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Frontiers in Oncology 2024Breast cancer is the leading cause of cancer death among women worldwide. Studies about the genomic landscape of metastatic breast cancer (MBC) have predominantly...
BACKGROUND
Breast cancer is the leading cause of cancer death among women worldwide. Studies about the genomic landscape of metastatic breast cancer (MBC) have predominantly originated from developed nations. There are still limited data on the molecular epidemiology of MBC in low- and middle-income countries. This study aims to evaluate the prevalence of mutations in the PI3K-AKT pathway and other actionable drivers in estrogen receptor (ER)+/HER2- MBC among Brazilian patients treated at a large institution representative of the nation's demographic diversity.
METHODS
We conducted a retrospective observational study using laboratory data (OC Precision Medicine). Our study included tumor samples from patients with ER+/HER2- MBC who underwent routine tumor testing from 2020 to 2023 and originated from several Brazilian centers within the Oncoclinicas network. Two distinct next-generation sequencing (NGS) assays were used: GS Focus (23 genes, covering , , , , , , , , but not ) or GS 180 (180 genes, including PTEN, tumor mutation burden [TMB] and microsatellite instability [MSI]).
RESULTS
Evaluation of tumor samples from 328 patients was undertaken, mostly (75.6%) with GS Focus. Of these, 69% were primary tumors, while 31% were metastatic lesions. The prevalence of mutations in the PI3K-AKT pathway was 39.3% (95% confidence interval, 33% to 43%), distributed as 37.5% in and 1.8% in . Stratification by age revealed a higher incidence of mutations in this pathway among patients over 50 (44.5% vs 29.1%, p=0.01). Among the mutations, 78% were canonical (included in the alpelisib companion diagnostic non-NGS test), while the remaining 22% were characterized as non-canonical mutations (identifiable only by NGS test). mutations were detected in 6.1%, exhibiting a higher frequency in metastatic samples (15.1% vs 1.3%, p=0.003). Additionally, mutations in , or were identified in 3.9% of cases, while mutations in were found in 2.1%. No mutations were detected, nor were TMB high or MSI cases.
CONCLUSION
We describe the genomic landscape of Brazilian patients with ER+/HER2- MBC, in which the somatic mutation profile is comparable to what is described in the literature globally. These data are important for developing precision medicine strategies in this scenario, as well as for health systems management and research initiatives.
PubMed: 38952553
DOI: 10.3389/fonc.2024.1372947 -
Frontiers in Aging Neuroscience 2024Studying the spatiotemporal patterns of amyloid accumulation in the brain over time is crucial in understanding Alzheimer's disease (AD). Positron Emission Tomography...
INTRODUCTION
Studying the spatiotemporal patterns of amyloid accumulation in the brain over time is crucial in understanding Alzheimer's disease (AD). Positron Emission Tomography (PET) imaging plays a pivotal role because it allows for the visualization and quantification of abnormal amyloid beta (Aβ) load in the living brain, providing a powerful tool for tracking disease progression and evaluating the efficacy of anti-amyloid therapies. Generative artificial intelligence (AI) can learn complex data distributions and generate realistic synthetic images. In this study, we demonstrate for the first time the potential of Generative Adversarial Networks (GANs) to build a low-dimensional representation space that effectively describes brain amyloid load and its dynamics.
METHODS
Using a cohort of 1,259 subjects with AV45 PET images from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we develop a 3D GAN model to project images into a latent representation space and generate back synthetic images. Then, we build a progression model on the representation space based on non-parametric ordinary differential equations to study brain amyloid evolution.
RESULTS
We found that global SUVR can be accurately predicted with a linear regression model only from the latent representation space ( = 0.08 ± 0.01). We generated synthetic PET trajectories and illustrated predicted Aβ change in four years compared with actual progression.
DISCUSSION
Generative AI can generate rich representations for statistical prediction and progression modeling and simulate evolution in synthetic patients, providing an invaluable tool for understanding AD, assisting in diagnosis, and designing clinical trials. The aim of this study was to illustrate the huge potential that generative AI has in brain amyloid imaging and to encourage its advancement by providing use cases and ideas for future research tracks.
