Faculty Profiles - ICHIHARA Eiki

Papers - ICHIHARA Eiki

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Effectiveness of G-CSF in chemotherapy for digestive system tumors: a systematic review of the Clinical Practice Guidelines for the Use of G-CSF 2022 delineated by the Japan Society of Clinical Oncology.

Mamoru Ito, Yuta Okumura, Kenta Nio, Eishi Baba, Yukinori Ozaki, Hiroshi Nishio, Eiki Ichihara, Yuji Miura, Makoto Endo, Shingo Yano, Dai Maruyama, Tetsuhiro Yoshinami, Nobuyuki Susumu, Munetaka Takekuma, Takashi Motohashi, Nobuaki Ochi, Toshio Kubo, Keita Uchino, Takahiro Kimura, Yutaro Kamiyama, Shinji Nakao, Shinobu Tamura, Hitomi Nishimoto, Yasuhisa Kato, Atsushi Sato, Toshimi Takano, Kenji Tsuchihashi

International journal of clinical oncology 29 ( 6 ) 689 - 699 2024.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) reportedly reduces the risk of neutropenia and subsequent infections caused by cancer chemotherapy. Although several guidelines recommend using G-CSF in primary prophylaxis according to the incidence rate of chemotherapy-induced febrile neutropenia (FN), the effectiveness of G-CSF in digestive system tumor chemotherapy remains unclear. To address these clinical questions, we conducted a systematic review as part of revising the Clinical Practice Guidelines for the Use of G-CSF 2022 published by the Japan Society of Clinical Oncology. METHODS: This systematic review addressed two main clinical questions (CQ): CQ1: "Is primary prophylaxis with G-CSF effective in chemotherapy?", and CQ2: "Is increasing the intensity of chemotherapy with G-CSF effective?" We reviewed different types of digestive system tumors, including esophageal, gastric, pancreatic, biliary tract, colorectal, and neuroendocrine carcinomas. PubMed, Cochrane Library, and Ichushi-Web databases were searched for information sources. Independent systematic reviewers conducted two rounds of screening and selected relevant records for each CQ. Finally, the working group members synthesized the strength of evidence and recommendations. RESULTS: After two rounds of screening, 5/0/3/0/2/0 records were extracted for CQ1 of esophageal/gastric/pancreatic/biliary tract/colorectal/ and neuroendocrine carcinoma, respectively. Additionally, a total of 2/6/1 records were extracted for CQ2 of esophageal/pancreatic/colorectal cancer, respectively. The strength of evidence and recommendations were evaluated for CQ1 of colorectal cancer; however, we could not synthesize recommendations for other CQs owing to the lack of records. CONCLUSION: The use of G-CSF for primary prophylaxis in chemotherapy for colorectal cancer is inappropriate.

DOI： 10.1007/s10147-024-02502-6

Comparison between a single dose of PEG G-CSF and multiple doses of non-PEG G-CSF: a systematic review and meta-analysis from Clinical Practice Guidelines for the use of G-CSF 2022.

Tetsuhiro Yoshinami, Kazuki Nozawa, Takamichi Yokoe, Yukinori Ozaki, Hiroshi Nishio, Kenji Tsuchihashi, Eiki Ichihara, Yuji Miura, Makoto Endo, Shingo Yano, Dai Maruyama, Nobuyuki Susumu, Munetaka Takekuma, Takashi Motohashi, Mamoru Ito, Eishi Baba, Nobuaki Ochi, Toshio Kubo, Keita Uchino, Takahiro Kimura, Yutaro Kamiyama, Shinji Nakao, Shinobu Tamura, Hitomi Nishimoto, Yasuhisa Kato, Atsushi Sato, Toshimi Takano

International journal of clinical oncology 29 ( 6 ) 681 - 688 2024.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUD: Granulocyte colony-stimulating factor (G-CSF) is widely used for the primary prophylaxis of febrile neutropenia (FN). Two types of G-CSF are available in Japan, namely G-CSF chemically bound to polyethylene glycol (PEG G-CSF), which provides long-lasting effects with a single dose, and non-polyethylene glycol-bound G-CSF (non-PEG G-CSF), which must be sequentially administrated for several days. METHODS: This current study investigated the utility of these treatments for the primary prophylaxis of FN through a systematic review of the literature. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis or meta-analysis was conducted to evaluate six outcomes. RESULTS: Through the first and second screenings, 23 and 18 articles were extracted for qualitative synthesis and meta-analysis, respectively. The incidence of FN was significantly lower in the PEG G-CSF group than in the non-PEG G-CSF group with a strong quality/certainty of evidence. The differences in other outcomes, such as overall survival, infection-related mortality, the duration of neutropenia (less than 500/μL), quality of life, and pain, were not apparent. CONCLUSIONS: A single dose of PEG G-CSF is strongly recommended over multiple-dose non-PEG G-CSF therapy for the primary prophylaxis of FN.

