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Nivolumab plus ipilimumab showed promising efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). The efficacy of the nivolumab plus ipilimumab combination regimen in NSCLC patients who relapse after durvalumab consolidation following concurrent chemoradiotherapy (CCRT) has not been determined. Between January 2021 and June 2022, clinical data were retrospectively extracted from the medical records of patients with NSCLC who received nivolumab plus ipilimumab after CCRT and durvalumab consolidation. A total of 30 patients were included in this analysis. The median number of durvalumab treatment cycles was 11. Median PFS and OS with nivolumab plus ipilimumab were 4.2 months (95% confidence interval [CI]: 0.7-7.7) and 18.5 months (95% CI: 3.5-33.5), respectively. The 6-month and 12-month PFS rates were 46.7% (95% CI: 28.8-64.5) and 36.4% (95% CI: 19.0-53.7). In multivariate analysis, a significant correlation was observed between a durvalumab treatment duration of 6 months or more and PFS ( p = 0.04) as well as OS ( p = 0.001). Grade 3 adverse events, including pneumonitis, dermatitis, and colitis, occurred in 10% of the patients. This study suggests that nivolumab plus ipilimumab is effective, especially in patients who have received durvalumab for 6 months or more, and tolerable for patients who relapsed after durvalumab following CCRT.

Background/aim: Chemo-immunotherapy, including the programmed death ligand 1 (PD-L1) antibody, is an effective treatment for patients with extensive-stage small-cell lung cancer (ES-SCLC). However, no biomarker has been established for the prediction of chemo-immunotherapy. Therefore, we investigated the potential of 18 F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) as a predictive marker., Patients and Methods: Forty-six patients with ES-SCLC who received 18 F-FDG-PET immediately before combined platinum-based chemotherapy with PD-L1 blockade as a first-line treatment were eligible, and the maximum standard uptake value (SUV max ), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) on 18 F-FDG uptake were evaluated., Results: PD-L1 and tumor infiltrative lymphocytes (TILs) were immunohistochemically analyzed in 36 of the 46 patients. A high MTV was significantly associated with poor performance status and low albumin levels, and there was a significant association between low albumin and high TLG. Univariate analysis identified sex, Brinkman index, and MTV as significant predictors of progression-free survival (PFS), and sex, SUV max , MTV, and TLG as significant factors of overall survival (OS). Multivariate analysis revealed that sex, Brinkman index, and MTV were independent prognostic factors for PFS, and sex, SUV max , MTV, and TLG were significant predictors of OS. SUV max was significantly higher in patients with positive PD-L1 expression than in those with negative expression but was not significantly different between positive and negative TILs. Moreover, the levels of MTV and TLG were not closely associated with the levels of PD-L1 and TILs., Conclusion: MTV or TLG metabolic tumor activity is suitable for the prediction of chemo-immunotherapy outcomes in patients with ES-SCLC., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Ramucirumab plus docetaxel (RD) can cause febrile neutropenia (FN), which frequently requires the prophylactic administration of pegfilgrastim. However, the effects of prophylactic pegfilgrastim on FN prevention, therapeutic efficacy, and prognosis after RD have not been fully evaluated in patients with advanced non-small-cell lung cancer (NSCLC). Two hundred and eighty-eight patients with advanced NSCLC who received RD as second-line therapy after platinum-based chemotherapy plus PD-1 blockade were included. Patients were divided into groups with and without prophylactic pegfilgrastim, and adverse events, efficacy, and prognosis were compared between both groups. Of the 288 patients, 247 received prophylactic pegfilgrastim and 41 did not. The frequency of grade 3/4 neutropenia was 62 patients (25.1%) in the pegfilgrastim group and 28 (68.3%) in the control group (p < 0.001). The frequency of FN was 25 patients (10.1%) in the pegfilgrastim group and 10 (24.4%) in the control group (p = 0.018). The objective response rate was 31.2% and 14.6% in the pegfilgrastim and control groups (p = 0.039), respectively. The disease control rate was 72.9% in the pegfilgrastim group and 51.2% in the control group (p = 0.009). Median progression free survival was 4.3 months in the pegfilgrastim group and 2.5 months in the control group (p = 0.002). The median overall survival was 12.8 and 8.1 months in the pegfilgrastim and control groups (p = 0.004), respectively. Prophylactic pegfilgrastim for RD reduced the frequency of grade 3/4 neutropenia and febrile neutropenia and did not appear to be detrimental to patient outcome RD.Clinical Trial Registration Number: UMIN000042333., (© 2024. The Author(s).)

Background: The relationship between antinuclear antibody (ANA) and the efficacy of programmed death-1 (PD-1) blockade remains controversial. Here, we investigated the prognostic significance of ANA titer in patients with non-small cell lung cancer (NSCLC) receiving pembrolizumab monotherapy as the first-line treatment, compared with that of platinum-based chemotherapy with PD-1 blockade., Methods: Our clinical data based on the ANA titer (1:80) were retrospectively reviewed for patients with advanced NSCLC, who were treated with first-line pembrolizumab monotherapy and platinum-based chemotherapy with PD-1 blockade. Immunohistochemical staining for tumor-infiltrating lymphocytes such as CD4, CD8 and Foxp3 was performed., Results: Among 106 patients treated with pembrolizumab, 19 (17.9%) tested high for ANA. Progression-free survival (PFS) and overall survival (OS) were significantly better in patients with high ANA than in those with low ANA, and high ANA was identified as an independent prognostic predictor, particularly in the subgroup with programmed death ligand-1 (PD-L1) ≥ 50%. However, no statistically significant difference in PFS and OS based on the ANA titer was observed in 59 patients treated with combinational chemotherapy and immunotherapy. High numbers of intratumoral Foxp3 and stromal CD8 were significantly associated with low ANA., Conclusions: Assessment of preexisting ANA titers was useful to prognose PD-1 blockade as a first-line setting, particularly for the PD-L1 ≥ 50% subgroup, but not in the case of combined immunotherapy and chemotherapy., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

The aim of the present study was to explore the relationship between tumor metabolic glycolysis and inflammatory or nutritional status in patients with advanced non-small cell lung cancer (NSCLC) who received programmed death-1 (PD-1) blockade. A total of 186 patients were registered in the present study. All of patients underwent 18 F-FDG PET imaging before initial PD-1 blockade, and maximum standardized uptake value (SUV max ), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were assessed as indicators of 18 F-FDG uptake. As inflammatory and nutritional index, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ration (PLR), systemic immune inflammation index (SII), prognostic nutritional index (PNI), advanced lung cancer inflammation index (ALI) and Glasgow prognostic score (GPS) were evaluated based on previous assessment. 18 F-FDG uptake by MTV and TLG significantly correlated with the scores of NLR, PLR, SII, PNI and ALI, in addition to the level of albumin, lactate dehydrogenase, C-reactive protein, white blood cells, neutrophils, lymphocytes and body mass index. The count of NLR, PLR and SII was significantly higher in patients with <1 year overall survival (OS) compared with in those with ≥1 year OS, and that of PNI and ALI was significantly lower in those with <1 year OS compared with those with ≥1 year OS. High MTV under the high PLR, SII and low ALI were identified as significant factors for predicting the decreased PFS and OS after PD-1 blockade in a first-line setting. In second or more lines, high MTV was identified as a significant prognostic predictor regardless of the levels of PLR, SII, ALI and GPS. In conclusion, metabolic tumor glycolysis determined by MTV was identified as a predictor for the outcome of PD-1 blockade under the high inflammatory and low nutritional conditions, in particular, when treated with a first-line PD-1 blockade. A high MTV under high PLR and SII and low ALI in the first-line setting could be more predictive of ICI treatment than other combinations., Competing Interests: KKa has received a speaker honorarium from Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd. and AstraZeneca, and received research grants from AstraZeneca. AM and OY have received a speaker honorarium from Chugai Pharmaceutical Co., Ltd. and AstraZeneca. HK has received research grants and a speaker honorarium from Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp and Dohme, Chugai Pharmaceutical Co., Ltd. and AstraZeneca. KKo has received research grants and a speaker honorarium from AstraZeneca, and Bristol-Myers Squibb., (Copyright © 2024, Spandidos Publications.)

