Faculty Profiles - SHIEN Kazuhiko

Papers - SHIEN Kazuhiko

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Long short-term memory algorithm for personalized tacrolimus dosing: A simple and effective time series forecasting approach post-lung transplantation

Haruki Choshi, Kentaroh Miyoshi, Maki Tanioka, Hayato Arai, Shin Tanaka, Kazuhiko Shien, Ken Suzawa, Mikio Okazaki, Seiichiro Sugimoto, Shinichi Toyooka

The Journal of Heart and Lung Transplantation 2025.3

Prognostic Analysis of Pathological Stage I Lung Adenocarcinoma Harboring Major EGFR Mutations. International journal

Shinkichi Takamori, Makoto Endo, Akira Hamada, Shuta Ohara, Shota Fukuda, Yasuaki Tomioka, Satoshi Takamori, Atsushi Osoegawa, Kotaro Nomura, Kosuke Fujino, Mao Yoshikawa, Ken Suzawa, Kazuhiko Shien, Kenichi Suda, Fumihiko Kinoshita, Kazuki Hayasaka, Hirotsugu Notsuda, Taichi Nagano, Kyoto Matsudo, Asato Hashinokuchi, Taichi Matsubara, Shinya Katsumata, Satoshi Shiono, Junichi Soh, Yasuhisa Ohde, Mototsugu Shimokawa

Clinical lung cancer 2024.12

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

BACKGROUND: While Epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma (LUAD) has favorable outcomes with targeted therapy, early-stage prognosis remains influenced by pathological factors and central nervous system (CNS) recurrence. The study aimed to clarify prognostic factors in pathological stage (pStage) I EGFR mutation-positive LUAD. METHODS: Between 2015 and 2018, 2,191 pStage I LUAD cases with known EGFR status (excluding EGFR testing after recurrence) who received anatomical resection were included from multiple institutions in Japan. Univariate and multivariate analyses of disease-free survival (DFS) and overall survival (OS) were performed. RESULTS: 1,073 (49.0%) cases harbored EGFR mutations, including 419 (19.1%) with 19del and 529 (24.1%) with L858R. In cases with major EGFR mutation (n = 948), multivariate analysis showed that the absence of noninvasive area (NIA) (hazard ratio [HR]: 1.778, 95% confidence interval [CI]: 1.174-2.692, P = .0065), pStage (IA2 vs. IA1, HR: 2.079, 95% CI: 1.129-3.827, P = .0345; IA3 vs. IA1, HR: 4.009, 95% CI: 2.088-7.696, P = .0001; IB vs. IA1, HR: 5.280, 95% CI: 2.871-9.709, P < .0001), and presence of lymphatic invasion (HR: 1.855, 95% CI: 1.103-3.119, P = .0197) were independent predictors of shorter DFS, and only advanced pStage was an independent predictor of CNS recurrence (relative risk for pStage IA3 or more: 9.729, P < .0001). CONCLUSION: In EGFR mutation-positive pStage I LUAD, those without NIA, with higher pStage and lymphatic invasion were independent predictive factors for DFS, and pStage ≥ IA3 was an independent predictor of CNS recurrence.

DOI： 10.1016/j.cllc.2024.12.011

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Prognostic impact of PD-L1 expression in surgically resected EGFR-mutant lung adenocarcinoma: A real-world database study in Japan (CReGYT-01 EGFR study). International journal

Kotaro Nomura, Kazuki Takada, Fumihiko Kinoshita, Satoshi Muto, Taichi Matsubara, Yasunobu Kouki, Shinya Katsumata, Akira Hamada, Naoki Haratake, Kosuke Fujino, Mao Yoshikawa, Ken Suzawa, Kazuhiko Shien, Kenichi Suda, Shuta Ohara, Shota Fukuda, Hiroyuki Suzuki, Tatsuro Okamoto, Fumihiko Hirai, Keiju Aokage, Satoshi Shiono, Junichi Soh, Masahiro Tsuboi, Mototsugu Shimokawa, Yasuhisa Ohde