DOI： 10.1007/s10147-024-02504-4

Treatment rationale and protocol design: an investigator-initiated phase II study of combination treatment of nivolumab and TM5614, a PAI-1 inhibitor for previously treated patients with non-small cell lung cancer. International journal

Takeshi Masuda, Taizo Hirata, Tomohiro Sakamoto, Yukari Tsubata, Eiki Ichihara, Toshiyuki Kozuki, Hiroyasu Shoda, Masanori Motonaga, Takako Yoshida, Miki Fukutani, Kazue Tsuji-Takayama, Atsushi Tamura, Harunobu Amagase, Hideki Fujihara, Gaku Aoki, Tomoyuki Akita, Yasushi Orihashi, Toshio Miyata, Noboru Hattori

Journal of thoracic disease 16 ( 5 ) 3381 - 3388 2024.5

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: There is no established standard 3rd line treatment for patients with advanced non-small cell lung cancer (NSCLC). Although cytotoxic chemotherapeutic agents that are not used as 1st or 2nd line treatment are administrated as 3rd line treatment, their anti-tumor efficacy is insufficient. Anti-programmed death ligand-1 (PD-L1)/programmed death-1 (PD1) treatment is more effective and less toxic than chemotherapy in anti-PD-L1/PD-1 treatment-naïve patients with NSCLC. Therefore, anti-PD-L1/PD-1 therapy is considered an appropriate 3rd line treatment. However, the anti-tumor efficacy is limited in patients previously treated with anti-PD-L1/PD-1 antibody. Today, new drugs are needed to increase the efficacy of anti-PD-L1/PD-1 antibodies. METHODS: This open-label, single-arm, investigator-initiated phase II study is designed to evaluate combination treatment of nivolumab and TM5614, a plasminogen activator inhibitor (PAI-1) inhibitor as 3rd or more line treatment in NSCLC patients who underwent standard treatment. The primary endpoint is the objective response rate and the secondary endpoints are progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. Recruitment began in September 2023 and is expected to continue for approximately three years. DISCUSSION: Currently, there is no standard 3rd line treatment for advanced NSCLC, and we hope that the findings of this study will facilitate more effective treatments in this setting. Ethics and dissemination: the study protocol conformed to the ethical principles outlined in the Declaration of Helsinki. All patients will provide written informed consent prior to enrollment. Results will be published in a peer-reviewed publication. TRIAL REGISTRATION: This study is registered to Japan Registry of Clinical Trials with number: jRCT2061230039 (19/July/2023).

DOI： 10.21037/jtd-23-1858

Osimertinib is associated with improved outcomes in pre-treated non-small cell lung cancer leptomeningeal metastases: A systematic review and meta-analysiss. International journal

David J H Bian, Anna-Maria Lazaratos, Sarah M Maritan, Andrea Quaiattini, Zhimin Zeng, Zhengfei Zhu, Ugur Sener, Rachna Malani, Yu Jung Kim, Eiki Ichihara, Victor Cohen, April A N Rose, Nathaniel Bouganim, Matthew Dankner

Heliyon 10 ( 9 ) e29668 2024.5

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Leptomeningeal metastasis (LM) is a severe complication of non-small cell lung cancer (NSCLC). In patients with NSCLC LM harboring epidermal growth factor receptor (EGFR) mutations, osimertinib is favored over alternative EGFR tyrosine kinase inhibitors (TKIs). However, the efficacy of osimertinib relative to other EGFR-TKIs is not well established for patients with LM. We aimed to compare the efficacy of EGFR-TKIs in EGFR-mutated NSCLC LM. METHODS: This systematic review and meta-analysis performed according to PRISMA guidelines included studies of adult patients with EGFR-mutated NSCLC and a diagnosis of LM who received an EGFR-TKI for the treatment of LM. We searched Medline ALL, Embase, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science Core Collection. The evaluation of biases was done by using the Ottawa-Newscastle scale. The hazard ratio was used as the parameter of interest for overall survival (OS) and central nervous system-specific progression-free survival (PFS). RESULTS: 128 publications were included with 243 patients and 282 lines of EGFR-TKI for NSCLC LM that met inclusion criteria. The median PFS in patients receiving any EGFR-TKI was 9.1 months, and the median OS was 14.5 months. In univariate analyses of the entire cohort, osimertinib treatment demonstrated significantly prolonged PFS, but not OS, compared to other EGFR-TKIs. Osimertinib demonstrated significantly prolonged PFS and OS in the subset of patients who were previously treated with EGFR-TKIs, but not in EGFR-TKI naïve patients. CONCLUSION: Osimertinib is associated with improved outcomes compared to other EGFR-TKIs, particularly in patients previously treated with EGFR-TKIs. An important limitation is that most patients were derived from retrospective reports. These results highlight the need for prospective studies for this difficult-to-treat patient population.

