研究者詳細 - 安田　浩之

論文 - 安田　浩之

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Initial single-institutional experience with salvage surgery for stage IV non-small-cell lung cancer

Hishida T., Oka N., Yano K., Omura S., Okubo Y., Masai K., Kaseda K., Ohgino K., Terai H., Yasuda H., Asakura K.

Interdisciplinary Cardiovascular and Thoracic Surgery 40 （ 3 ） 2025年03月

The purpose of this study was to assess surgical outcomes of salvage surgery for clinical stage IV non-small-cell lung cancer. A total of 14 patients who underwent lung resection following systemic therapy between 2010 and 2022 were included in this study. Systemic therapy prior to surgery included agents including epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in eight patients and non-TKI agents in six (chemotherapy alone: four, chemotherapy plus immune checkpoint inhibitors: two). During a median follow-up of 5.2 years, the EGFR-TKI group showed a favourable 5-year overall survival of 83%; however, it was due to treatment after relapse, and there were no 4-year relapse-free survivors. The non-EGFR-TKI group showed a 5-year relapse-free survival of 33%, and 2 patients have survived more than 3 years without any relapse and further treatment. When considering the role of surgery in multimodal treatment for initial c-stage IV non-small-cell lung cancer, salvage surgery following non-TKI therapy (chemotherapy with or without immune checkpoint inhibitor) can be regarded as genuine salvage surgery.

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Celecoxib prevents malignant progression of smoking-induced lung tumors via suppression of the COX-2/PGE<inf>2</inf> signaling pathway in mice

Sakurai K., Chubachi S., Miyata J., Hamamoto J., Naganuma T., Shimada T., Otake S., Nakayama S., Irie H., Tsutsumi A., Kameyama N., Hegab A.E., Shimoda M., Terai H., Yasuda H., Kanai Y., Arita M., Fukunaga K.

Frontiers in Immunology 16 1557790 2025年

Introduction: Lung cancer is characterized by a poor prognosis and is a significant comorbidity of chronic obstructive pulmonary disease (COPD). Therefore, effective chemopreventive agents are warranted. We evaluated the effects of the cyclooxygenase-2 (COX-2) inhibitor celecoxib on the prevention of lung-carcinoma development using an intermittent smoking-induced lung-carcinoma mouse model. Additionally, we explored COX-2’s role in lipid metabolism. Methods: Male A/J mice were exposed to sham air or mainstream cigarette smoke for 20 weeks. Vehicle or celecoxib was administered via intragastric feeding once daily. Lung tissues were analyzed for tumor nodules and emphysema; the bronchoalveolar lavage fluid was collected for cell counting. COX-2 expression was measured using real-time polymerase chain reaction and western blotting; lipidomic analysis was conducted using liquid chromatography-tandem mass spectrometry. Cell proliferation and colony-forming assays were performed on LA-4 cells to assess the effects of prostaglandins and COX-2 inhibitors. Results: Intermittent smoking exposure increased lung adenomas, adenocarcinomas, and COX-2 expression. Lung adenomas were characterized by abundant COX-2-positive cells. Celecoxib reduced intermittent smoking-induced inflammation, emphysema, and cell counts in the bronchoalveolar lavage fluid and decreased the incidence of lung adenocarcinomas, whereas the total number of observed lung tumors was unchanged. Celecoxib markedly suppressed single-smoke-induced prostaglandin E2 (PGE2) production in the airway. PGE2 increased LA-4 cell viability via the EP4 receptor and promoted colony formation. Discussion: Celecoxib effectively inhibited lung-carcinoma development, inflammation, and emphysema, demonstrating the potential for chemoprevention in smokers and patients with COPD. Further studies on EP4 inhibitors for the prevention of emphysema and lung cancer are warranted.

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Real-World Efficacy and Safety of Atezolizumab for Advanced Non-Small Cell Lung Cancer in Japan: A Retrospective Multicenter Analysis

Okada M., Ohgino K., Horiuchi K., Sayama K., Arai D., Watase M., Kobayashi K., Terashima T., Ishioka K., Miyawaki M., Sakamaki F., Masuzawa K., Terai H., Yasuda H., Soejima K., Fukunaga K.

