31 results on '"Ryota Shibaki"'
Search Results
2. Concurrent High PD-L1 Expression and CD8+ Immune Cell Infiltration Predict PD-1 Blockade Efficacy in Advanced EGFR-Mutant NSCLC Patients
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Yukiko Shimoda, Ryota Shibaki, Tatsuya Yoshida, Shuji Murakami, Masayuki Shirasawa, Masahiro Torasawa, Yuji Matsumoto, Ken Masuda, Yuki Shinno, Yusuke Okuma, Yasushi Goto, Hidehito Horinouchi, Noboru Yamamoto, Yuichiro Ohe, and Noriko Motoi
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Pulmonary and Respiratory Medicine ,Cancer Research ,Oncology - Published
- 2022
3. Impact of pre‐existing interstitial lung abnormal shadow on lung injury development and severity in patients of non‐small cell lung cancer treated with osimertinib
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Ryota Shibaki, Yuichi Ozawa, Susumu Noguchi, Yusuke Murakami, Eri Takase, Yuichiro Azuma, Masaru Maebeya, Takeya Sugimoto, Atsushi Hayata, Takahiro Hayakawa, Shinya Tamaki, Masanori Nakanishi, Shunsuke Teraoka, and Hiroaki Akamatsu
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ErbB Receptors ,Cancer Research ,Lung Neoplasms ,Oncology ,Carcinoma, Non-Small-Cell Lung ,Mutation ,Humans ,Radiology, Nuclear Medicine and imaging ,Protein Kinase Inhibitors ,Lung ,Retrospective Studies - Abstract
First-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) sometimes causes lung injury, thereby affecting survival. Although pre-existing interstitial lung abnormal shadow (pre-ILS) increases the risk of lung injury by EGFR-TKIs, its impact on osimertinib, a third-generation EGFR-TKI, remains unknown.This retrospective cohort study consecutively enrolled patients of EGFR-mutated non-small cell lung cancer treated with osimertinib. Computed tomography images were obtained and evaluated independently by three pulmonologists in a blinded manner. Factors associated with lung injury were assessed using a logistic regression model. Survival curves were calculated by the Kaplan-Meier method and compared using a log-rank test.Of the 195 patients, 40 had pre-ILS, and 21 (8 with and 13 without pre-ILS) developed lung injury during the observation period. Multivariate analysis revealed that pre-ILS was independently associated with lung injury (odds ratio, 3.1; 95% confidence interval [CI], 1.1-8.2; p = 0.025). Severe (≥Grade 3) lung injury was observed in eight (4.1%) patients, of whom, two (5%) and six (3.9%) had and did not have pre-ILS (p = 0.67), respectively. Grade 5 lung injury was not observed, and survival curves were similar between the patients who developed lung injury and those who did not (median 11 vs. 12 months; hazard ratio, 1.2; 95% CI, 0.56-2.7; p = 0.60).Pre-ILS increased the risk of lung injury in patients of non-small cell lung cancer treated with osimertinib, while the severity of lung injury was not clearly affected by the presence of pre-ILS.
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- 2022
4. A phase II study of High-Flow Nasal Cannula for relieving dyspnea in advanced cancer patients
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Eri Takase, Hiroaki Akamatsu, Shunsuke Teraoka, Keita Nakaguchi, Masanori Tanaka, Takahiro Kaki, Katsuyuki Furuta, Koichi Sato, Eriko Murakami, Takeya Sugimoto, Ryota Shibaki, Daichi Fujimoto, Atsushi Hayata, Nahomi Tokudome, Yuichi Ozawa, Yasuhiro Koh, Masanori Nakanishi, Kuninobu Kanai, Toshio Shimokawa, and Nobuyuki Yamamoto
- Abstract
Background: The efficacy and tolerability of high-flow nasal cannula (HFNC) for relieving dyspnea in advanced cancer patients with limited prognosis requires elucidation. Methods: Patients with advanced cancer who had dyspnea at rest (numeric rating scale, NRS≥3) and respiratory failure were enrolled. They were treated with HFNC for five days. Primary endpoint was change of mean modified Borg scale at 24 hours. Key secondary endpoints consisted of change in modified Borg scale during the study period and feasibility (Trial Identifier, UMIN000035738). Results: Between February 2019 and February 2022, 25 patients were enrolled and 21 were analyzed. Twenty patients used inspired oxygen and the mean fraction of inspired oxygen (FiO2) was 0.34 (range, 0.21–1.0). At baseline, mean NRS (dyspnea) was 5.9 (range, 3–10). Median survival time was 19 days (range, 3–657). The change of mean modified Borg scale was 1.4 (80% confidence interval [CI]: 0.8–1.9) at 24 hours, 11 patients showed 1.5 points improvement of modified Borg scale. Within 1 hour, nine patients showed 1.5 points improvement of modified Borg scale and such early responders were likely to maintain dyspnea improvement for 24 hours. Nineteen patients could continue HFNC for 24 hours and 11 patients completed five days of HFNC. Conclusion: To our knowledge, this trial is the first prospective study to show the efficacy and tolerability of HFNC regarding dyspnea for five days in patients under palliative care. HFNC can be a palliative treatment option in advanced cancer patients with dyspnea.
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- 2023
5. Pneumonitis associated with pembrolizumab plus chemotherapy for non-squamous non-small cell lung cancer
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Daichi Fujimoto, Satoru Miura, Keisuke Tomii, Hiromitsu Sumikawa, Kenichi Yoshimura, Kazushige Wakuda, Yuko Oya, Toshihide Yokoyama, Takashi Kijima, Tetsuhiko Asao, Motohiro Tamiya, Atsushi Nakamura, Hiroshige Yoshioka, Takaaki Tokito, Shuji Murakami, Akihiro Tamiya, Hiroshi Yokouchi, Satoshi Watanabe, Ou Yamaguchi, Ryotaro Morinaga, Takayuki Jodai, Kentaro Ito, Yoshimasa Shiraishi, Yoshihito Kogure, Ryota Shibaki, and Nobuyuki Yamamoto
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Multidisciplinary - Abstract
Studies elucidating detailed characteristics of pneumonitis in association with chemo-immunotherapy are limited. We aimed to investigate the characteristics of images, prognostic factors, and clinical course of combination therapy associated with pneumonitis. A multicenter, retrospective cohort study of patients with non-squamous non-small cell lung cancer who received a combination of platinum, pemetrexed, and pembrolizumab was conducted. Patients with confirmed pneumonitis established by an independent multidisciplinary team were enrolled. For 53 patients with pneumonitis, radiographic features at diagnosis predominantly comprised an organizing pneumonia pattern (62%, 33/53). Twelve (23%) patients experienced a worsening respiratory status during pneumonitis management, which was associated with a high mortality rate (58%, 7/12) during treatment. Severe grade at pneumonitis diagnosis (p p = 0.002), and disease extent ≥ 25% in the lungs (p = 0.009) were significantly associated with worsening respiratory status. Furthermore, post-diagnosis survival was significantly worse in severe pneumonitis (p = 0.02) than in mild and in patients with the DAD pattern than in those without (p
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- 2023
6. Osimertinib as first-line treatment for advanced epidermal growth factor receptor mutation–positive non–small-cell lung cancer in a real-world setting (OSI-FACT)
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Hirotaka Matsumoto, Hidekazu Suzuki, Yoko Tsukita, Daisuke Arai, Satoshi Hara, Takeshi Uenami, Motohiro Tamiya, Shinsuke Tsumura, Asuka Okada, Yoshihiko Sakata, Takashi Yokoi, Hideki Ikeda, Megumi Inaba, Yuki Sato, Shinya Sakata, Hirotaka Maruyama, Hiroshi Kobe, Go Saito, Takuro Sakagami, Jun Morinaga, Ryota Shibaki, and Yuko Oya
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Antineoplastic Agents ,Metastasis ,Cohort Studies ,Interquartile range ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,medicine ,Humans ,Osimertinib ,Progression-free survival ,Lung cancer ,Aged ,Retrospective Studies ,Acrylamides ,Aniline Compounds ,business.industry ,Hazard ratio ,Middle Aged ,medicine.disease ,Progression-Free Survival ,Confidence interval ,Discontinuation ,ErbB Receptors ,Treatment Outcome ,Female ,business - Abstract
Osimertinib is the standard of care in the initial treatment for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer. However, clinical data and reliable prognostic biomarkers are insufficient.We performed a retrospective multicentre cohort study for 538 EGFR mutation-positive patients, who received osimertinib as the initial treatment between August 2018 and December 2019. The main outcome was progression-free survival (PFS).The median observation period was 14.7 months (interquartile range 11.4-20.0). The median PFS was 20.5 months (95% confidence interval [CI] 18.6-not reached). Multivariate analysis showed that sex (male) (hazard ratio [HR] 1.99, 95% CI 1.35-2.93, P = 0.001), malignant effusions (HR 1.51, 95% CI 1.11-2.04, P = 0.008), liver metastasis (HR 1.55, 95% CI 1.03-2.33, P = 0.037), advanced unresectable cases (HR 1.71, 95% CI, 1.04-2.82, P = 0.036), mutation type and programmed cell death-ligand 1 (PD-L1) expression were associated with PFS. The L858R (HR 1.55, 95% CI 1.01-2.38, P = 0.043) and uncommon mutations (HR 3.15, 95% CI 1.70-5.83, P 0.001) were associated with PFS. PD-L1 expression of 1-49% (HR 1.66, 95% CI 1.05-2.63, P = 0.029), ≥50% (HR 2.24, 95% CI 1.17-4.30, P = 0.015) and unknown (HR 1.53, 95% CI 1.05-2.22, P = 0.026) was associated with PFS. The main reasons for treatment discontinuation among 219 patients were disease progression (44.3%), pneumonitis (25.5%) and other adverse events (16.0%).During initial treatment with osimertinib, PD-L1 expression is significantly related to PFS. Adverse events are a noteworthy reason for discontinuation.
