記述言語：英語   出版者・発行元：The Lancet Respiratory Medicine  

Background: The combination of platinum-based chemotherapy and an antibody to PD-1 or to its ligand PD-L1, with or without an antibody to CTLA-4, has improved the survival of individuals with metastatic non-small-cell lung cancer (NSCLC). However, no randomised controlled trial has evaluated the survival benefit of adding a CTLA-4 inhibitor to platinum-based chemotherapy plus a PD-1 or PD-L1 inhibitor. Methods: This open-label, randomised, phase 3 trial was conducted at 48 hospitals in Japan. Eligible patients were aged 20 years or older with previously untreated advanced NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with known driver oncogenes were excluded. Participants were randomly assigned (1:1) to receive platinum-based chemotherapy (four cycles) plus pembrolizumab (pembrolizumab group) or platinum-based chemotherapy (two cycles) plus nivolumab–ipilimumab (nivolumab–ipilimumab group). The primary endpoint was overall survival and assessed in all randomly assigned patients on an intention-to-treat basis. The trial is registered in the Japan Registry for Clinical Trials, jRCTs031210013, and is now closed to new enrolment and is ongoing. Findings: Between patient accrual initiation on April 6, 2021, and discontinuation of the trial on March 30, 2023, 11 (7%) of 148 patients in the nivolumab–ipilimumab group had a treatment-related death. Because of the high number of treatment-related deaths, patient accrual was terminated early, resulting in 295 patients (236 [80%] male and 59 [20%] female) enrolled; the primary analysis was done on the basis of 117 deaths (fewer than the required 329 deaths). By May 25, 2023 (data cutoff), overall survival did not differ significantly between the nivolumab–ipilimumab group and the pembrolizumab group (median 23·7 months [95% CI 17·6–not estimable] vs 20·5 months [17·6–not estimable], respectively; hazard ratio 0·98 [90% CI 0·72–1·34]; p=0·46). Non-haematological adverse events of grade 3 or worse occurred in 87 (60%) of 146 patients in the nivolumab–ipilimumab group and 59 (41%) of 144 patients in the pembrolizumab group. The pembrolizumab group tended to have a better quality of life compared with the nivolumab–ipilimumab group. Interpretation: The safety and efficacy data suggest an unfavourable benefit–risk profile for nivolumab–ipilimumab combined with platinum-based chemotherapy relative to pembrolizumab combined with platinum-based chemotherapy as a first-line treatment for patients with advanced NSCLC, although a definitive conclusion awaits an updated analysis of overall survival. Funding: The National Cancer Center Research and Development Fund and Japan Agency for Medical Research and Development.

DOI： 10.1016/S2213-2600(24)00185-1

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記述言語：英語   出版者・発行元：European Journal of Cancer  

Background: The effect of dual immunotherapy combined with platinum-based chemotherapy on untreated brain metastases derived from non–small cell lung cancer (NSCLC) has remained unclear. Methods: This multicenter single-arm phase 2 study enrolled patients with chemotherapy-naïve advanced NSCLC and at least one brain metastasis ≥ 5 mm in size that had not been previously treated. Patients received nivolumab plus ipilimumab combined with platinum-doublet chemotherapy (two cycles), followed by nivolumab-ipilimumab alone. The primary endpoint of the study was intracranial response rate as determined by modified Response Evaluation Criteria in Solid Tumors (RECIST) for brain metastases of ≥ 5 mm as target lesions. Results: A total of 30 patients from 18 institutions was enrolled in this study. The median age was 66.5 years (range, 47–83 years), and 26 patients (87 %) had a non–squamous cell carcinoma histology. The median size of all target brain lesions was 8.4 mm, with a range of 5–39 mm. The intracranial response rate assessed by modified RECIST was 50.0 % (95 % CI, 33.2–66.8 %), with the rate of complete response being 20.0 %, and the study met its primary endpoint. The systemic response rate was 53.3 % (95 % CI, 36.1–69.8 %), and responses for intracranial and extracranial lesions were generally consistent. The median intracranial progression-free survival was 8.1 months, and both the median intracranial duration of response and time to brain radiotherapy were not reached. Conclusion: Nivolumab plus ipilimumab combined with platinum-based chemotherapy showed promising intracranial activity in NSCLC patients with untreated brain metastases. Trial registration: jRCT071210019.

DOI： 10.1016/j.ejca.2024.115052

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DOI： 10.1016/j.annonc.2024.07.574

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記述言語：英語   出版者・発行元：Thoracic Cancer  

Background: Concurrent chemoradiotherapy is the standard therapy for locally advanced non-small cell lung cancer (NSCLC). However, there is little evidence supporting its use in older adults. Low-dose daily carboplatin combined with thoracic radiotherapy is considered a standard regimen for this population. To establish a simple and feasible carboplatin administration method, we conducted a study of weekly carboplatin and concurrent radiotherapy for older adults with locally advanced NSCLC. Methods: This prospective, single-arm, multicenter, phase II clinical trial included patients aged ≥75 years with unresectable stage III NSCLC and Eastern Cooperative Oncology Group performance status 0–1. Patients received chemoradiotherapy (60 Gy/30 fractions plus concurrent weekly carboplatin at an area under curve of 2 mg mL−1 min−1). The primary endpoint was the overall response rate (ORR). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: From July 2020 to June 2022, 37 patients were enrolled from 15 institutions, and 36 patients were evaluable for efficacy and safety. The ORR was 63.9% (95% confidence interval [CI] = 47.6–77.5). Median PFS was 14.6 months (95% CI = 9.1–18.1). Median OS was 25.5 months (95% CI = 17.4–not reached). Grade 4 leucopenia, neutropenia, and thrombocytopenia were observed in one patient (2.8%) each. Conclusion: Weekly carboplatin and concurrent radiation therapy was safe in older adults with locally advanced NSCLC, and promising activity was observed.

DOI： 10.1111/1759-7714.15444

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記述言語：英語   出版者・発行元：Clinical Lung Cancer  

The incidence of brain radiation necrosis is increasing in NSCLC patients undergoing radiotherapy for brain metastases. • [11C] methionine–PET and MRS are valuable tools for diagnosing brain radiation necrosis. • Bevacizumab is an effective treatment for brain radiation necrosis in patients with nonsquamous NSCLC.

DOI： 10.1016/j.cllc.2024.06.010

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DOI： 10.1016/j.clc.2024.06.010

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記述言語：英語   出版者・発行元：Lung Cancer  

Objectives: Predicting the prognosis of lung cancer is crucial for providing optimal medical care. However, a method to accurately predict the overall prognosis in patients with stage IV lung cancer, even with the use of machine learning, has not been established. Moreover, the inter-institutional generalizability of such algorithms remains unexplored. This study aimed to establish machine learning-based algorithms with inter-institutional generalizability to predict prognosis. Materials and Methods: This multicenter, retrospective, hospital-based cohort study included consecutive patients with stage IV lung cancer who were randomly categorized into the training and independent test cohorts with a 2:1 ratio, respectively. The primary metric to assess algorithm performance was the area under the receiver operating characteristic curve in the independent test cohort. To assess the inter-institutional generalizability of the algorithms, we investigated their ability to predict patient outcomes in the remaining facility after being trained using data from 15 other facilities. Results: Overall, 6,751 patients (median age, 70 years) were enrolled, and 1,515 (22 %) showed mutated epidermal growth factor receptor expression. The median overall survival was 16.6 (95 % confidence interval, 15.9–17.5) months. Algorithm performance metrics in the test cohort showed that the areas under the curves were 0.90 (95 % confidence interval, 0.88–0.91), 0.85 (0.84–0.87), 0.83 (0.81–0.85), and 0.85 (0.82–0.87) at 180, 360, 720, and 1,080 predicted survival days, respectively. The performance test of 16 algorithms for investigating inter-institutional generalizability showed median areas under the curves of 0.87 (range, 0.84–0.92), 0.84 (0.78–0.88), 0.84 (0.76–0.89), and 0.84 (0.75–0.90) at 180, 360, 720, and 1,080 days, respectively. Conclusion: This study developed machine learning algorithms that could accurately predict the prognosis in patients with stage IV lung cancer with high inter-institutional generalizability. This can enhance the accuracy of prognosis prediction and support informed and shared decision-making in clinical settings.

DOI： 10.1016/j.lungcan.2024.107896

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記述言語：英語   出版者・発行元：(一社)日本疫学会  

<Highlight>●preserved ratio impaired spirometry(PRISm)と認知症との関連は明らかにされていない。●本研究では、認知症のない65歳以上の日本人地域高齢住民1,202人を対象に、中央値5.0年間の追跡調査を行った。●PRISm群は、呼吸機能正常群と比べ認知症の発症リスクが約2倍であった。●PRISmは、認知症の発症リスクが高い集団であり、呼吸機能障害の重要なサブタイプといえる。(著者抄録)

記述言語：英語   出版者・発行元：Heliyon  

Pulmonary surfactant is essential for maintaining proper lung function. Alveolar epithelial type II (AE2) cells secrete surfactants via lamellar bodies (LBs). In tidal loading during each breath, the physiological cyclic stretching of AE2 cells promotes surfactant secretion. Excessive stretching inhibits surfactant secretion, which is considered to contribute to the development of lung damage. However, its precise mechanism remains unknown. This study tested whether actin polymerization and intracellular transport are required for pulmonary surfactant secretion and the association of actin polymerization and transport in identical human AE2-derived A549 cells using live-cell imaging, not in the bulk cells population. We found that overstretching approximately doubled actin polymerization into filaments (F-actin) and suppressed LB secretion by half in the fluorescent area ratio, compared with physiological stretching (F-actin: 1.495 vs 0.643 (P < 0.01); LB: 0.739 vs 0.332 (P < 0.01)). An inhibitor of actin polymerization increased LB secretion. Intracellular tracking using fluorescent particles revealed that cyclic stretching shifted the particle motion perpendicularly to the direction of stretching according to the orientation of the F-actin (proportion of perpendicular axis motion prior particle: 0h 40.12 % vs 2h 63.13 % (P < 0.01)), and particle motion was restricted over time in the cells subjected to overstretching, indicating that overstretching regulates intracellular transport dynamics (proportion of stop motion particle: 0h 1.01 % vs 2h 11.04 % (P < 0.01)). These findings suggest that overstretching changes secretion through the cytoskeleton: overstretching AE2 cells inhibits pulmonary surfactant secretion, at least through accelerating actin polymerization and decreasing intracellular trafficking, and the change in actin orientation would modulate intracellular trafficking.

DOI： 10.1016/j.heliyon.2024.e33499

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記述言語：英語   出版者・発行元：日本疫学会  

Background: Studies on the association between preserved ratio impaired spirometry (PRISm) and dementia are limited. Indeed, PRISm has often been overlooked or ignored as an index of lung function impairment. Therefore, we investigated the association of PRISm with the risk for the development of dementia in an older Japanese population. Methods: A total of 1,202 community-dwelling, older Japanese participants aged ≥65 years without dementia were followed up for a median of 5.0 years. Participants were categorized by spirometry as follows: normal spirometry (FEV1/FVC ≥0.70 and FEV1 ≥80% predicted), PRISm (≥0.70 and <80%), airflow limitation (AFL) Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 (<0.70 and ≥80%), and AFL GOLD 2 to 4 (<0.70 and <80%). Hazard ratios (HRs) and their 95% confidence intervals (CIs) were computed using a Cox proportional hazards model. Results: During the follow-up period, 122 participants developed dementia. The age-and sex-adjusted incidences of dementia in the participants with normal spirometry, PRISm, AFL GOLD 1, and AFL GOLD 2 to 4 were 20.5, 37.0, 18.4, and 28.6 per 1,000 person-years, respectively. Participants with PRISm had a higher risk of dementia (HR 2.04; 95% CI, 1.19–3.49) than those with normal spirometry after adjusting for confounders. Moreover, both reduced FEV1% predicted values and FVC% predicted values were associated with the risk of dementia. Conclusion: PRISm was associated with an increased risk of dementia in a general older Japanese population.

