CARD 2023: expanded curation, support for machine learning, and resistome prediction at the Comprehensive Antibiotic Resistance Database.

The Comprehensive Antibiotic Resistance Database (CARD; card.mcmaster.ca) combines the Antibiotic Resistance Ontology (ARO) with curated AMR gene (ARG) sequences and resistance-conferring mutations to provide an informatics framework for annotation and interpretation of resistomes. As of version 3.2.4, CARD encompasses 6627 ontology terms, 5010 reference sequences, 1933 mutations, 3004 publications, and 5057 AMR detection models that can be used by the accompanying Resistance Gene Identifier (RGI) software to annotate genomic or metagenomic sequences. Focused curation enhancements since 2020 include expanded ß-lactamase curation, incorporation of likelihood-based AMR mutations for Mycobacterium tuberculosis, addition of disinfectants and antiseptics plus their associated ARGs, and systematic curation of resistance-modifying agents. This expanded curation includes 180 new AMR gene families, 15 new drug classes, 1 new resistance mechanism, and two new ontological relationships: evolutionary_variant_of and is_small_molecule_inhibitor. In silico prediction of resistomes and prevalence statistics of ARGs has been expanded to 377 pathogens, 21,079 chromosomes, 2,662 genomic islands, 41,828 plasmids and 155,606 whole-genome shotgun assemblies, resulting in collation of 322,710 unique ARG allele sequences. New features include the CARD:Live collection of community submitted isolate resistome data and the introduction of standardized 15 character CARD Short Names for ARGs to support machine learning efforts.

Imaging features of the evolving patterns of metastatic prostate cancer.

The pattern of metastases in prostate cancer (PC) is evolving. Increased use of imaging, newer imaging techniques with higher sensitivity for disease detection and patients receiving multiple lines of novel therapies with increased life expectancy are likely to be contributory. Awareness of metastatic disease patterns improves early diagnosis, accurate staging, and initiation of appropriate therapy, and can inform prognostic information and anticipate potential disease complications. The aim of this review is to document the spectrum of metastases in PC including emerging and unusual patterns, and to highlight the role of novel imaging including prostate-specific membrane antigen (PSMA)-positron-emission tomography (PET) and whole-body magnetic resonance imaging (WB-MRI) to improve diagnostic and response assessment accuracy.

Slow gait speed is associated with worse postoperative outcomes in cardiac surgery: A systematic review and meta-analysis.

BACKGROUND: Frailty is associated with poorer outcomes in cardiac surgery, but the heterogeneity in frailty assessment tools makes it difficult to ascertain its true impact in cardiac surgery. Slow gait speed is a simple, validated, and reliable marker of frailty. We performed a systematic review and meta-analysis to examine the effect of slow gait speed on postoperative cardiac surgical patients. METHODS: PubMED, MEDLINE, and EMBASE databases were searched from January 2000 to August 2021 for studies comparing slow gait speed and "normal" gait speed. Primary outcome was in-hospital mortality. Secondary outcomes were composite mortality and major morbidity, AKI, stroke, deep sternal wound infection, prolonged ventilation, discharge to a healthcare facility, and ICU length of stay. RESULTS: There were seven eligible studies with 36,697 patients. Slow gait speed was associated with increased likelihood of in-hospital mortality (risk ratio [RR]: 2.32; 95% confidence interval [CI]: 1.87-2.87). Additionally, they were more likely to suffer from composite mortality and major morbidity (RR: 1.52; 95% CI: 1.38-1.66), AKI (RR: 2.81; 95% CI: 1.44-5.49), deep sternal wound infection (RR: 1.77; 95% CI: 1.59-1.98), prolonged ventilation >24 h (RR: 1.97; 95% CI: 1.48-2.63), reoperation (RR: 1.38; 95% CI: 1.05-1.82), institutional discharge (RR: 2.08; 95% CI: 1.61-2.69), and longer ICU length of stay (MD: 21.69; 95% CI: 17.32-26.05). CONCLUSION: Slow gait speed is associated with poorer outcomes in cardiac surgery. Frail patients are twofold more likely to die during hospital admission than nonfrail counterparts and are at an increased risk of developing various perioperative complications.

