Up to 30% of patients with breast cancer relapse after primary treatment. There are no sensitive and reliable tests to monitor these patients and detect distant metastases before overt recurrence. ...Here, we demonstrate the use of personalized circulating tumor DNA (ctDNA) profiling for detection of recurrence in breast cancer.
Forty-nine primary patients with breast cancer were recruited following surgery and adjuvant therapy. Plasma samples (
= 208) were collected every 6 months for up to 4 years. Personalized assays targeting 16 variants selected from primary tumor whole-exome data were tested in serial plasma for the presence of ctDNA by ultradeep sequencing (average >100,000X).
Plasma ctDNA was detected ahead of clinical or radiologic relapse in 16 of the 18 relapsed patients (sensitivity of 89%); metastatic relapse was predicted with a lead time of up to 2 years (median, 8.9 months; range, 0.5-24.0 months). None of the 31 nonrelapsing patients were ctDNA-positive at any time point across 156 plasma samples (specificity of 100%). Of the two relapsed patients who were not detected in the study, the first had only a local recurrence, whereas the second patient had bone recurrence and had completed chemotherapy just 13 days prior to blood sampling.
This study demonstrates that patient-specific ctDNA analysis can be a sensitive and specific approach for disease surveillance for patients with breast cancer. More importantly, earlier detection of up to 2 years provides a possible window for therapeutic intervention.
Sensitive methods for risk stratification, monitoring therapeutic efficacy, and early relapse detection may have a major impact on treatment decisions and patient management for stage III colorectal ...cancer patients. Beyond assessing the predictive power of postoperative ctDNA detection, we explored the added benefits of serial analysis: assessing adjuvant chemotherapy (ACT) efficacy, early relapse detection, and ctDNA growth rates.
We recruited 168 patients with stage III colorectal cancer treated with curative intent at Danish and Spanish hospitals between 2014 and 2019. To quantify ctDNA in plasma samples (
= 1,204), 16 patient-specific somatic single-nucleotide variants were profiled using multiplex-PCR, next-generation sequencing.
Detection of ctDNA was a strong recurrence predictor postoperatively HR = 7.0; 95% confidence interval (CI), 3.7-13.5;
< 0.001 and directly after ACT (HR = 50.76; 95% CI, 15.4-167;
< 0.001). The recurrence rate of postoperative ctDNA-positive patients treated with ACT was 80% (16/20). Only patients who cleared ctDNA permanently during ACT did not relapse. Serial ctDNA assessment after the end of treatment was similarly predictive of recurrence (HR = 50.80; 95% CI, 14.9-172;
< 0.001), and revealed two distinct rates of exponential ctDNA growth, slow (25% ctDNA-increase/month) and fast (143% ctDNA-increase/month;
< 0.001). The ctDNA growth rate was prognostic of survival (HR = 2.7; 95% CI, 1.1-6.7;
= 0.039). Serial ctDNA analysis every 3 months detected recurrence with a median lead-time of 9.8 months compared with standard-of-care computed tomography.
Serial postoperative ctDNA analysis has a strong prognostic value and enables tumor growth rate assessment. The novel combination of ctDNA detection and growth rate assessment provides unique opportunities for guiding decision-making.
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Emerging technologies focused on the detection and quantification of circulating tumor DNA (ctDNA) in blood show extensive potential for managing patient treatment decisions, informing risk of ...recurrence, and predicting response to therapy. Currently available tissue-informed approaches are often limited by the need for additional sequencing of normal tissue or peripheral mononuclear cells to identify non-tumor-derived alterations while tissue-naïve approaches are often limited in sensitivity. Here we present the analytical validation for a novel ctDNA monitoring assay, FoundationOne®Tracker. The assay utilizes somatic alterations from comprehensive genomic profiling (CGP) of tumor tissue. A novel algorithm identifies monitorable alterations with a high probability of being somatic and computationally filters non-tumor-derived alterations such as germline or clonal hematopoiesis variants without the need for sequencing of additional samples. Monitorable alterations identified from tissue CGP are then quantified in blood using a multiplex polymerase chain reaction assay based on the validated SignateraTM assay. The analytical specificity of the plasma workflow is shown to be 99.6% at the sample level. Analytical sensitivity is shown to be >97.3% at ≥5 mean tumor molecules per mL of plasma (MTM/mL) when tested with the most conservative configuration using only two monitorable alterations. The assay also demonstrates high analytical accuracy when compared to liquid biopsy-based CGP as well as high qualitative (measured 100% PPA) and quantitative precision (<11.2% coefficient of variation).
