Can quantitative analysis of multi-parametric MRI independently predict failure of focal salvage HIFU therapy in men with radio-recurrent prostate cancer?

OBJECTIVES: Focal salvage HIFU is a feasible therapeutic option in some men who have recurrence after primary radiotherapy for prostate cancer. We aimed to determine if multi-parametric quantitative parameters, in addition to clinical factors, might have a role in independently predicting focal salvage HIFU outcomes. METHODS: A retrospective registry analysis included 150 consecutive men who underwent focal salvage HIFU (Sonablate500) (2006-2015); 89 had mpMRI available. Metastatic disease was excluded by nodal assessment on pelvic MRI, a radioisotope bone-scan and/or choline or FDG PET/CT scan. All men had mpMRI and either transperineal template prostate mapping biopsy or targeted and systematic TRUS-biopsy. mpMRI included T2-weighted, diffusion-weighted and dynamic contrast-enhancement. Pre-HIFU quantitative mpMRI data was obtained using Horos DICOM Viewer v3.3.5 for general MRI parameters and IB DCE v2.0 plug-in. Progression-free survival (PFS) was defined by biochemical failure and/or positive localized or distant imaging results and/or positive biopsy and/or systemic therapy and/or metastases/prostate cancer-specific death. Potential predictors of PFS were analyzed by univariable and multivariable Cox-regression. RESULTS: Median age at focal salvage HIFU was 71 years (interquartile range [IQR] 65-74.5) and median PSA pre-focal salvage treatment was 5.8ng/ml (3.8-8). Median follow-up was 35 months (23-47) and median time to failure was 15 months (7.8-24.3). D-Amico low, intermediate and high-risk disease was present in 1% (1/89), 40% (36/89) and 43% (38/89) prior to focal salvage HIFU (16% missing data). 56% (50/89) failed by the composite outcome. A total of 22 factors were evaluated on univariable and 8 factors on multivariable analysis. The following quantitative parameters were included: Ktrans, Kep, Ve, Vp, IS, rTTP and TTP. On univariable analysis, PSA, prostate volume at time of radiotherapy failure and Ve (median) value were predictors for failure. Ve represents extracellular fraction of the whole tissue volume. On multivariable analysis, only Ve (median) value remained as an independent predictor. CONCLUSIONS: One pharmacokinetic quantitative parameter based on DCE sequences seems to independently predict failure following focal salvage HIFU for radio-recurrent prostate cancer. This likely relates to the tumor microenvironment producing heat-sinks which counter the heating effect of HIFU. Further validation in larger datasets and evaluating mechanisms to reduce heat-sinks are required

MIRC-X/CHARA: sensitivity improvements with an ultra-low noise SAPHIRA detector

This is the final version of the article. Available from Society of Photo Optical Instrumentation Engineers (SPIE) via the DOI in this record.MIRC-X is an upgrade of the six-telescope infrared beam combiner at the CHARA telescope array, the world's largest baseline interferometer in the optical/infrared, located at the Mount Wilson Observatory in Los Angeles. The upgraded instrument features an ultra-low noise and fast frame rate infrared camera (SAPHIRA detector) based on e-APD technology. We report the MIRC-X sensitivity upgrade work and first light results in detail focusing on the detector characteristics and software architecture.MIRC-X is funded, in parts, by a Starting Grant from the European Research Council (ERC; grant agreement No. 639889, PI: Kraus) and builds on earlier investments from the University of Michigan and the National Science Foundation (NSF, PI: Monnier). This research has made use of the Jean-Marie Mariotti Center OIFits Explorer service (http://www.jmmc.fr/oifitsexplorer)

Numeracy and COVID-19: examining interrelationships between numeracy, health numeracy and behaviour

During the COVID-19 pandemic, people across the globe have been exposed to large amounts of statistical data. Previous studies have shown that individuals' mathematical understanding of health-related information affects their attitudes and behaviours. Here, we investigate the relation between (i) basic numeracy, (ii) COVID-19 health numeracy, and (iii) COVID-19 health-related attitudes and behaviours. An online survey measuring these three variables was distributed in Canada, the United States (US) and the United Kingdom (UK) (n = 2032). In line with predictions, basic numeracy was positively related to COVID-19 health numeracy. However, predictions, neither basic numeracy nor COVID-19 health numeracy was related to COVID-19 health-related attitudes and behaviours (e.g. follow experts’ recommendations on social distancing, wearing masks etc.). Multi-group analysis was used to investigate mean differences and differences in the strength of the correlation across countries. Results indicate there were no between-country differences in the correlations between the main constructs but there were between-country differences in latent means. Overall, results suggest that while basic numeracy is related to one's understanding of data about COVID-19, better numeracy alone is not enough to influence a population's health-related attitudes about disease severity and to increase the likelihood of following public health advice

A Systematic Review of Side Effects of Nucleoside and Nucleotide Drugs Used for Treatment of Chronic Hepatitis B

