Kanagawa Prefectural Hospital Organization

Tissue factor (TF), a key initiator of the coagulation cascade, is frequently overexpressed in pancreatic cancer and linked to tumor progression and thrombosis. While TF has been recognized as a prognostic biomarker, its clinical relevance in surgically treated patients remains unclear. We retrospectively analyzed TF expression in resected pancreatic cancer specimens from 265 patients, including those with and without preoperative therapy, using immunohistochemistry. Tissue factor expression was semiquantitatively classified as negative, low, or high. Associations with clinicopathological features, treatment response, and survival were evaluated. High TF expression was observed in 17.4% of cases and was significantly associated with elevated CA19-9, biologically borderline resectable disease, and lymph node metastases. These patients had shorter overall survival (median overall survival: 20.6 vs. 38.8 vs. 53.6 months, p < 0.001). High TF expression remained an independent predictor of poor prognosis (hazard ratio [HR]: 2.21, p = 0.0002). Tissue factor-negative tumors were associated with favorable outcomes, including long-term survival despite recurrence. Tissue factor expression decreased following preoperative therapy but did not correlate with histological response. Tissue factor expression stratifies pancreatic cancer into biologically and prognostically distinct subgroups. While high TF expression indicates aggressive disease and poor survival, TF-negative tumors represent an indolent, treatment-sensitive subtype. These findings underscore the biological heterogeneity of pancreatic cancer and support TF as a clinically relevant prognostic biomarker.

Adipokines secreted by adipocytes have emerged as critical modulators of cancer progression, particularly in obesity-associated malignancies. However, their therapeutic relevance and the tumor types responsive to adipokine pathways remain unclear. To identify adipokine-driven cancers and assess the therapeutic potential of adipokine signaling, we conducted a pan-cancer transcriptome analysis of the expression of various adipokine receptors in 31 tumor types. AdipoR1 was most frequently amplified and overexpressed in breast cancer across molecular subtypes. In the functional analysis, AdipoR1 stimulation using the agonist AdipoRon activated AMPK signaling, suppressed proliferation and migration, and induced apoptosis in both hormone receptor (HR)-positive (MCF7, T47D) and triple-negative (MDA-MB-231, MDA-MB-468) breast cancer cells. Notably, RNA-Seq analysis revealed that AdipoR1 stimulation upregulated ferroptosis-related genes, DDIT3, HMOX1, and IRE1α, and downregulated proliferation-related genes, estrogen receptor and TROP2, in breast cancer cell lines. Immunoblotting confirmed these changes at the protein level. AdipoR1 activation enhanced the efficacy of chemotherapeutic agents. In vivo, AdipoRon significantly reduced tumor growth and induced necrotic cell death. AdipoR1 activation exerts multimodal antitumor effects by engaging cell death and hormone receptor signaling. These findings establish AdipoR1 as a valuable therapeutic target in breast cancer and support further development of adipokine receptor-targeting therapies.

Background/Objectives: Trastuzumab deruxtecan (T-DXd) is an effective antibody-drug conjugate for human epidermal growth factor receptor 2-expressing solid tumors; however, interstitial lung disease (ILD) remains a clinically significant adverse event. Although both clinical characteristics and genetic susceptibility have been implicated in drug-induced ILD, the factors specifically associated with T-DXd-induced ILD remain unclear. This study aimed to evaluate clinical and genetic factors associated with the development of ILD in patients treated with T-DXd. Methods: We retrospectively analyzed the clinical data of 54 patients treated with T-DXd. The baseline clinical and treatment-related characteristics of patients with ILD and those without were compared. Genome-wide single-nucleotide polymorphism (SNP) analyses with genotype imputation and targeted candidate SNP analyses were performed to evaluate genetic susceptibility. Results: ILD occurred in 15 patients (27.8%), with a median time to onset of 215 days (range, 48-1187). None of the baseline clinical or treatment-related factors were significantly associated with ILD development. Genome-wide analyses did not reveal any significant SNPs after correcting for multiple testing. Contrarily, a targeted analysis focusing on SNPs previously associated with drug-induced ILD identified one variant rs12625311 that was significantly associated with ILD in this cohort. Conclusions: In this exploratory study, baseline clinical characteristics alone were insufficient to discriminate the risk of ILD among patients treated with T-DXd. Although no high-penetrance genetic variants were identified, candidate-based genetic analyses suggested that host genetic factors may contribute to ILD susceptibility. Integrating genetic information with clinical assessment may help refine the risk stratification for T-DXd-induced ILD in future studies.