Transcriptional enhancers regulate spatio-temporal gene expression. While genomic assays can identify putative enhancers en masse, assigning target genes is a complex challenge. We devised a machine ...learning approach, McEnhancer, which links target genes to putative enhancers via a semi-supervised learning algorithm that predicts gene expression patterns based on enriched sequence features. Predicted expression patterns were 73-98% accurate, predicted assignments showed strong Hi-C interaction enrichment, enhancer-associated histone modifications were evident, and known functional motifs were recovered. Our model provides a general framework to link globally identified enhancers to targets and contributes to deciphering the regulatory genome.
Purpose of review
This study aims to summarize the recent peer-reviewed literature on workplace interventions for prevention of type 2 diabetes mellitus (T2DM), including studies that translate the ...Diabetes Prevention Program (DPP) curriculum to workplace settings (
n
= 10) and those that use different intervention approaches to achieve the specific objective of T2DM prevention among employees (
n
= 3).
Recent findings
Weight reduction was achieved through workplace interventions to prevent T2DM, though such interventions varied substantially in their effectiveness. The greatest weight loss was reported among intensive lifestyle interventions (i.e., at least 4 months in duration) that implemented the structured DPP curriculum (
n
= 3). Weight reduction was minimal among less intensive interventions, including those that substantially modified the DPP curriculum (
n
= 2) and those that used non-DPP intervention approaches to prevent T2DM (
n
= 3). Most studies (
n
= 12) reported increased levels of physical activity following the intervention.
Summary
Implementation of the DPP in workplaces may be an effective strategy to prevent T2DM among employees.
Optimal carbohydrate intake is an important and controversial area in the nutritional management of type 2 diabetes. Some evidence indicates that reducing overall carbohydrate intake with a low- or ...very low-carbohydrate eating plan can improve glycemic control compared to following eating plans that involve greater carbohydrate intake. However, critical knowledge gaps currently prevent clear recommendations about carbohydrate intake levels.
The LEGEND (Lifestyle Education about Nutrition for Diabetes) Trial aims to compare a very low-carbohydrate diet to a moderate-carbohydrate plate-method diet for glycemic control in adults with type 2 diabetes. This two-site trial plans to recruit 180 adults with type 2 diabetes. We will randomize participants to either a 20-session group-based diet and lifestyle intervention that teaches either a very low-carbohydrate diet or a moderate-carbohydrate plate-method diet. We will assess participants at study entry and 4 and 12 months later. The primary outcome is HbA1c, and secondary outcomes include inflammation (high sensitivity C-reactive protein), body weight, changes in diabetes medications, lipids (small particle LDL, HDL, triglycerides), skeletal metabolism (bone mineral density from dual-energy x-ray absorptiometry and bone turnover markers serum procollagen type I N propeptide and serum C-terminal telopeptide of type I collagen), and body composition (percent body fat, percent lean body mass).
The LEGEND trial is a randomized controlled trial to assess optimal carbohydrate intake in type 2 diabetes by evaluating the effects of a very low-carbohydrate diet vs. a moderate-carbohydrate plate-method diet over a year-long period. The research addresses important gaps in the evidence base for the nutritional management of type 2 diabetes by providing data on potential benefits and adverse effects of different levels of carbohydrate intake.
ClinicalTrials.gov NCT05237128. Registered on February 11, 2022.
Objectives(1) To estimate weight change from a low-carbohydrate diabetes prevention programme (LC-DPP) and (2) to evaluate the feasibility and acceptability of an LC-DPP.Research designSingle-arm, ...mixed methods (ie, integration of quantitative and qualitative data) pilot study.SettingPrimary care clinic within a large academic medical centre in the USA.ParticipantsAdults with pre-diabetes and Body Mass Index of ≥25 kg/m2.InterventionWe adapted the Centers for Disease Control and Prevention’s National Diabetes Prevention Program (NDPP)—an evidence-based, low-fat dietary intervention—to teach participants to follow a very low-carbohydrate diet (VLCD). Participants attended 23 group-based classes over 1 year.Outcome measuresPrimary outcome measures were (1) weight change and (2) percentage of participants who achieved ≥5% wt loss. Secondary outcome measures included intervention feasibility and acceptability (eg, attendance and qualitative interview feedback).ResultsOur enrolment target was 22. One person dropped out before a baseline weight was obtained; data from 21 individuals were analysed. Mean weight loss in kilogram was 4.3 (SD 4.8) at 6 months and 4.9 (SD 5.8) at 12 months. Mean per cent body weight changes were 4.5 (SD 5.0) at 6 months and 5.2 (SD 6.0) at 12 months; 8/21 individuals (38%) achieved ≥5% wt loss at 12 months. Mean attendance was 10.3/16 weekly sessions and 3.4/7 biweekly or monthly sessions. Among interviewees (n=14), three factors facilitated VLCD adherence: (1) enjoyment of low-carbohydrate foods, (2) diminished hunger and cravings and (3) health benefits beyond weight loss. Three factors hindered VLCD adherence: (1) enjoyment of high-carbohydrate foods, (2) lack of social support and (3) difficulty preplanning meals.ConclusionsAn LC-DPP is feasible, acceptable and may be an effective option to help individuals with pre-diabetes to lose weight. Data from this pilot will be used to plan a fully powered randomised controlled trial of weight loss among NDPP versus LC-DPP participants.Trial registration numberNCT03258918.
