論文

Background: Board certification in surgical oncology improves cancer outcomes, but the impact of medical oncologist certification on systemic therapy outcomes is unknown. We investigated whether the Japanese Society of Medical Oncology (JSMO) board certification of the enrolling physician was associated with treatment quality and survival. Methods: This retrospective cohort study used data from the SCRUM-Japan MONSTAR-SCREEN observational study, a nationwide multicenter genomic screening program enrolling patients from 2019 to 2022. Standard treatment implementation rates were compared across cancer types as a secondary outcome. The primary outcome was overall survival (OS) in patients with metastatic colorectal cancer (mCRC) using Kaplan–Meier analysis and Cox proportional hazards regression with sequential adjustment for clinical and molecular covariates. Results: Among 2,184 patients, standard treatment rates were comparable between board-certified and non–board-certified groups (97.0% vs. 96.9%). In 358 patients with mCRC, enrollment by a board-certified physician was associated with longer OS (median, 36.5 vs. 30.7 months; hazard ratio (HR): 0.66, 95% CI 0.50–0.87; log-rank p = 0.003) even after adjustment for age, sex, tumor sidedness, region, trial participation, molecular targeted therapy, metastatic organ count (HR, 0.73; 95% CI 0.55–0.97; p = 0.029), and after additional adjustment for RAS and BRAF V600E status (HR, 0.64; 95% CI 0.47–0.88; p = 0.005). Board-certified physicians used molecular targeted therapy more frequently (89.5% vs. 80.4%; p = 0.036). Conclusions: JSMO board certification was independently associated with improved OS in mCRC despite comparable guideline adherence, suggesting that specialist expertise extends beyond treatment selection.

Ultra-light particles, such as axions, form a macroscopic condensate around a highly spinning black hole by the superradiant instability. Due to its macroscopic nature, the condensate opens the possibility of detecting the axion through gravitational wave observations. However, the precise evolution of the condensate must be known for the actual detection. For future observation, we numerically study the influence of the self-interaction, especially interaction between different modes, on the evolution of the condensate in detail. First, we focus on the case when condensate starts with the smallest possible angular quantum number. For this case, we perform the non-linear calculation and show that the dissipation induced by the mode interaction is strong enough to saturate the superradiant instability, even if the secondary cloud starts with quantum fluctuations. Our result indicates that explosive phenomena such as bosenova do not occur in this case. We also show that the condensate settles to a quasi-stationary state mainly composed of two modes, one with the smallest angular quantum number for which the superradiant instability occurs and the other with the adjacent higher angular quantum number. We also study the case when the condensate starts with the dominance of the higher angular quantum number. We show that the dissipation process induced by the mode coupling does not occur for small gravitational coupling. Therefore, bosenova might occur in this case.

12Background: Postoperative circulating tumor DNA (ctDNA) positivity is strongly associated with increased recurrence risk, prompting a growing number of treatment escalation trials targeting patients (pts) with ctDNA-positive colorectal cancer (CRC). The phase III ALTAIR trial (NCT04457297) randomizes pts with post-surgical ctDNA-positivity to trifluridine/tipiracil versus placebo. We evaluated if fluctuating ctDNA status influences both eligibility and enrollment. Methods: GALAXY (UMIN000039205) study evaluates ctDNA monitoring post curative-intent surgery in pts with clinical stage II-IV CRC receiving standard-of-care (SOC) perioperative chemotherapy. ctDNA was assessed using a personalized, tumor-informed assay (Signatera, Natera, Inc.) in plasma collected at 1, 3, 6, 9, 12, 18, and 24 months after surgery. Pts from GALAXY with post-surgical ctDNA-positivity in the absence of clinical evidence of recurrence were eligible for enrollment into the ALTAIR study within 3 months of a ctDNA-positive result. We analyzed each pt’s postoperative ctDNA trajectory and calculated the proportion meeting ctDNA-based inclusion criteria. Results: Of 2, 016 pts enrolled in GALAXY at ALTAIR-participating sites as of April 2023, 290 (14.4%) were ctDNA-positive 2-10 weeks post-surgery (i.e., molecular residual disease, MRD, positive). Among 148 MRD-positive pts receiving adjuvant chemotherapy (ACT), 50 (33.8%) remained persistently ctDNA-positive, 39 (78%) of whom had no clinical relapse within 3 months of MRD detection. Eighty-five pts (57.4%) cleared ctDNA after ACT; 39 (45.9%) later reconverted to positive, 29 (74.3%) of whom remained relapse-free for ≥3 months after reconversion. Among 572 MRD-negative pts in GALAXY receiving ACT, 71 (12.4%) converted to ctDNA-positive, 55 (77.5%) of whom remained relapse-free for ≥3 months after molecular relapse. Overall, 14.8% of all pts from GALAXY study were ctDNA-positive without early clinical relapse post-SOC therapy and thus met ALTAIR ctDNA-based criteria. Stage-specific rates of meeting the ALTAIR ctDNA-based criteria were 13.0 % (stage II), 13.2 % (stage III), and 30.0 % (stage IV). Overall, 121 (6.0%) were enrolled in ALTAIR, including 24.1% (70/290) of MRD-positive and 3.0% (51/1, 726) of MRD-negative pts. Among pts who were ctDNA-positive, median ctDNA levels were significantly higher in those who relapsed within 3 months (31.8% of ctDNA-positive pts) compared with those who did not (68.2%) (2.1 versus 0.4 MTM/mL, P<0.001). Conclusions: Serial postoperative ctDNA monitoring in the GALAXY study reveals that 14.8% of pts were eligible for ALTAIR based on ctDNA positivity without early relapse post-SOC therapy. These data underscore the importance of longitudinal ctDNA assessment in trial design and may inform the planning of future ctDNA-guided adjuvant studies. Clinical trial information: NCT04457297.

