Saitama Cancer Center

<title>Abstract</title> Purpose This study was conducted to confirm the actual opioid conversion ratios (CRs) and opioid rotation ratios (ORRs) in clinical practice in Japan. Methods A cross-sectional survey was conducted between March 7th to 20th, 2024, targeting palliative care physicians and pharmacists in the following three societies: Japanese Society for Palliative Medicine, Japanese Society for Pharmaceutical Palliative Care and Sciences, and Japanese Association of Supportive Care in Cancer. The primary endpoint was to determine the CRs and ORRs used by participants, which were measured in the survey. Results 433 responses (68.1% physicians and 31.9% pharmacists) were received. 30.3% conducted &gt; 30 opioid rotations in the past 6 months. For most CRs and ORRs obtained from all the participants, values for the median, first quartile, third quartile, and mode were consistent. Among groups of professions and number of opioid rotations frequency, there were no differences in the median opioid ratios involving morphine, hydromorphone and oxycodone. However, there were significant differences in the ORRs involving intravenous (IV) fentanyl, specifically in the rotation ratios between IV fentanyl and IV morphine. Conclusion There was great consistency in the CRs and ORRs used by physicians and pharmacists in palliative care in Japan. This would suggest that education on the ratios is well established for medical professionals in Japan.

To investigate clinical outcomes, treatment, and survival rates of men aged ≥75 years with prostate cancer in Japan. The study used data from the Prostate Cancer Research International: Active Surveillance (PRIAS)-JAPAN, a nationwide, multicentre prospective cohort study of men with clinically localised prostate cancer managed with active surveillance (AS). The original eligibility criteria were clinical stage T1c-T2 disease, prostate-specific antigen (PSA) level ≤10 ng/mL, PSA density (PSAD) <0.20 ng/mL/mL, and Gleason Score ≤3 + 3 with two or fewer positive biopsy cores. In 2021, magnetic resonance imaging use expanded eligibility to include patients with a PSA level ≤20 ng/mL, PSAD <0.25 ng/mL/mL, and Gleason Score ≤3 + 4 with <50% of biopsy cores positive. PSA was monitored every 3-6 months, and biopsies were scheduled at 1, 4, 7, and 10 years, and every 5 years thereafter. The outcomes in those aged ≥75 years (older group) were compared with those aged <75 years (younger group). Of the 1274 eligible patients enrolled by 29 February 2024, 231 were in the older group and 1043 were in the younger group. In the older group, the median age at enrolment was 77 years. At diagnosis, patients in the older group had significantly larger prostate volumes, higher proportion of Gleason Score 3 + 4, and more T2 disease than those in the younger group. The protocol biopsy acceptance rate decreased over time (first: 82.9%, second: 63.6%, third: 42.2%, fourth: 22.4%), with no significant difference between age groups. The 10-year AS persistence rate in the older group was 8.8%. The overall survival was significantly lower in the older group than in the younger group (hazard ratio: 0.32, 95% confidence interval 0.14-0.74); however, the 10-year metastasis-free survival and cancer-specific survival rates in the older group were both 100%. In some patients aged ≥75 years an observation-focused management approach may be appropriate, in which AS is initiated as a structured monitoring phase with planned de-intensification and transition to watchful waiting, to prevent overtreatment while maintaining excellent cancer-specific outcomes.

Correction: Overall survival of palbociclib plus endocrine therapy in Japanese patients with HR+/HER2- advanced breast cancer in the first-or second-line setting: a multicenter observational study (P-BRIDGE study)

TPS244 Background: Comprehensive genomic profiling (CGP) using next-generation sequencing is recommended in metastatic colorectal cancer (mCRC) to identify actionable alterations. In Japan, CGP is reimbursed only once in a patient’s lifetime and generally after completion of standard systemic therapy, limiting its ability to capture temporal genomic changes. Liquid biopsy using circulating tumor DNA (ctDNA) enables repeated, minimally invasive genomic assessment and may detect emerging or disappearing actionable alterations during the disease course. There have been few prospective studies to assess the frequency and clinical impact of such changes before and after first-line chemotherapy in mCRC. We are therefore conducting a prospective observational study to evaluate the clinical utility of serial CGP testing using ctDNA. Methods: This is a prospective, multicenter observational study conducted at approximately 10 Japanese cancer genomic core and hub hospitals. Eligible patients are adults (≥18 years) with histologically confirmed unresectable mCRC, ECOG performance status 0–1, no prior systemic chemotherapy for metastatic disease, and adequate organ function. Patients undergo ctDNA analysis using the Guardant360 CDx assay at two time points: prior to initiation of first-line chemotherapy and after radiologic confirmation of disease progression on first-line therapy. Results are reviewed by institutional expert panels and returned to patients per local practice, including via telemedicine where applicable. The primary endpoint is the proportion of patients with a change in actionable genomic alterations (defined as OncoKB therapeutic level 1, 2, or R1, excluding variants of unknown significance/synonymous variants) between baseline and post–first-line testing. Secondary endpoints include: proportion of patients with actionable alterations at each time point; proportion with expert panel–recommended therapy and those who receive such therapy; objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) from expert panel–recommended therapy; and feasibility of telemedicine-based result disclosure. Based on prior retrospective data suggesting ~20% change in actionable alterations after systemic therapy, the target sample size is 200 patients, with ≥123 patients expected to have evaluable post–first-line ctDNA results. The study has 90% power at a one-sided α of 0.025 to detect a change proportion ≥15% versus a threshold of 6%. Patient enrollment began in November 2025, with a 12-month accrual period and 18-month follow-up. This trial will clarify the clinical utility of serial ctDNA CGP in mCRC and may support policy change to allow repeated CGP testing during the disease course. Clinical trial information: TBD .

