Regional Histopathology and Prostate MRI Positivity: A Secondary Analysis of the PROMIS Trial.

Background The effects of regional histopathologic changes on prostate MRI scans have not been accurately quantified in men with an elevated prostate-specific antigen (PSA) level and no previous biopsy. Purpose To assess how Gleason grade, maximum cancer core length (MCCL), inflammation, prostatic intraepithelial neoplasia (PIN), or atypical small acinar proliferation within a Barzell zone affects the odds of MRI visibility. Materials and Methods In this secondary analysis of the Prostate MRI Imaging Study (PROMIS; May 2012 to November 2015), consecutive participants who underwent multiparametric MRI followed by a combined biopsy, including 5-mm transperineal mapping (TPM), were evaluated. TPM pathologic findings were reported at the whole-prostate level and for each of 20 Barzell zones per prostate. An expert panel blinded to the pathologic findings reviewed MRI scans and declared which Barzell areas spanned Likert score 3-5 lesions. The relationship of Gleason grade and MCCL to zonal MRI outcome (visible vs nonvisible) was assessed using generalized linear mixed-effects models with random intercepts for individual participants. Inflammation, PIN, and atypical small acinar proliferation were similarly assessed in men who had negative TPM results. Results Overall, 161 men (median age, 62 years [IQR, 11 years]) were evaluated and 3179 Barzell zones were assigned MRI status. Compared with benign areas, the odds of MRI visibility were higher when a zone contained cancer with a Gleason score of 3+4 (odds ratio [OR], 3.1; 95% CI: 1.9, 4.9; P < .001) or Gleason score greater than or equal to 4+3 (OR, 8.7; 95% CI: 4.5, 17.0; P < .001). MCCL also determined visibility (OR, 1.24 per millimeter increase; 95% CI: 1.15, 1.33; P < .001), but odds were lower with each prostate volume doubling (OR, 0.7; 95% CI: 0.5, 0.9). In men who were TPM-negative, the presence of PIN increased the odds of zonal visibility (OR, 3.7; 95% CI: 1.5, 9.1; P = .004). Conclusion An incremental relationship between cancer burden and prostate MRI visibility was observed. Prostatic intraepithelial neoplasia contributed to false-positive MRI findings. ClinicalTrials.gov registration no. NCT01292291 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Harmath in this issue

Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study.

Background Men with high serum prostate specific antigen usually undergo transrectal ultrasound-guided prostate biopsy (TRUS-biopsy). TRUS-biopsy can cause side-effects including bleeding, pain, and infection. Multi-parametric magnetic resonance imaging (MP-MRI) used as a triage test might allow men to avoid unnecessary TRUS-biopsy and improve diagnostic accuracy.Methods We did this multicentre, paired-cohort, confirmatory study to test diagnostic accuracy of MP-MRI and TRUS-biopsy against a reference test (template prostate mapping biopsy [TPM-biopsy]). Men with prostate-specific antigen concentrations up to 15 ng/mL, with no previous biopsy, underwent 1·5 Tesla MP-MRI followed by both TRUS-biopsy and TPM-biopsy. The conduct and reporting of each test was done blind to other test results. Clinically significant cancer was defined as Gleason score ≥4 + 3 or a maximum cancer core length 6 mm or longer. This study is registered on ClinicalTrials.gov, NCT01292291.Findings Between May 17, 2012, and November 9, 2015, we enrolled 740 men, 576 of whom underwent 1·5 Tesla MP-MRI followed by both TRUS-biopsy and TPM-biopsy. On TPM-biopsy, 408 (71%) of 576 men had cancer with 230 (40%) of 576 patients clinically significant. For clinically significant cancer, MP-MRI was more sensitive (93%, 95% CI 88-96%) than TRUS-biopsy (48%, 42-55%; p<0·0001) and less specific (41%, 36-46% for MP-MRI vs 96%, 94-98% for TRUS-biopsy; p<0·0001). 44 (5·9%) of 740 patients reported serious adverse events, including 8 cases of sepsis.Interpretation Using MP-MRI to triage men might allow 27% of patients avoid a primary biopsy and diagnosis of 5% fewer clinically insignificant cancers. If subsequent TRUS-biopsies were directed by MP-MRI findings, up to 18% more cases of clinically significant cancer might be detected compared with the standard pathway of TRUS-biopsy for all. MP-MRI, used as a triage test before first prostate biopsy, could reduce unnecessary biopsies by a quarter. MP-MRI can also reduce over-diagnosis of clinically insignificant prostate cancer and improve detection of clinically significant cancer.Funding PROMIS is funded by the UK Government Department of Health, National Institute of Health Research-Health Technology Assessment Programme, (Project number 09/22/67). This project is also supported and partly funded by UCLH/UCL Biomedical Research Centre and The Royal Marsden and Institute for Cancer Research Biomedical Research Centre and is coordinated by the Medical Research Council Clinical Trials Unit (MRC CTU) at UCL. It is sponsored by University College London (UCL)