Introduction: Biomarkers for predicting the outcome of ipilimumab plus nivolumab (Nivo-Ipi) treatment in cancer patients have not been identified. Herein, we investigated the prognostic significance of inflammatory and nutritional markers in patients with advanced non-small cell lung cancer (NSCLC) receiving Nivo-Ipi., Methods: Our study retrospectively analyzed 101 patients with advanced NSCLC who received Nivo-Ipi at a single institution. Inflammatory and nutritional indices were correlated with patient outcomes and included the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), systemic immune-inflammation index (SII), prognostic nutritional index (PNI), advanced lung cancer inflammation index (ALI), and Glasgow prognostic score (GPS)., Results: The NLR significantly correlated with the PLR, SII, PNI, ALI, and GPS. Regarding therapeutic efficacy, the NLR, SII, and PNI predicted a partial response, and all indices predicted progressive disease. In subgroup analyses, the SII, PNI, and ALI predicted the outcome of patients with adenocarcinoma, whereas only the PNI predicted the outcome of patients with non-adenocarcinoma. The PNI and SII were the most useful indices in patients with a programmed death ligand-1 expression level of &lt;1% and ≥1%, respectively., Conclusion: The NLR, PLR, SII, PNI, ALI, and GPS were significantly associated with the outcome of Nivo-Ipi treatment in patients with NSCLC. The PNI was the most suitable marker regardless of histological type. The SII and PNI were the most promising markers for patients with and without PD-L1 expression, respectively., (© 2023 S. Karger AG, Basel.)

Introduction: Pembrolizumab (Pemb) therapy in conjunction with carboplatin and paclitaxel (PTX)/nab-PTX has been efficacious in treating non-small cell lung cancer (NSCLC). However, the response predictors of this combination therapy (Pemb-combination) remain undetermined. We aimed to evaluate whether Glasgow prognostic score (GPS), neutrophil-to-lymphocyte ratio (NLR), body mass index (BMI), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index (PNI) are potential factors in prognosticating the response to Pemb-combination therapy in advanced NSCLC patients., Methods: We retrospectively recruited 144 NSCLC patients receiving first-line treatment with Pemb-combination therapy from 13 institutions between December 1, 2018, and December 31, 2020. GPS, NLR, BMI, PLR, and PNI were assessed for their efficacy as prognostic indicators. Cox proportional hazard models and the Kaplan-Meier method were used to compare the progression-free survival (PFS) and overall survival (OS) of the patients., Results: The treatment exhibited a response rate of 63.1% (95% confidence interval [CI]: 55.0-70.6%). Following Pemb-combination administration, the median PFS and OS were 7.3 (95% CI: 5.3-9.4) and 16.5 (95% CI: 13.9-22.1) months, respectively. Contrary to PNI, NLR, GPS, BMI, and PLR did not display substantially different PFS in univariate analysis. However, multivariate analysis did not identify PNI as an independent prognostic factor for PFS. Furthermore, univariate analysis revealed that GPS, BMI, and PLR exhibited similar values for OS but not NLR and PNI. Patients with PNI ≥45 were predicted to have better OS than those with PNI &lt;45 (OS: 23.4 and 13.9 months, respectively, p = 0.0028). Multivariate analysis did not establish NLR as an independent prognostic factor for OS., Conclusion: The PNI evidently predicted OS in NSCLC patients treated with Pemb-combination as first-line therapy, thereby validating its efficiency as a prognostic indicator of NSCLC., (© 2023 S. Karger AG, Basel.)

