Tailoring biopsy strategy in the MRI-fusion prostate biopsy era: systematic, targeted or neither?

BACKGROUND: Magnetic  resonance imaging (MRI) followed by targeted biopsy (TBx) is utilized for prostate cancer (PCa) detection. However, the value of adding systematic biopsies (SBx) to targeted biopsy procedures (combined biopsy; CBx) in men with suspicious MRI findings has not been determined. METHODS: We analysed biopsy outcomes in 429 men with MRI lesions in the prospective multicenter STHLM3MRI pilot study, planned for prostate biopsy. Participants underwent 1.5T biparametric MRI without contrast enhancement, reported according to the PI-RADS v2, and with TBx plus SBx if the MRI lesion score was ≥ 3. The endpoints were clinically nonsignificant (nsPCa) and clinically significant PCa (csPCa), defined as ISUP grade groups 1 and ≥ 2, respectively. RESULTS: The median age was 65 years (59-70), and the median PSA 6.0 ng/ml (4.1-9.0). The detection rates of csPCa when using TBx or SBx combined were 18%, 46%, and 85% in men with PIRADS scores of 3 (n = 195), 4 (n = 121), and 5 (n = 113), respectively. This combined strategy detected csPCa in more men than TBx alone (43.6% vs 39.2%, p < 0.02), with similar detection of nsPCa (19.3% vs 17.7%, p = 0.2). In men with equivocal lesions (PI-RADS 3), the detection rates for csPCa were similar for the combined strategy and for TBx alone (17.9% and 15.4%, p = 0.06). However, there was an increase in the detection of nsPCa when using the combined strategy (21.0% vs 15.4%, p < 0.02). Men with equivocal lesions and a PSA density < 0.1 ng/ml2 or a Stockholm 3 test < 0.11 had a low risk of harboring csPCa. CONCLUSIONS: Supplementing targeted with systematic biopsies enhances clinically significant cancer detection. However, in men with equivocal lesions, this combination has potential for detecting nonsignificant disease. A subgroup of men with equivocal MRI findings may be identified as having a low risk for significant cancer and spared unnecessary biopsies.

Emergence of the physiological effects of elevated CO2 on land-atmosphere exchange of carbon and water.

Elevated atmospheric CO2 (eCO2 ) influences the carbon assimilation rate and stomatal conductance of plants, thereby affecting the global cycles of carbon and water. Yet, the detection of these physiological effects of eCO2 in observational data remains challenging, because natural variations and confounding factors (e.g., warming) can overshadow the eCO2 effects in observational data of real-world ecosystems. In this study, we aim at developing a method to detect the emergence of the physiological CO2 effects on various variables related to carbon and water fluxes. We mimic the observational setting in ecosystems using a comprehensive process-based land surface model QUINCY to simulate the leaf-level effects of increasing atmospheric CO2 concentrations and their century-long propagation through the terrestrial carbon and water cycles across different climate regimes and biomes. We then develop a statistical method based on the signal-to-noise ratio to detect the emergence of the eCO2 effects. The eCO2 effect on gross primary productivity (GPP) emerges at relatively low CO2 increase (∆[CO2 ] ~ 20 ppm) where the leaf area index is relatively high. Compared to GPP, the eCO2 effect causing reduced transpiration water flux (normalized to leaf area) emerges only at relatively high CO2 increase (∆[CO2 ] >> 40 ppm), due to the high sensitivity to climate variability and thus lower signal-to-noise ratio. In general, the response to eCO2 is detectable earlier for variables related to the carbon cycle than the water cycle, when plant productivity is not limited by climatic constraints, and stronger in forest-dominated rather than in grass-dominated ecosystems. Our results provide a step toward when and where we expect to detect physiological CO2 effects in in-situ flux measurements, how to detect them and encourage future efforts to improve the understanding and quantification of these effects in observations of terrestrial carbon and water dynamics.

Axion Wind Detection with the Homogeneous Precession Domain of Superfluid Helium-3.

Axions and axionlike particles may couple to nuclear spins like a weak oscillating effective magnetic field, the "axion wind." Existing proposals for detecting the axion wind sourced by dark matter exploit analogies to nuclear magnetic resonance (NMR) and aim to detect the small transverse field generated when the axion wind resonantly tips the precessing spins in a polarized sample of material. We describe a new proposal using the homogeneous precession domain of superfluid ^{3}He as the detection medium, where the effect of the axion wind is a small shift in the precession frequency of a large-amplitude NMR signal. We argue that this setup can provide broadband detection of multiple axion masses simultaneously and has competitive sensitivity to other axion wind experiments such as CASPEr-Wind at masses below 10^{-7} eV by exploiting precision frequency metrology in the readout stage.