Journal of Clinical Medicine 13 （ 24 ） 2024年12月

ISSN 2077-0383

Background/Objectives: Atezolizumab, an immune checkpoint inhibitor (ICI), was used in a phase III clinical trial, i.e., the OAK trial, of previously treated patients with non-small cell lung cancer. We aimed to evaluate the real-world efficacy and safety of atezolizumab in a non-selected population and identify the clinical characteristics that influence its efficacy. Methods: This was a multicenter, retrospective, single-arm observational study. Seventy-four patients with advanced non-small cell lung cancer, who received atezolizumab monotherapy at Keio University and affiliated hospitals in Japan between April 2018 and March 2019, were enrolled. The follow-up period was until 28 February 2024. The efficacy of treatment and adverse events were reviewed retrospectively. Statistical analyses using Pearson’s χ2 test, Fisher’s exact test, log-rank test, and Student’s t-test were performed. Results: The median age of patients was 70 (range, 45–85) years. The overall survival duration was 7.54 (95% confidence interval [CI], 5.14–11.3) months, and the median time to treatment failure (TTF) was 2.00 (95% CI, 1.75–2.54) months. Patients treated with atezolizumab as their first ICI had a longer TTF than those treated with atezolizumab as their second or subsequent ICI (p = 0.04). Conclusions: Atezolizumab may be more effective when used as the first ICI for previously treated patients and may be safely used in elderly patients with non-small cell lung cancer in real-world settings.

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Therapeutic Efficacy of IL7/CCL19-Expressing CAR-T Cells in Intractable Solid Tumor Models of Glioblastoma and Pancreatic Cancer

Ohta K., Sakoda Y., Adachi K., Shinozaki T., Nakajima M., Yasuda H., Nagano H., Tamada K.

Cancer Research Communications （American Association for Cancer Research (AACR)） 4 （ 9 ） 2514 - 2524 2024年09月

Cancer immunotherapy using immune checkpoint inhibitors and its combination with other anticancer therapies has emerged as a new standard of care because of the encouraging therapeutic effects in various solid cancers. Nonetheless, glioblastoma and pancreatic cancer remain resistant to immunotherapy and represent intractable cancers with the poorest prognosis. We investigated the therapeutic effects of nextgeneration chimeric antigen receptor (CAR) T cells producing IL7 and chemokine (C-C motif) ligand 19 (CCL19; referred to as 7 × 19 CAR-T) in these intractable cancers. Cytotoxic activities and therapeutic effects of 7 × 19 CAR-T were evaluated in vitro and in vivo, in a model using EGFR variant III (EGFRvIII)-positive glioblastoma and anti-EGFRvIII CAR-T generated from healthy donor peripheral blood mononuclear cells (PBMC), or a model using HER2-positive pancreatic cancer organoids and anti-HER2 CAR-T generated from the same patient's PBMC. Anti-EGFRvIII 7 × 19 CAR-T exhibited cytotoxic activity specific to EGFRvIII-positive tumor, induced complete rejection of glioblastoma with massive T-cell infiltration and tumor cell death in the tumor tissues, and consequently prolonged mouse survival. Anti-HER2 7 × 19 CAR-T demonstrated a potent cytotoxic activity against autologous HER2- positive pancreatic cancer organoids and induced complete rejection of autologous tumor along with prolonged mouse survival. Our results suggest that 7 × 19 CAR-T could become a therapeutic option for glioblastoma and pancreatic cancer. To the best of our knowledge, this is the first study to demonstrate the therapeutic efficacy of next-generation CAR-T in an autologous model using patient-derived tumor organoids and CAR-T generated from the same patient's PBMC, in which unwanted allogeneic immune responses are fully excluded.

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Development of a Machine Learning-Based Model for Predicting the Incidence of Peripheral Intravenous Catheter-Associated Phlebitis.

