AimThe phase 4 RESOLUTION trial showed that, in comparison with placebo, adding eptinezumab-an anti-calcitonin gene-related peptide monoclonal antibody-to a brief educational intervention (BEI) reduced the monthly frequency of migraine, headache, and acute medication use in participants with chronic migraine (CM) and medication-overuse headache (MOH). Herein, we report data from multiple patient-reported outcomes (PROs) evaluating treatment impact on disease burden and health-related productivity and quality of life in the RESOLUTION trial.MethodsRESOLUTION was a multi-national (conducted at 76 sites across 11 countries), double-blind, randomized, placebo-controlled trial. The trial comprised a 4-week screening period; a 12-week, double-blind, placebo-controlled period; a 12-week, open-label, extension period; and an 8-week, safety follow-up period, with results of the placebo-controlled period presented in this paper. Adults diagnosed with CM and MOH received a BEI and were randomized 1:1 to intravenous infusion with either eptinezumab 100 mg or placebo. Several PROs were assessed at baseline, Week 4, and Week 12, including the six-item Headache Impact Test (HIT-6), modified Migraine Disability Assessment (mMIDAS), Migraine-specific Work Productivity and Activity Impairment questionnaire (WPAI:M), Patient Global Impression of Change (PGIC; assessed only at follow-up), patient-identified most bothersome symptom (PI-MBS; assessed only at follow-up), Migraine-Specific Quality-of-Life questionnaire version 2.1 (MSQ v2.1), EQ-5D-5L visual analogue scale, and nine-item Treatment Satisfaction Questionnaire for Medication (TSQM-9; assessed only at follow-up). Post hoc analyses included responder rates for HIT-6 (i.e., participants with ≥5-point reduction from baseline), as well as for PGIC and PI-MBS (i.e., participants who reported "much improved" or "very much improved").ResultsOf 608 participants randomized, the full-analysis set included 302 participants in the eptinezumab arm and 300 in the placebo arm. Eptinezumab with BEI was associated with more favorable PRO scores compared to placebo with BEI, starting at Week 4 (p < 0.05 for all comparisons) and up to Week 12 (p < 0.01 for all comparisons except WPAI:M absenteeism). Responder rates for HIT-6, PGIC, and PI-MBS also favored eptinezumab versus placebo.ConclusionsIn participants with CM and MOH who also received patient education, eptinezumab treatment resulted in greater reductions in headache impact and migraine disability than placebo, with greater improvements in productivity, quality of life, overall disease status, and treatment satisfaction starting from Week 4 and sustained to Week 12. Eptinezumab in combination with patient education is an effective treatment for reducing disease burden and improving overall quality of life in people with CM and MOH.Trial registrationClinicalTrials.gov Identifier: NCT05452239 (https://clinicaltrials.gov/study/NCT05452239); EudraCT Number: 2021-003049-40 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=2021-003049-40).
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To perform an updated systematic review and meta-analysis of the efficacy and safety of intensive (INT) vs. conventional (CONV) blood glucose (BG) targets for critically ill adults on insulin infusions. We conducted a comprehensive search of Embase and OVID Medline databases from inception to October 16, 2023. We manually excluded studies published before 2000 due to potential lack of relevance as glycemic control in the ICU was not routinely practiced before 2000. We included randomized controlled trials (RCTs) evaluating adult, critically ill patients on insulin infusions comparing INT vs. CONV targets for efficacy and safety outcomes. Data were screened and extracted with accuracy confirmed by a second reviewer. Study methodological characteristics, patient population, interventions, and outcome data were recorded. Studies without numerical outcomes were summarized as text statements. Forty-five RCTs were included involving 32,215 patients. No differences were seen between INT and CONV targets for hospital mortality or ICU mortality. INT targets were associated with lower ICU length of stay (LOS), infections, and critical illness polyneuropathy (CIP); however, INT targets demonstrated a 3.6-fold higher risk of severe hypoglycemia. Most of the studies with significant differences contained serious inconsistencies or risk of bias. In the subgroup analyses, INT targets demonstrated favorable neurologic outcomes in neurologic ICU patients, lower ICU LOS in mixed ICU patients, and lower ICU mortality in the cardiac surgery subgroup. INT BG targets demonstrated mild to moderate improvements in several important morbidity secondary outcomes, including LOS, infections, and CIP, but were associated with a 3.6-fold higher risk of severe hypoglycemia. No differences were seen in ICU or hospital mortality. INT targets should not be routinely used over CONV targets when trying to minimize hypoglycemia as a marker of patient safety. However, as stated in the Society of Critical Care Medicine guidelines, a lower target within the INT range (110-140 mg/dL; 6.1-7.8 mmol/L) may be considered acceptable in select centers where the risk of hypoglycemia is documented to be negligible based on routine assessment and with the use of optimized glycemic management protocols.
