Citations

AbstractAdipoRon is an adiponectin receptor 1, 2 (ADIPOR1 and ADIPOR2) agonist with potential antifibrotic effects. Whether AdipoRon can mitigate joint stiffness in a rabbit model of arthrofibrosis is unknown. We examined the efficacy of intravenous (IV) AdipoRon at mitigating contracture in a rabbit model of knee arthrofibrosis. Fifty‐six female New Zealand White rabbits were divided into three dosing groups: vehicle (dimethyl sulfoxide, DMSO), 2.5 mg/kg AdipoRon, and 5 mg/kg AdipoRon. AdipoRon, in DMSO, was administered IV preoperatively and for 5 days postoperatively (30 rabbits, Aim 1). AdipoRon was again dosed similarly after Kirschner wire (K‐wire) removal at 8 weeks (26 rabbits; Aim 2). The primary outcome of joint passive extension angle (PEA,°) was measured at 8, 10, 12, 16, and 24 weeks following index surgery. At 24 weeks, rabbits were euthanized and limbs were harvested to measure posterior capsular stiffness (N cm/°). In Aim 1, the 5 mg/kg treated rabbits had a significant increase in PEA when compared to controls at 16‐week (p < 0.05). In Aim 2, the 5 mg/kg treated rabbits had a significant increase in PEA when compared to controls at 10‐week (p < 0.05). In both aims, no significant differences were observed at later time points. Capsular stiffness was no different in any group. We are the first to report the efficacy of IV AdipoRon in a rabbit model of arthrofibrosis. We identified a significant dose‐dependent decrease in joint PEA at early time points; however, no differences were observed between groups at later time points. Clinical Significance: The present investigation provided the first assessment of AdipoRon's efficacy in mitigating knee stiffness in the current gold standard rabbit model of arthrofibrosis. Results of this investigation provided further evidence as to the potential role of AdipoRon as a preventative for arthrofibrosis in large mammals.

AbstractBackgroundThe hidradenitis suppurativa (HS) clinical response (HiSCR) has come under scrutiny as several HS clinical trials failed to meet primary endpoints with high placebo responses. This may be due to limitations of the tool and raters' ability to accurately characterize and count lesions, rather than lack of efficacy of the studied drug. Due to HS lesion complexity and potential differences in rater training, it was hypothesized that there would be discrepancies in how providers characterize and count lesions for HS clinical trials.ObjectiveTo evaluate how HS providers and patients name and count HS lesions and to identify discrepancies among providers to initiate the development of consensus‐driven guidance for HS rater training.MethodsAn online survey was distributed to the members of HIdradenitis SuppuraTiva cORe outcomes set International Collaboration (HISTORIC). Respondents were asked to classify lesion images composed of multiple and different morphology types and answer questions regarding inclusion of associated dermatological conditions.ResultsForty‐seven HISTORIC members responded (29 providers; 18 patients). There was variability in how respondents classified HS lesions. Of 12 questions containing images, four had ≥50% of respondents choosing the same answer. With an image of a lesion composed of different morphologies, 45% of providers counted it as a single lesion and 45% counted it as multiple distinct lesions. With an image of multiple interconnected draining tunnels, 7% of providers classified it as a single draining tunnel while 79% categorized it as multiple draining tunnels with the number estimated by visual inspection. There was also variability in deciding whether lesions occurring in associated conditions should be considered separately or included in HS lesion counts. Patient responses were also variable.ConclusionsThe result of the current study reaffirms the gap in how providers characterize and count HS lesions for clinical trials and the need to develop consensus‐driven rater training related to HS outcome measures.