Background: The factors that predict the clinical response to ramucirumab plus docetaxel (RD) after first-line chemoimmunotherapy are unresolved. We explored whether the therapeutic efficacy of prior chemoimmunotherapy could predict the outcome of RD as sequential therapy in patients with advanced non-small cell lung cancer (NSCLC)., Methods: Our study comprised 288 patients with advanced NSCLC who received RD as the second-line treatment after first-line chemoimmunotherapy at 62 Japanese institutions. Chemoimmunotherapy consisted of a platinum-based regimen and immune checkpoint inhibitors (ICIs). The association between several variables and the therapeutic outcome of RD was determined via logistic regression analysis., Results: Of the 288 patients, 225 (78.1%) received maintenance therapy and 108 (37.5%) received both ICI treatment for >180 days and maintenance therapy. All of 108 patients having ICIs for >180 days received maintenance therapy. Univariate analysis identified performance status, histology (adenocarcinoma), maintenance therapy, and ICI treatment >180 days as significant predictors of better progression-free survival (PFS) and overall survival (OS) after RD administration. Multivariate analysis confirmed that these factors independently predicted favorable PFS and OS. The therapeutic response and PD-L1 expression were not closely associated with outcome after RD treatment. In particular, maintenance therapy >4 cycles was more predictive of the better prognosis for RD treatment., Conclusion: Extended ICI treatment after chemoimmunotherapy and maintenance therapy enhanced the efficacy of second-line RD treatment in patients with advanced NSCLC., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Molecular abnormalities in the Wnt/β-catenin pathway confer malignant phenotypes in lung cancer. Previously, we identified the association of leucine-rich repeat-containing G protein-coupled receptor 6 (LGR6) with oncogenic Wnt signaling, and its downregulation upon β-catenin knockdown in non-small cell lung cancer (NSCLC) cells carrying CTNNB1 mutations. The aim of this study was to explore the mechanisms underlying this association and the accompanying phenotypes., Methods: LGR6 expression in lung cancer cell lines and surgical specimens was analyzed using quantitative RT-PCR and immunohistochemistry. Cell growth was assessed using colony formation assay. Additionally, mRNA sequencing was performed to compare the expression profiles of cells subjected to different treatments., Results: LGR6 was overexpressed in small cell lung cancer (SCLC) and NSCLC cell lines, including the CTNNB1-mutated NSCLC cell lines HCC15 and A427. In both cell lines, LGR6 knockdown inhibited cell growth. LGR6 expression was upregulated in spheroids compared to adherent cultures of A427 cells, suggesting that LGR6 participates in the acquisition of cancer stem cell properties. Immunohistochemical analysis of lung cancer specimens revealed that the LGR6 protein was predominantly overexpressed in SCLCs, large cell neuroendocrine carcinomas, and lung adenocarcinomas, wherein LGR6 overexpression was associated with vascular invasion, the wild-type EGFR genotype, and an unfavorable prognosis. Integrated mRNA sequencing analysis of HCC15 and A427 cells with or without LGR6 knockdown revealed LGR6-related pathways and genes associated with cancer development and stemness properties., Conclusions: Our findings highlight the oncogenic roles of LGR6 overexpression induced by aberrant Wnt/β-catenin signaling in lung cancer., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Circulating tumor DNA (ctDNA) provides molecular information on tumor heterogeneity. The prognostic usefulness of ctDNA after first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are limited. Therefore, the present study evaluated ctDNA during osimertinib administration as a second-line or more setting to identify the relationship between EGFR mutation levels and outcomes in patients with advanced non-small cell lung cancer (NSCLC). Forty patients with EGFR T790M-positive NSCLC receiving osimertinib after prior EGFR-TKI treatment were registered. Plasma samples were collected at osimertinib pretreatment, after 1 month of treatment, and at the time of progressive disease (PD). ctDNA analysis was performed by digital polymerase chain reaction. The detection rate of copy numbers of exon 19 deletion, L858R, and T790M in plasma samples was significantly lower 1 month after osimertinib than at pretreatment, and significantly higher at PD than at 1 month, whereas that of C797S was significantly higher at PD than at 1 month. No statistically significant difference was observed in the copy numbers of exon 19 deletion, L858R, T790M, and C797S between complete response or partial response and stable disease or PD. The detection of T790M at PD after osimertinib initiation was a significant independent prognostic factor for predicting shorter prognosis, and the presence of major EGFR mutations at pretreatment and PD was closely linked to worse survival after osimertinib initiation. Molecular testing based on ctDNA is helpful for predicting outcomes of osimertinib treatment in T790M-positive NSCLC after previous EGFR-TKI treatment., (© 2023. The Author(s).)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Thymic carcinoma (TC) is a rare thymic epithelial tumor, and advanced or recurrent TC has limited prognosis. Treatment for chemotherapy-naïve, advanced, or recurrent TC remains unchanged with the combination of carboplatin and paclitaxel; therefore, a new treatment strategy is warranted. Immune checkpoint blockades inhibiting the programmed cell death-1 (PD-1) pathway (PD-1 and its ligand, PD-L1) have shown potential as a monotherapy for TC, although the efficacy of monotherapy was moderate for previously treated TC. We hypothesized that the combination of an anti-PD-L1 antibody, atezolizumab, with carboplatin and paclitaxel, would be effective in inducing immunogenic cell death in patients with advanced or recurrent TC., Methods: We initiated a multicenter, single-arm, open-label phase II study of atezolizumab combined with carboplatin and paclitaxel for metastatic or recurrent TC. Eligible patients will receive atezolizumab plus carboplatin and paclitaxel every 3 weeks for up to 6 cycles, followed by atezolizumab every 3 weeks for up to 2 years until progression or unacceptable toxicity. A total of 47 patients will be enrolled in this study, with a 24-month enrollment period and 12-month follow-up. The primary endpoint is the objective response rate (ORR), based on an independent central review. The secondary endpoints are the investigator-assessed ORR, disease control rate, progression-free survival, duration of response, overall survival, and safety., Results: This study aims to establish the safety and efficacy of atezolizumab combined with carboplatin and paclitaxel in patients with advanced or recurrent TC., Trial Registration: Japan Registry of Clinical Trials (jRCT), jRCT2031220144. Registered on June 18, 2022, https://jrct.niph.go.jp/en-latest-detail/jRCT2031220144., Competing Interests: Disclosure TA reports honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Merck Biopharma, MSD, Nippon Kayaku, Ono, Pfizer, Taiho, and Takeda. T Shukuya reports grant support for the current study from Chugai Pharmaceutical; grant support from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, MSD, Novartis; honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, MSD, Nippon Kayaku, Novartis, Ono, Pfizer, Taiho, and Takeda. YG reports grant support for the clinical trial group from AstraZeneca, Pfizer, institutional grant support from AbbVie, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Kyorin, Novartis, Ono, Pfizer, and Preferred Networks; honoraria from Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Eli Lilly, Merck, MSD, Novartis, Ono, Pfizer, Taiho, and Thermo Fischer; participation on an advisory board for AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Guardant Health, Illumina, MSD, Novartis, Ono, Pfizer, and Taiho; and leadership or fiduciary role at Cancer Net Japan and Japanese Association of Medical Technologists. HT reports institutional grant support from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Merck Biopharma, MSD, Ono, Taiho, and Takeda; honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Eli Lilly, Merck Biopharma, MSD, Novartis, Ono, Sun Pharmaceutical, Taiho, and Takeda. K Takayama reports grant support for Chugai Pharmaceutical; honoraria from Chugai Pharmaceutical. YT reports institutional grant support for Ono and Pfizer Health Research Foundation; honoraria from AstraZeneca, Chugai Pharmaceutical, and Daiichi Sankyo. MT reports honoraria from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Novartis, Ono, and Takeda. T Suzuki reports honoraria from AstraZeneca and Boehringer Ingelheim. KK reports honoraria from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Eli Lilly, Ono, and Taiho. RK reports grant support from AstraZeneca and MSD; honoraria from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi-Sankyo, Eli Lilly, MSD, Ono, Pfizer, Taiho, and Takeda. YZ reports grant support from Amgen, AstraZeneca, Daiichi Sankyo, Merck Biopharma, and MSD; honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Eli Lilly, Kyowa Kirin, MSD, Nihon Kayaku, Novartis, Pfizer, Taiho, and Takeda. HA reports grant support from Amgen, Chugai Pharmaceutica, and MSD; honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Nippon Kayaku, Novartis, Ono, Pfizer, Taiho and Takeda; data safety monitoring or advisory board participation with Amgen, Janssen, and Sandoz; and a leadership or fiduciary role with World Conference on Lung Cancer Patient Advocate Committee. JT reports honoraria from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Janssen Pharmaceutical, MSD, Nihon Medi-Physics, Ono, Nippon Boehringer-Ingelheim, Nippon Kayaku, Taiho, and Pfizer. SI reports institutional grant support for AstraZeneca and Chugai; honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Ono, Pfizer, and Takeda. SS reports honoraria from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Kyowa Kirin, Merck Biopharma, MSD, Nippon Kayaku, Novartis, Ono, Otsuka, Pfizer, Taiho, Takeda, Thermo Fisher Scientific, Towa Pharmaceutical, and Yakult Honsha. KM reports honoraria from Chugai Pharmaceutical, Eli Lilly, and Ono. K Takahashi reports grant support from Asahi Kasei Pharma, Bayer, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Kyorin, Nippon Kayaku, Kyowa Kirin, Nippon Pharma, Nippon Shinyaku, Novartis, Ono, Sanofi, Shionogi, Taiho, Takeda, Teijin, Tsumura, and Pfizer; honoraria from Abbott, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Janssen, Kyorin, Meiji Seika Pharma, Merck Biopharma, MSD, Nippon Kayaku, Novartis, Ono, Pfizer, Sumitomo Dainippon Pharma, Taiho, Takeda, Thermo Fisher Scientific and Viatris; patent with Oncolys BioPharma; and leadership or fiduciary role with The Japan Lung Cancer Society and The Japan Respiratory Society. All other authors (HM, TM) declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Vascular endothelial growth factor (VEGF) has been identified as one of the resistant mechanisms to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). However, the relationship between the efficacy of osimertinib and protein expression of VEGF family members in patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations remains unclear., Methods: A total of 76 patients with advanced NSCLC with EGFR major mutations (del19 or L858R) receiving first-line osimertinib were eligible as the osimertinib (Osi) group, whereas 43 patients receiving first- or second-generation EGFR-TKIs were compared with the control group. The expression of vascular endothelial growth factor receptor 2 (VEGFR2) and vascular endothelial growth factor C (VEGF-C) in the tumor specimens was analyzed using immunohistochemistry., Results: VEGFR2 and VEGF-C were highly expressed in 65.8% and 51.3% of patients, respectively, in the Osi group, and 69.7% and 76.7%, respectively, in the control group. High VEGFR2 and VEGF-C levels were significantly associated with poor performance status (PS) and female sex, respectively. In the Osi group, patients with co-high expression of VEGFR2 and VEGF-C showed significantly worse progression-free survival (PFS) and overall survival (OS) than those without co-high expression. In del19, VEGFR2 was a significant predictor of PFS and OS and independent predictor of OS in multivariate analysis. In L858R, co-high expression of VEGFR2 and VEGF-C was identified as a significant predictor of PFS and OS and independent predictor of PFS., Conclusion: VEGFR2 and VEGF-C are highly expressed in EGFR-mutant NSCLC cells. Increased expression of VEGFR2 was identified as a significant prognostic factor in patients with EGFR del19 mutation who received osimertinib, whereas co-high expression of VEGFR2 and VEGF-C was a significant predictor for those with EGFR L858R mutation., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Factors predicting the response to pembrolizumab plus platinum and pemetrexed combination therapy (Pemb-Plt-PEM) in nonsquamous non-small cell lung cancer (non-sq NSCLC) are unclear. We investigated the Glasgow Prognostic (GP) score, neutrophil-to-lymphocyte ratio (NLR), and body mass index (BMI) as predictors of response to initial treatment with combination therapy in individuals with advanced non-sq NSCLC., Methods: We retrospectively reviewed 236 patients who received initial treatment with combination therapy for non-sq NSCLC at 13 institutions between December 2018 and December 2020. The usefulness of the GP score, NLR, and BMI as prognostic indicators was assessed. Cox proportional hazard models and the Kaplan-Meier method were used to compare progression-free survival (PFS) and overall survival (OS)., Results: The response rate was 51.2% (95% CI: 44.9-57.5%). The median PFS and OS after beginning Pemb-Plt-PEM were 8.8 (95% CI: 7.0-11.9) months and 23.6 (95% CI: 18.7-28.6) months, respectively. The NLR independently predicted the efficacy of Pemb-Plt-PEM-the PFS and OS were more prolonged in individuals with NLR <5 than in those with NLR ≥5 (PFS: 12.8 vs. 5.3 months, p = 0.0002; OS: 29.4 vs. 12.0 months, p < 0.0001). BMI predicted the treatment response-individuals with BMI ≥22.0 kg/m 2 had longer OS than did those with BMI < 22.0 kg/m 2 (OS: 28.4 vs. 18.4 months, p = 0.0086)., Conclusions: The NLR significantly predicted PFS and OS, whereas BMI predicted OS, in individuals who initially received Pemb-Plt-PEM for non-sq NSCLC. These factors might be prognosis predictors in non-sq NSCLC., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Perioperative immune checkpoint inhibitors have been shown to improve prognosis in early-stage lung cancer. However, no biomarkers are known to indicate the requirement for treatment. This study aimed to identify T-cell clusters responsible for antitumor immunity in patients with early-stage lung cancer. Preoperative blood samples from 50 consecutive patients with lung cancer who were diagnosed as operable and underwent complete resection were analyzed by mass cytometry. Patients were divided into two groups: no recurrence at a minimum observation period of 851 days (median observation period: 1,031.5 days) and recurrence by the last observation date. Mass cytometry and single-cell RNA sequencing analysis of lymph nodes (LN) and tumor-infiltrating T cells were also performed. CCR4 - CCR6 + Th7R showed discriminative ability between recurrence and non-recurrence patients with lung cancer. Patients with more than 3.04% Th7R showed significantly favorable disease-free survival. Th7R was a major component of CD4 + T cells in tumor microenvironments and LNs adjacent to lung cancer tissues and was the only cluster that decreased in peripheral blood after the removal of cancer tissues, suggesting that Th7R was primed and proliferated in tumor-draining LNs in the presence of cancer tissues. Th7R had the kinetics that antitumor T cells should have, as indicated by the cancer immunity cycle; thus, peripheral blood Th7R could represent the potency of tumor immunity by reflecting priming and proliferation in tumor-draining LNs and Th7R in the tumor microenvironment. Prediction using peripheral Th7R before surgery could allow the selection of patients who require perioperative drug therapy and optimize therapeutic interventions with clinical implications., Significance: Peripheral Th7R, a Th1-like CD4 + T-cell cluster reflecting priming status in draining LNs and immune status in the tumor microenvironment, predicts disease-free survival after complete resection and has significant clinical relevance in selecting appropriate therapeutic interventions in patients with early-stage lung cancer., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Background: Ramucirumab plus docetaxel (RD) is a promising treatment for previously treated advanced non-small cell lung cancer (NSCLC). However, its clinical significance after platinum-based chemotherapy plus programmed death-1 (PD-1) blockade remains unclear., Research Question: What is the clinical significance of RD as a second-line treatment after the failure of chemo-immunotherapy in NSCLC?, Study Design and Methods: In this multicentre retrospective study, 288 patients with advanced NSCLC who received RDas second-line therapy after platinum-based chemotherapy plus PD-1 blockade, at 62 Japanese institutions from January 2017 to August 2020, were included. Prognostic analyses were performed using the log-rank test. Prognostic factor analyses were performed using a Cox regression analysis., Results: A total of 288 patients were enrolled: 222 were men (77.1%), 262 were aged <75 years (91.0%), 237 (82.3%) had smoking history and 269 (93.4%) had a performance status (PS) of 0-1. One hundred ninety-nine patients (69.1%) were classified as adenocarcinoma (AC) and 89 (30.9%) as non-AC. The types of PD-1 blockade used in the first-line treatment were anti-PD-1 antibody and anti-programmed death-ligand 1 antibody in 236 (81.9%) and 52 (18.1%) patients, respectively. The objective response rate for RD was 28.8% (95% confidence interval [CI], 23.7-34.4). The disease control rate was 69.8% (95% CI, 64.1-75.0).The median progression free survival and overall survival were 4.1 months (95% CI, 3.5-4.6) and 11.6 months (95% CI, 9.9-13.9), respectively. In a multivariate analysis, non-AC and PS 2-3 were independent prognostic factors for worse progression free survival , while bone metastasis on diagnosis, PS 2-3 and non-AC were identified as independent prognostic factors for poor overall survival., Interpretation: RD is a feasible second-line treatment in patients with advanced NSCLC who had received combined chemo-immunotherapy with PD-1 blockade., Clinical Trial Registration Number: UMIN000042333., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Pheromone-based technology benefits bee breeding and health to bolster food security.