Yasuda H, Rickard CM, Mimoz O, Marsh N, Schults JA, Drugeon B, Kashiura M, Kishihara Y, Shinzato Y, Koike M, Moriya T, Kotani Y, Kondo N, Sekine K, Shime N, Morikane K, Abe T

Journal of critical care medicine (Universitatea de Medicina si Farmacie din Targu-Mures) 10 （ 3 ） 232 - 244 2024年07月

ISSN 2393-1809

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Clinical practice guidelines for molecular tumor marker, 2nd edition review part 2.

Kikuchi Y, Shimada H, Yamasaki F, Yamashita T, Araki K, Horimoto K, Yajima S, Yashiro M, Yokoi K, Cho H, Ehira T, Nakahara K, Yasuda H, Isobe K, Hayashida T, Hatakeyama S, Akakura K, Aoki D, Nomura H, Tada Y, Yoshimatsu Y, Miyachi H, Takebayashi C, Hanamura I, Takahashi H

International journal of clinical oncology 29 （ 5 ） 512 - 534 2024年05月

ISSN 1341-9625

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Clinical utility of the Oncomine Dx Target Test multi-CDx system and the possibility of utilizing those original sequence data

Saito A., Terai H., Kim T.J., Emoto K., Kawano R., Nakamura K., Hayashi H., Takaoka H., Ogata A., Kinoshita K., Ito F., Shigematsu L., Okada M., Fukushima T., Mitsuishi A., Shinozaki T., Ohgino K., Ikemura S., Yasuda H., Kawada I., Soejima K., Nishihara H., Fukunaga K.

Cancer Medicine 13 （ 4 ） e7077 2024年02月

Background: Companion diagnostic tests play a crucial role in guiding treatment decisions for patients with non-small cell lung cancer (NSCLC). The Oncomine Dx Target Test (ODxTT) Multi-CDx System has emerged as a prominent companion diagnostic method. However, its efficacy in detecting driver gene mutations, particularly rare mutations, warrants investigation. Aims: This study aimed to assess the performance of the ODxTT in detecting driver gene mutations in NSCLC patients. Specifically, we aimed to evaluate its sensitivity in detecting epidermal growth factor receptor (EGFR) mutations, a key determinant of treatment selection in NSCLC. Materials and Methods: We conducted a retrospective analysis of NSCLC patients who underwent testing with the ODxTT at Keio University Hospital between May 2020 and March 2022. Patient samples were subjected to both DNA and RNA tests. Driver gene mutation status was assessed, and instances of missed mutations were meticulously examined. Results: Of the 90 patients, five had nucleic acid quality problems, while 85 underwent both DNA and RNA tests. Driver gene mutations were detected in 56/90 (62.2%) patients. Of the 34 patient specimens, driver mutations were not detected using the ODxTT; however, epidermal growth factor receptor (EGFR) mutations were detected using polymerase chain reaction-based testing in two patients, and a KRAS mutation was detected by careful examination of the sequence data obtained using the ODxTT in one patient. For the above three cases, carefully examining the gene sequence information obtained using the ODxTT could identify driver mutations that were not mentioned in the returned test results. Additionally, we confirmed comparable instances of overlook results for EGFR mutations in the dataset from South Korea, implying that this type of oversight could occur in other countries using the ODxTT. EGFR mutation was missed in ODxTT in Japan (6.3%, 2/32), South Korea (2.0%, 1/49), and overall (3.7%, 3/81). Conclusion: Even if sufficient tumor samples are obtained, rare EGFR mutations (which are excluded from the ODxTT's genetic mutation list) might not be detected using the current ODxTT system due to the program used for sequence analysis. However, such rare EGFR mutations can still be accurately detected on ODxTT's sequence data using next-generation sequencing.

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Pre-existing Interstitial Lung Abnormalities and Immune Checkpoint Inhibitor-Related Pneumonitis in Solid Tumors: A Retrospective Analysis

Horiuchi K., Ikemura S., Sato T., Shimozaki K., Okamori S., Yamada Y., Yokoyama Y., Hashimoto M., Jinzaki M., Hirai I., Funakoshi T., Mizuno R., Oya M., Hirata K., Hamamoto Y., Terai H., Yasuda H., Kawada I., Soejima K., Fukunaga K.