PubMed: 38952479
DOI: 10.3389/fnagi.2024.1410844 -
Frontiers in Endocrinology 2024The proposed expert opinion aimed to address the current knowledge on conceptual, clinical, and therapeutic aspects of diabetic peripheral neuropathy (DPN) and to... (Review)
Review
The proposed expert opinion aimed to address the current knowledge on conceptual, clinical, and therapeutic aspects of diabetic peripheral neuropathy (DPN) and to provide a guidance document to assist clinicians for the best practice in DPN care. The participating experts consider the suspicion of the disease by clinicians as a key factor in early recognition and diagnosis, emphasizing an improved awareness of the disease by the first-admission or referring physicians. The proposed "screening and diagnostic" algorithm involves the consideration of DPN in a patient with prediabetes or diabetes who presents with neuropathic symptoms and/or signs of neuropathy in the presence of DPN risk factors, with careful consideration of laboratory testing to rule out other causes of distal symmetric peripheral neuropathy and referral for a detailed neurological work-up for a confirmative test of either small or large nerve fiber dysfunction in atypical cases. Although, the first-line interventions for DPN are currently represented by optimized glycemic control (mainly for type 1 diabetes) and multifactorial intervention (mainly for type 2 diabetes), there is a need for individualized pathogenesis-directed treatment approaches for DPN. Alpha-lipoic acid (ALA) seems to be an important first-line pathogenesis-directed agent, given that it is a direct and indirect antioxidant that works with a strategy targeted directly against reactive oxygen species and indirectly in favor of endogenous antioxidant capacity for improving DPN conditions. There is still a gap in existing research in the field, necessitating well-designed, robust, multicenter clinical trials with sensitive endpoints and standardized protocols to facilitate the diagnosis of DPN via a simple and effective algorithm and to track progression of disease and treatment response. Identification of biomarkers/predictors that would allow an individualized approach from a potentially disease-modifying perspective may provide opportunities for novel treatments that would be efficacious in early stages of DPN, and may modify the natural course of the disease. This expert opinion document is expected to increase awareness among physicians about conceptual, clinical, and therapeutic aspects of DPN and to assist them in timely recognition of DPN and translating this information into their clinical practice for best practice in the management of patients with DPN.
Topics: Humans; Diabetic Neuropathies; Expert Testimony; Disease Management; Mass Screening; Diabetes Mellitus, Type 2
PubMed: 38952393
DOI: 10.3389/fendo.2024.1380929 -
Archives of Pathology & Laboratory... Jul 2024In 2022, 2 distinct guidelines for the diagnosis of myeloid neoplasms became available: the 5th edition of the World Health Organization guideline (WHO2022) solely and...
CONTEXT.—
In 2022, 2 distinct guidelines for the diagnosis of myeloid neoplasms became available: the 5th edition of the World Health Organization guideline (WHO2022) solely and the International Consensus Classification (ICC). Despite major overlap, there are important differences that can have important implications.
OBJECTIVE.—
To explore the current opinions and diagnostic practices of hemato-oncologists and hematopathologists across the United States.
DESIGN.—
An online anonymous survey was created using REDCap, and a secure link was shared via email to fellowship program leaderships and via posts on social media.
RESULTS.—
A total of 310 responses were obtained. Only 33 of 309 respondents (10.7%) reported using solely the 2016 World Health Organization guideline to make diagnoses, whereas 167 of 309 (54%) supplemented it with other guidelines. The rest were either not sure (17; 5.5%), used WHO2022 solely (46; 14.9%), or used ICC solely (6; 1.9%). The choice of guideline was not related to region (P = .15), practice setting (P = .86), or hospital size (P = .22). More than 90% reported it is a source of confusion in clinical diagnosis, management, trial design, and other areas.