Background: Constipation is a concern among patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 3 and 4. Objectives: To assess naldemedine's efficacy and safety in cancer patients on opioids with poor PS. Design: Multicenter, retrospective study. Setting/Subjects: Japanese cancer patients with ECOG performance status 3 or 4 who received naldemedine. Measurements: Frequency of defecations before/after naldemedine use. Responders were patients whose defecation frequency increased to ≥3 times/week, from baseline ≥1 defecations/week over seven days after naldemedine administration. Results: Seventy-one patients were analyzed; 66.1% were responders (95% confidence interval: 54.5%-76.1%). Defecation frequency increased significantly after naldemedine in the overall population (6 vs. 2, p  < 0.0001) and among those who defecated <3 times/week before naldemedine (4.5 vs. 1, p  < 0.0001). Diarrhea (38.0%) of all grades was the most common adverse event; 23 (85.2%) events were classified as Grade 1 or 2. Conclusion: Naldemedine is effective and safe among cancer patients with poor PS.

Background and Objectives : Opioid analgesics, which are used for cancer-related pain management, cause opioid-induced constipation (OIC). Naldemedine, a peripheral opioid receptor antagonist, is an OIC-modifying agent, but no focused efficacy and safety analysis has been conducted for its use in hepatobiliary pancreatic cancers. We performed a multi-institutional study on the efficacy and safety of naldemedine in patients with hepatobiliary pancreatic cancer using opioids in clinical practice. Materials and Methods : We retrospectively evaluated patients with hepatobiliary pancreatic cancer (including liver, biliary tract, and pancreatic cancers) treated with opioids and naldemedine during hospitalization at ten institutions in Japan from June 2017 to August 2019. We assessed the frequency of bowel movements before and after the initiation of naldemedine therapy. Responders were defined as patients who defecated ≥3 times/week, with an increase from a baseline of ≥1 defecations/week over seven days after the initiation of naldemedine administration. Results : Thirty-four patients were observed for one week before and one week after starting naldemedine. The frequency of bowel movements increased by one over the baseline frequency or to at least thrice per week in 21 patients. The response rate was 61.7% (95% confidence interval: 45.4-78.0%). The median number of weekly bowel movements before and after naldemedine treatment was 2 (range: 0-9) and 6 (range: 1-17), respectively, in the overall population (n = 34); the increase in the number of bowel movements following naldemedine administration was statistically significant (Wilcoxon signed-rank test, p < 0.0001). Diarrhea was the predominant gastrointestinal symptom, and 10 (29.4%) patients experienced grade 1, grade 2, or grade 3 adverse events. The only other adverse event included fatigue in one patient; grade 2-4 adverse events were absent. Conclusions : Naldemedine is effective, and its use may be safe in clinical practice for patients with hepatobiliary pancreatic cancer receiving opioid analgesics.

Purpose: To compare different response criteria using computed tomography (CT) and positron emission tomography (PET) in measuring response and survival in the early phase after programmed death-1 (PD-1) blockade monotherapy in patients with advanced non-small cell lung cancer (NSCLC)., Methods: A total of 54 patients with advanced NSCLC who had 2-deoxy-2-[fluorine-18]-fluoro-D-glucose PET or CT at baseline, and 4 and 9 weeks after PD-1 blockade, were registered. Therapeutic response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST), the immune-modified RECIST (irRECIST), the PET Response Criteria in Solid Tumors (PERCIST), the immune-modified PERCIST (iPERCIST), and the European Organization for Research and Treatment of Cancer (EORTC) criteria for dichotomous groups, such as responders vs. non-responders and controlled vs. uncontrolled diseases. Cohen's κ was used to evaluate the concordance among the different criteria., Results: The concordance between CT and PET response criteria was fair or slight for responders vs. non-responders, but the agreement between iPERCIST and irRECIST was moderate for controlled vs. uncontrolled diseases. The agreement between EORTC and PERCIST or iPERCIST in detecting responders was higher in the application of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) than in the standardized uptake value corrected for lean body mass (SUL) peak . To distinguish controlled from uncontrolled disease, RECIST, irRECIST, and PET criteria (PERCIST, iPERCIST, and EORTC) defined by MTV or TLG were found to be significant predictors of progression-free survival. To distinguish responders from non-responders, iPERCIST by SUL peak or EORTC by TLG were identified as significant indicators. The EORTC criteria using TLG for the detection of responders or uncontrolled diseases had a significantly higher predictive value for response assessment., Conclusions: The EORTC criteria based on TLG for the early detection of responders and uncontrolled disease were effective as a response assessment at 4 weeks after the PD-1 blockade. When SUL peak was not used but MTV or TLG was, the agreement between EORTC and PERCIST or iPERCIST was almost perfect., (© 2023. The Author(s).)

Mature sperm from Culex pipiens were isolated and analyzed by mass spectrometry to generate a mature sperm proteome dataset. In this study, we highlight subsets of proteins related to flagellar structure and sperm motility and compare the identified protein components to previous studies examining essential functions of sperm. The proteome includes 1700 unique protein IDs, including a number of uncharacterized proteins. Here we discuss those proteins that may contribute to the unusual structure of the Culex sperm flagellum, as well as potential regulators of calcium mobilization and phosphorylation pathways that regulate motility. This database will prove useful for understanding the mechanisms that activate and maintain sperm motility as well as identify potential molecular targets for mosquito population control., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Thaler et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

To the best of our knowledge, no published reports have examined the significance of additional immune checkpoint inhibitors in treating malignancies, including lung cancer. Therefore, the present study aimed to examine the efficacy and feasibility of adding atezolizumab to carboplatin and etoposide combination chemotherapy for small cell lung cancer with extensive disease (ED-SCLC). The present retrospective analysis examined 16 patients with ED-SCLC who received the addition of atezolizumab to carboplatin and etoposide therapy during treatment at four institutions between August 2019 and September 2020. The effectiveness of treatment was evaluated based on tumor response, survival time and adverse events. Within the study cohort, there were 14 males (87.5%) and 2 females (12.5%), with a median age of 73.5 years (range, 62-79 years); 7 patients had a performance status (PS) of 0-1 (43.8%) and 9 had a PS of 2-3 (56.3%). The median follow-up period was 12.1 months. The overall response rate, median progression-free survival time and median overall survival time were 75.0%, 5.3 and 13.0 months, respectively. Regarding the frequency of hematological adverse events, the occurrence of grade ≥3 adverse events was observed, including decreased neutrophil (56.3%), white blood cell (50.0%) and platelet (43.8%) counts, as well as febrile neutropenia (12.5%). Although 1 patient developed grade 3 pneumonitis as a serious adverse event, no treatment-related deaths were observed. Despite the aforementioned hematological toxicities, the addition of atezolizumab to carboplatin and etoposide therapy during treatment demonstrated favorable efficacy and acceptable toxicity in ED-SCLC. Thus, adding atezolizumab to carboplatin and etoposide combination chemotherapy may be a treatment option for ED-SCLC., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Tsuda et al.)