Abstract Background: We have previously reported that 177Lu-PSMA-617 given as a single-cycle, dose-intense regimen for patients (pts) with pretreated mCRPC is efficacious even without selection by PSMA (ESMO 2021). Quantitative analyses of pre-treatment PSMA PET may allow for better patient selection and prediction of toxicities. Analyses of sequential PET images may also provide insights that may be associated with longer term outcomes. Our previous analysis of 13 patients demonstrated association of PSMA PET signal with overall survival (OS) and PSA responses, as well as trends with adverse events (Nauseef GU ASCO 2022). Here we present long-term follow up data and expanded imaging correlatives from our completed phase I/II study. MethodsEntry criteria: progressive mCRPC after at least one prior potent AR pathway inhibitor and prior chemotherapy (excepting men ineligible for or refusing of chemotherapy) with allowance for prior radionuclides (incl. Ra223 and PSMA-TRTs). Treatment was fractionated-dose (D1 and D15) 177Lu-PSMA-617 (7.4-22.2 GBq). TRAQinform IQ (AIQ Solutions) was used to identify, track, and quantify regions of interest suspicious of cancer (lesion-ROI) on PSMA PET/CT images and quantify uptake in normal organs outside of lesion-ROI. Measurements included SUVmean across all lesion-ROI, volume of lesion-ROI, and SUVtotal (sum of SUV in all lesion-ROI), as well as changes after treatment, including in PSMA-expressing healthy tissues. Associations with survival were tested via Cox proportional hazard models in univariate analyses and associations with adverse events (AEs) and PSA responses were via assessed via Wilcoxon rank sum tests. Results32 pts (of 50 total in the study between 1/2017-2/2021) had pre- and post-treatment imaging suitable TRAQinform IQ analysis and associated survival analyses. Baseline characteristics were similar to the entire study cohort. PSA response of 50% was observed in 21/32 (66%) of which 16 were confirmed. No imaging variable predicted PSA30 or PSA50, although an association was observed in pretreatment SUVmean and lesion-ROI volume reduction. No imaging variable was significantly associated with OS (e.g., pretx SUVmean HR 0.9, p=0.10, pretx Volume HR 1.00, p=0.052). Pretx SUVmean was associated with mPFS (HR 0.85, 95% CI 0.74, 0.98, p=0.023). Among select AEs, anemia was associated with non-lesion-ROI skeleton SUVtotal in pre- (p=0.027) and post-tx (p=0.007). Higher pre-treatment salivary gland uptake (SUVmean) was associated with more xerostomia (p=0.11). Fatigue was associated with a variety of variables including salivary SUVs (mean, max, and total) and post-tx bowel SUVmax (p=0.030). ConclusionsPre-treatment and pre- to post-treatment 68Ga-PSMA11-PET data analyzed may be associated with outcome. While a strength of this study is the prospective nature of patient enrollment and fixed imaging timepoints, our associations are limited by small sample size. Expansion of this analysis to larger datasets may improve our ability to predict treatment response and toxicity by body-wide PSMA detection. Citation Format: Jones Trevor Nauseef, Charlene Thomas, Michael Sun, Nicole Jacobs, Andrés Ricaurte Fajardo, Sam Ruder, Escarleth Fernandez, Zachary Davidson, Amie Patel, A. Oliver Sartor, Shankar Vallabhajosula, Ana Molina, Cora N. Sternberg, David M. Nanus, Sandra Huicochea Castellanos, Joseph Osborne, Neil H. Bander, Timothy Perk, Scott Tagawa. Quantitative assessment of PSMA imaging before and after 177Lu-PSMA-617 treatment in a Ph I/II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT225.

Abstract DNA damage response (DDR) mechanisms are critical to maintenance of overall genomic stability, and their dysfunction can contribute to oncogenesis. Significant advances in our understanding of DDR pathways have raised the possibility of developing therapies that exploit these processes. In this expert-driven consensus review, we examine mechanisms of response to DNA damage, progress in development of DDR inhibitors in IDH-wild-type glioblastoma and IDH-mutant gliomas, and other important considerations such as biomarker development, preclinical models, combination therapies, mechanisms of resistance and clinical trial design considerations.