Neuroblastoma (NB) is a pediatric solid tumor originating from neural crest cells (NCCs), which are precursors of the sympathetic nervous system. MYCN amplification is a key factor contributing to the poor prognosis of NB. Anaplastic lymphoma kinase (ALK) alterations, including mutations and amplification, activate oncogenic signaling pathways that, together with MYCN amplification, further enhance tumor malignancy. NCCs are mainly classified into cranial NCCs (cNCCs) and trunk NCCs (tNCCs). Recent studies have reported NB development from tNCCs. However, the potential for NB development from cNCCs remains unexplored. In this study, we sought to mimic the tumorigenic process of NB by overexpressing MYCN and ALK in cNCCs derived from human induced pluripotent stem cells. These modified cells, when subcutaneously transplanted into immunodeficient mice, induced NB-like tumors and could thus be used as an invitro model to study this tumor. Through extensive gene expression profiling and whole-exome sequencing of MYCN/ALK-induced clones, we identified key features of NB, including loss of NF1 and gain of 17q chromosome, which are critical for the development of malignant tumor. This model provides a valuable platform for studying the biological mechanisms driving ALK and MYCN amplification in NB derived from cNCCs.

Cellular senescence is deeply involved in physiological homeostasis, development, tissue repair, aging, and diseases. Senescent cells (SnCs) accumulate in aged tissues and exert deleterious effects by secreting proinflammatory molecules that contribute to chronic inflammation and aging-related diseases. We revealed that an aberrant interaction between glycolytic PGAM1 and Chk1 kinase is augmented in SnCs associated with increased glycolysis, whose byproduct, lactate, promotes this binding in a noncell autonomous manner. The pseudo-Warburg effect of SnCs with enhanced PPP (pentose phosphate pathway) activity is maintained by HIF-2α phosphorylation by Chk1 and subsequent upregulation of glycolytic enzymes, creating a vicious cycle reprogramming the glycolytic pathway in SnCs. HIF-2α also activates FoxM1 expression, which transcriptionally suppresses proapoptotic profiles, including BIM, and upregulates DNA repair machineries in SnCs. FoxM1 thus supports the genomic integrity and survival capacity of SnCs during their glycolytic changes. Chemical abrogation of PGAM1-Chk1 binding reverts these phenotypes and eliminates SnCs through senolysis. Inhibition of the PGAM1-Chk1 interaction improves physiological parameters during aging and inhibits lung fibrosis in mouse models. Our study highlights a novel pathway contributing to the metabolic reprogramming of SnCs and how the use of a new senolytic molecule that targets the PGAM-Chk1 interaction creates a specific vulnerability of those cells to potentially fight age-related diseases.

Chronic background mucosal inflammation contributes to colorectal cancer (CRC) development in ulcerative colitis (UC), but its prognostic impact is unclear. We evaluated whether background mucosal inflammation documented at cancer diagnosis is associated with oncologic outcomes. This retrospective study analyzed 1189 UC patients diagnosed with CRC using a nationwide, multicenter database in Japan. Patients were classified as CRC within the UC-involved area (within-area) or outside the UC-involved area (outside-area), based on tumor location relative to the UC disease extent documented endoscopically at cancer diagnosis. The primary end point was 5-year recurrence-free survival (RFS), and the secondary end point was 5-year cancer-specific survival (CSS). In within-area cases, inflammation severity was assessed using the Mayo Endoscopic Score (MES), stratified as Inactive, Mild-Moderate, and Severe. Of the 723 eligible patients, 683 had within-area and 40 outside-area CRC. Five-year RFS was significantly lower in within-area than outside-area CRCs (75.1% vs 87.6%, P = 0.022). Multivariable Cox regression analysis of RFS revealed this classification as an independent prognostic factor (hazard ratio = 2.99, 95% confidence interval: 1.09-8.18, P = 0.030). A significant difference was also observed in 5-year CSS (P = 0.038). Among within-area cases, higher MES was associated with stepwise declines in RFS (P = 0.150), and a similar, statistically significant gradient in CSS (P = 0.048). Background mucosal inflammation at cancer diagnosis is associated with significantly worse prognosis of CRC in UC patients. Systematic endoscopic assessment at cancer diagnosis may aid prognostic stratification and inform management.

<h3>Background</h3> Human epidermal growth factor receptor 2 (HER2) is overexpressed in ∼20% of advanced gastroesophageal adenocarcinomas (GEAs). Trastuzumab (T-mab) is the standard first-line treatment for HER2-positive GEA, and trastuzumab deruxtecan (T-DXd) has demonstrated clinical efficacy in later-line settings. However, the potential loss of HER2 expression following T-mab treatment raises concerns about the subsequent effectiveness of T-DXd. The temporal dynamics of HER2 expression across treatment lines are not well understood. <h3>Design</h3> We designed a prospective, single-arm, multicenter study to investigate the association between the efficacy of third-line T-DXd and changes in HER2 status in tumor tissue and blood after first-line T-mab treatment in patients with HER2-positive GEA. The aim is to inform the optimal clinical use of T-DXd. Serial tumor and/or blood re-biopsies will be carried out at each line of treatment following first-line therapy. The study consists of two parts. In part 1, we will evaluate biomarker dynamics—specifically HER2 status and circulating tumor DNA alterations—during second-line therapy. In part 2, we will assess the efficacy and safety of third-line T-DXd in relation to these biomarker changes. Approximately 120 patients will be enrolled in part 1 and 50 in part 2.