Citations

Background: Chemotherapy-induced peripheral neuropathy (CIPN) from oxaliplatin and taxane drugs is a bothersome toxicity. Palmitoylethanolamide (PEA) has been reported to improve myelinated nerve fiber function in patients experiencing painful CIPN. We conducted a double-blind, placebo-controlled, randomized trial of PEA in patients with established CIPN. Methods: Eligible patients were adults who had pain, numbness, tingling, or other symptoms of CIPN for at least three months following completion of paclitaxel, oxaliplatin, or cisplatin-based chemotherapy. Study patients were randomized to one of the two treatment groups (PEA versus placebo, both administered either once or twice daily). The CIPN20 questionnaire was assessed weekly. Results: A total of 17 males and 71 females participated in the study; most had neuropathy from paclitaxel. Most (85%) finished 8 weeks of treatment. There was no suggestion that either of the PEA arms did any better than the combined placebo arms. There was no signal of significant toxicity differences between the three study arms. Quality of life outcome measures were similar between the study arms, as were cognitive function evaluations. Discussion: PEA failed to improve established CIPN. Future trials might explore whether PEA may be effective in preventing CIPN or cognitive changes based on data that suggest it may be helpful in this situation. Conclusions: PEA failed to improve established chemotherapy-induced neuropathy.

Background/Objectives: The enzyme ubiquitin-specific protease 44 (USP44) is a deubiquitinating enzyme with identified physiological roles as a tumor suppressor and an oncogene. While some binding partners and substrates are known for USP44, the identification of other interactions may improve our understanding of its role in cancer. We therefore performed a proximity biotinylation study that identified products of several known cancer genes that are associated with USP44, including a novel interaction between BRCA2 and USP44. Methods: We expressed a fusion protein that linked USP44 and mutant Escherichia coli biotin ligase BioID in SH-SY5Y neuroblastoma cells. Control experiments were performed using BioID alone. In duplicate experiments, cells were pulsed with biotin and biotinylated proteins were isolated under denaturing conditions and the proteins were identified by mass spectrometry. The resulting list of proteins were analyzed using Enrichr and cross-referenced with the COSMIC Cancer Gene Census. We validated the association with BRCA2 using immunoprecipitation. The role of USP44 in the Fanconi anemia DNA repair pathway was investigated using chromosome analysis of wild-type or Usp44-knockout cells after exposure to mitomycin C. Results: We identified 146 proteins that were selectively retrieved by the USP44 construct and compared with cells expressing the BioID ligase alone, including 15 gene products encoded by genes on tier 1 of the COSMIC Cancer Gene Census, including BRCA2. The association between USP44 and BRCA2 was validated through immunoprecipitation. We tested the functional role of USP44 in the Fanconi anemia DNA repair pathway through chromosome breakage analysis and found that cells lacking USP44 had a significant increase in chromosome breaks and radial chromosomes. We found that high BRCA2 transcript was correlated with poor survival in neuroblastoma, likely due to its tight association with proliferation in these tumors. Conclusions: Our results identified novel potential binding partners and potential substrates for USP44, including several with direct roles in cancer pathogenesis. Our results identified a novel association between BRCA2 and USP44, and a previously unknown role for USP44 in the Fanconi anemia DNA repair pathway that may contribute to its role in cancer.

Abstract Extant literature reveals how patients of marginalized social identities, socioeconomic status (SES), and medical experiences – especially patients of color and older adults – are underrepresented in cancer clinical trials (CCTs). Emerging evidence increasingly indicates CCT underrepresentation among patients of lower SES or rural origin, sexual and gender minorities, and patients with comorbid disability. This review applies an intersectional perspective to characterizing CCT representativeness across race and ethnicity, age, sexual and gender identity, SES, and disability. Four databases were systematically queried for articles addressing CCT participation inequities across these marginalizing indicators, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. One hundred one articles were included in a qualitative evaluation of CCT representativeness within each target population in the context of their intersectional impacts on participation. Findings corroborate strong evidence of CCT underrepresentation among patients of color, older age, lower SES, rural origin, and comorbid disabling conditions while highlighting systemic limitations in data available to characterize representativeness. Results emphasize how observed inequities interactively manifest through the compounding effects of minoritized social identity, inequitable economic conditions, and marginalizing medical experiences. Recommendations are discussed to more accurately quantify CCT participation inequities across underserved cancer populations and understand their underpinning mechanisms.