Mental health providers (MHPs) hold varying attitudes about suicide prevention, and these beliefs can impact personal and client well-being. To date, suicide prevention attitude measures are limited by appropriate population use, poor psychometrics and a lack of theoretical foundation. The present study rectified a measurement gap in the literature by articulating initial development of the Inventory of Clinician Attitudes about Suicide Prevention (ICASP). MHPs (N = 410) across three countries (United States, Canada and Australia) took part in a cross-sectional online survey about suicide prevention competencies. A community-engaged convenience sampling approach was used followed by splitting the sample to perform parallel exploratory factor analysis and item response theory analyses. Analyses yield a four-factor ICASP with 22 items: (1) Clinician's Approach (ω = 0.79); (2) Clinician Avoidance (ω = 0.76); (3) Moral Rights (ω = 0.84); and (4) Clinician Comfort (ω = 0.72). Exploratory findings suggest convergent validity via significant, yet modestly sized, correlations with attitudes glorifying suicide and three elements of compassion fatigue (i.e. compassion satisfaction, burnout and secondary traumatic stress). The ICASP represents a promising tool for measurement of MHP suicide prevention attitudes in clinical supervision, self-reflective practice and training evaluation. Findings support portions of the Dynamic Balance Model of MHP suicide prevention attitudes. Future psychometric research directions are discussed.
 Heart failure (HF) remains a major clinical and public health challenge. Guideline-directed medical therapy (GDMT) has been shown to improve outcomes in patients with HF; however, gaps in the prescription and implementation of these therapies persist. These treatment gaps may contribute to suboptimal disease management and adverse clinical outcomes, highlighting the need to better understand patterns of GDMT utilization in diverse patient populations. In this study, we assessed and evaluated the prescribing patterns of GDMTs to an underserved population at an urban federally qualified health center (FQHC). We conducted a retrospective chart review of patients diagnosed with HF from May 2022 to June 2024 to assess the prescription of GDMT. Patients were classified based on echocardiographic findings as HF with reduced ejection fraction (HFrEF) (< 50%) and HF with preserved ejection fraction (HFpEF) (≥ 50%). Baseline demographics and prescription of GDMTs were compared between the two HF diagnoses. Fifty patients with HF were identified in the study period, including 41 with HFrEF and nine with HFpEF. There was a significant difference in the mean age between patients diagnosed with HFpEF (68 years) as compared to patients with HFrEF (58 years) (p=0.02). Among patients with HFrEF, 93% (n=38) were prescribed beta-blockers (BB), 83% (n=34) were prescribed angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers/angiotensin receptor-neprilysin inhibitors (ACEi/ARB/ARNi), 29% (n=12) were prescribed mineralocorticoid receptor antagonists (MRA), and 34% (n=14) were prescribed sodium-glucose cotransporter-2 inhibitors (SGLT2). Prescriptions for these medical therapies were similar among patients with HFpEF, except that 0% were prescribed an SGLT2 medication (p=0.05 for comparison with patients with HFrEF). GDMT is under-prescribed in underserved populations, underscoring the need for specific interventions to address financial, systemic, and educational barriers. Interventions such as patient education initiatives, financial counseling support, provider training programs, and policy changes to improve medication affordability and access should be prioritized to help close these treatment gaps.
