Metastatic colorectal cancer (mCRC) differs clinically based on RAS and BRAF mutations or DNA methylation. However, in mCRC, the prognostic value and biological characteristics of genome-wide DNA methylation status (GWMS) in each RAS/BRAF genotype is unknown. To clarify this, primary tumor samples from patients with informed consent in the phase III TRICOLORE study were collected, and RAS and BRAF mutations, immunohistochemical staining of mismatch repair-related proteins, comprehensive gene expression, and genome-wide DNA methylation were analyzed. The tumor samples were classified into high-methylated colorectal cancer (HMCC) and low-methylated colorectal cancer (LMCC). Gene set enrichment analysis (GSEA) was conducted using microarray data. A total of 226 patients were included and classified into the RAS/BRAF wild-type (wt) (n = 125), RAS mutant (mt) (n = 87), and BRAF mt (n = 14), of whom 22 (17.6%), 30 (34.5%), and 14 (100%) had HMCC. HMCC exhibited significantly worse overall survival (OS) than that of LMCC in the RAS/BRAF wt group but not in the RAS mt group. In GSEA, RAS/BRAF wt HMCC was associated with microsatellite instability and BRAF V600E mutation. The poor prognosis of RAS/BRAF wt HMCC may be attributed to gene expression patterns associated with microsatellite instability and BRAF V600E mutation.

BACKGROUND:Airway mucus plugs on chest computed tomography (CT) are increasingly recognized for their impact and potential as treatable traits. However, radiation exposure warrants reasonable patient selection. OBJECTIVE:To develop and externally validate a practical clinical score to predict CT-detected mucus plug presence in 2 asthma cohorts and to evaluate its association with clinical outcomes. METHODS:This multicenter retrospective analysis used clinical and CT data from adult patients with stable asthma. The primary outcome was mucus plug presence on CT. We identified independent predictors using multivariable logistic regression, derived a practical scoring system in the exploratory cohort, and validated it in an independent cohort. RESULTS:The prevalence of mucus plugs was 50.8% (218 of 429) in the exploratory cohort and 76.5% (143 of 187) in the validation cohort. Age (A; maximum 2 points), body mass index (B; maximum 2 points), blood eosinophil count (E; maximum 2 points), fractional exhaled nitric oxide (N; maximum 1 point), and percent-predicted FEV1 (F; maximum 2 points) were independently associated with the presence of mucus plugs. The derived score (ABENF score; maximum 9 points) showed good discrimination in both cohorts (cohort 1: area under the receiver-operating characteristic curve, 0.781, 95% CI, 0.742-0.820; cohort 2: area under the receiver-operating characteristic curve, 0.836, 95% CI, 0.783-0.889). The high-score group (ABENF score ≥4) had a shorter time to first exacerbation (P = .046) and higher sputum eosinophil percentage (P < .001) in the validation cohort. CONCLUSIONS:The ABENF score could be a practical tool to estimate mucus plug presence, potentially supporting more selective CT use.

Introduction Chronic central serous chorioretinopathy (CSC) can cause progressive and permanent vision loss. Although photodynamic therapy (PDT) is a primary treatment option globally, it is not approved for CSC worldwide, limiting therapeutic access. The REPLAY trial is a phase III, investigator-initiated trial to evaluate the efficacy and safety of reduced-fluence PDT (rf-PDT) for chronic CSC to seek the first regulatory approval globally.Methods and analysis This study comprises two cohorts. The ‘untreated cohort’ is a multicentre, randomised, placebo-controlled, double-masked trial involving 60 patients with untreated, fovea-involving chronic CSC, randomised 2:1 to receive a single rf-PDT or placebo treatment. The ‘previously treated cohort’ is a single-arm, open-label trial for up to 10 patients with recurrent CSC after PDT. The primary endpoint for both cohorts is the proportion of eyes with a complete resolution of subfoveal fluid at 12 weeks post-treatment, assessed by optical coherence tomography. Secondary endpoints include changes in best-corrected visual acuity, central choroidal thickness, recurrence rates and incidence of adverse events over a 48 week follow-up.Ethics and dissemination The study protocol was approved by the Kyoto University Hospital Institutional Review Board, IRB of Chiba University Hospital, Tokyo Women’s Medical University Institutional Review Board and Institutional Review Board of Kansai Medical University Hospital. Written informed consent is obtained from all participants. The results will be disseminated through publication in a peer-reviewed journal and presentations at scientific conferences.Trial registration number jRCT2051230156 (URL: https://jrct.mhlw.go.jp/latest-detail/jRCT2051230156).