DOI： 10.1016/j.heliyon.2024.e29668

Impacts of probiotics on the efficacies of immune checkpoint inhibitors with or without chemotherapy for patients with advanced non-small-cell lung cancer. International journal

Ayako Morita, Eiki Ichihara, Koji Inoue, Keiichi Fujiwara, Toshihide Yokoyama, Daijiro Harada, Chihiro Ando, Hirohisa Kano, Naohiro Oda, Tomoki Tamura, Nobuaki Ochi, Haruyuki Kawai, Masaaki Inoue, Naofumi Hara, Nobukazu Fujimoto, Hirohisa Ichikawa, Isao Oze, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

International journal of cancer 154 ( 9 ) 1607 - 1615 2024.5

Language：English Publishing type：Research paper (scientific journal)

The relationships between the therapeutic effects of immune checkpoint inhibitors (ICIs) and the intestinal flora have attracted increasing attention. However, the effects of oral probiotics on the efficacies of ICIs used to treat non-small-cell lung cancer (NSCLC) remain unclear. We investigated the effects of probiotics on the efficacies of ICIs in patients treated with and without chemotherapy. We investigated patients with advanced NSCLC on ICI monotherapy or combination ICI and chemotherapy using the Okayama Lung Cancer Study Group Immunotherapy Database (OLCSG-ID) and the Okayama Lung Cancer Study Group Immunochemotherapy Database (OLCSG-ICD). In total, 927 patients (482 on ICI monotherapy, 445 on an ICI + chemotherapy) were enrolled. Most were male, of good performance status, smokers, and without epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutations. Probiotics were administered to 19% of patients on ICI monotherapies and 17% of those on ICIs + chemotherapy. Of the former patients, progression-free survival (PFS) and overall survival (OS) were significantly better in the probiotics group (PFS 7.9 vs. 2.9 months, hazard ratio [HR] 0.54, p < .001; OS not attained vs. 13.1 months, HR 0.45, p < .001). Among patients receiving ICI and chemotherapy, there were no significant differences in PFS between those on probiotics and not but OS was significantly better in the probiotics group (PFS 8.8 vs. 8.6 months, HR 0.89, p = .43; OS not attained vs. 22.6 months, HR 0.61, p = .03). Patients on probiotics experienced better outcomes following ICI treatment.

DOI： 10.1002/ijc.34842

肝切除後の難治性気管支胆汁瘻に対してEndobronchial Watanabe Spigotの挿入が感染制御に有効であった1例

宇野真梨, 槇本剛, 藤智和, 大森洋樹, 肥後寿夫, 本倉優美, 田中孝明, 森俊太, 大西桐子, 二宮貴一朗, 頼冠名, 市原英基, 田端雅弘, 宮原信明, 堀田勝幸, 大橋圭明

気管支学 46 ( Suppl. ) S337 - S337 2024.5

Effectiveness and safety of primary prophylaxis with G-CSF after induction therapy for acute myeloid leukemia: a systematic review and meta-analysis of the clinical practice guidelines for the use of G-CSF 2022 from the Japan society of clinical oncology.

Tomoya Maeda, Yuho Najima, Yutaro Kamiyama, Shinji Nakao, Yukinori Ozaki, Hiroshi Nishio, Kenji Tsuchihashi, Eiki Ichihara, Yuji Miumra, Makoto Endo, Dai Maruyama, Tatsuhiro Yoshinami, Nobuyuki Susumu, Munetaka Takekuma, Takashi Motohashi, Mamoru Ito, Eishi Baba, Nobuaki Ochi, Toshio Kubo, Keita Uchino, Takahiro Kimura, Shinobu Tamura, Hitomi Nishimoto, Yasuhisa Kato, Atsushi Sato, Toshimi Takano, Shingo Yano

International journal of clinical oncology 29 ( 5 ) 535 - 544 2024.5

Language：English Publishing type：Research paper (scientific journal)

Although granulocyte colony-stimulating factor (G-CSF) reduces the incidence, duration, and severity of neutropenia, its prophylactic use for acute myeloid leukemia (AML) remains controversial due to a theoretically increased risk of relapse. The present study investigated the effects of G-CSF as primary prophylaxis for AML with remission induction therapy. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis of pooled data was conducted, and the risk ratio with corresponding confidence intervals was calculated in the meta-analysis and summarized. Sixteen studies were included in the qualitative analysis, nine of which were examined in the meta-analysis. Although G-CSF significantly shortened the duration of neutropenia, primary prophylaxis with G-CSF did not correlate with infection-related mortality. Moreover, primary prophylaxis with G-CSF did not affect disease progression/recurrence, overall survival, or adverse events, such as musculoskeletal pain. However, evidence to support or discourage the use of G-CSF as primary prophylaxis for adult AML patients with induction therapy remains limited. Therefore, the use of G-CSF as primary prophylaxis can be considered for adult AML patients with remission induction therapy who are at a high risk of infectious complications.

DOI： 10.1007/s10147-023-02465-0

Effectiveness and safety of primary prophylaxis of granulocyte colony-stimulating factor during dose-dense chemotherapy for urothelial cancer: Clinical Practice Guidelines for the Use of G-CSF 2022.

