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At least 19 recordsLinked to original sources
PubMed2026

Clinically actionable genomic alterations in breast cancer brain metastases.

BACKGROUND: Breast cancer brain metastases (BCBMs) represent a critical unmet clinical need in metastatic breast cancer (MBC) and the identification of novel therapeutic targets is urgently needed in this context. In this study, we describe clinically actionable targets in BCBMs using comprehensive genomic profiling. PATIENTS AND METHODS: Genomic DNA was extracted from formalin-fixed paraffin-embedded archival BCBM samples and analyzed using the commercially available Agilent SureSelect V6 whole exome sequencing (WES) kit and an Illumina NovaSeq 6000 platform. Pathogenic alterations were classified as actionable alterations (AAs) if they met the updated MBC or tumor-agnostic ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) I or II criteria of the ESCAT scale. RESULTS: WES data from 56 BCBM samples were available [33.9% hormone receptor (HR)-negative/human epidermal growth factor receptor (HER)2-negative; 25.0% HR-positive/HER2-negative; and 38% HER2-positive]. ESCAT I/II AAs were detected in 76.8% (n = 43) of all BCBMs and the most frequently detected AAs were in genes involved in the homologous recombination repair pathway (BRCA1/BRCA2/PALB2; 53.6% overall). Biallelic inactivation of BRCA1, BRCA2, or PALB2 was observed in 19.6% of samples, with higher rates in HER2-negative BCBMs (26% in HR-negative /HER2-negative and 21% in HR-positive/HER2-negative). ESCAT I/II PIK3CA/AKT1/PTEN pathway alterations were present in 48.2% of samples and, in particular, in 50% of HR-positive/HER2-negative BCBMs. No ESR1 mutation was detected in HR-positive/HER2-negative BCBMs. The prognostic impact of previously described AAs was evaluated overall and according to breast cancer subtype. Twenty-three BCBMs (41%) were classified as HER2-positive; among these, 3 (13%) presented a hotspot PIK3CA mutation and 7 (30%) presented a PTEN deletion. Among patients with HER2-positive BCBMs, the identification of a hotspot PIK3CA mutation was significantly associated with worse prognosis. CONCLUSIONS: ESCAT I/II actionable genomic alterations are frequent in BCBMs, highlighting the potential for genomically targeted treatments in this setting.

ESCAT↗
PubMed2026

Comparative Analysis of Potential Clinical Actionability of Genomic Alterations in Early-Onset Versus Later-Onset GI Cancers.

PURPOSE: As biomarker-directed therapy increasingly shapes GI oncology, it remains unclear whether early-onset (EO) and later-onset (LO) GI cancers harbor comparable opportunities for clinically actionable targeting. We compared the landscape of potentially actionable genomic alterations in EO versus LO GI cancers using American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange v19.0. METHODS: GI tumor samples were assigned to 10 prespecified tumor groups using OncoTree codes. Samples were annotated with OncoKB therapeutic levels and classified as potentially actionable if they harbored at least one level 1-3B alteration. EO and LO disease were defined as age at sequencing <50 years and &#x2265;50 years, respectively. Group-wise comparisons used Wilcoxon rank-sum, chi-square, or Fisher exact testing as appropriate and with false discovery rate correction. Multivariable logistic regression evaluated age group associations overall and within tumor groups. RESULTS: Among 53,945 GI tumor samples, 10,573 (19.6%) were EO and 43,372 (80.4%) were LO. EO tumors had lower prevalence of potentially actionable alterations in colorectal (71% v 78.1%, q < 0.001), esophagogastric (53.3% v 57.9%, q = 0.0097), GI stromal tumor (GIST) (75.1% v 90.9%, q < 0.001), liver (25.4% v 35.4%, q = 0.0021), and pancreatic tumors (82.9% v 90.7%, q < 0.001). In the overall model, LO status was associated with higher odds of potential actionability (odds ratio, 1.39 [95% CI, 1.33 to 1.47]; P < .001). Tumor group-specific associations persisted in colorectal, GIST, liver, and pancreatic tumors after multivariable adjustment. CONCLUSION: Potential clinical actionability differs between EO and LO GI cancers in a tumor lineage-specific manner. Several major EO GI tumor groups appear relatively depleted of potentially actionable alterations, suggesting that the expanding therapeutic reach of precision oncology may not be distributed evenly across age-defined GI cancer populations and underscoring the need for EO-focused biomarker discovery and therapeutic development.

Humans↗
PubMed2026

Real-world pathogen spectrum, clinical actionability, and host correlates of first-time mNGS testing in hospitalized patients with hematologic diseases.

BACKGROUND: Patients with hematologic diseases are highly susceptible to infection. Conventional tests often have low sensitivity. Metagenomic next-generation sequencing (mNGS) can detect many pathogens at once, but its clinical value depends on how the results are interpreted. It is often hard to tell true infection from colonization or contamination. METHODS: We retrospectively studied hospitalized hematologic patients Only adult patients (&#x2265;18 years) who received mNGS for the first time. Detected organisms were reclassified using a clinical actionability system. We also analyzed the relationships between mNGS findings, host characteristics, and short-term outcomes. RESULTS: A total of 134 patients were included. At least one organism was detected in 87.3% of patients, but only 58.2% had highly actionable results. Bacteria were the most common findings, followed by viruses and fungi. Mixed detections were frequent. Actionable results were seen more often in respiratory specimens than in blood specimens. Viral detection was associated with immune status. Pathogen read counts were only weakly related to inflammatory markers and did not independently predict adverse outcomes. Age was the only independent risk factor for adverse outcome. CONCLUSION: mNGS had a high detection rate in hematologic patients, but not all positive findings were clinically important. Result interpretation should take specimen type and host status into account. Pathogen read counts alone were not useful for predicting short-term outcome.

Humans↗
PubMed1976

[Comparative evaluation of the clinical action of a series of beta-adrenergic blockaders].

A comparative clinical study of the efficacy of Benzoral, Trasicor, Viskene, Aptene, Eraldine and Inderal was conducted in the ischaemic heart disease patients. Their antiarrhythmic and antianginal effect was determined, as well as their optimum therapeutic dosages, the activity of their specific beta-adrenolytic properties, the effect of the drugs on the bronchi and the peripheral venous tone. Apart from the clinical study, electro- and polycardiography, functional pulmonary tests and the Schellong orthostatic test were used. All the drugs in question were found to produce a distinct specific beta-blocking effect. They are effective in cases of atrial and ventricular extrasystole, paroxysmal tachycardia, sinus tachycardia and tachyarrhythmic fibrillation, as well as for the prevention of anginal attacks and arrhythmic fibrillation. All the drugs produce a negative inotropic effect, Inderal--the strongest, Viskene and Benzoral--the weakest. All beta-blockers can impair bronchial patency in patients with bronchial obstruction. This effect is least pronounced with Eraldine that may be used as the drug of choice in such cases. In most cases the beta-blockers do not affect the peripheral venous tone, but in some cases they may reduce it.

Adrenergic beta-Antagonists↗
PubMed2025

Clinical Actionability of Genetic Findings in Cerebral Palsy: A Systematic Review and Meta-Analysis.

IMPORTANCE: Single gene variants can cause cerebral palsy (CP) phenotypes, yet the impact of genetic diagnosis on CP clinical management has not been systematically evaluated. OBJECTIVE: To evaluate how frequently genetic testing results would prompt changes in care for individuals with CP and the clinical utility of precision medicine therapies. DATA SOURCES: Published pathogenic or likely pathogenic variants in OMIM genes identified with exome sequencing in clinical (n&#x2009;=&#x2009;1345) or research (n&#x2009;=&#x2009;496) cohorts of CP were analyzed. A systematic literature review for evidence of effective therapies for specific genetic etiologies was performed. STUDY SELECTION: Nonstandard interventions that led to a detectable improvement in a defined outcome in individuals with variants in the gene of interest were included. DATA EXTRACTION AND SYNTHESIS: Literature was evaluated using PRISMA guidelines. A diverse, expert working group was established, scoring rubrics adapted, and scoring consensus built with a modified Delphi approach. MAIN OUTCOMES AND MEASURES: Overall clinical utility was calculated from metrics assessing outcome severity if left untreated, safety and practicality of the intervention, and anticipated intervention efficacy on a scale from 0 to 3. RESULTS: Of 1841 patients with CP who underwent exome sequencing, 502 (27%) had pathogenic or likely pathogenic variants related to their phenotype. A total of 243 different genes were identified. In 1841 patients with identified genetic etiologies of CP, 140 (8%) had a genetic etiology classified as actionable, defined as prompting a change in clinical management. Also identified were 58 of 243 genes with pathogenic or likely pathogenic variants with actionable treatment options: 16 targeting the primary disease mechanism, 16 with specific prevention strategies, and 26 with specific symptom management. The level of evidence was also graded according to ClinGen criteria; 45 of 101 interventions (44.6%) had evidence class D or below. The potential interventions have clinical utility with 98 of 101 outcomes (97%) being moderate-high severity if left untreated and 63 of 101 interventions (62%) predicted to be of moderate-high efficacy. Most interventions (72 of 101 [71%]) were considered moderate-high safety and practicality. CONCLUSIONS AND RELEVANCE: The findings indicate that actionable genetic findings occurred in 8% of individuals referred for genetic testing with CP. Evaluation of potential efficacy, outcome severity, and intervention safety and practicality indicates moderate-high clinical utility of these genetic findings. Genetic sequencing can identify precision medicine interventions that provide clinical benefit to individuals with CP. The relatively limited evidence base underscores the need for additional research.