We performed updated subgroup analyses of the EMERALD study to investigate efficacy, safety, and quality of life (QoL) in patients treated with eribulin (E) vs. either docetaxel (DTX) or paclitaxel (PTX). Patients with HER2+ locally advanced/metastatic breast cancer (LABC/MBC) were randomized to receive E or taxane (T) (physician’s choice of DTX or PTX; declared in advance at registration) in 21-day cycles, each combined with trastuzumab + pertuzumab. Survival outcomes, treatment patterns, antitumor efficacy, safety, and QoL were examined. The intention-to-treat (and safety) populations comprised 224 (224) patients who received E, 186 (184) who received DTX, and 36 (34) who received PTX. Baseline characteristics were balanced. Progression-free survival (E vs. DTX: 14.0 vs. 13.1 months; hazard ratio [HR], 0.94 [95

Background: Mutations in the FMS -like tyrosine kinase 3 ( FLT3 ) gene are present in approximately 30% of patients with newly diagnosed (ND) acute myeloid leukemia (AML), and are associated with worse therapy outcomes compared to the general AML population. Gilteritinib, a selective oral FLT3 inhibitor, is a promising treatment option for this patient population. Objectives: To assess the safety and efficacy of gilteritinib in combination with induction and consolidation chemotherapy in Asian patients with ND, FLT3 -mutated ( FLT3 mut+ ) AML. Design: This study was a phase I/II open-label, single-arm study. Herein, we present the final results from phase II. Methods: A total of 84 patients were enrolled in 33 centers across Japan, Korea, and Taiwan. All patients enrolled in phase II received induction and consolidation therapy with gilteritinib 120 mg/day plus chemotherapy (induction: ⩽2 cycles, idarubicin/cytarabine once-daily; consolidation: ⩽4 cycles, cytarabine twice-daily) followed by maintenance with gilteritinib 120 mg/day monotherapy (⩽26 cycles). The primary efficacy endpoint was the complete remission (CR) rate after induction therapy. Results: The primary endpoint of CR rate after induction was 50.0% (90% CI: 40.4–59.6). Gilteritinib in combination with chemotherapy achieved high composite CR (CRc; 86.6%, 95% CI: 77.3–93.1) rates after induction. The overall survival (OS) rate at 3 years was 71.6%, and the median OS was 48.2 months; however, due to the immaturity of the data, the median OS should be interpreted with caution. In addition, 51.2% of patients underwent hematopoietic stem cell transplantation during the study period. The safety profile of gilteritinib was as expected, and no new safety signals were identified. Conclusion: Induction and consolidation with gilteritinib plus chemotherapy, and maintenance with gilteritinib monotherapy were well tolerated in ND patients in Asia with FLT3 mut+ AML and had favorable efficacy compared with historical data. Trial registration: This trial was registered with the ClinicalTrials.gov identifier NCT02310321.

Oligodendrocytes are glial cells responsible for myelination in the central nervous system, and their dysfunction underlies various neurological disorders. However, existing human oligodendrocyte models are limited by low efficiency and insufficient standardization. Here, we developed a well-defined system for differentiating human oligodendrocytes from induced pluripotent stem cells using transient transcription factor expression. To recapitulate key structural aspects of oligodendrocyte-axon interactions, we cultured oligodendrocytes on nanofibers mimicking axonal topology. On this platform, ultrastructural, live-imaging, and transcriptomic analyses demonstrated dynamic oligodendrocyte-nanofiber interactions and ensheathment-like wrapping. This process was accompanied by aligned CLDN11 expression along nanofibers, providing a quantifiable structural readout without overt maturation. To validate the utility of the platform, we quantified the effects of white matter toxins and pro-ensheathment lipids. Our findings establish a robust system for evaluating oligodendrocyte ensheathment modulators, particularly those affecting cytoskeletal organization and initial sheath formation, and for investigating the pathophysiology of human oligodendrocyte-related disorders.