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The objective of this analysis was to describe the effects of methylphenidate-mediated symptom improvement on functional impairments in adults with ADHD. This is an exploratory study of self-reported functional impairment on the Weiss Functional Impairment Rating Scale (WFIRS-S) in 351 ADHD adults treated in a forced dose, double blind (DB), randomized, parallel clinical trial of a 16-hr methylphenidate stimulant (PRC-063) for 4 weeks followed by open-label (OL; N = 147) for 6 months. During the 4-week DB period, there was a statistically significant response to medication versus placebo in the WFIRS-S domain of "work." Forty percent of DB subjects, assigned a random dose of medication, showed functional improvement as defined by the Minimal Clinical Important Differences (MCID) of the WFIRS. At the end of DB, one third of subjects had scores below symptomatic and functional impairment thresholds and two thirds by the end of OL. Although the OL period was uncontrolled, when all subjects had been dose optimized with sufficient time for functional impairment to manifest, all WFIRS functional domains showed clinically-relevant improvements from baseline to end of the 6-month OL (p < .0001). There was a fair-to-moderate correlation between change in symptoms and change in function, but ADHD symptoms were about twice as sensitive to change. The strongest predictor of improvement in function was greater improvement in ADHD symptoms. Younger age predicted greater functional impairment. This study of the relationship between change in symptoms and functional outcome illustrates that improvement in symptoms may be associated with an almost cotemporaneous improvement in function, that increases over time. Identification of subjects who are symptom responders with residual functional impairment suggests the need for additional intervention to target residual functional difficulty. Further research needs to replicate this methodology using an individually dose optimized design to demonstrate full potential for change and to confirm the domains of functioning in adults with ADHD that are most responsive to stimulant treatment. https://clinicaltrials.gov/study/NCT02139124.
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Amphiphilic lipids are potent membrane-disrupting antibacterials, but their activity cannot normally be modulated after administration. Here we report photoswitchable amphiphilic lipids (PALs) that enable reversible, light-controlled modulation of antibacterial potency through photoinduced changes in molecular conformation. The PALs incorporate azobenzene photoswitches linking quaternary ammonium headgroups to variable alkyl chains, allowing their geometry and membrane affinity to be tuned by trans-cis isomerisation. Systematic studies against multidrug-resistant Gram-positive bacteria revealed a striking, chain-length-dependent photomodulation. Short-chain PALs lost activity upon irradiation, whereas long-chain derivatives became strongly antibacterial in their cis-enriched states, with up to 32-fold reductions in MICs. Molecular dynamics simulations correlated these changes with light-dependent differences in membrane insertion depth and molecular orientation, providing a structural basis for optical control of membrane disruption. These findings establish a mechanistic framework for designing photoswitchable amphiphiles that translate molecular photoisomerisation into controllable biological function, extending the reach of photopharmacology into antibacterial membrane-active agents.
Background/Objectives: Reliable biomarkers for longitudinal surveillance of neuroendocrine tumors (NETs) remain an unmet clinical need. Chromogranin A (CgA), the most widely used circulating biomarker, is limited by low sensitivity, substantial biologic variability, and poor concordance with radiologic progression. NETest2.0® is a blood-based multigene transcriptomic liquid biopsy designed to dynamically assess NET biologic activity. This study compared serial NETest2.0® measurements with CgA for monitoring disease progression in a real-world registry cohort. Methods: Patients with histologically confirmed NETs enrolled in the RegisterNET program (NCT02270567) who had paired blood samples and contemporaneous clinical assessment were included. NETest2.0® scores were derived from quantitative RT-PCR analysis of a 51-gene transcript panel and expressed on a 0-100 scale. Serum CgA levels were measured using standard clinical immunoassays. Imaging-based