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826 Background: After initial response to first line therapy with imatinib, GISTs commonly progress due to secondary resistance mutations in KIT. As the KIT mutation targeting profiles of bezuclastinib (type I TKI) and sunitinib are distinct, when combined they inhibit a broad spectrum of secondary KIT mutations. Herein we report extended experience of patients treated with 2 nd line combination bezuclastinib and sunitinib, including response assessment and safety. Methods: Peak (NCT05208047), a global randomized Phase 3, open-label study, aims to evaluate efficacy and safety of bezuclastinib + sunitinib vs sunitinib in GIST pts with imatinib intolerance or resistance. In Part 1a of the 3-part study, the dose of an optimized formulation of bezuclastinib was escalated in serial cohorts to achieve a target exposure comparable to that achieved at the RP2D established in the prior Phase 1b/2a study. Part 1b evaluated the interaction between bezuclastinib + sunitinib. Key inclusion: adult with locally advanced, metastatic and/or unresectable GIST, ≥1 measurable lesion according to modified RECIST v1.1, and ECOG PS 0 to 2. Part 1 completed enrollment in Apr 2023. Based upon PK and safety, a dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD was selected for Part 2. All Part 1 data reported herein are as of Aug 2023; updated safety and efficacy will be presented. Results: Part 1 has completed enrollment with 19 pts in Part 1a and 23 in 1b. In Part 1a, Cohort 1 included 5 pts starting at bezuclastinib 300 mg QD + sunitinib 37.5 mg QD; Cohort 2 included 14 pts at bezuclastinib 600 mg QD + sunitinib 37.5 mg QD. Pt characteristics in Part 1a+1b: median age - 60 yrs (range: 33-77); 81% men; 98% ECOG PS 0-1; 98% metastatic and 2% locally advanced. The majority of TEAEs were low grade and reversible with low rate (38%) of Grade 3+ events. There were limited (24%) dose reductions and infrequent (n=2) discontinuations due to TEAEs. Three pts experienced serious AEs possibly associated with study medications. In pts evaluable for response (received ≥1 cycle of study treatment and had assessments at baseline and post-baseline [n=40]), the objective response rate (ORR) was 20% (6 confirmed PRs, 2 unconfirmed PRs). Data remain immature to estimate median PFS for Part 1 pts. In a subset of pts with prior imatinib only (n=6), the closest approximation for pts enrolling in Part 2, the ORR was 33% (2 confirmed PRs). The majority of 2nd-line pts remain on treatment past 12 months. Conclusions: Data from Peak Part 1 show an encouraging safety and tolerability profile generally consistent with published sunitinib monotherapy experience. ORR in evaluable pts from Part 1 was 20%; ORR in 2 nd line pts was 33%. Part 2 of the Peak study is actively enrolling pts globally at the selected dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD versus sunitinib 37.5 mg QD. Clinical trial information: NCT05208047 .

ABSTRACTRationalePatient reported outcome (PRO) measures are a critical tool to understand the patient's experience of their illness. Our institution collects PRO measures for patients receiving spine care through several modalities, including direct patient outreaches.Aims and ObjectivesWe designed a quality project to increase the total number of patient outreaches within 1 year, without increasing program resources or costs, by utilizing a return‐to‐work program.MethodSpine PRO collection rate data was extracted from the electronic health record by a data science analyst. This data included how many direct patient outreaches were completed each month and the average number of patient outreaches being completed by the patient outreach representative. For the balancing measure, full‐time equivalent costs were monitored throughout the baseline and pilot periods.ResultsDuring the 6‐month baseline period, 3477 patient outreaches were made, representing 14.5% of possible outreaches. During the first 3‐month post‐intervention remeasure period, 6272 patient outreaches were made, an increase of 55.44%. During the second 3‐month post‐intervention period, 9099 outreaches were made, an increase of 38.21% from the first remeasure. There was no increase in cost to the program related to the project.ConclusionThis increase in patient outreaches by return‐to‐work employees will translate to improvement in overall PRO collection rates, which may ultimately improve individual and population health care delivery.