Immune checkpoint inhibitors (ICIs) have markedly improved survival in advanced non–small cell lung cancer (NSCLC), potentially modifying the prognostic impact of comorbid chronic obstructive pulmonary disease (COPD). We conducted a multicenter retrospective cohort study across four Japanese institutions including patients with spirometry-confirmed COPD and advanced or recurrent NSCLC, including stage IV disease, postoperative recurrence, recurrence after definitive concurrent chemoradiotherapy, or other advanced/recurrent status documented in the clinical records, treated between January 2007 and December 2020, excluding those with sensitizing EGFR variants or ALK fusions. COPD was diagnosed based on smoking history and airflow limitation, defined as a forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio of less than 70%, in accordance with the Japanese Respiratory Society guidelines and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. COPD treatment was defined as regular use of inhaled bronchodilators and/or inhaled corticosteroids initiated before or at the start of first-line therapy. Overall survival (OS) was measured from treatment initiation to death from any cause. Among 455 eligible patients with spirometry-confirmed COPD, 144 received regular inhaled COPD therapy and 311 did not. Median OS was longer in the COPD-treated group than in the untreated group (23.3 vs. 16.7 months; hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.57–0.93; P = 0.0105). However, patients receiving COPD treatment were more likely to receive ICIs during the disease course than untreated patients (109/144, 75.7% vs. 138/311, 44.4%), and ICI therapy remained a strong independent predictor of OS in conventional multivariable analysis. In an additional time-dependent Cox analysis accounting for the timing of ICI initiation, COPD treatment showed a modest association with longer OS, whereas ICI exposure showed a nonsignificant trend toward improved OS. When patients were stratified by ICI exposure, COPD-treated patients had longer OS than untreated patients in the non-ICI subgroup, whereas OS did not differ meaningfully by COPD treatment status among patients who received ICIs. These findings indicate that the survival association between COPD treatment and OS should be interpreted with careful consideration of the timing and line of ICI exposure in the ICI era.

With the advancement of precision medicine there is an increasing need for design and analysis methods in clinical trials with the objective of investigating effect heterogeneity and estimating subgroup effects. As this requires precise estimation of interaction effects, borrowing information from external data sources including retrospective studies and early phase clinical trials to enrich the trial in sparse subgroups is pertinent. Motivated by a trial in gastric cancer we consider a practical design and analysis framework for borrowing from external data sources that only partially inform the inference. As the analysis model we propose an individually weighted model where the external data are weighted based on their fit with the target population based on the distribution of a set of covariates. In a simulation study we assess the performance of the model under various scenarios and make comparisons to dynamic borrowing. In addition, we provide a Bayesian design framework where design priors are extracted from the external data to determine decision boundaries and sample sizes. The design procedure is demonstrated within the context of our motivating example.

Introduction Addition of bevacizumab and paclitaxel as induction therapy prior to standard atezolizumab and nab-paclitaxel in patients with programmed death-ligand 1 (PD-L1)-positive metastatic triple-negative breast cancer (mTNBC) may help to overcome vascular endothelial growth factor-associated resistance mechanisms that limit the immune-mediated antitumour efficacy of atezolizumab and nab-paclitaxel.Methods and analysis The Induction Therapy of PTX+BV Followed by Atezolizumab+Nab-PTX for PD-L1+TNBC (INDUCE) study is a multicentre, randomised, open-label, phase II trial designed to evaluate the efficacy and safety of two cycles of induction therapy with bevacizumab and paclitaxel followed by atezolizumab and nab-paclitaxel compared with standard atezolizumab and nab-paclitaxel in patients with PD-L1-positive mTNBC. The primary outcome of the study is progression-free survival (PFS) per Response Evaluation Criteria In Solid Tumours, V.1.1. We have estimated that 89 PFS events are needed to allow a power of 80% to detect a difference between treatment groups at a one-sided significance level of 10% in this study. The target sample size is set to 106 patients to account for dropouts.Ethics and dissemination The study protocol and informed consent form have been approved by the Certified Research Review Board at the Nagoya University Graduate School of Medicine, Nagoya, Japan. Study results will be presented at international conferences and published in a peer-reviewed journal.Trial registration number jRCTs041240039 NCT06793553.

Abemaciclib, a cyclin-dependent kinase 4/6 inhibitor, was previously examined in a randomized clinical trial for the adjuvant setting, using invasive disease-free survival (IDFS) as the primary endpoint. Analysis of these IDFS data using a piecewise hazard model suggested that the hazard ratio for IDFS remained reduced even after completion of the two-year abemaciclib treatment, possibly yielding a sustained recurrence-suppressive effect beyond the treatment period. Preclinical and clinical observations have implicated cancer stem cells (CSCs) in treatment-resistant recurrence, including late recurrence, in breast cancer. CSCs are believed to enter a dormant state, enabling them to evade therapeutic targeting and later give rise to recurrence. Therefore, recurrence events cannot be suppressed following treatment conclusion without therapeutic efficacy against dormant CSCs, even if recurrence-suppressive effects are observed during the treatment period. In the current study, we aimed to explore the possible mechanisms underlying the long-term suppressive effect of abemaciclib treatment on recurrence using an existing tumor recurrence prediction model with suitable modifications. This model was operated using CSC-related assumptions, specifically that two distinct sources of recurrence were present after primary tumor resection: (i) metastatic cells already in a proliferative state at the time of surgery and (ii) proliferative metastatic cells newly derived from CSCs after surgery. The results of prediction-based investigations, including the current study, have suggested that therapeutic effects targeting CSCs could at least partially account for the sustained suppression of recurrence observed with abemaciclib treatment of breast cancer.