Although nucleosides and nucleotides have a good safety record for the treatment of hepatitis B, there have been no systematic reviews on this topic. We searched Medline to include studies of the oral antiviral agents for hepatitis B and adverse events, with at least 48 weeks of follow-up from the initiation of treatment with the drug. Important toxicities include nephrotoxicity, myopathy, and resistance. It is often difficult to ascertain whether an adverse effect is from the study drug or the natural progression of the disease. Further safety data are needed for the newer agents and for all agents with regard to patients with decompensated liver disease, renal dysfunction, the elderly, children, and pregnant women

Conventional radical versus focal treatment for localised prostate cancer: a propensity score weighted comparison of 6-year tumour control

Background: For localised prostate cancer, focal therapy offers an organ-sparing alternative to radical treatments (radiotherapy or prostatectomy). Currently, there is no randomised comparative effectiveness data evaluating cancer control of both strategies. Methods: Following the eligibility criteria PSA < 20 ng/mL, Gleason score ≤ 7 and T-stage ≤ T2c, we included 830 radical (440 radiotherapy, 390 prostatectomy) and 530 focal therapy (cryotherapy, high-intensity focused ultrasound or high-dose-rate brachytherapy) patients treated between 2005 and 2018 from multicentre registries in the Netherlands and the UK. A propensity score weighted (PSW) analysis was performed to compare failure-free survival (FFS), with failure defined as salvage treatment, metastatic disease, systemic treatment (androgen deprivation therapy or chemotherapy), or progression to watchful waiting. The secondary outcome was overall survival (OS). Median (IQR) follow-up in each cohort was 55 (28–83) and 62 (42–83) months, respectively. Results: At baseline, radical patients had higher PSA (10.3 versus 7.9) and higher-grade disease (31% ISUP 3 versus 11%) compared to focal patients. After PSW, all covariates were balanced (SMD < 0.1). 6-year weighted FFS was higher after radical therapy (80.3%, 95% CI 73.9–87.3) than after focal therapy (72.8%, 95% CI 66.8–79.8) although not statistically significant (p = 0.1). 6-year weighted OS was significantly lower after radical therapy (93.4%, 95% CI 90.1–95.2 versus 97.5%, 95% CI 94–99.9; p = 0.02). When compared in a three-way analysis, focal and LRP patients had a higher risk of treatment failure than EBRT patients (p < 0.001), but EBRT patients had a higher risk of mortality than focal patients (p = 0.008). Conclusions: Within the limitations of a cohort-based analysis in which residual confounders are likely to exist, we found no clinically relevant difference in cancer control conferred by focal therapy compared to radical therapy at 6 years

Cellular Radiosensitivity: How much better do we understand it?

Purpose: Ionizing radiation exposure gives rise to a variety of lesions in DNA that result in genetic instability and potentially tumorigenesis or cell death. Radiation extends its effects on DNA by direct interaction or by radiolysis of H2O that generates free radicals or aqueous electrons capable of interacting with and causing indirect damage to DNA. While the various lesions arising in DNA after radiation exposure can contribute to the mutagenising effects of this agent, the potentially most damaging lesion is the DNA double strand break (DSB) that contributes to genome instability and/or cell death. Thus in many cases failure to recognise and/or repair this lesion determines the radiosensitivity status of the cell. DNA repair mechanisms including homologous recombination (HR) and non-homologous end-joining (NHEJ) have evolved to protect cells against DNA DSB. Mutations in proteins that constitute these repair pathways are characterised by radiosensitivity and genome instability. Defects in a number of these proteins also give rise to genetic disorders that feature not only genetic instability but also immunodeficiency, cancer predisposition, neurodegeneration and other pathologies. Conclusions: In the past fifty years our understanding of the cellular response to radiation damage has advanced enormously with insight being gained from a wide range of approaches extending from more basic early studies to the sophisticated approaches used today. In this review we discuss our current understanding of the impact of radiation on the cell and the organism gained from the array of past and present studies and attempt to provide an explanation for what it is that determines the response to radiation

Cultural adaptation and psychometric evaluation of the Swedish version of the Reproductive Concerns After Cancer (RCAC) scale

BACKGROUND: Reproductive concerns are common among young cancer survivors and include worries related to different aspects of fertility and parenthood. The Reproductive Concerns After Cancer (RCAC) scale is an 18-item scale with six dimensions, developed to capture a variety of such concerns. The aim of the present study was to describe the cultural adaptation of the RCAC scale into Swedish and evaluate its psychometric properties among young women who have undergone treatment for cancer. METHODS: The RCAC was forward translated from English into Swedish and assessed for cultural adaptation based on a two-panel approach followed by cognitive interviews with the target group. For the psychometric evaluation, a Swedish cohort of 181 female young adult breast cancer survivors completed a survey including the RCAC scale approximately 1.5 years post-diagnosis. Psychometric properties were examined by analyses of construct validity (confirmatory factor analysis and convergent validity), data quality (score distribution, floor and ceiling effects), reliability and known-groups validity. RESULTS: The confirmatory factor analysis yielded an acceptable fit (RMSEA 0.08, SRMR 0.09, CFI 0.92). Convergent validity was demonstrated by a negative correlation of moderate size (- 0.36) between the RCAC total score and the emotional function scale of the EORTC QLQ-C30. Reliability measured with Revelle Ω total was satisfactory (0.73-0.92) for five of the dimensions, and poor for the dimension Becoming pregnant (Revelle Ω total = 0.60); Cronbach's alpha showed a similar pattern. Known-groups validity was indicated by significant RCAC mean score differences (MD), reflecting more concerns among women with a certain (MD 4.56 [95% CI 3.13 to 5.99]) or uncertain (MD 3.41 [95% CI 1.68 to 5.14]) child wish compared to those with no wish for (additional) children. CONCLUSION: The translation and cultural adaptation of the Swedish RCAC has resulted in a scale demonstrating construct and known-groups validity, and satisfactory reliability for five of six dimensions. The dimension Becoming pregnant showed non-optimal internal consistency and should undergo further evaluation. The Swedish RCAC is recommended to be used in research settings for measurement of concerns related to fertility and parenthood in young women with cancer

