Citations

Abstract Measurement of D-dimer, a fibrin degradation product, is crucial for diagnosing thrombotic and fibrinolytic conditions. Despite its expanding utility, D-dimer testing faces challenges due to varying assay methodologies and nonstandardized reporting. To understand D-dimer reporting practices, the College of American Pathologists Hemostasis and Thrombosis Committee analyzed proficiency testing data from D-dimer surveys conducted between 2020 and 2023 across multiple laboratories. The data demonstrate that laboratories commonly report units that differ from the assay package insert when reporting their proficiency testing results. We sought to assess variability in reporting practices and opportunities for improvement in D-dimer reporting amongst participants. To accomplish this, we harmonized all D-dimer results to ng/mL fibrinogen equivalent units from one distributed sample and assessed distinct populations of entries per instrument/reagent combination. Notable trends emerged from this analysis. Data from laboratories using the same instrument/reagent combinations clustered around different means, suggesting issues with unit reporting and/or conversion. Entries reported in mg/L or ug/mL D-dimer units commonly exhibited significant deviations from the dominant population. For one instrument/reagent combination, most reported values differed by approximately twice the certificate of analysis value. This analysis highlights potential issues with D-dimer reporting in proficiency testing. Whether these issues translate into issues with clinical D-dimer reporting requires further study.

ABSTRACT Objective To evaluate demographic and clinical factors influencing survival in patients with major salivary gland tumors (MSGTs) using the surveillance, epidemiology, and end results (SEER) database. Study Design A retrospective cohort study using SEER data from 2000 to 2021. Setting Data were collected from the SEER registry, a comprehensive database capturing cancer statistics across the United States. Methods Patients diagnosed with major salivary gland malignancies were analyzed for demographic factors, including age, sex, race, marital status, and income, as well as clinical variables, including tumor grade and site. Stratification by sex was done to assess sex‐specific outcomes. Results The cohort included 13,869 patients. Key findings include that older age and male sex were associated with worse survival outcomes. Single patients had better survival than married individuals, likely due to younger age at diagnosis. Additionally, higher income and Asian/Pacific Islander race conferred a survival advantage. There were disparate impacts between males and females in income, marital status, and race, with higher income and marriage providing a survival advantage for male patients but none for females. Additionally, Black females but not Black males, and widowed females but not widowed males, had slightly increased hazard ratios compared to White individuals. Conclusion Men and women experience disparate effects that impact survival and outcomes in major salivary gland tumors. These findings highlight the need for targeted interventions to address disparities in care and improve survival outcomes while emphasizing the importance of further research to understand the underlying mechanisms driving these disparities.

Abstract Background Cardiovascular disease (CVD) is the leading cause of death globally for both men and women, yet women remain historically underrepresented in cardiovascular clinical trials (CV trials), despite facing a disproportionately high burden of morbidity and mortality in many forms of CVD. Purpose We aim to determine the representation of women across a broad range of CV trials. Methods The participation of women in CV trials registered on ClinicalTrials.gov from 2017 to 2023 was systematically determined through the extraction of publicly available information. Data was extracted to identify the country of study, disease type, trial size, clinical intervention and age of the participants. We calculated the proportion of women and the ratio of number of females to male participants (F:M ratio) for each trial. The female participation to prevalence ratio (PPR) was estimated for each trial based on the relative prevalence of the disease by sex in the specified region. Results We identified 1,079 registered CV trials, which included 1,396,104 participants, of whom 571,641 (41.0%) were women. The median F:M ratio was significantly lower for studies on arrhythmia (0.5), coronary heart disease (CHD) (0.39), acute coronary syndrome (ACS) (0.32) and heart failure (HF) (0.51), but was higher for obesity (1.44) and pulmonary hypertension (PH) (2.86) CV trials. F:M ratio was higher for trials on lifestyle intervention (1.51) than for drug trials. PPRs were low for clinical trials on CHD (0.66), ACS (0.79), and stroke (0.74). There was a trend to increasing PPR from 2017 to 2023, p=0.056. Conclusion Representation of women in CV trials varies by disease state, region, intervention, and sponsor type. Better understanding of reasons for these differences may enable more tailored interventions to improve representation of women globally and across therapeutic areas.Figure 1 Figure 2