Keita Uchino, Shingo Tamura, Shoji Kimura, Keisuke Shigeta, Takahiro Kimura, Yukinori Ozaki, Hiroshi Nishio, Kenji Tsuchihashi, Eiki Ichihara, Makoto Endo, Shingo Yano, Dai Maruyama, Tetsuhiro Yoshinami, Nobuyuki Susumu, Munetaka Takekuma, Takashi Motohashi, Mamoru Ito, Eishi Baba, Nobuaki Ochi, Toshio Kubo, Yutaro Kamiyama, Shinji Nakao, Shinobu Tamura, Hitomi Nishimoto, Yasuhisa Kato, Atsushi Sato, Toshimi Takano, Yuji Miura

International journal of clinical oncology 29 ( 5 ) 545 - 550 2024.5

Language：English Publishing type：Research paper (scientific journal)

Granulocyte colony-stimulating factor (G-CSF) decreases the incidence, duration, and severity of febrile neutropenia (FN); however, dose reduction or withdrawal is often preferred in the management of adverse events in the treatment of urothelial cancer. It is also important to maintain therapeutic intensity in order to control disease progression and thereby relieve symptoms, such as hematuria, infection, bleeding, and pain, as well as to prolong the survival. In this clinical question, we compared treatment with primary prophylactic administration of G-CSF to maintain therapeutic intensity with conventional standard therapy without G-CSF and examined the benefits and risks as major outcomes. A detailed literature search for relevant studies was performed using PubMed, Ichu-shi Web, and Cochrane Library. Data were extracted and evaluated independently by two reviewers. A qualitative analysis of the pooled data was performed, and the risk ratios with corresponding confidence intervals were calculated and summarized in a meta-analysis. Seven studies were included in the qualitative analysis, two of which were reviewed in the meta-analysis of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy, and one randomized controlled study showed a reduction in the incidence of FN. Primary prophylactic administration of G-CSF may be beneficial, as shown in a randomized controlled study of dose-dense MVAC therapy. However, there are no studies on other regimens, and we made a "weak recommendation to perform" with an annotation of the relevant regimen (dose-dense MVAC).

DOI： 10.1007/s10147-024-02491-6

Optimal timing of prophylactic pegylated G-CSF after chemotherapy administration for patients with cancer: a systematic review and meta-analysis from Clinical Practice Guidelines for the use of G-CSF 2022.

Yukinori Ozaki, Takamichi Yokoe, Tetsuhiro Yoshinami, Kazuki Nozawa, Hiroshi Nishio, Kenji Tsuchihashi, Eiki Ichihara, Yuji Miura, Makoto Endo, Shingo Yano, Dai Maruyama, Nobuyuki Susumu, Munetaka Takekuma, Takashi Motohashi, Mamoru Ito, Eishi Baba, Nobuaki Ochi, Toshio Kubo, Keita Uchino, Takahiro Kimura, Yutaro Kamiyama, Shinji Nakao, Shinobu Tamura, Hitomi Nishimoto, Yasuhisa Kato, Atsushi Sato, Toshimi Takano

International journal of clinical oncology 29 ( 5 ) 551 - 558 2024.5

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: The timing of prophylactic pegylated granulocyte colony-stimulating factor (G-CSF) administration during cancer chemotherapy varies, with Day 2 and Days 3-5 being the most common schedules. Optimal timing remains uncertain, affecting efficacy and adverse events. This systematic review sought to evaluate the available evidence on the timing of prophylactic pegylated G-CSF administration. METHODS: Based on the Minds Handbook for Clinical Practice Guideline Development, we searched the PubMed, Ichushi-Web, and Cochrane Library databases for literature published from January 1990 to December 2019. The inclusion criteria included studies among the adult population using pegfilgrastim. The search strategy focused on timing-related keywords. Two reviewers independently extracted and assessed the data. RESULTS: Among 300 initial search results, only four articles met the inclusion criteria. A meta-analysis for febrile neutropenia incidence suggested a potential higher incidence when pegylated G-CSF was administered on Days 3-5 than on Day 2 (odds ratio: 1.27, 95% CI 0.66-2.46, p = 0.47), with a moderate certainty of evidence. No significant difference in overall survival or mortality due to infections was observed. The trend of severe adverse events was lower on Days 3-5, without statistical significance (odds ratio: 0.72, 95% CI 0.14-3.67, p = 0.69) and with a moderate certainty of evidence. Data on pain were inconclusive. CONCLUSIONS: Both Day 2 and Days 3-5 were weakly recommended for pegylated G-CSF administration post-chemotherapy in patients with cancer. The limited evidence highlights the need for further research to refine recommendations.

DOI： 10.1007/s10147-024-02499-y

Effectiveness and safety of primary prophylaxis of G-CSF during chemotherapy for prostate cancer, Japanese clinical guideline for appropriate use of G-CSF: clinical practice guidelines for the use of G-CSF 2022.