Diagnostic Effects of Omitting Systematic Biopsies in Prostate Cancer Screening.

BACKGROUND AND OBJECTIVE: The optimal biopsy strategy in prostate cancer screening is unknown. This study aims to assess the diagnostic effects of omitting systematic biopsies in a screening cohort. METHODS: We used data from the STHLM3-MRI trial. A total of 7609 men aged 50-74 yr were randomised to undergo magnetic resonance imaging (MRI) if having an elevated risk of prostate cancer (prostate-specific antigen [PSA] ≥3 ng/ml or Stockholm3 ≥11%). Participants with Prostate Imaging Reporting and Data System (PI-RADS) ≥3 underwent targeted and systematic biopsies. Cancer detection rates from combined and targeted-only biopsies were presented as a risk ratio (RR). Subgroup analyses were stratified by age, PSA density (PSAd), and PI-RADS. Differences in reclassification rates at radical prostatectomy were calculated. KEY FINDINGS AND LIMITATIONS: The median age of the participants was 66 yr (interquartile range: 61-71) and PSA 3.8 ng/ml (2.9-5.8). Out of 395 men undergoing combined biopsies, 52 (13.2%) had International Society of Urological Pathology (ISUP) grade group (GG) 1 and 230 (58%) had ISUP GG ≥2 prostate cancer. Omission of systematic biopsies reduced cancer detection rates (RR of ISUP GG 1: 0.83 [95% confidence interval 0.64-1.07]; ISUP GG ≥2: 0.85 [0.81-0.90]; and ISUP GG ≥3: 0.86 [0.79-0.95]). Each case of averted ISUP GG 1 cancer was associated with 3.8 cases of missed ISUP GG ≥2 and 1.1 case of ISUP GG ≥3 cancer. Detection of fewer ISUP GG ≥2 cases than the number of avoided ISUP 1 cancer cases was observed in all subgroups when systematic biopsies were omitted. Using PSAd ≥0.05 ng/ml2 as a cut-off for a biopsy resulted in the same numbers of ISUP GG 1 tumours saved, with higher detection rates of ISUP GG ≥2 tumours. In 146 men undergoing radical prostatectomy, 46 (31.5%) versus 28 (19.2%) were upgraded following targeted biopsies versus a combined biopsy strategy (p < 0.05). CONCLUSIONS AND CLINICAL IMPLICATIONS: Complete omission of systematic biopsies in prostate cancer screening is associated with decreased detection of significant cancer, while reducing overdetection of insignificant cancer to a smaller extent. This strategy also increased the risk of histopathological misclassification. PATIENT SUMMARY: In a prostate cancer screening setting, we examined the diagnostic effects of systematic biopsies in addition to targeted biopsies in men with suspicious magnetic resonance imaging lesions. We found that exclusion of systematic biopsies led to reduced detection of clinically significant prostate cancer. Our findings emphasise the importance of incorporating systematic biopsies alongside targeted biopsies for improved diagnostic outcomes.

Prediagnostic Prostate-specific Antigen Testing and Clinical Characteristics in Men with Lethal Prostate Cancer.

Background and objective: Prostate cancer (PC) is the fifth leading cause of cancer-related mortality in men worldwide. Opportunistic testing with prostate-specific antigen (PSA) has limited impact on PC mortality. Our objective was to assess prediagnostic PSA testing patterns and clinical characteristics at diagnosis in men with lethal PC. Methods: We conducted a population-based observational study of all men dying from PC in Stockholm County, Sweden, from 2015 to 2019. Data were retrieved from the National Prostate Cancer Register and the Stockholm PSA and Biopsy Register. If the first PSA was registered within 1 yr before diagnosis, men were categorised as PSA naïve. If an elevated PSA level was registered >1 yr before diagnosis without leading to prostate biopsy or repeating PSA within 1 yr, men were categorised as having delayed diagnosis. If a normal PSA level was registered within 5 yr before diagnosis, followed by an elevated PSA level that resulted in PC diagnosis within 1 yr, men were categorised as PSA tested. Clinical characteristics at diagnosis were stratified with D'Amico risk group classification. Key findings and limitations: Among 1473 men dying from PC, PSA test history was available for 995. Of these men, 60% (n = 592) were PSA naïve, 25% (n = 250) received delayed diagnosis, and 15% (n = 153) were PSA tested. After examining all 1473 men, 25% (n = 350) were diagnosed with low- or intermediate-risk cancer, 48% (n = 687) with high-risk cancer, and 27% (n = 385) with metastatic disease. Limitations include the retrospective design. Conclusions and clinical implications: Many men with lethal PC lacked PSA testing before diagnosis or had been tested without subsequent follow-up. Nearly half of the study population was diagnosed with high-risk cancer and almost one-third with metastatic disease. These findings suggest further evaluation of the current opportunistic PSA testing approach. Patient summary: Data from a population-based observational study of men dying from prostate cancer showed that many of them did not undergo either prostate-specific antigen (PSA) testing before diagnosis or subsequent follow-up if tested. These findings implicate deficiencies in the current opportunistic PSA testing approach.