Background/aim: Efficacy and toxicity of concurrent chemoradiotherapy (CCRT) and durvalumab for locally advanced non-small cell lung cancer (LA-NSCLC) with N3 lymph node metastasis remain unclear. We aimed to evaluate the clinical outcomes of patients who received CCRT and durvalumab (durvalumab cohort) and compare their outcomes with those of patients who received CCRT alone (CCRT-alone cohort)., Patients and Methods: The data of patients who had received treatment between November 2008 and February 2022 and were followed up for at least 3 months were retrospectively analyzed. Local control, progression-free survival, and overall survival were evaluated using Kaplan-Meier analysis and compared using the log-rank test. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events version 5.0., Results: The data of 29 patients were analyzed (median follow-up period: 22 months). Among them, 17 received CCRT alone and 12 received CCRT and durvalumab. There were 14 patients with stage IIIB and 15 with stage IIIC LA-NSCLC. The durvalumab cohort (89%) had a significantly higher 1-year local control rate than the CCRT-alone cohort (47%; p=0.035). No significant difference was observed in either progression-free or overall survival between the two cohorts. Grade ≥2 pneumonitis was observed in 6 (50%) and 7 (41%) patients in the durvalumab and CCRT-alone cohorts, respectively., Conclusion: CCRT with durvalumab may be effective against LA-NSCLC with N3 lymph node metastasis. The incidence of grade 2 pneumonitis was slightly higher in the durvalumab cohort than in the CCRT-alone cohort, suggesting the need for careful patient monitoring after treatment., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The mammalian target of rapamycin (mTOR) is often activated in several cancers. We focused on two mTOR regulatory mechanisms: oxaliplatin-induced mTOR signaling and L-type amino acid transporter 1 (LAT1)-induced mTOR activation. High LAT1 expression in several cancers is associated with mTOR activation and resistance to chemotherapy. However, the significance of LAT1 has not yet been elucidated in colorectal cancer (CRC) patients treated with post-operative adjuvant chemotherapy. Immunohistochemistry was conducted to examine the significance of membrane LAT1 expression in 98 CRC patients who received adjuvant chemotherapy, including oxaliplatin. In vitro analysis was performed using CRC cell lines to determine the effects of LAT1 suppression on proliferation, oxaliplatin sensitivity, and mTOR signaling. LAT1 expression was associated with cancer aggressiveness and poor prognosis in 98 CRC patients treated with adjuvant chemotherapy. We found that positive LAT1 expression correlated with shorter survival in 43 patients treated with the capecitabine-plus-oxaliplatin (CAPOX) regimen. LAT1 suppression in CRC cells inhibited the proliferation potency and oxaliplatin-induced activation of mTOR signaling, and improved oxaliplatin sensitivity. LAT1 evaluation before adjuvant treatment may therefore be a sensitive marker for oxaliplatin-based regimens. Moreover, LAT1 may be a promising target for patients with refractory CRC.

Background: There are no established predictive biomarkers for the effectiveness of first-line atezolizumab plus carboplatin and etoposide therapy in patients with small-cell lung cancer (SCLC). Therefore, the current study aimed to investigate whether the Glasgow prognostic score (GPS), neutrophil-to-lymphocyte ratio (NLR), and body mass index (BMI) can predict the effectiveness of first-line atezolizumab plus carboplatin and etoposide therapy in patients with extensive-disease SCLC., Methods: We reviewed data from 84 patients who received first-line atezolizumab plus carboplatin and etoposide therapy for SCLC at nine Japanese institutions between August 2019 and May 2021. Further, we evaluated the prognostic value of the GPS, NLR, and BMI. The Kaplan-Meier and Cox proportional hazard models were used to examine differences in progression-free survival (PFS) and overall survival (OS). Moreover, the GPS, NLR, and BMI consisted of C-reactive protein and albumin concentrations, neutrophil and lymphocyte counts, and body weight and height, respectively., Results: The response rate was 72.6% (95% confidence interval: 63.0-82.1%). The median PFS and OS from the initiation of treatment were 5.4 (95% CI: 4.9-5.9) months and 15.4 (95% CI: 11.4-16.8) months, respectively. The GPS independently predicted the effectiveness of first-line atezolizumab plus carboplatin and etoposide treatment, as a favorable GPS (GPS 0-1) was correlated with significantly better PFS and OS rates compared to a poor GPS (GPS 2) (PFS: 5.8 vs. 3.8 months, p = 0.0005; OS: 16.5 vs. 8.4 months, p <0.0001)., Conclusions: This is the first analysis to evaluate the association between the GPS, NLR, and BMI and the treatment effectiveness of survival among patients receiving first-line atezolizumab plus carboplatin and etoposide therapy for SCLC. Among patients receiving this treatment for SCLC, GPS was significantly associated with the PFS and OS rates, suggesting that GPS might be useful for evaluating therapeutic outcomes in these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wasamoto, Imai, Tsuda, Nagai, Minemura, Yamada, Umeda, Kishikawa, Shiono, Kozu, Shiihara, Yamaguchi, Mouri, Kaira, Kanazawa, Taniguchi, Kaburagi, Minato and Kagamu.)

Aim: Tumor-infiltrating lymphocytes (TILs) in the tumor and stroma are expected to accurately predict the efficacy of programmed death-1 (PD-1) blockade therapy. However, little is known about the prognostic significance of TILs in first-line PD-1 therapy. We assessed TILs in patients with advanced or metastatic non-small cell lung cancer (NSCLC) treated with pembrolizumab in the palliative setting., Methods: Multiplex immunohistochemistry staining of TILs (CD4, CD8, Foxp3, and PD-1) and immunohistochemical staining of CK and PD-L1 in the tumor and stroma was performed in tumor specimens of 107 NSCLC patients and correlated with clinical outcomes, as a single-center retrospective study. TILs and programmed death ligand-1 (PD-L1) were assessed on biopsies (N = 93) or surgical resections (N = 14) before first-line pembrolizumab., Results: A low number of stromal CD4 TILs were significantly associated with bone metastasis and poor performance status (PS). The median progression-free survival (PFS) and overall survival (OS) were significantly higher in patients with a high number of stromal CD4 TILs (336 days and 731 days, respectively) than in those with low infiltration (204 days and 333 days, respectively). Patients with a high number of intratumoral CD8 TILs (731 days) yielded significantly better OS than those with low infiltration (333 days), but not for PFS. Multivariate analysis confirmed that stromal CD4 TILs were independent predictors of PFS, but not OS. Furthermore, intratumoral CD8 TILs were independent predictors of better OS. In the survival analysis of key subgroups, stromal CD4 TILs were identified as significant predictors of survival in patients with non-adenocarcinomatous histology and PD-L1 ≥ 50%., Conclusion: Stromal CD4 TILs were identified as a significant marker for predicting the PFS after pembrolizumab therapy, especially in patients with non-adenocarcinoma and high PD-L1 expression. In addition, intratumoral CD8 TILs were identified as significant predictors of OS., (© 2023. The Author(s).)