Treatment effect heterogeneity has often been observed in clinical settings, which can be explained, at least partially, by predictive biomarkers. Although a variety of continuous biomarkers are measured in clinical practice, using biomarkers to guide treatment decisions remains challenging. We consider specifying a statistically and clinically suitable cutpoint of a continuous biomarker by identifying a sensitive subpopulation. We use a Bayesian posterior probability to analyze a time-to-event outcome and biomarkers observed in a randomized clinical trial. The proposed method aims not only to control the false-positive rate under a desired level, thereby deriving a statistically suitable decision rule, but also to incorporate a minimum clinically important difference, thereby providing a clinically reasonable interpretation. Simulation studies are conducted to evaluate the operating characteristics of the proposed method under a wide range of clinical scenarios. For illustration, we apply the proposed method to data from a phase III randomized clinical trial involving patients with advanced breast cancer.

8528 Background: EGFR blockade enhances tumor antigen presentation and may potentiate PD-1 inhibition. This phase I/II study evaluated the safety and efficacy of adding necitumumab to pembrolizumab plus platinum-based chemotherapy in patients with previously untreated advanced squamous non–small cell lung cancer (NSCLC), a population with limited biomarker-driven treatment options. Methods: Patients received necitumumab (400–800 mg on days 1 and 8), pembrolizumab (200 mg on day 1), nab-paclitaxel (100 mg/m² on days 1, 8, and 15), and carboplatin (AUC 5 on day 1) every 3 weeks for four cycles, followed by necitumumab plus pembrolizumab maintenance. Phase I used a standard 3+3 dose-escalation design. Per protocol amendment, patients treated at the recommended dose (RD) in phase I (n = 6) and all phase II patients (n = 6) were pooled for efficacy analyses (n = 12). Tumor assessments were performed every 6 weeks per RECIST v1.1. Primary endpoints were safety and objective response rate (ORR). Data cutoff was September 14, 2025. Results: Twenty-one patients were enrolled, including 15 in phase I (400 mg, n = 6; 600 mg, n = 3; 800 mg, n = 6). One dose-limiting toxicity (DLT) occurred in the 800 mg cohort, which was determined as the RD and maximum tolerated dose (MTD). Among the 12 patients treated at the RD, the ORR was 75.0% (9/12; 95% CI, 42.8–94.5), with partial response in 9 patients, stable disease in 1 patient, and progressive disease in 2 patients. The disease control rate was 83.3%. The 24-week survival rate was 95.2%. Median progression-free survival and overall survival were not reached at the time of analysis. The most frequent adverse events (AEs) in 21 patients were hypomagnesemia (66.7%), acneiform dermatitis (66.7%), neutropenia (61.9%), decreased appetite (52.4%), anemia (52.4%), constipation (47.6%), stomatitis (42.9%), and leukopenia (42.9%). Grade 3 and 4 AEs occurred in 66.7% and 28.6% of patients, respectively, with no grade 5 events. Conclusions: The addition of necitumumab to pembrolizumab and platinum-based chemotherapy demonstrated manageable toxicity and resulted in a high ORR in patients with untreated squamous NSCLC. These findings support the potential activity of EGFR blockade–based immunochemotherapy and warrant further clinical investigation. Clinical trial information: 2031210387.