The World Health Organization (WHO) recommended coronavirus disease 2019 (COVID-19) booster dose vaccination after completing the primary vaccination series for individuals ≥18 years and most-at-risk ...populations. This study aimed to estimate the pooled proportion of COVID-19 vaccine booster dose uptake and intention to get the booster dose among general populations and healthcare workers (HCWs). We searched PsycINFO, Scopus, EBSCO, MEDLINE Central/PubMed, ProQuest, SciELO, SAGE, Web of Science, Google Scholar, and ScienceDirect according to PRISMA guidelines. From a total of 1079 screened records, 50 studies were extracted. Meta-analysis was conducted using 48 high-quality studies according to the Newcastle-Ottawa Scale quality assessment tool. Using the 48 included studies, the pooled proportion of COVID-19 vaccine booster dose acceptance among 198,831 subjects was 81% (95% confidence interval (CI): 75–85%, I2 = 100%). The actual uptake of the booster dose in eight studies involving 12,995 subjects was 31% (95% CI: 19–46%, I2 = 100%), while the intention to have the booster dose of the vaccine was 79% (95% CI: 72–85%, I2 = 100%). The acceptance of the booster dose of COVID-19 vaccines among HCWs was 66% (95% CI: 58–74%), I2 = 99%). Meta-regression revealed that previous COVID-19 infection was associated with a lower intention to have the booster dose. Conversely, previous COVID-19 infection was associated with a significantly higher level of booster dose actual uptake. The pooled booster dose acceptance in the WHO region of the Americas, which did not include any actual vaccination, was 77% (95% CI: 66–85%, I2 = 100%). The pooled acceptance of the booster dose in the Western Pacific was 89% (95% CI: 84–92%, I2 = 100), followed by the European region: 86% (95% CI: 81–90%, I2 = 99%), the Eastern Mediterranean region: 59% (95% CI: 46–71%, I2 = 99%), and the Southeast Asian region: 52% (95% CI: 43–61%, I2 = 95). Having chronic disease and trust in the vaccine effectiveness were the significant predictors of booster dose COVID-19 vaccine acceptance. The global acceptance rate of COVID-19 booster vaccine is high, but the rates vary by region. To achieve herd immunity for the disease, a high level of vaccination acceptance is required. Intensive vaccination campaigns and programs are still needed around the world to raise public awareness regarding the importance of accepting COVID-19 vaccines needed for proper control of the pandemic.
Across all eating patterns, individuals demonstrate marked differences in treatment response; some individuals gain weight and others lose weight with the same approach. Policy makers and research ...institutions now call for the development and use of personalized nutrition counseling strategies rather than one-size-fits-all dietary recommendations. However, challenges persist in translating some evidence-based eating patterns into the clinical practice due to the persistent notion that certain dietary approaches-regardless of individuals' preferences and health outcomes-are less healthy than others. For example, low- and very low-carbohydrate ketogenic diets (VLCKDs)-commonly defined as 10-26% and <10% total daily energy from carbohydrate, respectively-are recognized as viable lifestyle change options to support weight loss, glycemic control, and reduced medication use. Yet, critics contend that such eating patterns are less healthy and encourage general avoidance rather than patient-centered use. As with all medical treatments, the potential benefits and risks must be considered in the context of patient-centered, outcome-driven care; this is the cornerstone of evidence-based medicine. Thus, the critical challenge is to identify and safely support patients who may prefer and benefit from dietary carbohydrate restriction. In this Perspective, we propose a pragmatic, 4-stepped, outcome-driven approach to help health professionals use carbohydrate-restricted diets as one potential tool for supporting individual patients' weight loss and metabolic health.
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