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- 2021
7. Clinical Course of Acute Exacerbation of Fibrosing Interstitial Lung Disease
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Katsuyuki Furuta, Daichi Fujimoto, Atsushi Matsunashi, Takeshi Morimoto, Masanori Tanaka, Ryota Shibaki, Yuri Shimada, Kazuma Nagata, Keisuke Tomii, and Nobuyuki Yamamoto
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No large-scale studies have reported on the clinical course of acute exacerbation of fibrosing interstitial lung disease (AE-FILD). We aimed to elucidate the clinical course of AE-FILD. We retrospectively included patients admitted with AE-FILD diagnosis. The clinical courses of AE-FILD were classified as consistent improvement after response to treatment (responder group); no response to treatment (non-responder group); improvement after treatment followed by worsening respiratory status not attributable to AE-FILD (complication group); and improvement after treatment followed by worsening respiratory status attributable to AE-FILD relapse (second-attack group). Among 340 patients, 123 died within 90 days, 265 responded, and 75 were refractory to initial treatment. Among patients who responded to treatment, 191, 26, 46, and 2 belonged to the responder, complication, second-attack, and unknown groups, respectively. Multivariate analysis revealed that high lactate dehydrogenase, high C-reactive protein, and low PaO2/FiO2 were associated with 90-day mortality (odds ratio [OR] 2.27, p = 0.002; OR 2.01, p = 0.008; and OR 1.70, p = 0.042, respectively). Of patients who responded to treatment, a second attack was strongly associated with 90-day mortality (OR 18.54, p
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- 2022
8. The safety, tolerability and pharmacokinetics of niraparib in Japanese patients with solid tumours: results of a phase I dose-escalation study
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Kan Yonemori, Akihiko Shimomura, Ryota Shibaki, Takafumi Koyama, Shigehisa Kitano, Ashish Suri, Yoichi Kase, Noboru Yamamoto, Shunsuke Kondo, Kenji Tamura, Shuuji Sumino, Satoru Iwasa, Jun Sato, and Toshio Shimizu
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Adult ,Male ,Oncology ,PARP Inhibitor ,Cancer Research ,medicine.medical_specialty ,Indazoles ,pharmacokinetics, PARP ,neoplasms ,Cmax ,Poly(ADP-ribose) Polymerase Inhibitors ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Japan ,Piperidines ,Pharmacokinetics ,Internal medicine ,medicine ,AcademicSubjects/MED00300 ,Humans ,Radiology, Nuclear Medicine and imaging ,030212 general & internal medicine ,Adverse effect ,Aged ,business.industry ,clinical trial ,General Medicine ,Drug holiday ,phase I ,Middle Aged ,medicine.disease ,Clinical trial ,Tolerability ,030220 oncology & carcinogenesis ,Cohort ,Original Article ,Female ,niraparib ,business ,Progressive disease - Abstract
Background Niraparib is the only poly (adenosine diphosphate-ribose)-polymerase (PARP) inhibitor available as oral monotherapy for maintenance, regardless of BRCA mutational status. Methods This phase I, open-label, non-randomized, dose-escalation study was conducted in Japan using a 3 + 3 design. Adults (≥20 years) with metastatic or locally advanced solid tumours were enrolled. Niraparib 200 mg (cohort 1) or 300 mg (cohort 2) was administered once daily in 21-day cycles (no drug holiday between cycles) until progressive disease (PD) or unacceptable toxicity. The primary objective was to evaluate the safety and tolerability of niraparib in Japanese patients with advanced solid tumours. The number of patients with dose-limiting toxicities in cycle 1 and number with treatment-emergent adverse events were primary endpoints. Secondary endpoints were pharmacokinetics and tumour response. Results There were three patients in cohort 1 and six patients in cohort 2. Only one patient, in cohort 2, developed a dose-limiting toxicity (grade 4 platelet count decreased). All patients in both cohorts developed treatment-emergent adverse events. The most common treatment-related treatment-emergent adverse events were decreased appetite (n = 2) in cohort 1, and platelet count decreased as well as aspartate aminotransferase increased (both n = 5) in cohort 2. Mean Cmax and AUC0–24 of niraparib increased dose-proportionally after multiple doses (accumulation ratio of between 1.64 and 3.65); median tmax was 3–4 h. Two patients, both in cohort 2, had a partial response to treatment. Conclusions Niraparib (200 or 300 mg/day) was tolerable and had a favourable pharmacokinetic profile in Japanese patients with advanced solid tumours., This study investigated the safety of niraparib in Japanese patients with metastatic or locally advanced solid tumours. One patient receiving 300 mg/day developed a dose-limiting toxicity (platelet count decreased)
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- 2021
9. Association between serum level soluble programmed cell death ligand 1 and prognosis in patients with non‐small cell lung cancer treated with <scp>anti‐PD</scp> ‐1 antibody
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Yuji Matsumoto, Yuichiro Ohe, Hidehito Horinouchi, Ryota Shibaki, Shuji Murakami, Noboru Yamamoto, Yasushi Goto, Shintaro Kanda, Yutaka Fujiwara, and Tatsuya Yoshida
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non‐small cell lung cancer ,Adult ,Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Lung Neoplasms ,Multivariate analysis ,soluble PD‐L1 ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,Gastroenterology ,Programmed cell death ligand 1 ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,mental disorders ,medicine ,Humans ,Anti‐PD‐1 antibody ,In patient ,Lung cancer ,Aged ,Aged, 80 and over ,biology ,business.industry ,Hazard ratio ,Original Articles ,General Medicine ,PD‐L1 TPS ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Original Article ,Female ,Nivolumab ,Antibody ,business - Abstract
Background Programmed cell death ligand 1 (PD‐L1) is known to have soluble forms aside from its membrane‐bound forms. The aim of this study was to evaluate the predictive and prognostic values of serum soluble PD‐L1 (sPD‐L1) in patients with non‐small cell lung cancer (NSCLC) who were treated with anti‐PD‐1 antibody. Methods A total of 233 patients were enrolled in this study. We assessed the level of serum sPD‐L1 before anti‐PD‐1 antibody treatment (pembrolizumab or nivolumab) and evaluated the correlation with PD‐L1 expression on tumor cells, the response to anti‐PD‐1 antibody treatment, and patient outcome. Results The median serum sPD‐L1 concentration was 67.7 (range, 25 to 223) pg/mL. A weak correlation between serum sPD‐L1 and tumor PD‐L1 expression was observed. The disease control rate in the high sPD‐L1 group (≥90 pg/mL) was significantly lower than that in the low sPD‐L1 group (, The PFS and OS of the high sPD‐L1 group were significantly shorter than those of the low sPD‐L1 group. The high level of serum sPD‐L1 was independently associated with a shorter PFS and OS.
