Detection of ctDNA in plasma of patients with clinically localised prostate cancer is associated with rapid disease progression.

BACKGROUND DNA originating from degenerate tumour cells can be detected in the circulation in many tumour types, where it can be used as a marker of disease burden as well as to monitor treatment response. Although circulating tumour DNA (ctDNA) measurement has prognostic/predictive value in metastatic prostate cancer, its utility in localised disease is unknown. METHODS We performed whole-genome sequencing of tumour-normal pairs in eight patients with clinically localised disease undergoing prostatectomy, identifying high confidence genomic aberrations. A bespoke DNA capture and amplification panel against the highest prevalence, highest confidence aberrations for each individual was designed and used to interrogate ctDNA isolated from plasma prospectively obtained pre- and post- (24 h and 6 weeks) surgery. In a separate cohort (n = 189), we identified the presence of ctDNA TP53 mutations in preoperative plasma in a retrospective cohort and determined its association with biochemical- and metastasis-free survival. RESULTS Tumour variants in ctDNA were positively identified pre-treatment in two of eight patients, which in both cases remained detectable postoperatively. Patients with tumour variants in ctDNA had extremely rapid disease recurrence and progression compared to those where variants could not be detected. In terms of aberrations targeted, single nucleotide and structural variants outperformed indels and copy number aberrations. Detection of ctDNA TP53 mutations was associated with a significantly shorter metastasis-free survival (6.2 vs. 9.5 years (HR 2.4; 95% CIs 1.2-4.8, p = 0.014). CONCLUSIONS CtDNA is uncommonly detected in localised prostate cancer, but its presence portends more rapidly progressive disease

Kinetics of H2–O2–H2O redox equilibria and formation of metastable H2O2 under low temperature hydrothermal conditions

Author Posting. © The Author(s), 2010. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Geochimica et Cosmochimica Acta 75 (2011): 1594-1607, doi:10.1016/j.gca.2010.12.020.Hydrothermal experiments were conducted to evaluate the kinetics of H2(aq) oxidation in the homogeneous H2-O2-H2O system at conditions reflecting subsurface/near-seafloor hydrothermal environments (55-250 oC and 242-497 bar). The kinetics of the water-forming reaction that controls the fundamental equilibrium between dissolved H2(aq) and O2(aq), are expected to impose significant constraints on the redox gradients that develop when mixing occurs between oxygenated seawater and high- temperature anoxic vent fluid at near-seafloor conditions. Experimental data indicate that, indeed, the kinetics of H2(aq)-O2(aq) equilibrium become slower with decreasing temperature, allowing excess H2(aq) to remain in solution. Sluggish reaction rates of H2(aq) oxidation suggest that active microbial populations in near-seafloor and subsurface environments could potentially utilize both H2(aq) and O2(aq), even at temperatures lower than 40 oC due to H2(aq) persistence in the seawater/vent fluid mixtures. For these H2-O2 disequilibrium conditions, redox gradients along the seawater/hydrothermal fluid mixing interface are not sharp and microbially-mediated H2(aq) oxidation coupled with a lack of other electron acceptors (e.g. nitrate) could provide an important energy source available at low-temperature diffuse flow vent sites. More importantly, when H2(aq)-O2(aq) disequilibrium conditions apply, formation of metastable hydrogen peroxide is observed. The yield of H2O2(aq) synthesis appears to be enhanced under conditions of elevated H2(aq)/O2(aq) molar ratios that correspond to abundant H2(aq) concentrations. Formation of metastable H2O2 is expected to affect the distribution of dissolved organic carbon (DOC) owing to the existence of an additional strong oxidizing agent. Oxidation of magnetite and/or Fe++ by hydrogen peroxide could also induce formation of metastable hydroxyl radicals (•OH) through Fenton-type reactions, further broadening the implications of hydrogen peroxide in hydrothermal environments.This research was conducted with partial support from the NSF OCE-0752221 and the Geophysical Laboratory Postdoctoral Fellowship. We would also like to acknowledge contributions by the W.M. Keck Foundation and Shell towards supporting the hydrothermal lab at the Geophysical Lab. SMS acknowledges support from NSF OCE-0452333 and the Alfried-Krupp Wissenschaftskolleg Greifswald (Germany), while WES acknowledges support from NSF grants OCE-0549457 and OCE- 0813861

Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: A systematic analysis for the Global Burden of Disease Study 2013

Background Up-to-date evidence on levels and trends for age-sex-specific all-cause and cause-specific mortality is essential for the formation of global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013) we estimated yearly deaths for 188 countries between 1990, and 2013. We used the results to assess whether there is epidemiological convergence across countries. Methods We estimated age-sex-specific all-cause mortality using the GBD 2010 methods with some refinements to improve accuracy applied to an updated database of vital registration, survey, and census data. We generally estimated cause of death as in the GBD 2010. Key improvements included the addition of more recent vital registration data for 72 countries, an updated verbal autopsy literature review, two new and detailed data systems for China, and more detail for Mexico, UK, Turkey, and Russia. We improved statistical models for garbage code redistribution. We used six different modelling strategies across the 240 causes; cause of death ensemble modelling (CODEm) was the dominant strategy for causes with sufficient information. Trends for Alzheimer's disease and other dementias were informed by meta-regression of prevalence studies. For pathogen-specific causes of diarrhoea and lower respiratory infections we used a counterfactual approach. We computed two measures of convergence (inequality) across countries: the average relative difference across all pairs of countries (Gini coefficient) and the average absolute difference across countries. To summarise broad findings, we used multiple decrement life-tables to decompose probabilities of death from birth to exact age 15 years, from exact age 15 years to exact age 50 years, and from exact age 50 years to exact age 75 years, and life expectancy at birth into major causes. For all quantities reported, we computed 95% uncertainty intervals (UIs). We constrained cause-specific fractions within each age-sex-country-year group to sum to all-cause mortality based on draws from the uncertainty distributions. Findings Global life expectancy for both sexes increased from 65·3 years (UI 65·0-65·6) in 1990, to 71·5 years (UI 71·0-71·9) in 2013, while the number of deaths increased from 47·5 million (UI 46·8-48·2) to 54·9 million (UI 53·6-56·3) over the same interval. Global progress masked variation by age and sex: for children, average absolute differences between countries decreased but relative differences increased. For women aged 25-39 years and older than 75 years and for men aged 20-49 years and 65 years and older, both absolute and relative differences increased. Decomposition of global and regional life expectancy showed the prominent role of reductions in age-standardised death rates for cardiovascular diseases and cancers in high-income regions, and reductions in child deaths from diarrhoea, lower respiratory infections, and neonatal causes in low-income regions. HIV/AIDS reduced life expectancy in southern sub-Saharan Africa. For most communicable causes of death both numbers of deaths and age-standardised death rates fell whereas for most non-communicable causes, demographic shifts have increased numbers of deaths but decreased age-standardised death rates. Global deaths from injury increased by 10·7%, from 4·3 million deaths in 1990 to 4·8 million in 2013; but age-standardised rates declined over the same period by 21%. For some causes of more than 100 000 deaths per year in 2013, age-standardised death rates increased between 1990 and 2013, including HIV/AIDS, pancreatic cancer, atrial fibrillation and flutter, drug use disorders, diabetes, chronic kidney disease, and sickle-cell anaemias. Diarrhoeal diseases, lower respiratory infections, neonatal causes, and malaria are still in the top five causes of death in children younger than 5 years. The most important pathogens are rotavirus for diarrhoea and pneumococcus for lower respiratory infections. Country-specific probabilities of death over three phases of life were substantially varied between and within regions. Interpretation For most countries, the general pattern of reductions in age-sex specific mortality has been associated with a progressive shift towards a larger share of the remaining deaths caused by non-communicable disease and injuries. Assessing epidemiological convergence across countries depends on whether an absolute or relative measure of inequality is used. Nevertheless, age-standardised death rates for seven substantial causes are increasing, suggesting the potential for reversals in some countries. Important gaps exist in the empirical data for cause of death estimates for some countries; for example, no national data for India are available for the past decade. Funding Bill & Melinda Gates Foundation