Shoji Kimura, Keisuke Shigeta, Shingo Tamura, Keita Uchino, Takahiro Kimura, Yukinori Ozaki, Hiroshi Nishio, Kenji Tsuchihashi, Eiki Ichihara, Makoto Endo, Shingo Yano, Dai Maruyama, Tetsuhiro Yoshinami, Nobuyuki Susumu, Munetaka Takekuma, Takashi Motohashi, Mamoru Ito, Eishi Baba, Nobuaki Ochi, Toshio Kubo, Yutaro Kamiyama, Shinji Nakao, Shinobu Tamura, Hitomi Nishimoto, Yasuhisa Kato, Atsushi Sato, Toshimi Takano, Yuji Miura

International journal of clinical oncology 29 ( 5 ) 559 - 563 2024.5

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Docetaxel (DTX) is commonly used as a primary chemotherapy, and cabazitaxel (CBZ) has shown efficacy in patients who are DTX resistant. Primary prophylactic granulocyte colony stimulating factor (G-CSF) therapy is currently used with CBZ treatment in routine clinical care in Japan. METHODS: In this study, we performed a systematic review following the Minds guidelines to investigate the effectiveness and safety of primary prophylaxis with G-CSF during chemotherapy for prostate cancer and to construct G-CSF guidelines for primary prophylaxis use during chemotherapy. A comprehensive literature search of various electronic databases (PubMed, Cochrane Library, and Ichushi) was performed on January 10, 2020, to identify studies published between January 1990 and December 31, 2019 that investigate the impact of primary prophylaxis with G-CSF during CBZ administration on clinical outcomes. RESULTS: Ultimately, nine articles were included in the qualitative systematic review. Primary G-CSF prophylaxis during CBZ administration for metastatic castration-resistant prostate cancer was difficult to assess in terms of correlation with overall survival, mortality from infection, and patients' quality of life. These difficulties were owing to the lack of randomized controlled trials comparing patients with and without primary prophylaxis of G-CSF during CBZ administration. However, some retrospective studies have suggested that it may reduce the incidence of febrile neutropenia. CONCLUSION: G-CSF may be beneficial as primary prophylaxis during CBZ administration for metastatic castration resistant prostate cancer, and we made a "weak recommendation to perform" with an annotation of the relevant regimen.

DOI： 10.1007/s10147-024-02501-7

Effectiveness and safety of primary prophylaxis with G-CSF for lung cancer: a systematic review and meta-analysis to develop clinical practice guidelines for the use of G-CSF 2022

Eiki Ichihara, Nobuaki Ochi, Go Makimoto, Kenichiro Kudo, Daijiro Harada, Yukinori Ozaki, Hiroshi Nishio, Kenji Tsuchihashi, Yuji Miura, Makoto Endo, Shingo Yano, Dai Maruyama, Tetsuhiro Yoshinami, Nobuyuki Susumu, Munetaka Takekuma, Takashi Motohashi, Mamoru Ito, Eishi Baba, Keita Uchino, Takahiro Kimura, Yutaro Kamiyama, Shinji Nakao, Shinobu Tamura, Hitomi Nishimoto, Yasuhisa Kato, Atsushi Sato, Toshimi Takano, Toshio Kubo

International Journal of Clinical Oncology 29 ( 4 ) 355 - 362 2024.2

Efficacy and Safety of Re-administration of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) After EGFR-TKI-Induced Interstitial Lung Disease (CS-Lung-005). International journal

Nobuhiro Kanaji, Eiki Ichihara, Takaaki Tanaka, Takashi Ninomiya, Toshiyuki Kozuki, Nobuhisa Ishikawa, Kazuya Nishii, Hiroyasu Shoda, Kakuhiro Yamaguchi, Keita Kawakado, Yuko Toyoda, Masaaki Inoue, Nobuyuki Miyatake, Naoki Watanabe, Takuya Inoue, Hitoshi Mizoguchi, Yuta Komori, Kazuki Kojima, Norimitsu Kadowaki

Lung 202 ( 1 ) 63 - 72 2024.2

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: This study investigated the safety and efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) re-administration after recovery from EGFR-TKI-induced interstitial lung disease (ILD). METHODS: This multicenter retrospective study collected data from consecutive advanced NSCLC patients who underwent EGFR-TKI re-administration after recovery from EGFR-TKI-induced ILD. RESULTS: Fifty-eight patients were registered. The grades of initial TKI-induced ILD were grade 1 to 4. TKIs used for re-administration were erlotinib for 15 patients, osimertinib for 15, gefitinib for 14, afatinib for 13 patients, and dacomitinib for 1 patient. ILD recurred in 13 patients (22.4%), comprising 3 patients with grade 1, 6 patients with grade 2, and 4 patients with grade 3. No significant associations were found between ILD recurrence and age, smoking history, performance status, time from initial ILD to TKI re-administration, or concomitant corticosteroid use. However, the incidence of ILD recurrence was high in cases of repeated use of gefitinib or erlotinib or first time use of osimertinib at TKI re-administration. The ILD recurrence rate was lowest in patients treated with first time use of gefitinib (8%) or erlotinib (8%), followed by patients treated with repeated use of osimertinib (9%). The response rate, median progression-free survival by TKI re-administration, and median overall survival were 55%, 9.6 and 84.8 months, respectively. CONCLUSION: This study showed that EGFR-TKI re-administration is a feasible and effective treatment for patients who recovered from EGFR-TKI-induced ILD. Our results indicate that re-administration of EGFR-TKI is an important option for long-term prognosis after recovery from EGFR-TKI-induced ILD.

