Japanese Foundation For Cancer Research

In this nationwide retrospective study, we sought to evaluate the oncologic and functional outcomes and safety of transoral surgery (TOS) for hypopharyngeal and laryngeal squamous cell carcinomas in Japan and to clarify the appropriate indications for various TOS modalities. Data were obtained from the Head and Neck Cancer Registry of Japan. Patients who underwent transoral or endoscopic resection between 2011 and 2016 were selected. Detailed clinical information was collected from 55 institutions using web-based case report forms. Surgical modalities analyzed included endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), endoscopic laryngopharyngeal surgery (ELPS), transoral laser microsurgery (TLM), and transoral videolaryngoscopic surgery (TOVS). In total, 1825 patients were included (hypopharyngeal cancer, 62.5 %; laryngeal cancer, 37.5 %). Most cases (77.5 %) were T1 or lower, and 90.8 % were Stage II or earlier. TLM is predominantly used for glottic cancers, ELPS/ESD for superficial hypopharyngeal lesions, and TOVS for more advanced tumors, reflecting distinct indications for each modality. The 5-year disease-specific survival (DSS), recurrence-free survival (RFS), and overall survival (OS) were 97.1 %, 84.3 %, and 85.4 %, respectively. The laryngeal preservation rate was 98.2 %. Tracheostomy was performed in 5.0 % of cases, mainly for airway protection; major complications, including pneumonia (2.4 %), hemorrhage (1.1 %), fistula formation (0.4 %), and vocal cord fixation (2.6 %), occurred in <3 % of patients. Postoperative functional outcomes were favorable, with persistent dysphagia (Functional Outcome Swallowing Scale stage ≥ 3) in 1.6 % and tube feeding dependence in 1.8 %. Non-robot-assisted TOS demonstrated excellent oncologic control and functional preservation of the larynx with low complication rates in early-stage hypopharyngeal and laryngeal cancers. Each surgical modality has distinct indications depending on the tumor site, depth of invasion, and institutional expertise. These findings support the use of TOS as a safe and effective treatment option for selected patients. Further procedural standardization and data accumulation are required to refine the indications and facilitate their broader adoption in clinical practice.

Abstract Introduction Maintaining dose intensity is essential for the efficacy of adjuvant S-1 chemotherapy in gastric cancer. Although pharmacist interventions can reduce toxicity and improve adherence, multicenter evidence regarding their impact on dose maintenance is limited. Aim This study aimed to evaluate the impact of continuous pharmacist intervention on treatment completion and relative performance (RP) value in patients receiving adjuvant S-1 chemotherapy for gastric cancer. Methods This multicenter retrospective study analysed 225 patients across 12 institutions, categorised into continuous intervention (n=97) and non-continuous intervention (n=128) groups. Continuous intervention was defined as systematic monitoring and management for at least 50% of the treatment duration. Inverse probability of treatment weighting adjusted for baseline covariates. The primary and secondary endpoints were the eight-cycle completion rate and the RP value, respectively. Results Eight-cycle completion rate did not differ significantly between the continuous and non-continuous intervention groups (53.0% vs. 55.2%, p = 0.775), nor did the frequency of treatment modification events, including discontinuation or dose reduction. However, the RP value was significantly higher in the continuous intervention group than in the non-continuous intervention group (73.7% vs. 64.9%, p = 0.038), a finding robustly supported by sensitivity analysis between these two groups (75.1% vs. 61.1%, p = 0.0008). The continuous group maintained a high intervention rate (89.1%) throughout the final cycle, providing significantly more supportive care interventions than the non-continuous intervention group (53.2% vs. 4.9%, p &lt; 0.001). Conclusion Although continuous pharmacist intervention did not improve the binary completion rate, it was essential for maintaining RP values above the clinically essential 70% threshold through proactive toxicity management and dynamic dose optimization. These findings suggest that systematic pharmaceutical care contributes significantly to ensuring the quality and intensity of adjuvant chemotherapy.