Background Bacteremia is sometimes observed in patients with prosthetic joint infection (PJI), and it is associated with a lower likelihood of infection control. However, the prevalence and association of bacteremia in chronic PJI remain unknown. Questions/purposes (1) What percentage of patients are diagnosed with bacteremia at the time of hospital admission and before surgery for chronic PJI? (2) What clinical factors are associated with positive blood cultures? (3) To what degree are positive blood cultures associated with infection-free implant survival in patients with chronic PJI? Methods This prospective study was conducted at a single academic institution from June 2021 to August 2022. Within the study period, we treated 124 patients for chronic PJI, defined according to the modified Musculoskeletal Infection Society (MSIS) criteria. Of those, we considered patients who underwent revision surgery because of chronic PJI of the hip or knee as potentially eligible. All patients received two blood cultures within 48 hours after admission but before surgery. The second blood culture was performed on the contralateral arm 1 hour after the first was completed. Based on that, 87% (108 of 124) of patients were eligible; 13% (16 of 124) were excluded because of delayed blood sample transfers in 6% (7 of 124) of patients, contaminated samples in 2% (2 of 124), late hematogenous infection in 2% (3 of 124), and antibiotic use within 2 weeks before sampling in 3% (4 of 124). No patients were lost before the minimum study follow-up of 2 years without having reached a study endpoint (reinfection or persistent PJI) or had incomplete datasets, leaving 74% (92 of 124) for analysis here. The median (range) time from the index surgery (previous primary, debridement, or revision procedure) to the current revision for PJI in these patients was 16 months (2 to 180). Of the included patients, 40% (37 of 92) were men, 39% (36 of 92) had PJI of the hip, and 61% (56 of 92) had PJI of the knee. The mean age of patients was 65 ± 13 years, and the mean BMI was 28 ± 3 kg/m2. The interval between two cultures was at least 1 hour, and one culture was taken from each of the patient’s arms. Patients were divided into blood culture–positive and blood culture–negative groups based on preoperative blood culture results. The chi-square test and the independent t-test were used to compare demographic characteristics (gender, age, BMI, and affected joint) and clinical factors (American Society of Anesthesiologists [ASA] classification, hematological tests, comorbidities) between the two groups. Further multivariable logistic regression analysis was performed to assess the factors associated with positive blood cultures, which controlled for potential confounders including age, gender, BMI, and affected joint. The Firth penalized likelihood was employed when there was monotone likelihood in logistic regression analysis to reduce small-sample bias. A Kaplan-Meier curve tracked infection-free implant survival over 30 months, with differences evaluated using the log-rank test. Results Overall, 15% (14 of 92) of patients had positive blood cultures. After adjusting for age, gender, infection site, BMI, and intraoperative isolation of gram-positive cocci, we found that patients classified as ASA III (OR 4 [95% confidence interval (CI) 1 to 21]; p = 0.04) and those who had diabetes (OR 14 [95% CI 3 to 100]; p < 0.001) had a higher odds of positive blood cultures. We found no difference in the Kaplan-Meier estimate for infection-free implant survival at 30 months between those with positive blood cultures (86% [95% CI 76% to 95%]) and those with negative blood cultures (91% [95% CI 88% to 94%]; p = 0.51). Conclusion In this prospective, observational study, we found that chronic PJI can potentially lead to hematogenous dissemination of pathogens, particularly in patients with poor overall health (such as those classified as ASA III and patients diagnosed with diabetes). Therefore, selective preoperative blood cultures may be crucial in helping clinicians implement early intervention measures to prevent the serious consequences of bacteremia in patients with poor baseline health and those with other implanted devices. Larger studies with longer follow-up are needed to further validate these findings, ensure more robust estimates, and conduct comprehensive evaluations of the risk factors associated with positive blood cultures in chronic PJI. Level of Evidence Level II, therapeutic study.