BACKGROUND:Human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC) presents significant therapeutic challenges due to its molecular heterogeneity. Previous studies suggest that immune checkpoint inhibitors (ICIs) may enhance the efficacy of subsequent HER2-targeted therapy. However, evidence suggesting an optimal sequence for nivolumab and trastuzumab deruxtecan (T-DXd) treatment is limited. This exploratory analysis of EN-DEAVOR evaluated the effectiveness and safety of administering T-DXd relative to the timing of prior ICI administration. METHODS:This study assessed real-world outcomes of T-DXd in patients with HER2-positive AGC stratified by prior ICI exposure: within 2 months of nivolumab (Group A), >2 months (Group B), and no prior nivolumab (Group C). The primary effectiveness endpoints included real-world progression-free survival (rwPFS) and objective response rate (ORR). Safety endpoints included grade ≥ 3 adverse events (AEs). RESULTS:Among 311 eligible patients, Group A showed the longest median rwPFS (n = 63; 6.9 months) compared with Group B (n = 63; 4.6 months) and Group C (n = 185; 4.2 months). The risk of progression was significantly lower in Group A compared with Group B (hazard ratio [95% confidence interval]: 0.6 [0.4-0.9]; P = .0074). ORR was numerically highest in Group A (54.9%) versus Group B (30.8%) and Group C (43.4%). More patients in Group B (58.7%) experienced grade ≥ 3 AEs than in Group A (50.8%) and Group C (43.8%). No new safety signals were observed. CONCLUSIONS:Initiating T-DXd within 2 months post-ICI may enhance therapeutic efficacy in HER2-positive AGC without affecting safety, supporting a potential sequencing option after ICI therapy.

BACKGROUND:Retreatment with pertuzumab has demonstrated survival benefit in previously treated human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer, but its effect on health-related quality of life (HRQoL) is not well established. METHODS:This secondary analysis of the randomized, open-label phase III PRECIOUS trial evaluated HRQoL in women previously treated with pertuzumab, trastuzumab, and chemotherapy. Patients were randomized 1:1 to pertuzumab plus trastuzumab plus chemotherapy (PTC) or trastuzumab plus chemotherapy (TC). HRQoL was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B). The primary endpoint was time-to-deterioration (TTD) in the Breast-Trial Outcome Index (B-TOI), defined as a ≥5-point decline. Secondary endpoints included TTD in the FACT-B total score, General Subscale, and Breast Cancer Subscale. Longitudinal changes were analyzed using linear mixed-effects models. RESULTS:Of 217 eligible patients, 178 were included in the HRQoL analysis (median age: 57 years in PTC and 60 years in TC). No significant between-group differences in TTD for B-TOI were observed (hazard ratio, 1.22; 95% CI, 0.86-1.90; p = 0.23). Secondary TTD endpoints also showed no differences. Mixed-effects models indicated that TC had better B-TOI and Breast Cancer Subscale scores at week 6, but these early differences were not sustained beyond week 12. CONCLUSION:Pertuzumab retreatment was not associated with clinically meaningful deterioration in HRQoL. These findings support the use of dual HER2 blockade beyond progression in appropriately selected patients.

Information on the maintenance of tissue homeostasis is important for developing effective therapeutic methods. However, reports on the cellular composition and tissue stem cells of the larynx are scarce. Therefore, we analyzed mouse laryngeal mucosa using single-cell RNA- sequencing and spatial transcriptomics by photo-isolation chemistry, and we also generated laryngeal organoids as an in vitro model. Consequently, we found a SOX9-positive basal cell subpopulation and a Lgr5-positive cell subpopulation in the mouse vocal fold, and obtained three types of epithelial organoids from laryngeal epithelium. We also confirmed the differences in pseudostratified ciliated columnar epithelium characters between the supraglottis and subglottis of the mouse larynx. These findings provide valuable insights and tools for future research in laryngology and stem cell biology.

To address the challenge of early predicting systemic treatment response in metastatic castration-sensitive prostate cancer (mCSPC), this study evaluated the predictive value of prostate-specific antigen halving time (PSAHT) as a biomarker. We retrospectively analyzed data for 719 patients with de novo mCSPC, of whom 495 received androgen deprivation therapy alone or combined androgen blockade (the ADT/CAB cohort) and 224 received ADT combined with an androgen receptor signaling inhibitor or docetaxel (the upfront cohort). PSAHT was estimated using log-transformed PSA values at baseline and 1 and 3 months later using a linear mixed-effects model. Individual slopes were used to calculate PSAHT, defined as log(2)/|slope|. Each cohort was divided into short and long PSAHT groups based on the median PSAHT. The primary endpoint was time to castration-resistant prostate cancer (CRPC). A multivariable Cox proportional hazards model was used to assess PSAHT as a predictive biomarker. Log-transformed PSA decreased in a linear manner for up to 3 months post-treatment initiation and then plateaued. Median PSAHT was 0.47 months in the ADT/CAB cohort and 0.41 months in the upfront cohort. CRPC-free survival was more favorable in the short PSAHT group in both cohorts (ADT/CAB, 21.7 months vs. 15.9 months, P = 0.03; upfront, not reached vs. 27.1 months, P < 0.01). In multivariable Cox proportional hazards analysis, PSAHT was associated with time to CRPC in both cohorts. PSAHT may have modest prognostic value in de novo mCSPC, although further validation is required.

