Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): In-depth sinus surgery analysis.

BACKGROUND: Patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) often require repeat sinus surgery. Mepolizumab reduced the need for sinus surgery in the SYNAPSE trial; this analysis sought to provide a more in-depth assessment of surgery endpoints in SYNAPSE. METHODS: SYNAPSE was a double-blind Phase III trial (NCT03085797) in adults with recurrent, refractory, severe, CRSwNP eligible for repeat sinus surgery despite standard of care treatments and previous surgery. Patients were randomized (1:1) to mepolizumab 100 mg subcutaneously or placebo, plus standard of care, every 4 weeks for 52 weeks. Time to first inclusion on a waiting list for sinus surgery and time to first actual sinus surgery (both up to week 52) were assessed; the latter endpoint was also analyzed post hoc according to time since last sinus surgery before study screening and baseline blood eosinophil count. RESULTS: Among 407 patients (mepolizumab: 206; placebo: 201), mepolizumab versus placebo reduced the risk of being included on a waiting list for sinus surgery (week 52 Kaplan-Meier probability estimate [95% confidence interval]: 13.9% [9.8%, 19.5%] vs. 28.5% [22.7%, 35.4%]). Mepolizumab versus placebo reduced the risk of sinus surgery irrespective of time (<3 vs ≥3 years) since patients' last sinus surgery prior to study screening (hazard ratios [95% confidence intervals] 0.28 [0.09, 0.84] and 0.50 [0.26, 0.98], respectively) and baseline blood eosinophil count. CONCLUSIONS: Mepolizumab reduced the risk of further sinus surgery in patients with recurrent, refractory, severe CRSwNP, irrespective of the patient baseline characteristics assessed.

Mepolizumab for chronic rhinosinusitis with nasal polyps: Treatment efficacy by comorbidity and blood eosinophil count.

BACKGROUND: In the phase III SYNAPSE study, mepolizumab reduced nasal polyp (NP) size and nasal obstruction in chronic rhinosinusitis with NP. OBJECTIVE: We sought to assess the efficacy of mepolizumab in patients from SYNAPSE grouped by comorbid asthma, aspirin-exacerbated respiratory disease (AERD), and baseline blood eosinophil count (BEC). METHODS: SYNAPSE, a randomized, double-blind, 52-week study (NCT03085797), included patients with severe bilateral chronic rhinosinusitis with NP eligible for surgery despite intranasal corticosteroid treatment. Patients received 4-weekly subcutaneous mepolizumab 100 mg or placebo plus standard of care for 52 weeks. Coprimary end points were change in total endoscopic NP score (week 52) and nasal obstruction visual analog scale score (weeks 49-52). Subgroup analyses by comorbid asthma and AERD status, and post hoc by BEC, were exploratory. RESULTS: Analyses included 407 patients (289 with asthma; 108 with AERD; 371 and 278 with BEC counts ≥150 or ≥300 cells/µL, respectively). The proportion of patients with greater than or equal to 1-point improvement from baseline in NP score was higher with mepolizumab versus placebo across comorbid diseases (asthma: 52.9% vs 29.5%; AERD: 51.1% vs 20.6%) and baseline BEC subgroups (<150 cells/µL: 55.0% vs 31.3%; ≥150 cells/µL: 49.5% vs 28.1%; <300 cells/µL: 50.7% vs 29.0%; ≥300 cells/µL: 50.4% vs 28.1%). A similar trend was observed in patients without comorbid asthma or AERD. More patients had more than 3-point improvement in nasal obstruction VAS score with mepolizumab versus placebo across comorbid subgroups. CONCLUSIONS: Mepolizumab reduced polyp size and nasal obstruction in chronic rhinosinusitis with NP regardless of the presence of comorbid asthma or AERD.

Real-world characterisation of patients with chronic rhinosinusitis with nasal polyps with and without surgery in England.