Anteroposterior Versus Anterolateral Electrode Position for Direct Current Cardioversion of Atrial Fibrillation: A Meta-Analysis of Randomised Controlled Trials.

OBJECTIVE: Data regarding optimal electrode positioning for direct current cardioversion (DCCV) of atrial fibrillation (AF) has been inconsistent. This meta-analysis was conducted to systematically compare the efficacy of anteroposterior (AP) versus anterolateral (AL) electrode placement for DCCV of AF. METHODS: Electronic databases were searched for randomised controlled trials (RCTs) comparing AP versus AL electrode positioning in patients undergoing DCCV for AF. Primary endpoints were first-shock success and overall DCCV success. Subgroup analysis was performed by defibrillator waveform (monophasic versus biphasic). Meta-regression analyses were performed to assess for significant moderators. RESULTS: Twelve (12) RCTs, including a total of 2,046 patients, met inclusion criteria. Neither first-shock success (relative risk [RR] 0.92; 95% CI 0.79-1.07; p=0.28) nor overall DCCV success (RR 1.01; 95% CI 0.96-1.05; p=0.78) were significantly different with AP versus AL electrode positioning. The mean number of shocks (mean difference [MD] 0.3, 95% CI -0.4 to 0.9), energy level of first successful shock (MD 3 joules; 95% CI -20 to 27) and cumulative energy delivered (MD 39 joules; 95% CI -168 to 246) were similar in AP versus AL arms. In subgroup analysis of six RCTs using biphasic defibrillators, improvement in first-shock success (RR 0.85; 95% CI 0.69-1.03; p=0.10) and overall DCCV success (RR 0.97; 95% CI 0.93-1.01; p=0.09) with AL electrode positioning did not reach statistical significance. Meta-regression analyses identified older age, higher body mass index, and longer AF duration as significant moderators favouring AL electrode positioning. CONCLUSIONS: Pooled analysis of randomised data overall does not show a significant difference in efficacy between AP versus AL electrode positioning. Meta-regression and subgroup analyses suggest that, in contemporary practice with use of biphasic defibrillators, there may be a subset of AF patients in whom AL electrode positioning improves efficacy of DCCV.

Catheter Ablation for Ventricular Tachycardia in Ischaemic Versus Non-Ischaemic Cardiomyopathy: A Systematic Review and Meta-Analysis.

BACKGROUND: There are differences in substrate and ablation approaches for ventricular tachycardia (VT) in ischaemic (ICM) and non-ischaemic cardiomyopathy (NICM). OBJECTIVE: To perform a systematic review and meta-analysis comparing clinical and procedural characteristics/outcomes of VT ablation in ICM versus NICM. METHODS: Electronic databases were searched for comparative studies reporting outcomes of VT ablation in patients with ICM and NICM. Primary outcomes were acute procedural success, VT recurrence and long-term mortality. Meta-analyses were performed using random-effects modelling. RESULTS: Thirty-one (31) studies (7,473 patients; 4,418 ICM and 3,055 NICM) were included. Patients with ICM were significantly older (67.0 vs 55.3 yrs), more commonly male (89% vs 79%), had lower left ventricular ejection fraction (29% vs 38%) were less likely to undergo epicardial access (11% vs 36%) and were more likely to require haemodynamic support during ablation (relative risk [RR] 1.30; 95% CI 1.01-1.69). Acute procedural success (i.e. non-inducibility of VT) was higher in the ICM cohort (RR 1.10, 95% CI 1.05-1.15). Recurrence of VT at follow-up was significantly lower in the ICM cohort (RR 0.77; 95% CI 0.70-0.84). Peri-procedural mortality, incidence of procedural complications and long-term mortality were not significantly different between the cohorts. CONCLUSIONS: NICM and ICM patients undergoing VT ablation are fundamentally different in their clinical characteristics, ablation approaches, acute procedural outcomes and likelihood of VA recurrence. VT ablation in NICM has a lower likelihood of procedural success with increased risk of VA recurrence, consistent with known challenging arrhythmia substrate.

Parallel implementation of L + S signal recovery in dynamic MRI.

