In assessing species susceptibility for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and in the search for an appropriate animal model, multiple research groups around the world ...inoculated a broad range of animal species using various SARS-CoV-2 strains, doses and administration routes. Although in silico analyses based on receptor binding and diverse in vitro cell cultures were valuable, exact prediction of species susceptibility based on these tools proved challenging. Here, we assessed whether precision-cut lung slices (PCLS) could facilitate the selection of animal models, thereby reducing animal experimentation. Pig, hamster and cat PCLS were incubated with SARS-CoV-2 and virus replication was followed over time. Virus replicated efficiently in PCLS from hamsters and cats, while no evidence of replication was obtained for pig PCLS. These data corroborate the findings of many research groups that have investigated the susceptibility of hamsters, pigs and cats towards infection with SARS-CoV-2. Our findings suggest that PCLS can be used as convenient tool for the screening of different animal species for sensitivity to newly emerged viruses. To validate our results obtained in PCLS, we employed the hamster model. Hamsters were inoculated with SARS-CoV-2 via the intranasal route. Susceptibility to infection was evaluated by body weight loss, viral loads in oropharyngeal swabs and respiratory tissues and lung pathology. The broadly used hamster model was further refined by including activity tracking of the hamsters by an activity wheel as a very robust and sensitive parameter for clinical health. In addition, to facilitate the quantification of pathology in the lungs, we devised a semi-quantitative scoring system for evaluating the degree of histological changes in the lungs. The inclusion of these additional parameters refined and enriched the hamster model, allowing for the generation of more data from a single experiment.
Objective
To investigate whether combination treatment of prostate‐specific membrane antigen (PSMA)‐based radioguided surgery (RGS) with short‐term androgen deprivation therapy (ADT) improves ...oncological outcomes in men with oligorecurrent prostate cancer (PCa) as compared to treatment with short‐term ADT only.
Methods
The TRACE‐II study is an investigator‐initiated, prospective, randomised controlled clinical trial. Patients (aged >18 years) with hormone‐sensitive recurrent PCa after radical prostatectomy or radiotherapy (brachytherapy or external beam radiotherapy), with involvement of ≤2 lymph nodes or local oligorecurrent disease within the pelvis as determined by PSMA positron emission tomography (PET)/computed tomography (CT) are randomly assigned in a 1:1 ratio between 6‐month ADT (Arm A) or 6‐month ADT plus RGS (Arm B). The primary objective is to determine clinical progression‐free survival (CPFS) at 24 months. After PSMA‐RGS, CPFS is defined as the time between the start of treatment and the appearance of a re‐recurrence (any N1 or M1) as suggested by PSMA‐PET/CT or symptoms related to progressive PCa, or death from any cause. The secondary objectives include metastasis‐free survival at 2, 5 and 10 years, biochemical progression‐free survival at 2 years, and patient‐reported quality of life at 2, 5 and 10 years. A total of 60 patients, 30 per arm, will be included. The trial is powered (80%) to detect at least a 30% absolute difference in CPFS between the two study arms in the period 2 years after randomisation. We expect to enrol the required participants in 3 years. The study has an expected duration of 5 years in total.
Conclusions
Combining RGS with short‐term ADT might be oncologically beneficial for patients with oligorecurrent PCa. In this first randomised controlled trial, we are investigating the potential oncological benefits of this combined treatment, while also focusing on maintaining quality of life.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Repeat liver resection is often the best treatment option for patients with recurrent colorectal liver metastases (CRLM). Repeat resections can be complex, however, owing to adhesions and ...altered liver anatomy. It remains uncertain whether the advantages of a laparoscopic approach are upheld in this setting. The aim of this retrospective, propensity score‐matched study was to compare the short‐term outcome of laparoscopic (LRLR) and open (ORLR) repeat liver resection.
Methods
A multicentre retrospective propensity score‐matched study was performed including all patients who underwent LRLRs and ORLRs for CRLM performed in nine high‐volume centres from seven European countries between 2000 and 2016. Patients were matched based on propensity scores in a 1 : 1 ratio. Propensity scores were calculated based on 12 preoperative variables, including the approach to, and extent of, the previous liver resection. Operative outcomes were compared using paired tests.
Results
Overall, 425 repeat liver resections were included. Of 271 LRLRs, 105 were matched with an ORLR. Baseline characteristics were comparable after matching. LRLR was associated with a shorter duration of operation (median 200 (i.q.r. 123–273) versus 256 (199–320) min; P < 0·001), less intraoperative blood loss (200 (50–450) versus 300 (100–600) ml; P = 0·077) and a shorter postoperative hospital stay (5 (3–8) versus 6 (5–8) days; P = 0·028). Postoperative morbidity and mortality rates were similar after LRLR and ORLR.
