High Diagnostic Performance of Short Magnetic Resonance Imaging Protocols for Prostate Cancer Detection in Biopsy-naive Men: The Next Step in Magnetic Resonance Imaging Accessibility

Background: To make magnetic resonance imaging (MRI) more accessible to men at risk of high-grade prostate cancer (PCa), there is a need for quicker, simpler, and less costly MRI protocols. Objective: To compare the diagnostic performance of monoplanar (“fast” biparametric MRI [bp-MRI]) and triplanar noncontrast bp-MRI with that of the current contrast-enhanced multiparametric MRI (mp-MRI) in the detection of high-grade PCa in biopsy-naïve men. Design, setting, and participants: A prospective, multireader, head-to-head study included 626 biopsy-naïve men, between February 2015 and February 2018. Intervention: Men underwent prebiopsy contrast-enhanced mp-MRI. Prior to biopsy, two blinded expert readers subsequently assessed “fast” bp-MRI, bp-MRI, and mp-MRI. Thereafter, systematic transrectal ultrasound-guided biopsies (SBs) were performed. Men with suspicious mp-MRI (Prostate Imaging Reporting and Data System 3–5 lesions) also underwent MR-in-bore biopsy (MRGB). Outcome measurements and statistical analysis: Primary outcome was the diagnostic performance of each protocol for the detection of high-grade PCa. Secondary outcomes included the difference in biopsy avoidance, detection of low-grade PCa, acquisition times, decision curve analyses, inter-reader agreement, and direct costs. Results from combined MRGB and SB were used as the reference standard. High-grade PCa was defined as grade 2. Results and limitations: Sensitivity for high-grade PCa for all protocols was 95% (180/ 190; 95% confidence interval [CI]: 91–97%). Specificity was 65% (285/436; 95% CI: 61–70%) for “fast” bp-MRI and 69% (299/436; 95% CI: 64–73%) for bp-MRI and mp-MRI. With fast bp-MRI, 0.96% (6/626) more low-grade PCa was detected. Biopsy could be avoided in 47% for the fast bp-MRI and in 49% for the bp-MRI and mp-MRI protocols. Fast bp-MRI and bp-MRI can be performed in 8 and 13 min, respectively, instead of 16

Update to a randomized controlled trial of lutetium-177-PSMA in Oligo-metastatic hormone-sensitive prostate cancer:the BULLSEYE trial

Background: The BULLSEYE trial is a multicenter, open-label, randomized controlled trial to test the hypothesis if 177Lu-PSMA is an effective treatment in oligometastatic hormone-sensitive prostate cancer (oHSPC) to prolong the progression-free survival (PFS) and postpone the need for androgen deprivation therapy (ADT). The original study protocol was published in 2020. Here, we report amendments that have been made to the study protocol since the commencement of the trial. Changes in methods and materials: Two important changes were made to the original protocol: (1) the study will now use 177Lu-PSMA-617 instead of 177Lu-PSMA-I&T and (2) responding patients with residual disease on 18F-PSMA PET after the first two cycles are eligible to receive additional two cycles of 7.4 GBq 177Lu-PSMA in weeks 12 and 18, summing up to a maximum of 4 cycles if indicated. Therefore, patients receiving 177Lu-PSMA-617 will also receive an interim 18F-PSMA PET scan in week 4 after cycle 2. The title of this study was modified to; “Lutetium-177-PSMA in Oligo-metastatic Hormone Sensitive Prostate Cancer” and is now partly supported by Advanced Accelerator Applications, a Novartis Company. Conclusions: We present an update of the original study protocol prior to the completion of the study. Treatment arm patients that were included and received 177Lu-PSMA-I&T under the previous protocol will be replaced. Trial registration: ClinicalTrials.gov NCT04443062. First posted: June 23, 2020

Lutetium-177-PSMA-I&T as metastases directed therapy in oligometastatic hormone sensitive prostate cancer, a randomized controlled trial

