Citations

Abstract The cumulative impact of baseline comorbidities on outcomes of chimeric antigen receptor T-cell (CAR-T) therapy is not well established. Therefore, we developed and validated a Cellular Therapy Comorbidity Index (CT-CI) to predict outcomes following CD19-directed CAR-T therapy for large B-cell lymphoma (LBCL). Patients aged 18 or older receiving commercial CAR-T therapy for LBCL during 2017 to 2020 were selected from the Center for International Blood and Marrow Transplant Research registry. Patients were randomly assigned to training or validation cohorts. Comorbidities given weighted scores comprised the CT-CI, which was then validated for overall survival (OS) prognostication. A total of 1916 patients from 97 medical centers were included, with a median age of 64 years (19-91 years). About 70% of patients had comorbidities, such as cardiac disease (12%); diabetes (14%); hepatic dysfunction (mild, 8%; moderate to severe, 2%); psychiatric disturbance (18%); and pulmonary dysfunction (moderate, 15%; severe, 12%). The CT-CI was calculated, stratified patients in 3 categories, and was associated with increased mortality. Patients with higher CT-CI scores had worse OS (CT-CI 1: hazard ratio [HR], 1.37 [95% confidence interval [CI], 1.16-1.62; P< .001]; CT-CI 2: HR, 1.49 [95% CI, 1.17-1.89; P = .001]; CT-CI ≥ 3: HR, 2.55 [95% CI, 1.90-3.42; P< .001]). Higher CT-CI scores predicted treatment-related mortality and relapse. There was no correlation between the CT-CI score and CAR-T–related toxicities. The novel CT-CI score stratifies the effect of patient comorbidities on survival after CAR-T therapy and can be used for clinical decision-making and treatment selection in high-risk populations. However, comorbidities and fear of increased toxicity should not preclude patients from this effective therapy.

Objectives Guidelines advise repeat screening within four months if Papanicolaou (Pap) results are unsatisfactory for evaluation. This utilizes healthcare system resources and may decrease patient satisfaction due to needing a second clinic appointment. We assessed unsatisfactory Pap test (UPT) rates and associations with clinician and patient characteristics to inform future interventions to decrease UPTs. Setting Multisite midwestern United States primary care practice. Methods Retrospective analysis of women aged 21–65 with a Pap between 7/1/2021 and 6/30/2023. Bivariate and multivariable logistic regression analyses were conducted to assess for associations between UPTs and clinician gender, degree, residency status, and experience. Results Of 51,195 Paps completed, 2.3% were unsatisfactory. Female clinicians performed the most Pap tests (83.2%) with slightly less likelihood of UPTs compared with male clinicians ( p = 0.015). There was no significant difference comparing physicians to advanced practice providers in UPTs ( p = 0.18). Residency training level did not affect UPT rates ( p = 0.95). Clinician experience was associated with higher UPT rates in first and fourth quartiles (least and most Paps performed) compared to middle two quartiles ( p = 0.004). UPTs were more likely among women aged > 50 years old ( p < 0.001), married ( p < 0.001), and Asian ( p < 0.001). Conclusions Clinician characteristics played a small role in predicting UPTs but patient age may be the factor most amenable to intervention to lower UPTs. Transitioning to primary human papillomavirus (HPV) screening in peri/post-menopausal women could decrease UPTs given Paps are performed on the clinician-collected cervical specimen only if HPV testing is positive.

Diabetic foot ulcers (DFUs) are common complications of suboptimally controlled diabetes, characterised by non-healing, high morbidity, infection, recurrence (40–50%) and mortality. Ultrasonic debridement technology has been used for >30 years to treat cataracts safely and effectively, and animal studies have suggested that ultrasound debridement stimulates collagen turnover. This technology was applied in developing a system for soft tissue removal in tendons and elsewhere, with intended use in the elbow, knee, ankle, foot and shoulder. It was then modified for the treatment of DFUs. In this study, the rationale behind using this technology is discussed, the procedural technique is described, and photographic examples of treatment outcomes presented.