Dynamic MRI is useful to diagnose different diseases, e.g. cardiac ailments, by monitoring the structure and function of the heart and blood flow through the valves. Faster data acquisition is highly desirable in dynamic MRI, but this may lead to aliasing artifacts due to under-sampling. Advanced image reconstruction algorithms are required to obtain aliasing-free MR images from the acquired under-sampled data. One major limitation of using the advanced reconstruction algorithms is their computationally expensive and time-consuming nature, which make them infeasible for clinical use, especially for applications like cardiac MRI. L + S decomposition model is an approach provided in literature which separates the sparse and low-rank information in dynamic MRI. However, L + S decomposition model is a computationally complex process demanding significant computation time. In this paper, a parallel framework is proposed to accelerate the image reconstruction process of L + S decomposition model using GPU. Experiments are performed on cardiac perfusion dataset ([Formula: see text]) and cardiac cine dataset ([Formula: see text]) using NVIDIA's GeForce GTX780 GPU and Core-i7 CPU. The results show that the proposed method provides up to 18 × speed-up including the memory transfer time (i.e. data transfer between the CPU and GPU) and ~ 46 × speed-up without memory transfer for the cardiac perfusion dataset in our experiments. This level of improvement in the reconstruction time will increase the usefulness of L + S reconstruction by making it feasible for clinical applications.

Respiratory motion-corrected, compressively sampled dynamic MR image reconstruction by exploiting multiple sparsity constraints and phase correlation-based data binning.

INTRODUCTION: Cardiac magnetic resonance imaging (cMRI) is a standard method that is clinically used to evaluate the function of the human heart. Respiratory motion during a cMRI scan causes blurring artefacts in the reconstructed images. In conventional MRI, breath holding is used to avoid respiratory motion artefacts, which may be difficult for cardiac patients. MATERIALS AND METHODS: This paper proposes a method in which phase correlation-based binning, followed by image registration-based sparsity along with spatio-temporal sparsity, is incorporated into the standard low rank + sparse (L+S) reconstruction for free-breathing cardiac cine MRI. The proposed method is validated on clinical data and simulated free-breathing cardiac cine data for different acceleration factors (AFs). The reconstructed images are analysed using visual assessment, artefact power (AP) and root-mean-square error (RMSE). The results of the proposed method are compared with the contemporary motion-corrected compressed sensing (MC-CS) method given in the literature. RESULTS: Our results show that the proposed method successfully reconstructs the motion-corrected images from respiratory motion-corrupted, compressively sampled cardiac cine MR data, e.g., there is 26% and 24% improvement in terms of AP and RMSE values, respectively, at AF = 4 and 20% and 16.04% improvement in terms of AP and RMSE values, respectively, at AF = 8 in the reconstruction results from the proposed method for the cardiac phantom cine data. CONCLUSION: The proposed method achieves significant improvement in the AP and RMSE values at different AFs for both the phantom and in vivo data.

Updated systematic review and meta-analysis of the impact of contact force sensing on the safety and efficacy of atrial fibrillation ablation: discrepancy between observational studies and randomized control trial data.

AIMS: Despite widespread adoption of contact force (CF) sensing technology in atrial fibrillation (AF) ablation, randomized data suggests lack of improvement in clinical outcomes. We aimed to assess the safety and efficacy of CF-guided vs. non CF-guided AF ablation. METHODS AND RESULTS: Electronic databases were searched for randomized controlled trials (RCTs) and controlled observational studies (OS) comparing outcomes of AF ablation performed with vs. without CF guidance. The primary efficacy endpoint was freedom from AF at follow-up. The primary safety endpoint was major peri-procedural complications. Secondary endpoints included procedural, fluoroscopy, and ablation duration. Subgroup analyses were performed by AF type and study design. Nine RCTs (n = 903) and 26 OS (n = 8919) were included. Overall, CF guidance was associated with improved freedom from AF [relative risk (RR) 1.10; 95% confidence interval (CI) 1.02-1.18], and reduced total procedure duration [mean difference (MD) 15.33 min; 95% CI 6.98-23.68], ablation duration (MD 3.07 min; 95% CI 0.29-5.84), and fluoroscopy duration (MD 5.72 min; 95% CI 2.51-8.92). When restricted to RCTs however, CF guidance neither improved freedom from AF (RR 1.03; 95% CI 0.95-1.11), independent of AF type, nor did it reduce procedural, fluoroscopy, or ablation duration. Contact force guidance did not reduce the incidence of major peri-procedural complications (RR 0.89; 95% CI 0.64-1.24). CONCLUSION: Meta-analysis of randomized data demonstrated that CF guidance does not improve the safety or efficacy of AF ablation, despite initial observational data showing dramatic improvement. Rigorous evaluation in randomized trials is needed before widespread adoption of new technologies.