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- 2020
10. Concurrent High PD-L1 Expression and CD8
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Yukiko, Shimoda, Ryota, Shibaki, Tatsuya, Yoshida, Shuji, Murakami, Masayuki, Shirasawa, Masahiro, Torasawa, Yuji, Matsumoto, Ken, Masuda, Yuki, Shinno, Yusuke, Okuma, Yasushi, Goto, Hidehito, Horinouchi, Noboru, Yamamoto, Yuichiro, Ohe, and Noriko, Motoi
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ErbB Receptors ,Lung Neoplasms ,Carcinoma, Non-Small-Cell Lung ,Mutation ,Programmed Cell Death 1 Receptor ,Tumor Microenvironment ,Humans ,CD8-Positive T-Lymphocytes ,B7-H1 Antigen ,Retrospective Studies - Abstract
The effectiveness of PD-1 blockade therapy in advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is limited. We investigated whether patient characteristics, PD-L1 expression, and immune cell (IC) status in the tumor microenvironment (TME) were associated with PD-1 blockade therapy outcomes.We retrospectively reviewed patients with advanced EGFR-mutant NSCLC treated with PD-1 blockade (nivolumab or pembrolizumab) between January 2016 and March 2018. The PD-L1 expression tumor proportion score (TPS) and types and distribution of ICs (CD8, PD-1, CD204, tumoral, and stromal) in the TME were analyzed.Among 57 EGFR-mutant NSCLC patients treated with PD-1 blockade, 39 patients had sufficient tissues for analyzing the TME. The overall response rate (ORR) of PD-1 blockade was 12.3%. Only tumoral CD8 positive (CD8Concurrent high PD-L1 expression and high tumoral CD8
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- 2022
11. Immune-Related Adverse Events by Immune Checkpoint Inhibitors Significantly Predict Durable Efficacy Even in Responders with Advanced Non-Small Cell Lung Cancer
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Nahomi Tokudome, Nobuyuki Yamamoto, Eri Takase, Atsushi Hayata, Eriko Murakami, Yuichi Ozawa, Masanori Tanaka, Ryota Shibaki, Shunsuke Teraoka, Takeya Sugimoto, Takahiro Kaki, Nao Yamagata, Jun Oyanagi, Yasuhiro Koh, Katsuyuki Furuta, Hiroaki Akamatsu, Keita Mori, Yuhei Harutani, and Yuka Okuda
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Drug-Related Side Effects and Adverse Reactions ,Immune checkpoint inhibitors ,Predictive marker ,Immune checkpoint inhibitor ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Carcinoma, Non-Small-Cell Lung ,Neoplasms ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Adverse effect ,Lung cancer ,Immune Checkpoint Inhibitors ,Retrospective Studies ,business.industry ,Hazard ratio ,medicine.disease ,Immuno‐Oncology ,Confidence interval ,030104 developmental biology ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,business ,Immune‐related adverse event - Abstract
Background Although predictive value of immune‐related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) have been suggested by several studies, their assessments were insufficient because patients were categorized only by the occurrence of irAEs. It has not been elucidated whether irAEs also play a significant role even in responders. Materials and Methods Between December 2015 and September 2018, 106 patients with advanced non‐small cell lung cancer treated with ICIs were enrolled in our prospective biomarker study. Twenty‐three of these were responders, defined as those with complete or partial response. We investigated the proportion of irAEs among overall and responders. For responders, progression‐free survival (PFS) and overall survival of ICIs were compared between those with and without irAEs. As an exploratory analysis, we measured 41 proteins from peripheral blood before and after ICI treatment. Results The proportion of irAEs was significantly higher in responders than nonresponders (65.2% vs. 19.3%, p < .01). Among responders, clinical characteristics did not differ regardless of the occurrence of irAEs. However, there was a significant difference in PFS among responders (irAE group 19.1 months vs. non‐irAE group 5.6 months; hazard ratio: 0.30 [95% confidence interval: 0.10–0.85]; p = .02). Of 41 protein analyses, fibroblast growth factor‐2 at baseline and monocyte chemoattractant protein fold change showed significant differences between them (p < .04). Conclusion Although this is a small sample–sized study, irAE might be a predictive factor of durable efficacy, even in patients who responded to ICIs. Investigation into the significance of irAEs in responders will contribute to the establishment of optimal administration of ICI. Implications for Practice Although the predictive value of immune‐related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) has been suggested by several studies, it has not been elucidated whether irAEs also play a significant role even in responders. This study showed that more than 60% of responders had irAEs. It demonstrated the strong correlation between irAEs and efficacy even in responders. Investigation into the significance of irAEs in responders will contribute to the establishment of optimal administration of ICI., Immune‐related adverse events might be a predictive factor of efficacy, even I patients who respond to immune checkpoint inhibitor therapy. This study investigated the significance of immune‐related adverse events in patients with non‐small cell lung cancer who had complete or partial response after treatment with immune checkpoint inhibitors.
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- 2019
12. Association of immune-related pneumonitis with the presence of preexisting interstitial lung disease in patients with non-small lung cancer receiving anti-programmed cell death 1 antibody
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Ryota Shibaki, Hidehito Horinouchi, Yuji Matsumoto, Noboru Yamamoto, Yuichiro Ohe, Tatsuya Yoshida, Shuji Murakami, Yasushi Goto, Shintaro Kanda, Masahiko Kusumoto, Yutaka Fujiwara, and Nobuyuki Yamamoto
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Time Factors ,Programmed Cell Death 1 Receptor ,Immunology ,behavioral disciplines and activities ,Gastroenterology ,Antineoplastic Agents, Immunological ,Immune system ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Humans ,Immunology and Allergy ,Medicine ,Diffuse alveolar damage ,Lung ,Aged ,Retrospective Studies ,Pneumonitis ,Aged, 80 and over ,biology ,business.industry ,Incidence ,Incidence (epidemiology) ,Interstitial lung disease ,Pneumonia ,Middle Aged ,respiratory system ,medicine.disease ,respiratory tract diseases ,body regions ,Oncology ,Non small lung cancer ,biology.protein ,Female ,Antibody ,Lung Diseases, Interstitial ,business ,Hypersensitivity pneumonitis - Abstract
The safety of anti-programmed cell death 1 (PD-1) antibody for patients with preexisting interstitial lung disease (ILD) remains unknown. The aim of this study was to evaluate the dependence of preexisting ILD on anti-PD-1 antibody-induced pneumonitis in non-small cell lung cancer (NSCLC) patients. We retrospectively reviewed the association of preexisting ILD with the incidence, radiographic pattern, and outcome of pneumonitis in NSCLC patients receiving anti-PD-1 antibody. A total of 331 patients were included in this study. Of these patients, 17 had preexisting ILD. The incidence of pneumonitis was higher among the patients with preexisting ILD than among those without preexisting ILD (29% vs. 10%, P = 0.027). The distributions of the CT appearances at the onset of anti-PD-1 antibody-induced pneumonitis were as follows: for the patients with preexisting ILD, two patients (40%) had diffuse alveolar damage (DAD), one patient each with organizing pneumonia-like (OP), hypersensitivity pneumonitis (HP), and other patterns (20% each); for the patients without preexisting ILD, 19 patients (61%) had OP, 8 (26%) had HP, 3 (10%) had DAD, and 1 (3.2%) had other patterns. The median onset time from the initiation of anti-PD-1 antibody treatment until the development of pneumonitis was 1.3 months (range 0.3-2.1 months) for the patients with preexisting ILD and 2.3 months (range 0.2-14.6 months) for the patients without preexisting ILD. Careful attention to the development of pneumonitis is needed, especially within the first 3 months after the start of anti-PD-1 antibody treatment, when using anti-PD-1 antibody to treat patients with preexisting ILD.
