for prostate cancer (PCa) incorporating magnetic resonance imaging (MRI) data have been introduced. However, these have not been validated externally, and their clinical benefit compared with alternative approaches remains unclear.

Objective: To assess previously published PCa RCs incorporating MRI data, and compare their performance with traditional RCs (European Randomized Study of Screening for Prostate Cancer [ERSPC] 3/4 and Prostate Biopsy Collaborative Group [PBCG]) and the blood-based Stockholm3 test.

Design, Setting, And Participants: RCs were tested in a prospective multicenter cohort including 532 men aged 45-74 yr participating in the Stockholm3-MRI study between 2016 and 2017.

Outcome Measurements And Statistical Analysis: The probabilities of detection of clinically significant PCa (csPCa) defined as Gleason score ≥3 + 4 were calculated for each patient. For each RC and the Stockholm3 test, discrimination was assessed by area under the curve (AUC), calibration by numerical and graphical summaries, and clinical usefulness by decision curve analysis (DCA).

Results And Limitations: The discriminative ability of MRI RCs 1-4 for the detection of csPCa was superior (AUC 0.81-0.87) to the traditional RCs (AUC 0.76-0.80). The observed prevalence of csPCa in the cohort was 37%, but calibration-in-the-large predictions varied from 14% to 63% across models. DCA identified only one model including MRI data as clinically useful at a threshold probability of 10%. The Stockholm3 test achieved equivalent performance for discrimination (AUC 0.86) and DCA, but was underpredicting the actual risk.

Conclusions: Although MRI RCs discriminated csPCa better than traditional RCs, their predicted probabilities were variable in accuracy, and DCA identified only one model as clinically useful.

Patient Summary: Novel risk calculators (RCs) incorporating imaging improved the ability to discriminate clinically significant prostate cancer compared with traditional tools. However, all but one predicted divergent compared with actual risks, suggesting that regional modifications be implemented before usage. The Stockholm3 test achieved performance comparable with the best MRI RC without utilization of imaging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.euf.2020.05.002DOI Listing
May 2021

The economic burden of prostate cancer - a Swedish prevalence-based register study.

BMC Health Serv Res 2020 May 20;20(1):448. Epub 2020 May 20.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, 171 65, Stockholm, Sweden.

Background: Incidence and prevalence of prostate cancer in Sweden have increased markedly due to prostate-specific antigen (PSA) testing. Moreover, new diagnostic tests and treatment technologies are expected to further increase the overall costs. Our aims were (i) to estimate the societal costs for existing testing, diagnosis, management and treatment of prostate cancer, and (ii) to provide reference values for future cost-effectiveness analyses of prostate cancer screening and treatment.

Methods: Taking a societal perspective, this study aimed to investigate the annual cost of prostate cancer in Sweden using a prevalence-based cost-of-illness approach. Resource utilisation and related costs within Stockholm Region during 2016 were quantified using data from the Stockholm PSA and Biopsy Register and other health and population registers. Costs included: (i) direct medical costs for health care utilisation at primary care, hospitals, palliative care and prescribed drugs; (ii) informal care; and (iii) indirect costs due to morbidity and premature mortality. The resource utilisation was valued using unit costs for direct medical costs and the human capital method for informal care and indirect costs. Costs for the Stockholm region were extrapolated to Sweden based on cancer prevalence and the average costs by age and resource type.

Results: The societal costs due to prostate cancer in Stockholm in 2016 were estimated to be €64 million Euro (€Mn), of which the direct medical costs, informal care and productivity losses represented 62, 28 and 10% of the total costs, respectively. The total annual costs extrapolated to Sweden were calculated to be €281 Mn. The average direct medical cost, average costs for informal care and productivity losses per prevalent case were €1510, €828 and €271, respectively. These estimates were sensitive to assumptions related to the proportion of primary care visits associated with PSA testing and the valuation method for informal care.

Conclusion: The societal costs due to prostate cancer were substantial and constitute a considerable burden to Swedish society. Data from this study are relevant for future cost-effectiveness evaluations of prostate cancer screening and treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12913-020-05265-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238534PMC
May 2020
-->