OBJECTIVES: To characterise the real-world burden of chronic rhinosinusitis with nasal polyps (CRSwNP) in the UK, stratified by number of surgeries. DESIGN: Retrospective cohort study. SETTING: UK Clinical Practice Research Datalink Aurum database with Hospital Episodes Statistics linkage (2007-2019). PARTICIPANTS: Adults ≥18 years of age with a first NP diagnosis (index) and 365 days of baseline and ≥180 days of follow-up data. Follow-up continued until disenrollment, death or end of data collection. MAIN OUTCOME MEASURES: Primary: primary care physician prescribed CRSwNP-related treatments, and all-cause healthcare resource utilisation (HCRU) in 90 days post-index, stratified by surgeries during follow-up. Secondary: rate of surgery and CRSwNP point prevalence. Baseline patient demographics, clinical characteristics and comorbidities were also assessed. RESULTS: Of the 33 107 patients included, 23.5% and 2.2% had ≥1 and ≥2 surgeries during follow-up, respectively (mean follow-up: 5.3 years). Patients with more surgeries (≥2/≥1/0) during follow-up were more likely to be male (67.3%/69.0%/58.0%), have asthma (37.8%/28.2%/20.2%) and have baseline blood eosinophil counts ≥300 cells/µL (68.5%/66.0%/51.5%). During the first 90-days post-index as surgery number increased, the proportion of patients using oral corticosteroids (25.8%/20.7%/14.2%) and mean (SD) number of all-cause healthcare visits (5.9 [4.2]/5.4 [4.0]/4.9 [4.2]) increased. Time between surgeries was shorter among patients with more surgeries. CRSwNP prevalence on 31 December 2018 was 476 cases per 100 000 persons. CONCLUSION: A small proportion of patients in the UK required multiple surgeries for CRSwNP and this was associated with increasing comorbidity burden, baseline blood eosinophil counts, CRSwNP-related treatment and HCRU use.

From DREAM to REALITI-A and beyond: Mepolizumab for the treatment of eosinophil-driven diseases.

Effective treatment of inflammatory diseases is often challenging owing to their heterogeneous pathophysiology. Understanding of the underlying disease mechanisms is improving and it is now clear that eosinophils play a complex pathophysiological role in a broad range of type 2 inflammatory diseases. Standard of care for these conditions often still includes oral corticosteroids (OCS) and/or cytotoxic immune therapies, which are associated with debilitating side effects. Selective, biological eosinophil-reducing agents provide treatment options that improve clinical symptoms associated with eosinophilic inflammation and reduce OCS use. Mepolizumab is a humanized monoclonal antibody that binds to and neutralizes interleukin-5, the major cytokine involved in eosinophil proliferation, activation, and survival. Mepolizumab is approved for the treatment of severe eosinophilic asthma, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. Additionally, the efficacy of add-on mepolizumab has been observed in patients with severe chronic rhinosinusitis with nasal polyposis and chronic obstructive pulmonary disease with an eosinophilic phenotype. Here, we review the development, approval, and real-world effectiveness of mepolizumab for the treatment of patients with severe eosinophilic asthma, from the DREAM to REALITI-A studies, and describe how knowledge from this journey extended to the use of mepolizumab and other biologics across a broad spectrum of eosinophilic diseases.

Evaluating enrollment and outcome criteria in trials of biologics for chronic rhinosinusitis with nasal polyps.

OBJECTIVE: Treatment for chronic rhinosinusitis with nasal polyps (CRSwNP) generally involves intranasal corticosteroids (INCS) and saline irrigation, followed by short courses of systemic corticosteroids (SCS) or surgery with postoperative medical therapy for patients who do not respond to INCS. However, both SCS use and surgery are associated with a range of adverse effects or complications, have a high recurrence rate, and are unsuitable for some patients. Biologics targeting the underlying pathophysiology are promising treatment alternatives for these patients. Dupilumab, omalizumab, and mepolizumab are approved for use in patients with severe, uncontrolled CRSwNP. However, the lack of a consistent definition of severe CRSwNP makes the decision to initiate biologic treatment particularly complex. Furthermore, the position of each biologic in the overall management of CRSwNP remains to be clarified. DATA SOURCES: Publications reporting results of phase III trials of dupilumab, omalizumab, mepolizumab, and benralizumab in the treatment of CRSwNP. STUDY SELECTIONS: Randomized, controlled phase III trials of biologics approved for CRSwNP. RESULTS: These trials all used different enrollment criteria. We discuss the complexities of assessing CRSwNP disease severity and highlight how these impact comparisons of the populations and outcomes of the phase III biologic trials. CONCLUSION: To position biologic agents appropriately within the existing CRSwNP treatment paradigm, future trials will need to include comparable patient populations and standardized outcome measures. Such trials will help to ensure that biologic treatment is targeted appropriately to support optimal clinical outcomes.