DOI： 10.2188/jea.je20230207

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記述言語：英語   出版者・発行元：Scandinavian Journal of Rheumatology  

Objective: This study aimed to analyse whether initiating nintedanib treatment at a reduced dose could improve the treatment continuation rate while maintaining efficacy in patients with connective tissue disease (CTD)-associated interstitial lung disease. Method: In total, 51 patients (age 61.6 ± 13.2 years; 38 women, 13 men) were retrospectively analysed. The primary endpoint was the cumulative discontinuation rate due to adverse events. Secondary endpoints included changes in drug dosage, efficacy evaluated based on annual changes in forced vital capacity (FVC), and safety assessed based on the frequency of adverse events. Results: Eighteen patients who started treatment at the standard dose of 300 mg (standard dosage group) were compared with 33 patients who started treatment at a reduced dose (reduced dosage group). Systemic sclerosis was the most common CTD (n = 32), followed by idiopathic inflammatory myopathies and, rarely, rheumatoid arthritis. Both groups exhibited comparable cumulative discontinuation rates due to adverse events and similar frequencies of adverse events. No significant differences were observed in maintenance doses between the two groups; however, patients in the reduced dosage group had a lower cumulative dose for up to 52 weeks than those in the standard dosage group. No significant differences were observed in changes in FVC between the two groups. Conclusion: There was no evidence for a difference between the two groups in terms of discontinuation rates, efficacy, and safety. To provide further evidence, future studies using more precise dose-escalation protocols are warranted.

DOI： 10.1080/03009742.2024.2327159

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記述言語：英語   出版者・発行元：Oxford University Press  

DOI： 10.1200/JCO.2024.42.17_suppl.LBA5

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DOI： 10.1200/JCO.2024.42.17_suppl.LBA8050

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記述言語：英語   出版者・発行元：Clinical Lung Cancer  

Introduction: Although the standard treatment for patients with resectable early-stage non–small-cell lung cancer (NSCLC) is pulmonary lobectomy, recent clinical trials have demonstrated the efficacy of anatomical segmentectomy for small-sized early-stage NSCLC measuring ≤2 cm. Segmentectomy is gaining attention as an alternative procedure to lobectomy for early-stage NSCLC. Patients and Methods: In January 2024, we have initiated a randomized phase III trial in Japan to confirm the noninferiority of anatomical segmentectomy to lobectomy in patients with peripheral clinical stage IA3 pure-solid NSCLC (tumor measuring >2 cm and ≤3 cm; consolidation-to-tumor ratio = 1.0). We plan to enroll 520 patients from 61 institutions over a period of 5 years. The primary endpoint is overall survival, and the secondary endpoints include relapse-free survival, postoperative respiratory function, proportion of patients with respiratory failure and cerebrovascular disease, cumulative incidence of death from other diseases, cumulative incidence of local recurrence, proportion of patients who undergo segmentectomy, number of resected segments, operative time, blood loss, and adverse events. This trial has been registered in the UMIN Clinical Trials Registry under the code UMIN000052064. Conclusions: This trial will help establish a novel treatment strategy for patients with peripheral clinical stage IA3 pure-solid NSCLC.

DOI： 10.1016/j.cllc.2024.01.004

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記述言語：英語   出版者・発行元：Clinical Lung Cancer  

Background: In advanced non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations, those with impaired performance status (PS) treated with EGFR-tyrosine kinase inhibitors (TKIs) have demonstrated comparable activities to good-PS patients. Due to the limited sample size and inclusion of older adult patients with good PS, these findings may not accurately depict the efficacy of EGFR-TKI in poor-PS patients. We investigated the benefit of EGFR-TKIs in this population and identified relevant prognostic factors. Patients and Methods: This nationwide prospective registry study included 9872 patients with local or advanced NSCLC. Outcomes were compared between poor- and good-PS patients treated with EGFR-mutated lung cancer therapies. Results: Of 9872 NSCLC patients, 1965 (19.9%) had EGFR mutations, with 1846 (93.9%) presenting common EGFR mutations. Poor PS (PS score ≥ 3) was noted in 171 patients (8.7%) and identified as an independent prognostic factor; those with poor PS had a significantly lower 1-year survival rate. The median overall survival (OS) for EGFR-TKI-treated good-PS patients was 31.5 (95% confidence interval, 29.6-33.4) months. Among poor-PS patients with EGFR mutations, 135 (78.9%) of whom were treated with EGFR-TKI had an OS of 15.5 (12.7-18.3) months, while those receiving only supportive care had an OS of 2.5 (1.4-3.6) months (P < .001). Hypoalbuminemia (< 3.5 g/dL), liver metastasis, and uncommon EGFR mutations were associated with poor prognosis. Conclusion: Poor PS at diagnosis was rare and associated with limited EGFR-TKI efficacy and a dismal prognosis. Liver metastasis and hypoalbuminemia may reduce EGFR-TKI efficacy in these patients.

DOI： 10.1016/j.cllc.2024.01.005

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記述言語：英語  

DOI： 10.7759/cureus.61470

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記述言語：英語   出版者・発行元：一般社団法人 日本内科学会  

We present the case of a 61-year-old man who developed coronavirus disease 2019 (COVID-19) and died during treatment for relapsing polychondritis. The patient was intubated and treated with steroid pulse therapy, remdecivir, antibacterial agents, baricitinib, and tocilizumab. However, his respiratory condition worsened, and he died 108 days after disease onset. An autopsy revealed diffuse alveolar damage in the fibrotic phase in all lung lobes, diffuse pulmonary ossification, and cytomegalovirus-infected cells in the middle lobe of the right lung. We herein discuss the clinical features and pathological findings of COVID-19 in immunosuppressed patients.

DOI： 10.2169/internalmedicine.3096-23

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：エルゼビア・ジャパン(株)  

初回治療でオシメルチニブを投与したEGFR遺伝子変異陽性非小細胞肺癌(NSCLC)患者21例を対象に、中枢神経系への転移に対するオシメルチニブの再投与の有効性を検討した。対象はオシメルチニブによる初回治療後に少なくとも1サイクル以上の化学療法を施行した患者で、オシメルチニブの初回または再投与時に他の抗癌剤を併用した症例は除外した。EGFR遺伝子変異はエクソン19欠失が13例、L858R変異が8例であった。治療効果は固形がんにおける効果判定規準であるRECISTにより評価した。21例のうち16例で標的病変を認め、オシメルチニブの再投与により8例(50%)で腫瘍径の縮小を認めた。部分奏効は1例(6.3%)で達成し、安定が7例、進行が8例であった。患者全体の無増悪生存期間中央値は3.8ヵ月、全生存期間中央値は13.9ヵ月であった。中枢神経系(CNS)への転移は8例で認め、そのうち5例は軟髄膜転移であった。CNS転移例の全奏効率は100%で、1例で完全奏効、3例で部分奏効を達成した。CNS転移病変の無増悪期間中央値は24.7ヵ月に対して非CNS病変は10.5ヵ月であった。CNS転移患者の全生存期間中央値は15.7ヵ月であった。

記述言語：英語   出版者・発行元：(一社)日本内科学会  

症例は61歳男性で、再発性多発軟骨炎と診断され、免疫抑制療法を行っていた。2日前に発熱し、その2日後に呼吸困難が出現して緊急搬送されてきた。SARS-CoV-2のPCR検査が陽性であったため、新型コロナウイルス感染症と診断した。挿管して換気補助を行い、ステロイドパルス療法、レムデシビル、メロペネム、ヘパリンの投与を行った。ステロイド療法後に呼吸状態、炎症マーカーレベル、胸部放射線学的所見は改善したが、ステロイド減量により悪化し、ステロイドパルス療法を再施行した。炎症コントロールのためにバリシチニブとトシリズマブを追加投与したが、呼吸状態の悪化が持続した。サイトメガロウイルス感染も認め、ガンシクロビル投与を行ったが、108日目に多臓器不全により死亡した。剖検では、全肺葉における線維化期のび漫性肺胞障害、び漫性肺骨化、右肺中葉のサイトメガロウイルス感染細胞が認められた。

記述言語：英語   出版者・発行元：Thoracic Cancer  

Tracheomediastinal fistula is a rare but life-threatening complication of cancer. We report a case of tracheomediastinal fistula induced by concurrent chemoradiotherapy in limited stage small cell lung cancer. Despite the treatment response, the metastatic paratracheal lymph node increased gradually during concurrent chemoradiotherapy, resulting in the occurrence of tracheomediastinal fistula and mediastinitis. Without any surgical intervention, the patient achieved successful recovery from mediastinitis through antibiotic treatment, although the tracheomediastinal fistula remained open. In this report, we also review previous studies of tracheomediastinal and bronchomediastinal fistulas and summarize the clinical features.

DOI： 10.1111/1759-7714.15270

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記述言語：英語   出版者・発行元：Clinical Lung Cancer  

Introduction: Atezolizumab following platinum chemotherapy and complete pulmonary resection has become the new standard of adjuvant care for patients with stage II-III non-small cell lung cancer (NSCLC) expressing programmed death-ligand 1 (PD-L1). However, the efficacy and safety of postoperative adjuvant therapy and subsequent atezolizumab in patients aged 75 and older have not been established. Methods: Patients with completely resected stage II–III NSCLC aged 75 and older will be prospectively registered in this single-arm phase II study. The enrolled patients will receive cisplatin plus vinorelbine (CDDP + VNR) followed by atezolizumab for up to 12 months. PD-L1 expression in at least 1% of cells will be confirmed by immunohistochemical staining. We plan to enroll 33 patients over 1 year at 25 institutions in Japan. The primary endpoint is the completion rate of adjuvant treatment (CDDP + VNR initiation to atezolizumab completion). Conclusion: The present study represents the first prospective trial of the tolerability of postoperative adjuvant therapy with immune checkpoint inhibitors in elderly individuals. The results of this trial might help promote postoperative adjuvant immunotherapy in the future for the elderly.

DOI： 10.1016/j.cllc.2024.01.009

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記述言語：英語   出版者・発行元：Respiratory Investigation  

Background: Osimertinib shows pronounced efficacy for EGFR mutation–positive non–small cell lung cancer (NSCLC) including associated central nervous system (CNS) metastases. Tumors inevitably develop resistance to the drug, however. Osimertinib is sometimes readministered after completion of standard chemotherapy. To clarify which patients might receive benefit from osimertinib readministration, we have retrospectively assessed its efficacy with a focus on CNS metastases. Methods: A retrospective analysis of medical records was performed for 21 patients who underwent osimertinib readministration at Kyushu University Hospital between March 2016 and April 2023. CNS metastases were evaluated according to modified Response Evaluation Criteria in Solid Tumors (RECIST). Results: Among the 21 enrolled patients, 16 individuals had target lesions on the basis of RECIST. One (6.3%) of these 16 patients achieved a partial response to osimertinib readministration, with the remaining 15 patients showing stable or progressive disease. The median overall progression-free survival (PFS) and median overall survival for all 21 patients were 3.8 and 13.9 months, respectively. The efficacy of osimertinib readministration for CNS metastases was evaluable in eight patients including five individuals with leptomeningeal metastases. The objective response rate for CNS metastases and the improvement rate for leptomeningeal metastases were both 100%. The median PFS with regard to CNS or non-CNS lesions for these eight patients was 24.7 and 10.5 months, respectively. Conclusions: Osimertinib readministration showed limited efficacy for non-CNS lesions but excellent efficacy for CNS metastases, suggesting that such treatment is an option for EGFR-mutated NSCLC patients with CNS metastases.