DOI： 10.1007/s00408-023-00669-9

Protracted coronavirus disease 2019 after chimeric antigen receptor-T cell therapy successfully treated with sequential multidrug therapy. International journal

Masahiro Yamashita, Hisao Higo, Nobuharu Fujii, Chiaki Matsumoto, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Kammei Rai, Eiki Ichihara, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Nobuaki Miyahara

Respiratory medicine case reports 51 102104 - 102104 2024

Language：English Publishing type：Research paper (scientific journal)

A 56-year-old woman who received CD19 chimeric antigen receptor-T cell therapy for refractory diffuse large B-cell lymphoma developed severe coronavirus disease 2019 (COVID-19) and was treated with nirmatrelvir/ritonavir in April 2022. However, she experienced persistent fatigue and cough and fever in June. Computed tomography revealed bilateral ground-glass opacities (GGO), and the patient was treated with corticosteroids for organizing pneumonia after COVID-19. Partial improvement was observed, but new GGO appeared despite corticosteroid therapy. Genome analysis of severe acute respiratory syndrome coronavirus 2 detected Omicron variant BA.1.1.2, which was prevalent at the time of initial infection. The patient was diagnosed with protracted COVID-19 and was treated with remdesivir, molnupiravir, nirmatrelvir/ritonavir, and tixagevimab/cilgavimab. These treatments appeared to contribute to the improvement of protracted COVID-19.

DOI： 10.1016/j.rmcr.2024.102104

Prospective observational study to explore genes and proteins predicting efficacy and safety of brigatinib for ALK-gene rearranged non-small-cell lung cancer: study protocol for ABRAID study (WJOG11919L). International journal

Yuichi Ozawa, Yasuhiro Koh, Tetsunari Hase, Kenji Chibana, Kyoichi Kaira, Kyoichi Okishio, Eiki Ichihara, Shuji Murakami, Mototsugu Shimokawa, Nobuyuki Yamamoto

Therapeutic advances in medical oncology 16 17588359231225046 - 17588359231225046 2024

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: ALK-tyrosine kinase inhibitors (ALK-TKIs) are effective for treating non-small-cell lung cancer with ALK gene rearrangement; however, resistance is inevitable. Brigatinib is a unique ALK-TKI that is effective against many resistance mutations. However, data on factors associated with its efficacy and resistance mechanisms are limited. OBJECTIVES: This study will evaluate the efficacy and safety of brigatinib in the real world and explore factors related to its efficacy, safety, and resistance mechanisms. DESIGN: Prospective observational study. ETHICS: This study is approved by the Ethics Committee of Wakayama Medical University. Written informed consent will be obtained from all patients before study-related procedures. METHODS AND ANALYSIS: This study comprises three cohorts. Cohorts A, B, and 0 will enroll patients receiving alectinib as the first ALK-TKI, receiving alectinib as the first ALK-TKI and subsequently cytotoxic agents and/or lorlatinib after alectinib, and without a history of ALK-TKI, respectively. Overall, 100, 30, and 50 patients will be enrolled in Cohorts A, B, and 0, respectively. Circulating tumor DNA before starting brigatinib and at disease progression will be analyzed in all cohorts using a hypersensitive next-generation sequencing (NGS) PGDx Elio plasma resolve panel. Serum protein levels will be analyzed using the Milliplex xMAP assay system with a Luminex 200 (Luminex, Austin, USA). The enrollment period is 31 months and the patients will be observed for 2 years after enrollment. Archived tissues will be collected for NGS analysis, gene expression analysis, and immunohistochemistry staining 1 year after completion of registration. Quality of life and safety evaluation using electronic patient-reported outcomes will be investigated. DISCUSSION: This study will elucidate predictors of ALK-TKI efficacy and resistance mechanisms and evaluate the efficacy and safety of brigatinib in a real-world setting. The results will provide crucial information for establishing treatment strategies, discovering novel biomarkers, and developing new therapeutic agents. TRIAL REGISTRATION: UMIN000042439.