Hardware complications and reoperations following precontoured plate fixation of the olecranon: a population-based study.

BACKGROUND: Several fixation techniques have been described to treat acute olecranon fractures. Plate fixation is often used because of its superior mechanical properties. The reported rates of reoperation after olecranon plate fixation have been quite heterogeneous. The purpose of this study was to establish an updated reoperation rate based on modern precontoured plate constructs. METHODS: This retrospective cohort study used population-level administrative data to identify all surgically treated adult patients with olecranon fractures at 4 hospitals in Edmonton, AB, Canada, between 2010 and 2015. Radiographic review was conducted to identify patients who underwent precontoured olecranon plate fixation. Fracture characteristics including Mayo fracture classification and other concomitant upper-extremity injuries were identified. Chart reviews were performed to determine patient characteristics and patients who required reoperation. The primary reason for and type of reoperation were determined. RESULTS: Six hundred patients were surgically treated for olecranon fractures. Precontoured plate fixation was used in 321 patients. The average age of included patients was 56 years (standard deviation [SD], 19.4 years), and there were 173 female patients (53.9%). Reoperation was required in 90 patients (28%). For 50 patients, implant-related irritation was the primary reason for reoperation, representing 55.6% of the patients who underwent reoperation (50 of 90) and 15.6% of the total cohort (50 of 321). Other reasons for reoperation included hardware failure in 17 patients (5.3%), infection in 9 (2.8%), and contracture in 9 (2.8%). Patients who required reoperation were significantly younger (52.9 years [SD, 18.1 years] vs. 57.7 years [SD, 19.4 years]; P = .048) and had significantly higher rates of type III olecranon fractures (17.8% [16 of 90] vs. 8.2% [19 of 231]; P = .04) and Monteggia fractures (13.3% [12 of 90] vs. 4.8% [11 of 231]; P = .008). A multivariate logistic regression model also demonstrated increased odds ratios (ORs) for overall reoperation in patients with Monteggia fractures (OR, 2.99 [95% confidence interval, 1.25-7.17]; P = .014) and for reoperation due to implant-related irritation in younger patients (OR, 0.98 [95% confidence interval, 0.96-0.996]; P = .018). No discerning factors were identified for the 50 patients who underwent hardware removal for implant-related irritation compared with the whole reoperation group (n = 90). CONCLUSION: This study found that patients with olecranon fractures treated with precontoured plates experienced a hardware removal rate of 15.6% for implant-related irritation. Patients who sustained more complex fractures, such as Monteggia injuries, demonstrated higher rates of reoperation. Increasing age may be associated with lower rates of reoperation. In patients who required reoperation, there were no identifiable radiographic or clinical characteristics that were associated with implant-related irritation as their primary reason for reoperation.

A positron emission tomography imaging study to confirm target engagement in the lungs of patients with idiopathic pulmonary fibrosis following a single dose of a novel inhaled αvß6 integrin inhibitor.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvß6) integrin inhibitor, in participants with IPF. METHODS: This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvß6-specific ligand, [18F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (VT), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in VT > 0%) of ≥80%. RESULTS: Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected VT at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI: - 9 to 42%). The posterior probability that the true % reduction in VT > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination. CONCLUSIONS: This study demonstrated engagement of the αvß6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug. TRIAL REGISTRATION: clinicaltrials.gov: NCT03069989; date of registration: 3 March 2017.

Understanding the Patient Experience of Severe, Recurrent, Bilateral Nasal Polyps: A Qualitative Interview Study in the United States and Germany.