DOI： 10.1016/j.resinv.2024.02.001

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記述言語：英語   出版者・発行元：Respirology Case Reports  

We report the first case of drug-induced interstitial lung disease attributed to lemborexant. A 66-year-old man reported to our hospital with the acute onset of cough and breathlessness with ground-glass opacity on radiological examination. Symptoms were identified after taking lemborexant for 2 consecutive days. The patient had undergone lemborexant treatment 2 years prior and had exhibited no symptoms at that time. The drug-induced lymphocyte stimulation test for lemborexant was positive. He showed rapid improvement upon treatment with steroid. With the rise in prescriptions of lemborexant for insomnia, lemborexant should be considered as a possible cause of drug-induced interstitial lung disease.

DOI： 10.1002/rcr2.1334

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記述言語：英語   出版者・発行元：eLife  

Anticancer treatments can result in various adverse effects, including infections due to immune suppression/dysregulation and drug-induced toxicity in the lung. One of the major opportunistic infections is Pneumocystis jirovecii pneumonia (PCP), which can cause severe respiratory complications and high mortality rates. Cytotoxic drugs and immune-checkpoint inhibitors (ICIs) can induce interstitial lung diseases (ILDs). Nonetheless, the differentiation of these diseases can be difficult, and the pathogenic mechanisms of such diseases are not yet fully understood. To better comprehend the immunophenotypes, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid from patients with PCP, cytotoxic drug-induced ILD (DI-ILD), and ICI-associated ILD (ICI-ILD) using two panels containing 64 markers. In PCP, we observed an expansion of the CD16+ T cell population, with the highest CD16+ T proportion in a fatal case. In ICI-ILD, we found an increase in CD57+ CD8+ T cells expressing immune checkpoints (TIGIT+ LAG3+ TIM-3+ PD-1+), FCRL5+ B cells, and CCR2+ CCR5+ CD14+ monocytes. These findings uncover the diverse immunophenotypes and possible pathomechanisms of cancer treatment-related pneumonitis.

DOI： 10.7554/eLife.87288

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記述言語：英語   出版者・発行元：JTO Clinical and Research Reports  

Introduction: Immune checkpoint inhibitors have recently been approved for the treatment of early-stage NSCLC in the perioperative setting on the basis of phase 3 trials. However, the characteristics of such patients who are susceptible to recurrence after adjuvant chemotherapy or who are likely to benefit from postoperative immunotherapy have remained unclear. Methods: This biomarker study (WJOG12219LTR) was designed to evaluate cancer stem cell markers (CD44 and CD133), programmed death-ligand 1 (PD-L1) expression on tumor cells, CD8 expression on tumor-infiltrating lymphocytes, and tumor mutation burden in completely resected stage II to IIIA NSCLC with the use of archived DNA and tissue samples from the prospective WJOG4107 trial. Tumors were classified as inflamed or noninflamed on the basis of the PD-L1 tumor proportion score and CD8+ tumor-infiltrating lymphocyte density. The association between each potential biomarker and relapse-free survival (RFS) during adjuvant chemotherapy was assessed by Kaplan-Meier analysis. Results: A total of 117 patients were included in this study. The median RFS was not reached (95% confidence intervals [CI]: 22.4 mo–not reached; n = 39) and 23.7 months (95% CI: 14.5–43.6; n = 41) in patients with inflamed or noninflamed adenocarcinoma, respectively (log-rank p = 0.02, hazard ratio of 0.52 [95% CI: 0.29–0.93]). Analysis of the combination of tumor inflammation category and TP53 mutation status revealed that inflamed tumors without TP53 mutations were associated with the longest RFS. Conclusions: PD-L1 expression on tumor cells, CD8+ T cell infiltration, and TP53 mutation status may help identify patients with early-stage NSCLC susceptible to recurrence after adjuvant chemotherapy.

DOI： 10.1016/j.jtocrr.2024.100658

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記述言語：英語   出版者・発行元：Japanese Journal of Clinical Oncology  

Objective: large-scale multicentre clinical trials conducted by cooperative groups have generated a lot of evidence to establish better standard treatments. The Clinical Trials Act was enforced on 1 April 2018, in Japan, and it has remarkably increased the operational burden on investigators, but its long-term impact on cancer cooperative groups is unknown. Methods: a survey was conducted across the nine major cooperative groups that constitute the Japan Cancer Trials Network to assess the impact of Clinical Trials Act on the number of newly initiated trials from fiscal year (from 1 April to 31 March) 2017 to 2022 and that of ongoing trials on 1 April in each year from 2018 to 2023. Results: the number of newly initiated trials dropped from 38 trials in fiscal year 2017 to 26 trials in fiscal year 2018, surged to 50 trials in fiscal year 2019, but then gradually decreased to 25 trials by fiscal year 2022. Specified clinical trials decreased from 32 trials in fiscal year 2019 to 12 trials in fiscal year 2022. The number of ongoing trials was 220 trials in 2018, peaked at 245 trials in 2020, but then gradually decreased to 219 trials by 2023. The number of specified clinical trials has been in consistent decline. By April 2023, of the 20 ongoing non-specified clinical trials, nine adhered to Clinical Trials Act and 11 followed the Ethical Guidelines for Medical and Health Research Involving Human Subjects. Conclusion: the number of multicentre clinical trials in oncology gradually decreased after the Clinical Trials Act’s enforcement, which underscores the need for comprehensive amendment of the Clinical Trials Act to streamline the operational process.

DOI： 10.1093/jjco/hyae034

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記述言語：英語   出版者・発行元：npj Precision Oncology  

EGFR tyrosine kinase inhibitors (TKIs) are effective against EGFR-mutated lung cancer, but tumors eventually develop resistance to these drugs. Although TP53 gain-of-function (GOF) mutations promote carcinogenesis, their effect on EGFR-TKI efficacy has remained unclear. We here established EGFR-mutated lung cancer cell lines that express wild-type (WT) or various mutant p53 proteins with CRISPR-Cas9 technology and found that TP53-GOF mutations promote early development of resistance to the EGFR-TKI osimertinib associated with sustained activation of ERK and expression of c-Myc. Gene expression analysis revealed that osimertinib activates TNF-α–NF-κB signaling specifically in TP53-GOF mutant cells. In such cells, osimertinib promoted interaction of p53 with the NF-κB subunit p65, translocation of the resulting complex to the nucleus and its binding to the TNF promoter, and TNF-α production. Concurrent treatment of TP53-GOF mutant cells with the TNF-α inhibitor infliximab suppressed acquisition of osimertinib resistance as well as restored osimertinib sensitivity in resistant cells in association with attenuation of ERK activation and c-Myc expression. Our findings indicate that induction of TNF-α expression by osimertinib in TP53-GOF mutant cells contributes to the early development of osimertinib resistance, and that TNF-α inhibition may therefore be an effective strategy to overcome such resistance in EGFR-mutant lung cancer with TP53-GOF mutations.

DOI： 10.1038/s41698-024-00557-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：JAMA Oncology  

Importance: The combination of an antibody to programmed cell death-1 (PD-1) or to its ligand (PD-L1) with chemotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC). Bevacizumab is expected to enhance the efficacy not only of chemotherapy but also of PD-1/PD-L1 antibodies through blockade of vascular endothelial growth factor-mediated immunosuppression, but further data are needed to support this. Objective: To evaluate the efficacy and safety of bevacizumab administered with platinum combination therapy and atezolizumab in patients with advanced nonsquamous NSCLC. Design, Setting, and Participants: An open-label phase 3 randomized clinical trial was conducted at 37 hospitals in Japan. Patients with advanced nonsquamous NSCLC without genetic driver alterations or those with genetic driver alterations who had received treatment with at least 1 approved tyrosine kinase inhibitor were enrolled between January 20, 2019, and August 12, 2020. Interventions: Patients were randomly assigned to receive either atezolizumab plus carboplatin with pemetrexed (APP) or atezolizumab, carboplatin plus pemetrexed, and bevacizumab (APPB). After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab was administered until evidence of disease progression, development of unacceptable toxic effects, or the elapse of 2 years from the initiation of protocol treatment. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the intention-to-treat (ITT) population. Results: A total of 412 patients were enrolled (273 men [66%]; median age, 67.0 [range, 24-89] years) and randomly assigned, with 205 in the APPB group and 206 in the APP group of the ITT population after exclusion of 1 patient for good clinical practice violation. The median BICR-assessed PFS was 9.6 months with APPB vs 7.7 months with APP (stratified hazard ratio [HR], 0.86; 95% CI, 0.70-1.07; 1-sided stratified log-rank test; P =.92). According to prespecified subgroup analysis of BICR-assessed PFS, an improved PFS with APPB vs APP was apparent specifically in driver oncogene-positive patients (median, 9.7 vs 5.8 months; stratified HR, 0.67; 95% CI, 0.46-0.98). Toxic effects related to bevacizumab were increased in the APPB group. Conclusions and Relevance: The findings of this trial did not show superiority of APPB over APP for patients with nonsquamous NSCLC; however, this regimen showed a similar tolerability and improved survival relative to APP in patients with driver oncogenes. Trial Registration: Japan Registry of Clinical Trials Identifier: jRCT2080224500.

DOI： 10.1001/jamaoncol.2023.5258

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DOI： 10.1055/s-0044-1781395

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記述言語：英語   出版者・発行元：Thoracic Cancer  

Metastatic inflammatory myofibroblastic tumor (IMT) is very rare and detailed reports on diagnosis and treatment are limited. Here, we report a case of metastatic IMT with ALK rearrangement. A 73-year-old woman was diagnosed with IMT involving a brain metastasis. Next generation sequencing (NGS) panel testing with Oncomine dx target test revealed that her tumor was positive for EML4-ALK. Treatment with alectinib was initiated, resulting in remarkable shrinkage of both the primary tumor and the brain metastasis. This report is the first to identify ALK rearrangement in IMT using a commercially available NGS panel testing, followed by treatment with alectinib. This case suggests that NGS panel testing may be useful in the diagnosis and treatment of patients with metastatic IMT.

DOI： 10.1111/1759-7714.15203

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記述言語：英語   出版者・発行元：Journal of Thoracic Oncology  

We conducted a phase 3 clinical trial to compare the efficacy of platinum-based combination chemotherapy together with nivolumab plus ipilimumab relative to that of platinum-based combination chemotherapy together with pembrolizumab in previously untreated patients with advanced NSCLC. The trial was terminated prematurely after treatment of 295 patients because of a high proportion of treatment-related deaths, three of which were due to cytokine release syndrome (CRS), in the nivolumab plus ipilimumab treatment arm. In addition, we encountered two cases of CRS that were effectively managed, for a total of five cases (3.4%) among the 148 patients in the nivolumab plus ipilimumab arm. We here provide details of these five cases. Although patient background and timing of CRS onset differed, fever was observed before the emergence of CRS in all five cases. Oncologists should thus be aware that the development of fever during treatment of patients with nivolumab plus ipilimumab may herald the onset of CRS.