DOI： 10.1177/17588359231225046

CDK4/6 signaling attenuates the effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer. International journal

Naofumi Hara, Eiki Ichihara, Hirohisa Kano, Chihiro Ando, Ayako Morita, Tatsuya Nishi, Sachi Okawa, Takamasa Nakasuka, Atsuko Hirabae, Masaya Abe, Noboru Asada, Kiichiro Ninomiya, Go Makimoto, Masanori Fujii, Toshio Kubo, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Translational lung cancer research 12 ( 10 ) 2098 - 2112 2023.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations, such as exon 19 deletion and exon 21 L858R, are driver oncogenes of non-small cell lung cancer (NSCLC), with EGFR tyrosine kinase inhibitors (TKIs) being effective against EGFR-mutant NSCLC. However, the efficacy of EGFR-TKIs is transient and eventually leads to acquired resistance. Herein, we focused on the significance of cell cycle factors as a mechanism to attenuate the effect of EGFR-TKIs in EGFR-mutant NSCLC before the emergence of acquired resistance. METHODS: Using several EGFR-mutant cell lines, we investigated the significance of cell cycle factors to attenuate the effect of EGFR-TKIs in EGFR-mutant NSCLC. RESULTS: In several EGFR-mutant cell lines, certain cancer cells continued to proliferate without EGFR signaling, and the cell cycle regulator retinoblastoma protein (RB) was not completely dephosphorylated. Further inhibition of phosphorylated RB with cyclin-dependent kinase (CDK) 4/6 inhibitors, combined with the EGFR-TKI osimertinib, enhanced G0/G1 cell cycle accumulation and growth inhibition of the EGFR-mutant NSCLC in both in vitro and in vivo models. Furthermore, residual RB phosphorylation without EGFR signaling was maintained by extracellular signal-regulated kinase (ERK) signaling, and the ERK inhibition pathway showed further RB dephosphorylation. CONCLUSIONS: Our study demonstrated that the CDK4/6-RB signal axis, maintained by the MAPK pathway, attenuates the efficacy of EGFR-TKIs in EGFR-mutant NSCLC, and targeting CDK4/6 enhances this efficacy. Thus, combining CDK4/6 inhibitors and EGFR-TKI could be a novel treatment strategy for TKI-naïve EGFR-mutant NSCLC.

DOI： 10.21037/tlcr-23-99

未治療Uncommon EGFR遺伝子変異陽性NSCLCへのアファチニブとプラチナ併用のランダム化第III相試験(ACHILLES/TORG1834)

吉岡弘鎮, 三浦理, 三角俊裕, 倉田宝保, 時任高章, 福原達朗, 佐藤悠城, 白石祥理, 楠原政一郎, 寺岡俊輔, 加藤晃史, 堀之内秀仁, 滝口裕一, 後藤康洋, 田中謙太郎, 金津正樹, 池田慧, 市原英基, 田中洋史, 岡本浩明

肺癌 63 ( 5 ) 427 - 427 2023.10

Efficacy of gilteritinib in comparison with alectinib for the treatment of ALK-rearranged non-small cell lung cancer. International journal

Chihiro Ando, Eiki Ichihara, Tatsuya Nishi, Ayako Morita, Naofumi Hara, Kenji Takada, Takamasa Nakasuka, Hiromi Watanabe, Hirohisa Kano, Kazuya Nishii, Go Makimoto, Takumi Kondo, Kiichiro Ninomiya, Masanori Fujii, Toshio Kubo, Kadoaki Ohashi, Ken-Ichi Matsuoka, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Cancer science 2023.9

Language：English Publishing type：Research paper (scientific journal)

Gilteritinib is a multitarget tyrosine kinase inhibitor (TKI), approved for the treatment of FLT3-mutant acute myeloid leukemia, with a broad range of activity against several tyrosine kinases including anaplastic lymphoma kinase (ALK). This study investigated the efficacy of gilteritinib against ALK-rearranged non-small cell lung cancers (NSCLC). To this end, we assessed the effects of gilteritinib on cell proliferation, apoptosis, and acquired resistance responses in several ALK-rearranged NSCLC cell lines and mouse xenograft tumor models and compared its efficacy to alectinib, a standard ALK inhibitor. Gilteritinib was significantly more potent than alectinib, as it inhibited cell proliferation at a lower dose, with complete attenuation of growth observed in several ALK-rearranged NSCLC cell lines and no development of drug tolerance. Immunoblotting showed that gilteritinib strongly suppressed phosphorylated ALK and its downstream effectors, as well as mesenchymal-epithelial transition factor (MET) signaling. By comparison, MET signaling was enhanced in alectinib-treated cells. Furthermore, gilteritinib was found to more effectively abolish growth of ALK-rearranged NSCLC xenograft tumors, many of which completely receded. Interleukin-15 (IL-15) mRNA levels were elevated in gilteritinib-treated cells, together with a concomitant increase in the infiltration of tumors by natural killer (NK) cells, as assessed by immunohistochemistry. This suggests that IL-15 production along with NK cell infiltration may constitute components of the gilteritinib-mediated antitumor responses in ALK-rearranged NSCLCs. In conclusion, gilteritinib demonstrated significantly improved antitumor efficacy compared with alectinib against ALK-rearranged NSCLC cells, which can warrant its candidacy for use in anticancer regimens, after further examination in clinical trial settings.