Circulating Angiopoietins-1 and -2, Angiopoietin Receptor Tie-2 and Vascular Endothelial Growth Factor-A as Biomarkers of Acute Myocardial Infarction: a Prospective Nested Case-Control Study

<p>Abstract</p> <p>Background</p> <p>Angiogenesis is up-regulated in myocardial ischemia. However, limited data exist assessing the value of circulating angiogenic biomarkers in predicting future incidence of acute myocardial infarction (AMI). Our aim was to examine the association between circulating levels of markers of angiogenesis with risk of incident acute myocardial infarction (AMI) in men and women.</p> <p>Methods</p> <p>We performed a case-control study (nested within a large cohort of persons receiving care within Kaiser Permanente of Northern California) including 695 AMI cases and 690 controls individually matched on age, gender and race/ethnicity.</p> <p>Results</p> <p>Median [inter-quartile range] serum concentrations of vascular endothelial growth factor-A (VEGF-A; 260 [252] vs. 235 [224] pg/mL; p = 0.01) and angiopoietin-2 (Ang-2; 1.18 [0.66] vs. 1.05 [0.58] ng/mL; p < 0.0001) were significantly higher in AMI cases than in controls. By contrast, endothelium-specific receptor tyrosine kinase (Tie-2; 14.2 [3.7] vs. 14.0 [3.1] ng/mL; p = 0.07) and angiopoietin-1 levels (Ang-1; 33.1 [13.6] vs. 32.5 [12.7] ng/mL; p = 0.52) did not differ significantly by case-control status. After adjustment for educational attainment, hypertension, diabetes, smoking, alcohol consumption, body mass index, LDL-C, HDL-C, triglycerides and C-reactive protein, each increment of 1 unit of Ang-2 as a Z score was associated with 1.17-fold (95 percent confidence interval, 1.02 to 1.35) increased odds of AMI, and the upper quartile of Ang-2, relative to the lowest quartile, was associated with 1.63-fold (95 percent confidence interval, 1.09 to 2.45) increased odds of AMI.</p> <p>Conclusions</p> <p>Our data support a role of Ang-2 as a biomarker of incident AMI independent of traditional risk factors.</p

Prime movers : mechanochemistry of mitotic kinesins

Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation

Severity Assessment of Lower Respiratory Tract Infection in Malawi: Derivation of a Novel Index (SWAT-Bp) Which Outperforms CRB-65

OBJECTIVE: To assess the validity of CRB-65 (Confusion, Respiratory rate >30 breaths/min, BP<90/60 mmHg, age >65 years) as a pneumonia severity index in a Malawian hospital population, and determine whether an alternative score has greater accuracy in this setting. DESIGN: Forty three variables were prospectively recorded during the first 48 hours of admission in all patients admitted to Queen Elizabeth Central Hospital, Malawi, for management of lower respiratory tract infection over a two month period (N = 240). Calculation of sensitivity and specificity for CRB-65 in predicting mortality was followed by multivariate modeling to create a score with superior performance in this population. RESULTS: Median age 37, HIV prevalence 79.9%, overall mortality 18.3%. CRB-65 predicted mortality poorly, indicated by the area under the ROC curve of 0.649. Independent predictors of death were: Male sex, “S” (AOR 2.6); Wasting, “W” (AOR 6.6); non-ambulatory, “A” (AOR 2.5); Temp >38°C or <35°C, “T” (AOR 3.2); BP<100/60, “Bp” (AOR 3.7). Combining these factors to form a severity index (SWAT-Bp) predicted mortality with high sensitivity and specificity (AUC: 0.867). Mortality for scores 0–5 was 0%, 3.3%, 7.4%, 29.2%, 61.5% and 87.5% respectively. A score ≥3 was 84% sensitive and 77% specific for mortality prediction, with a negative predictive value of 95.8%. CONCLUSION: CRB-65 performs poorly in this population. The SWAT-Bp score can accurately stratify patients; ≤2 indicates non-severe infection (mortality 4.4%) and ≥3 severe illness (mortality 45%)