CONCLUSIONS.—
Overall, our study found that having 2 distinct guidelines could be a source of confusion for physicians and calls for a unified diagnostic language.
PubMed: 38952288
DOI: 10.5858/arpa.2024-0031-OA -
Trials Jun 2024Randomised trials are essential to reliably assess medical interventions. Nevertheless, interpretation of such studies, particularly when considering absolute effects,... (Comparative Study)
Comparative Study
Clinical trial results in context: comparison of baseline characteristics and outcomes of 38,510 RECOVERY trial participants versus a reference population of 346,271 people hospitalised with COVID-19 in England.
BACKGROUND
Randomised trials are essential to reliably assess medical interventions. Nevertheless, interpretation of such studies, particularly when considering absolute effects, is enhanced by understanding how the trial population may differ from the populations it aims to represent.
METHODS
We compared baseline characteristics and mortality of RECOVERY participants recruited in England (n = 38,510) with a reference population hospitalised with COVID-19 in England (n = 346,271) from March 2020 to November 2021. We used linked hospitalisation and mortality data for both cohorts to extract demographics, comorbidity/frailty scores, and crude and age- and sex-adjusted 28-day all-cause mortality.
RESULTS
Demographics of RECOVERY participants were broadly similar to the reference population, but RECOVERY participants were younger (mean age [standard deviation]: RECOVERY 62.6 [15.3] vs reference 65.7 [18.5] years) and less frequently female (37% vs 45%). Comorbidity and frailty scores were lower in RECOVERY, but differences were attenuated after age stratification. Age- and sex-adjusted 28-day mortality declined over time but was similar between cohorts across the study period (RECOVERY 23.7% [95% confidence interval: 23.3-24.1%]; vs reference 24.8% [24.6-25.0%]), except during the first pandemic wave in the UK (March-May 2020) when adjusted mortality was lower in RECOVERY.
CONCLUSIONS
Adjusted 28-day mortality in RECOVERY was similar to a nationwide reference population of patients admitted with COVID-19 in England during the same period but varied substantially over time in both cohorts. Therefore, the absolute effect estimates from RECOVERY were broadly applicable to the target population at the time but should be interpreted in the light of current mortality estimates.
TRIAL REGISTRATION
ISRCTN50189673- Feb. 04, 2020, NCT04381936- May 11, 2020.
Topics: Humans; COVID-19; Male; England; Female; Middle Aged; Aged; Hospitalization; Aged, 80 and over; SARS-CoV-2; Comorbidity; Adult; Randomized Controlled Trials as Topic; Frailty
PubMed: 38951929
DOI: 10.1186/s13063-024-08273-9 -
Cardiovascular Diabetology Jul 2024The available evidence on the impact of specific non-pharmacological interventions on glycaemic control is currently limited. Consequently, there is a need to determine... (Meta-Analysis)
Meta-Analysis Review
The available evidence on the impact of specific non-pharmacological interventions on glycaemic control is currently limited. Consequently, there is a need to determine which interventions could provide the most significant benefits for the metabolic health of young individuals with type 1 diabetes mellitus. The aim of this study was to identify optimal nonpharmacological interventions on glycaemic control, measured by glycated haemoglobin (HbA1c), in children and adolescents with type 1 diabetes. Systematic searches were conducted in PubMed, Web of Science, Scopus, and SPORTDiscus from inception to July 1, 2023. Randomised clinical trials (RCT) investigating nonpharmacological interventions (e.g., physical activity, nutrition, and behavioural therapies) were included. Primary outcome was change in HbA1c levels. Secondary outcome was change in daily insulin dose requirement. Seventy-four RCT with 6,815 participants (49.43% girls) involving 20 interventions were analysed using a network meta-analysis. Most interventions showed greater efficacy than standard care. However, multicomponent exercise, which includes aerobic and strength training (n = 214, standardised mean difference [SMD] =- 0.63, 95% credible interval [95% CrI] - 1.09 to - 0.16) and nutritional supplements (n = 146, SMD =- 0.49, - 0 .92 to - 0.07) demonstrated the greatest HbA1c reductions. These interventions also led to the larger decreases in daily insulin needs (n = 119, SMD =- 0.79, 95% CrI - 1.19 to - 0.34) and (n = 57, SMD =- 0.62, 95% CrI - 1.18 to - 0.12, respectively). The current study underscores non-pharmacological options such as multicomponent exercise and nutritional supplements, showcasing their potential to significantly improve HbA1c in youth with type 1 diabetes. Although additional research to confirm their efficacy is required, these approaches could be considered as potential adjuvant therapeutic options in the management of type 1 diabetes among children and adolescents.