International journal of cancer 2024.11

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

The expression of programmed cell death-ligand 1 (PD-L1) and mutation in epidermal growth factor receptor (EGFR) are biomarkers used for perioperative treatment of lung adenocarcinoma. However, the clinical significance of PD-L1 expression in surgically resected EGFR-mutant lung adenocarcinoma remains unclear. We conducted a real-world database of patients with surgically resected lung adenocarcinoma from 2015 to 2018 was constructed across 21 centers in Japan. The association among PD-L1 expression, EGFR mutations, and prognosis was evaluated. Among 847 patients, PD-L1 expression was negative (tumor proportion score [TPS] < 1%) in 429 (51%), weakly positive (TPS = 1%-49%) in 275 (32%), and strongly positive (TPS ≥50%) in 143 (17%) patients. EGFR mutations were detected in 331 (39%) patients. PD-L1 expression was associated with poor recurrence-free survival (RFS) (p < .001) in both EGFR-mutant and wild-type patients. However, in EGFR-mutant patients, PD-L1 expression was not associated with overall survival (OS) (p = .506). Multivariable analysis confirmed an association between PD-L1 expression and RFS but not OS. Furthermore, in EGFR-mutant patients treated with EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment post-relapse, PD-L1 expression was not associated with overall response rate (p = .714), disease control rate (p = .554), or progression-free survival (p = .660). In conclusion, PD-L1 expression predicted poor RFS-independent EGFR status but did not show any association with OS in EGFR-mutant patients. The efficacy of post-relapse EGFR-TKI treatment was independent of PD-L1 expression. The significance of PD-L1 expression in perioperative EGFR-TKI therapy should be evaluated.

DOI： 10.1002/ijc.35270

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胸腺上皮性腫瘍:再発治療、周術期治療、新規治療胸腺癌の術式と術後予後に関する多施設共同後ろ向き観察研究胸腺癌に対しての縮小手術は許容されるか

林龍也, 岡崎幹生, 土生智大, 枝園和彦, 諏澤憲, 山本寛斉, 大塚智昭, 渡邉元嗣, 山田英司, 藤原俊哉, 葉山牧夫, 山根正修, 井野川英利, 平見有二, 青江基, 山下素弘, 佐野由文, 中田昌男, 豊岡伸一