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- 2019
13. Clinical course and outcomes of acute exacerbation of fibrosing interstitial lung disease
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Yuri Shimada, Masanori Tanaka, Keisuke Tomii, Ryota Shibaki, Kazuma Nagata, Daichi Fujimoto, Nobuyuki Yamamoto, Atsushi Matsunashi, and Katsuyuki Furuta
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medicine.medical_specialty ,Exacerbation ,business.industry ,Internal medicine ,medicine ,Interstitial lung disease ,Clinical course ,medicine.disease ,business - Published
- 2021
14. Pre-treatment serum protein levels predict survival of non-small cell lung cancer patients without durable clinical benefit by PD-1/L1 inhibitors
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Yuhei Harutani, Yuichi Ozawa, Eriko Murakami, Koichi Sato, Jun Oyanagi, Hiroaki Akamatsu, Takanori Yoshikawa, Ryota Shibaki, Takeya Sugimoto, Katsuyuki Furuta, Shunsuke Teraoka, Nahomi Tokudome, Atsushi Hayata, Hiroki Ueda, Masanori Nakanishi, Yasuhiro Koh, and Nobuyuki Yamamoto
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Cancer Research ,Follistatin ,Antineoplastic Agents, Immunological ,Lung Neoplasms ,Oncology ,Carcinoma, Non-Small-Cell Lung ,Immunology ,Programmed Cell Death 1 Receptor ,Biomarkers, Tumor ,Immunology and Allergy ,Humans ,Prospective Studies ,B7-H1 Antigen - Abstract
While PD-1/L1 inhibitors are characterized by durable tumor control, they also prolong survival without prolongation of progression-free survival (PFS) in part of patients. However, little is known about the factors and mechanisms involved in this. Between December 2015 and September 2018, 106 patients with advanced non-small cell lung cancer treated with ICI monotherapy were enrolled in a prospective-observational study. Sixty-nine of whom progressed or died within 6 months after ICI initiation were defined as patients without durable clinical benefit (NDBs). Clinical factors and 39 serum proteins before ICI initiation and at the time of progressive disease (PD) were explored for an association with overall survival (OS) and OS after PD (OS-PD). As a result, median PFS, OS, and OS-PD were 44 days [95% confidence interval (CI): 39-56), 211 days (95% CI: 158-425), and 193 days (95% CI: 118-349), respectively. By multivariate analysis for OS, CRP ( 1.44 mg/dl) [HR 2.59 (95% CI:1.33-5.04), P = 0.005] and follistatin ( 685 pg/ml) [HR 2.29 (95% CI:1.12-4.69), P = 0.023] before ICI initiation were significantly predictive. Notably, no serum protein at the time of PD was predictive for OS-PD. There were also no serum predictive factors of OS in the 33 patients with durable clinical benefit. In conclusion, serum levels of CRP and follistatin before ICI initiation, not at the time of PD, are predictive for OS in NDBs, suggesting long-term survivor in NDBs are predetermined by the immune status before ICI initiation.
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- 2021
15. Malignant pleural effusion as a predictor of the efficacy of anti‐PD‐1 antibody in patients with non‐small cell lung cancer
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Hidehito Horinouchi, Ryota Shibaki, Shuji Murakami, Yasushi Goto, Noboru Yamamoto, Noriko Motoi, Yuji Matsumoto, Shintaro Kanda, Yuichiro Ohe, Yutaka Fujiwara, and Yuki Shinno
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Adult ,Male ,non‐small cell lung cancer ,medicine.medical_specialty ,Lung Neoplasms ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,Gastroenterology ,lcsh:RC254-282 ,B7-H1 Antigen ,03 medical and health sciences ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,Malignant pleural effusion ,Humans ,Anti‐PD‐1 antibody ,malignant pleural effusion ,Lung cancer ,Survival analysis ,Aged ,Retrospective Studies ,Aged, 80 and over ,nivolumab ,business.industry ,Hazard ratio ,Cancer ,General Medicine ,Original Articles ,Middle Aged ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Survival Analysis ,Confidence interval ,Pleural Effusion, Malignant ,030104 developmental biology ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Female ,Original Article ,pembrolizumab ,Nivolumab ,business - Abstract
Background The aim of this study was to evaluate the usefulness of the presence of malignant pleural effusion (MPE) as a negative predictor of anti-PD-1 antibody efficacy. Methods A retrospective review of patients with advanced or recurrent non-small cell lung cancer treated with an anti-PD-1 antibody between December 2015 and March 2018 at the National Cancer Center Hospital, Japan, was conducted. Progression-free survival (PFS) and overall survival (OS) were compared between patients with and without MPE. Additional survival analysis according to PD-L1 expression status was conducted. Univariate and multivariate analyses were performed. Results A total of 252 patients were identified before the commencement of anti-PD-1 antibody treatment: 33 with MPE and 219 without MPE. PFS and OS were significantly shorter in patients with MPE than in patients without MPE (median PFS 3.0 vs. 5.8 months, hazard ratio [HR] 1.7, P = 0.014; median OS 7.9 vs. 15.8 months, HR 2.1, P = 0.001). In patients with PD-L1 expression in ≥ 1% of their tumor cells, the PFS of patients with MPE was significantly shorter than of patients without MPE (median PFS 3.1 vs. 6.5 months, HR 2.0, 95% confidence interval 1.0-3.5; P = 0.021). The presence of MPE was independently associated with a shorter PFS and OS in multivariate analysis. Conclusion The presence of MPE in patients administered an anti-PD-1 antibody is associated with shorter PFS and OS, regardless of the presence of PD-L1 expression ≥ 1% of tumor cells.
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- 2019
16. A phase II study of cisplatin plus vinorelbine combined with atezolizumab as adjuvant therapy for completely resected non-small-cell lung cancer with
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Ryota, Shibaki, Hiroaki, Akamatsu, Terufumi, Kato, Kazumi, Nishino, Morihito, Okada, Tetsuya, Mitsudomi, Kazushige, Wakuda, Kenichi, Yoshimura, Nobuyuki, Yamamoto, and Kazuhiko, Nakagawa
- Subjects
adjuvant chemotherapy ,atezolizumab ,vinorelbine ,Study Protocol ,cisplatin ,Immunotherapy for lung cancer: progress, opportunities and challenges ,EGFR mutation ,respiratory tract diseases - Abstract
Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is a standard treatment in EGFR-mutated advanced non-small-cell lung cancer (NSCLC); however, previous data have suggested that EGFR-TKI has limited potential as adjuvant therapy. On the contrary, based on subset analysis with the immune checkpoint inhibitor (ICI) plus platinum-doublet chemotherapy in advanced NSCLC with EGFR mutation, we hypothesized that this combination was worth testing as adjuvant therapy in patients with EGFR-mutated NSCLC. Methods: Herein, we introduce our phase II study of cisplatin plus vinorelbine combined with atezolizumab as adjuvant therapy for completely resected NSCLC with EGFR mutation. Accrued patients will be pathological stage II–IIIA with completely resected NSCLC and whose tumors have EGFR mutation. Treatment comprises four cycles of cisplatin plus vinorelbine combined with atezolizumab followed by maintenance with atezolizumab. The primary endpoint is the disease-free survival (DFS) rate at 2 years. Secondary endpoints are DFS, overall survival, and safety. In total, 18 patients will be enrolled in this study. Discussion: Ongoing phase III trials of adjuvant ICI allow the inclusion of patients with EGFR mutation, but our current trial will provide the earliest clinical data on the efficacy of platinum-doublet chemotherapy with atezolizumab.