Oncologist 29 （ 1 ） E108 - E117 2024年01月

ISSN 10837159

Background: Immune checkpoint inhibitors (ICIs) have demonstrated efficacy over previous cytotoxic chemotherapies in clinical trials among various tumors. Despite their favorable outcomes, they are associated with a unique set of toxicities termed as immune-related adverse events (irAEs). Among the toxicities, ICI-related pneumonitis has poor outcomes with little understanding of its risk factors. This retrospective study aimed to investigate whether pre-existing interstitial lung abnormality (ILA) is a potential risk factor for ICI-related pneumonitis. Materials and Methods: Patients with non-small cell lung cancer, malignant melanoma, renal cell carcinoma, and gastric cancer, who was administered either nivolumab, pembrolizumab, or atezolizumab between September 2014 and January 2019 were retrospectively reviewed. Information on baseline characteristics, computed tomography findings before administration of ICIs, clinical outcomes, and irAEs were collected from their medical records. Pre-existing ILA was categorized based on previous studies. Results: Two-hundred-nine patients with a median age of 68 years were included and 23 (11.0%) developed ICI-related pneumonitis. While smoking history and ICI agents were associated with ICI-related pneumonitis (P = .005 and .044, respectively), the categories of ILA were not associated with ICI-related pneumonitis (P = .428). None of the features of lung abnormalities were also associated with ICI-related pneumonitis. Multivariate logistic analysis indicated that smoking history was the only significant predictor of ICI-related pneumonitis (P = .028). Conclusion: This retrospective study did not demonstrate statistically significant association between pre-existing ILA and ICI-related pneumonitis, nor an association between radiologic features of ILA and ICI-related pneumonitis. Smoking history was independently associated with ICI-related pneumonitis. Further research is warranted for further understanding of the risk factors of ICI-related pneumonitis.

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Prognostic factors affecting survival in patients with non-small cell lung cancer treated with salvage surgery after drug therapy: a multi-institutional retrospective study

Suzuki S., Asakura K., Okui M., Izawa N., Sawafuji M., Sakamaki H., Shigenobu T., Tajima A., Oka N., Masai K., Kaseda K., Hishida T., Yasuda H., Fukunaga K., Asamura H.

World Journal of Surgical Oncology 21 （ 1 ） 290 - 290 2023年12月

Background: The prevalence of salvage surgeries after drug therapy for non-small cell lung cancer (NSCLC) has risen, mainly due to recent progress in molecular-targeted drugs and immune checkpoint inhibitors for NSCLC. While the safety and effectiveness of salvage surgery after drug therapy for NSCLC have been studied, its indications remain unclear. We aimed to identify the prognostic factors affecting survival in patients with advanced-stage (stages III–IV) NSCLC treated with salvage surgery after drug therapy. Methods: A retrospective investigation was conducted on patients who received salvage surgery after drug therapy at four hospitals between 2007 and 2020. Salvage surgery was defined as surgery after drug therapy for local progression, tumor conversion to resectable status, and discontinuation of prior drug therapy owing to serious complications. Results: Thirty-two patients received cytotoxic agents alone (n = 12 [38%]), tyrosine kinase inhibitors (TKIs; n = 16 [50%]), or immune checkpoint inhibitors (n = 4 [13%]) as prior drug therapy. In 11 (34%) and 21 (66%) patients, the clinical stage before treatment was III or IV, respectively. The median initial and preoperative serum carcinoembryonic antigen (CEA) levels were 10.2 (range, 0.5–1024) ng/mL and 4.2 (range, 0.6–92.5) ng/mL, respectively. Among the patients, 28 (88%) underwent lobectomy, 2 (6%) underwent segmentectomy, and 2 (6%) underwent wedge resection. Complete resection of the primary lesion was accomplished in 28 (88%) patients. Postoperative complications were documented in six (19%) patients. Mortality rates were 0% at 30 days and 3% at 90 days post-operation. The 5-year overall survival rate stood at 66%, while the 5-year progression-free survival rate was 21%. Multivariate analyses showed that prior TKI therapy and preoperative serum CEA level < 5 ng/mL were prognostic factors influencing overall survival (hazard ratio [95% confidence interval]: 0.06 [0.006–0.68] and 0.03 [0.002–0.41], respectively). The 5-year overall survival in the 11 patients with both favorable prognosticators was 100%. Conclusions: In this study, prior TKI therapy and preoperative serum CEA level < 5 ng/mL were favorable prognostic factors for overall survival in patients with NSCLC treated with salvage surgery. Patients with these prognostic factors are considered good candidates for salvage surgery after drug therapy.