Utility and Clinical Application of Circulating Tumor DNA (ctDNA) in Advanced Prostate Cancer

The treatment landscape for metastatic prostate cancer has undergone significant changes in recent years. The availability of next-generation imaging techniques and the emergence of novel therapies have led to earlier and more aggressive treatment approaches for patients. However, despite these advancements, drug resistance and progression to castration-resistant disease remain inevitable. Understanding the molecular landscape of advanced prostate cancer lies at the forefront of being able to deliver personalized therapies and more robustly risk-stratify patients, when combined with clinical factors. Advanced prostate cancer is characterized by inter- and intratumoral heterogeneity, posing challenges in comprehensively analyzing the genomic tumor profile using a solitary tissue sample. Additionally, the disease often manifests as bone-predominant metastatic tumors, making biopsies impractical in many cases. Moreover, archival tissue samples from a prostatectomy specimen may not accurately represent the current state of the tumor. To overcome these limitations, liquid biopsies using plasma samples have emerged as a minimally invasive surrogate approach to obtain real-time information on the genomic tumor profile. Growing evidence confirms the excellent concordance of liquid biopsies with tissue samples, making them an attractive alternative to traditional tissue biopsies. These assays can provide predictive and prognostic information that may enhance patient discussions and influence treatment decisions. This review focuses on the evolution and utility of circulating tumor-derived DNA (ctDNA) liquid biopsy assays in metastatic prostate cancer

Large retroperitoneal lymphadenopathy and increased risk of venous thromboembolism in patients receiving first-line chemotherapy for metastatic germ cell tumors: A study by the global germ cell cancer group (G3)

BACKGROUND Metastatic germ cell tumor (mGCT) patients receiving chemotherapy have increased risk of life-threatening venous thromboembolism (VTE). Identifying VTE risk factors may guide thromboprophylaxis in this highly curable population. METHODS Data were collected from mGCT patients receiving first-line platinum-based chemotherapy at 22 centers. Predefined variables included International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification, long-axis diameter of largest retroperitoneal lymph node (RPLN), Khorana score, and use of indwelling vascular access device (VAD). VTE occurring at baseline, during chemotherapy and within 90 days, was analyzed. RESULTS Data from 1135 patients were collected. Median age was 31 years (range 10-74). IGCCCG risk was 64% good, 20% intermediate, and 16% poor. VTE occurred in 150 (13%) patients. RPLN >3.5 cm demonstrated highest discriminatory accuracy for VTE (AUC 0.632, P < .001) and was associated with significantly higher risk of VTE in univariable analysis (22% vs 8%, OR 3.0, P < .001) and multivariable analysis (OR 1.8, P = .02). Other significant risk factors included, Khorana score ≥3 (OR 2.6, P = .008) and VAD use (OR 2.7, P < .001). CONCLUSIONS Large RPLN and VAD use are independent risk factors for VTE in mGCT patients receiving chemotherapy. VAD use should be minimized in this population and thromboprophylaxis might be considered for large RPLN

Tissue- and blood-derived genomic biomarkers for metastatic hormone-sensitive prostate cancer : a systematic review