Abstract Background Management of acute cardiogenic shock for post-cardiotomy and post-transplant patients remains challenging. The use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for circulatory support is a key intervention, yet the optimal cannulation strategy—central vs. peripheral—remains debated. This study evaluates outcomes associated with each approach to inform clinical decision-making. Methods A retrospective analysis was conducted on 319 patients who received VA-ECMO for CS intraoperatively or within 24 hours postoperatively at Mayo Clinic (2010–2023). Patients were categorized into central (n=241) and peripheral (n=78) ECMO groups. Propensity score (PS) weighting using stabilized inverse probability of treatment weighting was applied to minimize baseline imbalances. Outcomes included in-hospital mortality, bleeding requiring reoperation, limb ischemia, prolonged ventilation (>7 days), and sepsis. Results The median age at ECMO initiation was 68.5 years, with 37.3% female patients. Right ventricular (RV) dysfunction was the predominant indication for ECMO initiation (p<0.001). After PS weighting, no significant difference was observed in in-hospital mortality (49.8% vs. 44.5%, p=0.416) or other major complications between central and peripheral ECMO (see Table 1). Stroke was more frequent in central ECMO (P = 0.159), though not statistically significant. Reoperation for bleeding occurred significantly more often in central ECMO in the unweighted analysis (P = 0.047), but the difference lost statistical significance after weighting (P = 0.071). Renal failure was comparable between groups (P = 0.888). Notably, sternal infection rates were comparable between groups (P=0.921). Acute limb ischemia was more common in the peripheral group (P = 0.209). Limb ischemia associated with central ECMO was not caused by the ECMO cannulas but was instead related to concomitant use of femoral intra-aortic balloon pump. Conclusions After propensity score weighting, analysis showed no significant differences in mortality or complications between central ECMO and peripheral ECMO for post-cardiotomy and post-transplant cardiogenic shock.

Abstract Introduction: Total knee arthroplasty (TKA) for knee osteoarthritis (OA) provides pain relief and functional improvement for many patients. The endocannabinoid system (ECS) regulates pain and inflammation through central and peripheral mechanisms and may be affected by acetaminophen. There is limited information on how surgery and perioperative care affect the ECS. Objective: We designed this study to examine the effect of surgery and acetaminophen on the ECS and determine whether perioperative endocannabinoids were associated with pain resolution after surgery. Methods: Forty adult patients with OA undergoing TKA were enrolled in a prospective observational cohort study and provided preoperative cerebrospinal fluid (CSF) and blood samples at 3 time points (before surgery, after intravenous acetaminophen, and 24 hours postoperative). Defense and Veterans Pain Rating Scale scores at rest and with activity were recorded in the preoperative holding area, in the operating room after intravenous acetaminophen before spinal anesthesia, and 24 to 48 hours postoperatively. Cerebrospinal fluid and plasma endocannabinoids were quantified using a validated liquid chromatography/mass spectrometry assay. We analyzed the data using linear regression models with sex, age, and body mass index as covariates. Results: Patients undergoing TKA have higher CSF and plasma concentrations of N-acylethanolamines anandamide and its congeners compared with control subjects. Patients with higher pain scores had lower CSF anandamide levels before and after surgery and higher levels of 2-arachidonoylglycerol before surgery but not after. Conclusion: Chronic pain, acetaminophen, and surgery are associated with endogenous endocannabinoid levels and may present an opportunity for developing targeted nonopioid perioperative analgesia after TKA.

ABSTRACT Objectives The purpose of this study is to compare the economics of in‐office tympanostomy tube placement using single use devices versus standard placement in the operating room (OR). Methods A retrospective chart review was completed for all pediatric patients who underwent in‐office tympanostomy tube placement (CPT 69433) along with insurance and date matched patients with placement in the OR (CPT 69436) between 12/1/21–3/1/24. Financial data were compared among the public vs. private insurance cohorts using the Wilcoxon rank‐sum test with a two‐sided significance level of 5%. Results One hundred and thirty‐six in‐office patients were identified, 102 private versus 34 public, and compared with 136 insurance and date matched OR patients. The average total payment for both privately insured patients, $647.14 in‐office versus $6873.45 in the OR, and publicly insured patients, $312.74 in‐office versus $2656.34 in the OR, was statistically significant. The average insurance payment for both privately insured patients, $301.58 in‐office versus $5445.73 in the OR, and publicly insured patients, $310.63 in‐office versus $2258.65 in the OR, was statistically significant. For the patient payment, public insurance usually has 0 copay and is therefore excluded. The patient payment of the private insurance cohort, $308.30 in‐office versus $670.61 in the OR, was not found to be statistically significant. Conclusion As expected, this study demonstrates significant reductions in overall cost with in‐office tympanostomy tube placement even with the added cost of single‐use devices compared to the standard placement in the OR, particularly for insurance companies, suggesting the potential benefit of providing reimbursement for these devices. Level of Evidence N/A.

ABSTRACT The limited efficacy of current therapies against cholangiocarcinoma (CCA) necessitates the development of novel treatment strategies. Src family kinases (SFKs) contribute significantly to tumor progression and resistance in CCA. Therefore, we investigated the novel, first-in-class SFK ‘OFF’ inhibitor NXP900 in diverse preclinical CCA models, including those with acquired resistance. This study evaluated the therapeutic effects of NXP900 and detailed adaptive molecular responses to SFK inhibitor therapy. We also aimed to identify biomarkers predictive of drug sensitivity using integrated multiomic profiling and develop strategies to overcome resistance. NXP900 inhibited YAP activity through direct inhibition of tyrosine phosphorylation and indirect activation of the Hippo pathway via LATS. These effects were associated with decreased tumor cell viability in CCA cell lines and several in vivo models. Notably, IDH -mutant patient-derived xenograft CCA models were particularly sensitive to NXP900. NXP900 also synergized with gemcitabine/cisplatin chemotherapy, enhancing antitumor efficacy in both in vitro and in vivo models. Multiomic analyses combining transcriptomics, global proteomics, and phosphoproteomics identified molecular features associated with primary response and acquired resistance. IL13RA-AKT signaling was upregulated in resistant models; NXP900 sensitivity could be restored with AKT or IL13RA2 inhibition. Together, these findings demonstrate the therapeutic potential of NXP900 as a novel YAP inhibitor in CCA and support further investigation in a clinical trial. Graphical Abstract