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Safety evaluation of immune-cell therapy for malignant tumor in the Cancer Immune-cell Therapy Evaluation Group (CITEG)

Takimoto R., Kamigaki T., Ito H., Saito M., Takizawa K., Soejima K., Yasuda H., Ohgino K., Terai H., Tomita K., Miura M., Mizukoshi E., Miyashita T., Nakamoto Y., Hayashi K., Miwa S., Kitahara M., Takeuchi A., Kimura H., Mochizuki T., Sugie H., Seino K.i., Yamada T., Takeuchi S., Makita K., Naitoh K., Yasumoto K., Yoshida Y., Inoue H., Kotake K., Ohshima K., Noda S.e., Okamoto M., Yoshimoto Y., Okada S., Ibe H., Oguma E., Goto S.

Cytotherapy 25 （ 11 ） 1229 - 1235 2023年11月

ISSN 14653249

Background aims: With the aim of strengthening the scientific evidence of immune-cell therapy for cancer and further examining its safety, in October 2015, our hospital jointly established the Cancer Immune-Cell Therapy Evaluation Group (CITEG) with 39 medical facilities nationwide. Methods: Medical information, such as patients’ background characteristics, clinical efficacy and therapeutic cell types obtained from each facility, has been accumulated, analyzed and evaluated by CITEG. In this prospective study, we analyzed the adverse events associated with immune-cell therapy until the end of September 2022, and we presented our interim safety evaluation. Results: A total of 3839 patients with malignant tumor were treated with immune-cell therapy, with a median age of 64 years (range, 13–97 years) and a male-to-female ratio of 1:1.08 (1846:1993). Most patients’ performance status was 0 or 1 (86.8%) at the first visit, and 3234 cases (84.2%) were advanced or recurrent cases, which accounted for the majority. The total number of administrations reported in CITEG was 31890, of which 960 (3.0%) showed adverse events. The numbers of adverse events caused by treatment were 363 (1.8%) of 19661 administrations of αβT cell therapy, 9 of 845 administrations of γδT-cell therapy (1.1%) and 10 of 626 administrations of natural killer cell therapy (1.6%). The number of adverse events caused by dendritic cell (DC) vaccine therapy was 578 of 10748 administrations (5.4%), which was significantly larger than those for other treatments. Multivariate analysis revealed that αβT cell therapy had a significantly greater risk of adverse events at performance status 1 or higher, and patients younger than 64 years, women or adjuvant immune-cell therapy had a greater risk of adverse events in DC vaccine therapy. Injection-site reactions were the most frequently reported adverse events, with 449 events, the majority of which were associated with DC vaccine therapy. Among all other adverse events, fever (228 events), fatigue (141 events) and itching (131 events) were frequently reported. In contrast, three patients had adverse events (fever, abdominal pain and interstitial pneumonia) that required hospitalization, although they were weakly related to this therapy; rather, it was considered to be the effect of treatment for the primary disease. Conclusions: Immune-cell therapy for cancer was considered to be a safe treatment without serious adverse events.