AbstractBackgroundUndifferentiated embryonal sarcoma of the liver (UESL) is a rare tumor for which there are few evidence‐based guidelines. The aim of this study was to define current management strategies and outcomes for these patients using a multi‐institutional dataset curated by the Pediatric Surgical Oncology Research Collaborative.MethodsData were collected retrospectively for patients with UESL treated across 17 children's hospitals in North America from 1989 to 2019. Factors analyzed included patient and tumor characteristics, PRETEXT group, operative details, and neoadjuvant/adjuvant regimens. Event‐free and overall survival (EFS, OS) were the primary and secondary outcomes, respectively.ResultsSeventy‐eight patients were identified with a median age of 9.9 years [interquartile range [IQR): 7–12]. Twenty‐seven patients underwent resection at diagnosis, and 47 patients underwent delayed resection, including eight liver transplants. Neoadjuvant chemotherapy led to a median change in maximum tumor diameter of 1.6 cm [IQR: 0.0–4.4] and greater than 90% tumor necrosis in 79% of the patients undergoing delayed resection. R0 resections were accomplished in 63 patients (81%). Univariate analysis found that metastatic disease impacted OS, and completeness of resection impacted both EFS and OS, while multivariate analysis revealed that R0 resection was associated with decreased expected hazards of experiencing an event [hazard ratio (HR): 0.14, 95% confidence interval (CI): 0.04–0.6]. At a median follow‐up of 4 years [IQR: 2–8], the EFS was 70.0% [95% CI: 60%–82%] and OS was 83% [95% CI: 75%–93%].ConclusionComplete resection is associated with improved survival for patients with UESL. Neoadjuvant chemotherapy causes minimal radiographic response, but significant tumor necrosis.

Abstract Exposure to repetitive head impacts in contact sports is associated with neurodegenerative disorders including chronic traumatic encephalopathy (CTE), which currently can be diagnosed only at post-mortem. American football players are at higher risk of developing CTE given their exposure to repetitive head impacts. One promising approach for diagnosing CTE in vivo is to explore known neuropathological abnormalities at post-mortem in living individuals using structural MRI. MRI brain morphometry was evaluated in 170 male former American football players ages 45–74 years (n = 114 professional; n = 56 college) and 54 same-age unexposed asymptomatic male controls (n = 54, age range 45–74). Cortical thickness and volume of regions of interest were selected based on established CTE pathology findings and were assessed using FreeSurfer. Group differences and interactions with age and exposure factors were evaluated using a generalized least squares model. A separate logistic regression and independent multinomial model were performed to predict each traumatic encephalopathy syndrome (TES) diagnosis, core clinical features and provisional level of certainty for CTE pathology using brain regions of interest. Former college and professional American football players (combined) showed significant cortical thickness and/or volume reductions compared to unexposed asymptomatic controls in the hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus, insula, temporal pole and superior frontal gyrus. Post hoc analyses identified group-level differences between former professional players and unexposed asymptomatic controls in the hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus, insula and superior frontal gyrus. Former college players showed significant volume reductions in the hippocampus, amygdala and superior frontal gyrus compared to the unexposed asymptomatic controls. We did not observe Age × Group interactions for brain morphometric measures. Interactions between morphometry and exposure measures were limited to a single significant positive association between the age of first exposure to organized tackle football and right insular volume. We found no significant relationship between brain morphometric measures and the TES diagnosis core clinical features and provisional level of certainty for CTE pathology outcomes. These findings suggested that MRI morphometrics detect abnormalities in individuals with a history of repetitive head impact exposure that resemble the anatomic distribution of pathological findings from post-mortem CTE studies. The lack of findings associating MRI measures with exposure metrics (except for one significant relationship) or TES diagnosis and core clinical features suggested that brain morphometry must be complemented by other types of measures to characterize individuals with repetitive head impacts.