A user-friendly integrated monitor-adhesive patch for long-term ambulatory electrocardiogram monitoring.

BACKGROUND: Compliance to long-term ambulatory electrocardiogram monitoring is important for diagnosis in patients with cardiac arrhythmia. This requires a system with a minimal impact on daily activities. OBJECTIVE: The aim of this study was to investigate if a lightweight integrated adhesive monitor for long-term use without unacceptable adverse effects is feasible. METHODS: The participants wore either a prototype lightweight monitor or a control system for a total of up to 30 days, changing patches once (investigational device) or twice (control) weekly. Comfort, skin irritation, and impact on quality of life were recorded. RESULTS: The new monitor can be worn by most participants for periods of at least 6 days. Skin irritation and comfort rating were comparable, and impact on the quality of life was low compared with the control. Patients considered the device comfortable. CONCLUSION: An integrated adhesive monitor that can be worn on the skin up to 7 days with minimal side effects is feasible.

Pulmonary tumour embolism and lymphangitis carcinomatosa: a case report and review of the literature.

BACKGROUND: Pulmonary tumour embolism and lymphangitis carcinomatosa are complications of malignancy that may mimic the clinical presentation of pulmonary embolism. CASE PRESENTATION: We present the case of a 52-year-old male patient with acute-onset right ventricular strain and dyspnoea with elevated D-dimer and without signs of pulmonary embolism on computed tomography pulmonary angiogram (CTPA) and ventilation/perfusion scintigraphy. The patient died eleven days after initial presentation. The diagnosis of pulmonary tumour embolism and lymphangitis carcinomatosa due to carcinoma of unknown origin was made post-mortem by immunohistochemical examination. CONCLUSION: Pulmonary tumour embolism and lymphangitis carcinomaosa are complications of malignancy and potential causes of acute right ventricular strain. Radiological signs are unspecific and the clinical course usually fatal. These differential diagnoses should be considered in patients with acute right ventricular strain, dyspnoea and positive D-dimer if there are no signs of pulmonary embolism on CTPA.

External Validation of the Prostate Biopsy Collaborative Group Risk Calculator and the Rotterdam Prostate Cancer Risk Calculator in a Swedish Population-based Screening Cohort.

Background: External validation of risk calculators (RCs) is necessary to determine their clinical applicability beyond the setting in which these were developed. Objective: To assess the performance of the Rotterdam Prostate Cancer RC (RPCRC) and the Prostate Biopsy Collaborative Group RC (PBCG-RC). Design setting and participants: We used data from the prospective, population-based STHLM3 screening study, performed in 2012-2015. Participants with prostate-specific antigen ≥3 ng/ml who underwent systematic prostate biopsies were included. Outcome measurements and statistical analysis: Probabilities for clinically significant prostate cancer (csPCa), defined as International Society of Urological Pathology grade ≥2, were calculated for each participant. External validity was assessed by calibration, discrimination, and clinical usefulness for both original and recalibrated models. Results and limitations: Out of 5841 men, 1054 (18%) had csPCa. Distribution of risk predictions differed between RCs; median risks for csPCa using the RPCRC and PBCG-RC were 3.3% (interquartile range [IQR] 2.1-7.1%) and 20% (IQR 15-28%), respectively. The correlation between RC risk estimates on individual level was moderate (Spearman's r = 0.55). Using the RPCRC's recommended risk threshold of ≥4% for finding csPCa, 36% of participants would get concordant biopsy recommendations. At 10% risk cut-off, RCs agreed in 23% of cases. Both RCs showed good discrimination, with areas under the curves for the RPCRC of 0.74 (95% confidence interval [CI] 0.72-0.76) and the PBCG-RC of 0.70 (95% CI 0.68-0.72). Calibration was adequate using the PBCG-RC (calibration slope: 1.13 [95% CI 1.03-1.23]), but the RPCRC underestimated the risk of csPCa (calibration slope: 0.73 [0.68-0.79]). The PBCG-RC showed a net benefit in a decision curve analysis, whereas the RPCRC showed no net benefit at clinically relevant risk threshold levels. Recalibration improved clinical benefit, and differences between RCs decreased. Conclusions: Assessment of calibration is essential to ensure the clinical value of risk prediction tools. The PBCG-RC provided clinical benefit in its current version online. On the contrary, the RPCRC cannot be recommended in this setting. Patient summary: Predicting the probability of finding prostate cancer on biopsy differed between two assessed risk calculators. After recalibration, the agreement of the models improved, and both were shown to be clinically useful.