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Comprehensive analysis of long COVID in a Japanese nationwide prospective cohort study

Terai H., Ishii M., Takemura R., Namkoong H., Shimamoto K., Masaki K., Tanosaki T., Chubachi S., Matsuyama E., Hayashi R., Shimada T., Shigematsu L., Ito F., Kaji M., Takaoka H., Kurihara M., Nakagawara K., Tomiyasu S., Sasahara K., Saito A., Otake S., Azekawa S., Okada M., Fukushima T., Morita A., Tanaka H., Sunata K., Asaoka M., Nishie M., Shinozaki T., Ebisudani T., Akiyama Y., Mitsuishi A., Nakayama S., Ogawa T., Sakurai K., Irie M., Yagi K., Ohgino K., Miyata J., Kabata H., Ikemura S., Kamata H., Yasuda H., Kawada I., Kimura R., Kondo M., Iwasaki T., Ishida N., Hiruma G., Miyazaki N., Ishibashi Y., Harada S., Fujita T., Ito D., Bun S., Tabuchi H., Kanzaki S., Shimizu E., Fukuda K., Yamagami J., Kobayashi K., Hirano T., Inoue T., Haraguchi M., Kagyo J., Shiomi T., Lee H., Sugihara K., Omori N., Sayama K., Otsuka K., Miyao N., Odani T., Watase M., Mochimaru T., Satomi R., Oyamada Y., Masuzawa K., Asakura T., Nakayama S., Suzuki Y., Baba R., Okamori S., Arai D., Nakachi I., Kuwahara N., Fujiwara A., Oakada T., Ishiguro T., Isosno T., Makino Y., Mashimo S., Kaido T., Minematsu N., Ueda S., Minami K., Hagiwara R., Manabe T., Fukui T.

Respiratory Investigation 61 （ 6 ） 802 - 814 2023年11月

ISSN 22125345

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly since 2019, and the number of reports regarding long COVID has increased. Although the distribution of long COVID depends on patient characteristics, epidemiological data on Japanese patients are limited. Hence, this study aimed to investigate the distribution of long COVID in Japanese patients. This study is the first nationwide Japanese prospective cohort study on long COVID. Methods: This multicenter, prospective cohort study enrolled hospitalized COVID-19 patients aged ≥18 years at 26 Japanese medical institutions. In total, 1200 patients were enrolled. Clinical information and patient-reported outcomes were collected from medical records, paper questionnaires, and smartphone applications. Results: We collected data from 1066 cases with both medical records and patient-reported outcomes. The proportion of patients with at least one symptom decreased chronologically from 93.9% (947/1009) during hospitalization to 46.3% (433/935), 40.5% (350/865), and 33.0% (239/724) at 3, 6, and 12 months, respectively. Patients with at least one long COVID symptom showed lower quality of life and scored higher on assessments for depression, anxiety, and fear of COVID-19. Female sex, middle age (41–64 years), oxygen requirement, and critical condition during hospitalization were risk factors for long COVID. Conclusions: This study elucidated the symptom distribution and risks of long COVID in the Japanese population. This study provides reference data for future studies of long COVID in Japan.

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CGP検査の結果により遺伝カウンセリング推奨となった胸部悪性腫瘍症例の考察

福島貴大, 寺井秀樹, 中村康平, 川野竜太郎, 江本桂, 石川麻倫, 緒方暁彦, 高岡初誉, 齋藤彩夏, 扇野圭子, 安田浩之, 川田一郎, 副島研造, 西原広史, 福永興壱

肺癌（(NPO)日本肺癌学会） 63 （ 5 ） 461 - 461 2023年10月

ISSN 0386-9628

CGP検査の結果により遺伝カウンセリング推奨となった胸部悪性腫瘍症例の考察

肺癌（(NPO)日本肺癌学会） 63 （ 5 ） 461 - 461 2023年10月

ISSN 0386-9628

EGFR遺伝子変異陽性肺腺癌に対するEGFR-TKI治療後,小細胞肺癌への形質転化と肺腺癌成分の再増大を繰り返し交互に認め,両組織型への治療を組み合わせる必要があった1例

渡邊素子, 小山薫, 木下雄仁, 緒方暁彦, 高岡初誉, 扇野圭子, 寺井秀樹, 安田浩之, 川田一郎, 福永興壱

肺癌（(NPO)日本肺癌学会） 63 （ 2 ） 135 - 135 2023年04月

ISSN 0386-9628

Genotype-phenotype mapping of a patient-derived lung cancer organoid biobank identifies NKX2-1-defined Wnt dependency in lung adenocarcinoma

Ebisudani T., Hamamoto J., Togasaki K., Mitsuishi A., Sugihara K., Shinozaki T., Fukushima T., Kawasaki K., Seino T., Oda M., Hanyu H., Toshimitsu K., Emoto K., Hayashi Y., Asakura K., Johnson T.A., Terai H., Ikemura S., Kawada I., Ishii M., Hishida T., Asamura H., Soejima K., Nakagawa H., Fujii M., Fukunaga K., Yasuda H., Sato T.