Abstract Purpose An exploratory analysis of the phase III CONSOLE study indicated that the triplet antiemetic regimen including fosnetupitant (FosNTP) may be effective across extended overall period (0–168 h) for highly emetogenic chemotherapy-induced nausea and vomiting (CINV); however, its impact during the long-delayed phase (&gt; 168 h) remains unclear. This study aimed to prospectively explore the benefits of FosNTPs in preventing CINV beyond 168 h in patients undergoing oxaliplatin-based chemotherapy. Methods This single-center, single-arm, prospective observational study recruited patients scheduled to receive oxaliplatin-based chemotherapy. The primary endpoint was the long-delayed (120–336 h) complete control (CC) rate. Key secondary endpoints included the long-delayed complete response (CR) rate and the overall (0–336 h) CC, CR, and total control (TC) rates. Relative risks for emetogenic events were assessed using a logistic regression model. Results The analysis included 100 patients. Most eligible patients received CapeOX (oxaliplatin + capecitabine) (92.0%). The long-delayed CC rate was 76.3%. The long-delayed CR and TC rates were 84.7% and 75.4%, respectively. Risk factors for CINV in participants who did not achieve CC during the long-delayed phase included age (odds ratio 0.954 [95% confidence interval 0.909–0.998]), female sex (8.808 [2.446–41.992]), and history of motion sickness (5.050 [1.118–27.548]). Conclusion The triplet regimen involving FosNTP demonstrated sufficient efficacy in preventing CINV in patients receiving oxaliplatin-based chemotherapy, including during the long-delayed phase. However, participants with high emetic risk factors—such as younger age, female sex, or a history of motion sickness—continued to experience suboptimal control. Trial registration number and date of registration : jRCT1030230130

Although the spleen has been implicated in myeloid malignancy progression, the underlying mechanisms and microenvironmental remodeling remain poorly understood. Here, we investigated how splenic mesenchymal stromal/progenitor cells (MSPCs) expressing the transcription factor T-cell leukemia homeobox 1 (Tlx1) influence hematopoiesis and myeloid disease progression. We assessed their impact on hematopoietic stem/progenitor cells (HSPCs), leukemic cell recruitment, and disease progression. In vitro, Tlx1-overexpressing splenic stromal cells promoted the proliferation and survival of HSPCs. In vivo, using a murine acute myeloid leukemia (AML) model, AML progression induced extramedullary hematopoiesis (EMH) in the spleen through Tlx1 upregulation in MSPCs. This Tlx1-dependent remodeling facilitated leukemic cell recruitment and retention, whereas Tlx1 ablation in MSPCs significantly reduced leukemic cell accumulation in the spleen. Prolonged EMH in vivo was associated with the development of a myeloid malignancy. Collectively, these findings demonstrate that Tlx1-driven remodeling of the splenic microenvironment supports HSPC expansion and fosters conditions that promote myeloid malignancy development. Thus, targeting Tlx1-mediated alterations in the splenic niche may represent a therapeutic strategy for AML and related myeloid malignancies.

BackgroundNudge strategies are well-established in behavioral economics as effective approaches for promoting desirable behaviors. However, the potential benefits of integrating nudge-based strategies into pharmacist-led patient education have not yet been demonstrated. Here, we present a study protocol for an interventional trial to address this issue.MethodsThe PHARM-NUDGE study is a multicenter, randomized, parallel-group, single-blind, controlled trial prospectively designed to evaluate whether nudge-based pharmacist-led education can promote patients’ preventive behaviors against skin toxicities associated with cancer chemotherapy. The key inclusion criteria are as follows: (1) patients who are men or women and aged 18 years or older and (2) patients scheduled to receive a chemotherapy regimen containing capecitabine, liposomal doxorubicin, lenvatinib, cetuximab, or panitumumab in outpatient chemotherapy units or during hospitalization. The enrolled patients are randomly assigned in a 2:1 ratio to the nudge-based education or standard education groups. Pharmacists responsible for patient education utilize special educational tools that incorporate nudge strategies and provide skincare education to patients assigned to the nudge-based education group. Patients assigned to the standard education group receive skincare education with equivalent content but without nudges. The primary endpoint is the proportion of patients in each group who achieve four or more of the five predefined behavioral criteria.ConclusionsThe PHARM-NUDGE study is the first randomized controlled trial to evaluate the potential benefits of integrating nudge strategies into pharmacist-led skincare education for patients undergoing cancer chemotherapy with a high risk of skin toxicity, with patient enrollment initiated on October 15, 2025. Completion of the trial and acquisition of the final results are eagerly anticipated.Trial registrationThis trial was registeredwith the Japan Registry of Clinical Trials (clinical trial number: jRCT1040250089, registration date: September 3, 2025).Supplementary InformationThe online version contains supplementary material available at 10.1186/s40780-026-00556-4.