Identifying good predictive baseline covariates to optimize the target population for a new treatment is an important aim in precision medicine. Early post-baseline biomarker responses may serve as a supportive guide for physicians to decide whether to continue a treatment. We propose an exploratory two-stage subgroup analysis method as a statistical tool to investigate the predictive value of such a short-term response for the benefit of a new treatment in terms of long-term outcomes. We use a flexible probability model, Bayesian additive regression trees (BART), to derive predictive conditional treatment effects (PCTE) based on a short-term post-baseline biomarker response using counterfactual modeling of responses to new and standard treatments for each patient. Constructing patient subgroups according to the PCTE, we analyze an observed long-term outcome to identify a sensitive subpopulation. We carry out extensive simulation studies to examine the operating characteristics of the proposed method. For illustration, we apply the proposed method to data from a randomized clinical trial in patients with locally advanced or metastatic breast cancer. These findings support the predictive value of short-term responses and provide a statistical approach for identifying patients expected to benefit from a new treatment in terms of a long-term outcome.

To investigate long-term outcomes for triple‑negative breast cancer (TNBC) patients enrolled in JBCRG-22. TNBC (cT1c–T3, cN0–1, M0) patients were stratified by homologous recombination deficiency (HRD) and germline BRCA mutation (gBRCAm) status. Group A patients (aged < 65 years with HRD-positive tumors, or those with gBRCAm, if available) were randomized to receive 4 cycles of weekly paclitaxel (group A1) or eribulin (group A2), both with carboplatin, followed by 4 cycles of anthracycline. Group B patients (aged < 65 years with HRD-negative tumors or aged ≥ 65 years) were randomized to receive 6 cycles of eribulin plus cyclophosphamide (group B1) or eribulin plus capecitabine (group B2). Five-year invasive disease-free survival (IDFS), distant disease-free survival (DDFS), and overall survival (OS) were assessed. Additionally, data were analyzed by biomarker levels including lymphocyte count (LC) and neutrophil-to-lymphocyte ratio (NLR). Ninety-nine patients were followed for a median of 5.6 years. In patients who received eribulin-based therapy (groups A2 + B1 + B2), 5-year IDFS and OS rates, respectively, were 95 https://www.umin.ac.jp/ctr/index-j.htm ) with unique trial number UMIN000023162. The Japan Breast Cancer Research Group trial number is JBCRG-22.

Although taxanes are a mainstay treatment for locally advanced or metastatic breast cancer (LABC/MBC), they often impair quality of life (QoL). Treatments that avoid taxane-related QoL deteriorations would be valuable. The JBCRG-M06/EMERALD trial (NCT03264547, UMIN000027938) compared eribulin with a taxane, each combined with trastuzumab and pertuzumab, in patients with human epidermal growth factor receptor type 2 (HER2)-positive LABC/MBC. QoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Module C30 (EORTC QLQ-C30) version 3.0. QoL deterioration was defined as a decrease in the Global Health Status (GHS) score by ≥ 10 points (minimum clinically important difference), disease progression, or death. QoL data were available for 210 (of 224 randomized) and 205 (of 222 randomized) patients in the eribulin and taxane groups, respectively. The median (95

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of B-cell malignancies, but its success in acute myeloid leukemia (AML) remains limited. Durable responses depend on the formation of long-lived memory T cells, whereas T cell exhaustion contributes to non-response and relapse. In patients with AML who achieved remission after cord blood transplantation, we here first observe enrichment of memory T cells with high expression of the chemokine receptor CXCR4. Next, we show that engineering CAR-T cells to co-express CXCR4 enhances their persistence and anti-leukemic activity in patient-derived xenograft models. Using single-cell profiling and metabolic analysis, we find that CXCR4 promotes memory-associated transcriptional programs, reduces exhaustion, and supports oxidative metabolism. These effects are observed with CAR-T cells targeting CD25 or CD96 as AML-associated targets. Our results indicate that CXCR4 strengthens CAR-T cell memory and durability, offering a strategy to improve immunotherapy outcomes in AML and beyond. CAR-T cell efficacy is often limited by the inability to maintain a memory T cell program. Here, the authors show that intrinsic CXCR4 expression enhances CAR-T cell persistence and memory differentiation in acute myeloid leukemia.