disease assessment was performed using CT, MRI, and/or 68Ga-somatostatin receptor PET/CT with RECIST 1.1 criteria applied where appropriate. Longitudinal percentage changes (Δ) between sequential measurements were evaluated using predefined NETest2.0® thresholds and compared with the conventional CgA threshold (>50%). NETest2.0 Δ thresholds of >0% and >5% were evaluated a priori: >0% as a high-sensitivity threshold capturing any upward transcriptomic drift, and >5% as a more conservative threshold intended to reduce minor biological or analytical fluctuation. Receiver operating characteristic (ROC) analysis, operating characteristics, multivariable analysis (MVA), and logistic regression analysis (LRA) were performed. Results: A total of 191 patients were analyzed. Exploratory ROC analysis demonstrated superior discrimination for progression using serial NETest2.0® changes compared with changes in CgA (AUC: 0.893 vs. 0.538; p < 0.0001). In the primary surveillance analysis, NETest2.0® thresholds of >0% and >5% achieved AUCs of 0.860 (95% CI: 0.803-0.906) and 0.822 (95% CI: 0.760-0.873), respectively, both significantly superior to CgA (AUC: 0.553, 95% CI: 0.480-0.625; both p < 0.0001). NETest2.0® >0% demonstrated the highest sensitivity (86.4%), whereas NETest2.0® >5% achieved the optimal balance of sensitivity (70.5%), specificity (93.9%), and overall accuracy (88.5%). In multivariable and logistic regression analyses, changes in NETest2.0® were the strongest independent predictor of progression (all p < 0.0001; odds ratios: 52.99-61.26), whereas CgA did not significantly contribute to progression prediction. Conclusions: Serial NETest2.0® assessment significantly outperformed CgA for monitoring NET disease activity and progression. These findings support the integration of NETest2.0® into molecularly informed surveillance strategies to complement imaging and improve longitudinal monitoring of patients with NETs.
Inflammation and fibrinolytic imbalance, which are frequently caused by oxidative stress and increased pro-inflammatory mediators, are major factors in the onset and progression of chronic illnesses. The study evaluated the phytochemical profile of Urena lobata L. leaf extracts using qualitative chemical tests and spectroscopic analysis, including FT-IR and MC-MS profiling. The pharmacological assessments were performed by antioxidant, anti-inflammatory, and thrombolytic capabilities of extracts using various in vitro assay methods along with in silico approaches, including molecular docking and ADMET-based pharmacokinetic assessments. The methanolic extract of Urena lobata L. (ULM) was fractionated using n-hexane, chloroform, ethyl acetate, and water to obtain the n-hexane (ULH), chloroform (ULC), ethyl acetate (ULE), and aqueous (ULW) fractions. Phytochemical analysis exhibited the presence of flavonoids, steroids, terpenoids, alkaloids, glycosides, and phenols in various fractions. FTIR analysis revealed the presence of a variety of groups, including aliphatic, aromatic, amide, nitrate, methylene, alcohols, phenols, etc. GC-MS study revealed significant bioactive chemicals, including β-amyrenonol acetate derivative, 14-deoxy-12-hydroxyandrographolide, 9,12-octadecadienoic acid, and N-(5-methyl-1,3-thiazol-2-yl)-2-phenylacetamide. In in vitro antioxidant assay, ULE had the highest antioxidant activity among the investment fractions, with IC50 values of 1.17 µg/mL (DPPH) and 2.60 µg/mL (hydroxyl radical), followed by ULM, ULC, and ULH fractions. In vitro anti-inflammatory studies indicated that the ULE efficiently stabilized human red blood cell membranes (~ 91.57%), comparable to that of the standard medication diclofenac. Additionally, thrombolytic assays revealed considerable clot lysis for ULE (28.40%) and ULM (28.26%) fractions. Molecular docking revealed that β-amyrenonol acetate derivative had a stronger binding affinity to COX-2 (-10.1 kcal/mol) than conventional diclofenac and plasminogen (-9.8 kcal/mol), whereas other elements showed synergistic interactions. ADMET calculation validated favorable pharmacokinetic features and low toxicity risk. Notably, this study presents the first in silico investigation of U. lobata L. phytochemicals as potential thrombolytic agents. Overall, the ethyl acetate fraction of U. lobata L. has substantial antioxidant, anti-inflammatory, and thrombolytic properties, highlighting its promise as a multifunctional therapeutic agent and justifying additional bioassay-guided isolation, mechanistic research, and clinical testing.