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: Tumor-infiltrating lymphocytes (TILs) reflect host immune response and are associated with prognosis and treatment response in HER2-positive and triple-negative breast cancer (TNBC). While the International Immuno-Oncology Biomarker Working Group recommends evaluating stromal TILs in tumor areas, intratumoral heterogeneity and small sample size in core needle biopsy (CNB) specimens limit consistent assessment. It remains unclear whether central tumor (CT) or invasive margin (IM) regions should be prioritized and what cut-off values are clinically relevant. Ultrasonographic (US) features may also reflect the immune microenvironment. We previously proposed a TILs-US score based on three US features that predicts lymphocyte-predominant breast cancer (LPBC). This study evaluated the clinical utility of TILs assessment from CT and IM regions, appropriate cut-off values for predicting response in HER2-positive and TNBC using CNB, and explored optimal biopsy targeting through pathologic and US comparisons. Methods: In this multicenter retrospective study, we analyzed 239 patients (124 HER2-positive, 115 TNBC) with cT1-3/cN0-2 breast cancer who underwent surgery after neoadjuvant chemotherapy (NAC). TILs were evaluated using CNB specimens obtained before NAC and assessed separately in the central tumor (CT) and invasive margin (IM) regions. The IM was defined as a 1-mm-wide area centered on the interface between the tumor and surrounding stroma, while the CT was defined as the remaining intratumoral area within the IM boundary. TILs were analyzed using binary cut-offs of 30% and 50%, as well as a three-tier classification: low (0-10%), intermediate (11-49%), and high (≥50%). Pre-treatment ultrasound (US) findings included tumor shape (scored 0-2), internal echo (0-2), and posterior echo (0-3), which were used to calculate a composite TILs-US score ranging from 0 to 7. Associations between TIL levels, US features, and pathological complete response (pCR) were analyzed. Results: Overall, 104 patients achieved pCR (HER2-positive: 39; TNBC: 65). Using a 30% cut-off, TILs were evenly distributed both CT and IM, while ≥50% cases were relatively rare especially CT (CT: 10%; IM: 20%). CT TILs ≥30% was significantly associated with pCR (p=0.001), whereas the ≥50% cut-off was not (p=0.128). In contrast, both 30% and 50% cut-offs in the IM region were predictive of pCR (p&amp;lt;0.001 and p=0.009, respectively). Subtype analysis revealed that in TNBC, TILs ≥30% in both CT and IM regions were significantly correlated with pCR. In HER2-positive cases, however, only IM TILs ≥30% was predictive of pCR. Similar trends were observed with the three-tier classification. Among US features, a small lobulated shape was associated with high TILs levels in both CT and IM regions, while an enhanced posterior echo was correlated with high TILs in the IM region. Conclusion: Our findings suggest that TILs assessment should include the IM in addition to the CT, especially in CNB specimens as provide valuable information. Given the limited tissue area available in CNB specimen, using a 30% cut-off for TILs may offer a clinically meaningful threshold to predict treatment response. In cases where US findings suggest central fibrosis, targeting only the tumor center may result in sampling fibrotic areas with sparse immune and tumor cells, potentially hindering proper evaluation. Therefore, selecting the biopsy target based on US imaging is essential. Especially in HER2-positive breast cancer, as well as TNBC, it is important for operators to consider the optimal needle insertion angle and sampling site to ensure appropriate sampling of viable tumor tissue and immune microenvironment for accurate pathological and immunological evaluation. Citation Format: Y. Kimura, R. Yamaguchi, K. Fukui, A. Kanou, M. Noma, S. Akashi-Tanaka, K. Arihiro, N. Iwamoto, Y. Ohta, T. Okuno, S. Kashiwagi, Y. Kamei, Y. Tanada, S. Nakano, A. Nagata, A. Murakami, Y. Mochitomi, A. Yamakawa, M. Yamaguchi, H. Shima, A. Emi. Ultrasound-guided biopsy-based tils assessment at tumor margins as a predictive biomarker of neoadjuvant treatment response in early her2-positive and triple-negative breast cancer: a multicenter 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 PS3-13-18.