OBJECTIVES: To qualitatively explore patient experiences of severe, recurrent, bilateral nasal polyps (NP). METHODS: A targeted literature review of published qualitative studies and online blogs describing patient experiences of NP was conducted. Semistructured concept elicitation interviews were conducted in the United States and Germany with participants ≥18 years with severe, recurrent, bilateral NP to explore their symptom experience and impacts on health-related quality of life (HRQoL; NCT03221192). A subset of 10 participants reported symptoms and impacts using a smartphone or tablet application (app) over a 10-day period. RESULTS: A paucity of qualitative evidence regarding patient experience of NP was identified from the literature or blog review. Twenty-seven participant interviews were conducted. Thirty-six symptoms were identified, including 7 primary symptoms (nasal congestion [n = 27 of 27], breathing difficulties [n = 27 of 27], postnasal drip [n = 25 of 27], runny nose [n = 24 of 27], head/facial pressure [n = 23 of 27], loss of smell [n = 23 of 27], loss of taste [n = 22 of 27]) and 29 secondary symptoms (the most common were mucus/catarrh and nose bleeds [both n = 20 of 27]). Most symptoms were reported to vary both within and between days. Sixty impacts of severe NP were reported, including impacts on sleep (n = 22 of 27), physical functioning (n = 21 of 27), activities of daily living (n = 21 of 27), emotional well-being (n = 27 of 27), treatment (n = 23 of 27), social life (n = 26 of 27), and work (n = 19 of 27). Symptoms/impacts reported using the app were consistent with interview findings, although new symptoms were identified (ear pain, throat pain, nasal scabs, and nasal burning). These results supported the development of a conceptual model outlining concepts related to symptoms, impacts, and treatment of NP. CONCLUSIONS: Severe, recurrent, bilateral NP are associated with a range of symptoms that have significant detrimental impact on HRQoL.

Stratifying Minimal Versus Severe Pain in Knee Osteoarthritis Using a Musculoskeletal Ultrasound Protocol.

OBJECTIVE: The aim of this cross-sectional correlational study was to determine the association of pain with morphologic and inflammatory sonographic findings in patients with knee osteoarthritis. METHODS: A total of 113 participants with knee osteoarthritis were assessed using visual analog scale pain score and sonography. Ultrasound evaluation included morphologic changes (ie, articular cartilage degeneration, medial and lateral meniscal protrusion, and presence of osteophytes on the joint margins) and inflammatory changes (ie suprapatellar effusion and/or synovitis, Baker cyst, superficial and deep infrapatellar effusion, pes anserine tendinopathy, and Hoffa panniculitis). RESULTS: Cluster analysis via Ward's method grouped patients with minimal pain (visual analog scale score, 0-4) and with substantial pain (visual analog scale score, 5-10). Stepwise logistic regression yielded 5 variables that significantly explained the variation in the probability of perceived substantial pain at 10% level of significance: lateral cartilage clarity (LCC; P = .025), medial cartilage clarity (MCC; P = .20), medial cartilage thickness (MCT; P = .041), medial meniscus protrusion (MMP) (P = .029), and osteophytes at medial femoral margin (P = .082), with 63% overall prediction accuracy. When age and sex were added, 4 variables remained significant at a 10% level of significance: LCC, MCC, MCT, and MMP, with 65% overall prediction accuracy. The receiver operating characteristic curve of this model was 0.667. CONCLUSION: The study was able to demonstrate that morphologic abnormalities in the ultrasound parameters for LCC, MCC, MCT, and MMP were able to predict significant joint pain in knee osteoarthritis. There were no inflammatory changes that contributed to significant joint pain in this study.

Assessment of the efficacy and safety of fluticasone propionate and salmeterol delivered as a combination dry powder via a capsule-based inhaler versus a multi-dose inhaler in patients with chronic obstructive pulmonary disease.