DOI： 10.1016/j.jtho.2023.10.010

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記述言語：英語   出版者・発行元：Scientific Reports  

Mucin overproduction is a common feature of chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), and exacerbates their underlying respiratory condition. Surfactant protein D (SP-D) protects against airway diseases through modulation of immune reactions, but whether it also exerts direct effects on airway epithelial cells has remained unclear. Therefore, we sought to investigate the inhibitory role of SP-D on mucin production in airway epithelial cells. We prepared air–liquid interface (ALI) cultures of human primary bronchial epithelial cells (HBECs), which recapitulated a well-differentiated human airway epithelium. Benzo(a)pyrene (BaP), a key toxicant in cigarette smoke, induced mucin 5AC (MUC5AC) production in ALI-cultured HBECs, airway secretory cell lines, and airway epithelia of mice. Then, the protective effects of SP-D against the BaP-induced mucin overproduction were examined. BaP increased MUC5AC production in ALI cultures of HBECs, and this effect was attenuated by SP-D. SP-D also suppressed the BaP-induced phosphorylation of extracellular signal-regulated kinase (ERK) and MUC5AC expression in NCI-H292 goblet-like cells, but not in NCI-H441 club-like cells. Signal regulatory protein α (SIRPα) was found to be expressed in HBECs and NCI-H292 cells but absent in NCI-H441 cells. In NCI-H292 cells, SP-D activated SH2 domain-containing tyrosine phosphatase-1 (SHP-1), downstream of SIRPα, and knockdown of SIRPα abolished the suppressive effects of SP-D on BaP-induced ERK phosphorylation and MUC5AC production. Consistent with these in vitro findings, intratracheal instillation of SP-D prevented the BaP-induced phosphorylation of ERK and Muc5ac expression in airway epithelial cells in a mouse model. SP-D acts directly on airway epithelial cells to inhibit mucin secretion through ligation of SIRPα and SHP-1-mediated dephosphorylation of ERK. Targeting of SIRPα is therefore a potential new therapeutic approach to suppression of mucin hypersecretion in chronic airway diseases such as COPD and asthma.

DOI： 10.1038/s41598-024-52328-5

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記述言語：英語   出版者・発行元：Respirology Case Reports  

A 54-year-old woman with no history of lung disease including bronchial asthma developed left bacterial pleural empyema due to the perforation of a lung abscess in the left lower lobe. Chest tube drainage and antibiotics improved the pleural empyema. Two months following discharge from the hospital, she developed a cough and left chest pain. Chest computed tomography revealed high-attenuation mucus plugs, atelectasis in the left lower lobe, and an increased peripheral blood eosinophil count. Bronchoscopy revealed a mucoid impaction in B8 of the left lower lobe, confirming the presence of Aspergillus fumigatus. A diagnosis of allergic bronchopulmonary aspergillosis was made, and treatment with oral prednisolone was initiated, resulting in the resolution of the mucus plugs and improvement of atelectasis.

DOI： 10.1002/rcr2.1264

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記述言語：英語   出版者・発行元：Journal of Clinical Oncology  

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The JIPANG study is an open-label phase III trial evaluating the efficacy of pemetrexed plus cisplatin (PemP) versus vinorelbine plus cisplatin (NP) as adjuvant chemotherapy in patients with stage II-IIIA nonsquamous non-small-cell lung cancer (NSCLC). Here, we report the long follow-up overall survival (OS) data. Eligible patients were randomly assigned to receive either PemP or NP. The primary end point was recurrence-free survival (RFS), and the secondary end point included OS. This analysis was performed using data collected 5 years after the last patient enrollment. Among 804 patients enrolled, 783 patients were eligible (384 for NP and 389 for PemP). The updated median RFS was 37.5 months in the NP arm and 43.4 months in the PemP arm with a hazard ratio of 0.95 (95% CI, 0.79 to 1.14). At a median follow-up of 77.3 months, the OS rates at 3 and 5 years were 84.1% and 75.6% versus 87.0% and 75.0% with a hazard ratio of 1.04 (95% CI, 0.81 to 1.34). This long-term follow-up analysis showed that PemP had similar efficacy to NP in both RFS and OS for this population, with one of the longest OS data compared with the historical data.

DOI： 10.1200/JCO.23.00179

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記述言語：英語   出版者・発行元：The Japan Society for Respiratory Endoscopy  

<p>Among various types of aspergillosis, the clinical features of patients with obstructive bronchial aspergillosis remain unclear. Originally, it was reported to occur only in severely immunocompromised patients, such as acquired immunodeficiency syndrome (AIDS) or post-organ transplantation; however, recent reports have suggested that this disease could also affect patients seen in daily practice of pulmonary medicine. We describe a case of a 76-year-old woman with obstructing bronchial aspergillosis. This patient presented to the hospital with a productive cough during asthma and advanced lung cancer treatment. Chest CT showed stenosis of the bronchial lumen. Bronchoscopy showed no recurrence of lung cancer, and aspergillus was found in the granulation tissue. The cough improved with debridement of the lesion by bronchoscopy and oral antifungal medication treatment. Our review of previous case reports, including this case, revealed that obstructing bronchial aspergillosis might occur when patients have several factors inducing immunosuppression, such as solid tumors under anticancer treatment, inhaled corticosteroids, and aging. Since patients may be at risk of progressing to invasive aspergillosis, physicians must properly diagnose obstructing bronchial aspergillosis to deliver appropriate treatment.</p>

DOI： 10.58585/respend.2023-0020

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記述言語：英語   出版者・発行元：The Japan Society for Respiratory Endoscopy  

<p>The case involves a 57-year-old man with a history of laryngeal and lung cancers. He underwent a laryngectomy and right upper lobectomy and developed tracheal methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) colonization. He also underwent endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) to diagnose right mediastinal lymph node adenopathy. His recovery was complicated by a mediastinal infection caused by MRSA five days post-procedure. Combining triple antibiotics comprising MEPM, DAP, and VCM for three weeks gradually improved the mediastinal infection. To our knowledge, this is the first report of mediastinal infection caused by MRSA after EBUS-TBNA. Our successful treatment of EBUS-TBNA-related infectious complications gives us information regarding rare complications management caused by EBUS-TBNA.</p>

DOI： 10.58585/respend.2023-0007

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記述言語：英語   出版者・発行元：Biochemical and Biophysical Research Communications  

Mechanisms underlying the growth and survival of non-small cell lung cancer (NSCLC) cells positive for activating mutations of the epidermal growth factor receptor gene (EGFR) have remained unclear. We here examined the functional relation between such mutant forms of EGFR and Yes-associated protein (YAP), a transcriptional coactivator of the Hippo signaling pathway that regulates cell proliferation and survival. Under the condition of serum deprivation, epidermal growth factor (EGF) induced activation of YAP in NSCLC cell lines positive for mutated EGFR but not in those wild type (WT) for EGFR. Similar EGF-induced activation of YAP was apparent in A549 lung cancer cells forcibly expressing mutant EGFR but not in those overexpressing the WT receptor. Furthermore, EGF induced apoptotic cell death in serum-deprived A549 cells overexpressing the WT form of EGFR but not in those expressing mutant EGFR, and knockdown of YAP rendered the latter cells sensitive to this effect of EGF. Our results thus suggest that activation of YAP mediates resistance of EGFR-mutated NSCLC cells to EGF-induced apoptosis and thereby contributes specifically to the survival of such cells.

DOI： 10.1016/j.bbrc.2023.09.067

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.annonc.2023.10.588

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記述言語：英語   出版者・発行元：(一社)日本呼吸器内視鏡学会  

症例は57歳男性。11年前に右喉頭癌を放射線療法と化学療法で治療されていた。4年前には右肺腺癌に対し切除術と地固め化学療法を受けていた。さらに1年前には左喉頭癌と診断され喉頭全摘出術と永久気管切開術が行われたが、その術後10日目にメチシリン耐性黄色ブドウ球菌(MRSA)による手術部位感染が発生し、洗浄とデブリードマンで治癒していた。喉頭全摘出術から1年が経過した今回の経過観察受診時に縦隔リンパ節が1個腫大していることが判明した。そのリンパ節は16mm大で右傍気管領域に位置しており、FDG-PET所見でも陽性(SUVmax 3.97)が示されたことから癌の再発が疑われた。FDG-PET画像上、他の領域には癌再発を疑わせる所見は示されなかった。気管瘻孔を利用して超音波気管支鏡ガイド下経気管支吸引針生検(EBUS-TBNA)を行い、合併症なく、また予防的抗生物質投与も行われずに同日退院していた。その5日後に高熱を訴え当院を受診した。白血球数とC反応性蛋白の高値が示され、造影CTでは縦隔感染を示唆する所見が示された。EBUS-TBNA処置に関連した縦隔リンパ節および縦隔の感染症と診断し、抗生物質3剤併用療法(MEPM、VCM、DAP)を3週間行ったところ同感染症は徐々に改善していった。生検結果からは右喉頭癌の再発と最終診断し、ペムブロリズマブの投与を開始した。

記述言語：英語   出版者・発行元：(一社)日本呼吸器内視鏡学会  

症例は77歳女性。喘息の持病があった。約5年前、慢性咳嗽の症状で当院を受診し、左肺下葉の肺腺癌(cT2aN1M0、病期IIA)と診断された。根治的放射線療法を受けたが、約2年前には肺癌が再発したため標準的な免疫化学療法(シスプラチン、ペメトレキセド、ペムブロリズマブ)と維持化学療法(ペメトレキセド+ペムブロリズマブ)が1年間行われた。本年になってから咳嗽が悪化しており、聴診所見から気管支喘息の増悪を疑って吸入皮質ステロイド療法を強化したが症状はさらに悪化した。血液検査ではアスペルギルスの抗原と特異的IgEはいずれも陰性所見であった。胸部CT画像では気管支腔の狭窄が示され、肺癌の気管支内への進行が疑われた。しかし、気管支鏡検査では肺癌の再発は認められず、代わりに左気管支の上葉支の内部に1個の白色病変が発見された。その病変の検体を採取したが、その際には抵抗を感じることなく採取することができた。その病理学的診断は閉塞性気管支アスペルギルス症とされた。白色病変のデブリードマン処置を行い、経口ボリコナゾールを開始したところ咳嗽は徐々に改善し、上昇していた白血球数とC反応性蛋白値も正常化した。6ヵ月後の気管支鏡評価では左上葉支にわずかな白色苔癬が観察されたが、生検ではアスペルギルスの菌糸は発見されなかった。そのためボリコナゾールを終了する判断をした。

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記述言語：英語   出版者・発行元：BMJ Open Respiratory Research  

Objective Few prospective cohort studies with relatively large numbers of patients with non-idiopathic pulmonary fibrosis (non-IPF) of idiopathic interstitial pneumonia (IIP) have been described. We aimed to assess disease progression and cause of death for patients with non-IPF IIPs or IPF under real-life conditions. Methods Data were analysed for a prospective multi-institutional cohort of 528 IIP patients enrolled in Japan between September 2013 and April 2016. Diagnosis of IPF versus non-IPF IIPs was based on central multidisciplinary discussion, and follow-up surveillance was performed for up to 5 years after patient registration. Survival and acute exacerbation (AE) were assessed. Results IPF was the most common diagnosis (58.0%), followed by unclassifiable IIPs (35.8%) and others (6.2%). The 5-year survival rate for non-IPF IIP and IPF groups was 72.8% and 53.7%, respectively, with chronic respiratory failure being the primary cause of death in both groups. AE was the second most common cause of death for both non-IPF IIP (24.1%) and IPF (23.5%) patients. The cumulative incidence of AE did not differ significantly between the two groups (p=0.36), with a 1-year incidence rate of 7.4% and 9.0% in non-IPF IIP and IPF patients, respectively. We found that 30.2% and 39.4% of non-IPF IIP and IPF patients, respectively, who experienced AE died within 3 months after an AE event, whereas 55.8% and 66.7% of such patients, respectively, died within 5 years after registration. Conclusion Closer monitoring of disease progression and palliative care interventions after AE are important for non-IPF IIP patients as well as for IPF patients.