AbstractThe APOE4 allele is recognized as a significant genetic risk factor to Alzheimer's disease (AD) and influences longevity. Nonetheless, some APOE4 carriers exhibit resistance to AD even in advanced age. Humanin, a mitochondrial‐derived peptide comprising 24 amino acids, has variants linked to cognitive resilience and longevity. Our research uncovered a unique humanin variant, P3S, specifically enriched in centenarians with the APOE4 allele. Through in silico analyses and subsequent experimental validation, we demonstrated a strong affinity between humanin P3S and APOE4. Utilizing an APOE4‐centric mouse model of amyloidosis (APP/PS1/APOE4), we observed that humanin P3S significantly attenuated brain amyloid‐beta accumulation compared to the wild‐type humanin. Transcriptomic assessments of mice treated with humanin P3S highlighted its potential mechanism involving the enhancement of amyloid beta phagocytosis. Additionally, in vitro studies corroborated humanin P3S's efficacy in promoting amyloid‐beta clearance. Notably, in the temporal cortex of APOE4 carriers, humanin expression is correlated with genes associated with phagocytosis. Our findings suggest a role of the rare humanin variant P3S, especially prevalent among individuals of Ashkenazi descent, in mitigating amyloid beta pathology and facilitating phagocytosis in APOE4‐linked amyloidosis, underscoring its significance in longevity and cognitive health among APOE4 carriers.

Abstract Background Nocardia tends to cause infection in immunocompromised patients or those with chronic pulmonary disease. Nocardia is known to recur, prompting the practice of secondary prophylaxis in patients perceived at high risk. However, few data exist regarding the epidemiology of recurrent nocardiosis or the effectiveness of secondary prophylaxis. Methods We performed a multicenter, retrospective cohort study of adults diagnosed with nocardiosis from November 2011 to April 2022, including patients who completed primary treatment and had at least 30 days of posttreatment follow-up. Propensity score matching was used to analyze the effect of secondary prophylaxis on Nocardia recurrence. Results Fifteen of 303 (5.0%) patients developed recurrent nocardiosis after primary treatment. Most recurrences were diagnosed either within 60 days (N = 6/15, 40.0%) or between 2 to 3 years (N = 4/15, 26.7%). Patients with primary disseminated infection tended to recur within 1 year, whereas later recurrences were often nondisseminated pulmonary infection. Seventy-eight (25.7%) patients were prescribed secondary prophylaxis, mostly trimethoprim-sulfamethoxazole (N = 67/78). After propensity-matching, secondary prophylaxis was not associated with reduced risk of recurrence (hazard ratio, 0.96; 95% confidence interval, .24–3.83), including in multiple subgroups. Eight (53.3%) patients with recurrent nocardiosis required hospitalization and no patients died from recurrent infection. Conclusions Recurrent nocardiosis tends to occur either within months because of the same Nocardia species or after several years with a new species. Although we did not find evidence for the effectiveness of secondary prophylaxis, the confidence intervals were wide. However, outcomes of recurrent nocardiosis are generally favorable and may not justify long-term antibiotic prophylaxis for this indication alone.

Abstract Labral tears most commonly occur anteriorly between the 12‐ and 3‐o'clock positions, with the 12‐o'clock position denoted as superior and the 3‐o'clock position denoted as anterior. When approaching the 3‐o'clock position and beyond, suture anchor placement becomes difficult given the challenging arthroscopic trajectory and an overall thin anterior rim of cortical bone for anchor purchase, resulting in a narrow angle of safe drilling. The purpose of this technical note is to present a safe and reproducible method of suture anchor placement during acetabular labral repair approaching the 3‐ and 4‐o'clock positions, with the 12‐o'clock position representing the superior anatomic location and the 3‐o'clock position representing the anterior anatomic location regardless of hip laterality. We use an inside‐out anchor placement technique to place far medial anchors, which differs from the conventional techniques (e.g., outside‐in technique) in which anchor placement is performed along the external margin of the acetabular labrum. Technique Video video See video under supplementary data.