Citations

Abstract INTRODUCTION: The Oncotype DX Breast Recurrence Score® (RS) assay is validated to predict risk of distant recurrence at 10 years and the benefit of adjuvant chemotherapy in patients with estrogen receptor (ER)+, HER2- early breast cancer who receive 5 years of endocrine therapy. The feasibility of Oncotype DX® testing with diagnostic core needle biopsies (CNB) was demonstrated through analysis of a large commercial laboratory experience. The neoadjuvant ADAPT study showed the clinical utility of deriving the Recurrence Score® (RS) result from CNB as well. However, data are limited on concordance of RS results from paired CNB and surgical samples. Our primary objective was to determine the degree of concordance of RS results between paired tissue samples from the same primary breast tumor of patients with early stage, ER+, HER2- invasive breast cancer who had a CNB and subsequent surgical excision (SE; lumpectomy or mastectomy) without intervening systemic therapy. METHODS: Patients with a commercial RS result on either CNB or subsequent SE were identified through medical record and clinical database review. A pathologist reviewed archival tissue samples to confirm eligibility and selected the other paired CNB or SE block most representative of the tumor tissue for subsequent study Oncotype DX testing. Descriptive statistics were used to summarize patient and tumor characteristics. Wilcoxon signed rank, McNemar’s and Cochran-Mantel-Haenszel tests were used to compare RS between SE and CNB paired samples. Cohen’s Kappa and 95% confidence intervals (CIs) were used to compare the agreement of categorical RS (0-25 and 26-100) result between SE and CNB paired samples. Lin’s concordance correlation and 95% CIs were used to compare agreement of continuous RS between paired samples. RESULTS: A total of 134 patients were identified with paired CNB and SE samples with a median time of 34 (range 5-103) days between collections. Of the 134 patients, a commercial RS result was available for 25 (18.7%) with CNB and 109 (81.3%) with SE. A study RS result was then generated on the other paired sample. Median age was 62 years (range 33-99; 23 patients [17%] were age ≤50 vs. 111 [83%] age >50). Cases were predominantly node negative (107/134 node negative vs. 26/134 node positive; 1/134 unknown) invasive ductal carcinomas (104/134 ductal vs. 18/134 classic lobular vs. 12/134 other). Mean RS results were 15.6 (range 0-56) and 16.6 (range 0-59) for CNB and SE, respectively (p = 0.003), with no statistically significant differences in RS category defined as low vs. high risk (119/134 CNB vs. 114/134 SE for RS 0-25 and 15/134 CNB vs 20/134 SE for RS 26-100; p = 0.13) or low vs. intermediate vs. high risk (85/134 CNB vs. 78/134 SE for RS 0-17 and 43/134 CNB vs. 48/134 SE for RS 18-30 and 6/134 CNB vs. 8/134 SE for RS 31-100; p = 0.19). No differences were observed based on age relative to 50 years or nodal status (data not shown). Cohen’s Kappa statistic k = 0.64 (95% CI, 0.44-0.83) supports substantial agreement between the CNB and SE samples. Lin’s concordance correlation coefficient (CCC) demonstrates similar agreement for the continuous RS result between paired samples (CCC = 0.86 [0.80-0.90]). Overall percent agreement was 91.8% (87.1-96.4%). CONCLUSIONS: Studies evaluating the level of concordance of ER, progesterone receptor, and HER2 biomarker status between CNB and SE samples have found high concordance rates, albeit varied. We now provide data demonstrating high concordance of RS results between CNB and SE specimens obtained from the same breast primary tumor without intervening systemic therapy. This supports use of either biopsy source for testing with a genomic predictor to identify those patients who will most likely benefit from chemotherapy and which patients may be spared. Citation Format: Aziza Nassar, Jodi Carter, Paige Innis, Satish Seerapu, Christy Russell, Helena Hanna, Abigail Lochala, Minetta Liu. Concordance analysis of paired breast cancer core needle biopsies and surgical excision samples using the Oncotype DX Breast Recurrence Score® assay [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-08-09.