日本胸部外科学会定期学術集会 77回 LPD2 - 3 2024.11

肺癌周術期治療の現在と未来術前導入化学放射線療法の経験に基づく当院の肺がん周術期治療の現状と工夫

枝園和彦, 柳光剛志, 富岡泰章, 田中真, 諏澤憲, 三好健太郎, 岡崎幹生, 杉本誠一郎, 豊岡伸一

日本癌治療学会学術集会抄録集 62回 OSY1 - 5 2024.10

局所進行肺癌に対する治療を再考する切除可能局所進行肺癌に対する導入化学放射線療法の長期成績

諏澤憲, 岡田和大, 柳光剛志, 富岡泰章, 田中真, 枝園和彦, 三好健太郎, 岡崎幹生, 杉本誠一郎, 豊岡伸一

日本癌治療学会学術集会抄録集 62回 OPD5 - 5 2024.10

臓器移植レシピエントの感染症肺移植レシピエントにおける新型コロナウイルス感染症 5類移行後の現状

妹尾知哉, 杉本誠一郎, 調枝治樹, 柳光剛志, 富岡泰章, 田中真, 石原恵, 堂口佳子, 枝園和彦, 諏澤憲, 三好健太郎, 岡崎幹生, 豊岡伸一

移植 59 ( 総会臨時 ) 161 - 161 2024.9

肺移植後長期管理 Up to date 肺移植後の慢性腎臓病に対する長期管理 up to date

杉本誠一郎, 柳光剛志, 富岡泰章, 田中真, 石原恵, 堂口佳子, 諏澤憲, 枝園和彦, 三好健太郎, 岡崎幹生, 豊岡伸一

移植 59 ( 総会臨時 ) 173 - 173 2024.9

再肺移植後急性期に膵頭部癌による出血性膵炎を繰り返したNightmare case

林龍也, 田中真, 石原恵, 堂口佳子, 梅田将志, 調枝治樹, 柳光剛志, 富岡泰章, 枝園和彦, 諏澤憲, 三好健太郎, 岡崎幹生, 杉本誠一郎, 豊岡伸一

移植 59 ( 総会臨時 ) 255 - 255 2024.9

脳死片肺移植後の抗体関連型拒絶反応に対する集学的治療の経験

調枝治樹, 杉本誠一郎, 柳光剛志, 富岡泰章, 田中真, 堂口佳子, 石原恵, 枝園和彦, 諏澤憲, 三好健太郎, 岡崎幹生, 豊岡伸一

移植 59 ( 総会臨時 ) 294 - 294 2024.9

両側脳死肺移植後のサイトメガロウイルス感染症の予防にレテルモビルが有効だった一例

俣野貴慶, 杉本誠一郎, 田中真, 柳光剛志, 調枝治樹, 富岡泰章, 堂口佳子, 石原恵, 諏澤憲, 枝園和彦, 三好健太郎, 岡崎幹生, 豊岡伸一

移植 59 ( 総会臨時 ) 373 - 373 2024.9

肺移植後の機能性ディスペプシアに対しPEG-J留置が奏功した一例

柳光剛志, 杉本誠一郎, 田中真, 富岡泰章, 石原恵, 堂口佳子, 枝園和彦, 諏澤憲, 三好健太郎, 岡崎幹生, 豊岡伸一

移植 59 ( 総会臨時 ) 374 - 374 2024.9

Prophylactic effect of tissue flap in the prevention of bronchopleural fistula after surgery for lung cancer. Reviewed

Tomohiro Habu, Hiromasa Yamamoto, Kentaro Nakata, Kohei Hashimoto, Shin Tanaka, Kazuhiko Shien, Ken Suzawa, Kentaroh Miyoshi, Mikio Okazaki, Seiichiro Sugimoto, Shinichi Toyooka

Surgery today 2024.8

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

PURPOSE: Bronchopleural fistula (BPF) is a serious complication of lung resection. To avoid BPF, the bronchial stump/anastomotic site is often covered with a flap of surrounding tissue. One risk factor for BPF is radical lung resection after induction chemoradiotherapy for lung cancer. We retrospectively reviewed our database to elucidate the characteristics of tissue flaps that prevent BPF. METHODS: This retrospective study included 152 patients treated between 1999 and 2019. We examined the clinicopathological characteristics, including the type and thickness of the tissue flap used to cover the bronchial stump/anastomotic site, and postoperative complications, including BPF. RESULTS: BPF occurred in 5 patients (3.3%). All 5 patients had complications that could have affected delayed wound healing, such as pneumonia. The covering tissue flap thickness was significantly greater in patients without BPF than in those who developed BPF (p = 0.0290). Additionally, the tissue flap thickness was significantly greater than in those with BPF (p = 0.0077), even in high-risk patients who developed pneumonia or radiation pneumonitis on the operative side within 6 months postoperatively. CONCLUSION: Perioperative management is crucial to avoid complications affecting the healing of the bronchial stump/anastomotic site, and the covering tissue flap thickness may be an important factor in avoiding or minimizing BPF.

DOI： 10.1007/s00595-024-02927-6

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Augmented humoral response to third and fourth dose of SARS-CoV-2 mRNA vaccines in lung transplant recipients. Reviewed International journal

Shinichi Kawana, Seiichiro Sugimoto, Kei Matsubara, Haruki Choshi, Shin Tanaka, Megumi Ishihara, Tomohiro Habu, Kohei Hashimoto, Ken Suzawa, Kazuhiko Shien, Kentaroh Miyoshi, Mikio Okazaki, Masanori Nakayama, Shinichi Toyooka