Topics: Humans; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Adolescent; Child; Network Meta-Analysis; Female; Male; Treatment Outcome; Blood Glucose; Randomized Controlled Trials as Topic; Biomarkers; Bayes Theorem; Hypoglycemic Agents; Glycemic Control; Age Factors; Insulin; Dietary Supplements; Exercise Therapy; Exercise; Child, Preschool
PubMed: 38951907
DOI: 10.1186/s12933-024-02301-3 -
Journal of Cardiothoracic Surgery Jul 2024In this study, we compared the analgesic effects of intercostal nerve block (ICNB), ultrasound-guided paravertebral nerve block (PVB), and epidural block (EB) following... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Comparative analysis of the analgesic effects of intercostal nerve block, ultrasound-guided paravertebral nerve block, and epidural block following single-port thoracoscopic lung surgery.
OBJECTIVE
In this study, we compared the analgesic effects of intercostal nerve block (ICNB), ultrasound-guided paravertebral nerve block (PVB), and epidural block (EB) following single-port thoracoscopic lung surgery.
METHOD
A total of 120 patients who underwent single-hole thoracoscopic lung surgery were randomly and equally divided into three groups: ICNB group, the PVB group, and the EB group. ICNB was performed under direct thoracoscopic visualization before the conclusion of the surgery in the ICNB group, while PVB and EB were performed after general anesthesia in the PVB and EB groups, respectively. Patient-controlled intravenous analgesia (PCIA) was used following the surgery in all the groups. The following indicators were recorded: Intraoperative sufentanil dosage, anesthesia awakening time, postoperative intubation time, nerve block operation time, postoperative visual analog scale (VAS) pain scores during resting and coughing at regular intervals of 0, 2, 4, 8, 24, and 48 h, the time until first PCIA, number of effective compressions within 24 h postoperatively, number of rescue analgesia interventions, and the side effects.
RESULTS
In comparison to the ICNB group, the PVB and EB groups had a lower intraoperative sufentanil dosage, significantly shorter anesthesia awakening time, and postoperative intubation time, but longer nerve block operation time, lower VAS scores when resting and coughing within 24 h postoperatively (all p-values less than 0.05). Conversely, there were no statistically significant differences in VAS scores during resting and coughing after 24 h (all p-values greater than 0.05). Time to first PCIA, number of effective compressions and number of rescue analgesia at the 24-hour mark postoperatively were significantly better in the PVB and EB groups than that in the ICNB group (P < 0.05). However, there was a higher incidence of side effects observed in the EB group (P < 0.05).
CONCLUSION
The analgesic effect of PVB and EB following single-port thoracoscopic lung surgery is better than that of ICNB. PVB causes fewer side effects and complications and is safer and more effective.
Topics: Humans; Nerve Block; Female; Male; Middle Aged; Intercostal Nerves; Ultrasonography, Interventional; Pain, Postoperative; Thoracic Surgery, Video-Assisted; Aged; Pain Measurement; Adult; Thoracoscopy; Lung
PubMed: 38951892
DOI: 10.1186/s13019-024-02877-7 -
Journal of Orthopaedic Surgery and... Jun 2024It remains unclear whether the use of an orthopaedic traction table (TT) in direct anterior approach (DAA) total hip arthroplasty (THA) results in better outcomes. The... (Meta-Analysis)
Meta-Analysis Comparative Study
Indirect comparisons of traction table versus standard table in total hip arthroplasty through direct anterior approach: a systematic review and frequentist network meta-analysis.