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- 2020
17. CD24, not CD47, negatively impacts upon response to PD-1/L1 inhibitors in non-small-cell lung cancer with PD-L1 tumor proportion score 50
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Nahomi Tokudome, Shunsuke Teraoka, Ryota Shibaki, Eriko Murakami, Jun Oyanagi, Masanori Nakanishi, Yuhei Harutani, Nobuyuki Yamamoto, Toshiaki Takakura, Yuka Okuda, Takeya Sugimoto, Kouichi Sato, Masanori Tanaka, Yuichi Ozawa, Atsushi Hayata, Yuka Kitamura, Hiroaki Akamatsu, Yasuhiro Koh, Katsuyuki Furuta, Hiroki Ueda, and Junya Fukuoka
- Subjects
0301 basic medicine ,Oncology ,Male ,Vascular Endothelial Growth Factor A ,Cancer Research ,Lung Neoplasms ,Angiogenesis ,Programmed Cell Death 1 Receptor ,B7-H1 Antigen ,chemistry.chemical_compound ,0302 clinical medicine ,Basic and Clinical Immunology ,Carcinoma, Non-Small-Cell Lung ,Prospective Studies ,skin and connective tissue diseases ,CD47 ,Aged, 80 and over ,Predictive marker ,biology ,CD24 ,General Medicine ,Middle Aged ,Progression-Free Survival ,Vascular endothelial growth factor ,030220 oncology & carcinogenesis ,Female ,Original Article ,CCL2 ,Adult ,medicine.medical_specialty ,CD47 Antigen ,03 medical and health sciences ,Immune system ,Internal medicine ,PD-L1 ,medicine ,Humans ,Lung cancer ,Propensity Score ,Aged ,business.industry ,CD24 Antigen ,medicine.disease ,lung cancer ,030104 developmental biology ,chemistry ,PD‐L1 ,biology.protein ,business - Abstract
CD24, a heavily glycosylated glycosylphosphatidylinositol–anchored surface protein, inhibits phagocytosis as potently as CD47. The relationship between such anti‐phagocytic factors and the immune response with immune–checkpoint inhibitors (ICI) remains unexplored. We evaluated CD24 and CD47 tumor proportion scores (TPS) in 68 of the 106 patients with advanced non–small‐cell lung cancer who participated in a prospective observational study of ICI treatment. We also explored the impact of CD24 TPS and CD47 TPS on ICI efficacy and serum cytokine changes. CD24 positivity (TPS ≥ 1) was negatively associated with progression–free survival (PFS) of ICI when PD‐L1 TPS was, We evaluated tumor proportion score (TPS) of CD24 and CD47 in 68 patients with advanced, non–small‐cell lung cancer who participated in a prospective observational study for treatment with ICI, and we also explored the impact of CD24 TPS and CD47 TPS on the efficacy of ICI and serum cytokine alterations. CD24 positivity (TPS ≥ 1) was negatively associated with progression–free survival of ICI when PD‐L1 TPS
- Published
- 2020
18. MO18-5 Establishment of organoids derived from patients with advanced thoracic malignancies
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Yuichi Ozawa, Daichi Fujimoto, Takeya Sugimoto, Koichi Sato, Jun Oyanagi, Atsushi Hayata, Nahomi Tokudome, Ryota Shibaki, Hiroaki Akamatsu, Yasuhiro Koh, Katsuyuki Furuta, Hiroki R. Ueda, Nobuyuki Yamamoto, Masanori Tanaka, and Shunsuke Teraoka
- Subjects
Pathology ,medicine.medical_specialty ,Oncology ,business.industry ,Organoid ,medicine ,Hematology ,business - Published
- 2021
19. Abstract 2976: Establishment of organoids derived from patients with advanced thoracic malignancies
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Jun Oyanagi, Yasuhiro Koh, Koichi Sato, Masanori Tanaka, Katsuyuki Furuta, Takeya Sugimoto, Ryota Shibaki, Shunsuke Teraoka, Daichi Fujimoto, Nahomi Tokudome, Hiroaki Akamatsu, Atsushi Hayata, Yuichi Ozawa, Hiroki Ueda, and Nobuyuki Yamamoto
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Cancer Research ,Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Pleural effusion ,medicine.medical_treatment ,Cancer ,Thoracentesis ,medicine.disease ,Malignancy ,Oncology ,Cell culture ,Biopsy ,Organoid ,Medicine ,Osimertinib ,business - Abstract
Background: In the past decade, three-dimensional organoid culture derived from various tumors has been applied to cancer research. Compared to the conventional two-dimensional cell culture, organoid culture recapitulates in vivo system and furthermore, its high establishment rate may hold the potential to help decision-making for precision medicine. However, it remains challenging to establish organoids from advanced thoracic malignancies due to a limited amount of biopsy specimens. Here, we report the attempt to establish organoids from endoscopic biopsy specimens and pleural effusions in patients with advanced thoracic malignancies Methods: Organoid culture was attempted using biopsy specimens or pleural effusions from patients who underwent transbronchial biopsy, thoracoscopic biopsy or thoracentesis. After confirming the presence of malignant cells by rapid on-site evaluation, biopsy specimens were digested with collagenase and dispase at 37°C followed by being harvested and cultured in Matrigel. As for pleural effusions, mononuclear cells were isolated by ficoll density gradient centrifugation and CD45+ cells were depleted using anti-CD45 magnetic beads. Then, the resultant cells were cultured in Matrigel. Next-generation sequencing was performed to confirm cancer-related somatic mutations using Ion PGM system. Cell viability assay was performed by resazurin assay. Results:142 patients were registered in the study between May 2019 and October 2020 at Wakayama Medical University. Fifty-one cases were excluded because of negative diagnosis for malignancy, retraction of the consent or risk of bleeding associated with biopsy. We attempted to culture organoids using 98 samples from 91 patients. The types of malignancies were as follows: non-small cell lung cancers (NSCLC)/SCLC/others, 80/8/3. A total of 33 organoids were successfully cultured with sustainable proliferation and 16 were successfully cryopreserved. Established organoids were confirmed to harbor the same mutations as detected by clinical testing with tissue samples and to form tumors in a xenotransplantation model. HLCO-75, established from pleural effusion at disease progression after osimertinib treatment was genotyped and found to gain ERBB2 V777L mutation in exon 20 in addition to original EGFR L858R mutation. Marked growth-inhibitory effect by poziotinib, a HER2 tyrosine kinase inhibitor with IC50 value 6 nM was observed whereas not by TAS6417, another EGFR/HER2 exon 20 inhibitor, suggesting the potential of organoid culture for decision-making in cancer precision medicine. Conclusion: Our results suggest that organoid culture is feasible from small biopsy specimens and these organoids could be applied for personalized medicine. Citation Format: Jun Oyanagi, Yasuhiro Koh, Koichi Sato, Masanori Tanaka, Katsuyuki Furuta, Takeya Sugimoto, Ryota Shibaki, Shunsuke Teraoka, Daichi Fujimoto, Nahomi Tokudome, Hiroaki Akamatsu, Atsushi Hayata, Atsushi Hayata, Yuichi Ozawa, Hiroki Ueda, Nobuyuki Yamamoto. Establishment of organoids derived from patients with advanced thoracic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2976.
- Published
- 2021
20. Tumor expression of cGAS, not STING, negatively impacts on the efficacy of PD-1/L1 inhibitors in non-small cell lung cancer with PD-L1 TPS ≥50
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Nahomi Tokudome, Yuichi Ozawa, Ryota Shibaki, Yuka Kitamura, Junya Fukuoka, Yuhei Harutani, Koichi Sato, Shunsuke Teraoka, Hiroki Ueda, Hiroaki Akamatsu, Masanori Nakanishi, Takeya Sugimoto, Nobuyuki Yamamoto, Daichi Fujimoto, Eriko Murakami, Atsushi Hayata, Yasuhiro Koh, and Jun Oyanagi
- Subjects
Cancer Research ,Innate immune system ,biology ,business.industry ,medicine.medical_treatment ,medicine.disease ,chemistry.chemical_compound ,Sting ,Cytokine ,Oncology ,chemistry ,Cytoplasm ,PD-L1 ,medicine ,biology.protein ,Cancer research ,Non small cell ,Lung cancer ,business ,DNA - Abstract
e21048 Background: The cGAS/STING pathway is an innate immune pathway that promotes cytokine production in response to cytoplasmic DNA, and its activation is important for the induction of anti-tumor immunity. However, predictivity of cGAS/STING tumor expression on the efficacy of PD-1/L1 inhibitors and subsequent immune responses (e.g., changes in serum cytokines) remain to be elucidated. Non-small cell lung cancer with PD-L1 tumor proportion score (TPS) of 50% or higher respond well to immune checkpoint inhibitor (ICI) monotherapy, but there is still a poor response group among them, and the extraction of such patients is an urgent issue. Methods: This is a post hoc analysis of prospective biomarker study, which enrolled 106 patients with advanced non-small cell lung cancer (NSCLC) who were treated with ICI monotherapy between December 2015 and September 2018. We investigated in 68 patients with preserved evaluable tissue samples taken before start of ICI treatment. cGAS, STING, and PD-L1 expression in tumors were stained by immunohistochemistry. cGAS and STING were evaluated by H-score. Using peripheral blood which was collected by the observational study, 41 serum proteins at the time of PD-1/L1 inhibitors initiation and in 4 – 6 weeks later were quantified. Results: The median cGAS and STING H-SCORE were 220 (5 – 300) and 190 (0 – 300), respectively. There were no differences in cGAS or STING H-SCORE between PD-L1 high (TPS ≥50) and low (TPS < 50) groups ( p= 0.990 and 0.283). Cases were divided into two groups according to median of the H-SCORE, respectively, and compared. Unexpectedly, cGAS high (H-SCORE ≥220) patients showed significantly shorter progression free survival of ICI when PD-L1 TPS ≥50 (median progression free survival (PFS); 143 days vs. not reached, p = 0.028) and progression free rate at 18 months was 7 and 53%, while no association was observed when PD-L1 TPS < 50 (median PFS; 47 vs. 61 days, p= 0.798). STING tumor expression was not associated with PFS regardless of PD-L1 TPS. In cytokine analysis, cGAS high was associated with significantly higher serum concentrations of TGF-β1 and β2 before ICI initiation (47.5 vs. 22.3hg/l, p= 0.023; 2118 vs. 882rg/ml, p= 0.037), and H-SCORE of cGAS, not STING, were significantly correlated with TGF-β1 and β2 basal levels (r = 0.447, p= 0.009; r = 0.373, p= 0.033). Analysis about fold change from baseline to 4 – 6 weeks later of 41 cytokines revealed that leptin significantly increased in cGAS high tumor while no difference was seen in all of cytokines between STING high and low tumor. Conclusions: Tumor expression (H-Score) of cGAS, not STING, is a candidate for predictor of poor response to ICI monotherapy in NSCLC with PD-L1 high (TPS ≥50). cGAS tumor expression may be associated with TGF-β producing, immune-suppressive tumor microenvironment in NSCLC. Clinical trial information: UMIN000024414.