BACKGROUND: This study tested the clinical non-inferiority of the fluticasone propionate/salmeterol combination 50/250 µg (FSC) Rotacaps®/Rotahaler® system, a single unit dose inhaler, with the multi-dose FSC Diskus® inhaler in adults with chronic obstructive pulmonary disease (COPD). METHODS: This multi-centre, randomised, double-blind, double-dummy, two-way cross-over study compared 12 weeks' treatment of FSC administered twice daily using Rotacaps/Rotahaler or Diskus. The primary endpoint was change from baseline in trough morning forced expiratory volume in 1 s (FEV1) at Day 85, and the pre-defined non-inferiority criteria was: the lower limit of the confidence interval (CI) for the treatment difference (Rotacaps/Rotahaler-Diskus) in least squares (LS) mean change from baseline, being greater than -45 mL. Secondary endpoints included change in breathlessness (as measured by transition dyspnoea index (TDI)) and COPD-specific health status measures. RESULTS: The LS mean increase from baseline in trough FEV1 at Day 85 was 116 mL in the Rotacaps/Rotahaler group and 91 mL in the Diskus group (difference in model-adjusted LS mean change: 25 mL (95% CI 2 mL, 47 mL)), the lower limit of the CI for the treatment difference being greater than the protocol-defined criterion for non-inferiority i.e. -45 mL. Data for breathlessness, COPD-specific health status and safety parameters were similar following FSC treatment via either inhaler. CONCLUSIONS: This study demonstrated the clinical non-inferiority of FSC 50/250 µg when administered using Rotacaps/Rotahaler compared with Diskus in patients with COPD. The risk:benefit profile for the two inhalers was comparable.

Social networking and Internet use among pelvic floor patients: a multicenter survey.

BACKGROUND: Internet resources are becoming increasingly important for patients seeking medical knowledge. It is imperative to understand patient use and preferences for using the Internet and social networking websites to optimize patient education. OBJECTIVES: The purpose of this study was to evaluate social networking and Internet use among women with pelvic floor complaints to seek information for their conditions as well as describe the likelihood, preferences, and predictors of website usage. STUDY DESIGN: This was a cross-sectional, multicenter study of women presenting to clinical practices of 10 female pelvic medicine and reconstructive surgery fellowship programs across the United States, affiliated with the Fellows' Pelvic Research Network. New female patients presenting with pelvic floor complaints, including urinary incontinence, pelvic organ prolapse, and fecal incontinence were eligible. Participants completed a 24 item questionnaire designed by the authors to assess demographic information, general Internet use, preferences regarding social networking websites, referral patterns, and resources utilized to learn about their pelvic floor complaints. Internet use was quantified as high (≥4 times/wk), moderate (2-3 times/wk), or minimal (≤1 time/wk). Means were used for normally distributed data and medians for data not meeting this assumption. Fisher's exact and χ2 tests were used to evaluate the associations between variables and Internet use. RESULTS: A total of 282 surveys were analyzed. The majority of participants, 83.3%, were white. The mean age was 55.8 years old. Referrals to urogynecology practices were most frequently from obstetrician/gynecologists (39.9%) and primary care providers (27.8%). Subjects were well distributed geographically, with the largest representation from the South (38.0%). Almost one third (29.9%) were most bothered by prolapse complaints, 22.0% by urgency urinary incontinence, 20.9% by stress urinary incontinence, 14.9% by urgency/frequency symptoms, and 4.1% by fecal incontinence. The majority, 75.0%, described high Internet use, whereas 8.5% moderately and 4.8% minimally used the Internet. Women most often used the Internet for personal motivations including medical research (76.4%), and 42.6% reported Google to be their primary search engine. Despite this, only 4.9% primarily used the Internet to learn about their pelvic floor condition, more commonly consulting an obstetrician-gynecologist for this information (39.4%). The majority (74.1%) held a social networking account, and 45.9% visited these daily. Nearly half, 41.7%, expressed the desire to use social networking websites to learn about their condition. Women <65 years old were significantly more likely to have high Internet use (83.4% vs 68.8%, P = .018) and to desire using social networking websites to learn about their pelvic floor complaint (P = .008). The presenting complaint was not associated with Internet use (P = .905) or the desire to use social networking websites to learn about pelvic floor disorders (P = .201). CONCLUSION: Women presenting to urogynecology practices have high Internet use and a desire to learn about their conditions via social networking websites. Despite this, obstetrician-gynecologists remain a common resource for information. Nonetheless, urogynecology practices and national organizations would likely benefit from increasing their Internet resources for patient education in pelvic floor disorders, though patients should be made aware of available resources.

Assessment of the efficacy and safety of fluticasone propionate and salmeterol delivered as a combination dry powder via a capsule-based inhaler and a multi-dose inhaler in patients with asthma.