Abstract Background: Saruparib (AZD5305) is a highly selective, potent inhibitor and trapper of PARP1. Camizestrant is an oral next generation SERD and complete ER antagonist. PETRA (NCT04644068) is a Phase 1/2a, modular, open label, multicenter study of saruparib as monotherapy or in combination with anticancer agents in pts with advanced solid malignancies. We present safety and preliminary efficacy of saruparib + camizestrant in pts with advanced/relapsed ER+/HER2- breast cancer. Methods: Pts were aged ≥18 years with histologically/cytologically confirmed breast adenocarcinoma, a locally-documented ER+ and HER2- tumor and an ECOG PS 0/1. Pts were required to have recurrence or progression on ≥1 line of endocrine therapy, and were allowed ≤2 prior lines of chemotherapy in the advanced setting and ≤1 prior PARP inhibitor. Pts could receive prior CDK4/6 inhibitors or fulvestrant, but not oral SERDs. Pts received 60 mg saruparib + 75 mg camizestrant daily orally. The primary objective was assessment of safety and tolerability; secondary objectives included pharmacokinetic (PK) assessments and preliminary antitumor activity. Results: At data cutoff (Mar 31, 2025), 38 pts had received ≥1 dose of the combination. Median age was 56 years; median prior lines of therapy was 3.5 (range, 1-13). BRCA1/BRCA2 mutation (m) and PALB2m were detected in 8 (21.1%) and 2 (5.3%) pts, respectively, based on local testing. Safety is summarized in the Table. Hematological toxicities included anemia and neutropenia; gastrointestinal toxicities included nausea and vomiting. PK data showed no evidence of drug interaction between saruparib and camizestrant. Saruparib exposure was comparable following single-dose saruparib versus saruparib at steady-state in combination with camizestrant, for AUC (42,219 vs 41,703 h*ng/mL) and Cmax (2,834 vs 3,250 ng/mL). Eight of 35 evaluable pts achieved confirmed partial responses (by RECIST v1.1) for an objective response rate (ORR) of 22.9%; median duration of response was 5.5 months. In addition, 12 pts (34.3%) achieved stable disease for a disease control rate of 57.1%. An ORR of 33.3% was reported in 9 pts with measurable disease and BRCA1/BRCA2m or PALB2m. The median progression-free survival was 4.4 months (80% CI, 2.0-5.6) overall and 6.1 months (80% CI, 4.4-7.3) in pts with mutations. Conclusion: Saruparib + camizestrant was well tolerated with no new safety signals versus prior monotherapy studies of each drug. PK of saruparib in combination with camizestrant was consistent with monotherapy data. Preliminary efficacy of the combination was promising and compared favorably with camizestrant monotherapy. This combination is being tested in a randomized Phase 3 trial in pts with ER+/HER2- and BRCA1m/BRCA2m or PALB2m (EvoPAR-Breast01; NCT06380751). Citation Format: T. A. Yap, K. Yonemori, W. Li, S. Kitano, F. Lynce, A. Sharp, A. Falcón, J. Garcia-Corbacho, R. D. Baird, J. Balmaña, S. Nanda, I. Song, K. Sugibayashi, L. Womersley, M. Squatrito, E. Gangl, T. Milenkova, S. J. Luen. Phase 1/2a trial of new generation PARP1-selective inhibitor saruparib + next generation selective ER degrader (SERD) camizestrant in patients (pts) with advanced/relapsed ER+/HER2-negative or low (HER2−) breast cancer (PETRA Module 6) [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 PS1-10-28.

The mechanisms of peritoneal dissemination in pancreatic ductal adenocarcinoma (PDAC) remain unclear partly owing to the lack of patient-derived models that recapitulate this process. This study aimed to establish an orthotopic model of PDAC peritoneal dissemination and to uncover the transcriptional and regulatory programs underlying this process. Organoids were established from primary pancreatic tumors and malignant effusions of patients with PDAC and orthotopically transplanted into the pancreas of immunodeficient mice to generate patient-derived orthotopic xenograft (PDOX) models. Subsequently, the organoids were rederived from pancreatic and peritoneal lesions of a representative model (PDOX12) and orthotopically reimplanted to assess the dissemination capacity. Single-nucleus RNA sequencing (snRNA-seq) and single-cell ATAC sequencing (scATAC-seq) were performed to analyze the tumors from these models. The organoids that were derived from malignant effusions reproducibly generated peritoneal metastases after orthotopic implantation. To dissect this process more precisely, we focused on one representative model (PDOX12) and rederived organoids from its pancreatic and peritoneal lesions. These organoids generated matched PDOX models that differed only in dissemination potential when reimplanted orthotopically. The results of snRNA-seq revealed a distinct subpopulation enriched in the high-dissemination model, which was characterized by the coordinated activation of genes involved in cytoskeletal dynamics, extracellular matrix remodeling, and plasticity-related signaling—suggesting a dissemination-primed state. Integration with scATAC-seq identified STAT3, SMAD3, and SOX2 as potential upstream regulators of this gene program. This study established PDOX models that isolate the peritoneal dissemination phenotype and reveal the transcriptional and regulatory programs driving this process.