Silviculture of south american temperate native forests

Background: South America has the largest area of temperate forests in the Southern Hemisphere, which grow in diverse site conditions. The aim of this paper is to review the practices of silviculture applied and recommended for these temperate forests, and to discuss prospects to develop new silvicultural proposals to improve sustainability, adaptation and in-situ conservation of forest ecosystems. Methods: We reviewed the silviculture knowledge in four major forest types: 1) The Nothofagus-dominated forests of south-central Chile; 2) the Angiosperm-dominated evergreen forests; 3) the Nothofagus and Austrocedrus chilensis (D.Don) Pic. Serm. & Bizzarri forests in the Argentinean Northern Patagonia; and 4) the Cool temperate Nothofagus forests and Magellanic rainforests. Results: In Chile, both Nothofagus-dominated and Angiosperm-dominated evergreen forests are diverse in tree species, and mixed-species silviculture with commercially valuable species of variable shade tolerance is most promising. Some secondary forests can reach growth rates as high as 20 m(3)ha(-1)yr(-1). After thinnings, stands with 35-60% of residual densities have shown the best responses in growth. Even-aged silvicultural methods have shown a rapid reorganization and development of new cohorts, although, where Chusquea species are conspicuous, regeneration establishment requires controlling competing vegetation. Preliminary results also show interesting prospects for single-tree selection cuts in uneven-aged forests. East of the Andes, in Argentina, mixed Nothofagus forests and pure and mixed Nothofagus and A. chilensis forests occur. The shelterwood method has been the most practised and successful in the mixed Nothofagus forests, with abundant regeneration, and good growth rates. For A. chilensis forests, an adaptive management approach is proposed, conditioned by the cypress disease attack (e.g., Phytophthora austrocedri). Conversion of pure A. chilensis to mixed A. chilensis-N. dombeyi forests could increase growth considerably. Finally, in the cool temperate Nothofagus forests and Magellanic rainforests, shared by Chile and Argentina, the regular shelterwood cuts have been the most common silvicultural method, with massive regeneration a decade after the regeneration felling. Since the two major Nothofagus species in these forests regenerate well in gaps, uneven-aged silviculture seems also promising. Conclusions: There is abundant knowledge about the silviculture of these forest types. However, there are opportunities for several silvicultural systems to better contribute to sustainable forest management, reverse forest degradation, and cope with climate change challenges, primarily through developing mixed and single-species productive and carbon-rich forests, with greater adaptive capacity.Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) CONICYT FONDECYT 1210147 11181140Versión publicada - versión final del edito

Multiparametric MRI to improve detection of prostate cancer compared with transrectal ultrasound-guided prostate biopsy alone: the PROMIS study.