BackgroundThis study compared treatment persistence of individuals newly initiating treatment with rimegepant or lasmiditan for the acute treatment of migraine.MethodsA retrospective cohort analysis was conducted on individuals from MarketScan (commercial and managed Medicare) newly initiating treatment with rimegepant or lasmiditan between March 2020 and December 2022. Treatment persistence was defined as the proportion of individuals with ≥1 medication refill within 12 months of the index prescription. Subgroups included individuals with chronic migraine, index lasmiditan dose (50 and 100 mg) and individuals with a history of two or more uses of controlled substances (prior repeated use of controlled substances [PRUCS] defined here as opioids, butalbital, nausea medications with central nervous system action). Treatment persistence was compared between inverse probability of treatment weighting (IPTW)-adjusted cohorts using odds ratios (ORs) and 95% confidence intervals (CIs).ResultsThe primary analysis included 16,603 rimegepant and 716 lasmiditan users. A significantly higher proportion of individuals in the rimegepant cohort were treatment persistent compared with the lasmiditan cohort (OR 3.79 [95% CI 3.23-4.41]). This finding remained consistent across lasmiditan dosages (50 mg: 5.05 [3.87-6.60]; 100 mg: 3.33 [2.78-4.00]), chronic migraine diagnosis (3.89 [3.21-4.71]), or PRUCS (ORs ranged from 2.78 to 4.63; all statistically significant).ConclusionRimegepant users demonstrated higher treatment persistence over 12 months compared to lasmiditan users, which could reflect better real-world treatment satisfaction.
Cariprazine is effective in a number of conditions and has shown efficacy in the treatment of negative symptoms. Data on its use as an adjunct to other antipsychotics is growing. To evaluate the effectiveness of add-on cariprazine in patients with predominant negative symptoms, we assessed a series of patients prescribed adjunctive cariprazine using the Schedule for the Assessment of Negative Symptoms (SANS). Patients had few positive symptoms, but negative symptoms were considered to have a major effect on functioning. SANS scores were calculated at baseline, 12 weeks and 24 weeks. We compared median scores using the Wilcoxon signed-rank test. Ten consecutive patients were evaluated. Median baseline SANS score was 87 (IQR 32), 66 (IQR 23) at week 12 (p = 0.002 vs baseline) and 57 (IQR 33) at week 24 (p = 0.006 vs baseline). At Week 12, 70% of the patients were still prescribed the initial starting dose of 1.5 mg daily, and at Week 24, 30% of the patients remained on the 1.5 mg/day dose. Adjunctive cariprazine was effective in the treatment of residual negative symptoms in people with minimal positive symptoms.
This Research Communication addresses the hypothesis that calf faeces can be used as a microbial inoculum in the in vitro gas production (GP) technique to model rumen digestibility in calves. In vitro GP is a valuable method of screening dietary interventions in ruminants. However, the technique requires a microbial inoculum, typically obtained from the rumens of fistulated animals. Using faecal inocula that can be collected non-invasively would be ethically and economically preferable, if it provided equivalent results. The aim of this pilot study was to compare in vitro GP from faecal and ruminal inocula obtained from dairy calves that were killed either pre-weaning or post-weaning. Ruminal content and faeces were collected from calves aged 4, 7 and 13 weeks old, and incubated with calf starter concentrates in the ANKOMRF system. A weak relationship between inocula was seen for all modelled GP kinetic parameters (R2 < 0.53), although modelling indicated that incubations using faecal and rumen inocula from pre-weaned calves had similar lag times and rates of degradation. In weaned calves, aged 13 weeks, faecal incubations produced less gas, lag times were longer, and the rate of degradation of the slowly degradable fraction of calf starter was slower, compared to rumen incubations. Weak relationships, and kinetic differences, between rumen and faecal inocula would likely hinder the use of faeces to model calf rumen fermentation.