Cell Reports 42 （ 3 ） 112212 - 112212 2023年03月

Human lung cancer is a constellation of tumors with various histological and molecular properties. To build a preclinical platform that covers this broad disease spectrum, we obtained lung cancer specimens from multiple sources, including sputum and circulating tumor cells, and generated a living biobank consisting of 43 lines of patient-derived lung cancer organoids. The organoids recapitulated the histological and molecular hallmarks of the original tumors. Phenotypic screening of niche factor dependency revealed that EGFR mutations in lung adenocarcinoma are associated with the independence from Wnt ligands. Gene engineering of alveolar organoids reveals that constitutive activation of EGFR-RAS signaling provides Wnt independence. Loss of the alveolar identity gene NKX2-1 confers Wnt dependency, regardless of EGFR signal mutation. Sensitivity to Wnt-targeting therapy can be stratified by the expression status of NKX2-1. Our results highlight the potential of phenotype-driven organoid screening and engineering for the fabrication of therapeutic strategies to combat cancer.

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Population Pharmacokinetics, Pharmacogenomics, and Adverse Events of Osimertinib and its Two Active Metabolites, AZ5104 and AZ7550, in Japanese Patients with Advanced Non-small Cell Lung Cancer: a Prospective Observational Study

Ishikawa E., Yokoyama Y., Chishima H., Kasai H., Kuniyoshi O., Kimura M., Hakamata J., Nakada H., Suehiro N., Nakaya N., Nakajima H., Ikemura S., Kawada I., Yasuda H., Terai H., Jibiki A., Kawazoe H., Soejima K., Muramatsu H., Suzuki S., Nakamura T.

Investigational New Drugs 41 （ 1 ） 122 - 133 2023年02月

ISSN 01676997

Background: Potential novel strategies for adverse event (AE) management of osimertinib therapy, including therapeutic drug monitoring and the use of biomarkers, have not yet been fully investigated. This study aimed to evaluate (1) the relationship between exposure to osimertinib, especially its active metabolites (AZ5104 and AZ7550), and AEs, and (2) the relationship between germline polymorphisms and AEs. Methods: We conducted a prospective, longitudinal observational study of 53 patients with advanced non-small cell lung cancer receiving osimertinib therapy from February 2019 to April 2022. A population pharmacokinetic model was developed to estimate the area under the serum concentration–time curve from 0 to 24 h (AUC0–24) of osimertinib and its metabolites. Germline polymorphisms were analyzed using TaqMan® SNP genotyping and CycleavePCR® assays. Results: There was a significant association between the AUC0–24 of AZ7550 and grade ≥ 2 paronychia (p = 0.043) or anorexia (p = 0.011) and between that of osimertinib or AZ5104 and grade ≥ 2 diarrhea (p = 0.026 and p = 0.049, respectively). Furthermore, the AUC0–24 of AZ5104 was significantly associated with any grade ≥ 2 AEs (p = 0.046). EGFR rs2293348 and rs4947492 were associated with severe AEs (p = 0.019 and p = 0.050, respectively), and ABCG2 rs2231137 and ABCB1 rs1128503 were associated with grade ≥ 2 AEs (p = 0.008 and p = 0.038, respectively). Conclusion: Higher exposures to osimertinib, AZ5104, and AZ7550 and polymorphisms in EGFR, ABCG2, and ABCB1 were related to higher severity of AEs; therefore, monitoring these may be beneficial for osimertinib AE management.