Background: In recent years, there is increasing evidence showing a beneficial outcome (e.g. progression free survival; PFS) after metastases-directed therapy (MDT) with external beam radiotherapy (EBRT) or targeted surgery for oligometastatic hormone sensitive prostate cancer (oHSPC). However, many patients do not qualify for these treatments due to prior interventions or tumor location. Such oligometastatic patients could benefit from radioligand therapy (RLT) with 177Lu-PSMA; a novel tumor targeting therapy for end-stage metastatic castration-resistant prostate cancer (mCRPC). Especially because RLT could be more effective in low volume disease, such as the oligometastatic status, due to high uptake of radioligands in smaller lesions. To test the hypothesis that 177Lu-PSMA is an effective treatment in oHSPC to prolong PFS and postpone the need for androgen deprivation therapy (ADT), we initiated a multicenter randomized clinical trial. This is globally, the first prospective study using 177Lu-PSMA-I&T in a randomized multicenter setting. Methods & design: This study compares 177Lu-PSMA-I&T MDT to the current standard of care (SOC); deferred ADT. Fifty-eight patients with oHSPC (≤5 metastases on PSMA PET) and high PSMA uptake (SUVmax > 15, partial volume corrected) on 18F-PSMA PET after prior surgery and/or EBRT and a PSA doubling time of < 6 months, will be randomized in a 1:1 ratio. The patients randomized to the interventional arm will be eligible for two cycles of 7.4GBq 177Lu-PSMA-I&T at a 6-week interval. After both cycles, patients are monitored every 3 weeks (including adverse events, QoL- and xerostomia questionnaires and laboratory testing) at the outpatient clinic. Twenty-four weeks after cycle two an end of study evaluation is planned together with another 18F-PSMA PET and (whole body) MRI. Patients in the SOC arm are eligible to receive 177Lu-PSMA-I&T after meeting the primary study objective, which is the fraction of patients who show disease progression during the study follow up. A second primary objective is the time to disease progression. Disease progression is defined as a 100% increase in PSA from baseline or clinical progression. Discussion: This is the first prospective randomized clinical study assessing the therapeutic efficacy and toxicity of 177Lu-PSMA-I&T for patients with oHSPC. Trial registration: Clinicaltrials.gov identifier: NCT04443062

Metabolic engineering of Clostridium autoethanogenum for ethyl acetate production from CO

Abstract Background Ethyl acetate is a bulk chemical traditionally produced via energy intensive chemical esterification. Microbial production of this compound offers promise as a more sustainable alternative process. So far, efforts have focused on using sugar-based feedstocks for microbial ester production, but extension to one-carbon substrates, such as CO and CO2/H2, is desirable. Acetogens present a promising microbial platform for the production of ethyl esters from these one-carbon substrates. Results We engineered the acetogen C. autoethanogenum to produce ethyl acetate from CO by heterologous expression of an alcohol acetyltransferase (AAT), which catalyzes the formation of ethyl acetate from acetyl-CoA and ethanol. Two AATs, Eat1 from Kluyveromyces marxianus and Atf1 from Saccharomyces cerevisiae, were expressed in C. autoethanogenum. Strains expressing Atf1 produced up to 0.2 mM ethyl acetate. Ethyl acetate production was barely detectable (&lt; 0.01 mM) for strains expressing Eat1. Supplementation of ethanol was investigated as potential boost for ethyl acetate production but resulted only in a 1.5-fold increase (0.3 mM ethyl acetate). Besides ethyl acetate, C. autoethanogenum expressing Atf1 could produce 4.5 mM of butyl acetate when 20 mM butanol was supplemented to the growth medium. Conclusions This work offers for the first time a proof-of-principle that autotrophic short chain ester production from C1-carbon feedstocks is possible and offers leads on how this approach can be optimized in the future

The TRacking Adolescents' Individual Lives Survey (TRAILS):Design, Current Status, and Selected Findings

Objectives: The objectives of this study were as follows: to present a concise overview of the sample, outcomes, determinants, non-response and attrition of the ongoing TRacking Adolescents' Individual Lives Survey (TRAILS), which started in 2001; to summarize a selection of recent findings on continuity, discontinuity, risk, and protective factors of mental health problems; and to document the development of psychopathology during adolescence, focusing on whether the increase of problem behavior often seen in adolescence is a general phenomenon or more prevalent in vulnerable teens, thereby giving rise to diverging developmental pathways. Method: The first and second objectives were achieved using descriptive statistics and selective review of previous TRAILS publications; and the third objective by analyzing longitudinal data on internalizing and externalizing problems using Linear Mixed Models (LMM). Results: The LMM analyses supported the notion of diverging pathways for rule-breaking behaviors but not for anxiety, depression, or aggression. Overall, rule-breaking (in both genders) and withdrawn/depressed behavior (in girls) increased, whereas aggression and anxious/depressed behavior decreased during adolescence. Conclusions: TRAILS has produced a wealth of data and has contributed substantially to our understanding of mental health problems and social development during adolescence. Future waves will expand this database into adulthood. The typical development of problem behaviors in adolescence differs considerably across both problem dimensions and gender. Developmental pathways during adolescence suggest accumulation of risk (i.e., diverging pathways) for rule-breaking behavior. However, those of anxiety, depression and aggression slightly converge, suggesting the influence of counter-forces and changes in risk unrelated to initial problem levels and underlying vulnerability. J. Am. Acad. Child Adolesc. Psychiatry, 2012; 51(10):1020-1036

Value of PCA3 to Predict Biopsy Outcome and Its Potential Role in Selecting Patients for Multiparametric MRI