- Published
- 2021
21. Nivolumab-induced autoimmune encephalitis in an anti-neuronal autoantibody-positive patient
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Yuichiro Ohe, Koichi Oki, Ryota Shibaki, and Shuji Murakami
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Autoimmune encephalitis ,Cancer Research ,biology ,business.industry ,Immune checkpoint inhibitors ,Autoantibody ,General Medicine ,Positive patient ,medicine.disease ,Oncology ,Immunology ,medicine ,biology.protein ,Radiology, Nuclear Medicine and imaging ,Nivolumab ,Antibody ,business ,Encephalitis - Published
- 2019
22. Tumor expression and usefulness as a biomarker of programmed death ligand 1 in advanced non-small cell lung cancer patients with preexisting interstitial lung disease
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Yuji Matsumoto, Shintaro Kanda, Yuichiro Ohe, Ryota Shibaki, Yasushi Goto, Noriko Motoi, Shuji Murakami, Masahiko Kusumoto, Yutaka Fujiwara, Nobuyuki Yamamoto, Hidehito Horinouchi, and Noboru Yamamoto
- Subjects
Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Programmed Cell Death 1 Receptor ,Pembrolizumab ,B7-H1 Antigen ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Interquartile range ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,Biomarkers, Tumor ,Humans ,Lung cancer ,Aged ,Retrospective Studies ,Aged, 80 and over ,Hematology ,biology ,business.industry ,Interstitial lung disease ,General Medicine ,Middle Aged ,medicine.disease ,Immunohistochemistry ,respiratory tract diseases ,Survival Rate ,Treatment Outcome ,030220 oncology & carcinogenesis ,biology.protein ,Biomarker (medicine) ,Female ,Nivolumab ,Antibody ,Neoplasm Recurrence, Local ,business ,Lung Diseases, Interstitial - Abstract
In non-small cell lung cancer (NSCLC) patients, the expression of tumor programmed death ligand 1 (PD-L1) is an important parameter for deciding the timing of the use of anti-programmed cell death 1 (PD-1) antibody. There has been increasing concern over the benefit of anti-PD-1 antibody in high-risk patients, such as those with preexisting interstitial lung disease (ILD). However, the status and value of PD-L1 as a predictive biomarker and the efficacy of anti-PD-1 antibody in NSCLC patients with preexisting ILD remains uncertain. We retrospectively reviewed the medical records of advanced/recurrent NSCLC patients who had undergone analysis of the tumor PD-L1 expression. We identified 358 patients with advanced/recurrent NSCLC who had undergone analysis of tumor PD-LI expression. Of these, 210 received anti-PD-1 antibody. Tumor-cell PD-L1 expression was similar between the groups with and without preexisting ILD (median, 35%; interquartile range, 0–70%; vs. median, 10%; interquartile range, 1–68%; p = 0.66). Of the 210 patients who received anti-PD-1 antibody, 14 patients had preexisting ILD. The progression-free survival (PFS) showed no significant difference between the patients receiving anti-PD-1 antibody with and without preexisting ILD (median PFS, 4.3 vs. 5.3 months; HR, 0.97; p = 0.84). Within the patients with preexisting ILD, the PFS was tended to be longer in the patients with tumor PD-L1 expression ≥ 50% than in those with tumor PD-L1 expression
- Published
- 2019
23. Differential Efficacy of Pembrolizumab According to Metastatic Sites in Patients With PD-L1 Strongly Positive (TPS ≥ 50%) NSCLC
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Yasushi Goto, Noriko Motoi, Hidehito Horinouchi, Noboru Yamamoto, Yuichiro Ohe, Ryota Shibaki, Yuki Takeyasu, Yuji Matsumoto, Shintaro Kanda, and Tatsuya Yoshida
- Subjects
Adult ,Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,B7-H1 Antigen ,Metastasis ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,PD-L1 ,Humans ,Medicine ,Epidermal growth factor receptor ,Lung cancer ,Immune Checkpoint Inhibitors ,Aged ,Retrospective Studies ,Aged, 80 and over ,Chemotherapy ,biology ,business.industry ,Liver Neoplasms ,Hazard ratio ,Middle Aged ,medicine.disease ,Progression-Free Survival ,Confidence interval ,Treatment Outcome ,030104 developmental biology ,030220 oncology & carcinogenesis ,Multivariate Analysis ,biology.protein ,Female ,business - Abstract
Background Pembrolizumab has shown significantly better efficacy than platinum doublet chemotherapy in patients with programmed cell death ligand 1 (PD-L1) strongly positive (tumor proportion score ≥ 50%) non–small-cell lung cancer (NSCLC). However, the predictors of response to pembrolizumab have not yet been fully elucidated for patients with PD-L1 strongly positive NSCLC. Patients and Methods We retrospectively analyzed 145 patients who had been treated with pembrolizumab for PD-L1 strongly positive (TPS ≥ 50%) NSCLC without an EGFR (epidermal growth factor receptor) mutation or ALK rearrangement from February 2017 to March 2020. Various clinical characteristics, including Eastern Cooperative Oncology Group performance status, treatment line, PD-L1 expression, C-reactive protein level, neutrophil/lymphocyte ratio, and metastatic sites, and the clinical outcome of pembrolizumab treatment were examined. Results Patients with higher PD-L1 expression (≥ 75%; n = 90) had a higher objective response rate (ORR) and longer progression-free survival (PFS) compared with those with lower expression (50%-74%; n = 55; ORR, 51% vs. 33%; P = .0305; median PFS, 13.9 months vs. 5.2 months; P = .0111). In addition, 15 patients with liver metastasis (LM) had a significantly lower ORR and shorter PFS than the 130 patients without LM (ORR, 20% vs. 47%; P = .0468; median PFS, 3.4 months vs. 9.4 months; P = .0018). A multivariate analysis indicated that PD-L1 expression and LM were significant predictors of PFS after pembrolizumab treatment (higher PD-L1 expression: hazard ratio, 0.58; 95% confidence interval, 0.38-0.91; P = .0183; presence of LM: hazard ratio, 2.05; 95% confidence interval, 1.03-3.82; P = .0420). Conclusion PD-L1 expression and LM status were predictors of the efficacy of pembrolizumab in patients with PD-L1 strongly positive NSCLC.
- Published
- 2021
24. A phase II study of cisplatin plus vinorelbine combined with atezolizumab as adjuvant therapy for completely resected non-small-cell lung cancer with EGFR mutation (West Japan Oncology Group 11719L/ADJUST study)
- Author
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Terufumi Kato, Ryota Shibaki, Morihito Okada, Kazumi Nishino, Kenichi Yoshimura, Nobuyuki Yamamoto, Kazuhiko Nakagawa, Hiroaki Akamatsu, Tetsuya Mitsudomi, and Kazushige Wakuda
- Subjects
Oncology ,Cisplatin ,medicine.medical_specialty ,biology ,business.industry ,Standard treatment ,Phases of clinical research ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Vinorelbine ,lcsh:RC254-282 ,respiratory tract diseases ,Atezolizumab ,Internal medicine ,medicine ,Adjuvant therapy ,biology.protein ,Epidermal growth factor receptor ,business ,Lung cancer ,medicine.drug - Abstract
Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is a standard treatment in EGFR-mutated advanced non-small-cell lung cancer (NSCLC); however, previous data have suggested that EGFR-TKI has limited potential as adjuvant therapy. On the contrary, based on subset analysis with the immune checkpoint inhibitor (ICI) plus platinum-doublet chemotherapy in advanced NSCLC with EGFR mutation, we hypothesized that this combination was worth testing as adjuvant therapy in patients with EGFR-mutated NSCLC. Methods: Herein, we introduce our phase II study of cisplatin plus vinorelbine combined with atezolizumab as adjuvant therapy for completely resected NSCLC with EGFR mutation. Accrued patients will be pathological stage II–IIIA with completely resected NSCLC and whose tumors have EGFR mutation. Treatment comprises four cycles of cisplatin plus vinorelbine combined with atezolizumab followed by maintenance with atezolizumab. The primary endpoint is the disease-free survival (DFS) rate at 2 years. Secondary endpoints are DFS, overall survival, and safety. In total, 18 patients will be enrolled in this study. Discussion: Ongoing phase III trials of adjuvant ICI allow the inclusion of patients with EGFR mutation, but our current trial will provide the earliest clinical data on the efficacy of platinum-doublet chemotherapy with atezolizumab.