Respiratory investigation 62 ( 5 ) 804 - 810 2024.7

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

BACKGROUND: Since lung transplant recipients (LTRs) exhibit low immunogenicity after two doses of SARS-CoV-2 mRNA vaccines, optimal vaccine strategies for SARS-CoV-2 are required in LTRs. This study aimed to investigate the efficacy and safety of the third and fourth doses of the SARS-CoV-2 mRNA vaccines in LTRs. METHODS: We conducted a single-center study of 73 LTRs and 23 healthy controls (HCs). Participants received two-to-four doses of SARS-CoV-2 mRNA vaccines. The LTRs were divided into three groups based on the number of vaccine dose. IgG titers against SARS-CoV-2 spike protein were measured, and adverse events were assessed. Factors associated with humoral response were analyzed using univariate and multivariate analyses. RESULTS: The Dose 4 group (n = 27) had a higher humoral response rate (P = 0.018) and higher levels of anti-SARS-CoV-2 IgG antibody (P = 0.04) than the Dose 2 group (n = 14). The Dose 3 group (n = 32) had lower humoral response rates (P = 0.005) and levels of anti-SARS-CoV-2 IgG antibody (P = 0.0005) than the HCs (n = 23) even after the same dose. Systemic adverse events were milder in the LTRs than in the HCs (P < 0.05). Increased number of vaccine dose was identified as a predictor of positive humoral response (P = 0.021). CONCLUSION: Booster doses of SARS-CoV-2 mRNA vaccines may enhance humoral response with mild adverse events in LTRs. Repeated vaccination might be warranted for LTRs to prevent SARS-CoV-2 infection.

DOI： 10.1016/j.resinv.2024.07.004

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Utility of neutrophil-to-lymphocyte ratio as an indicator of tumor immune status in non-small cell lung cancer. Reviewed International journal

Kazuma Iwata, Ken Suzawa, Kohei Hashimoto, Shin Tanaka, Kazuhiko Shien, Kentaroh Miyoshi, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Shinichi Toyooka

Japanese journal of clinical oncology 54 ( 8 ) 895 - 902 2024.5

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

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been reported as a prognostic biomarker in non-small cell lung cancer (NSCLC); however, the underlying biological rationale remains unclear. The present study aimed to explore the potential utility of NLR as a surrogate biomarker for immune response to cancer and to elucidate the underlying mechanism. METHODS: This retrospective study included the medical records of 120 patients with NSCLC who underwent surgery at the study institution in 2012. NLR in peripheral blood was determined from blood test within 30 days before surgery. Tumor immune status was evaluated using immunohistochemical staining to identify CD3+, CD8+ and FOXP3+ tumor-infiltrating lymphocytes (TILs), and the relationship of NLR, with clinicopathologic characteristics including 5-year overall survival (OS), and the tumor immune status was investigated. The median values of NLR and TIL count were used as cutoff points. RESULTS: The 5-year OS was significantly better in patients with low NLR (<2.2) than in those with high NLR (≥2.2) (70.1% vs. 56.8%, P = 0.042) and in patients with high CD3+ TIL count (≥242) than in those with low CD3+ TIL count (<242) (70% vs. 56.8%, P = 0.019). Additionally, the CD3+ TIL count was negatively correlated with preoperative NLR (P = 0.005). CONCLUSION: NLR might potentially reflect the immune status of tumor microenvironment, explaining its impact on prognosis of patients with NSCLC.

DOI： 10.1093/jjco/hyae058

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Postoperative Complications in Living Donors for Lung Transplantation. Reviewed International journal

Shin Tanaka, Kento Fujii, Megumi Ishihara, Haruki Choshi, Kei Matsubara, Kohei Hashimoto, Shuji Okahara, Kazuhiko Shien, Ken Suzawa, Kentaroh Miyoshi, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Shinichi Toyooka

Transplantation direct 10 ( 5 ) e1617 2024.5

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

BACKGROUND: Living donor lobar lung transplantation is a life-saving procedure for critically ill patients. This requires 2 healthy donors exposed to risks and without medical benefit. Therefore, the donor's safety and minimal postoperative complications are crucial. This study aimed to investigate the short-term outcomes and identify the risk factors affecting these outcomes. METHODS: The data of 175 living donors enrolled between 1998 and 2022 were analyzed. Donors were divided into era 1 (1998-2009) and era 2 (2010-2022). RESULTS: The overall incidence of postoperative complications was 39%, of which 7% were major complications. Donors who underwent surgery on the right side had a higher incidence of delayed pulmonary fistulae (P = 0.01) and elevated liver enzyme levels (P = 0.028). Living donor surgery on the right side (P = 0.01), era 2 (P = 0.01), and the need for plasty (P = 0.04) were predictors of postoperative complications. CONCLUSIONS: Updated data on complications and their correlation with postoperative quality of life from this study could aid in the selection of potential donors and facilitate informed consent.