Conclusion
LRLR for CRLM is feasible in selected patients and may offer advantages over an open approach.
Repeat liver resection is a challenging procedure and the role of laparoscopy remains unclear. This retrospective propensity score‐matched study aimed to compare the short‐term outcomes of laparoscopic versus open repeat liver resection.
Feasible in selected patients
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Despite multiple studies evaluating the effectiveness of Robot-Assisted Radical Prostatectomy (RARP), there is no definitive conclusion about the added value of RARP. A retrospective cluster study ...was conducted to evaluate long-term sexual and urinary functioning after RARP and Laparoscopic Radical Prostatectomy (LRP) based on real-world data from 12 Dutch hospitals.
Data was collected from patients who underwent surgery between 2010 and 2012. A mixed effect model was used to evaluate differences between groups on urinary and sexual functioning (EPIC-26). Additionally, a regression analysis was conducted to evaluate the relationship between these functional outcomes and, among others, hospital volume.
1370 (65.1%) patients participated, 907 underwent RARP and 463 LRP, with a median follow-up time of 7.08 years (SD = 0.98). The RARP group showed a statistically and clinically significant better urinary functioning compared to the LRP group (p = 0.002). RARP showed also a shorter procedure time (p=<0.001), reduced blood loss (p=<0.001), and a higher chance of neurovascular bundle preservation (39.8% vs 29.1%; p=<0.01).
RARP resulted in better long-term urinary function compared to LRP. Based on the results from this study, guidelines concerning the preferred surgery type and the position on reimbursement may change, especially when RARP proves to be cost-effective.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The DROP-IN gamma probe facilitates minimally invasive, robot-assisted prostate-specific membrane antigen–targeted radioguided surgery in patients with recurrent prostate cancer. This procedure holds ...promise for improving the intraoperative identification and removal of prostate cancer lesions.
It has been proven that intraoperative prostate-specific membrane antigen (PSMA)-targeted radioguidance is valuable for the detection of prostate cancer (PCa) lesions during open surgery. Rapid extension of robot-assisted, minimally invasive surgery has increased the need to make PSMA-radioguided surgery (RGS) robot-compliant.
To evaluate whether the miniaturized DROP-IN gamma probe facilitates translation of PSMA-RGS to robotic surgery in men with recurrent PCa.
This prospective feasibility study included 20 patients with up to three pelvic PCa recurrences (nodal or local) on staging PSMA positron emission tomography (PET) after previous curative-intent therapy.
Robot-assisted PSMA-RGS using the DROP-IN gamma probe was carried out 19–23 h after intravenous injection of 99mtechnetium PSMA-Investigation & Surgery (99mTc-PSMA-I&S).
The primary endpoint was the feasibility of robot-assisted PSMA-RGS. Secondary endpoints were a comparison of the radioactive status (positive or negative) of resected specimens and final histopathology results, prostate-specific antigen (PSA) response following PSMA-RGS, and complications according to the Clavien-Dindo classification.
Using the DROP-IN probe, 19/21 (90%) PSMA-avid lesions could be resected robotically. On a per-lesion basis, the sensitivity and specificity of robot-assisted PSMA-RGS was 86% and 100%, respectively. A prostate-specific antigen (PSA) reduction of >50% and a complete biochemical response (PSA <0.2 ng/ml) were seen in 12/18 (67%) and 4/18 (22%) patients, respectively. During follow-up of up to 15 mo, 4/18 patients (22%) remained free of biochemical recurrence (PSA ≤0.2 ng/ml). One patient suffered from a Clavien-Dindo grade >III complication.
The DROP-IN probe helps in realizing robot-assisted PSMA-RGS. The procedure is technically feasible for intraoperative detection of nodal or local PSMA-avid PCa recurrences.