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Successful Steroid Treatment of Pembrolizumab-induced Agranulocytosis That Developed after Splenectomy in a Patient with Non-small-cell Lung Cancer

Okuzumi S., Kamata H., Emoto K., Shimizu T., Otake S., Irie H., Chubachi S., Ikemura S., Yasuda H., Fukunaga K.

Internal Medicine 62 （ 14 ） 2113 - 2121 2023年

ISSN 09182918

Neutropenia, a rare immune-related adverse event, affects patients receiving treatment with immune checkpoint inhibitors (ICIs). We herein report a case of pembrolizumab-induced agranulocytosis. An 83-year-old man was diagnosed with advanced-stage lung carcinoma concomitant with splenomegaly complicated by hypersplenism, causing pancytopenia. To avoid the risk of bone marrow suppression due to cytotoxic chemotherapy, pembrolizumab monotherapy was chosen. However, the patient developed agranulocytosis despite the resolution of pancytopenia through splenectomy performed after the fourth pembrolizumab cycle. Neutrophil counts improved after steroid treatment but not after granulocyte colony-stimulating factor treatment. This case demonstrated that neutropenia can sometimes develop abruptly after several ICI therapy cycles.

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Most Important Things and Associated Factors With Prioritizing Daily Life in Patients With Advanced Lung Cancer

Kameyama N., Sato T., Arai D., Fujisawa D., Takeuchi M., Nakachi I., Kawada I., Yasuda H., Ikemura S., Terai H., Nukaga S., Nakano Y., Hirano T., Minematsu N., Asakura T., Kamatani T., Tanaka K., Suzuki S., Miyawaki M., Naoki K., Fukunaga K., Soejima K.

JCO Oncology Practice 18 （ 12 ） E1977 - E1986 2022年12月

ISSN 26881527

PURPOSE:Patients' values and priorities in their lives should be appreciated from an early phase of incurable diseases such as advanced cancer. However, studies examining these characteristics have been lacking. This study attempted to determine what patients with advanced lung cancer valued most, once they had been diagnosed, and any associated factors.METHODS:Patients with newly diagnosed advanced lung cancer (N = 248) were enrolled in a questionnaire survey conducted at 16 hospitals in Japan. Their priorities were assessed using a free-text response to the question what is the most important thing to you now? at the time of diagnosis and 3 months after diagnosis. The free-text responses were classified into 10 categories for quantification. The clinical characteristics associated with the category describing daily life were further examined.RESULTS:Free-text comments were obtained from 103 (44.0%) and 66 (42.6%) patients at the time of diagnosis and at 3 months, respectively. The most frequent categories were family (at diagnosis: 50.5%; at 3 months: 50.0%) and daily life (at diagnosis: 33.0%; at 3 months: 36.4%), followed by health (at diagnosis: 32.0%; at 3 months: 27.3%) at both time points. The patients mentioning daily life, the issues related to how to spend daily life, showed significantly higher total scores and functional well-being subscale scores on the Functional Assessment of Cancer Therapy-Lung scale at both time points and lower depression scores at diagnosis and lower anxiety scores at 3 months on the Hospital Anxiety and Depression Scale.CONCLUSION:Family and daily life were highly valued by patients with advanced lung cancer at diagnosis. A better quality of life and better mood were associated with mentioning daily life, which should be taken into account in care planning to maintain patients' involvement in daily life even with incurable diseases.

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Comparison of the effects of lidocaine and amiodarone for out-of-hospital cardiac arrest patients with shockable rhythms: a retrospective observational study from a multicenter registry.

Kishihara Y, Kashiura M, Amagasa S, Fukushima F, Yasuda H, Moriya T

BMC cardiovascular disorders 22 （ 1 ） 466 2022年11月

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A burden of fluid, sodium, and chloride due to intravenous fluid therapy in patients with respiratory support: a post-hoc analysis of a multicenter cohort study.

Sakuraya M, Yoshihiro S, Onozuka K, Takaba A, Yasuda H, Shime N, Kotani Y, Kishihara Y, Kondo N, Sekine K, Morikane K, AMOR-VENUS study group

Annals of intensive care 12 （ 1 ） 100 2022年10月

ISSN 2110-5820

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