Humans↗
PubMed2026

Clinically actionable stratification of uncommon MET fusions: a precision oncology framework.

BACKGROUND: MET fusions represent emerging therapeutic targets in solid tumors; however, functional interpretation of non-canonical variants remains poorly understood, posing a major challenge for precision oncology. METHODS: We conducted a multicenter, pan-cancer study analyzing 23,299 clinical samples using DNA-based next-generation sequencing (NGS) to profile MET fusions. Transcriptional validation was performed using RNA-based NGS on available samples. Preliminary clinical outcomes were assessed in four patients with advanced malignancies harboring uncommon MET fusions who received MET tyrosine kinase inhibitor therapy. RESULTS: We identified 116&#x2009;MET fusions (incidence: 0.5%), with 55.2% (64/116) classified as uncommon fusions. These uncommon fusions were stratified into: Group A (5&#x2019;-retained, n&#x2009;=&#x2009;12), Group B (intergenic/exonic breakpoints, n&#x2009;=&#x2009;19), Group C (rare partners, n&#x2009;=&#x2009;23), and Group D (dual fusions, n&#x2009;=&#x2009;10). RNA validation revealed an overall low transcriptional consistency of 43.8% (14/32) for uncommon fusions, versus 100% for canonical fusions (PTPRZ1::MET, CAPZA2::MET). Notably, most 5&#x2019;-retained fusions were transcriptionally silent, while some intergenic fusions resolved into expressed canonical partners (e.g. PTPRZ1::MET). Therapeutically, all four MET inhibitor-treated patients achieved partial responses, including pediatric diffuse midline gliomas (DMG) (median OS: 11.2&#x2009;months) and lung adenocarcinoma (median OS: 34&#x2009;months), demonstrating preliminary clinical activity. CONCLUSIONS: uncommon MET fusions are heterogeneous at genomic and transcriptional levels. DNA-level findings often do not predict functional transcripts, underscoring the necessity of RNA-based confirmation for clinical interpretation. Despite low overall consistency, a subset retains therapeutic potential. We propose a refined diagnostic framework integrating DNA-based stratification and RNA validation to guide the management of MET-altered cancers in precision oncology workflows.

Humans↗
PubMed2026

Comparison of Performance of Publicly Available Polygenic Risk Scores to Predict Clinically Actionable Coronary Artery Calcium Scores: The BioHEART-CT Cohort.