A device called the DROP-IN probe facilitates minimally invasive, robot-assisted surgery guided by radioactive tracers in patients with recurrent prostate cancer. This procedure holds promise for improving the intraoperative identification and removal of prostate cancer lesions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
An association study between SNP markers and feather condition score on the back, rump and belly of laying hens was performed. Feather condition score is a measure of feather damage, which has been ...shown to be closely related to feather pecking behaviour in hens housed in groups. A population of 662 hens was genotyped for 1536 SNPs of which 1022 could be used for the association study. The analysis was conducted across 9 different lines of White Leghorn and Rhode Island Red origin. Across lines linkage disequilibrium is conserved at shorter distances than within lines; therefore, SNPs significantly associated with feather condition score across lines are expected to be closer to the functional mutations. The SNPs that had a significant across-line effect but did not show significant SNP-by-line interaction were identified, to test that the association was consistent across lines. Both the direct effect of the individual’s genotype on its plumage condition, and the associative effect of the genotype of the cage mates on the individual’s plumage condition were analysed. The direct genetic effect can be considered as the susceptibility to be pecked at, whereas the associative genetic effect can be interpreted as the propensity to perform feather pecking. Finally, 11 significant associations between SNPs and behavioural traits were detected in the direct model, and 81 in the associative model. A role of the gene for the serotonin receptor 2C (HTR2C) on chromosome 4 was found. This supports existing evidence of a prominent involvement of the serotonergic system in the modulation of this behavioural disorder in laying hens. The genes for IL9, IL4, CCL4 and NFKB were found to be associated to plumage condition, revealing relationships between the immune system and behaviour.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Two-dimensional and three-dimensional Rayleigh–Bénard convection is compared using results from direct numerical simulations and previous experiments. The phase diagrams for both cases are reviewed. ...The differences and similarities between two- and three-dimensional convection are studied using
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•Pharmacological repair of CFTR function beyond F508del/F508del-VX809/VX770 in intestinal organoids with homozygous PTC mutations.•The read-through agent ELXds-02, the NMD-inhibitor SMG1i and the ...CFTR modulators therapy VX-661/VX-445/VX-770 were required for maximal efficacy.•W1282X-CFTR function is partially rescued with the NMD-inhibitor SMG1i combined with the CFTR-modulators VX-661/VX-445/VX770.
Background: Pharmacotherapies for people with cystic fibrosis (pwCF) who have premature termination codons (PTCs) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are under development. Thus far, clinical studies focused on compounds that induce translational readthrough (RT) at the mRNA PTC location. Recent studies using primary airway cells showed that PTC functional restoration can be achieved through combining compounds with multiple mode-of-actions. Here, we assessed induction of CFTR function in PTC-containing intestinal organoids using compounds targeting RT, nonsense mRNA mediated decay (NMD) and CFTR protein modulation. Methods: Rescue of PTC CFTR protein was assessed by forskolin-induced swelling of 12 intestinal organoid cultures carrying distinct PTC mutations. Effects of compounds on mRNA CFTR level was assessed by RT-qPCRs. Results: Whilst response varied between donors, significant rescue of CFTR function was achieved for most donors with the quintuple combination of a commercially available pharmacological equivalent of the RT compound (ELX-02-disulfate or ELX-02ds), NMD inhibitor SMG1i, correctors VX-445 and VX-661 and potentiator VX-770. The quintuple combination of pharmacotherapies reached swelling quantities higher than the mean swelling of three VX-809/VX-770-rescued F508del/F508del organoid cultures, indicating level of rescue is of clinical relevance as VX-770/VX-809-mediated F508del/F508del rescue in organoids correlate with substantial improvement of clinical outcome. Conclusions: Whilst variation in efficacy was observed between genotypes as well as within genotypes, the data suggests that strong pharmacological rescue of PTC requires a combination of drugs that target RT, NMD and protein function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This study aimed to evaluate the histopathological concordance rates between prostate biopsies and radical prostatectomy specimens according to the applied biopsy approach (transrectal or ...transperineal).
We studied patients who had been newly diagnosed with clinically significant prostate cancer and who underwent a radical prostatectomy between 2018 and 2022. Patients were included if they underwent a prebiopsy magnetic resonance imaging and if they had not been previously treated for prostate cancer. Histopathological grading on prostate biopsies was compared with that on radical prostatectomy specimens. Univariable and multivariable logistic regression analyses were performed to assess the effect of the applied biopsy approach on histopathological concordance. Additional analyses were performed to assess the effect of the applied biopsy approach on American Urological Association risk group migration, defined as any change in risk group after radical prostatectomy.
In total, 1058 men were studied, of whom 49.3% (522/1058) and 50.7% (536/1058) underwent transrectal and transperineal prostate biopsies, respectively. Histopathological disconcordance was observed in 37.8% (400/1058) of men while American Urological Association risk group migration was observed in 30.2% (320/1058) of men. A transperineal biopsy approach was found to be independently associated with higher histopathological concordance rates (OR 1.33 95% CI 1.01-1.75, p = 0.04) and less American Urological Association risk group migration (OR 0.70 95% CI 0.52-0.93, p = 0.01).
The use of a transperineal biopsy approach improved histopathological concordance rates compared to the use of a transrectal biopsy approach. A transperineal biopsy approach may provide more accurate risk stratification for clinical decision-making. Despite recent improvements, histopathologic concordance remains suboptimal and should be considered before initiating management.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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