BACKGROUND: In developing countries, there is a need for access to affordable inhaled respiratory medicines. This study tested the clinical non-inferiority of fluticasone propionate/salmeterol combination (FSC) 50/250 µg Rotacaps®/Rotahaler® compared with FSC 50/250 µg Diskus®. METHODS: A multi-centre, randomised, double-blind, double-dummy study evaluated 12 weeks, twice daily treatment of FSC 50/250 µg administered using Rotacaps/Rotahaler or Diskus inhaler in a crossover design in patients with asthma (pre-bronchodilator forced expiratory volume in 1 s (FEV1) 40%-85% of predicted, FEV1 reversibility ≥12%, prior stable dose with inhaled corticosteroid (ICS) or ICS/long acting beta-agonist). The primary efficacy endpoint, change from baseline in trough morning FEV1 at Day 85, was analysed using a model for repeated measures analysis. The pre-defined criterion for non-inferiority was the lower limit of the CI (0.025, one-sided significance level) for the treatment difference (Rotacaps/Rotahaler-Diskus) in least squares (LS) mean change from baseline, being greater than -125 mL. Secondary endpoints included serial FEV1 measurements, morning peak expiratory flow (PEF), rescue medication use, day- and night-time asthma symptoms, Asthma Control Test (ACT) scores, and serial cortisol measured over 12 h (area under the curve (AUC0-12)). RESULTS: Treatment with FSC 50/250 µg via Rotacaps/Rotahaler or Diskus resulted in a similar LS mean increase from baseline in trough FEV1 at Day 85 (231 mL and 203 mL respectively). The difference in the model-adjusted LS mean change was 28 mL (95% CI -24 mL, 80 mL), fulfilling the criterion for non-inferiority. Data for all secondary endpoints were similar for the two treatments, supporting the primary endpoint findings. Both treatments were well tolerated and demonstrated similar safety profiles. CONCLUSION: This study demonstrated the clinical non-inferiority of FSC 50/250 µg when administered using Rotacaps/Rotahaler compared with administration using Diskus in patients with asthma, and suggests there is no difference in the risk:benefit profile between the two FSC inhalers.

A Review of Radiation Protection Solutions for the Staff in the Cardiac Catheterisation Laboratory.

Adverse health effects of radiation exposure to staff in cardiac catheterisation laboratories have been well documented in the literature. Examples include increased risk of cataracts as well as possible malignancies. These risks can be partly mitigated by reducing scatter radiation exposure to staff during diagnostic and interventional cardiac procedures. There are currently commercially available radiation protection tools, including radioprotective caps, gloves, eyewear, thyroid collars, aprons, mounted shields, table skirts and patient drapes to protect staff from excessive radiation exposure. Furthermore, real-time dose feedback could lead to procedural changes that reduce operator dose. The objective of this review is to examine the efficacy of these tools and provide practical recommendations to reduce occupational radiation exposure with the aim of minimising long-term adverse health outcomes.

Kinetics of tumor destruction by chimeric antigen receptor-modified T cells.

The use of chimeric antigen receptor (CAR)-modified T cells as a therapy for hematologic malignancies and solid tumors is becoming more widespread. However, the infusion of a T-cell product targeting a single tumor-associated antigen may lead to target antigen modulation under this selective pressure, with subsequent tumor immune escape. With the purpose of preventing this phenomenon, we have studied the impact of simultaneously targeting two distinct antigens present on tumor cells: namely mucin 1 and prostate stem cell antigen, both of which are expressed in a variety of solid tumors, including pancreatic and prostate cancer. When used individually, CAR T cells directed against either tumor antigen were able to kill target-expressing cancer cells, but tumor heterogeneity led to immune escape. As a combination therapy, we demonstrate superior antitumor effects using both CARs simultaneously, but this was nevertheless insufficient to achieve a complete response. To understand the mechanism of escape, we studied the kinetics of T-cell killing and found that the magnitude of tumor destruction depended not only on the presence of target antigens but also on the intensity of expression-a feature that could be altered by administering epigenetic modulators that upregulated target expression and enhanced CAR T-cell potency.

Pharmacokinetics of fluticasone propionate and salmeterol delivered as a combination dry powder via a capsule-based inhaler and a multi-dose inhaler.