AIM: Coronary artery disease (CAD) remains the leading cause of morbidity and mortality globally. Polygenic Risk Scores (PRS) have been trained against major adverse cardiovascular outcomes (MACE) in large cohorts. Few studies have examined the effectiveness of these CAD MACE PRS tools in detecting individuals with subclinical coronary calcification. An association would provide an opportunity for clinical translation and targeting of CT imaging to new patients at risk for subclinical disease. METHODS: An analysis of 53 publicly available CAD PRS tools was completed in participants of the BioHEART-CT Discovery 1000 cohort presenting for clinically referred CT coronary angiography (CCTA). Associations between PRS and two binary CACS outcomes reflecting clinically significant coronary calcification were assessed: a) Absolute CACS (CACS &#x2265;100 Agatston units [AU]; and b) Percentile CACS (CACS &#x2265;75th age-/sex-adjusted percentile). Models were adjusted for genetic principal components, modifiable cardiovascular risk factors, and age/sex (in Absolute CACS). A subgroup analysis was performed using Framingham Risk Score (FRS) at baseline. RESULTS: Among 803 BioHEART-CT Discovery 1000 participants, 487 (60.6%) had any detectable coronary calcium. Most PRS tools demonstrated significant association with CACS outcomes, particularly evident when PRS was modelled as a continuous predictor. For Percentile CACS, 94.3% of PRS tools were significantly associated after full adjustment (median OR per PRS SD 1.41 (IQR 1.23-1.60). Quintile-based analysis revealed that individuals in the Top Quintile PRS had up to 7.99-fold increased odds of Percentile CACS &#x2265;75th compared to those in the Bottom Quintile. Analysis by FRS group revealed positive performance, especially in individuals of Low FRS wherein incorporating a PRS increased pre-test probability from 14% to 26%. CONCLUSION: Whilst most CAD PRS tools have been developed against clinical events, we show their ability to predict clinically relevant coronary calcification. Utility appears strongest in individuals traditionally considered lower risk, presenting an opportunity for clinical translation for improved diagnosis in the primary prevention setting, with the potential to triage individuals into a CACS screening pathway.

coronary artery disease↗
PubMed1976

The influence of three antacids on the absorption and clinical action of oral diazepam.

Diazepam 10 mg given orally alone or with one of the three antacids (aluminium hydroxide 40 ml, magnesium trislicate 30 ml, sodium cirate 30 ml) was given in a single dose at random to 200 women undergoing minor gynaecological procedures. The concomitant use of aluminium hydroxide or sodium citrate hastened the onset of the soporific effect of diazepam marginally, while magnesium trisilicate tended to delay it. The estimation of plasma diazepam concentrations over 90 min in a similar series of 67 patients showed that the absorption of diazepam was increased significantly by the use of aluminium hydroxide, but there were no striking differences in the four groups. The clinical implications of these findings are discussed.

Administration, Oral↗
PubMed1976

Pentobarbitone premedication for anaesthesia. The influence of the preparation and route of administration on its clinical action.

Studies were carried out in the pre-operative period on patients premedicated with 100 mg pentobarbitone given by mouth or by intramuscular injection into the buttock. The injections were given by doctors using a 4 cm needle or by nurses using the needle of their choosing and two preparations were used. One was a freshly prepared aqueous solution and the other the commercially available organic solution (Nembutal) with propylene glycol, alcohol and water as solvents. An unacceptably high incidence of persistent injection site pain occurred after the use of the organic preparation but not with the aqueous solution. Otherwise no difference was detected between the effects of the two preparations. Drugs injected by doctors were, on the whole, more effective as premedicants than those injected by nurses. Oral pentobarbitone was not as effective a premedicant as the intramuscular preparation and its anxiolytic action did not differ from that of the placebo. Relief of apprehension was disappointing with all preparations of 100 mg pentobarbitone and was not as good as with diazepam. This may be attributed to the use of too small doses but larger injection volumes would have caused their own problems.

Administration, Oral↗
PubMed1975

The influence of the route of administration on the clinical action of diazepam.

The relative efficacy of diazepam 10 mg as a premedicant was assessed following its oral and intramuscular administration, using a "double-blind, double-dummy" technique, as well as its effect when given by both routes. Drugs were given to a standard patient population who were undergoing the same type of operation and receiving a standard anaesthetic. The most rapid onset of soporific action occurred when diazepam was given by mouth and this produced the best effect throughout the period of the study although its efficacy began to pass off after 60 minutes. It was superior in effect to the same dose injected into the thigh. The combined effect of oral and intramuscular diazepam was not notably greater than tht of the single oral dose. The injection of diazepam was followed by an unacceptably high incidence of pain, particularly when this was given into the thigh. There were no significant differences in either the course of anaesthesia or the incidence of post-operative nausea and vomiting. When the undesired effects are taken into consideration, the oral administration of diazepam should be the route of choice.

Administration, Oral↗
PubMed1977

The nutrition problem in Latin America: definition, causes, and remedial actions.

Clinical, dietary, and biochemical surveys have shown that on the whole Latin America faces a serious nutrition problem. This article reviews the nature and extent of that problem, especially its effects on maternal and child health, and suggests various approaches for researchers, health professionals, and political authorities that would contribute to its resolution.

Child↗