- Published
- 2021
25. EP1.01-51 Efficacy Impact of Serum VEGF for Elderly or Poor PS Patients Receiving Anti-PD-1 Antibody with Advanced Non-Small Cell Lung Cancer
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Shuji Murakami, Ryota Shibaki, Yasushi Goto, Hidehito Horinouchi, Yuichiro Ohe, Noboru Yamamoto, Shintaro Kanda, Yuji Matsumoto, Tatsuya Yoshida, and Yuki Shinno
- Subjects
Pulmonary and Respiratory Medicine ,Oncology ,biology ,business.industry ,VEGF receptors ,Anti pd 1 ,Cancer research ,biology.protein ,medicine ,Non small cell ,Lung cancer ,medicine.disease ,business - Published
- 2019
26. Association of immune-related pneumonitis with the phenotypic appearance of concurrent ILD in patients treated with anti-PD-1 antibody
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Shuji Murakami, Ryota Shibaki, Y. Matsumoto, Shintaro Kanda, Yasushi Goto, N. Yamamoto, Yuichiro Ohe, Hidehito Horinouchi, and Yutaka Fujiwara
- Subjects
Immune system ,Oncology ,business.industry ,Immunology ,Anti pd 1 ,Medicine ,In patient ,Hematology ,business ,medicine.disease ,Phenotype ,Pneumonitis - Published
- 2018
27. Nivolumab induced radiation recall pneumonitis after two years of radiotherapy
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M. Fujimoto, Ryota Shibaki, Hiroaki Akamatsu, Nobuyuki Yamamoto, and Yasuhiro Koh
- Subjects
0301 basic medicine ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Hematology ,medicine.disease ,Radiation recall ,Radiation therapy ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Medicine ,Radiology ,Nivolumab ,business ,Pneumonitis - Published
- 2017
28. Predictive impact of PD-L1-expressing circulating tumor cells in NSCLC patients treated with nivolumab
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Ryota Shibaki, Hiroaki Akamatsu, Nahomi Tokudome, Masanori Nakanishi, Satomi Yagi, Hiroki Ueda, Keiichiro Akamatsu, Yasuhiro Koh, Atsushi Hayata, Kazuki Kurita, Masayuki Higuchi, Nobuyuki Yamamoto, Hisashige Kanbara, and Kuninobu Kanai
- Subjects
0301 basic medicine ,Cancer Research ,biology ,business.industry ,Tumor tissue ,Blockade ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Circulating tumor cell ,Oncology ,030220 oncology & carcinogenesis ,PD-L1 ,biology.protein ,Cancer research ,Medicine ,Nivolumab ,business - Abstract
11541 Background: PD-L1 expression on tumor tissue is associated with response to PD-1 blockade in NSCLC. Here, we conducted a serial evaluation of PD-1-expressing circulating tumor cells (CTCs) as a potential real-time diagnostic modality in NSCLC patients treated with nivolumab. Methods: Advanced NSCLC patients after failure of at least one prior chemotherapy regimen received nivolumab monotherapy (3mg/kg, q2W) until progressive disease (PD) or unacceptable toxicity. Peripheral whole blood (3 mL) was collected for CTC evaluation at baseline and at week 4. CTCs were detected using microcavity array system (Hitachi Chemical Co., Ltd, Chikusei, Japan). PD-L1 expression was immunohistochemically examined on both tumor tissues and CTCs. This study was registered at UMIN (ID: 000024414). Results: Thirty patients were registered in the study between January 2016 and September 2016 at Wakayama Medical University Hospital and 29 were included in the analysis. Demographics of the patients were as follows: median age 70 (range, 49 to 86); male 73 %; stage IV, 100 %; squamous/non-squamous, 27/73 %. At baseline, CTCs were detected in all patients (median, 15; range, 1 to 90) and PD-L1-expressing CTCs were detected in 87% of patients. Tumor proportion score (TPS) of PD-L1 expression on CTCs ranged from 6% to 100%, indicating intrapatient heterogeneity. Matched tumor tissues were available from 14 patients and 7 showed the PD-L1 TPS ≥ 50%. No positive correlation was observed on PD-L1 expression between tumor tissues and CTCs based on TPS (R2 = 0.0035). Overall response rate was 25% (7/29), and disease control rate was 54% (15/29). Total CTC count was significantly decreased after nivolumab treatment at week 4 (p < 0.05), but no significant change was observed in PD-L1 TPS on CTC. Patients harboring CTCs with PD-L1 TPS 50% or more at baseline were significantly more likely to achieve non-PD than those harboring CTCs with TPS less than 50% (p < 0.05). Conclusions: This is the first report on a serial monitoring of PD-L1 expression on CTCs in patients treated with nivolumab. PD-L1-expressing CTCs are suggested to hold potential for predicting clinical benefit. Clinical trial information: 000024414.
- Published
- 2017
29. Abstract 2257: Differential expression of PD-L1 on circulating tumor cells among patients with advanced lung cancer
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Hisashige Kanbara, Satomi Yagi, Masanori Nakanishi, Takashi Kikuchi, Yasuhiro Koh, Nobuyuki Yamamoto, Woong Kim, Hiroki Ueda, Masayuki Higuchi, Keiichiro Akamatsu, Atsushi Hayata, Hiroaki Akamatsu, Kuninobu Kanai, Ryota Shibaki, and Ayaka Tanaka
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Pathology ,biology ,business.industry ,medicine.medical_treatment ,Cancer ,medicine.disease ,Cytokeratin ,Circulating tumor cell ,Internal medicine ,PD-L1 ,medicine ,biology.protein ,Antibody ,Lung cancer ,business ,Whole blood - Abstract
Background and purpose: Immune-checkpoint blockade with anti-programmed death-1 (PD-1) antibodies is rapidly emerging for the treatment of human malignancies including lung cancer. Although programmed death-ligand 1 (PD-L1) has been studied as a predictive biomarker, detection and evaluation of PD-L1 expression level on tissue samples remain challenging due to its dynamic and unstable expression. Thus the diagnostic tool for real-time monitoring of PD-L1 expression is critically needed. Here, we assessed the expression pattern of PD-L1 on circulating tumor cells (CTCs) by using microcavity array (MCA) system in patients with advanced non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Experimental procedure: PD-L1 staining on CTCs was established using NSCLC cell lines H820, H441, A549 and H23 expressing varying levels of PD-L1 spiked in the peripheral blood obtained from healthy donors. For clinical evaluation, 3 ml of peripheral whole blood was collected from 20 advanced lung cancer patients prior to the initiation of chemotherapy and from 10 healthy donors. Cells were captured and immuno-stained by using the automated MCA system (Hitachi Chemical Co., Ltd). CTCs were defined as those positive for DAPI and cytokeratin (CK) and negative for CD45. PD-L1 expression level on CTCs was visualized by addition of PD-L1 immunocytochemistry procedure. High-resolution fluorescent images were obtained using fluorescence microscope (Carl Zeiss Microscopy Co., Ltd). Results: Characteristics of 20 lung cancer patients enrolled in clinical study were as follows: median age 74 (range, 48 to 84); male 60%; stage III/IV, 10/90%; NSCLC/SCLC, 70/30%. More than 2 CTCs were identified in 14 patients (median 22.5; range, 4 to 71), and PD-L1 positive CTCs were detected in 12 patients (median 5; range, 2 to 15). No correlation was detected between the number of total CTCs and that of PD-L1 positive CTCs in each patient (R2 = 0.05). We found a total of 25 CTC clusters from 20 patients, of which PD-L1 expression was both homogenous and heterogeneous. It is noteworthy that clustered CTCs have larger proportion of PD-L1 positive CTCs per whole clustered CTCs than that of non-clustered CTCs (24/54, 44% versus 51/347, 15%, respectively). We further focused on CTC-interacting white blood cells, which intensively bound with aggregated CTCs rather than single CTC (12/54, 22% versus 43/337, 13%, respectively). Our data implicate that PD-L1 expression on CTC correlates with aggregation of CTCs (p < 0.05). Conclusions: Our results showed that PD-L1 expression on CTCs was detectable and there is intrapatient heterogeneity of its expression in patients with advanced lung cancer. Further investigation is warranted to better understand the biological importance of the correlation between PD-1 expression and CTC aggregation and CTC bound to white blood cells. Citation Format: Woong Kim, Yasuhiro Koh, Hiroaki Akamatsu, Satomi Yagi, Ayaka Tanaka, Kuninobu Kanai, Atsushi Hayata, Ryota Shibaki, Masayuki Higuchi, Hisashige Kanbara, Takashi Kikuchi, Keiichiro Akamatsu, Masanori Nakanishi, Hiroki Ueda, Nobuyuki Yamamoto. Differential expression of PD-L1 on circulating tumor cells among patients with advanced lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2257.