Mechanical Circulatory Support During Catheter Ablation of Ventricular Tachycardia: Indications and Options.

Mapping of scar-related ventricular tachycardia (VT) in structural heart disease is fundamentally driven by identifying the critical isthmus of conduction that supports re-entry in and around myocardial scar. Mapping can be performed using activation and entrainment techniques during VT, or by substrate mapping performed in stable sinus or paced rhythm. Activation and entrainment mapping requires the patient to be in continuous VT, which may not be haemodynamically tolerated, or, if tolerated, may lead to adverse sequelae related to impaired end organ perfusion. Mechanical circulatory support (MCS) devices may facilitate haemodynamic stability and preserve end organ perfusion during sustained VT to permit mapping for long periods. Available options for haemodynamic support include an intra-aortic balloon pump (IABP), TandemHeart left atrial to femoral artery bypass system (CardiacAssist Inc., Pittsburgh, PA, USA), Impella left ventricle (LV) to aorta flow-assist system (Abiomed, Danvers, MA, USA), and extracorporeal membrane oxygenation (ECMO); the bypass and assist devices provide far better augmentation of cardiac output than IABP. MCS has potential key advantages including maintenance of vital organ perfusion, reduction of intra-cardiac filling pressures, reduction of LV volumes, wall stress, and myocardial consumption of oxygen, and improvement of coronary perfusion during prolonged periods of VT induction and/or mapping. Observational studies show MCS allows for longer duration of mapping, and increased likelihood of VT termination, without an increased risk of peri-procedural mortality or VT recurrence in follow-up, despite being used in a significantly sicker cohort of patients. However, MCS has increased risk of complications related to vascular access, bleeding, thromboembolic risk, mapping system interference, increase procedural complexity and increased cost. Acute haemodynamic decompensation occurs in ∼11% of patients undergoing VT ablation, and is associated with increased mortality. Prospectively identifying patients at risk of acute haemodynamic decompensation in the peri-procedural period may allow prophylactic MCS. Although observational studies of MCS in patients at high risk of haemodynamic decompensation are encouraging, its benefit needs to be proven in randomised trials. This review will summarise the indication for MCS, forms of MCS, procedural outcomes, complications and utility of MCS during VT ablation.

Catheter Ablation Versus Medical Therapy for Atrial Fibrillation in Patients With Heart Failure: A Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: Catheter ablation (CA) is highly efficacious for symptomatic atrial fibrillation (AF) but data predominantly comes from patients with preserved ventricular function. We performed an updated systematic review and meta-analysis of randomised controlled trials (RCT) comparing CA versus medical therapy for AF associated with heart failure (HF). METHODS: Medline, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for RCTs reporting clinical outcomes of CA versus medical therapy for AF in HF patients with ≥6 months' follow-up (atrioventricular-node ablation/device therapy studies excluded). Primary endpoint was change in left ventricular ejection fraction (LVEF). Secondary endpoints were 6-minute walk test (6MWT) distance, quality of life (QoL; measured by the Minnesota Living with Heart Failure Questionnaire [MLHFQ]), peri-procedural mortality, major peri-procedural complications and mid-term (≥1-year) survival. RESULTS: Six RCTs (n=772 patients; mean age 62±11years, LVEF 30±9%) were included. Catheter ablation, compared to medical therapy was associated with: greater improvement in LVEF (mean difference [MD] 5.67%; 95% Confidence Interval [CI], 3-8; I2=87%; p<0.001), greater increase in 6MWT distance (MD 25.1 metres; 95% CI, 0.6-50; I2=94%; p=0.04), improved QoL with greater reduction in MLHFQ scores (MD 9.03; 95% CI, 2.5-15.6; I2=47%; p=0.007), and significantly reduced mid-term mortality (relative risk 0.52; 95% CI, 0.4-0.8; I2=0%; p=0.001). Freedom from AF after ≥1 procedure was 71%; major complications occurred in 8% of patients. CONCLUSION: Catheter ablation is superior to medical therapy for AF in patients with heart failure resulting in greater improvement in LVEF, quality of life and functional status, with a survival benefit.