DOI： 10.1136/bmjresp-2023-001864

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記述言語：英語   出版者・発行元：Annals of Oncology  

DOI： 10.1016/j.annonc.2023.08.012

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.annonc.2023.10.061

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記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

転移性非小細胞肺癌患者に対するファーストライン治療としてニボルマブ(Nivo)とイピリムマブ(Ipi)の併用療法を評価した第III相CheckMate 227試験Part1の日本人患者における有効性と安全性を解析した。EGFR/ALK異常のないステージIV/再発非小細胞肺癌患者143例のうち、66例(年齢42～81歳)がNivo+Ipiの併用群、77例(年齢33～78歳)が化学療法群に無作為に割り付けられた。PD-L1≧1%の患者の5年全生存率(OS)は、Nivo+Ipi併用群で46%、化学療法群で34%であり、PD-L1<1%の患者の5年OSは、Nivo+Ipi併用群で36%、化学療法群で19%であった。奏効期間中央値はPD-L1≧1%患者では、Nivo+Ipi併用群で59.1ヵ月、化学療法群で7.1ヵ月であり、PD-L1<1%患者では、Nivo+Ipi併用群で17.3ヵ月、化学療法群で3.0ヵ月であった。Nivo+Ipi併用群の5年生存者(PD-L1≧1%および<1%;27例)では、59%(95%CI 39～75%)が3年以上治療を中断し、その後の治療を受けなかった。新たな安全性シグナルは認められなかった。以上より、5年間の追跡調査において、Nivo+Ipiは腫瘍のPD-L1発現にかかわらず、化学療法に対して長期にわたる持続的な臨床的有用性を示した。

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

肺癌におけるCD155発現を転写後レベルで調節している可能性があるマイクロRNA(miR)の同定を試みた。標的予測プログラムを用いた網羅的miRスクリーニングを行い、さらに二重ルシフェラーゼレポーターアッセイを施行した。その結果、CD155 mRNAの3'-UTRに結合するmiRとして4種(miR-346、miR-328-3p、miR-326、miR-330-5p)が同定された。これらのmiRを複数の肺癌細胞株で強制発現させるとCD155の発現が抑制された。肺腺癌患者57名の組織検体でCD155を標的とする免疫組織化学解析を行った。その結果、CD155の腫瘍割合スコアの中央値は68%となった。これらの組織検体のうちCD155発現レベルが低い検体では高い検体よりもmiR-326が豊富に存在していた(p<0.005)。本研究結果から、肺腺癌ではmiR-326はCD155発現を負方向へ調節していることが示唆された。CD155発現の亢進はPD-1/PD-L1阻害剤耐性の機序になっていることから、miR-326はその耐性の出現に際して何らかの役割を果たしていると考えられた。

DOI： 10.1016/j.annonc.2023.09.2536

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記述言語：英語   出版者・発行元：Cancer Science  

Treatment with immune checkpoint inhibitors induces a durable response in some patients with non-small-cell lung cancer, but eventually gives rise to drug resistance. Upregulation of CD155 expression is implicated as one mechanism of resistance to programmed death receptor-1 (PD-1)/PD-1 ligand (PD-L1) inhibitors, and it is therefore important to characterize the mechanisms underlying regulation of CD155 expression in tumor cells. The aim of this study was to identify microRNAs (miRNAs) that might regulate CD155 expression at the posttranscriptional level in lung cancer. Comprehensive miRNA screening with target prediction programs and a dual-luciferase reporter assay identified miR-346, miR-328-3p, miR-326, and miR-330-5p as miRNAs that bind to the 3′-UTR of CD155 mRNA. Forced expression of these miRNAs suppressed CD155 expression in lung cancer cell lines. Immunohistochemical staining of CD155 in tissue specimens from 57 patients with lung adenocarcinoma revealed the median tumor proportion score for CD155 to be 68%. The abundance of miR-326 in these specimens with a low level of CD155 expression was significantly greater than in specimens with a high level (p < 0.005). Our results thus suggest that miR-326 negatively regulates CD155 expression in lung adenocarcinoma and might therefore play a role in the development of resistance to PD-1/PD-L1 inhibitors.

DOI： 10.1111/cas.15921

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記述言語：英語   出版者・発行元：Annals of Hematology  

DOI： 10.1007/s00277-023-05391-3

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記述言語：英語   出版者・発行元：International Journal of Clinical Oncology  

Background: In CheckMate 227 Part 1 (NCT02477826), first-line nivolumab plus ipilimumab demonstrated long-term durable overall survival (OS) benefit versus chemotherapy in patients with metastatic non-small cell lung cancer (NSCLC), regardless of tumor programmed death ligand 1 (PD-L1) expression. We report results in Japanese patients with ≥ 5-year follow-up. Methods: Adults with stage IV/recurrent NSCLC without EGFR/ALK aberrations were randomized 1:1:1 to nivolumab plus ipilimumab, nivolumab alone, or chemotherapy (patients with tumor PD-L1 ≥ 1%), or nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (patients with tumor PD-L1 < 1%). Five-year efficacy and safety were assessed in Japanese patients. Results: At 62.1 months’ minimum follow-up, 143 Japanese patients with PD-L1 ≥ 1% or < 1% were randomized to nivolumab plus ipilimumab (n = 66) or chemotherapy (n = 77). Five-year OS rates were 46% with nivolumab plus ipilimumab versus 34% with chemotherapy (PD-L1 ≥ 1%) and 36% versus 19% (PD-L1 < 1%). Median duration of response was 59.1 versus 7.1 months (PD-L1 ≥ 1%) and 17.3 versus 3.0 months (PD-L1 < 1%). Among 5-year survivors treated with nivolumab plus ipilimumab (PD-L1 ≥ 1% and < 1%; n = 27), 59% (95% CI, 39%–75%) were off treatment for ≥ 3 years without receiving subsequent therapy. No new safety signals were observed. Conclusions: At 5-year follow-up, nivolumab plus ipilimumab continued to show long-term durable clinical benefit versus chemotherapy, regardless of tumor PD-L1 expression. Consistent with findings for the global population, these data support the use of nivolumab plus ipilimumab as first-line treatment in Japanese patients with metastatic NSCLC.

DOI： 10.1007/s10147-023-02390-2

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DOI： 10.1183/13993003.congress-2023.PA4399

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DOI： 10.1183/13993003.congress-2023.PA2887

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記述言語：英語   出版者・発行元：ERJ Open Research  

DOI： 10.1183/23120541.00500-2023

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記述言語：英語   出版者・発行元：Clinical Cancer Research  

Purpose: Plasma circulating tumor DNA (ctDNA) analysis is used for genotyping advanced non-small cell lung cancer (NSCLC); monitoring dynamic ctDNA changes may be used to predict outcomes. Patients and Methods: This was a retrospective, exploratory analysis of two phase III trials [AURA3 (NCT02151981), FLAURA (NCT02296125)]. All patients had EGFR mutationpositive (EGFRm; ex19del or L858R) advanced NSCLC; AURA3 also included T790M-positive NSCLC. Osimertinib (FLAURA, AURA3), or comparator EGFR-tyrosine kinase inhibitor (EGFR-TKI; gefitinib/erlotinib; FLAURA), or platinum-based doublet chemotherapy (AURA3) was given. Plasma EGFRm was analyzed at baseline and Weeks 3/6 by droplet digital PCR. Outcomes were assessed by detectable/non-detectable baseline plasma EGFRm and plasma EGFRm clearance (non-detection) at Weeks 3/6. Results: In AURA3 (n = 291), non-detectable versus detectable baseline plasma EGFRm had longer median progression-free survival [mPFS; HR, 0.48; 95% confidence interval (CI), 0.33-0.68; P < 0.0001]. In patients withWeek 3 clearance versus non-clearance (n= 184), respectively, mPFS (months; 95% CI) was 10.9 (8.3-12.6) versus 5.7 (4.1-9.7) with osimertinib and 6.2 (4.0-9.7) versus 4.2 (4.0-5.1) with platinum-pemetrexed. In FLAURA (n = 499), mPFS was longer with non-detectable versus detectable baseline plasma EGFRm (HR, 0.54; 95% CI, 0.41-0.70; P < 0.0001). For Week 3 clearance versus non-clearance (n = 334), respectively, mPFS was 19.8 (15.1 to not calculable) versus 11.3 (9.5-16.5) with osimertinib and 10.8 (9.7-11.1) versus 7.0 (5.6-8.3) with comparator EGFR-TKI. Similar outcomes were observed byWeek 6 clearance/non-clearance. Conclusions: Plasma EGFRm analysis as early as 3 weeks ontreatment has the potential to predict outcomes in EGFRm advanced NSCLC.

DOI： 10.1158/1078-0432.CCR-22-3146

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記述言語：英語   出版者・発行元：Immunotherapy  

Aim: We pooled patient-level data from three randomized controlled studies to evaluate the combination of pembrolizumab plus chemotherapy in patients with untreated advanced/metastatic non-small-cell lung cancer (NSCLC) and programmed cell death ligand 1 (PD-L1) tumor proportion score <1% in East Asia. Methods: The analysis included 107 patients from China, Japan, Korea, Thailand and Taiwan (pembrolizumab plus chemotherapy, n = 56; chemotherapy alone, n = 51). Results: For pembrolizumab plus chemotherapy versus chemotherapy alone, median overall survival was 21.3 versus 12.6 months (HR, 0.55 [95% CI: 0.35-0.87]) and median progression-free survival was 8.4 versus 6.0 months (HR, 0.64 [95% CI: 0.43-0.96]). Conclusion: The analysis supports the use of pembrolizumab in combination with platinum-based chemotherapy for East Asian patients with PD-L1-negative, advanced NSCLC.

DOI： 10.2217/imt-2023-0043

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記述言語：英語   出版者・発行元：Cell Reports  

Small cell lung cancer (SCLC) is one of the deadliest human cancers, with a 5-year survival rate of ∼7%. Here, we performed a targeted proteomics analysis of human SCLC samples and thereby identified hypoxanthine phosphoribosyltransferase 1 (HPRT1) in the salvage purine synthesis pathway as a factor that contributes to SCLC malignancy by promoting cell survival in a glutamine-starved environment. Inhibition of HPRT1 by 6-mercaptopurine (6-MP) in combination with methotrexate (MTX), which blocks the de novo purine synthesis pathway, attenuated the growth of SCLC in mouse xenograft models. Moreover, modulation of host glutamine anabolism with the glutamine synthetase inhibitor methionine sulfoximine (MSO) in combination with 6-MP and MTX treatment resulted in marked tumor suppression and prolongation of host survival. Our results thus suggest that modulation of host glutamine anabolism combined with simultaneous inhibition of the de novo and salvage purine synthesis pathways may be of therapeutic benefit for SCLC.

DOI： 10.1016/j.celrep.2023.112899

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：Thoracic Cancer  

Therapy related-acute myeloid leukemia (t-AML) and myelodysplastic syndrome (t-MDS) are complications of chemotherapy and/or radiation therapy for malignant diseases. In this report, we describe a patient with advanced lung adenocarcinoma who developed autoimmune hemolytic anemia and MDS associated with a combination of atezolizumab and platinum-based chemotherapy. The patient showed progression from t-MDS to t-AML 20 months after the treatment was initiated. A combination of immune checkpoint inhibitor (ICI) and chemotherapy may increase the risk of developing therapy-related myeloid neoplasms. As the prognosis of t-AML and t-MDS is poorer than that of de novo AML and MDS, proper surveillance, follow-up, and treatment are needed throughout the course of immunotherapy.