AIM: To compare salmeterol (SALM) and fluticasone propionate (FP) systemic exposure following inhaled salmeterol/fluticasone propionate combination (SFC) from a unit-dose capsule-based inhaler (Rotacaps(®)/Rotahaler(®)) and a multi-dose dry powder inhaler (Diskus(®)) in healthy volunteers. METHODS: An open-label, randomised, repeat-dose, cross-over, adaptive design study (n = 36 in each part) evaluated SFC 50/250 µg and SFC 50/100 µg in Rotacaps used with two types of Rotahaler inhalers (airflow resistance similar to (S) and lower than (L) Diskus) versus the Diskus. Primary endpoints were area under the concentration-time curve over the dosing interval [AUC0-τ] and maximum plasma concentration [Cmax]. RESULTS: SFC 50/250 µg Rotacaps/Rotahaler (S) showed 1.2-1.9-fold greater FP and SALM systemic exposure compared with Diskus. FP and SALM systemic exposure were comparable to DISKUS following SFC 50/250 µg Rotacaps/Rotahaler (L) (90% CI of ratio of Rotahaler to DISKUS within 0.8-1.25) for salmeterol (AUC0-τ and Cmax) and FP (AUC0-τ). Following SFC 50/100 µg Rotacaps/Rotahaler (L), FP and SALM systemic exposures were 1.2-1.4 fold higher in terms of FP (AUC0-τ and Cmax) and salmeterol (Cmax) compared with Diskus. SFC at both doses and via both inhalers was well tolerated. CONCLUSIONS: SFC 50/250 µg Rotacaps/Rotahaler (L) showed comparable systemic exposure to Diskus in terms of FP AUC and SALM AUC and Cmax. These results merit further progression of SFC 50/250 µg Rotacaps/Rotahaler (L) to phase 3 clinical evaluation in asthma and COPD patients. The lack of pharmacokinetic comparability between the inhalers for SFC 50/100 µg requires further evaluation.

The effects of ulnar styloid fractures on patients sustaining distal radius fractures.

PURPOSE: To determine if ulnar styloid fractures (USF) affect clinical outcome following distal radius fracture (DRF) in adults under 65 years of age. METHODS: This study involved 312 patients (aged 18-64) with surgically and nonsurgically treated DRFs. Patients were followed prospectively at baseline and 3, 6, and 12 months. The primary outcome was the Patient-Rated Wrist Evaluation (PRWE), and secondary outcomes were range of motion and grip strength. The USFs were classified by location (tip, middle, and base) and union status. RESULTS: There were 170 patients with isolated DRFs and 142 with associated USF (64 tip, 32 middle, and 46 base fractures). The mean age of the entire cohort was 48 years with 218 (70%) women. All USFs were treated nonoperatively. There was a trend of higher PRWE scores in DRFs associated with USFs compared to isolated DRFs throughout the study. Associated ulnar styloid base fractures had higher but clinically insignificant PRWE scores than isolated DRFs at 6 and 12 months. Patients with an associated USF had a slower recovery of wrist flexion and grip strength compared to isolated DRF, but values were comparable at 12 months. United USFs and nonunited USFs had similar PRWE scores at all time points. CONCLUSIONS: Adults under 65 years old with DRFs and associated USFs initially have greater pain and disability than those with isolated DRFs; however, this difference dissipated over time and was not significant at one year. No long-term differences in measured impairments were observed, but the presence of an associated USF resulted in a slower recovery of grip strength and wrist flexion. Presence of a USF nonunion did not significantly affect outcomes. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II.

Biomechanical Comparison of Distal Radioulnar Joint Reconstruction Graft Preparation Techniques.