ESMO Consensus Conference on testicular germ cell cancer: diagnosis, treatment and follow-up.

The European Society for Medical Oncology (ESMO) consensus conference on testicular cancer was held on 3-5 November 2016 in Paris, France. The conference included a multidisciplinary panel of 36 leading experts in the diagnosis and treatment of testicular cancer (34 panel members attended the conference; an additional two panel members [CB and K-PD] participated in all preparatory work and subsequent manuscript development). The aim of the conference was to develop detailed recommendations on topics relating to testicular cancer that are not covered in detail in the current ESMO Clinical Practice Guidelines (CPGs) and where the available level of evidence is insufficient. The main topics identified for discussion related to: (1) diagnostic work-up and patient assessment; (2) stage I disease; (3) stage II-III disease; (4) post-chemotherapy surgery, salvage chemotherapy, salvage and desperation surgery and special topics; and (5) survivorship and follow-up schemes. The experts addressed questions relating to one of the five topics within five working groups. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel. A consensus vote was obtained following whole-panel discussions, and the consensus recommendations were then further developed in post-meeting discussions in written form. This manuscript presents the results of the expert panel discussions, including the consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

Heart Valve Surgery Performed by Trainee Surgeons: Meta-Analysis of Clinical Outcomes.

BACKGROUND: Cardiac surgical units must balance trainee education with the duty to provide optimal patient care. This is particularly challenging with valvular surgery, given the lower volume and increased complexity of these procedures. The present meta-analysis was conducted to assess the impact of trainee operator status on clinical outcomes following valvular surgery. METHODS: Medline, Embase and CENTRAL databases were systematically searched for studies reporting clinical outcomes according to the training status of the primary operator (consultant or trainee). Data were extracted and meta-analysed according to pre-defined endpoints. RESULTS: Eleven observational studies met the inclusion criteria, reporting on five patient cohorts undergoing mitral valve surgery (n=3975), six undergoing aortic valve replacement (AVR) (n=6236) and three undergoing combined AVR and coronary artery bypass grafting (CABG) (n=3495). Perioperative mortality was not significantly different between trainee and consultant cases for mitral valve surgery (odds ratio [OR] 0.92; 95% confidence interval [CI], 0.62-1.37), AVR (OR 0.67; 95% CI, 0.37-1.24), or combined AVR and CABG (OR 1.07; 95% CI, 0.40-2.85). The incidences of perioperative stroke, myocardial infarction, arrhythmias, acute renal failure, reoperation or wound infection were not significantly different between trainee and consultant cases. There was a paucity of mid-term survival data. CONCLUSIONS: Valvular surgery cases performed primarily by trainees were not associated with adverse perioperative outcomes. These findings suggest the rigorous design of cardiac surgical trainee programs can sufficiently mitigate trainee deficiencies. However, studies with longer follow-up duration and echocardiographic data are required to assess long-term durability and safety.

Effect of Water Sorption and Solubility on Color Stability of Bulk-Fill Resin Composite.

AIM: The objective of this study is to compare the bulk-fill resin composite to a conventional one, as regards; water sorption, solubility, and their effect on color stability. MATERIALS AND METHODS: This study was conducted using two types of composites: Bulk-fill composite (Filtek Bulk-Fill) and nanohybrid composite for control (Filtek Z250 XT). Specimens were prepared using a ring mold, 10 from each material. Specimens were desiccated, then weighed in a digital balance until a stable mass was acquired. For water sorption test, specimens were immersed in distilled water and placed in a lightproof incubator at 37 ± 1°C and the mass was measured weekly for 8 weeks. For solubility test, specimens were desiccated again in the desiccator until a stable mass was achieved. A spectropho-tometer was used to record the baseline color measurements prior to water immersion and weekly for 8 weeks. RESULTS: Bulk-fill composite showed higher water sorption value and lower water solubility values compared with that of the conventional one. No statistically significant difference was found for water sorption (p = 0.104) or water solubility (p = 0.098) between groups. The mean ΔE was lower in bulk-fill than conventional composite, and results showed a statistically significant difference (p = 0.009). CONCLUSION: Bulk-fill resin composite yielded better color stability and similar water sorption and solubility values. CLINICAL SIGNIFICANCE: Bulk-fill resin composite can be used in esthetically concerned patients.