Background: Reporting the 50 most cited manuscripts on virtual surgical planning (VSP) for craniofacial surgery, thereby providing a comprehensive review of landmark papers. Methods: The Web of Science Citation Index was used to identify the 50 most cited manuscripts on VSP in craniofacial surgery. These were classified by level of evidence, type of study, topic of interest, and anatomic site. Results: The mean number of citations was 126.3 ± SD 51.7. Twenty were clinical papers: 9 reviews, and 21 workflow or technology. The most common level of evidence (LoE) was 4 ( n = 12), followed by 3 ( n = 6), 2 ( n = 1), and 5 ( n = 1). Thirty-nine of 50 articles focused on the maxillomandibular area of the face, 5 zygomatic, 5 orbit, 2 cranial vault, and 1 nasal ethmoid bone. The majority of articles (37 of 50) were on orthognathic surgery, 11 facial reconstruction, 2 calvarium reconstruction or craniosynostosis, and 2 free flap procedures. Year of publication ranged from 2000 to 2019; 34 articles were published in craniomaxillofacial journals. Conclusion: VSP is a relatively new technology and most highly cited articles on this topic pertain to workflow, technology, and protocols, as these are necessary for its integration into clinical practice. In our list, VSP was most used in orthognathic surgery; however, due to the potential increased efficiency and accuracy, it is being explored in other areas of craniofacial surgery such as facial reconstruction and craniosynostosis. Accordingly, we expect to see increasingly widespread usage of VSP in other areas of surgery, which could potentially lead to highly cited papers.

Abstract Background: Tracheobronchomalacia (TBM) presents diagnostic challenges due to its nonspecific symptoms and variability in diagnostic methods. This study evaluates physician concordance in TBM diagnosis and phenotyping using chest computed tomography (CT) scans with dynamic expiratory views. Methods: We conducted a retrospective cross-sectional study at Mayo Clinic Rochester, analyzing 150 patients with dynamic expiratory CT scans. Three specialists—a thoracic radiologist, a bronchoscopist, and a pulmonologist—reviewed identical CT scans, blinded to prior interpretations. Inter-rater agreement was assessed using Fleiss's Kappa for TBM diagnosis and Cohen's Kappa for TBM phenotype classification into six categories: No TBM, Excessive Dynamic Airway Collapse (EDAC), Crescent Type, Circumferential Type, Saber-Sheath Type, and Mixed Type. Results: Among the 150 patients, 54 (36%) were diagnosed with TBM or EDAC. TBM was more prevalent in males, older individuals, and smokers. Agreement among specialists was substantial for TBM diagnosis (Fleiss’s Kappa = 0.61, p < 0.001) but moderate for phenotype classification (Fleiss’s Kappa = 0.52, p < 0.001). The highest concordance was between the thoracic radiologist and the pulmonologist (Cohen's Kappa = 0.68), while the lowest was between the bronchoscopist and other specialists. Conclusion: There is substantial agreement in TBM diagnosis using chest CT scans with dynamic expiratory views, but moderate variability in phenotyping. Standardizing criteria and integrating pulmonary function testing could enhance diagnostic consistency and clinical relevance.

Indications for and implications of germline genetic testing (GGT) in patients with prostate cancer have expanded over the past decade, particularly related to precision therapies and management. GGT has become the standard of care for many cancers such as breast, ovarian, colorectal, pancreatic, and metastatic prostate cancer, and it is imperative that patients be offered timely and equitable access to testing as it can inform patient-physician shared decision making for management of the current cancer as well as anticipatory guidance for disease progression. Additionally, GGT guides screening for and prevention of secondary malignancies for the patient and cascade testing for at-risk family members. Here, we present data supporting the notion that clinicians should offer all patients with prostate cancer the opportunity to undergo comprehensive GGT for pathogenic germline variants known to be associated with familial cancer and/or known to have implications for treatment and management.