Abstract Aims Mobile devices such as smartphones and watches can now record single-lead electrocardiograms (ECGs), making wearables a potential screening tool for cardiac and wellness monitoring outside of healthcare settings. Because friends and family often share their smart phones and devices, confirmation that a sample is from a given patient is important before it is added to the electronic health record. Methods and results We sought to determine whether the application of Siamese neural network would permit the diagnostic ECG sample to serve as both a medical test and biometric identifier. When using similarity scores to discriminate whether a pair of ECGs came from the same patient or different patients, inputs of single-lead and 12-lead medians produced an area under the curve of 0.94 and 0.97, respectively. Conclusion The similar performance of the single-lead and 12-lead configurations underscores the potential use of mobile devices to monitor cardiac health.

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established treatment for the motor symptoms of Parkinson’s disease (PD). While PD is primarily characterized by motor symptoms such as tremor, rigidity, and bradykinesia, it also involves a range of non-motor symptoms, and anxiety is one of the most common. The relationship between PD and anxiety is complex and can be a result of both pathological neural changes and the psychological and emotional impacts of living with a chronic progressive condition. Managing anxiety in PD is critical for improving the patients’ quality of life. However, patients undergoing STN DBS can occasionally experience increased anxiety. Methods: This study investigates changes in risk-avoidant behavior following STN DBS in a pre-motor animal model of PD under chronic and acute unilateral high frequency stimulation. Results: No significant changes in risk-avoidant behaviors were observed in rats who underwent STN DBS compared with sham stimulation controls. Chronic stimulation prevented sensitization in the elevated zero maze. Conclusions: These results suggest that unilateral stimulation of the STN may have minimal effects on risk-avoidant behaviors in PD. However, additional research is required to fully understand the mechanisms responsible for changes in anxiety during STN DBS for PD.

Importance Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement. Objectives To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. Design, Setting, and Participants This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. Main Outcomes and Measures Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). Results Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = −0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = −0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02). Conclusions and Relevance Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.

Importance The association of tumor-infiltrating lymphocyte (TIL) abundance in breast cancer tissue with cancer recurrence and death in patients with early-stage triple-negative breast cancer (TNBC) who are not treated with adjuvant or neoadjuvant chemotherapy is unclear. Objective To study the association of TIL abundance in breast cancer tissue with survival among patients with early-stage TNBC who were treated with locoregional therapy but no chemotherapy. Design, Setting, and Participants Retrospective pooled analysis of individual patient-level data from 13 participating centers in North America (Rochester, Minnesota; Vancouver, British Columbia, Canada), Europe (Paris, Lyon, and Villejuif, France; Amsterdam and Rotterdam, the Netherlands; Milan, Padova, and Genova, Italy; Gothenburg, Sweden), and Asia (Tokyo, Japan; Seoul, Korea), including 1966 participants diagnosed with TNBC between 1979 and 2017 (with follow-up until September 27, 2021) who received treatment with surgery with or without radiotherapy but no adjuvant or neoadjuvant chemotherapy. Exposure TIL abundance in breast tissue from resected primary tumors. Main Outcomes and Measures The primary outcome was invasive disease-free survival [iDFS]. Secondary outcomes were recurrence-free survival [RFS], survival free of distant recurrence [distant RFS, DRFS], and overall survival. Associations were assessed using a multivariable Cox model stratified by participating center. Results This study included 1966 patients with TNBC (median age, 56 years [IQR, 39-71]; 55% had stage I TNBC). The median TIL level was 15% (IQR, 5%-40%). Four-hundred seventeen (21%) had a TIL level of 50% or more (median age, 41 years [IQR, 36-63]), and 1300 (66%) had a TIL level of less than 30% (median age, 59 years [IQR, 41-72]). Five-year DRFS for stage I TNBC was 94% (95% CI, 91%-96%) for patients with a TIL level of 50% or more, compared with 78% (95% CI, 75%-80%) for those with a TIL level of less than 30%; 5-year overall survival was 95% (95% CI, 92%-97%) for patients with a TIL level of 50% or more, compared with 82% (95% CI, 79%-84%) for those with a TIL level of less than 30%. At a median follow-up of 18 years, and after adjusting for age, tumor size, nodal status, histological grade, and receipt of radiotherapy, each 10% higher TIL increment was associated independently with improved iDFS (hazard ratio [HR], 0.92 [0.89-0.94]), RFS (HR, 0.90 [0.87-0.92]), DRFS (HR, 0.87 [0.84-0.90]), and overall survival (0.88 [0.85-0.91]) (likelihood ratio test, P < 10e-6). Conclusions and Relevance In patients with early-stage TNBC who did not undergo adjuvant or neoadjuvant chemotherapy, breast cancer tissue with a higher abundance of TIL levels was associated with significantly better survival. These results suggest that breast tissue TIL abundance is a prognostic factor for patients with early-stage TNBC.