DOI： 10.1111/1759-7714.15005

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記述言語：英語   出版者・発行元：Thoracic Cancer  

Background: The Oncomine Dx Target Test Multi-CDx System (ODxTT) is a next-generation sequencing panel approved as a companion diagnostic for drugs targeted to corresponding gene alterations in non–small cell lung cancer. However, appropriate slide conditions for ODxTT have remained unclear. Methods: We focused on the production of the number of tumor cells on a formalin-fixed paraffin-embedded (FFPE) section and the number of prepared slides, designated the TS value, and determined a TS value of ≥4000 as a target slide condition for ODxTT. We evaluated the impact of this condition on ODxTT testing with tumor specimens found to have a TS of <4000 (n = 23) or a TS of ≥4000 (n = 142). Results: A positive correlation was apparent between the TS value and the concentrations of both DNA and RNA. Among the 142 samples with a TS of ≥4000, a sufficient concentration of DNA or RNA for ODxTT analysis was achieved in 100% and 98% samples, respectively. Among samples explored for driver gene alterations after determination of the target slide condition (TS ≥4000), most (84.9%) had a TS of ≥4000 and were submitted for ODxTT analysis. Conclusion: Our findings indicate that a TS of ≥4000 is a feasible and relevant criterion for ODxTT testing, and its adoption should help to improve the success rate of such testing in clinical practice.

DOI： 10.1111/1759-7714.15014

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：Lung Cancer  

Background: Damage-associated molecular pattern (DAMP)-related immunogenic cell death triggers secondary adaptive immune responses. The relationship between DAMP levels and prognosis in patients with non-small cell lung cancer (NSCLC) who undergo a combination therapy of immune checkpoint inhibitors (ICI) and chemotherapy remains unclear. Methods: Serial plasma samples were prospectively collected from 45 patients treated with ICI combination therapy for advanced NSCLC. Plasma concentrations of high-mobility group box 1 (HMGB1), calreticulin (CRT), annexin A1, and heat shock protein 70 were measured. Associations between increases in plasma DAMP levels and the efficacy of the ICI combination therapy were evaluated. Results: The maximum fold changes in plasma levels differed across individuals but demonstrated a marked increase, especially for CRT (mean ± SEM, 11.61 ± 46.15). Increased plasma DAMP levels were not clearly associated with clinical responses. There was a significant correlation between the maximum fold change in CRT levels and progression-free survival (PFS; r = 0.49, P < 0.001). Median PFS and overall survival (OS) rates were higher in patients with a ≥ 2-fold increase in plasma CRT levels than in those with a < 2-fold increase (PFS, 14.9 versus 6.0 months, hazard ratio (HR), 0.58; P = 0.17; OS, not reached versus 21.6 months, HR, 0.31, P = 0.02). Conclusions: Plasma CRT level monitoring has the potential to predict the efficacy of ICI combination therapy and shed light on the mechanisms underlying DAMP-related immunogenic cell death.

DOI： 10.1016/j.lungcan.2023.107264

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記述言語：英語   出版者・発行元：Cancer Medicine  

Background: Immunotherapy has become a standard-of-care for patients with non-small-cell lung cancer (NSCLC). Although several biomarkers, such as programmed cell death-1, have been shown to be useful in selecting patients likely to benefit from immune checkpoint inhibitors (ICIs), more useful and reliable ones should be investigated. The prognostic nutritional index (PNI) is a marker of the immune and nutritional status of the host, and is derived from serum albumin level and peripheral lymphocyte count. Although several groups reported its prognostic role in patients with NSCLC receiving a single ICI, there exist no reports which have demonstrated its role in the first-line ICI combined with or without chemotherapy. Materials and Methods: Two-hundred and eighteen patients with NSCLC were included in the current study and received pembrolizumab alone or chemoimmunotherapy as the first-line therapy. Cutoff value of the pretreatment PNI was set as 42.17. Results: Among 218 patients, 123 (56.4%) had a high PNI (≥42.17), while 95 (43.6%) had a low PNI (<42.17). A significant association was observed between the PNI and both the progression-free survival (PFS; hazard ratio [HR] = 0.67, 95% confidence interval [CI]: 0.51–0.88, p = 0.0021) and overall survival (OS; HR = 0.46, 95% CI: 0.32–0.67, p < 0.0001) in the entire population, respectively. The multivariate analysis identified the pretreatment PNI as an independent prognosticator for the PFS (p = 0.0011) and OS (p < 0.0001), and in patients receiving either pembrolizumab alone or chemoimmunotherapy, the pretreatment PNI remained an independent prognostic factor for the OS (p = 0.0270 and 0.0006, respectively). Conclusion: The PNI might help clinicians appropriately identifying patients with better treatment outcomes when receiving first-line ICI therapy.

DOI： 10.1002/cam4.6110

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記述言語：英語   出版者・発行元：Frontiers in Immunology  

Introduction: Programmed cell death–ligand 1 (PD-L1) is a biomarker for prediction of the clinical efficacy of immune checkpoint inhibitors in various cancer types. The role of cytokines in regulation of PD-L1 expression in tumor cells has not been fully characterized, however. Here we show that interleukin-1β (IL-1β) plays a key role in regulation of PD-L1 expression in non–small cell lung cancer (NSCLC). Methods: We performed comprehensive screening of cytokine gene expression in NSCLC tissue using available single-cell RNA-Sequence data. Then we examined the role of IL-1β in vitro to elucidate its induction of PD-L1 on NSCLC cells. Results: The IL-1β gene is highly expressed in the tumor microenvironment, particularly in macrophages. The combination of IL-1β and interferon-γ (IFN-γ) induced a synergistic increase in PD-L1 expression in NSCLC cell lines. IL-1β and IFN-γ also cooperatively activated mitogen-activated protein kinase (MAPK) signaling and promoted the binding of downstream transcription factors to the PD-L1 gene promoter. Furthermore, inhibitors of MAPK signaling blocked upregulation of PD-L1 by IL-1β and IFN-γ. Discussion: Our study reports high levels of IL-1β in the tumor microenvironment may cooperate with IFN-γ to induce maximal PD-L1 expression in tumor cells via activation of MAPK signaling, with the IL-1β–MAPK axis being a promising therapeutic target for attenuation of PD-L1–mediated suppression of antitumor immunity.

DOI： 10.3389/fimmu.2023.1192861

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出版者・発行元：Current Problems in Cancer: Case Reports  

We report a case of bronchiolitis obliterans (BO) due to afatinib treatment. A 42-year-old woman was diagnosed with stage IVB lung adenocarcinoma (cT1bN3M1c) positive for the L861Q mutation of EGFR and was treated with afatinib. Seven months after the onset of afatinib therapy, she presented with a cough that gradually worsened despite treatment for bronchial asthma. Pulmonary function tests showed severe obstructive patterns that were not improved with inhaled bronchodilators. Chest computed tomography revealed a mosaic attenuation pattern, and pulmonary ventilation-perfusion scintigraphy showed a matched defect. She had no underlying causes of secondary BO, and she was therefore diagnosed with afatinib-induced BO. Respiratory function did not deteriorate further after discontinuation of afatinib or after subsequent treatment with osimertinib. This case indicates that afatinib is a potential trigger for BO. Clinical oncologists should therefore bear in mind the possible development of this potentially fatal adverse event in patients undergoing afatinib treatment; they should be alert to respiratory symptoms and consider periodic pulmonary function tests.

DOI： 10.1016/j.cpccr.2023.100231

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出版者・発行元：Current Problems in Cancer: Case Reports  

DOI： 10.1016/j.cpccr.2023.100236

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記述言語：英語   出版者・発行元：Journal of Cachexia, Sarcopenia and Muscle  

Background: Cancer cachexia is a syndrome that does not fully recover with nutritional support and causes appetite loss and body weight loss. It worsens a patient's quality of life and prognosis. In this study, the epidemiology of cachexia in lung cancer, its risk factors and its impact on chemotherapy response rate and prognosis were examined using the national database of the Japan Lung Cancer Society. Understanding these things related to cancer cachexia is important as a starting point in overcoming cancer cachexia in patients with lung cancer. Methods: In 2012, 12 320 patients from 314 institutions in Japan were registered in a nationwide registry database (Japanese Lung Cancer Registry Study). Of these, data on body weight loss within 6 months were available for 8489 patients. We defined the patients with body weight loss ≥ 5% within 6 months, which is one of the three criteria listed in the 2011 international consensus definition of cancer cachexia, as cachectic in this study. Results: Approximately 20.4% of the 8489 patients had cancer cachexia. Sex, age, smoking history, emphysema, performance status, superior vena cava syndrome, clinical stage, site of metastasis, histology, epidermal growth factor receptor (EGFR) mutation status, primary treatment method and serum albumin levels were significantly different between patients with and without cachexia. Logistic analyses showed that smoking history, emphysema, clinical stage, site of metastasis, histology, EGFR mutation, serum calcium and albumin levels were significantly associated with cancer cachexia. The response to initial therapy, including chemotherapy, chemoradiotherapy or radiotherapy, was significantly poorer in the patients with cachexia than in those without cachexia (response rate: 49.7% vs. 41.5%, P < 0.001). Overall survival was significantly shorter in the patients with cachexia than in those without cachexia in both univariate and multivariable analyses (1-year survival rate: 60.7% vs. 37.6%, Cox proportional hazards model, hazard ratio: 1.369, 95% confidence interval: 1.274–1.470, P < 0.001). Conclusions: Cancer cachexia was seen in approximately one fifth of the lung cancer patients and was related to some baseline patient characteristics. It was also associated with a poor response to initial treatment, resulting in poor prognosis. The results of our study may be useful for early identification and intervention in patients with cachexia, which may improve their response to treatment and their prognosis.

DOI： 10.1002/jcsm.13216

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記述言語：英語   出版者・発行元：Translational Lung Cancer Research  

Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), such as erlotinib, are standard-of-care for patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC), but most patients progress within 1 year. Previously, we demonstrated that erlotinib plus bevacizumab (EB) improved progression-free survival (PFS) in patients with EGFR-positive non-squamous NSCLC in the randomized JO25567 study. To understand this effect, we conducted comprehensive exploratory biomarker analyses. Methods: Using blood and tissue specimens from patients enrolled in the JO25567 study, angiogenesis-related serum factors, plasma vascular endothelial growth factor-A (pVEGFA), angiogenesis-related gene polymorphisms, and messenger RNAs (mRNAs) in tumor tissue were analyzed. Interactions between potential predictors and treatment effect on PFS were analyzed in a Cox model. Continuous variable predictors were evaluated by multivariate fractional polynomial interaction methodology and subpopulation treatment effect pattern plotting (STEPP). Results: Overall, 152 patients treated with EB or erlotinib alone (E) were included in the analysis. Among 26 factors analyzed in 134 baseline serum samples, high follistatin and low leptin were identified as potential biomarkers for worse and better outcomes with EB, with interaction P values of 0.0168 and 0.0049, respectively. Serum concentrations of 12 angiogenic factors were significantly higher in patients with high follistatin. Low pVEGFA levels related to better outcomes with EB, interaction P=0.033. VEGF-A165a was the only predictive tissue mRNA, showing a similar trend to pVEGFA. No valid results were obtained in 13 polymorphisms of eight genes. Conclusions: EB treatment showed better treatment outcomes in patients with low pVEGFA and serum leptin, and limited efficacy in patients with high serum follistatin.