ABSTRACT Objective To evaluate the long‐term safety and clinical effect of INO‐3107 immunotherapy in adults with recurrent respiratory papillomatosis (RRP). Methods RRP‐002 was a retrospective, observational extension study that followed patients enrolled in the 52‐week RRP‐001 study. Patients with moderate to severe juvenile or adult‐onset RRP who had undergone ≥ 2 surgical interventions in the year preceding dosing were eligible for enrollment in RRP‐001. Participants underwent surgical debulking within 14 days prior to initial dosing and then received INO‐3107 on Day 0, Weeks 3, 6, and 9. Efficacy assessments during RRP‐002 follow‐up were the frequency of surgical interventions and alternative medication use. The safety evaluation included reported serious adverse events (SAEs). Results Twenty‐eight (28) of 32 participants from the 52‐week RRP‐001 study were enrolled in RRP‐002. The median follow‐up time for RRP‐002 was 1.8 years (range: 1.2–2.4 years) for a total median assessment time of 2.8 years (range: 1.0–3.5 years). There were no SAEs or long‐term safety concerns identified. The mean number of surgeries was reduced from 4.1 in the pre‐treatment period to 1.7 in the first year post‐INO‐3107 treatment (Year 1) to 0.9 in the second year (Year 2). The complete response rate (0 surgeries per year) increased from 28% (9/32) in Year 1 to 50% (14/28) in Year 2. Conclusion INO‐3107 is well tolerated and provides a continued clinical effect against HPV‐6 and 11 RRP that results in further reduction of the surgical burden observed in Year 1. These data support the role of INO‐3107 immunotherapy for adult patients with RRP. Level of Evidence: III.

Abstract Sex differences in cancer outcome, including that of glioblastoma (GBM), are shaped by biological, hormonal, and immunological factors and impact disease progression, treatment responses, survival, and tumor microenvironment (TME) interactions. Platelets regulate the immune responses and tumor progression in many cancers, but it is not clear how they contribute to these sex-based differences by affecting the dynamics of the TME. Here, we show that GBM patients exhibit heightened platelet reactivity driven by PAR4 signaling. In murine GBM models, both pharmacological inhibition of PAR4 using BMS986120 and genetic deletion of PAR4 significantly prolong survival in females but not males. This survival advantage is estrogen dependent: it is preserved in chromosomal male-hormonal female mice within the four-core genotype model and is rescued in ovariectomized mice treated with estrogen. The survival benefit is TME specific and is mediated by platelet-driven enhancement of CD8⁺ T cell infiltration into the tumor. Inhibition of platelet PAR4 signaling increases calcium signaling through an estrogen-dependent interaction between PAR4 and estrogen receptor β (ERβ)—a receptor interaction not previously described. PAR4-activated platelets within the TME suppress CD8⁺ T cell function, and depletion of CD8⁺ T cells abolishes both the tumor-induced platelet reactivity and the survival benefit conferred by PAR4 inhibition. These findings establish platelet-mediated PAR4 signaling as a critical driver of tumor progression and identify sex-specific immune responses as key to therapeutic efficacy.