Abstract Chimeric antigen receptor (CAR) T-cell therapy enriched for a memory-like phenotype may persist and function longer than a nonenriched product, thereby improving duration of response (DOR). We conducted a phase I study with bb21217 (NCT03274219), an anti–B-cell maturation antigen CAR T-cell therapy manufactured in the presence of the phosphoinositide 3-kinase inhibitor bb007 to enrich for T cells with a memory-like phenotype, in patients with relapsed/refractory multiple myeloma (N = 72). No new safety concerns were raised with bb21217 therapy (three cases each of grade ≥3 cytokine release syndrome and grade ≥3 neurotoxicity were observed). The objective response rate was 69.4% and the median DOR was 23.8 (95% confidence interval, 16.8–34.8) months. Analysis of the drug product established an association between early memory phenotype and robust expansion and depth of response. Examination of baseline characteristics indicated that tumor burden and prior therapies influenced DOR. The data indicate that generation of CAR T cells early in a disease course when tumor burden is lower and source material exhibits a more naïve phenotype may maximize the clinical benefit potential of the drug product.

OBJECTIVE: Volatile anesthetics (VAs) are gaining renewed interest as a sedation strategy in the intensive care, offering an alternative to traditional IV agents. VAs provide several pharmacologic advantages, including rapid onset and offset, minimal systemic metabolism, and favorable recovery profiles. Advances in delivery systems enabled the safe and practical administration of volatile agents in the ICU. Thus, we aimed to describe the pharmacology and safety aspects of inhaled agents as well as the systems designed to deliver VAs in the ICU. DATA SOURCES: Relevant literature was identified through PubMed and MEDLINE databases. STUDY SELECTION: Original research, review articles, commentaries, and guidelines addressing safety, efficacy, and use of VAs in adult ICU patients were included. DATA EXTRACTION: Studies were reviewed by the authors, with key findings summarized and organized by pharmacologic properties, delivery systems, and safety domains. DATA SYNTHESIS: VAs are halogenated hydrocarbons whose mechanism of action is not fully understood. Although the CNS is the primary site of action, the end-tidal concentration of exhaled anesthetic is used to monitor clinical effects such as immobility to a noxious stimulus. Inhaled agents have unique pharmacokinetics, minimal metabolisms, and distinct recovery. The side effect profile is also unique, with malignant hyperthermia being the most feared, yet rare complication. Two systems for inhalational sedation delivery are available internationally, with one currently under evaluation in the United States. The systems are composed of a miniature vaporizer, delivery controller, and a monitor. The systems have distinct safety considerations, such as tidal volume limits. CONCLUSIONS: VAs can be used as sedative agents in the ICU. This article comprehensively reviews the pharmacology of VAs along with their safety profile and describes the structure and function of miniature vaporizers currently available on the world market.

Abstract Purpose: Rearranged during transfection (RET) alterations are oncogenic drivers across solid tumors. Selective RET inhibitors (SRI) selpercatinib and pralsetinib have transformed outcomes for patients with RET-altered malignancies. Limited knowledge exists on genomic mechanisms of resistance to SRI. Experimental Design: We established “RETgistry,” a global consortium of patients with advanced RET-altered solid tumors who received SRI and underwent postprogression tissue or plasma biopsies assessed by next-generation sequencing. Frequencies of secondary RET resistance mutations and acquired non-RET gene alterations were determined. Progression-free survival (PFS) and time to treatment discontinuation (TTD) on first SRI were estimated with the Kaplan–Meier method. Results: RETgistry included 109 patients with RET-altered advanced solid tumors (lung, n = 94; thyroid, n = 15) who underwent 143 post-SRI progression biopsies (tissue, 91; plasma, 52). The median PFS and TTD were 13.9 months [95% confidence interval (CI), 10.1–16.6] and 17.3 months (95% CI, 14–20.2), respectively. Secondary RET mutations were detected in 20 (14%) biopsies [lung cancer, 15 (12.4%) and thyroid carcinoma, 5 (22.7%)]. Common acquired off-target alterations involved MET (18.2%; amplification, 15%), TP53 (8.2%), APC (7.6%), KRAS (7.1%), KEAP1 (5.9%), and CDKN2A/B (5.3%). MET alterations were enriched in post-SRI versus pre-SRI specimens (full cohort, 17.6% vs. 2.0%, P = 0.022; lung cancer, 19.1% vs. 2.1%, P = 0.022). Conclusions: The prevalence of secondary RET mutations after SRI was low, underscoring a greater role for off-target resistance. Recurrent acquired alterations involving tumor suppressor genes or upstream regulators of MAPK and PI3K pathways were identified, most commonly MET amplification. Continued efforts to characterize SRI resistance biology are critical to guide the development of novel therapeutic strategies.