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Increasing Special Pathogen Preparedness at a Frontline Hospital: A Quality Improvement Project
No full textPegloticase and Methotrexate Cotherapy in Patients With Uncontrolled Gout With Prior Pegloticase Monotherapy Failure: Findings of an Open-Label Trial.
No full textOBJECTIVE: Patients with uncontrolled gout have few treatment options. Pegloticase lowers serum urate (SU) levels, but antidrug antibodies limit SU-lowering response and increase infusion reaction (IR) risk. Methotrexate (MTX) cotherapy increases pegloticase response rates and lowers IR risk in pegloticase-naïve patients. Therefore, the question of re-treating patients with previous pegloticase monotherapy failure has arisen. The ADVANCE open-label trial examined pegloticase plus MTX cotherapy efficacy and safety following pegloticase monotherapy failure.
METHODS: Patients with uncontrolled gout (SU levels ≥6 mg/dL, oral urate-lowering therapy failure or intolerance, and ≥1 gout sign or symptom) who previously lost SU-lowering response to pegloticase monotherapy were included. Key exclusion criteria were moderate-to-severe IR or anaphylaxis to pegloticase, MTX contraindication, immunosuppressant administration, glucose-6-phosphate dehydrogenase deficiency, and estimated glomerular filtration rate/min/1.73m
RESULTS: Eleven patients began pegloticase plus MTX treatment (91% male patients, mean age 58.6 ± 11.3 years, mean ± SD SU levels 8.5 ± 3.2 mg/dL, 91% tophaceous). Previous pegloticase course was 2 to 27 infusions, with the last infusion admins being a mean ± SD of 3.7 ± 2.4 years before. One patient (9%) maintained response during month 6; 10 patients prematurely discontinued treatment (loss of SU lowering [n = 8], IR [n = 2]). Eight patients (73%) experienced ≥1 AE, most commonly gout flare. All AEs were mild or moderate.
CONCLUSION: Pegloticase plus MTX response rate following failed monotherapy was lower (9% vs 71%) and IR rate was higher (18% vs 4%) than in pegloticase-naïve patients. These findings demonstrate the challenge of overcoming established antipegloticase antibodies and emphasize the importance of initiating immunomodulation before the first pegloticase exposure
Cushing\u27s Disease Clinical Phenotype and Tumor Behavior Vary with Age: Diagnostic and Perioperative Implications.
No full textCONTEXT: Little is known about presenting clinical characteristics, tumor biology, and surgical morbidity of Cushing\u27s disease (CD) with aging.
OBJECTIVE: Using a large multi-institutional dataset, we assessed diagnostic and prognostic significance of age in CD through differences in presentation, laboratory results, tumor characteristics, and postoperative outcomes.
DESIGN: Data from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID) were reviewed for patients with CD treated with transsphenoidal tumor resection at 11 centers between 2003 and 2023. Outcomes assessed included comorbidities, presenting features, preoperative endocrine evaluations, perioperative characteristics, postoperative endocrine laboratory values, and complications.
RESULTS: Of the 608 patients evaluated, 496 (81.6%) were female; median age at surgery was 44 years (range, 10-78). Increasing age was associated with increasing comorbidities, frailty, rates of postoperative thromboembolic disease, Knosp grade, tumor size, and postoperative cortisol and ACTH nadirs. Conversely, increasing age was associated with decreased hallmark CD features, preoperative 24-hour urinary free cortisol, Ki-67 indices, and arginine vasopressin deficiency. Younger patients presented more frequently with weight gain, facial rounding/plethora, abdominal striae, hirsutism, menstrual irregularities, dorsocervical fat pad, and acne. Obstructive sleep apnea and infections were more common with increasing age.
CONCLUSIONS: There are age-dependent differences in clinical presentation, tumor behavior, and postoperative outcomes in patients with CD. Compared to younger patients, older patients present with a less classical phenotype characterized by fewer hallmark features, more medical comorbidities, and larger tumors. Notably, age-related differences suggest a more indolent tumor behavior in older patients, potentially contributing to delayed diagnosis and increased perioperative risk. These findings underscore the need for tailored diagnostic and therapeutic approaches across age groups, with a focus on managing long-term comorbidities and optimizing surgical outcomes
A phase 1 study of the CDK9 inhibitor voruciclib in relapsed/refractory acute myeloid leukemia and B-cell malignancies.