Background Graft preparation techniques for the Adams-Berger distal radioulnar joint (DRUJ) reconstruction vary among surgeons with insufficient evidence to support any specific technique. Questions/Purposes We compared survival with cyclic loading, absolute elongation, elongation rate, and modes of failure of four graft preparation techniques. Methods Fifteen porcine extensor tendons were divided into three equal groups: tendon only; tendon augmented along its full length with nonlocking 2-0 FiberLoop suture spaced at 6 mm intervals; and tendon with suture at 12 mm intervals. Suture only was also tested. Samples were woven through custom radius- and ulna-simulating jigs mounted on a mechanical testing machine. Samples underwent a staircase cyclic loading protocol and were then inspected visually for the mode of failure. Survival with cyclic loading, absolute elongation, and elongation rate was compared. Results Average survival with cyclic loading of suture-augmented tendon was significantly higher than tendon only. All tendon groups had significantly higher survival compared with suture only. Absolute elongation was subject to variability due to initial nonlinear elongation behavior of samples. The elongation rate was significantly lower with suture compared with all tendon groups. Modes of failure included rupture of the tendon and/or suture at the simulated graft-bone interface and elongation of the entire construct without rupture. Conclusions In this biomechanical study, augmentation of porcine tendons with suture spaced at either 6 or 12 mm for DRUJ reconstruction significantly increased survival to a staircase cyclic loading protocol Clinical Relevance For the Adams-Berger reconstruction, tendon grafts augmented along their entire length by nonabsorbable braided suture are biomechanically superior to tendon alone.

Validity Evidence for Procedure-specific Competence Assessment Tools in Orthopaedic Surgery: A Scoping Review.

INTRODUCTION: Competency-based training requires frequent assessment of residents' skills to determine clinical competence. This study reviews existing literature on procedure-specific competence assessment tools in orthopaedic surgery. METHODS: A systematic search of eight databases up to May 2023 was conducted. Two reviewers independently assessed validity evidence and educational utility of each assessment tool and evaluated studies' methodological quality. RESULTS: Database searching identified 2,556 unique studies for title and abstract screening. Full texts of 290 studies were reviewed; 17 studies met the inclusion criteria. Bibliography review identified another five studies, totaling 22 studies examining 24 assessment tools included in the analysis. These tools assessed various orthopaedic surgery procedures within trauma, sports medicine, spine, and upper extremity. Overall validity evidence was low across all studies, and was lowest for consequences and highest for content. Methodological quality of studies was moderate. Educational utility assessment was not explicitly done for most tools. DISCUSSION: The paucity of current procedure-specific assessment tools in orthopaedic surgery lacks the validity evidence required to be used reliably in high-stake summative assessments. Study strengths include robust methodology and use of an evidence-based validity evidence framework. Poor-quality existing evidence is a limitation and highlights the need for evidence-based tools across more subspecialties.

Sustained efficacy of mepolizumab in patients with severe chronic rhinosinusitis with nasal polyps: SYNAPSE 24-week treatment-free follow-up.

BACKGROUND: In the 52-week Phase III SYNAPSE study, mepolizumab given every 4 weeks (100 mg subcutaneously) reduced nasal polyp (NP) size, improved symptoms and quality of life (QoL), and reduced corticosteroid use and number of sinus surgeries in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP), versus placebo. Because the durability of mepolizumab's efficacy after discontinuation is poorly understood in CRSwNP, the efficacy of mepolizumab after discontinuation was analyzed in severe CRSwNP, over a 24-week follow-up. METHODS: Changes from SYNAPSE baseline to end of treatment (week 52) and end of follow-up (week 76) were assessed for total endoscopic NP score, nasal obstruction and overall symptoms visual analog scale scores, and 22-item Sino-Nasal Outcome Test score. Time to first sinus surgery, time to first corticosteroid use, and geometric mean blood eosinophil counts (BECs) were also assessed. RESULTS: Among 134 follow-up patients, clinical improvements observed with mepolizumab versus placebo were partially evident 24 weeks after discontinuation despite BEC returning to baseline. The mean (95% confidence interval [CI]) change from baseline in NP score (week 52: -1.3 [1.8 to -0.9] vs. -0.3 [-0.6 to 0.1]; week 76: -1.2 [-1.6 to -0.7] vs. -0.1 [-0.5 to 0.3]) and the proportion of patients having sinus surgery (week 52: 4% vs. 25%; week 76: 9% vs. 31%) remained substantially improved with mepolizumab versus placebo. Mepolizumab-associated improvements in overall symptoms, quality of life, and corticosteroid use versus placebo were partially sustained at week 76. CONCLUSION: Fifty-two weeks of mepolizumab treatment is associated with sustained clinical benefits up to 24 weeks after discontinuation in patients with severe CRSwNP, which should be considered by physicians when making treatment decisions.