DOI： 10.21037/tlcr-22-632

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記述言語：英語   出版者・発行元：ERJ Open Research  

DOI： 10.1183/23120541.00033-2023

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記述言語：英語   出版者・発行元：European Journal of Cancer  

Background: This multicenter phase 2 trial evaluated the safety and efficacy of osimertinib and platinum-based chemotherapy (OPP) in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer (NSCLC). Patients and methods: Patients received osimertinib 80 mg once daily (QD), with either cisplatin 75 mg/m2 (arm A) or carboplatin (area under the curve [AUC] = 5; arm B), plus pemetrexed 500 mg/m2 for four cycles and maintenance therapy of osimertinib 80 mg QD with pemetrexed 500 mg/m2 every 3 weeks. The primary end-points were safety and objective response rate (ORR), and the secondary end-points were complete response rate (CRR), disease control rate (DCR), and progression-free survival (PFS). Results: In total, 67 patients (34 in arm A and 33 in arm B) were enrolled between July 2019 and February 2020. At the data cutoff (28th February 2022), 35 (52.2%) patients had discontinued the protocol treatment, including 10 (14.9%) due to adverse events. No treatment-related deaths occurred. In the full analysis set, the ORR, CRR, and DCR were 90.9% (95% confidence interval [CI], 84.0–97.8), 3.0% (0.0–7.2), and 97.0% (92.8–100.0), respectively. Based on updated survival data (data cutoff on August 31, 2022, median follow-up time: 33.4 months), the median PFS was 31.0 months (95% CI, 26.8 months–not reached) and median overall survival was not reached. Conclusions: This is the first study to show that OPP has excellent efficacy with acceptable toxicity in previously untreated EGFR-mutated advanced non-squamous NSCLC patients.

DOI： 10.1016/j.ejca.2023.02.023

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記述言語：英語   出版者・発行元：Microbiology Spectrum  

Under the strict quarantine policy imposed to combat the COVID-19 (coronavirus disease 2019) pandemic in Japan, the prevalence of respiratory infections by viruses other than SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has been largely unknown. However, such information on viral circulation is important in order to develop better management policies that are based on scientific data. Here, we retrospectively investigated respiratory virus infections in individuals who visited a community hospital with respiratory symptoms between June of 2020 and September of 2021 with the use of the BioFire FilmArray Respiratory Panel 2.1. Virus was detected in 65 out of a total of 328 subjects, with SARS-CoV-2 (67.7%), rhino/enterovirus (18.5%), and parainfluenza virus 3 (7.7%) accounting for most of the infections. No influenza virus or respiratory syncytial virus (RSV) infections were detected. The monthly cases of rhino/enterovirus infection were highest from winter to spring, with this temporal pattern differing from that of SARS-CoV-2. SARS-CoV-2 was detected more frequently (P , 0.001) in subjects with cough (31/104 cases, 29.8%) than in those without cough (13/ 224 cases, 5.8%), suggesting that cough might contribute to the prediction of COVID-19. Our findings also suggest that testing for rhino/enterovirus and parainfluenza virus 3, in addition to SARS-CoV-2, may be important for the rigorous diagnosis of respiratory virus infections. IMPORTANCE Influenza virus, RSV, adenovirus, and rhino/enterovirus were the major respiratory viruses before COVID-19 pandemic. Circulating respiratory viruses may have been affected by our strong quarantine policy during the COVID-19 pandemic. We checked the circulating respiratory viruses from our outpatients by using a multiplex PCR kit that had recently been released. SARS-CoV-2 was the most frequently detected virus, and it was followed by rhino/enterovirus and parainfluenza virus 3. No influenza virus or RSV infections were detected during our study period, suggesting that influenza virus and RSV became almost extinct. COVID-19 cases frequently experienced cough, and this frequency was statistically significantly higher than that observed in the cases without SARS-CoV-2 detection. The cough can be an indicator of COVID-19.

DOI： 10.1128/spectrum.04162-22

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記述言語：英語   出版者・発行元：Nature  

Sex chromosome disorders severely compromise gametogenesis in both males and females. In oogenesis, the presence of an additional Y chromosome or the loss of an X chromosome disturbs the robust production of oocytes1–5. Here we efficiently converted the XY chromosome set to XX without an additional Y chromosome in mouse pluripotent stem (PS) cells. In addition, this chromosomal alteration successfully eradicated trisomy 16, a model of Down’s syndrome, in PS cells. Artificially produced euploid XX PS cells differentiated into mature oocytes in culture with similar efficiency to native XX PS cells. Using this method, we differentiated induced pluripotent stem cells from the tail of a sexually mature male mouse into fully potent oocytes, which gave rise to offspring after fertilization. This study provides insights that could ameliorate infertility caused by sex chromosome or autosomal disorders, and opens the possibility of bipaternal reproduction.

DOI： 10.1038/s41586-023-05834-x

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記述言語：英語   出版者・発行元：Frontiers in Immunology  

Immune cells have been implicated in interstitial lung diseases (ILDs), although their phenotypes and effector mechanisms remain poorly understood. To better understand these cells, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF), connective-tissue disease (CTD)-related ILD, and sarcoidosis, using two panels including 64 markers. Among myeloid cells, we observed the expansion of CD14+ CD36hi CD84hiCCR2– monocyte populations in IPF. These CD14+ CD36hi CD84hi CCR2– subsets were also increased in ILDs with a progressive phenotype, particularly in a case of acute exacerbation (AEx) of IPF. Analysis of B cells revealed the presence of cells at various stages of differentiation in BALF, with a higher percentage of IgG memory B cells in CTD-ILDs and a trend toward more FCRL5+ B cells. These FCRL5+ B cells were also present in the patient with AEx-IPF and sarcoidosis with advanced lung lesions. Among T cells, we found increased levels of IL-2R+ TIGIT+ LAG3+ CD4+ T cells in IPF, increased levels of CXCR3+ CD226+ CD4+ T cells in sarcoidosis, and increased levels of PD1+ TIGIT+ CD57+ CD8+ T cells in CTD-ILDs. Together, these findings underscore the diverse immunopathogenesis of ILDs.

DOI： 10.3389/fimmu.2023.1145814

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

悪性胸膜中皮腫(MPM)に対するコクサッキーウイルスA11(CVA11)の腫瘍溶解活性の特徴や免疫賦活活性の可能性について検討した。その結果、CVA11感染は、調べた6株のMPM細胞すべてで細胞毒性を示し、ヒト正常細胞に対しては細胞毒性を示さないか、最小限の細胞毒性に止まった。細胞間接着分子ICAM-1の細胞表面発現量が多いMPM細胞は、CVA11による細胞毒性に対して感受性が高い傾向があり、ICAM-1の中和抗体により細胞毒性が減弱した。CVA11感染ではAktや細胞外シグナル調節キナーゼ(ERK)経路が活性化されたが、それらのシグナル伝達を阻害することによりCVA11による細胞毒性も抑制された。さらに、CVA11感染により、アポトーシス、ピロトーシス、ネクロトーシスの複数の腫瘍細胞死が引き起こされ、その細胞死には炎症性サイトカインのインターロイキン1βや免疫原性細胞死の特徴であるカルレティキュリン、high mobility group box-1、アネキシンA1、熱ショックタンパク質70というダメージ関連分子パターンの放出や露出を伴った。さらに、SCIDマウスに作製したヒトMPM異種移植片に対するCVA11の腫瘍内注入により腫瘍増殖が顕著に抑制された。以上より、CVA11がMPM患者の治療に有望な腫瘍溶解ウイルスであることが示唆された。

記述言語：英語   出版者・発行元：Cancer Science  

Malignant pleural mesothelioma (MPM) is an aggressive solid cancer with a poor prognosis, whereas coxsackievirus A11 (CVA11) is a potential oncolytic virus for cancer treatment. We here investigated the oncolytic activity of CVA11 with human MPM cell lines. CVA11 infection was cytotoxic in all six MPM cell lines examined and showed no or minimal cytotoxicity toward normal human normal cell lines. MPM cells with a higher surface level of intercellular adhesion molecule-1 (ICAM-1) expression tended to be more susceptible to CVA11-induced cytotoxicity, and a neutralizing antibody to ICAM-1 attenuated such cytotoxicity. CVA11 infection activated signaling by Akt and extracellular signal-regulated kinase (ERK) pathways, and inhibitors of such signaling also abrogated CVA11-mediated cytotoxicity. Furthermore, CVA11 infection-triggered multiple modes of tumor cell death including apoptosis, pyroptosis, and necroptosis, and such death was accompanied by the release or exposure of the proinflammatory cytokine interleukin-1β and damage-associated molecular patterns such as calreticulin, high-mobility group box-1, annexin A1, and heat shock protein 70, which are hallmarks of immunogenic cell death. Notably, in vivo treatment of human MPM xenografts with intratumoral CVA11 injection resulted in significant suppression of tumor growth in SCID mice, and all mice infected with CVA11 showed no significant change in body weight. Our findings collectively suggest that the oncolytic activity of CVA11 for MPM is dependent on ICAM-1 as a virus receptor, as well as on Akt and ERK signaling, and that oncolytic virotherapy with CVA11 is a promising treatment modality with immunostimulatory activity for human MPM.

DOI： 10.1111/cas.15645

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記述言語：英語   出版者・発行元：Nature Communications  

Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. This analysis evaluates acquired resistance mechanisms to second-line osimertinib (n = 78) in patients with EGFR T790M advanced non-small cell lung cancer (NSCLC) from AURA3 (NCT02151981), a randomized phase 3 study comparing osimertinib with chemotherapy. Plasma samples collected at baseline and disease progression/treatment discontinuation are analyzed using next-generation sequencing. Half (50%) of patients have undetectable plasma EGFR T790M at disease progression and/or treatment discontinuation. Fifteen patients (19%) have >1 resistance-related genomic alteration; MET amplification (14/78, 18%) and EGFR C797X mutation (14/78, 18%).

DOI： 10.1038/s41467-023-35962-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：Lung Cancer  

Introduction: Human epidermal growth factor receptor 2 (HER2) forms homodimers and is retained at the surface of cancer cells positive for HER2 amplification. The dimerization, internalization, and intracellular trafficking of HER2 in cancer cells without HER2 amplification have remained uncharacterized, however. Materials and methods: HER2 homodimers and heterodimers were detected in various cell lines with the use of an in situ proximity ligation assay. The effects of wild-type or mutant forms of epidermal growth factor receptor (EGFR) on intracellular trafficking of HER2 were examined by live-cell imaging. The sensitivity of cell lines without HER2 amplification to ado-trastuzumab emtansine (T-DM1), an anti-HER2 (trastuzumab)–cytotoxic drug conjugate (ADC) was also investigated. Results: HER2 preferentially formed heterodimers with EGFR rather than homodimers and was rapidly internalized together with EGFR in cells without HER2 amplification. HER2-EGFR heterodimers were more abundant and HER2 was more efficiently transferred to lysosomes in such cells with than in those without EGFR activating mutations. T-DM1 showed a high cytotoxic efficacy in the cells with EGFR mutations, suggesting that mutant forms of EGFR promote the transfer of HER2-bound T-DM1 to lysosomes through efficient formation of HER2-EGFR heterodimers. Conclusion: Our findings reveal that HER2 trafficking is affected by EGFR, especially by mutant forms of the receptor, and they provide a rationale for the use of HER2-targeting ADCs in the treatment of EGFR-mutated lung cancer.

DOI： 10.1016/j.lungcan.2022.11.018

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記述言語：英語   出版者・発行元：Respiratory Medicine Case Reports  

Pleuroparenchymal fibroelastosis (PPFE) is a rare form of interstitial pneumonitis. Although most cases of PPFE are idiopathic, some cases of PPFE occur secondary to stem cell transplantation. We report a 41-year-old woman developed pneumonia after autologous peripheral blood system cell transplantation (PBSCT). Eleven years after PBSCT, she presented with dyspnea. A computed tomographic scan showed pleuroparenchymal thickening and predominantly in the upper lobes. She was diagnosed with PPFE secondary to PBSCT. She was started nintedanib and administered oxygen therapy. Most cases of PPFE secondary to stem cell transplantation have been reported. However, we experienced the case of PPFE post-autologous PBSCT.