Background Men with suspected prostate cancer usually undergo transrectal ultrasound (TRUS)-guided prostate biopsy. TRUS-guided biopsy can cause side effects and has relatively poor diagnostic accuracy. Multiparametric magnetic resonance imaging (mpMRI) used as a triage test might allow men to avoid unnecessary TRUS-guided biopsy and improve diagnostic accuracy.Objectives To (1) assess the ability of mpMRI to identify men who can safely avoid unnecessary biopsy, (2) assess the ability of the mpMRI-based pathway to improve the rate of detection of clinically significant (CS) cancer compared with TRUS-guided biopsy and (3) estimate the cost-effectiveness of a mpMRI-based diagnostic pathway.Design A validating paired-cohort study and an economic evaluation using a decision-analytic model.Setting Eleven NHS hospitals in England.Participants Men at risk of prostate cancer undergoing a first prostate biopsy.Interventions Participants underwent three tests: (1) mpMRI (the index test), (2) TRUS-guided biopsy (the current standard) and (3) template prostate mapping (TPM) biopsy (the reference test).Main outcome measures Diagnostic accuracy of mpMRI, TRUS-guided biopsy and TPM-biopsy measured by sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) using primary and secondary definitions of CS cancer. The percentage of negative magnetic resonance imaging (MRI) scans was used to identify men who might be able to avoid biopsy.Results Diagnostic study - a total of 740 men were registered and 576 underwent all three tests. According to TPM-biopsy, the prevalence of any cancer was 71% [95% confidence interval (CI) 67% to 75%]. The prevalence of CS cancer according to the primary definition (a Gleason score of ≥ 4 + 3 and/or cancer core length of ≥ 6 mm) was 40% (95% CI 36% to 44%). For CS cancer, TRUS-guided biopsy showed a sensitivity of 48% (95% CI 42% to 55%), specificity of 96% (95% CI 94% to 98%), PPV of 90% (95% CI 83% to 94%) and NPV of 74% (95% CI 69% to 78%). The sensitivity of mpMRI was 93% (95% CI 88% to 96%), specificity was 41% (95% CI 36% to 46%), PPV was 51% (95% CI 46% to 56%) and NPV was 89% (95% CI 83% to 94%). A negative mpMRI scan was recorded for 158 men (27%). Of these, 17 were found to have CS cancer on TPM-biopsy. Economic evaluation - the most cost-effective strategy involved testing all men with mpMRI, followed by MRI-guided TRUS-guided biopsy in those patients with suspected CS cancer, followed by rebiopsy if CS cancer was not detected. This strategy is cost-effective at the TRUS-guided biopsy definition 2 (any Gleason pattern of ≥ 4 and/or cancer core length of ≥ 4 mm), mpMRI definition 2 (lesion volume of ≥ 0.2 ml and/or Gleason score of ≥ 3 + 4) and cut-off point 2 (likely to be benign) and detects 95% (95% CI 92% to 98%) of CS cancers. The main drivers of cost-effectiveness were the unit costs of tests, the improvement in sensitivity of MRI-guided TRUS-guided biopsy compared with blind TRUS-guided biopsy and the longer-term costs and outcomes of men with cancer.Limitations The PROstate Magnetic resonance Imaging Study (PROMIS) was carried out in a selected group and excluded men with a prostate volume of > 100 ml, who are less likely to have cancer. The limitations in the economic modelling arise from the limited evidence on the long-term outcomes of men with prostate cancer and on the sensitivity of MRI-targeted repeat biopsy.Conclusions Incorporating mpMRI into the diagnostic pathway as an initial test prior to prostate biopsy may (1) reduce the proportion of men having unnecessary biopsies, (2) improve the detection of CS prostate cancer and (3) increase the cost-effectiveness of the prostate cancer diagnostic and therapeutic pathway. The PROMIS data set will be used for future research; this is likely to include modelling prognostic factors for CS cancer, optimising MRI scan sequencing and biomarker or translational research analyses using the blood and urine samples collected. Better-quality evidence on long-term outcomes in prostate cancer under the various management strategies is required to better assess cost-effectiveness. The value-of-information analysis should be developed further to assess new research to commission.Trial registration Current Controlled Trials ISRCTN16082556 and NCT01292291.Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 22, No. 39. See the NIHR Journals Library website for further project information. This project was also supported and partially funded by the NIHR Biomedical Research Centre at University College London (UCL) Hospitals NHS Foundation Trust and UCL and by The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research Biomedical Research Centre and was co-ordinated by the Medical Research Council's Clinical Trials Unit at UCL (grant code MC_UU_12023/28). It was sponsored by UCL. Funding for the additional collection of blood and urine samples for translational research was provided by Prostate Cancer UK

Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions

BACKGROUND: Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk. METHODS: We analyzed data on 60 919 CHD cases and 80 243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to be associated with CHD risk. We also studied 5 loci associated with smoking behavior. Study-specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P value of <1.0x10(-3) (Bonferroni correction for 50 tests). RESULTS: We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (P= 1.3x10(-16)) in comparison with 5% in ever-smokers (P= 2.5x10(-4)), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction P value= 8.7x10(-5)). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7. CONCLUSIONS: Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.Peer reviewe

Feasibility and acceptability of telephone‐delivered cognitive‐behavioral‐based physical therapy for patients with traumatic lower extremity injury

Purpose To determine feasibility and acceptability of a telephone-based Cognitive-Behavioral-Based Physical Therapy program for patients following traumatic lower extremity injury (CBPT-Trauma). Methods Patients were screened for high psychosocial risk factors and then completed the 6-week CBPT-Trauma program. Physical function, pain, and psychosocial outcomes were assessed at baseline and 6-months follow-up. Descriptive statistics assessed change in outcomes. Results Recruitment rate was 59%. Twenty-seven patients (73%) had a high psychosocial risk profile. Twelve patients completed the program and the follow-up assessment at 6 months and found the program to be very or extremely helpful to their overall recovery. All demonstrated a clinically meaningful increase in physical function. Six patients demonstrated a clinically relevant decrease in pain intensity, pain catastrophizing, and fear of movement. Seven patients reported a clinically meaningful increase in pain self-efficacy. Discussion Findings suggest that recruitment is feasible for CBPT-Trauma program. However, engagement in the CBPT-Trauma study was low. For those that completed the program, patients were satisfied with the CBPT-Trauma program and experienced meaningful improvement in psychosocial factors and patient-reported outcomes. This open pilot study highlights the importance of targeted treatment for patients at high-risk for poor outcomes and the potential for increased access to services through telephone-delivery.This work was funded in part by the Department of Defense through the Peer Reviewed Orthopaedic Research Program of the Congressional Directed Medical Research Programs (CDMRP) under Award No. W81XWH-16-2-0060. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense