Systemic deficits in lipid homeostasis promote aging-associated impairments in B cell progenitor development.

Organismal aging has been associated with diverse metabolic and functional changes across tissues. Within the immune system, key features of physiological hematopoietic cell aging include increased fat deposition in the bone marrow, impaired hematopoietic stem and progenitor cell (HSPC) function, and a propensity towards myeloid differentiation. This shift in lineage bias can lead to pre-malignant bone marrow conditions such as clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenias of undetermined significance (CCUS), frequently setting the stage for subsequent development of age-related cancers in myeloid or lymphoid lineages. At the systemic as well as sub-cellular level, human aging has also been associated with diverse lipid alterations, such as decreased phospholipid membrane fluidity that arises as a result of increased saturated fatty acid (FA) accumulation and a decay in n-3 polyunsaturated fatty acid (PUFA) species by the age of 80 years, however the extent to which impaired FA metabolism contributes to hematopoietic aging is less clear. Here, we performed comprehensive multi-omics analyses and uncovered a role for a key PUFA biosynthesis gene, ELOVL2 , in mouse and human immune cell aging. Whole transcriptome RNA-sequencing studies of bone marrow from aged Elovl2 mutant (enzyme-deficient) mice compared with age-matched controls revealed global down-regulation in lymphoid cell markers and expression of genes involved specifically in B cell development. Flow cytometric analyses of immune cell markers confirmed an aging-associated loss of B cell markers that was exacerbated in the bone marrow of Elovl2 mutant mice and unveiled CD79B, a vital molecular regulator of lymphoid progenitor development from the pro-B to pre-B cell stage, as a putative surface biomarker of accelerated immune aging. Complementary lipidomic studies extended these findings to reveal select alterations in lipid species in aged and Elovl2 mutant mouse bone marrow samples, suggesting significant changes in the biophysical properties of cellular membranes. Furthermore, single cell RNA-seq analysis of human HSPCs across the spectrum of human development and aging uncovered a rare subpopulation (<7%) of CD34 + HSPCs that expresses ELOVL2 in healthy adult bone marrow. This HSPC subset, along with CD79B -expressing lymphoid-committed cells, were almost completely absent in CD34 + cells isolated from elderly (>60 years old) bone marrow samples. Together, these findings uncover new roles for lipid metabolism enzymes in the molecular regulation of cellular aging and immune cell function in mouse and human hematopoiesis. In addition, because systemic loss of ELOVL2 enzymatic activity resulted in down-regulation of B cell genes that are also associated with lymphoproliferative neoplasms, this study sheds light on an intriguing metabolic pathway that could be leveraged in future studies as a novel therapeutic modality to target blood cancers or other age-related conditions involving the B cell lineage.

Pharmacology of PIEZO1 channels.

PIEZO1 is a eukaryotic membrane protein that assembles as trimers to form calcium-permeable, non-selective cation channels with exquisite capabilities for mechanical force sensing and transduction of force into effect in diverse cell types that include blood cells, endothelial cells, epithelial cells, fibroblasts and stem cells and diverse systems that include bone, lymphatics and muscle. The channel has wide-ranging roles and is considered as a target for novel therapeutics in ailments spanning cancers and cardiovascular, dental, gastrointestinal, hepatobiliary, infectious, musculoskeletal, nervous system, ocular, pregnancy, renal, respiratory and urological disorders. The identification of PIEZO1 modulators is in its infancy but useful experimental tools emerged for activating, and to a lesser extent inhibiting, the channels. Elementary structure-activity relationships are known for the Yoda series of small molecule agonists, which show the potential for diverse physicochemical and pharmacological properties. Intriguing effects of Yoda1 include the stimulated removal of excess cerebrospinal fluid. Despite PIEZO1's broad expression, opportunities are suggested for selective positive or negative modulation without intolerable adverse effects. Here we provide a focused, non-systematic, narrative review of progress with this pharmacology and discuss potential future directions for research in the area.

Exploring antiviral and antiparasitic activity of gold N-heterocyclic carbenes with thiolate ligands.

Gold(I) N-heterocyclic carbenes have been explored for their therapeutic potential against several diseases. Neglected tropical diseases, including leishmaniasis, Chagas disease, and viral infections, such as zika, mayaro, and chikungunya, urgently require new treatment options. The emergent SARS-CoV-2 also demands significant attention. Gold complexes have shown promise as alternative treatments for these conditions. Previously, gold(I)(1,3-bis(mesityl)imidazole-2-ylidene)Cl (AuIMesCl) demonstrated significant leishmanicidal and anti-Chikungunya virus activities. In this study, we synthesized and fully characterized a series of gold(I)(1,3-bis(mesityl)imidazole-2-ylidene)(SR) complexes, where SR includes thiolate donor species such as 1,3-thiazolidine-2-thione, 1,3-benzothiazole-2-thione, 2-mercaptopyrimidine, and 2-thiouracil. These compounds were stable in solution, and ligand exchange reactions with N-acetyl-L-cysteine indicated that complexes with SR ligands are more labile than those with chloride. Although the reactions are rapid, they reach equilibrium at varying molar ratios depending on the SR ligand. The increased lability of these compounds results in higher cytotoxicity to host cells, such as Vero E6 and bone marrow-differentiated macrophages, compared to AuIMesCl. Despite this, the compounds effectively inhibited viral replication, achieving 95.5% inhibition of Zika virus replication at 2 µM with 96% host cell viability. Although active at low concentrations (∼2 µM) against Leishmania (L.) amazonensis and Trypanosoma cruzi, their high cytotoxicity for macrophages confirmed AuIMesCl as a better candidate with a higher selectivity index. This work correlates the coordination chemistry of pyrimidines and thiazolidines with their in vitro biological activities against significant diseases.

Hypothalamic AgRP neurons regulate the hyperphagia of lactation.

OBJECTIVE: The lactational period is associated with profound hyperphagia to accommodate the energy demands of nursing. These changes are important for the long-term metabolic health of the mother and children as altered feeding during lactation increases the risk of mothers and offspring developing metabolic disorders later in life. However, the specific behavioral mechanisms and neural circuitry mediating the hyperphagia of lactation are incompletely understood. METHODS: Here, we utilized home cage feeding devices to characterize the dynamics of feeding behavior in lactating mice. A combination of pharmacological and behavioral assays were utilized to determine how lactation alters meal structure, circadian aspects of feeding, hedonic feeding, and sensitivity to hunger and satiety signals in lactating mice. Finally, we utilized chemogenetic, immunohistochemical, and in vivo imaging approaches to characterize the role of hypothalamic agouti-related peptide (AgRP) neurons in lactational-hyperphagia. RESULTS: The lactational period is associated with increased meal size, altered circadian patterns of feeding, reduced sensitivity to gut-brain satiety signals, and enhanced sensitivity to negative energy balance. Hypothalamic AgRP neurons display increased sensitivity to negative energy balance and altered in vivo activity during the lactational state. Further, using in vivo imaging approaches we demonstrate that AgRP neurons are directly activated by lactation. Chemogenetic inhibition of AgRP neurons acutely reduces feeding in lactating mice, demonstrating an important role for these neurons in lactational-hyperphagia. CONCLUSIONS: Together, these results show that lactation collectively alters multiple components of feeding behavior and position AgRP neurons as an important cellular substrate mediating the hyperphagia of lactation.

Molecular characteristics and improved survival prediction in a cohort of 2023 ependymomas.

The diagnosis of ependymoma has moved from a purely histopathological review with limited prognostic value to an integrated diagnosis, relying heavily on molecular information. However, as the integrated approach is still novel and some molecular ependymoma subtypes are quite rare, few studies have correlated integrated pathology and clinical outcome, often focusing on small series of single molecular types. We collected data from 2023 ependymomas as classified by DNA methylation profiling, consisting of 1736 previously published and 287 unpublished methylation profiles. Methylation data and clinical information were correlated, and an integrated model was developed to predict progression-free survival. Patients with EPN-PFA, EPN-ZFTA, and EPN-MYCN tumors showed the worst outcome with 10-year overall survival rates of 56%, 62%, and 32%, respectively. EPN-PFA harbored chromosome 1q gains and/or 6q losses as markers for worse survival. In supratentorial EPN-ZFTA, a combined loss of CDKN2A and B indicated worse survival, whereas a single loss did not. Twelve out of 200 EPN-ZFTA (6%) were located in the posterior fossa, and these tumors relapsed or progressed even earlier than supratentorial tumors with a combined loss of CDKN2A/B. Patients with MPE and PF-SE, generally regarded as non-aggressive tumors, only had a 10-year progression-free survival of 59% and 65%, respectively. For the prediction of the 5-year progression-free survival, Kaplan-Meier estimators based on the molecular subtype, a Support Vector Machine based on methylation, and an integrated model based on clinical factors, CNV data, and predicted methylation scores achieved balanced accuracies of 66%, 68%, and 73%, respectively. Excluding samples with low prediction scores resulted in balanced accuracies of over 80%. In sum, our large-scale analysis of ependymomas provides robust information about molecular features and their clinical meaning. Our data are particularly relevant for rare and hardly explored tumor subtypes and seemingly benign variants that display higher recurrence rates than previously believed.

Nucleosome repositioning in chronic lymphocytic leukemia.

The location of nucleosomes in the human genome determines the primary chromatin structure and regulates access to regulatory regions. However, genome-wide information on deregulated nucleosome occupancy and its implications in primary cancer cells is scarce. Here, we conducted a genome-wide comparison of high-resolution nucleosome maps in peripheral blood B cells from patients with chronic lymphocytic leukemia (CLL) and healthy individuals at single-base-pair resolution. Our investigation uncovered significant changes of nucleosome positioning in CLL. Globally, the spacing between nucleosomes-the nucleosome repeat length (NRL)-is shortened in CLL. This effect is stronger in the more aggressive IGHV-unmutated CLL subtype than in the IGHV-mutated CLL subtype. Changes in nucleosome occupancy at specific sites are linked to active chromatin remodeling and reduced DNA methylation. Nucleosomes lost or gained in CLL marks differential binding of 3D chromatin organizers such as CTCF as well as immune response-related transcription factors and delineated mechanisms of epigenetic deregulation. The principal component analysis of nucleosome occupancy in cancer-specific regions allowed the classification of samples between cancer subtypes and normal controls. Furthermore, patients could be better assigned to CLL subtypes according to differential nucleosome occupancy than based on DNA methylation or gene expression. Thus, nucleosome positioning constitutes a novel readout to dissect molecular mechanisms of disease progression and to stratify patients. Furthermore, we anticipate that the global nucleosome repositioning detected in our study, such as changes in the NRL, can be exploited for liquid biopsy applications based on cell-free DNA to stratify patients and monitor disease progression.

Effect of Clinician-Expressed Empathy in Advanced Cancer on Different Ethnic Groups: Results from an Experimental Video-Vignette Study.

Background: In advanced cancer, clinician-expressed empathy can improve patients' psychological outcomes. It remains unknown whether all patients benefit equally from empathy. Objective: To explore whether the effect of clinician-expressed empathy on patients' psychological outcomes is moderated by patient ethnicity. Methods: Using an experimental video-vignette design, 160 participants watched a consultation-video with/without added empathy. Using regression analysis, the moderating effect of ethnicity (non-Western- vs. Dutch/Western-immigration background) on the relationship between empathy and psychological outcomes was assessed. Results: The main effect of empathy on satisfaction (p = 0.001), trust (p = 0.002), and self-efficacy (p < 0.001) was moderated by ethnicity (satisfaction, p = 0.050; trust, p = 0.066; self-efficacy, p = 0.075). No main effect of empathy nor moderation by ethnicity was found for anxiety (state anxiety: p = 0.284, p = 0.319; current anxiety: p = 0.357, p = 0.949). No main effects of ethnicity (satisfaction, p = 0.942; trust, p = 0.724; self-efficacy, p = 0.244; state anxiety, p = 0.812; current anxiety p = 0.523) were found. Conclusion: In advanced cancer, non-Western patients might benefit most from empathy. Dutch Trial Registration Number: NTR NL8992.

A Qualitative Analysis of Hospitalist Perceptions of Self-Directed Discharge Among Inpatients with Opioid Use Disorder.

Background: People with opioid use disorder (OUD) have high rates of hospital admissions and high rates of patient-directed discharge, leading to significant morbidity and mortality. In this study, we aimed to understand hospitalist attitudes toward patients with OUD leaving before treatment completion and their willingness to collaborate with patients in future initiatives focused on improving the experience of hospital-based care for patients with OUD. Methods: We conducted semi-structured interviews with hospitalists at two hospitals in Philadelphia, PA to explore their perspectives on social and structural factors that contribute to patients with OUD leaving the hospital before treatment completion. Interviews were recorded, transcribed, and coded with NVivo using conventional content analysis. Results: Twenty-two hospitalists (64% female, 72.7% White, mean age 37) were interviewed between February and April 2021. Hospitalists listed the following as reasons for patients with OUD leaving before treatment completion: untimely and inadequate pain/withdrawal treatment, limited prescribing options in medications for OUD, restrictive visitor and smoking policies, and patient social and other obligations. Twenty out of 22 hospitalists were willing to engage in collaborative patient-centered care but noted institutional barriers. Conclusion: Hospitalists stated willingness to collaborate with patients on identifying and developing systems-level solutions that would allow for patient-centered care. In-hospital access to addiction consult service, staff with lived experience, and other culturally competent resources are key to reducing self-directed discharge, as is training to address stigma and reframe perceptions of appropriate dosing for pain and withdrawal. Hospitalists note a need for transitions to outpatient care after hospital discharge.

A 10-Year Review of Designated Leadership Positions of the American Orthopaedic Foot & Ankle Society (AOFAS).

Background: In 2019 the majority of US medical students were women (50.5%). However, despite this representation, female representation within orthopaedic surgery remains low when compared to male counterparts. Previously, the American Society for Surgery of the Hand (ASSH) and Pediatric Orthopaedic Society of North America (POSNA) published their gender diversity data. No such study has been conducted in the American Orthopaedic Foot & Ankle Society (AOFAS), which is the largest membership organization for foot and ankle-trained orthopaedic surgeons. This study sought to investigate whether increased female representation in the AOFAS membership roster is reflected in different levels within the organization. Methods: The 2012-2022 membership rosters were obtained from the AOFAS and compared by gender. Volunteer, elected, and appointed leadership positions as well as rates of engagement were compared for each of the activities. Leadership positions were defined as committee chair, vice chair, or board of directors (BOD). When available, time for advancement through leadership positions to the presidential role was analyzed by gender. Comparative data were available for 2 other respective subspecialty groups, ASSH and POSNA, from previously published studies. Results: Between 2012 and 2022, the percentage of female membership in the AOFAS has continued to increase from 7.5% (n=76) to 13% (n=163). Engagement in committee membership positions during this time has more than doubled from 11 of 26 (14.4%) to 57 of 163 (34.9%). When participation trends were evaluated by gender, women showed higher rates of committee involvement than their male counterparts. In 2021 compared to 2012, the percentage of female committee members more than doubled compared with their male counterparts (female 34.9% to male 23.2% vs female 14.4% to male 16.8%). This increase in female gender committee composition trend has been seen in the ASSH and POSNA, but it is more pronounced in the AOFAS. Representation of women in committee chair positions and elected positions has not seen this same parallel increase. Conclusion: The female membership of the AOFAS has a similar gender composition to other orthopaedic subspecialities. Female membership within the society has increased over the past 10 years. The rates of female involvement within committee membership positions have seen a parallel increase. It will take time to mature into leadership roles as we continue to increase diversity within our respective subspecialty organizations. Inception of the AOFAS Diversity Equity and Inclusion and Women's Subcommittee demonstrate a continued emphasis on this core value within the society. Level of Evidence: Level IV, cohort study.

The added value of SLN mapping with indocyanine green in low- and intermediate-risk endometrial cancer management: a systematic review and meta-analysis.

OBJECTIVE: The aim of this study was to assess the SLN detection rate in presumed early stage, low- and intermediate-risk endometrial cancers, the incidence of SLN metastases, and the negative predictive value of SLN mapping performed with indocyanine green (ICG). METHODS: A systematic review with meta-analyses was conducted. Study inclusion criteria were A) low- and intermediate-risk endometrial cancer, B) the use of ICG per cervical injection; C) a minimum of twenty included patients per study. To assess the negative predictive value of SLN mapping, D) a subsequent lymphadenectomy was an additional inclusion criterion. RESULTS: Fourteen studies were selected, involving 2,117 patients. The overall and bilateral SLN detection rates were 95.6% (95% confidence interval [CI]=92.4%-97.9%) and 76.5% (95% CI=68.1%-84.0%), respectively. The incidence of SLN metastases was 9.6% (95% CI=5.1%-15.2%) in patients with grade 1-2 endometrial cancer and 11.8% (95% CI=8.1%-16.1%) in patients with grade 1-3 endometrial cancer. The negative predictive value of SLN mapping was 100% (95% CI=98.8%-100%) in studies that included grade 1-2 endometrial cancer and 99.2% (95% CI=97.9%-99.9%) in studies that also included grade 3. CONCLUSION: SLN mapping with ICG is feasible with a high detection rate and negative predictive value in low- and intermediate-risk endometrial cancers. Given the incidence of SLN metastases is approximately 10% in those patients, SLN mapping may lead to stage shifting with potential therapeutic consequences. Given the high negative predictive value with SLN mapping, routine lymphadenectomy should be omitted in low- and intermediate-risk endometrial cancer.

Talipes Equinovarus in Loeys-Dietz Syndrome.

BACKGROUND: Loeys-Dietz syndrome (LDS) commonly presents with foot deformities, such as talipes equinovarus (TEV), also known as "clubfoot." Although much is known about the treatment of idiopathic TEV, very little is known about the treatment of TEV in LDS. Here, we summarize the clinical characteristics of patients with LDS and TEV and compare clinical and patient-reported outcomes of operative versus nonoperative treatment. METHODS: We identified 47 patients with TEV from a cohort of 252 patients with LDS who presented to our academic tertiary care hospital from 2010 to 2016. A questionnaire, electronic health records, clinical photos and radiographs, and telephone calls were used to collect baseline, treatment, and outcome data. The validated disease-specific instrument was used to determine patient-reported foot/ankle functional limitations after treatment. Patients were categorized into nonoperative and operative groups, with the operative group subcategorized according to whether the posteromedial release was performed. RESULTS: Within our TEV cohort, bilateral TEV was present in 40 patients (85%). Thirty-seven patients underwent surgery (14 involving posteromedial release), and 10 were treated nonoperatively. The operative group had a higher incidence of posttreatment foot/ankle functional limitation (71%) than the nonoperative group (25%) ( P =0.04). The pain was the most common functional limitation (54%). The posteromedial release was associated with a higher incidence of developing hindfoot valgus compared with surgery not involving posteromedial release (43% vs. 8.7%, P =0.04) and compared with nonoperative treatment (43% vs. 0.0%, P =0.02). CONCLUSIONS: We found that patients with LDS have a high incidence of bilateral TEV. Operative treatment was associated with posttreatment foot/ankle functional limitations, and posteromedial release was associated with hindfoot valgus overcorrection deformity. These findings could have implications for the planning of surgery for TEV in LDS patients. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Comprehensive profiling of myxopapillary ependymomas identifies a distinct molecular subtype with relapsing disease.

BACKGROUND: Myxopapillary ependymoma (MPE) is a heterogeneous disease regarding histopathology and outcome. The underlying molecular biology is poorly understood, and markers that reliably predict the patients' clinical course are unknown. METHODS: We assembled a cohort of 185 tumors classified as MPE based on DNA methylation. Methylation patterns, copy number profiles, and MGMT promoter methylation were analyzed for all tumors, 106 tumors were evaluated histomorphologically, and RNA sequencing was performed for 37 cases. Based on methylation profiling, we defined two subtypes MPE-A and MPE-B, and explored associations with epidemiological, clinical, pathological, and molecular characteristics of these tumors. RESULTS: MPE-A occurred at a median age of 27 years and were enriched with tumors demonstrating papillary morphology and MGMT promoter hypermethylation. Half of these tumors could not be totally resected, and 85% relapsed within 10 years. Copy number alterations were more common in MPE-A. RNA sequencing revealed an enrichment for extracellular matrix and immune system-related signatures in MPE-A. MPE-B occurred at a median age of 45 years and included many tumors with a histological diagnosis of WHO grade II and tanycytic morphology. Patients within this subtype had a significantly better outcome with a relapse rate of 33% in 10 years (P = 3.4e-06). CONCLUSIONS: We unraveled the morphological and clinical heterogeneity of MPE by identifying two molecularly distinct subtypes. These subtypes significantly differed in progression-free survival and will likely need different protocols for surveillance and treatment.

Evaluation of Myeloperoxidase as Target for Host-Directed Therapy in Tuberculosis In Vivo.

Due to the rise of tuberculosis cases infected with multi and extensively drug-resistant Mycobacterium tuberculosis strains and the emergence of isolates resistant to antibiotics newly in clinical use, host-directed therapies targeting pathogenesis-associated immune pathways adjunct to antibiotics may ameliorate disease and bacterial clearance. Active tuberculosis is characterized by neutrophil-mediated lung pathology and tissue destruction. Previously, we showed that preventing M. tuberculosis induced necrosis in human neutrophils by inhibition of myeloperoxidase (MPO) promoted default apoptosis and subsequent control of mycobacteria by macrophages taking up the mycobacteria-infected neutrophils. To translate our findings in an in vivo model, we tested the MPO inhibitor 4-aminobenzoic acid hydrazide (ABAH) in C3HeB/FeJ mice, which are highly susceptible to M. tuberculosis infection manifesting in neutrophil-associated necrotic granulomas. MPO inhibition alone or as co-treatment with isoniazid, a first-line antibiotic in tuberculosis treatment, did not result in reduced bacterial burden, improved pathology, or altered infiltrating immune cell compositions. MPO inhibition failed to prevent M. tuberculosis induced neutrophil necrosis in C3Heb/FeJ mice in vivo as well as in murine neutrophils in vitro. In contrast to human neutrophils, murine neutrophils do not respond to M. tuberculosis infection in an MPO-dependent manner. Thus, the murine C3HeB/FeJ model does not fully resemble the pathomechanisms in active human tuberculosis. Consequently, murine infection models of tuberculosis are not necessarily adequate to evaluate host-directed therapies targeting neutrophils in vivo.

Sentinel Lymph Node Mapping in Presumed Low- and Intermediate-Risk Endometrial Cancer Management (SLIM): A Multicenter, Prospective Cohort Study in The Netherlands.

The aim was to investigate the incidence of sentinel lymph node (SLN) metastases and the contribution of SLN mapping in presumed low- and intermediate-risk endometrial cancer (EC). A multicenter, prospective cohort study in presumed low- and intermediate-risk EC patients was performed. Patients underwent SLN mapping using cervical injections of indocyanine green and a minimally invasive hysterectomy with bilateral salpingo-oophorectomy. The primary outcome was the incidence of SLN metastases, leading to adjusted adjuvant treatment. Secondary outcomes were the SLN detection rate and the occurrence of complications. Descriptive statistics and univariate general linear model analyses were used. A total of 152 patients were enrolled, with overall and bilateral SLN detection rates of 91% and 61%, respectively. At final histology, 78.9% of patients (n = 120) had truly low- and intermediate-risk EC. Macro- and micro-metastases were present in 11.2% (n = 17/152), and three patients had isolated tumor cells (2.0%). Nine patients (5.9%) had addition of adjuvant radiotherapy based on SLN metastases only. In 2.0% of patients with high-risk disease, adjuvant therapy was more limited due to negative SLNs. This study emphasizes the importance of SLN mapping in presumed early-stage, grade 1 and 2 EC, leading to individualized adjuvant management, resulting in less undertreatment and overtreatment.

Lymphovascular invasion has a significant prognostic impact in patients with early breast cancer, results from a large, national, multicenter, retrospective cohort study.

BACKGROUND: We determined the prognostic impact of lymphovascular invasion (LVI) in a large, national, multicenter, retrospective cohort of patients with early breast cancer (BC) according to numerous factors. PATIENTS AND METHODS: We collected data on 17 322 early BC patients treated in 13 French cancer centers from 1991 to 2013. Survival functions were calculated using the Kaplan-Meier method and multivariate survival analyses were carried out using the Cox proportional hazards regression model adjusted for significant variables associated with LVI or not. Two propensity score-based matching approaches were used to balance differences in known prognostic variables associated with LVI status and to assess the impact of adjuvant chemotherapy (AC) in LVI-positive luminal A-like patients. RESULTS: LVI was present in 24.3% (4205) of patients. LVI was significantly and independently associated with all clinical and pathological characteristics analyzed in the entire population and according to endocrine receptor (ER) status except for the time period in binary logistic regression. According to multivariate analyses including ER status, AC, grade, and tumor subtypes, the presence of LVI was significantly associated with a negative prognostic impact on overall (OS), disease-free (DFS), and metastasis-free survival (MFS) in all patients [hazard ratio (HR) = 1.345, HR = 1.312, and HR = 1.415, respectively; P < 0.0001], which was also observed in the propensity score-based analysis in addition to the association of AC with a significant increase in both OS and DFS in LVI-positive luminal A-like patients. LVI did not have a significant impact in either patients with ER-positive grade 3 tumors or those with AC-treated luminal A-like tumors. CONCLUSION: The presence of LVI has an independent negative prognostic impact on OS, DFS, and MFS in early BC patients, except in ER-positive grade 3 tumors and in those with luminal A-like tumors treated with AC. Therefore, LVI may indicate the existence of a subset of luminal A-like patients who may still benefit from adjuvant therapy.