An electrochemical sensor for nitrobenzene using π-conjugated polymer-embedded nanosilver.

A novel electrochemical sensing platform for nitrobenzene has been developed using silver nanoparticles (AgNPs) embedded in the poly(amic) acid (PAA) polymer matrix (PAA-AgNPs). PAA was synthesized via the polycondensation reaction of para-phenylenediamine and benzene-1,2,4,5-tetracarboxylic dianhydride. PAA-AgNP nanocomposites were synthesized by the in situ reduction of a silver precursor by the polymer at room temperature in a one-step approach without using an extraneous reducing or capping agent. The composite was subsequently characterized in solution and as a thin film. The X-ray diffraction technique revealed the crystalline nature of the PAA films with the embedded AgNPs. Unlike conventional polymers, the synthesized PAA membrane exhibits significant UV/Vis spectroscopic response. The sequestered nanoparticles also show the characteristic surface plasmon resonance (SPR) peaks confirming the presence of AgNPs. Integrated charge areas were 4.826 mC and 2.176 C for PAA/GC and PAA-AgNPs/GC respectively. The charge at the PAA-AgNP/GC electrode is 451 times greater than that at the PAA/GC electrode suggesting that the AgNP composite exhibits higher electroactivity. When tested as a sensor for nitrobenzene, the PAA-AgNP modified GC electrode showed promising potential as an electrochemical sensor. The electrochemical sensors exhibit a wide linear dynamic range (10-600 µM) with a correlation coefficient of 0.9735, a detection limit of 1.68 µM and a sensitivity of 7.88 µA µM(-1). The sensor also exhibited minimal interference effects on structurally-similar nitroaromatic compounds and metal species such as 4-nitroaniline (4-NA), 2-nitrophenol (2-NP), dinitrobenzene (DNB), Pb(2+) and Cd(2+).

Brief Report: Meta-analysis of Antacid Use and Alzheimer's Disease: Implications for the Aluminum Hypothesis.

BACKGROUND: Exposure to aluminum remains a controversial risk factor for Alzheimer's disease. Antacids are aluminum-rich medications that are widely used in substantial amounts, but their association with Alzheimer's disease has not been systematically quantified. METHODS: We conducted electronic searches of PubMed, Embase, and Cochrane Library up to January 2015 for case-control and cohort studies published in any language. Summary risk estimates were derived using random-effects models. RESULTS: Seven case-control studies (n = 5,468; 829 Alzheimer's disease cases) and two cohort studies (n = 842; 110 Alzheimer's disease cases) met the criteria for inclusion. Study quality was limited by imprecise characterization of the timing and duration of antacid use. Regular antacid use was not associated with Alzheimer's disease in either case-control (odds ratio = 1.0; 95% confidence interval = 0.8, 1.2) or cohort studies (relative risk = 0.8; 95% confidence interval = 0.4, 1.8). Sensitivity analysis including studies specifically examining aluminum-containing antacids did not reveal an association. CONCLUSIONS: Although the findings of this meta-analysis do not support an association between aluminum intake and Alzheimer's disease, prospective studies with longer follow-up and more precise characterization of exposure are required to definitively exclude an etiologic role for aluminum.

Progressive computed tomography (CT) appearances preceding malignant spinal cord compression (MSCC) in men with castration-resistant prostate cancer.

AIM: To test the hypothesis that computed tomography (CT)-based signs might precede symptomatic malignant spinal cord compression (MSCC) in men with metastatic castration-resistant prostate cancer (mCRPC). MATERIALS AND METHODS: A database was used to identify suitable mCRPC patients. Staging CT images were retrospectively reviewed for signs preceding MSCC. Signs of malignant paravertebral fat infiltration and epidural soft-tissue disease were defined and assessed on serial CT in 34 patients with MSCC and 58 control patients. The presence and evolution of the features were summarized using descriptive statistics. RESULTS: In MSCC patients, CT performed a median of 28 days prior to the diagnostic magnetic resonance imaging (MRI) demonstrated significant epidural soft tissue in 28 (80%) patients. The median time to MSCC from a combination of overt malignant paravertebral and epidural disease was 2.7 (0-14.6) months. Conversely, these signs were uncommon in the control cohort. CONCLUSIONS: Significant malignant paravertebral and/or epidural disease at CT precede MSCC in up to 80% of mCRPC patients and should prompt closer patient follow-up and consideration of early MRI evaluation. These CT-based features require further prospective validation.