DOI： 10.1111/cas.15958

Severe Cytokine Release Syndrome and Immune Effector Cell-associated Neurotoxicity Syndrome in a Man Receiving Immune Checkpoint Inhibitors for Lung Cancer: A Case Report.

Takaaki Tanaka, Masataka Taoka, Go Makimoto, Kiichiro Ninomiya, Hisao Higo, Masanori Fujii, Eiki Ichihara, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda

Internal medicine (Tokyo, Japan) 2023.9

Language：English Publishing type：Research paper (scientific journal)

A 55-year-old man with stage IV lung adenocarcinoma was treated with cisplatin, pemetrexed, nivolumab, and ipilimumab. Approximately 100 days after treatment initiation, he became disoriented and presented to the emergency department with a high fever. Blood tests revealed liver and kidney dysfunctions. Subsequently, the patient developed generalized convulsions that required intensive care. He was clinically diagnosed with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Organ damage was gradually controlled with immunosuppressive drugs, including steroids, and the patient was discharged. Successful treatment is rare in patients with CRS, including ICANS, during immune checkpoint inhibitor treatment for solid tumors.

DOI： 10.2169/internalmedicine.2429-23

Efficacy of immune checkpoint inhibitor monotherapy in elderly patients with non-small-cell lung cancer. International journal

Toshio Kubo, Eiki Ichihara, Daijiro Harada, Koji Inoue, Keiichi Fujiwara, Sinobu Hosokawa, Daizo Kishino, Haruyuki Kawai, Nobuaki Ochi, Naohiro Oda, Naofumi Hara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Respiratory investigation 61 ( 5 ) 643 - 650 2023.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Limited information on anticancer therapy for super-elderly patients with non-small-cell lung cancer is available. Immune checkpoint inhibitors offer long-term survival to elderly patients aged ≥65 years with non-small-cell lung cancer. However, the efficacy and safety of immune checkpoint inhibitors in more elderly patients are not well understood. METHODS: We retrospectively evaluated the efficacy and safety of immune checkpoint inhibitors in patients aged ≥85 years with advanced non-small-cell lung cancer at nine centers using the Okayama Lung Cancer Study Group-Immunotherapy Database. RESULTS: Among 531 patients who received immune checkpoint inhibitors, 16 were aged ≥85 years (median, 86.5 years; range, 85-93 years). Many had high programmed death-ligand 1 expression and received pembrolizumab as first-line therapy. The objective response rate, median progression-free survival, and median survival time were 25% (95% confidence interval: 1-49), 2.8 months (95% confidence interval: 1.7-4.5), and not reached (95% confidence interval: 4.7-not reached), respectively. Moreover, the 4-year overall survival rate was 60.8% (95% confidence interval: 29.3-81.7), and a long-lasting effect of immune checkpoint inhibitors was observed even in patients aged ≥85 years. The incidence of immune-related and grade ≥3 immune-related adverse events was 32% and 6%, respectively. CONCLUSIONS: The effect and toxicity of immune checkpoint inhibitors for patients aged ≥85 years were acceptable. Immune checkpoint inhibitors may be a treatment option for patients aged ≥85 years.

DOI： 10.1016/j.resinv.2023.06.005

Low frequency of intracranial progression in advanced NSCLC patients treated with cancer immunotherapies. International journal

Naoya Kemmotsu, Kiichiro Ninomiya, Kei Kunimasa, Takamasa Ishino, Joji Nagasaki, Yoshihiro Otani, Hiroyuki Michiue, Eiki Ichihara, Kadoaki Ohashi, Takako Inoue, Motohiro Tamiya, Kazuko Sakai, Youki Ueda, Hiromichi Dansako, Kazuto Nishio, Katsuyuki Kiura, Isao Date, Yosuke Togashi

International journal of cancer 2023.8

Language：English Publishing type：Research paper (scientific journal)

Intracranial metastases are common in nonsmall-cell lung cancer (NSCLC) patients, whose prognosis is very poor. In addition, intracranial progression is common during systemic treatments due to the inability to penetrate central nervous system (CNS) barriers, whereas the intracranial effects of cancer immunotherapies remain unclear. We analyzed clinical data to evaluate the frequency of intracranial progression in advanced NSCLC patients treated with PD-1 blockade therapies compared with those treated without PD-1 blockade therapies, and found that the frequency of intracranial progression in advanced NSCLC patients treated with PD-1 blockade therapies was significantly lower than that in patients treated with cytotoxic chemotherapies. In murine models, intracranial rechallenged tumors after initial rejection by PD-1 blockade were suppressed. Accordingly, long-lived memory precursor effector T cells and antigen-specific T cells were increased by PD-1 blockade in intracranial lesions. However, intracranial rechallenged different tumors are not suppressed. Our results indicate that cancer immunotherapies can prevent intracranial progression, maintaining long-term effects intracranially as well as systemically. If intracranial recurrence occurs during the treatment with PD-1 blockade therapies, aggressive local therapies could be worthwhile.

DOI： 10.1002/ijc.34700

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