- Published
- 2016
30. Abstract 2244: Development of an automated device for size-based enrichment and isolation of circulating tumor cells in lung cancer patients
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Satomi Yagi, Takashi Kikuchi, Kuninobu Kanai, Hiroki Ueda, Ryota Shibaki, Woong Kim, Keiichiro Akamatsu, Hisashige Kanbara, Ayaka Tanaka, Yasuhiro Koh, Hiroaki Akamatsu, Nobuyuki Yamamoto, Masanori Nakanishi, Masayuki Higuchi, and Atsushi Hayata
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Pathology ,business.industry ,medicine.medical_treatment ,Cancer ,medicine.disease ,Peripheral blood ,Metastasis ,Circulating tumor cell ,Internal medicine ,medicine ,Stage (cooking) ,Lung cancer ,business ,Whole blood - Abstract
Background and Purpose: Circulating tumor cells (CTCs) are relatively rare cells defined as tumor cells circulating in the peripheral blood of patients with solid tumors. Diagnosis utilizing CTCs is expected to help guide decision-making for precision cancer medicine. We developed an automated microcavity array (MCA) system to detect CTCs based on the differences in size and deformability between tumor cells and normal blood cells. Here we evaluated its performance using preclinical spike-in model and blood samples from non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients. Material and method: The automated MCA system consists of components such as chambered cartridge containing micro metal filter, reagent and waste reservoirs, and peristaltic pump. To evaluate the recovery of CTCs, preclinical experiments using NSCLC cells, NCI-H820, A549, NCI-H441 and NCI-H23 spiked into peripheral whole blood from healthy volunteers were performed. For clinical evaluation, 6 mL of peripheral whole blood was collected from 50 advanced lung cancer patients prior to the initiation of chemotherapy and from 10 healthy donors. Samples were collected in an EDTA-containing tube and were processed within 3 hours of blood draw. Recovered cells on the filter were then fixed, permeabilized, and stained automatically and high-resolution fluorescent images were obtained using fluorescence microscope. We defined CTC as DAPI-positive, cytokeratin-positive and CD45-negative cell. Results: Results of the preclinical study showed that up to 90% of spiked-in tumor cells were recovered, confirming that the detection sensitivity by this automated device is on par with that by previous manual detection procedure. Demographics of 50 lung cancer patients enrolled in clinical study were as follows: median age 72 (range, 48 to 85); male 66%; stage III/IV 12/88%; NSCLC/SCLC 78/22%. Cells defined as CTC were detected in 2 cases out of 10 healthy volunteers, of which CTC count was 1 and 2 / 6 mL, respectively. Three or more CTCs were detected in 71% of patients with advanced lung cancer (39 out of 50) and five or more CTCs were detected in 52% of patients (26 out of 50) (median CTC count 13.5). Among stage IV NSCLC patients, patients with extrathoracic metastasis tend to have more CTCs than in those with intrathoracic metasitasis (median CTC count, 8 versus 4, p = 0.058). A head-to-head comparison between CellSearch system and our system was conducted in NSCLC patients, showing the superiority of our system (median CTC count, 0 versus 11.25, p = 0.0001, n = 17). Conclusions Our results suggest that the automated MCA device has a clinical potential for CTCs diagnosis towards precision medicine in lung cancer. This device also enables higher throughput owing to its automated procedure. Further clinical evaluation including the detection of PD-L1 expression will be performed in an expansion cohort. Citation Format: Satomi Yagi, Yasuhiro Koh, Hiroaki Akamatsu, Woong Kim, Ayaka Tanaka, Kuninobu Kanai, Atsushi Hayata, Ryota Shibaki, Masayuki Higuchi, Hisashige Kanbara, Takashi Kikuchi, Keiichiro Akamatsu, Masanori Nakanishi, Hiroki Ueda, Nobuyuki Yamamoto. Development of an automated device for size-based enrichment and isolation of circulating tumor cells in lung cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2244.
- Published
- 2016
31. Abstract B138: Evaluation of a novel automated device for size-based enrichment and isolation of CTCs in patients with advanced lung cancer
- Author
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Keiichiro Akamatsu, Nobuyuki Yamamoto, Satomi Yagi, Hiroaki Akamatsu, Hisashige Kanbara, Takashi Kikuchi, Ayaka Tanaka, Masanori Nakanishi, Atsushi Hayata, Yasuhiro Koh, Woong Kim, Kuninobu Kanai, Masayuki Higuchi, and Ryota Shibaki
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Cancer ,medicine.disease ,Primary tumor ,Metastasis ,Circulating tumor cell ,Internal medicine ,Immunology ,Cancer cell ,Medicine ,Stage (cooking) ,business ,Lung cancer - Abstract
Circulating tumor cells (CTCs) are associated with prognosis of patients with advanced solid tumors including lung cancer and reflect characteristics of the respective primary tumor and its metastatic deposits. Assessment of CTCs is expected to improve effectiveness of anticancer therapy and to sophisticate our knowledge to cancer metastasis. We previously reported that detection of CTCs using microcavity array (MCA) system yielded the superior sensitivity than FDA-approved CellSearch system in patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Here we developed the automated CTCs detection device and evaluated its performance using preclinical spike-in model and blood samples from NSCLC and SCLC patients. The feasibility study on the assessement of PD-L1 expression level was also performed. To evaluate the recovery of CTCs preclinically, NSCLC cells, H1975, A549, H441 and PC-14 were spiked into 6 mL of peripheral whole blood obtained from healthy volunteers. Then, cells were captured and immuno-stained by using automated MCA system. CTCs were defined as those positive for DAPI and cytokeratin (CK) and negative for CD45. Additionally, normal blood cells and cancer cells were distinguished according to their size. For clinical evaluation, 6 mL of peripheral whole blood was collected from 10 healthy donors and 30 advanced lung cancer patients prior to the initiation of chemotherapy. Head-to-head comparison with CellSearch system was also conducted. PD-L1 immunostaining was established in a preclinical spike-in study using NSCLC cell lines, H820, A549, H441, and H23 with varying PD-L1 expression levels and tested as an exploratory objective in a subset of patients enrolled in a clinical study. We confirmed that up to 90% of spiked-in tumor cells were recovered by the automated MCA system, suggesting that the detection sensitivity by this automated device is on par with that by previous detection procedure. Characteristics of 30 lung cancer patients in clinical study were as follows: median age 71 (range, 48 to 85); male 70%; stage III/IV 17/83%; NSCLC/SCLC 83/17%. Cells defined as CTC were detected in 2 cases out of 10 healthy volunteers, of which CTC count was 1 and 2 in 6 mL of peripheral blood, respectively. More than 2 CTCs were detected in 77% of patients with advanced lung cancer (n = 23/30) and more than 5 CTCs were detected in 50% of patients (n = 15/30) (median CTC count 5.5). Significantly more CTCs were detected by the automated MCA system than by CellSearch system. Among stage IV NSCLC patients, patients with extrathoracic metastasis tend to have more CTCs than in those without one (median CTC count, 8 versus 4, p = 0.058). No difference in CTC counts between NSCLC and SCLC was observed in this study cohort. PD-L1 expression was assessed in a subset of patients and intra-patient heterogeneity of PD-L1 staining among CTCs was observed in patients who harbor PD-L1-positive CTCs. Our results suggest that the automated MCA device for size-based enrichment and isolation of CTCs has a clinical potential for CTCs diagnosis towards precision medicine in lung cancer. This also enables us to deal with more samples owing to its automated procedure and higher throughput. Further clinical evaluation including PD-L1 expression will be performed in an expansion cohort and the biology of CTCs will be investigated utilizing this device. Citation Format: Woong Kim, Yasuhiro Koh, Hiroaki Akamatsu, Satomi Yagi, Ayaka Tanaka, Kuninobu Kanai, Atsushi Hayata, Ryota Shibaki, Masayuki Higuchi, Hisashige Kanbara, Takashi Kikuchi, Keiichiro Akamatsu, Masanori Nakanishi, Nobuyuki Yamamoto. Evaluation of a novel automated device for size-based enrichment and isolation of CTCs in patients with advanced lung cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B138.
- Published
- 2015
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