Abstract The link between regional tau load and clinical manifestation of Alzheimer’s disease (AD) highlights the importance of characterizing spatial tau distribution across disease variants. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicentres. However, given the limited spatial heterogeneity of tau in typical AD, atypical (non-amnestic-predominant) AD variants with distinct tau patterns provide a key opportunity to investigate the universality of connectivity as a scaffold for tau progression. In this large-scale, multicentre study across 14 international sites, we included cross-sectional tau-PET data from 320 individuals with atypical AD (n = 139 posterior cortical atrophy/PCA-AD; n = 103 logopenic variant primary progressive aphasia/lvPPA-AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS-AD), with a subset of individuals (n = 78) having longitudinal tau-PET data. Additionally, as an independent sample, we included regional post-mortem tau stainings from 93 atypical AD patients from two sites (n = 19 PCA-AD, n = 32 lvPPA-AD, n = 23 bvAD, n = 19 CBS-AD). Gaussian mixture modelling was used to harmonize different tau-PET tracers by transforming tau-PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether brain regions with stronger resting-state functional MRI-based functional connectivity, derived from healthy elderly controls in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology. Furthermore, we examined whether functional connectivity of tau-PET epicentres (i.e. the top 5% of regions with the highest baseline tau load) and tau-PET accumulation epicentres (i.e. the top 5% of regions with the highest tau accumulation rates) was associated with cross-sectional and longitudinal tau patterns. Our findings show that tau-PET epicentres aligned with clinical variants, e.g. a visual network predominant pattern in PCA-AD (‘visual AD’) and left-hemispheric temporal predominance, particularly within the language network, in lvPPA-AD (‘language AD’). Moreover, more strongly functionally connected regions showed correlated concurrent tau-PET levels (confirmed with post-mortem data) and tau-PET accumulation rates. The functional connectivity profile of tau-PET epicentres and accumulation epicentres corresponded to tau-PET progression patterns, with higher tau-PET levels and accumulation rates in functionally close regions, and lower tau-PET levels and accumulation rates in functionally distant regions. Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicentres, across all AD clinical variants. Since tau proteinopathy is a major driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific end points in clinical trials.

Abstract » A thorough understanding of glenoid deformity is essential to anticipate intraoperative needs and manage bony deficiencies. Management strategies include eccentric reaming, alternate scapular line baseplate orientation, bone grafting, or metallic augmentation as either “off-the-shelf” or custom baseplates. Accurate implantation of the glenoid component in the presence of glenoid bone loss (GBL) may also benefit from shoulderspecific guides, navigation, or robotic assistance. » GBL can negatively affect outcomes due to compromised bony fixation, altered soft tissue tensioning, and component malposition, which can contribute to impingement, dislocation, aseptic loosening, polyethylene wear, and component failure. » In this article, we provide a comprehensive review of published literature regarding the management of GBL in primary RSA and provide additional insight on the effectiveness of current approaches to manage bony deficiency.

ABSTRACT Background Geriatric screening and multidisciplinary assessment of older adults in the Emergency Department (ED) decrease hospitalizations and ED revisits. The impact on patient‐reported outcomes of health‐related quality of life (HRQoL) and functional status is not known. Methods A hybrid type II implementation/effectiveness prospective cohort study was conducted in an academic ED. The intervention bundle was geriatric screening for delirium, fall risk, and transition of care needs, and multidisciplinary assessment. All older adults (≥ 65 years) placed in the ED observation unit were eligible. HRQoL and functional status were obtained at the ED visit, 30, and 90 days, and were compared between the pre‐ and post‐intervention implementation cohorts. Secondary outcomes included ED revisits, falls, mortality, and intervention adoption measures. Results From 2019 to 2023, 368 adults participated in the study: Most were community‐dwelling (97%) and had multiple comorbidities. The pre ( n = 138) and post ( n = 230) cohorts did not differ in baseline functional status or HRQoL. The rate of geriatric screening improved from 12.3% in the pre‐implementation cohort to 91.3% in the post‐implementation cohort ( p < 0.01). Multispecialty consultation also increased (68.1%–91.3%, p < 0.01). The proportion who had a post‐ED visit decline in functional status did not differ between cohorts. Physical HRQoL declined similarly in both cohorts (−0.73 vs. −0.33, p = 0.61) at 90 days. Mental HRQoL improved in both cohorts; improvement was greater in the pre‐cohort (2.35 vs. 0.32, p = 0.02). ED revisits and re‐hospitalizations were unchanged (30 days: 23.0% vs. 17.2%, p = 0.18, and 90 days: 37.8% vs. 34.8%, p = 0.57). The intervention decreased falls at 30 and 90 days (30 days: 9.7% vs. 3.2%, p = 0.04; 90 days: 22.1% vs. 7.9%, p < 0.01). Conclusions Geriatric screening in the ED increased identification of geriatric syndromes and multidisciplinary consultation. The intervention was associated with decreased falls but did not affect HRQoL or reduce functional decline post ED visit. Trial Registration clinicaltrials.gov : NCT04068311