Immune checkpoint inhibitors (ICIs) play a central role in various cancers. ICIs can cause immune-related adverse events (irAEs). As severe irAEs can be life-threatening, biomarkers for estimating irAE onset are crucial. The neutrophils-to-lymphocytes ratio (NLR) reflects the systemic immune condition and known as a prognostic marker in ICI treatment. Our study evaluated if the NLR corresponded with irAEs, and its feasibility as a biomarker for irAE onset. We retrospectively analyzed 275 cancer patients treated with anti-PD-1 monotherapy. We observed 166 irAEs in 121 patients. The NLR was significantly elevated during irAEs. Patients experiencing interstitial pneumonitis showed NLR elevation 4 weeks before initial symptoms and diagnosis. Analyzing receiver operating characteristics curves revealed that elevated NLR distinguished subsequent pneumonitis severity with high accuracy (AUC 0.93, sensitivity 88.9%, specificity 88.2%, cut-off 2.37, p = 0.0004). After a severe irAE occurred, two NLR trends were observed. Patients who showed a prompt reduction in elevated NLRs had favorable progression-free survival (hazard ratio 0.32, 95% CI 0.10–1.01, p = 0.0140) and overall survival (hazard ratio 0.23, 95% CI 0.06–0.86, p = 0.0057) compared to the patients who maintained elevated NLRs. These findings suggest that continuous monitoring of NLR trends may predict irAE onset and severity and subsequent prognosis.

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and PROGRESSIVE arm, respectively. 46/76 patients (61%) randomly assigned to the PROGRESSIVE arm have entered the second year of therapy. 47/166 patients (28%) went out of the study during the first year (Table 1). 39/166 cases (23%) lost MR3.0. Thus the probability of loosing the MR3.0 while on OPTkIMA was 19% at one year (Figure 1). All the 39 patients resumed TKIs continuously and all obtained at least the MR3.0 response, within 6 months. The intermittent treatment was well tolerated, with 7 serious adverse events, none of which treatment-related. None of the patients experienced the TKI withdrawn syndrome. QoL analysis was based on 166 patients with currently available QoL data. The top three most prevalent baseline symptoms (EO-RTC QLQ-C30) were fatigue (80%), pain (51%) and sleep disturbance (48%). With regard to QoL disease-specific domains (EORTC QLQ-CML24), no statistically significant changes were noted during the first year of treatment. Further QoL analyses are currently ongoing. Summary/Conclusion: According to this first interim report, we found that a policy of intermittent TKIs administration in elderly patients is safe and well tolerated. After the 1 st year, 28/166 patients (23%) lost MR3.0 and all of them re-gained the major molecular response within 6 months from resumption of continuous treatment. Thus, the probability of MR3.0 loss while on OPTkIMA at 1 year was 19%, comparable to the 20% of the previously published INTERIM trial.

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Background: In recent years, anti-PD-1 antibody, an immune checkpoint inhibitor, has been developed for the treatment of various types of cancer, including breast cancer. Synergistic effects of nivolumab, paclitaxel and bevacizumab are expected, based on various preclinical data, when these drugs are administered in combination. A biomarker study is ongoing to evaluate the immune status of patients participating in the NEWBEAT trial, which is a phase II trial of nivolumab + paclitaxel + bevacizumab therapy as first-line treatment for patients with metastatic or recurrent HER2-negative breast cancer. Methods: HER2-negative breast cancer patients from the WJOG9917B (NEWBEAT) trial are enrolled in this biomarker study. To explore new biomarkers for combined treatment of breast cancer with immune-checkpoint inhibitors and anti-vascular endothelial growth factor antibodies, we propose to conduct multicolor immunohistochemistry (IHC) assays for immunomonitoring of the intra-tumor environment, such as the expressions of PD-L1, CD4 and CD8. Blood samples are collected before the start of treatment and at four time-points during the treatment, to determine, using a multicolor flow cytometry panel, the numbers of circulating immunosuppressive cells, such as regulatory T cells, myeloid-derived suppressor cells and tumor-associated macrophages (M2). In the NEWBEAT trial, patients receive nivolumab 240 mg/body on days 1 and 15, paclitaxel 90 mg/m2 on days 1, 8 and 15, and bevacizumab 10 mg/kg on days 1 and 15 every 4 weeks until disease progression. The primary endpoint is the objective response rate, and the key secondary endpoints include progression-free survival, overall survival, and toxicity of the protocol treatment. A total of 51 patients will be enrolled and the enrollment period will be one year. This trial opened to accrual in February 2018. Clinical trial registry number: UMIN000029590 Citation Format: Ozaki Y, Kitano S, Matsumoto K, Takahashi M, Mukohara T, Futamura M, Masuda N, Tsurutani J, Yoshimura K, Minami H, Takano T. Biomarker study of patients with HER2-negative metastatic breast cancer receiving combination therapy with nivolumab, bevacizumab and paclitaxel as first-line treatment (WJOG9917BTR) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-12-02.

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We conducted a 3-to 5-year study of the transfer factors (TF) of 137 Cs in Japanese chestnut, satsuma mandarin and Japanese persimmon trees planted 1 to 2 years after the Fukushima Dai-ichi Nuclear Power Plant accident. The TFs of these fruit trees were on the order of 10 −4 and 10 −3 across the several years and showed annual variations. Comparison of the TFs between two Japanese persimmon cultivars, Hachiya and Hiratanenashi, seemed to be higher TFs values of the fruit and leaves in the former than in the latter cultivar. We further investigated the effect of topsoil management (plowing, topsoil removal, and topsoil return) on 137 Cs concentration in Hachiya fruit and the planted soil. The soil 137 Cs concentration in the topsoil removal treatment was lower than that in the plowing and topsoil return treatments, but the topsoil management had no effect on the 137 Cs concentration of Hachiya fruit in this experiment.