Neoadjuvant carboplatin before radiotherapy in stage IIA and IIB seminoma.

BACKGROUND: Extended field radiotherapy is a standard of care for low volume stage II testicular seminoma. We hypothesized that neoadjuvant carboplatin might reduce the recurrence risk. PATIENTS AND METHODS: In a single-arm study, 51 patients were treated between May 1996 and November 2011 with a single cycle of carboplatin followed by radiotherapy. The radiation field was reduced from an extended abdomino-pelvic field to just the para-aortic region, and the radiation dose from 35 Gy to 30 Gy in 39 patients. RESULTS: After a median follow-up of 55 months (range 8-151 months) with 38 (74%) of the patients having been followed for >2 years, there have been no relapses (95% confidence limits of 5-year relapse-free survival of 93%-100%). Toxicity has been low with grade 3 toxicity limited to four patients with grade 3 haematological toxicity (with no clinical sequelae) and one patient with grade 3 nausea (during radiotherapy). No patients experienced grade 4 toxicity. CONCLUSIONS: The results of this pilot study suggest that a single cycle of neoadjuvant carboplatin before radiotherapy may reduce recurrence risk compared with radiotherapy alone and permit a smaller radiation field, and this approach is proposed for further investigation.

Prostate MRI: who, when, and how? Report from a UK consensus meeting.

The current pathway for men suspected of having prostate cancer [transrectal biopsy, followed in some cases by magnetic resonance imaging (MRI) for staging] results in over-diagnosis of insignificant tumours, and systematically misses disease in the anterior prostate. Multiparametric MRI has the potential to change this pathway, and if performed before biopsy, might enable the exclusion of significant disease in some men without biopsy, targeted biopsy in others, and improvements in the performance of active surveillance. For the potential benefits to be realized, the setting of standards is vital. This article summarizes the outcome of a meeting of UK radiologists, at which a consensus was achieved on (1) the indications for MRI, (2) the conduct of the scan, (3) a method and template for reporting, and (4) minimum standards for radiologists.

Mechanisms of estrogen receptor antagonism toward p53 and its implications in breast cancer therapeutic response and stem cell regulation.

Estrogen receptor alpha (ERalpha) plays an important role in the onset and progression of breast cancer, whereas p53 functions as a major tumor suppressor. We previously reported that ERalpha binds to p53, resulting in inhibition of transcriptional regulation by p53. Here, we report on the molecular mechanisms by which ERalpha suppresses p53's transactivation function. Sequential ChIP assays demonstrated that ERalpha represses p53-mediated transcriptional activation in human breast cancer cells by recruiting nuclear receptor corepressors (NCoR and SMRT) and histone deacetylase 1 (HDAC1). RNAi-mediated down-regulation of NCoR resulted in increased endogenous expression of the cyclin-dependent kinase (CDK)-inhibitor p21(Waf1/Cip1) (CDKN1A) gene, a prototypic transcriptional target of p53. While 17beta-estradiol (E2) enhanced ERalpha binding to p53 and inhibited p21 transcription, antiestrogens decreased ERalpha recruitment and induced transcription. The effects of estrogen and antiestrogens on p21 transcription were diametrically opposite to their known effects on the conventional ERE-containing ERalpha target gene, pS2/TFF1. These results suggest that ERalpha uses dual strategies to promote abnormal cellular proliferation: enhancing the transcription of ERE-containing proproliferative genes and repressing the transcription of p53-responsive antiproliferative genes. Importantly, ERalpha binds to p53 and inhibits transcriptional activation by p53 in stem/progenitor cell-containing murine mammospheres, suggesting a potential role for the ER-p53 interaction in mammary tissue homeostasis and cancer formation. Furthermore, retrospective studies analyzing response to tamoxifen therapy in a subset of patients with ER-positive breast cancer expressing either wild-type or mutant p53 suggest that the presence of wild-type p53 is an important determinant of positive therapeutic response.