Circulating microRNA (miR)-1246, a fragment of U2 small nuclear RNA, represents a promising biomarker for certain cancers, including lung adenocarcinoma. The gene that encodes miR-1246, RNU2-1, is located on human chromosome 17q21.31 and is organized as a tandem array that exhibits copy number variations (CNVs). The range of copy numbers has been reported to be quite wide, ranging from 5 to 82 per haploid genome. The present study analyzed the correlation between RNU2-1 copy numbers and serum miR-1246 levels in healthy controls and patients with stage IV lung adenocarcinoma. Serum miR-1246 levels were quantified using reverse transcription-quantitative polymerase chain reaction (PCR), and RNU2-1 copy numbers per diploid genome were measured via digital PCR using blood-derived DNA. The median copy numbers were 50 and 49 in the control and lung adenocarcinoma groups, respectively, with no significant difference observed between the groups. In addition, no correlation between RNU2-1 copy number and serum miR-1246 level was identified in either group. These results suggest that CNVs of RNU2-1 do not affect serum levels of the lung adenocarcinoma biomarker miR-1246.

This study aimed to identify patient groups in which myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC) regimens induced superior progression-free survival (PFS) in patients with acute myeloid leukemia (AML) in complete remission (CR) using a machine-learning approach. Our study included 3273 patients aged 40–69 with AML in CR. The patients were divided into training (N = 2020) and validation cohorts (N = 1253). We employed a machine learning-based group identification model in the training cohort. Subsequently, in the validation cohort, we estimated the impact of the optimal conditioning group compared with the non-optimal conditioning group on PFS using an inverse probability weight analysis. The developed model was consistent with the eight factors and combinations, and the high score suggested that RIC was more appropriate than MAC. In the validation cohort, 127 patients with high scores and who received RIC and 769 patients with low scores and who received MAC were categorized into the optimal conditioning group (896, 71.5%). The weighted hazard ratio for PFS was 0.73 (95% confidence interval: 0.57–0.94) in the optimal conditioning group compared with the non-optimal conditioning group (P = 0.016). In conclusion, we developed an easy-to-use model that helps the physician choose a patient-specific conditioning regimen for patients with AML in CR.

Abstract Background: The DESTINY-Breast04 (DB-04) trial established trastuzumab deruxtecan (T-DXd) as the standard of care for patients (pts) with the metastatic breast cancer (mBC) newly classified as HER2-low status (HER2 IHC 1+, or 2+/ISH−). However, in the DB-04 trial, the number of pts with hormone receptor-negative (HR−)/HER2-low mBC was limited, and pts with stable brain metastases (BMs) were included, while those with active BMs were excluded. The HALLOW study (UMIN000051259) is a large-scale ongoing prospective observational study conducted in Japan with the aim of providing effectiveness and safety data for T-DXd in these clinically important populations, which were underrepresented in the DB-04 trial. Here, we report the interim analysis results for pts with BMs. Methods: The HALLOW study enrolled, from June 2023, approximately 600 pts diagnosed with HER2-low mBC (HR+/−, with/without BMs, including active BMs) who had previously received chemotherapy and were scheduled to receive T-DXd treatment. This interim analysis included pts diagnosed with BMs (current or past) by local investigators. For the effectiveness analysis, only those with BMs confirmed by Brain-independent central review (ICR) based on brain MRI and/or CT images were included. Active BMs were defined as cases where no local treatment was performed on the brain lesion or where there was regrowth or symptom worsening after local treatment. Effectiveness outcomes included intracranial progression-free survival (IC-PFS) and intracranial objective response rate (IC-ORR) assessed by Brain-ICR according to RECIST version 1.1, while progression-free survival (PFS) and overall survival (OS) were assessed by investigators. For the safety analysis, pts who had received T-DXd at least once were included. Safety outcomes include incidence of treatment-emergent adverse events (TEAEs) graded by CTCAE, including ≥ grade (Gr) 3 TEAEs, ≥ Gr1 interstitial lung disease (ILD), and ≥ Gr1 TEAEs that led to discontinuation of T-DXd treatment. Follow-up plan will continue until July 2026. Results: At the data cutoff date of August 31, 2024, 42 pts had physician-diagnosed BMs, of whom 33 were Brain-ICR confirmed and met the criteria for active BMs. In this set, the median age was 55 (range: 42-79) years; the median prior line of chemotherapy in the metastatic setting was 2 (range: 0-7); HER2 status at each local site was IHC 2+/ISH− in 7 pts (21%) and IHC 1+ in 26 pts (79%); 25 pts (76%) were HR+, 8 pts (24%) were HR−. 5 pts (15%) had Brain-ICR-confirmed leptomeningeal disease. At a median follow-up period of 4.1 months (mo) (range: 1.4-12.6), the median IC-PFS was 8.0 mo (95% confidence interval [CI]: 3.9-not estimated), and the 6-mo IC-PFS rate was 57.6% (95% CI: 30.7-77.4) until the data cutoff date. A total of 22 pts was eligible for proper tumor evaluation during the follow-up period by Brain-ICR. Among the 22 pts who could be properly evaluated, the IC-ORR was 9.1% (complete response n=0, partial response n=2; 95% CI: 1.1-29.2). The median PFS was 6.7 mo (95% CI: 4.0-11.1), with a 6-mo PFS rate of 59.0% (95% CI: 34.9-76.7). The median OS was not reached, and the 6-mo survival rate was 77.1% (95% CI: 51.5-90.3). In the safety analysis set (n=42; median follow-up period: 4.1 mo [range: 0.4-12.6]), ≥ Gr3 TEAEs and ≥ Gr3 TEAEs related to T-DXd treatment occurred in 18 (43%) and 11 (26%) pts, respectively. ≥ Gr1 ILD occurred in 2 pts (5%), 1 (2%) of whom experienced Gr 5 ILD, and ≥ Gr1 TEAEs that led to T-DXd discontinuation occurred in 3 pts (7%), with two of these being ILD and the other seizure. Conclusions: While longer follow-up and additional data are needed to confirm these findings, the current data provide tentative support for the effectiveness and safety of T-DXd in this BMs population including active BMs, which was not included in the DB-04 trial. Citation Format: N. Niikura, T. Yamanaka, Y. Aoyama, A. Kataoka, T. Toyama, S. Sakai, M. Endo, K. Kaneko, H. Iwata, T. Yamashita, J. Tsurutani, R. Horii, Y. Kikawa, Y. Hirakawa, S. Yamazaki, W. Hashimoto, E. Tokuda, S. Saji. Interim analysis results for the effectiveness and safety of trastuzumab deruxtecan in patients with HER2-low breast cancer and brain metastases: The HALLOW study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD13-11.