No full textThe antiapoptotic protein, myeloid cell leukemia-1 (Mcl-1), contributes to the pathophysiology of acute myeloid leukemia (AML) and certain B-cell malignancies. Tumor dependence on Mcl-1 is associated with resistance to venetoclax. Voruciclib, an oral cyclin-dependent kinase (CDK) inhibitor targeting CDK9, indirectly decreases Mcl-1 protein expression and synergizes with venetoclax in preclinical models. This dose escalation study evaluated voruciclib in patients with previously treated hematologic malignancies. Initially, voruciclib was administered daily, continuously, on a 28-day cycle (group 1). After 2 patients with prior allogeneic stem cell transplantation had a dose-limiting toxicity (DLT) of interstitial pneumonitis at 100 mg, voruciclib administration was changed to days 1 to 14 of a 28-day cycle (group 2). Forty patients, 21 with AML and 19 with B-cell malignancies, were enrolled. Patients had a median of 3 prior lines of therapy (range, 1-8). Dose escalation in group 2 was stopped at 200 mg, a dose that achieved plasma concentrations sufficient for target inhibition, without DLTs observed. The most common adverse events were diarrhea (30%), nausea (25%), anemia (22%), fatigue (22%), constipation (17%), dizziness (15%), and dyspnea (15%). In AML, 1 patient achieved a morphologic leukemia-free state, and 2 had stable disease. Voruciclib treatment led to a decrease in MCL1 messenger RNA expression, downregulation of myelocytomatosis (MYC) and NF-κB transcriptional gene sets, and reduced phosphorylation of RNA polymerase 2. Voruciclib on intermittent dosing was well tolerated, with no DLTs, paving the way for evaluation of the combination of voruciclib with venetoclax for patients with previously treated AML. This trial was registered at www.clinicaltrials.gov as #NCT03547115
A Microfluidic, Multi-Antibody Cell Capture Method to Evaluate Tumor Cells in Cerebrospinal Fluid in Patients With Suspected Leptomeningeal Metastases.
No full textCONTEXT.—: Leptomeningeal disease (LMD) is a clinical sequela of central nervous system metastasis involving the cerebrospinal fluid (CSF), often seen in late-stage solid tumors. It has a grave prognosis without urgent treatment. Standard of care methodologies to diagnose LMD include CSF cytology, magnetic resonance imaging, and clinical evaluation. These methods offer limited sensitivity and specificity for the evaluation of LMD. Here, we describe the analytic performance characteristics of a microfluidic-based tumor cell enrichment and detection assay optimized to detect epithelial cells in CSF using both contrived samples as well as CSF from patients having suspected or confirmed LMD from carcinomas.
OBJECTIVE.—: To demonstrate the feasibility of using a microfluidic, multi-antibody cell capture assay to identify and quantify tumor cells in CSF.
DESIGN.—: An artificial CSF solution was spiked with 34 different human carcinoma cell lines at different concentrations and assayed for the ability to detect tumor cells to assess analytic accuracy. Two cell lines were selected to assess linearity, intra-assay precision, interinstrument precision, and sample stability. Clinical verification was performed on 65 CSF specimens from patients. Parameters assessed included the number of tumor cells, coefficient of variation percentage, and percentage of tumor cell capture (TCC).
RESULTS.—: Among contrived samples, average tumor cell capture ranged from 50% to 82% (261 of 522; 436 of 531), and coefficients of variation ranged from 7% to 67%. The cell capture assay demonstrated a sensitivity of 92% and a specificity of 95% among clinical samples.
CONCLUSIONS.—: This assay demonstrated the ability to detect and enumerate epithelial cells in contrived and clinical specimens in an accurate and reproducible fashion. The use of cell capture assays in CSF may be useful as a sensitive test for the diagnosis and longitudinal monitoring of LMD from solid tumors
Indexing GFR Using Extracellular Volume versus Body Surface Area in a Population with Type 1 Diabetes and Diabetic Kidney Disease.
No full textSex-Related Differences in Efficacy and Safety Outcomes in Axial Spondyloarthritis Randomized Clinical Trials: A Systematic Literature Review and Meta-Analysis.
No full textOBJECTIVE: We aimed to assess differences in baseline characteristics, efficacy, and safety of advanced therapies between male and female patients with axial spondyloarthritis (axSpA) in randomized controlled trials (RCTs).