The early-life rumen microbiome is highly dynamic, shaped by dietary transitions and maternal influences. Several dietary additives have been studied during the pre- and post-weaning periods to improve animal welfare, growth performance, and farming efficiencies. This study investigated microbial community assembly and growth performance of lambs provided with a mannan-rich fraction (MRF) supplement, either through maternal supplementation, directly, or via a combination of both. Using metagenomic sequencing and gas chromatography, we found differences in rumen microbial alpha and beta diversity related to both sampling time point and MRF supplementation (p < 0.05). At week 8, lamb microbiomes showed greater variance in their Shannon alpha diversity, with direct MRF supplementation only to the lamb resulting in a significantly greater diversity (p < 0.05). At week 20, combined maternal and lamb supplementation resulted in the highest Shannon diversity and was different compared to all other groups (p < 0.05). Beta diversity analyses combined with differential abundance analyses revealed that microbial community structures are driven by both diet and time, with maternal MRF supplementation associated with enrichment of taxa involved in carbohydrate fermentation and succinate metabolism, including Succiniclasticum ruminis, Succinovibrio dextrinosolvens, and Fibrobacter succinogenes. Generalized linear modeling identified significant associations between microbial alpha diversity metrics and total volatile fatty acids in lambs, particularly butyrate and valerate. Furthermore, at week 8, there was a significant positive correlation between alpha diversity metrics and propionate and valerate. In this study, lambs receiving MRF through maternal and direct supplementation had the highest growth performance, measured as the median average daily gains (kg) and final weights (kg) of lambs. These findings suggest that MRF supplementation, especially when provided both maternally and directly, may influence the lamb rumen microbiome and alter its metabolic potential with potential implications for optimizing early-life nutrition strategies in ruminant production systems.
Antimicrobial resistance (AMR) is a critical global health challenge that compromises the effectiveness of widely used biocides such as chlorhexidine (CHX). The emergence of CHX-resistant bacterial strains, often mediated by efflux mechanisms and membrane adaptations, necessitates the development of new chemical entities capable of overcoming these resistance pathways. Here, we report the rational design, synthesis, and biological evaluation of structurally modified CHX analogues. These analogues were designed by substituting the terminal chlorophenyl rings of CHX with strategically selected aromatic groups bearing fluorine and methyl substituents to enhance membrane permeability, modulate physicochemical properties, and reduce efflux susceptibility. A library of 13 compounds was prepared using biscyanoguanidine chemistry and aniline-based substitutions via microwave-assisted synthesis, and was fully characterized by LC-MS, HRMS, and NMR. Antibacterial activity was assessed using minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assays against a panel of Gram-positive and Gram-negative bacteria, including CHX-resistant Klebsiella pneumoniae and Pseudomonas aeruginosa strains harboring smvR, phoQ, and pmrB mutations. Selected analogues, particularly compounds 8 and 11, demonstrated potent antibacterial activity. Compound 11 showed MIC values predominantly in the range of 4-8 μg/mL across wild-type strains and retained activity in resistant isolates, with MIC values of 4-8 μg/mL in P. aeruginosa and 64 μg/mL in CHX-resistant K. pneumoniae. MBC values were generally comparable to MIC values for the fluorinated analogues, consistent with a biocidal mode of action, while chlorhexidine showed elevated MBC values in resistant strains. Molecular modeling suggests that these compounds form favorable interactions within hydrophobic regions of the SmvA efflux pump in K. pneumoniae, potentially reducing efflux susceptibility. Structure-activity relationship analysis highlights the importance of combining fluorine and methyl substituents to optimize physicochemical properties associated with antibacterial activity and resistance bypass. Collectively, these findings establish a foundation for the development of next-generation CHX-based biocides with improved efficacy against multidrug-resistant pathogens and support further translational evaluation.
Adjuvant abemaciclib decreases recurrence rates and improves overall survival for patients with high-risk early-stage hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. However, toxicity, particularly diarrhea, may lead to dose reductions and early discontinuation. Primary results of the TRADE trial demonstrated that early dose escalation of abemaciclib can help patients reach and maintain the target dose of 150 mg twice daily (b.i.d.) by 12 weeks on therapy. In this article, we report a preplanned analysis of clinical outcomes at 24 weeks of the study. TRADE is a prospective, investigator-initiated, single-arm, phase II trial that enrolled patients with early-stage node-positive HR-positive/HER2-negative breast cancer who were candidates for adjuvant abemaciclib. Patients initiated abemaciclib at 50 mg b.i.d. for 2 weeks, then 100 mg b.i.d. for 2 weeks, before escalating to 150 mg b.i.d. for the planned 2-year duration of therapy. We report key endpoints at 24 weeks. Among 89 evaluable patients, 16 (18.0%) had discontinued abemaciclib by 24 weeks on therapy, including 7 (7.9%) who discontinued for adverse events. Among the 73 participants (82.0%) who were still receiving abemaciclib at 24 weeks, 47 (64.4%) were receiving 150 mg b.i.d., 18 (24.7%) were receiving 100 mg b.i.d., and 8 (11.0%) were receiving 50 mg b.i.d. Among all 89 assessable participants, 29 (32.6%) required at least one abemaciclib dose reduction, including 22 participants (24.7%) who had initially reached the 150 mg b.i.d. dose and then reduced. Patient-reported outcomes indicated no clinically meaningful change in quality of life from baseline through month 5 on therapy. Findings from the adjuvant TRADE study at 24 weeks of follow-up continue to demonstrate the utility of an early dose-escalation strategy during the initiation of adjuvant abemaciclib in optimizing patient persistence with and tolerability of therapy. Longer-term follow-up will continue to evaluate treatment outcomes over the planned 2 years of therapy.