Identifying Prostate Cancer Among Men with Lower Urinary Tract Symptoms.

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, n = 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, p <  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.

Anti-Acanthamoeba disinfection: hands, surfaces and wounds.

Acanthamoebae are facultative parasites causing rare but serious infections such as keratitis and encephalitis and are also known as vectors for several bacterial pathogens, including legionellae and pseudomonads. Acanthamoeba cysts are particularly resilient and enable the amoebae to withstand desiccation and to resist disinfection and therapy. While the search for new therapeutic options has been intensified in the past years, hand and surface disinfectants as well as topical antiseptics for preventing infections have not been studied in detail to date. The aim of this study was to screen well-known and commonly used antimicrobial products in various formulations and different concentrations for their efficacy against Acanthamoeba trophozoites and cysts, including aliphatic alcohols, quaternary ammonium compounds (QACs), peracetic acid (PAA), potassium peroxymonosulfate sulfate (PPMS) and octenidine dihydrochloride (OCT). Of all products tested, OCT and QACs showed the highest efficacy, totally eradicating both trophozoites and cysts within 1 min. The determined 50% effective concentration (EC50) for cysts was 0.196 mg/mL for OCT and 0.119 mg/mL for QACs after 1 min of exposure. PAA and PPMS showed reliable cysticidal efficacies only with prolonged incubation times of 30 min and 60 min, respectively. Aliphatic alcohols generally had limited efficacy, and only against trophozoites. In conclusion, OCT and QACs are potent actives against Acanthamoeba trophozoites and cysts at concentrations used in commercially available products, within contact times suitable for surface and hand disinfection as well as topical antisepsis.

Lower urinary tract symptoms (LUTS) are not associated with an increased risk of prostate cancer in men 50-69 years with PSA ≥3 ng/ml.

Background: There is conflicting evidence about the association between prostate cancer and Lower Urinary Tract Symptoms (LUTS). We aimed to describe the prevalence of LUTS and its association with prostate cancer risk.Methods: We studied the association between International Prostate Symptom Score (IPSS) and prostate cancer in a population-based sample of men (n = 45,595) aged 50-69 years from the Stockholm3 study. Men with PSA ≥3 ng/ml (n = 4579) underwent systematic prostate biopsies. We used the International Society of Urological Pathology Gleason Grading (ISUP grade) and performed regression analysis for risk of any cancer (n = 1797), ISUP grade ≥2 (n = 840) and advanced cancer, defined as ISUP grade ≥3 or cT ≥3 (n = 353).Results: 74.6% of all men had no or mild LUTS (IPSS ≤7) and 3.2% had severe LUTS (IPSS >19). Men with any, ISUP grade ≥2 or advanced cancer had lower median IPSS compared to men with benign biopsy (any cancer: 4 (IQR 2-9); ISUP grade ≥2: 4 (2-8); advanced cancer: 4 (2-8); benign biopsy: 6 (3-11); p < 0.05). IPSS was not associated with increased risk of cancer in multivariate analyses (OR (any cancer) 0.97; 95% CI 0.96-0.98; OR (ISUP grade ≥2) 0.97; 95% CI 0.96-0.99; OR (advanced cancer) 0.99; 95% CI 0.99-1.01).Conclusions: Three-quarters of men aged 50-69 years report no or mild LUTS. Our data do not support any clinically meaningful association between LUTS and prostate cancer. Specifically, men with advanced prostate cancer did not exhibit more urinary symptoms than men without cancer.