Purpose: The aim of this study was to assess the effectiveness and tolerability of atezolizumab plus carboplatin and etoposide combination chemotherapy in elderly patients with extensive-disease (ED) small-cell lung cancer (SCLC)., Methods: This retrospective study evaluated 65 SCLC patients who received atezolizumab, carboplatin, and etoposide for ED-SCLC in nine study institutions between August 2019 and September 2020. Clinical efficacy, assessed according to response rate and survival, and toxicity were compared between the elderly (n = 36 patients; median age: 74 years [range: 70-89 years]) and the non-elderly group (n = 29 patients; median age: 67 years [range: 43-69 years])., Results: The response rate was 73.8% (80.5% in the elderly group and 65.5% in the non-elderly group). There was no significant difference in both the median progression-free survival (5.5 months vs. 4.9 months, p = 0.18) and the median overall survival (15.4 months vs. 15.9 months, p = 0.24) between the elderly group and the non-elderly group. The frequencies of grade ≥3 hematological adverse events in the elderly patients were as follows: decreased white blood cells, 36.1%; decreased neutrophil count, 61.1%; decreased platelet count, 8.3%; and febrile neutropenia, 8.3%. One treatment-related death due to lung infection occurred in the elderly group., Conclusion: Despite hematologic toxicities, especially decreased neutrophil count, atezolizumab, carboplatin, and etoposide combination chemotherapy demonstrates favorable effectiveness and acceptable toxicity in elderly patients. Thus, atezolizumab plus carboplatin and etoposide could be the preferred standard treatment modality for elderly patients with ED-SCLC., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Nivolumab, an immune checkpoint inhibitor is the first-line therapy for platinum-resistant recurrent/metastatic head and neck cancer, and highly effective for some patients. However, no factors have been identified that could predict response or prognosis after nivolumab administration. We retrospectively investigated the association between tumor infiltrating lymphocytes (TILs) of initial pathology and prognosis in patients treated with nivolumab. Twenty-eight patients with human papilloma virus and Epstein-Barr virus unrelated head and neck squamous cell carcinoma were enrolled. CD8 + cells, FoxP3 + cells and FoxP3 - CD4 + cells in the tumoral and peritumoral stromal area and PD-L1 were measured. In result, FoxP3 - CD4 + TIL, FoxP3 + TIL, and CD8 + TIL were not correlated with survival in either intratumoral and stromal area. In univariate analysis, objective response was significant prognostic factor both in progression-free survival and overall survival (p = 0.01, 0.006, respectively). PD-L1 was also significant prognostic factor both in progression-free survival and overall survival (p = 0.01, 0.01, respectively). ECOG Performance status was a significant prognostic factor in overall survival (p = 0.0009). In the combined analysis of stromal CD8 + TIL and PD-L1, PD-L1 positive with high stromal CD8 + TIL subgroups had a better prognosis than PD-L1 negative with low stromal CD8 + TIL subgroups in progression-free survival (p = 0.006). Although these results require a further investigation, PD-L1 and ECOG Performance status and the combination of stromal CD8 + TIL and PD-L1 positivity have potential as useful prognostic markers in patients of virus unrelated head and neck squamous cell carcinoma treated with nivolumab., (© 2022. The Author(s).)

Background: The standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT) followed by durvalumab, based on the PACIFIC study. Although multiple Japanese phase II studies have shown high efficacy and tolerability of CRT with cisplatin plus S-1 (SP), no prospective study using durvalumab after SP-based CRT has been reported., Objectives: We conducted a multicenter phase II study of this approach, the interim analysis of which showed a high transition rate to durvalumab consolidation therapy. Here, we report the primary analysis results., Design: In treatment-naïve LA-NSCLC, cisplatin (60 mg/m 2 , day 1) and S-1 (80-120 mg/body, days 1-14) were administered with two 4-week cycles with concurrent thoracic radiotherapy (60 Gy) followed by durvalumab (10 mg/kg) every 2 weeks for up to 1 year., Methods: The primary endpoint was 1-year progression-free survival (PFS). The expected 1-year PFS and its lower limit of the 80% confidence interval (CI) were set as 63% and 47%, respectively, based on the results of TORG1018 study., Results: In all, 59 patients were enrolled, with 51 (86.4%) proceeding to durvalumab. The objective response rate throughout the study was 72.9% (95% CI: 59.7-83.6%). After median follow-up of 21.9 months, neither median PFS nor OS was reached. The 1-year PFS was 72.5% (80% CI: 64.2-79.2%, 95% CI: 59.1-82.2%), while the 1-year overall survival was 91.5% (95% CI: 80.8-96.4%). No grade 5 adverse events were observed throughout the study. The most common adverse event during the consolidation phase was pneumonitis (any grade, 78.4%; grade ⩾3, 2.0%). Eventually, 52.5% of patients completed 1-year durvalumab consolidation therapy from CRT initiation., Conclusion: This study of durvalumab after SP-based CRT met its primary endpoint and found a 1-year PFS of 73% from CRT initiation. This study provides the first prospective data on the prognosis and tolerability of durvalumab consolidation from the initiation of CRT., Trial Registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127., Competing Interests: H.T. received personal fees as honoraria from Boehringer Ingelheim, AstraZeneca, Pfizer, Chugai Pharmaceutical, Bristol-Myers Squibb, and Ono Pharmaceutical. S.T. received research funding from AstraZeneca, and personal fees as honoraria from AstraZeneca, Chugai Pharmaceutical, Taiho Pharmaceutical, and Eli Lilly. T.Misu. received personal fees as honoraria from Chugai Pharmaceutical and AstraZeneca. S.K. received personal fees as honoraria from Chugai Pharmaceutical, Bristol-Myers Squibb, Boehringer Ingelheim, AstraZeneca, Pfizer, Eli Lilly, MSD, Taiho Pharmaceutical, Sanofi, Kyowa Kirin, Hisamitsu Pharmaceutical, Daiichi Sankyo, Nippon Kayaku, and Novartis. N.I. received personal fees as honoraria from AstraZeneca. K.Kusa. received personal fees as honoraria from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, and Nippon Kayaku. N.F. received personal fees as honoraria from Bristol-Myers Squibb, Ono Pharmaceutical, Boehringer Ingelheim, and AstraZeneca. Y.F. received personal fees as honoraria from Bristol-Myers Squibb, Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Novartis, Merck Biopharma, MSD, Boehringer Ingelheim, Taiho Pharmaceutical, and Daiichi Sankyo. T.T. received personal fees as honoraria from Chugai Pharmaceutical. K.Shib. received personal fees as honoraria from AstraZeneca, Taiho Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, and Ono Pharmaceutical. A.B. received research funding from AstraZeneca and personal fees as honoraria from AstraZeneca and Taiho Pharmaceutical. K.Kair. received research funding from AstraZeneca and Nihon Medi-Physics and personal fees as honoraria from Ono Pharmaceutical, Boehringer Ingelheim, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, AstraZeneca, and Pfizer. N.S. received research funding from Ono Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Chugai Pharmaceutical, Eisai, Daiichi Sankyo, Takeda Pharmaceutical, Shionogi, Nippon Kayaku, and Pfizer, and personal fees as honoraria from Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Boehringer Ingelheim, MSD, Daiichi Sankyo, Novartis, Bristol-Myers Squibb, Pfizer, Takeda Pharmaceutical, and Nippon Kayaku. No potential conflicts of interest were disclosed by the other authors., (© The Author(s), 2022.)

Background: Biomarkers that can accurately predict the efficacy of immune checkpoint inhibitors (ICIs) against programmed death 1 (PD-1) ligand in cancer immunotherapy are urgently needed. We have previously reported a novel formula that predicts the response to treatment with second-line nivolumab with high sensitivity and specificity in patients with non-small cell lung cancer (NSCLC) previously treated with chemotherapy. The formula was based on the percentages of CD62L low CD4 + T cells (effector T cells; %Teff) and CD4 + CD25 + FOXP3 + T cells (regulatory T cells; %Treg) in the peripheral blood before treatment estimated using the peripheral blood mononuclear cell (PBMC) method. Here, we investigated the applicability of the formula (K-index) to predict the response to treatment with another ICI to expand its clinical applicability. Furthermore, we developed a simpler assay method based on whole blood (WB) samples to overcome the limitations of the PBMC method, such as technical difficulties, in obtaining the K-index., Methods: The K-index was evaluated using the PBMC method in 59 patients with NSCLC who received first-line pembrolizumab treatment. We also assessed the K-index using the WB method and estimated the correlation between the measurements obtained using both methods in 76 patients with lung cancer., Results: This formula consistently predicted the response to first-line pembrolizumab therapy in patients with NSCLC. The WB method correlated well with the PBMC method to obtain %Teff, %Treg, and the formula value. The WB method showed high repeatability (coefficient of variation, < 10%). The data obtained using WB samples collected in tubes containing either heparin or EDTA-2K and stored at room temperature (18-24 °C) for one day after blood sampling did not differ. Additionally, the performance of the WB method was consistent in different flow cytometry instruments., Conclusions: The K-index successfully predicted the response to first-line therapy with pembrolizumab, as reported earlier for the second-line therapy with nivolumab in patients with NSCLC. The WB method established in this study can replace the cumbersome PBMC method in obtaining the K-index. Overall, this study suggests that the K-index can predict the response to anti-PD-1 therapy in various cancers, including NSCLC., (© 2022. The Author(s).)

CD4+ T-cell immunity helps clonal proliferation, migration, and cancer cell killing activity of CD8+ T cells and is essential in antitumor immune responses. To identify CD4+ T-cell clusters responsible for antitumor immunity, we simultaneously analyzed the naïve-effector state, Th polarization, and T-cell receptor clonotype based on single-cell RNA-sequencing data. Unsupervised clustering analysis uncovered the presence of a new CD4+ T-cell metacluster in the CD62Llow CD4+ T-cell subpopulation, which contained multicellular clonotypes associated with efficacy of programmed death-ligand 1 (PD-1) blockade therapy. The CD4+ T-cell metacluster consisted of CXCR3+CCR4-CCR6+ and CXCR3-CCR4-CCR6+ cells and was characterized by high expression of IL7 receptor and TCF7. The frequency of these cells in the peripheral blood significantly correlated with progression-free survival and overall survival of patients with lung cancer after PD-1 blockade therapy. In addition, the CD4+ metacluster in the peripheral blood correlated with CD4+ T-cell infiltration in the tumor microenvironment, whereas peripheral Th1 correlated with local CD8+ T-cell infiltration. Together, these findings suggest that CD62Llow CCR4-CCR6+ CD4+ T cells form a novel metacluster with predictive potential of the immune status and sensitivity to PD-1 blockade, which may pave the way for personalized antitumor immunotherapy strategies for patients., Significance: The identification of a new CD4+ T-cell metacluster that corresponds with immune status could guide effective tumor treatment by predicting response to immunotherapy using peripheral blood samples from patients., (©2022 The Authors; Published by the American Association for Cancer Research.)