METHODS: We conducted a systematic literature search for RCTs assessing the efficacy of advanced therapies in patients with axSpA until March 19, 2023. We extracted the following outcomes by sex: baseline participant characteristics, Assessment in Spondylarthritis International Society (ASAS) 20/40 criteria, and Axial Spondyloarthritis Disease Activity Score low disease activity or inactive disease (ASDAS-LDA/ID). Random-effects models were used to calculate pooled effects for responses in men versus women for different medication classes.
RESULTS: We included 79 RCTs (n = 23,748 patients, 69.7% male). Only 9 trials (11.4%), 22 trials (28%), and 9 trials (11.4%) reported baseline characteristics, efficacy end points, and safety end points by sex, respectively. At baseline, women were significantly older and had higher pain scores, whereas men had higher C-reactive protein levels. Overall, male patients were more likely to achieve an ASAS40 response compared to female patients for all advanced therapies (odds ratio [OR] 1.88, 95% confidence interval [CI] 1.44-2.46) and for interleukin-17A (IL-17A) inhibitors (IL-17Ai) (OR 1.82) and tumor necrosis factor inhibitor (TNFi) (OR 2.42), and male patients had numerically higher values for IL-17A/Fi. Male patients were also more likely to achieve an ASDAS-LDA/ID (OR 2.19, 95% CI 1.47-3.26) across all advanced therapies and for IL-17Ai (OR 2.08) and TNFi (OR 2.42) individually.
CONCLUSION: Female patients with axSpA are less likely to achieve efficacy outcomes on advanced therapies compared to their male counterparts, with similar differences across medication classes. Future studies should study the biologic (sex-related) and sociocultural (gender-related) mechanisms underlying these differences
Clinical Validation and Outcome Measures From Bend Ease: A Novel, Sensor-Based Digital Measurement Tool for Assessing At-Home Morning Stiffness and Spinal Range of Motion in Axial Spondyloarthritis.
No full textINTRODUCTION: To evaluate the accuracy, reliability, and usability of Bend Ease, a novel smartphone-based digital health technology (DHT), which objectively self-measures spinal range of motion (SRoM) and remotely assesses morning stiffness.
METHODS: This phase 1 study involved healthy volunteers (HV) and patients with axial spondyloarthritis (axSpA). Participants used Bend Ease by placing a phone against their chest during a forward-flexion bend, and the application collected and processed accelerometry data to measure bend angle in both clinical and at-home settings. Bend Ease measurements were compared to the video-based method (gold standard) and functional ability questionnaires.
RESULTS: The study included 30 HV and 30 patients with axSpA. Bend Ease accurately measured forward-flexion bend angles, demonstrating strong correlation (r = 0.74) and concordance (ρ
CONCLUSIONS: Bend Ease is an accurate, reliable, and user-friendly tool for assessing SRoM. As the first DHT to objectively evaluate morning stiffness upon waking, Bend Ease provides valuable assessments of spinal mobility when it is most impaired
Genomic comparison of the temperate coral Astrangia poculata with tropical corals yields insights into winter quiescence, innate immunity, and sexual reproduction.
No full textFacultatively symbiotic corals provide important experimental models to explore the establishment, maintenance, and breakdown of the mutualism between corals and members of the algal family Symbiodiniaceae. Here, we report the de novo chromosome-scale genome assembly and annotation of the facultatively symbiotic, temperate coral Astrangia poculata. Though widespread segmental/tandem duplications of genomic regions were detected, we did not find strong evidence of a whole genome duplication (WGD) event. Comparison of the gene arrangement between A. poculata and the tropical coral Acropora millepora revealed considerable conserved colinearity despite ∼415 million years of divergence. Gene families related to sperm hyperactivation and innate immunity, including lectins, were found to contain more genes in A. millepora relative to A. poculata. Sperm hyperactivation in A. millepora is expected given the extreme requirements of gamete competition during mass spawning events in tropical corals, while lectins are important in the establishment of coral-algal symbiosis. By contrast, gene families involved in sleep promotion, feeding suppression, and circadian sleep/wake cycle processes were expanded in A. poculata. These expanded gene families may play a role in A. poculata\u27s ability to enter a dormancy-like state ( winter quiescence ) to survive freezing temperatures at the northern edges of the species\u27 range