Abstract Background Hepcidin, a key regulator of iron homeostasis, is often overexpressed in non‐small cell lung cancer (NSCLC). While hepcidin renders cells susceptible to ferroptosis, which is linked to the activity of programmed cell death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) inhibitors, its clinical impact on immunotherapy efficacy remains unclear. Methods We retrospectively analyzed patients with advanced NSCLC who received anti‐PD‐1/PD‐L1 monotherapy. Patients were stratified into two groups based on immunohistochemical analysis: high hepcidin expression (tumour proportion score [TPS] = 50%, n = 6) and none‐to‐moderate expression (TPS 0–49%, n = 39). Treatment duration, progression‐free survival (PFS), and overall survival (OS) were compared. In vitro mechanisms were also explored using hepcidin and interferon‐gamma (IFNg) co‐culture models. Results The high‐hepcidin group exhibited a longer median treatment duration (42 vs. 5 days; p = 0.051). This group also showed improved PFS (2222 vs. 126 days; hazard ratio [HR], 0.35 [95% CI, 0.16–0.79]; p = 0.0643) and OS (not reached vs. 459 days; HR, 0.46 [95% CI, 0.18–1.16]; p = 0.0994), although these differences did not reach statistical significance. In vitro experiments revealed that hepcidin enhanced IFNg‐induced reactive oxygen species production and cytotoxicity in A549 cells. Conclusion Advanced NSCLC patients with high hepcidin expression may derive greater benefit from anti‐PD‐1/PD‐L1 monotherapy. Our findings suggest that cellular sensitivity to IFNg varies by hepcidin expression levels.

ABSTRACTGPR143, originally identified as the gene product of ocular albinism 1 (OA1), a G protein‐coupled receptor (GPCR), can function as a receptor for l‐3,4‐dihydroxyphenylalanine (DOPA), a precursor of dopamine (DA). To examine the physiological and pathophysiological roles of GPR143, we analyzed the behavior of Gpr143 gene‐deficient (Gpr143−/y) mice. We performed comprehensive behavioral analyses including the prepulse inhibition test, sucrose preference test, light–dark exploration test, etc. and microarray analysis. Gpr143−/y mice displayed a mixed psychosis‐like phenotype: impaired prepulse inhibition (a characteristic of schizophrenia) combined with reward system aberrations, depression, and heightened aggression (characteristic of mood disorders). By microarray analysis, we identified 17 downregulated and 20 upregulated genes in the forebrain of Gpr143−/y mice, genes putatively involved in serotonergic and/or dopaminergic transmission. These findings suggest that GPR143 plays a role in mesolimbic and mesocortical functions underlying sensory gating, reward, social hierarchy, cognition, and emotional regulation. These data further suggest both a new animal model and a unique therapeutic focus for a heretofore difficult to study and treat mixed psychosis‐like condition.