Abstract During the humoral immune response, B cells undergo rapid metabolic reprogramming with a high demand for nutrients, which are vital to sustain the formation of the germinal centers (GCs). Rag-GTPases sense amino acid availability to modulate the mechanistic target of rapamycin complex 1 (mTORC1) pathway and suppress transcription factor EB (TFEB) and transcription factor enhancer 3 (TFE3), members of the microphthalmia (MiT/TFE) family of HLH-leucine zipper transcription factors. However, how Rag-GTPases coordinate amino acid sensing, mTORC1 activation, and TFEB/TFE3 activity in humoral immunity remains undefined. Here, we show that B cell-intrinsic Rag-GTPases are critical for the development and activation of B cells. RagA/RagB deficient B cells fail to form GCs, produce antibodies, and generate plasmablasts in both T-dependent (TD) and T-independent (TI) humoral immune responses. Deletion of RagA/RagB in GC B cells leads to abnormal dark zone (DZ) to light zone (LZ) ratio and reduced affinity maturation. Mechanistically, the Rag-GTPase complex constrains TFEB/TFE3 activity to prevent mitophagy dysregulation and maintain mitochondrial fitness in B cells, which are independent of canonical mTORC1 activation. TFEB/TFE3 deletion restores B cell development, GC formation in Peyer’s patches and TI humoral immunity, but not TD humoral immunity in the absence of Rag-GTPases. Collectively, our data establish Rag-GTPase-TFEB/TFE3 axis as an mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells.

ImportanceRedirection of care refers to withdrawal, withholding, or limiting escalation of treatment. Whether maternal social determinants of health are associated with redirection of care discussions merits understanding.ObjectiveTo examine associations between maternal social determinants of health and redirection of care discussions for infants born extremely preterm.Design, Setting, and ParticipantsThis is a retrospective analysis of a prospective cohort of infants born at less than 29 weeks’ gestation between April 2011 and December 2020 at 19 National Institute of Child Health and Human Development Neonatal Research Network centers in the US. Follow-up occurred between January 2013 and October 2023. Included infants received active treatment at birth and had mothers who identified as Black or White. Race was limited to Black and White based on service disparities between these groups and limited sample size for other races. Maternal social determinant of health exposures were education level (high school nongraduate or graduate), insurance type (public/none or private), race (Black or White), and ethnicity (Hispanic or non-Hispanic).Main Outcomes and MeasuresThe primary outcome was documented discussion about redirection of infant care. Secondary outcomes included subsequent redirection of care occurrence and, for those born at less than 27 weeks’ gestation, death and neurodevelopmental impairment at 22 to 26 months’ corrected age.ResultsOf the 15 629 infants (mean [SD] gestational age, 26 [2] weeks; 7961 [51%] male) from 13 643 mothers, 2324 (15%) had documented redirection of care discussions. In unadjusted comparisons, there was no significant difference in the percentage of infants with redirection of care discussions by race (Black, 1004/6793 [15%]; White, 1320/8836 [15%]) or ethnicity (Hispanic, 291/2105 [14%]; non-Hispanic, 2020/13 408 [15%]). However, after controlling for maternal and neonatal factors, infants whose mothers identified as Black or as Hispanic were less likely to have documented redirection of care discussions than infants whose mothers identified as White (Black vs White adjusted odds ratio [aOR], 0.84; 95% CI, 0.75-0.96) or as non-Hispanic (Hispanic vs non-Hispanic aOR, 0.72; 95% CI, 0.60-0.87). Redirection of care discussion occurrence did not differ by maternal education level or insurance type.Conclusions and RelevanceFor infants born extremely preterm, redirection of care discussions occurred less often for Black and Hispanic infants than for White and non-Hispanic infants. It is important to explore the possible reasons underlying these differences.