DOI： 10.1097/TXD.0000000000001617

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Adrenergic microenvironment driven by cancer‐associated Schwann cells contributes to chemoresistance in patients with lung cancer Reviewed International journal

Yusuke Otani, Haruyoshi Katayama, Yidan Zhu, Rongsheng Huang, Takafumi Shigehira, Kazuhiko Shien, Ken Suzawa, Hiromasa Yamamoto, Tadahiko Shien, Shinichi Toyooka, Atsushi Fujimura

Cancer Science 115 ( 7 ) 2333 - 2345 2024.4

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

Doublecortin (DCX)-positive neural progenitor-like cells are purported components of the cancer microenvironment. The number of DCX-positive cells in tissues reportedly correlates with cancer progression; however, little is known about the mechanism by which these cells affect cancer progression. Here we demonstrated that DCX-positive cells, which are found in all major histological subtypes of lung cancer, are cancer-associated Schwann cells (CAS) and contribute to the chemoresistance of lung cancer cells by establishing an adrenergic microenvironment. Mechanistically, the activation of the Hippo transducer YAP/TAZ was involved in the acquisition of new traits of CAS and DCX positivity. We further revealed that CAS express catecholamine-synthesizing enzymes and synthesize adrenaline, which potentiates the chemoresistance of lung cancer cells through the activation of YAP/TAZ. Our findings shed light on CAS, which drive the formation of an adrenergic microenvironment by the reciprocal regulation of YAP/TAZ in lung cancer tissues.

DOI： 10.1111/cas.16164

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Effective division of the intersegmental plane using a robotic stapler in robotic pulmonary segmentectomy. Reviewed

Mikio Okazaki, Ken Suzawa, Kazuhiko Shien, Kohei Hashimoto, Shin Tanaka, Kentaroh Miyoshi, Hiromasa Yamamoto, Seiichiro Sugimoto, Shinichi Toyooka

Surgery today 2024.4

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

PURPOSES: Robot-assisted thoracoscopic (RATS) segmentectomy is becoming increasingly common because of the expanded indications for segmentectomy and the widespread adoption of robotic surgery. The precise division of the intersegmental plane is necessary to ensure oncologic margins from the tumor and to preserve the lung function. In this study, we present a strategy for accurately dividing the intersegmental plane using a robotic stapler and review the surgical outcomes. METHODS: RATS portal segmentectomy was performed using the Da Vinci Xi system and the intersegmental plane was dissected using a robotic stapler. We evaluated the perioperative outcomes in 92 patients who underwent RATS portal segmentectomy between May 2020 and January 2023. These results were compared with those of 82 patients who underwent complete video-assisted thoracoscopic surgery (CVATS) during the same period. RESULTS: The operative and console times were 162 and 97 min, respectively. No intraoperative complications occurred, and postoperative complications were observed in four cases (4.3%). The operative time, blood loss, postoperative complications, and maximum incision size were significantly lower in the RATS group than in the CVATS group. However, RATS requires a significantly higher number of staplers than CVATS. CONCLUSIONS: The division of the intersegmental plane using a robotic stapler in RATS portal segmentectomy was, therefore, found to be safe and effective.

DOI： 10.1007/s00595-024-02840-y

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Impact of the neutrophil-to-lymphocyte ratio on patients with locally advanced non-small cell lung cancer who suffer radiation pneumonitis during the course of induction chemoradiotherapy followed by surgery. Reviewed

Yujiro Kubo, Hiromasa Yamamoto, Kei Matsubara, Kohei Hashimoto, Shin Tanaka, Kazuhiko Shien, Ken Suzawa, Kentaroh Miyoshi, Mikio Okazaki, Seiichiro Sugimoto, Kuniaki Katsui, Takao Hiraki, Katsuyuki Kiura, Shinichi Toyooka