Background: Reverse shoulder arthroplasty (RSA) is increasingly used in the treatment of proximal humerus fractures (PHFs) with reliable clinical improvement. Lateralized RSA implants have conferred superior outcomes compared with the original Grammont design in patients with nontraumatic indications. However, in the setting of a PHF, lateralized components can place increased tension across the tuberosity fracture site and potentially compromise tuberosity healing and outcomes. This systematic review and meta-analysis sought to determine the effect of implant design on clinical outcomes after RSA for PHFs. Methods: A systematic review was performed per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed/MEDLINE, EMBASE, Web of Science, and Cochrane were queried for clinical studies on RSA performed for PHFs that reported implant manufacturer details. Our primary outcomes included postoperative external rotation (ER), forward elevation (FE), abduction, Constant score, rate of greater tuberosity (GT) healing, and the incidence of complications compared between medialized vs. lateralized global implant design. Results: Globally lateralized RSA cohorts (478 RSAs total with cumulative lateral offset achieved through humeral or glenoid lateralization or both humeral and glenoid lateralization) were found to have a greater mean postoperative Constant score compared with globally medialized (medialized glenoid and medialized humerus) RSA cohorts with 1,494 total medialized RSAs (66 vs. 59, p = 0.006), but there was no significant difference regarding mean postoperative ER (30° vs. 22°, p = 0.078), FE (117° vs. 119°, p = 0.708), or abduction (103° vs. 107°, p = 0.377). On meta-regression, neither implant design nor tuberosity status significantly influenced postoperative ER, FE, abduction, or Constant score on meta-regression independent of mean follow-up and age at surgery. The rate of GT healing was greater in lateralized compared with medialized RSAs (88% vs. 72%, p < 0.001). On meta-regression, medialized RSA design was associated with a 73% lower odds of GT healing (odds ratio = 0.27, 95% confidence interval = 0.11-0.68, p = 0.007) independent of mean follow-up and age at surgery. Conclusion: Lateralized RSA implants conferred no significant functional benefit over medialized implants when used in patients with PHFs. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Abstract Nerve conduction F-wave studies contain crucial information about subclinical motor dysfunction that can be used to diagnose patients with amyotrophic lateral sclerosis (ALS). However, F-wave responses are highly variable in morphology, making waveform interpretation challenging. Artificial intelligence techniques can extract time–frequency features to provide new insights into ALS diagnosis and prognosis. A retrospective analysis was performed on F-wave responses from 46 802 patients. Discrete wavelet transforms were applied to time-series waveform responses after stimulating ulnar, median, fibular and tibial nerves. Wavelet coefficient statistics, onset age, sex and body mass index were features for training a Gradient Boosting Machine model on 40 095 patients (5329 diagnosed with motor neuron disease). Model performance was tested on responses from 689 ALS patients meeting Gold Coast criteria and 689 age- and sex-matched controls. An exploratory analysis examined model performance on cohorts of patients with inclusion body myositis, cervical radiculopathy, lumbar radiculopathy or peripheral neuropathy, which can mimic ALS symptoms. Factors affecting survival were estimated through Cox proportional hazards regression. The model trained using wavelet features on the full waveform had 90% recall, 87% precision and 88% accuracy. Similar model performance was measured using features from only the M-wave or F-wave. Classification probabilities for ALS patients were statistically different from the diagnoses mimicking ALS symptoms (P &lt; 0.001, ANOVA, Tukey’s post hoc test). Higher model classification probabilities of ALS, older age at onset, and family history of ALS alone or with frontotemporal dementia were factors decreasing survival. Longer diagnostic delay and upper limb onset site were factors increasing survival. Model scores two standard deviations below the mean had 4 months increased survival (two standard deviations below had 3 months decreased survival). Artificial intelligence techniques extracted important information from F-wave responses to estimate a patient’s likelihood of ALS and their survival risks. Although the model can make predictions at a specific decision threshold as presented here, the true strength of such a model lies in its ability to provide probabilities about whether a patient is likely to have ALS in comparison to other mimicking diagnoses, such as inclusion body myositis, cervical or lumbar radiculopathy or peripheral neuropathy. These probabilities provide clinicians with additional information that they can use to make the final diagnosis with greater confidence and precision. Integrating such a model into the clinical workflow could help clinicians to diagnose ALS sooner and manage treatment based on estimated survival, which might improve outcomes and the quality of life of patients.