Both untargeted "discovery" and targeted lipid analyses were performed on liver extracts obtained from mice, following the intravenous administration (10 mg/kg) of the tyrosine kinase inhibitor gefitinib, to maximize coverage of the liver lipidome. Untargeted lipid analysis by RP-UHPLC-IM-MS in both +ve and -ve ESI showed time-related changes in lipid profiles, including reductions in the abundances of PCs and PEs and a concomitant rise in the LPCs. Targeted analysis by HILIC-UHPLC-MS using +ve ESI also showed time-related effects on the lipid profiles of gefitinib-dosed mice with PCs, SMs, TGs, and LPCs, particularly for the lipids PC(34:1), PC(32:1), SM(40:1), TG(48:1), and PC(32:0), and effects on a number of acyl carnitines were also noted. In addition, time-related effects were seen using -ve ESI on a range of lipids, including PGs, PCs, LPEs, PEs, and FFAs. The resulting data suggest widespread effects on fatty acid utilization and metabolism may occur in the liver of mice as a result of exposure to gefitinib.
Background/Objectives: The NETest is a blood-based, machine learning-enhanced multigene transcript assay designed to detect and monitor neuroendocrine tumors (NETs). This study evaluated the accuracy of the recently validated NETest2.0® (2025) to (1) detect the presence of disease and (2) assess its utility as a clinically meaningful tool for monitoring NET status across diverse patient cohorts, including post-surgical surveillance, observation ("watch-and-wait"), and treatment settings. Methods: This registry study (NCT02270567) evaluated two objectives. For Objective 1, 1290 samples from 886 patients, of which 404 had paired follow-up samples, were analyzed for concordance between NETest2.0® and imaging-detectable disease. For Objective 2, paired blood samples (n = 404; median interval 7 months [IQR 4-13.8]) from NET patients across specialized centers were assessed. NETest2.0® scores were correlated with clinically adjudicated disease status using imaging as the comparator. Cohorts included post-surgical residual disease detection (n = 71), post-surgical recurrence monitoring (n = 44), observation (n = 72), and treatment monitoring (n = 217; somatostatin analogs, PRRT, and other therapies). Analyses were performed by cohort and in aggregate. Results: For Objective 1, NETest2.0® (cut-off ≥ 50) demonstrated an AUC of 0.96, sensitivity of 91.9%, specificity of 94.9%, PPV of 98.4%, NPV of 77.1%, and overall accuracy of 92.5%. Performance was consistent across tumor grades and sites. For Objective 2, 286 patients (70.8%) were stable, and 118 (29.2%) had progression or recurrence. NETest2.0® score changes correlated significantly with outcomes: scores decreased in stable patients (median -14.6%) and increased in progressive disease (median + 15.4%; p < 0.0001). Any increase (>0%) in score was associated with progression. Diagnostic performance for detecting progression reached a sensitivity of 78.0%, specificity of 98.3%, PPV of 91.1%, NPV of 90.2%, and accuracy of 83.9%. Conclusions: NETest2.0® accurately detects disease and provides a clinically actionable tool for monitoring NETs. Its high specificity and predictive performance support risk-adapted surveillance, potentially reducing unnecessary imaging while identifying early progression across diverse clinical settings.