Context: Multiple studies have reported on the genomic characteristics of metastatic hormone-sensitive prostate cancer (mHSPC). The impact of these findings on prognostication, treatment selection, and clinical trial design remains unclear. Objective: To summarise genomic alteration prevalences in liquid and/or tissue biopsies, infer their clinical implications, and compare genomic alteration frequencies across different disease states and clinical phenotypes. Evidence acquisition: The PubMed and Web of Knowledge databases were systematically searched up to January 2021. Quality assessment was performed using the Joanna Briggs Institute Critical Appraisal tools. Evidence synthesis: In total, 11 studies encompassing 1682 mHSPC patients were included. High-volume disease was associated with more frequent alterations in TP53, DNA damage repair, and Wnt pathways. Tumours from patients with de novo mHSPC were enriched for alterations in TP53 and CDK12 compared with recurrent disease. Alterations in AR, TP53, cell cycle signalling, and MYC were associated with a poorer clinical outcome. A comparative analysis of gene alteration frequencies across disease states revealed a relative increase from localised to castration-resistant tumours, with noteworthy enrichment of CTNNB1 alterations in mHSPC (5%), which warrants further investigation. This study was limited by variability in methodology and definitions used among the eligible studies, including differences in sequencing methods, analytes (being either tissue or liquid), alteration calling thresholds, and target patient populations with a relative under-representation of recurrent metastatic disease. Conclusions: Several genomic alterations are associated with differential prognosis and clinical phenotypes in mHSPC. We urge that emerging data on these potential predictive biomarkers must be validated in biomarker-driven randomised controlled trials before any clinical implementation. Alignment of the assay methodology and reporting will be critical for ensuring rapid scalability. Patient summary: We reviewed current data on genomic alterations of metastatic hormone-sensitive prostate cancer, and summarised key genomic subtypes that associate with specific clinical phenotypes and treatment outcomes. (C) 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved

Identification of <em>BRCA1/2</em> Founder Mutations in Southern Chinese Breast Cancer Patients Using Gene Sequencing and High Resolution DNA Melting Analysis

<div><h3>Background</h3><p>Ethnic variations in breast cancer epidemiology and genetics have necessitated investigation of the spectra of <em>BRCA1</em> and <em>BRCA2</em> mutations in different populations. Knowledge of <em>BRCA</em> mutations in Chinese populations is still largely unknown. We conducted a multi-center study to characterize the spectra of <em>BRCA</em> mutations in Chinese breast and ovarian cancer patients from Southern China.</p> <h3>Methodology/Principal Findings</h3><p>A total of 651 clinically high-risk breast and/or ovarian cancer patients were recruited from the Hong Kong Hereditary Breast Cancer Family Registry from 2007 to 2011. Comprehensive <em>BRCA1</em> and <em>BRCA2</em> mutation screening was performed using bi-directional sequencing of all coding exons of <em>BRCA1</em> and <em>BRCA2</em>. Sequencing results were confirmed by in-house developed full high resolution DNA melting (HRM) analysis. Among the 451 probands analyzed, 69 (15.3%) deleterious <em>BRCA</em> mutations were identified, comprising 29 in <em>BRCA1</em> and 40 in <em>BRCA2</em>. The four recurrent <em>BRCA1</em> mutations (c.470_471delCT, c.3342_3345delAGAA, c.5406+1_5406+3delGTA and c.981_982delAT) accounted for 34.5% (10/29) of all <em>BRCA1</em> mutations in this cohort. The four recurrent <em>BRCA2</em> mutations (c.2808_2811delACAA, c.3109C>T, c.7436_7805del370 and c.9097_9098insA) accounted for 40% (16/40) of all <em>BRCA2</em> mutations. Haplotype analysis was performed to confirm 1 <em>BRCA1</em> and 3 <em>BRCA2</em> mutations are putative founder mutations. Rapid HRM mutation screening for a panel of the founder mutations were developed and validated.</p> <h3>Conclusion</h3><p>In this study, our findings suggest that <em>BRCA</em> mutations account for a substantial proportion of hereditary breast/ovarian cancer in Southern Chinese population. Knowing the spectrum and frequency of the founder mutations in this population will assist in the development of a cost-effective rapid screening assay, which in turn facilitates genetic counseling and testing for the purpose of cancer risk assessment.</p> </div