BACKGROUND
It remains unclear whether the use of an orthopaedic traction table (TT) in direct anterior approach (DAA) total hip arthroplasty (THA) results in better outcomes. The aim of this systematic review and network meta-analysis was to compare the THA outcomes through DAA on a standard operating table and the THA outcomes through DAA on a TT.
METHODS
PubMed, Epistemonikos, and Google Scholar were searched for relevant randomized controlled trials (RCTs) up to 01 January 2024. An indirect comparison in network meta-analysis was performed to assess treatment effects between DAA on a TT and DAA on a standard table, using fixed-effects and random-effects models estimated with frequentist approach and consistency assumption. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were estimated for continuous variables and odds ratios (ORs) with 95% CIs were estimated for binary variables.
RESULTS
The systematic review of the literature identified 43 RCTs with a total of 2,258 patients. DAA with TT had a 102.3 mL higher intraoperative blood loss and a 0.6 mmol/L lower Hb 3 days postoperatively compared with DAA without TT (SMD = 102.33, 95% CI 47.62 to 157.04; SMD = - 0.60, 95% CI - 1.19 to - 0.00). DAA with TT had a 0.15 lower periprosthetic fracture OR compared with DAA without TT (OR 0.15, 95% CI 0.03 to 0.86). There were no further significant differences in surgical, radiological, functional outcomes and in complication rates.
CONCLUSION
Based on our findings and taking into account the limitations, we recommend that particular attention be paid to the risk of periprosthetic fracture in DAA on a standard operating table and blood loss in DAA with TT. Since numerous other surgical, radiological, functional outcome parameters and other complication rates studied showed no significant difference between DAA on a standard operating table and DAA with TT, no recommendation for a change in surgical technique seems justified.
LEVEL OF EVIDENCE
Level I evidence, because this is a systematic review and meta-analysis of randomized controlled trials.
Topics: Humans; Arthroplasty, Replacement, Hip; Network Meta-Analysis; Traction; Treatment Outcome; Blood Loss, Surgical; Operating Tables; Randomized Controlled Trials as Topic; Postoperative Complications
PubMed: 38951886
DOI: 10.1186/s13018-024-04852-3 -
Journal of Experimental & Clinical... Jun 2024During targeted treatment, HER2-positive breast cancers invariably lose HER2 DNA amplification. In contrast, and interestingly, HER2 proteins may be either lost or...
BACKGROUND
During targeted treatment, HER2-positive breast cancers invariably lose HER2 DNA amplification. In contrast, and interestingly, HER2 proteins may be either lost or gained. To longitudinally and systematically appreciate complex/discordant changes in HER2 DNA/protein stoichiometry, HER2 DNA copy numbers and soluble blood proteins (aHER2/sHER2) were tested in parallel, non-invasively (by liquid biopsy), and in two-dimensions, hence HER2-2D.
METHODS
aHER2 and sHER2 were assessed by digital PCR and ELISA before and after standard-of-care treatment of advanced HER2-positive breast cancer patients (n=37) with the antibody-drug conjugate (ADC) Trastuzumab-emtansine (T-DM1).
RESULTS
As expected, aHER2 was invariably suppressed by T-DM1, but this loss was surprisingly mirrored by sHER2 gain, sometimes of considerable entity, in most (30/37; 81%) patients. This unorthodox split in HER2 oncogenic dosage was supported by reciprocal aHER2/sHER2 kinetics in two representative cases, and an immunohistochemistry-high status despite copy-number-neutrality in 4/5 available post-T-DM1 tumor re-biopsies from sHER2-gain patients. Moreover, sHER2 was preferentially released by dying breast cancer cell lines treated in vitro by T-DM1. Finally, sHER2 gain was associated with a longer PFS than sHER2 loss (mean PFS 282 vs 133 days, 95% CI [210-354] vs [56-209], log-rank test p=0.047), particularly when cases (n=11) developing circulating HER2-bypass alterations during T-DM1 treatment were excluded (mean PFS 349 vs 139 days, 95% CI [255-444] vs [45-232], log-rank test p=0.009).