Contains fulltext : 117934.pdf (publisher's version ) (Open Access)PCA3 (prostate cancer gene 3) and multiparametric 3 tesla MRI are new promising diagnostic tools in the detection of PCa. Our aim was to study the clinical value of the Progensa PCA3-test: its predictive value for biopsy outcome, Gleason score and MRI outcome. We evaluated, retrospectively, 591 patients who underwent a Progensa PCA3-test at the Radboud University Nijmegen Medical Centre between May 2006 and December 2009. Prostate biopsies were performed in 290 patients; a multiparametric 3 tesla MRI of the prostate was performed in 163/591 patients. The PCA3-score was correlated to biopsy results and MRI outcome. The results show that PCA3 was highly predictive for biopsy outcome (p < 0.001); there was no correlation with the Gleason score upon biopsy (p = 0.194). The PCA3-score of patients with a suspicious region for PCa on MRI was significantly higher (p < 0.001) than in patients with no suspicious region on MRI (52 vs. 21). In conclusion, PCA3 is a valuable diagnostic biomarker for PCa; it did not correlate with the Gleason score. Furthermore, multiparametric MRI outcome was significantly correlated with the PCA3-score. Thus, PCA3 could be used to select patients that require MRI. However, in patients with a negative PCA3 and high clinical suspicion of PCa, a multiparametric MRI should also be done

Clinical implementation of pre-biopsy magnetic resonance imaging pathways for the diagnosis of prostate cancer

Objective: To assess the outcomes of pre-biopsy magnetic resonance imaging (MRI) pathways, as a tool in biopsy-naïve men with suspicion of prostate cancer, in routine clinical practice. Secondary outcomes included a comparison of transrectal MRI-directed biopsy (TR-MRDB) and transperineal (TP)-MRDB in men with suspicious MRI. Patients and Methods: We retrospectively assessed a two-centre cohort of consecutive biopsy-naïve men with suspicion of prostate cancer who underwent a Prostate Imaging-Reporting and Data System version 2 (PI-RADS v2) compliant pre-biopsy MRI in a single, high-volume centre between 2015 and 2019 (Centre 1). Men with suspicious MRI scans underwent TR-MRDB in Centre 1 and TP-MRDB with additional random biopsies (RB) in Centre 2. The MRI and histopathology were assessed in the same institution (Centre 1). Outcomes included: (i) overall detection rates of Grade Group (GG) 1, GG ≥2, and GG ≥3 cancer in men with suspicious MRI; (ii) Biopsy-avoidance due to non-suspicious MRI; and (iii) Cancer detection rates and biopsy-related complications between TR- and TP-MRDB. To reduce confounding bias for MRDB comparisons, inverse probability weighting (IPW) was performed for age, digital rectal examination, prostate-specific antigen (PSA), prostate volume, PSA density, and PI-RADS category. Results: Of the 2597 men included, the overall GG 1, GG ≥2, and GG ≥3 prevalence was 8% (210/2597), 27% (697/2597), and 15% (396/2597), respectively. Biopsy was avoided in 57% (1488/2597) of men. After IPW, the GG 1, GG ≥2 and GG ≥3 detection rates after TR- and TP-MRDB were comparable at 24%, 57%, and 32%; and 18%, 64%, and 38%, respectively; with mean differences of −5.7% (95% confidence interval [CI] −13% to 1.4%), 6.1% (95% CI −2.1% to 14%), and 5.7% (95% CI −1.7% to 13%). Complications were similar in TR-MRDB (0.50%) and TP-MRDB with RB (0.62%; mean difference 0.11%, 95% CI −0.87% to 1.1%). Conclusion: This high-volume, two-centre study shows pre-biopsy MRI as a decision tool is implementable in daily clinical practice. Compared to recent trials, a substantially higher biopsy avoidance rate was achieved without compromising GG ≥2/GG ≥3 detection and coinciding with lower over detection rates of GG 1 cancer. Prostate cancer detection and complication rates were comparable for TR- and TP-MRDB

Additional file 1 of Metabolic engineering of Clostridium autoethanogenum for ethyl acetate production from CO

Additional file 1: Table S1. List of primers used in this study. Table S2. Sequences of genes expressed in this study. Figure S1. Image of Sanger sequencing results showed the nature of the in-frame deletion in the pta gene (CAETHG_3358). Figure S2. Image of Sanger sequencing results showed the nature of the in-frame deletion in the Ald subunit of the adhE1 gene (CAETHG_3747). Figure S3. Change in CO headspace pressure for C. autoethanogenum strains carrying plasmids for AAT expression on CO as main carbon source. Figure S4. Screening of ethyl acetate production by C. autoethanogenum strains carrying plasmids for AAT expression on 40 mM fructose. Figure S4. Investigating growth of C. autoethanogenum on CO and ethyl acetate. Figure S5. Investigating ethyl acetate degradation by C. autoethanogenum grown on CO. Figure S6. Eat1 in vivo alcoholysis assay for C. autoethanogenum and E. coli. Figure S7. Investigating the effects of ethanol supplementation on growth of C. autoethanogenum [PThl-Atf1] grown on CO. Figure S8. Investigating the effects of ethanol supplementation on ethyl acetate production by C. autoethanogenum [PThl-Atf1] grown on C