Abstract Emerging studies have identified the critical roles of tissue-resident memory CD8+ T (TRM) and B (BRM) cells in the protection against mucosal viral infections, but the underlying mechanisms regulating robust development of TRM and BRM cells remain incompletely understood. We have recently shown that tissue-resident helper CD4+ T (TRH) cells, developed following influenza virus infection, function to sustain the optimal maintenance of TRM and BRM cells at the mucosal surface. In this study, we have explored the cellular and molecular cues modulating lung TRH persistence after influenza infection in C57BL/6 mice. We found that TRH cells were colocalized in tertiary lymphoid structures (TLSs) with local B cells. Abolishing TLSs or the depletion of B cells impaired lung TRH cell numbers. Of note, we found that persistent TCR signaling is needed for the maintenance of TRH cells after the clearance of infectious influenza virus. Furthermore, selective ablation of B cell–derived MHC class II resulted in partial reduction of lung TRH cell number after influenza infection. Our findings suggest that the interaction between lung-resident TRH cells and B cells, along with persistent Ag stimulation, is required to maintain TRH cells after respiratory viral infection.

BACKGROUND Lipomatosis of nerve (LN) is a rare disorder characterized by the massive enlargement of peripheral nerves, frequently accompanied by generalized fibroadipose proliferation and skeletal overgrowth. OBSERVATIONS The authors have been routinely following a 20-year-old male for lipomatosis of median nerve at the wrist noted shortly after birth. He had undergone resection of the lesion accompanied by sural nerve grafting at another institution. Clinically, although his neurological loss of function has been stable, he has had continued soft tissue growth. Serial magnetic resonance imaging has revealed persistent LN proximal to the repair sites with evidence of fatty proliferation in the sural grafts and continued LN and fatty proliferation distally. There has been a progressive circumferential pattern of fibrosis around the proximal and distal suture lines, which has a similar radiological pattern to desmoid type fibromatosis (a pattern recently described in neuromuscular choristoma [NMC] desmoid-type fibromatosis). LESSONS Considering the similar reaction of nerve in both LN and NMC despite differing genetic cascades, the authors believe a unifying process occurs in both lesions. The pattern of circumferential fibroproliferation would be most consistent with neuron-mediated growth from unspecified trophic factors, supporting a previously reported a nerve-derived “inside-out mechanism.” The clinical consequences of this unifying process are presented.

Abstract Context Circulating lactate concentration is an important determinant of exercise tolerance. Objective This work aimed to determine the role of hyperglycemia on lactate metabolism during exercise in individuals with type 1 diabetes (T1D). Methods The protocol at the University of Virginia compared 7 T1D participants and 7 participants without diabetes (ND) at euglycemia (5.5 mM) or hyperglycemia (9.2 mM) in random order in T1D and at euglycemia in ND. Intervention included [1-13C] lactate infusion, exercise at 65% maximal oxygen uptake (VO2max), euglycemia, and hyperglycemia visits. The main outcome measure was lactate turnover before, during, and after 60 minutes of exercise at 65% VO2max. Results A 2-compartment model with loss only from the peripheral compartment described lactate kinetics. Volume of distribution of the accessible compartment was similar between T1D and ND individuals (P = .76) and concordant with plasma volume (∼40 mL/kg). Circulating lactate concentrations were higher (P < .001) in T1D participants during exercise at hyperglycemia than euglycemia. Exercise-induced lactate appearance did not differ (P = .13) between hyperglycemia and euglycemia. However, lactate clearance (CL) was lower (P = .03) during hyperglycemia than euglycemia in T1D participants. There were no differences in any of the aforementioned parameters between T1D and ND participants during euglycemia. Conclusion Hyperglycemia modulates lactate metabolism during exercise by lowering CL, leading to higher circulating lactate concentrations in T1D individuals. This novel observation implies that exercise during hyperglycemia can lead to higher circulating lactate concentrations thus increasing the likelihood of reaching the lactate threshold sooner in T1D, and has high translational relevance both for providers and recreationally active people with T1D.