Modulating immune function is a critical strategy in cancer and atherosclerosis treatments. For cancer, boosting or maintaining the immune system is crucial to prevent tumor growth. However, in vascular disease, mitigating immune responses can decrease inflammation and slow atherosclerosis progression. Anti-inflammatory therapy, therefore, presents a unique dilemma for cancer survivors: while it may decrease cardiovascular risk, it might also promote cancer growth and metastasis by suppressing the immune response. Senescence presents a potentially targetable solution to this challenge; senescence increases the risk of both cancer therapy resistance and vascular disease. Exercise, notably, shows promise in delaying this premature senescence, potentially improving cancer outcomes and lowering vascular disease risk post-treatment. This review focuses on the long-term impact of cancer therapies on vascular health. We underscore the importance of modulating senescence to balance cancer treatment’s effectiveness and its vascular impact, and we emphasize investigating the role of exercise-mediated suppression of senescence in improving cancer survivorship.

Abstract Autoimmunity affects 10% of the population. Within this umbrella, autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the developmental pathway of disease-causing B cells and autoantibodies. While such autoreactivities are believed to be generated during germinal centre reactions, the roles of earlier immune checkpoints in autoantigen-specific B cell tolerance are poorly understood. We address this concept in patients with CASPR2-autoantibody encephalitis and healthy controls. In both groups, comparable and high (∼0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with heterogenous binding kinetics. These effector molecules possessed epitope-dependent pathogenic effects in vitro neuronal cultures and in vivo. The unmutated common ancestors of these memory B cells showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results are the first to propose mechanisms underlying autoantigen-specific tolerance in humans. We identify permissive central tolerance, defective peripheral tolerance and heterogenous autoantibody binding properties as sequential pathogenic steps which licence CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches in CASPR2-antibody diseases. This paradigm is applicable across autoimmune conditions.

Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261

OBJECTIVE Cervical spondylotic myelopathy (CSM) shows varying levels of improvement after surgical treatment. While some patients improve soon after surgery, others may take months to years to show any signs of improvement. The goal of this study was to evaluate postoperative improvement, patient-reported outcomes, and patient satisfaction up to 2 years after surgical treatment for CSM, which will help optimize the current treatment strategies and effectively manage patient expectations. METHODS This was a retrospective study of prospectively collected data using the Quality Outcomes Database. The primary outcomes of interest were achievement of the minimal clinically important difference (MCID) for the numeric rating scale for neck and arm pain, modified Japanese Orthopaedic Association, Neck Disability Index, and EQ-5D scores and postoperative satisfaction (North American Spine Society scale). Early and sustained improvement was defined as MCID achievement in at least one patient-reported outcome measure (PROM) at the 3-, 12-, and 24-month follow-ups. Transient improvement was defined as MCID achievement only at the 3-month and/or 12-month follow-up but not at the 24-month follow-up. Late improvement was defined as MCID achievement in at least one PROM only at the 24-month follow-up. RESULTS There were 630 patients included in the comparative analysis. A total of 463 (73.5%) patients achieved early and sustained improvement, 105 (16.7%) patients experienced transient improvement with subsequent decline, 25 (4.0%) patients reported late improvement, and 37 (5.9%) patients did not report any clinically meaningful improvement after surgery. Patients with an anterior approach were more likely to be in the early and sustained improvement group. African American patients (OR 2.98, 95% CI 1.14–7.76; p = 0.03) were more likely to report late improvement when compared with White patients. The overall satisfaction rate at the 24-month follow-up was 87.8%. CONCLUSIONS These findings indicate that 73.5% of patients achieve early and sustained improvement, and 87.8% of patients are satisfied with surgery 24 months postoperatively.