Angiogenesis serves a crucial role in cancer progression. Vascular endothelial growth factor (VEGF) exhibits an immunosuppressive function in patients with cancer. However, it remains unclear whether expression of VEGF in tumor tissue can predict the outcome of programmed death‑1 blockade in patients with advanced non‑small cell lung cancer (NSCLC). A training (n=32) and validation (n=76) cohort of patients with advanced NSCLC who received first‑line pembrolizumab were enrolled. Immunohistochemical staining for VEGF receptor 2 (VEGFR2) and tumor‑infiltrating lymphocytes (TILs; CD4, CD8 and FOXP3) was performed in tumor specimens of both cohorts and association with clinical outcomes was assessed. The percentages of high VEGFR2 expression were 34.3% (11/32) in training cohort and 25.0% (19/76) in validation cohort. No statistically significant difference in objective response between high and low VEGFR2 expression was observed for training (27.2 vs. 45.0%) and validation (31.2 vs. 35.7%) cohorts. The positive rate of intratumoral FOXP3 was significantly associated with high VEGFR2 expression for validation cohort, but not training cohort. In validation cohort, high VEGFR2 expression in patients with non‑adenocarcinoma (non‑AC) was significantly correlated with positive FOXP3 TILs in intratumoral and stromal sites, but not CD4 and CD8. High VEGFR2 expression in both cohorts indicated a significantly worse overall survival (OS) than low VEGFR2 expression. VEGFR2 was identified as an independent prognostic marker associated with worse OS. High VEGFR2 expression was a significant marker for predicting worse OS in patients treated with first‑line pembrolizumab, particularly in those with non‑AC.

Background: In this study, we developed a simple method for evaluating achievement degree of lung dose optimization in individual patients with locally advanced non-small cell lung cancer (NSCLC) treated with intensity modulated radiotherapy (IMRT)., Methods: Data of 28 patients with stage IIB to IIIC NSCLC were retrospectively analyzed. All patients were treated with IMRT and a simulated three-dimensional conformal radiotherapy (3D-CRT) plan created for them. Dose-volume parameters of lung were analyzed for their correlation with radiation pneumonitis (RP)., Results: Over a median follow-up of 14 months, grade 1 pneumonitis was diagnosed in 14 patients (50%), grade 2 pneumonitis in 11 (39%), and grade 3 pneumonitis in one (4%). Two patients did not develop pneumonitis. None of the patients developed grade 4 or 5 pneumonitis. Regarding dose-volume parameter ratios between IMRT and simulated 3D-CRT, receiver operating characteristic analysis showed that mean lung dose (MLD) IMRT /MLD 3D-CRT had the largest area under curve (0.750). Cumulative 6-month incidences of grade 2 or greater RP were 78.4% versus 19.5% (MLD IMRT /MLD 3D-CRT, ≥1.0 or less); this difference was significant (p < 0.05)., Conclusions: We found that cutoff values for dose volume parameter ratios significantly predict grade 2 or greater RP. We believe that these parameter ratios could be useful in assisting evaluation of achievement degree of lung dose optimization in IMRT for LA-NSCLC., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Combined chemotherapy plus programmed death-1 (PD-1) blockade is an established treatment against patients with advanced non-small cell lung cancer (NSCLC). However, a promising predictor besides programmed death ligand-1 expression remains uncertain. We examined the prognostic significance of baseline 18 F-FDG-positron emission tomography for predicting first-line combined chemotherapy plus PD-1 blockade in NSCLC patients. Forty-five patients with advanced NSCLC who received 18 F-FDG-positron emission tomography immediately before combined platinum-based chemotherapy with PD-1 blockade as first-line setting were eligible for this study, and assessment of maximum of standard uptake value (SUV max ), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) on 18 F-FDG uptake was performed. The objective response rate, median progression-free survival, and overall survival were 51.2%, 206 days, and 681 days, respectively. High SUV max , TLG, and MTV significantly correlated with age and performance status (PS), C-reactive protein (CRP), and PS, CRP, albumin, and baseline tumor size, respectively. Univariate analysis identified albumin, TLG and MTV as significant predictors of progression-free survival, and CRP, albumin, TLG and MTV as significant factors for predicting overall survival. High TLG was confirmed as an independent factor associated with poor prognosis in multivariate analysis. In particular, TLG is identified as the most powerful predictor in patients with good PS, adenocarcinoma, programmed death ligand-1≥1%, and low baseline tumor size. The tumor metabolic volume by MTV and TLG at pretreatment was clarified as a significant predictor for combined chemotherapy with PD-1 blockade, but not maximal glycolytic level by SUV max ., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The effect of first-line chemotherapy on overall survival (OS) may be significantly influenced by subsequent therapy for patients with extensive disease small cell lung cancer (ED-SCLC). Therefore, we evaluated the relationship between progression-free survival (PFS), post-progression survival (PPS), and OS of ED-SCLC patients treated with atezolizumab plus carboplatin and etoposide as first-line therapy., Methods: We analyzed the data of 57 patients with relapsed ED-SCLC treated with atezolizumab plus carboplatin and etoposide (AteCE) as first-line chemotherapy between August 2019 and September 2020. The respective correlations between PFS-OS and PPS-OS following first-line AteCE treatment were examined at the individual patient level., Results: Spearman's rank correlation analysis and linear regression analysis showed that PPS strongly correlated with OS (r = 0.93, p < 0.05, R 2  = 0.85) and that PFS moderately correlated with OS (r = 0.55, p < 0.05, R 2  = 0.28). Performance status at relapse (0-1/≥2), number of cycles of atezolizumab maintenance therapy (<3/≥3), and platinum rechallenge chemotherapy all significantly positively correlated with PPS (p < 0.05)., Conclusions: Upon comparing OS-PFS and OS-PPS in this patient population, OS and PPS were found to have a stronger correlation. These results suggest that performance status at relapse, atezolizumab maintenance, or chemotherapy rechallenge could affect PPS., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

This study examined the activity and safety of amrubicin monotherapy among relapsed small-cell lung cancer (SCLC) patients who had previously been treated with atezolizumab plus carboplatin and etoposide (AteCE). This retrospective study evaluated patients with relapsed SCLC who were treated with previously AteCE combination therapy followed by amrubicin monotherapy between August 2019 and May 2021. Clinical efficacy and toxicity were analyzed. Overall, 40 patients were included: 12 and 28 patients had sensitive and refractory relapse, respectively. The response rate was 32.5% (25.0% in the sensitive group and 35.7% in the refractory group). The median progression-free survival (PFS) and overall survival (OS) from the first amrubicin treatment was 3.4 months (95% CI: 1.9-4.9 months) and 9.9 months (95% CI: 4.5-11.5 months), respectively. There was no significant between-group difference in median PFS (3.6 months vs. 3.2 months, p = 0.42) or median OS (11.2 months vs. 7.3 months, p = 0.78). Grade ≥ 3 hematological adverse events occurred as follows: decreased white blood cells in 52.5% of patients; decreased neutrophil count in 57.5%; and febrile neutropenia in 10.0%. Grade 3 pneumonitis was observed in one patient. There were no treatment-related deaths. Amrubicin is feasible and effective for relapsed SCLC patients previously treated with AteCE therapy. Although immune checkpoint inhibitor treatment (ICI) does not improve the effect of amrubicin, the toxicity is not increased, suggesting that amrubicin remains effective even after ICI administration. Thus, amrubicin after AteCE could be the preferred standard chemotherapeutic choice in patients with relapsed SCLC., (© 2022. The Author(s).)