Surgery today 54 ( 9 ) 995 - 1004 2024.3

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

PURPOSE: Radiation pneumonitis (RP) is an obstacle for patients after surgery following induction chemoradiotherapy for locally advanced non-small cell lung cancer (LA-NSCLC). We performed a comparative analysis of the association between clinicopathological factors, including the neutrophil-to-lymphocyte ratio (NLR) and prognosis, in LA-NSCLC patients with or without RP during induction chemoradiotherapy followed by surgery. METHODS: The subjects of this analysis were 168 patients undergoing trimodality therapy for LA-NSCLC between January, 1999 and May, 2019. Patients were divided into two groups: the RP group (n = 41) and the non-RP group (n = 127). We compared the clinicopathological factors including the NLR between the groups and analyzed the association between the NLR and prognosis. RESULTS: The RP group had more patients with tumors located in the lower lobe, more bilobar resections, shorter operative times, no implementation of postoperative adjuvant chemotherapy, and a higher postoperative NLR than the non-RP group. There were no significant differences in serious postoperative complications and the prognosis. Patients with a low postoperative NLR had a significantly better prognosis in the non-RP group, and a trend toward a better prognosis even in the RP group. CONCLUSION: Postoperative NLR may be a useful prognostic factor, even for patients who suffer RP after trimodality therapy for LA-NSCLC.

DOI： 10.1007/s00595-024-02816-y

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Impact of central nervous system metastasis after complete resection of lung adenocarcinomas harboring common EGFR mutation - A real-world database study in Japan: The CReGYT-01 EGFR study. Reviewed International journal

Shinya Katsumata, Mototsugu Shimokawa, Akira Hamada, Naoki Haratake, Kotaro Nomura, Kosuke Fujino, Mao Yoshikawa, Ken Suzawa, Kazuhiko Shien, Kenichi Suda, Shuta Ohara, Shota Fukuda, Fumihiko Kinoshita, Kazuki Hayasaka, Hirotsugu Notsuda, Shinkichi Takamori, Satoshi Muto, Yusuke Takanashi, Kiyomichi Mizuno, Akikazu Kawase, Takamitsu Hayakawa, Keigo Sekihara, Michihito Toda, Somei Matsuo, Kyoshiro Takegahara, Masaki Hashimoto, Kenta Nakahashi, Makoto Endo, Hiroki Ozawa, Ryo Fujikawa, Yasuaki Tomioka, Kei Namba, Taichi Matsubara, Jun Suzuki, Hikaru Watanabe, Kazuki Takada, Hironobu Hoshino, Taisuke Kaiho, Takahide Toyoda, Yasunobu Kouki, Satoshi Shiono, Junichi Soh, Yasuhisa Ohde

European journal of cancer (Oxford, England : 1990) 201 113951 - 113951 2024.2

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

OBJECTIVES: To clarify the impact of central nervous system (CNS) metastasis on performance status (PS) at relapse, on subsequent treatment(s), and on survival of patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutation. METHODS: We conducted the multicenter real-world database study for patients with radical resections for lung adenocarcinomas between 2015 and 2018 at 21 centers in Japan. EGFR mutational status was examined at each center. RESULTS: Of 4181 patients enrolled, 1431 underwent complete anatomical resection for lung adenocarcinoma harboring common EGFR mutations. Three-hundred-and-twenty patients experienced disease relapse, and 78 (24%) had CNS metastasis. CNS metastasis was significantly more frequent in patients with conventional adjuvant chemotherapy than those without (30% vs. 20%, P = 0.036). Adjuvant chemotherapy did not significantly improve relapse-free survival at any pathological stage (adjusted hazard ratio for stage IA2-3, IB, and II-III was 1.363, 1.287, and 1.004, respectively). CNS metastasis did not affect PS at relapse. Subsequent treatment, mainly consisting of EGFR-tyrosine kinase inhibitors (TKIs), could be equally given in patients with or without CNS metastasis (96% vs. 94%). Overall survival after relapse was equivalent between patients with and without CNS metastasis. CONCLUSION: The efficacy of conventional adjuvant chemotherapy may be limited in patients with lung adenocarcinoma harboring EGFR mutations. CNS metastasis is likely to be found in practice before deterioration in PS, and may have little negative impact on compliance with subsequent EGFR-TKIs and survival after relapse. In this era of adjuvant TKI therapy, further prospective observational studies are desirable to elucidate the optimal management of CNS metastasis.

DOI： 10.1016/j.ejca.2024.113951

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