Background: Standard adjuvant treatment of stage III colon cancer (CC) is fluoropyrimidine with oxaliplatin. Recently, stage III was subdivided into low-risk (T1-3, N1) and high-risk (T4 and/or N2), with the benefit of adding oxaliplatin varying across these substages. In this study, we aimed to assess the impact of oxaliplatin on survival outcomes in subdividing stage III CC patients based on T and N staging. Patients and methods: A total of 4942 stage III CC patients were pooled from the three randomized pivotal trials of oxaliplatin. Kaplan–Meier curves, Cox models stratified by study, and interaction tests were used to assess the oxaliplatin effect across subgroups based on T and N stages. The primary endpoint was overall survival (OS). Results: The prevalence of tumor stages was T1-2 12.4%, T3 74.4%, and T4 13.1%; nodal stages were N1 64.7% and N2 35.3%. A significant OS benefit from oxaliplatin was seen only in T3 (5-year OS = 77.2% versus 73.0%, P < 0.001): T3N1 (hazard ratio 0.72, 95% confidence interval 0.62-0.85, P < 0.001) and T3N2 (hazard ratio 0.81, 95% confidence interval 0.69-0.95, P = 0.010). No benefit was observed for T1-2 (5-year OS = 87.8% versus 88.7%, P = 0.644) or T4 patients (5-year OS = 62.6% versus 60.2%, P = 0.648). Subgroup analysis revealed a significant interaction between T stage and the effect of oxaliplatin treatment on OS, whereas no such interaction was observed for N stage. Conclusions: Our analysis revealed that oxaliplatin-based chemotherapy offers a significant survival benefit in stage III CC patients with T3 tumors. In contrast, no survival benefit was observed for T1-2 or T4 patients. These results suggested that T stage plays a more crucial role than N stage in predicting treatment benefit, highlighting the need for tailored treatment strategies based on tumor characteristics.

We launched SCRUM-Japan platform for the cancer genome profiling (CGP) test screening followed by the enrollment to genomically-matched clinical trials in 2015. More than 30,000 tissue-based and 10,000 liquid-based CGP tests have already been performed for enrolling to a total of 127 industry-/investigator-initiated registration trials, which resulted in regulatory approvals of 12 new agents with 14 indications in Japan. Using the clinical-genomic database, a new driver gene was recently discovered with dramatic response by genomically-matched agent. Our comparative study with tissue-based CGPs revealed more usefulness of liquid biopsy in terms of less invasive manner, shorter turn-round time, and higher enrollment rate for matched treatments than tissue-based in gastrointestinal cancers. For detecting minimal/molecular residual disease (MRD) after surgery, post-surgical monitoring with tumor-informed liquid biopsy assay in association with two randomized control trials have also started in 2020 (CIRCULATE-Japan). The observational cohort study showed obvious efficacy of the MRD monitoring for predicting recurrence, leading to change clinical practice in patient selection who should receive adjuvant therapy in the near future.

The impact of venous thromboembolism in Japanese colorectal cancer patients has not been elucidated. This prespecified subanalysis of the Cancer-VTE Registry aimed to report venous thromboembolism and event data after 1 year of follow-up in 2477 patients with colorectal cancer and investigate risk factors of venous thromboembolism. Of 2477 patients, 158 (6.4%) had venous thromboembolism in venous thromboembolism screening at enrollment. Asymptomatic distal deep-vein thrombosis accounted for 123/158 (77.8%) of venous thromboembolism cases. During the follow-up period, symptomatic, incidental events requiring treatment and composite venous thromboembolism incidences were 0.3%, 0.8%, and 1.0%, respectively. The incidence of bleeding events, cerebral infarction/transient ischemic attack/systemic embolic event, and all-cause death were 1.0%, 0.3%, and 4.8%, respectively. These results were consistent with the main study results. In multivariable analysis, venous thromboembolism at baseline was a risk factor of composite venous thromboembolism during the follow-up period. Japanese patients with colorectal cancer and advancing cancer stage before treatment had more frequent venous thromboembolism complications at baseline, higher incidence of venous thromboembolism events during cancer treatment, and higher mortality.

In Europe and the United States, the Foundation Aide et Recherche en Cancérologie Digestive(ARCAD)database project was initiated in 2006 and 43,488 patient data(IPD)for metastatic colorectal cancer from 59 trials have been collected and constructed as the integrated database. The ARCAD-Asia was launched in 2021 and has been actively collecting Asian clinical trials and converted IPD are stored into the integrated database. In addition, the ARCAD-Asian data are transferred to ARCAD and IPD are integrated to ARCAD global database. All the data are shared with 3 data centers of ARCAD-Asia and ARCAD, located in France, the United States and Japan. In the ARCAD database, there are 1,673 IPD treated with placebo in a salvage line setting. We are now planning to utilize placebo IPD as the synthetic control arms(SCAs)to compare the efficacies of active agents. Furthermore, we will continue to collect the Asian IPD and will expand the cancer type, leading to more comprehensive global database.