CONCLUSIONS
HER2 gain is adaptively selected in tumor tissues and recapitulated in blood by sHER2 gain. Possibly, an increased oncogenic dosage is beneficial to the tumor during anti-HER2 treatment with naked antibodies, but favorable to the host during treatment with a strongly cytotoxic ADC such as T-DM1. In the latter case, HER2-gain tumors may be kept transiently in check until alternative oncogenic drivers, revealed by liquid biopsy, bypass HER2. Whichever the interpretation, HER2-2D might help to tailor/prioritize anti-HER2 treatments, particularly ADCs active on aHER2-low/sHER2-low tumors.
TRIAL REGISTRATION
NCT05735392 retrospectively registered on January 31, 2023 https://www.
CLINICALTRIALS
gov/search?term=NCT05735392.
Topics: Humans; Female; Breast Neoplasms; Receptor, ErbB-2; Liquid Biopsy; Middle Aged; Ado-Trastuzumab Emtansine; Aged; Trastuzumab; Adult; Biomarkers, Tumor
PubMed: 38951853
DOI: 10.1186/s13046-024-03105-9 -
Cardiovascular Diabetology Jun 2024Glucokinase (GK) plays a key role in glucose metabolism. In the liver, GK is regulated by GK regulatory protein (GKRP) with nuclear sequestration at low plasma glucose...
BACKGROUND
Glucokinase (GK) plays a key role in glucose metabolism. In the liver, GK is regulated by GK regulatory protein (GKRP) with nuclear sequestration at low plasma glucose level. Some GK activators (GKAs) disrupt GK-GKRP interaction which increases hepatic cytoplasmic GK level. Excess hepatic GK activity may exceed the capacity of glycogen synthesis with excess triglyceride formation. It remains uncertain whether hypertriglyceridemia associated with some GKAs in previous clinical trials was due to direct GK activation or impaired GK-GKRP interaction.
METHODS
Using publicly available genome-wide association study summary statistics, we selected independent genetic variants of GCKR and GCK associated with fasting plasma glucose (FPG) as instrumental variables, to mimic the effects of impaired GK-GKRP interaction and direct GK activation, respectively. We applied two-sample Mendelian Randomization (MR) framework to assess their causal associations with lipid-related traits, risks of metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular diseases. We verified these findings in one-sample MR analysis using individual-level statistics from the Hong Kong Diabetes Register (HKDR).
RESULTS
Genetically-proxied impaired GK-GKRP interaction increased plasma triglycerides, low-density lipoprotein cholesterol and apolipoprotein B levels with increased odds ratio (OR) of 14.6 (95% CI 4.57-46.4) per 1 mmol/L lower FPG for MASLD and OR of 2.92 (95% CI 1.78-4.81) for coronary artery disease (CAD). Genetically-proxied GK activation was associated with decreased risk of CAD (OR 0.69, 95% CI 0.54-0.88) and not with dyslipidemia. One-sample MR validation in HKDR showed consistent results.
CONCLUSIONS
Impaired GK-GKRP interaction, rather than direct GK activation, may worsen lipid profiles and increase risks of MASLD and CAD. Development of future GKAs should avoid interfering with GK-GKRP interaction.
Topics: Mendelian Randomization Analysis; Humans; Genome-Wide Association Study; Adaptor Proteins, Signal Transducing; Risk Factors; Genetic Predisposition to Disease; Risk Assessment; Blood Glucose; Glucokinase; Biomarkers; Lipids; Phenotype; Carrier Proteins; Polymorphism, Single Nucleotide; Time Factors; Dyslipidemias; Fatty Liver
PubMed: 38951793
DOI: 10.1186/s12933-024-02321-z