The linear ubiquitin chain assembly complex (LUBAC), which is composed of RING finger protein 31 (RNF31), RANBP2-type and C3HC4-type zinc finger containing 1 and SHANK-associated RH domain interactor subunits, is the only ubiquitin ligase to generate Met1-linked linear ubiquitin chains. Linear ubiquitin chains regulate canonical NF-κB activation and cell death. Single nucleotide polymorphisms in RNF31, such as Q584H and Q622L, are known to cause the activated B cell-like subtype of diffuse large B cell lymphoma (ABC-DLBCL) because of enhanced LUBAC-mediated NF-κB activation. The present study identified a novel Q622H polymorphism of RNF31 in two patients with lung cancer, one of whom had concurrent ABC-DLBCL. Immunohistochemical analyses revealed that although the expression of RNF31 was elevated in both patients, only the ABC-DLBCL specimen showed increased NF-κB activation. Cancer panel analysis showed that the Q622H-related ABC-DLBCL did not harbor co-mutations that were previously reported in Q584H-/Q622L-related ABC-DLBCL. Furthermore, in contrast to Q584H and Q622L, Q622H showed no enhancement effects on LUBAC and NF-κB activity in vitro compared with wild-type RNF31. The present study's structural prediction suggested that the electrostatic interaction related to the Q622 residue may not have had an important role in LUBAC formation. In conclusion, the molecular mechanism and mutational background of RNF31 Q622H differed from that of RNF31 Q584H or Q622L. Furthermore, RNF31 Q622H appeared not to induce NF-κB activation in lung cancer., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Nakazawa et al.)

Honey bee colonies are prone to invasion by pests and pathogens. The combination of the parasitic mite Varroa destructor (Varroa) and the multiple viruses it vectors, is a major driver of colony losses. Breeding for hygienic behavior to reduce Varroa populations is considered a sustainable way to reduce the impact of Varroa on honey bee health. However, hygienic behavior may have a cost to the health of individual bees, both in terms of viral infection risk and immune function. To determine whether selection for hygienic behavior at the colony level is associated with trade-offs in honey bee viral infection and immune function, we compared Varroa populations, viral loads, and individual immune function between honey bee colonies that were bred for high and low hygienic behavior. Specifically, we measured Varroa infestation, Deformed wing virus DWV-A, DWV-B, Acute bee paralysis virus (ABPV), and Israeli acute paralysis virus IAPV viral genome levels in bee samples from artificially inseminated queens in our bi-directional selection program for hygienic behavior in Israel. In addition, we evaluated the expression of 12 genes from the Jak-STAT, Toll, IMD and RNAi immune pathways. We found significantly lower Varroa infestation and DWV loads in highly hygienic colonies than in colonies exhibiting low hygienic behavior. In addition, workers of the hygienic colonies had significantly higher expression of the immune genes PGRP-S2 and hymenoptaecin compared to workers from low hygienic colonies. These results indicate no trade-offs in breeding for hygienic behavior. Hygienic honey bees were associated with reduced Varroa populations and reduced DWV prevalence or load at the colony level. Individual immunity of hygienic bees was increased, which could also contribute to lower virus levels, although lower Varroa levels due to social immunity presumably contributed as well. In sum, we demonstrate multiple health benefits of breeding for honey bee hygiene., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Evaluation of cancer therapy with imaging is crucial as a surrogate marker of effectiveness and survival. The unique response patterns to therapy with immune-checkpoint inhibitors have facilitated the revision of response evaluation criteria using FDG-PET, because the immune response recalls reactive cells such as activated T-cells and macrophages, which show increased glucose metabolism and apparent progression on morphological imaging. Cellular metabolism and function are critical determinants of the viability of active cells in the tumor microenvironment, which would be novel targets of therapies, such as tumor immunity, metabolism, and genetic mutation. Considering tumor heterogeneity and variation in therapy response specific to the mechanisms of therapy, appropriate response evaluation is required. Radiomics approaches, which combine objective image features with a machine learning algorithm as well as pathologic and genetic data, have remarkably progressed over the past decade, and PET radiomics has increased quality and reliability based on the prosperous publications and standardization initiatives. PET and multimodal imaging will play a definitive role in personalized therapeutic strategies by the precise monitoring in future cancer therapy.

Background: We conducted a multicenter, retrospective study on the efficacy and safety of naldemedine in thoracic cancer patients using opioids in clinical practice., Methods: We retrospectively evaluated thoracic cancer patients treated with naldemedine at 10 institutions in Japan. Clinical data of patients administered naldemedine between June 2017 and August 2019 were extracted from electronic medical records. Inclusion criteria were as follows: (i) patients hospitalized for at least seven days before and after naldemedine administration, and (ii) those whose frequency of defecation was entered in the medical records., Results: Forty patients were analyzed, and defecation frequency was observed for at least seven days before and after naldemedine administration. The response rate was 65.0% (95% CI: 50.2%-79.7%). The number of defecations increased significantly after naldemedine administration in the overall population, as well as among only those who defecated <3 times/week before naldemedine administration, and those that were administered ≥30 mg/day of morphine equivalent. Diarrhea was the most common adverse event in all grades, occurring in 11 patients (27.5%), of which 9 (81.8%) were grade 1 or 2. None of the patients experienced grade 4 or higher adverse events., Conclusion: The efficacy and safety of naldemedine for thoracic cancer patients in clinical practice were comparable with those of prospective studies, which suggest that naldemedine may be effective and feasible for most thoracic cancer patients., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: The standard of care for unresectable, locally advanced non-small cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT) followed by durvalumab, based on the PACIFIC trial. Disease progression and pneumonitis were reported as the main reasons to preclude the initiation of durvalumab in multiple retrospective studies. However, the transition rate and the reasons for failure to proceed to consolidation therapy with durvalumab after CRT were not evaluated prospectively. Although phase II studies in Japan have shown high efficacy and tolerability of CRT with cisplatin + S-1 (SP), no prospective study using durvalumab after SP-based CRT has yet been reported. We therefore conducted a phase II study to verify the efficacy and safety of durvalumab following SP-based CRT. In this interim analysis, we report the transition rate and the reasons for its failure., Methods: In treatment-naïve LA-NSCLC, cisplatin (60 mg/m 2 , day 1) and S-1 (80-120 mg/body, days 1-14) were administered with two 4-week cycles with concurrent thoracic radiotherapy (60 Gy) followed by durvalumab every 2 weeks for up to 12 months. The primary endpoint was 12 month progression-free survival rate., Results: Fifty-nine patients were enrolled, of whom 86.4% (51/59) proceeded to durvalumab. All of them initiated durvalumab within 42 days after CRT [median 18 days (range: 3-38)], including 27.5% (14/51) in <14 days. Common reasons for failure to proceed to durvalumab were disease progression (2/59, 3.4%) and adverse events (6/59, 10.2%). Among the latter cases, four resumed treatment and proceeded to durvalumab within 42 days on off-protocol. The objective response rate and the disease control rate were 62.7% and 93.2%, respectively. The incidences of ⩾grade 3 pneumonitis, febrile neutropenia, and esophagitis were 0%, 8.5%, and 3.4%, respectively., Conclusion: Regarding durvalumab after CRT, this interim analysis of the SAMURAI study clarified the high transition rate, early introduction, and reasons for failure to proceed to consolidation therapy, which were not determined in the PACIFIC trial., Trial Registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127., Competing Interests: Competing Interests: ST received research funding from AstraZeneca and personal fees as honoraria from AstraZeneca, Chugai Pharmaceutical, Taiho Pharmaceutical, and Eli Lilly. SK received personal fees as honoraria from Chugai Pharmaceutical, Bristol-Myers Squibb, Boehringer Ingelheim, AstraZeneca, Pfizer, Eli Lilly, MSD, Taiho Pharmaceutical, Sanofi, Kyowa Kirin, Hisamitsu Pharmaceutical, DAIICHI SANKYO, Nippon Kayaku, and Novartis. NI received personal fees as honoraria from AstraZeneca. KK received personal fees as honoraria from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, and Nippon Kayaku. TY received research funding from Bristol-Myers Squibb, MSD, Chugai Pharmaceutical, Takeda Pharmaceutical, and Delta-Fly Pharma and personal fees as honoraria from Bristol-Myers Squibb, Ono Pharmaceutical, Nippon Kayaku, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Novartis, and Takeda Pharmaceutical. TT received personal fees as honoraria from Chugai Pharmaceutical. KS received personal fees as honoraria from AstraZeneca, Taiho Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, and Ono Pharmaceutical. AB received research funding from AstraZeneca and personal fees as honoraria from AstraZeneca and Taiho Pharmaceutical. KK received research funding from AstraZeneca, and Nihon Medi-Physics and personal fees as honoraria from Ono Pharmaceutical, Boehringer Ingelheim, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, AstraZeneca, and Pfizer. TM received personal fees as honoraria from Chugai Pharmaceutical and AstraZeneca. NS received research funding from Ono Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Chugai Pharmaceutical, Eisai, DAIICHI SANKYO, Takeda Pharmaceutical, SHIONOGI, Nippon Kayaku, and Pfizer and personal fees as honoraria from Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Boehringer Ingelheim, MSD, DAIICHI SANKYO, Novartis, Bristol-Myers Squibb, Pfizer, Takeda Pharmaceutical, and Nippon Kayaku. No potential conflicts of interest were disclosed by other authors., (© The Author(s), 2022.)