Abstract Background We sought to evaluate key performance indicators related to an internally developed and deployed artificial intelligence (AI)-augmented kidney stone composition test system for potential improvements in test quality, efficiency, cost-effectiveness, and staff satisfaction. Methods We compared quality, efficiency, staff satisfaction, and financial data from the 6 months after the AI-augmented laboratory test system was deployed (test period) with data from the same 6-month period in the previous year (control period) to determine if AI-augmentation improved key performance indicators of this laboratory test. Results In the 6 months following the deployment (test period) of the AI-augmented kidney stone composition test system, 44 830 kidney stones were analyzed. Of these, 92% of kidney stones were eligible for AI-assisted interpretation. Out of these AI-eligible stones, 45% were able to be auto-released by the AI-augmented test system without human secondary review. Furthermore, the new AI-augmented kidney stone test system resulted in an apparent 40% reduction in incorrect laboratory results. Additionally, the new AI-augmented test system improved laboratory efficiency by 20%, improved staff satisfaction, and reduced the average analysis cost per kidney stone by $0.23. Conclusions The AI-augmented test system improved test quality, efficiency, cost-effectiveness and staff satisfaction related to this kidney stone composition test.

Inconsistency in the calculation of time spent in moderate to vigorous physical activity (MVPA) limits interstudy comparability and interpretation of surveillance data. This study assesses whether combining multiple individual methods results in a more accurate estimate of MVPA, while considering the influence of device brand and wear location. Participants (n = 30, age = 49.2 ± 19.5 years) wore two accelerometers (GENEActiv, ActiGraph) on each wrist during two laboratory visits. Individual classification methods (11 for left wrist, eight for right wrist) estimated minutes of MVPA using three approaches (cut-point, two-regression, and machine learning), two types of input (count and raw), and five epoch lengths (1, 5, 15, 30, and 60 s). The consensus estimate was calculated as the mean or median (due to skew) across all individual estimates. No individual or consensus estimates were statistically equivalent to direct observation (mean 38.2 min), with 81%–95% of individual methods overestimating MVPA. The best-performing individual methods were raw acceleration cut-points, with a bias of −3.2 to 2.4 min across devices and wrists. Correlation coefficients between individual methods and the criterion were .35–.71 for the left and .12–.67 for the right wrist, compared to .65–.70 and .58–.66 for consensus methods, respectively. Correlations between device brands were .23–.99 for individual methods and .70–.86 for consensus methods, while correlations between locations were .55–.86 and .73–.87, respectively. Better methods are required for estimating MVPA from wrist-worn accelerometers given the consistent overestimation of MVPA observed. While a consensus method for wrist-worn data was not able to fully resolve these issues, it improves interwrist or interbrand comparability.

Abstract Asthma is a heterogeneous disease with variable presentation and characteristics. There is a critical need to identify underlying molecular endotypes of asthma. We performed the largest transcriptomic analysis of 808 bronchial epithelial cell samples across 11 independent cohorts, including 3 cohorts from the Severe Asthma Research Program. Using seven datasets (218 patients with asthma, 148 healthy control subjects) as discovery cohorts, we identified 505 differentially expressed genes, which we validated in the remaining four datasets. Unsupervised clustering using the 505 differentially expressed genes identified four reproducible clusters of patients with asthma across all datasets, corresponding to healthy control subjects, patients with mild/moderate asthma, and patients with severe asthma with significant differences in several clinical markers of severity, including pulmonary function, Type 2 inflammation, fractional exhaled nitric oxide, and maximum bronchodilator reversibility. Importantly, we found the same clusters in pediatric patients using nasal lavage fluid cells, demonstrating the gene signature and clusters are not confounded by age and are conserved in both lower and upper airways. The four asthma clusters may represent a unifying framework for understanding the molecular heterogeneity of asthma. Further study could potentially enable a precision medicine approach of matching therapies with patients with asthma most likely to benefit.