DOI： 10.1016/j.rmcr.2023.101845

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記述言語：英語   出版者・発行元：Thoracic Cancer  

Background: Recently, the addition of antiprogrammed cell death-ligand 1 (PD-L1) monoclonal antibodies, including durvalumab and atezolizumab to platinum-based chemotherapy, has demonstrated clinical benefits in patients with untreated advanced small cell lung cancer (SCLC). However, these clinical trials comprised small populations of elderly patients with SCLC. Therefore, the safety of anti-PD-L1 immunotherapy plus platinum and etoposide in elderly patients remains unclear. Methods: This prospective, multicenter, single-arm study was designed to evaluate the safety and efficacy of durvalumab plus carboplatin and etoposide in untreated elderly patients (aged > 75) with extensive stage (ES) SCLC. A total of 40 patients were recruited. Patients received up to four cycles of durvalumab 1500 mg and carboplatin at a dose equivalent to an area under the curve of 5 on day 1, and etoposide 80 mg/m2 on days 1 to 3 every 3 weeks as induction treatment, followed by durvalumab maintenance treatment every 4 weeks. The primary endpoint was safety as measured by adverse events according to the Common Terminology Criteria for Adverse Events version 5.0, laboratory analyses, vital signs, and physical examination. Key secondary endpoints were objective response rate, median progression-free survival, 12-month overall survival rate, and the completion rate for four cycles of induction chemotherapy. Discussion: The present study was designed to evaluate the safety of durvalumab plus carboplatin and etoposide in elderly patients with ES-SCLC.

DOI： 10.1111/1759-7714.14727

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記述言語：英語   出版者・発行元：Science Translational Medicine  

Despite the success of cancer immunotherapies such as programmed cell death-1 (PD-1) and PD-1 ligand 1 (PDL1) inhibitors, patients often develop resistance. New combination therapies with PD-1/PD-L1 inhibitors are needed to overcome this issue. Bezafibrate, a ligand of peroxisome proliferator-activated receptor-γ coactivator 1α/peroxisome proliferator-activated receptor complexes, has shown a synergistic antitumor effect with PD-1 blockade in mice that is mediated by activation of mitochondria in T cells. We have therefore now performed a phase 1 trial (UMIN000017854) of bezafibrate with nivolumab in previously treated patients with advanced non-small cell lung cancer. The primary end point was the percentage of patients who experience dose-limiting toxicity, and this combination regimen was found to be well tolerated. Preplanned comprehensive analysis of plasma metabolites and gene expression in peripheral cytotoxic T cells indicated that bezafibrate promoted T cell function through up-regulation of mitochondrial metabolism including fatty acid oxidation and may thereby have prolonged the duration of response. This combination strategy targeting T cell metabolism thus has the potential to maintain antitumor activity of immune checkpoint inhibitors and warrants further validation.

DOI： 10.1126/scitranslmed.abq0021

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：European Respiratory Journal  

背景
特発性肺線維症（IPF）は肺癌の独立した危険因子として関与している致死的な肺疾患である。しかし、IPF進行肺がんに対する最適な治療法は確立されていない。我々はIPFを有する進行性非小細胞肺がん（NSCLC）に対するニンテダニブ＋化学療法（実験群）と化学療法単独（標準治療群）の有効性と安全性を評価する無作為化第3相試験（J-SONIC）を実施しました。

方法
IPFを有する化学療法未実施の進行NSCLC患者を、カルボプラチン＋ナノ粒子アルブミン結合パクリタキセル（nab-paclitaxel）の3週間ごとの投与とニンテダニブ（150mg1日2回、毎日）の併用、非併用を割り振った。主要評価項目はIPF無増悪生存期間（EFS）であった。

結果：
2017年5月から2020年2月にかけて、243人の患者が登録された。IPF無増悪生存期間中央値はニンテダニブ＋化学療法群で14.6カ月、化学療法群で11.8カ月（ハザード比（HR）0.89、90％CI 0.67-1.17、p＝0.24）、一方無増悪生存期間中央値はそれぞれ6.2カ月と5.5カ月（HR 0.68 、95％CI 0.50-0.92 ）でした。全生存期間は、非扁平上皮組織（HR 0.61、95% CI 0.40-0.93）およびGAPステージIの患者において、ニンテダニブにより改善した（HR 0.61, 95% CI 0.38-0.98 ）。240人中7人（2.9%）が試験治療中にIPFの急性増悪を経験した。

結論
本試験の主要評価項目は達成されなかった。しかし、カルボプラチン＋nab-パクリタキセルは、IPFを有する進行NSCLC患者において有効かつ忍容性があることが判明した。さらに、ニンテダニブとこのような化学療法を併用することで、非扁平上皮組織型の患者の全生存期間が改善された。

DOI： 10.1183/13993003.00380-2022

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：Clinical Lung Cancer  

Background: Renal impairment can affect treatment tolerability and outcome in individuals with cancer. We aimed to assess the safety and efficacy of nab-paclitaxel for previously treated patients with advanced non–small cell lung cancer (NSCLC) and renal impairment enrolled in a phase 3 trial of nab-paclitaxel vs. docetaxel. Patients and Methods: Previously treated NSCLC patients were randomly allocated (1:1) to receive docetaxel (60 mg/m²) on day 1 or nab-paclitaxel (100 mg/m²) on days 1, 8, and 15 of a 21-day cycle. Safety and efficacy outcomes of treatment were evaluated according to renal function. Results: Among the 503 patients enrolled in the phase 3 trial, 17.3% had moderate renal impairment (creatinine clearance of ≤50 mL/min, n = 49 for docetaxel and n = 38 for nab-paclitaxel) and 53.1% had mild renal impairment (creatinine clearance of >50 to ≤80 mL/min, n = 133 for docetaxel and n = 134 for nab-paclitaxel). For patients with renal impairment, the incidence of febrile neutropenia was lower in the nab-paclitaxel group than in the docetaxel group. The difference in treatment efficacy for nab-paclitaxel vs. docetaxel among patients with moderate or mild renal impairment was similar to that among the overall study population. Conclusion: Nab-paclitaxel was found to be tolerable and beneficial for previously treated patients with advanced NSCLC and mild or moderate renal impairment.

DOI： 10.1016/j.cllc.2022.08.011

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DOI： 10.1016/j.annonc.2022.10.368

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記述言語：英語   出版者・発行元：Translational Lung Cancer Research  

Background: Thyroid transcription factor-1 (TTF-1) expression in advanced non-squamous non-small cell lung cancer (NSCLC) has been associated with the efficacy of pemetrexed plus platinum chemotherapy. However, the relation between TTF-1 expression and efficacy of the combination of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors plus pemetrexed and platinum chemotherapy, a standard first-line treatment regimen for advanced non-squamous NSCLC, has remained unclear. Methods: We retrospectively evaluated TTF-1 expression in tumor tissue of patients with advanced or recurrent non-squamous NSCLC treated with PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in the first-line setting. Clinical characteristics and pathological data for each patient were assessed, and progression-free survival (PFS) was evaluated. Bias due to patient background was minimized by application of inverse probability of treatment weighting (IPTW) analysis. Results: A total of 122 patients, 75 (61.5%) of whom were positive for TTF-1 immunostaining in tumor specimens, was included in this multicenter study. At the time of analysis, 89 (73.0%) patients had experienced progression events and 44 (36.1%) had died [median follow-up 14.6 months (range, 0.53–29.5 months)]. PFS was longer for TTF-1-positive patients than for TTF-1-negative patients [median, 12.2 vs. 6.0 months; hazard ratio (HR) =0.63 (95% CI: 0.37–1.06); log-rank P=0.028]. IPTW-adjusted PFS was significantly longer for TTF-1-positive than for TTF-1–negative patients [HR =0.62 (95% CI: 0.46–0.83); log-rank P=0.024]. Conclusions: TTF-1 expression in advanced non-squamous NSCLC can serve as a basis for prediction of PFS in patients treated with PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in the first-line setting.

DOI： 10.21037/tlcr-22-393

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記述言語：英語   出版者・発行元：BMC Cancer  

Background: First-line treatment of nonsquamous non–small cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination therapy together with immune checkpoint inhibitors (ICIs). However, phase III studies of combinations of cytotoxic chemotherapy and ICIs have included only patients with maintained organ function, not those with renal impairment. Methods: Cytotoxic chemotherapy–naïve advanced nonsquamous NSCLC patients aged 20 years or older with impaired renal function (creatinine clearance of 15 to 45 mL/min) are prospectively registered in this single-arm phase II study and receive combination therapy with carboplatin, nanoparticle albumin-bound (nab-) paclitaxel, and atezolizumab. Individuals with known genetic driver alterations including those affecting EGFR, ALK, ROS1, BRAF, MET, RET, and NTRK are excluded. We plan to enroll 40 patients over 2 years at 32 oncology facilities in Japan. The primary end point is confirmed objective response rate. Discussion: If the study demonstrates efficacy and safety of carboplatin/nab-paclitaxel/atezolizumab, then this combination regimen may become a treatment option even for nonsquamous NSCLC patients with impaired renal function. Trial registration: Registered with Japan Registry for Clinical Trials on 25 February 2021 (jRCTs071200102).

DOI： 10.1186/s12885-022-10056-x

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記述言語：英語   出版者・発行元：Oncologist  

Background: Interstitial pneumonia (IP) is a poor prognostic comorbidity in patients with non-small cell lung cancer (NSCLC) and is also a risk factor for pneumonitis. The TORG1936/AMBITIOUS trial, the first known phase II study of atezolizumab in patients with NSCLC with comorbid IP, was terminated early because of the high incidence of severe pneumonitis. Methods: This study included patients with idiopathic chronic fibrotic IP, with a predicted forced vital capacity (%FVC) of >70%, with or without honeycomb lung, who had previously been treated for NSCLC. The patients received atezolizumab every 3 weeks. The primary endpoint was the 1-year survival rate. Results: A total of 17 patients were registered; the median %FVC was 85.4%, and 41.2% had honeycomb lungs. The 1-year survival rate was 53.3% (95% CI, 25.9-74.6). The median overall and progression-free survival times were 15.3 months (95% CI, 3.1-not reached) and 3.2 months (95% CI, 1.2-7.4), respectively. The incidence of pneumonitis was 29.4% for all grades, and 23.5% for grade ≥3. Tumor mutational burden and any of the detected somatic mutations were not associated with efficacy or risk of pneumonitis. Conclusion: Atezolizumab may be one of the treatment options for patients with NSCLC with comorbid IP, despite the high risk of developing pneumonitis. This clinical trial was retrospectively registered in the Japan Registry of Clinical Trials on August 26, 2019, (registry number: jRCTs031190084, https://jrct.niph.go.jp/en-latest-detail/jRCTs031190084).

DOI： 10.1093/oncolo/oyac118

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DOI： 10.1016/j.annonc.2022.08.051

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DOI： 10.1016/j.annonc.2022.07.1311

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DOI： 10.1016/j.annonc.2022.07.1057

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DOI： 10.1016/j.annonc.2022.07.1151

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記述言語：英語   出版者・発行元：European Journal of Cancer  

Background: We previously validated in European patients with NSCLC treated with programmed death-1 (PD-1) checkpoint inhibitors the cumulative detrimental effect of concomitant medications. Materials and methods: We evaluated the prognostic ability of a “drug score” computed on the basis of baseline corticosteroids, proton pump inhibitors, and antibiotics, in an independent cohort of Japanese patients with advanced NSCLC treated with PD-1 monotherapy. Subsequently, we assessed the impact of baseline probiotics on the score's diagnostic ability and their interaction with antibiotics in influencing survival. Results: Among the 293 eligible patients, good (19.5 months), intermediate (13.4 months), and poor (3.7 months) risk groups displayed a significantly different overall survival (OS) (log-rank test for trend: p = 0.016), but with a limited diagnostic ability (C-index: 0.57, 95%CI: 0.53–0.61), while no significant impact on progression-free survival (PFS) was reported (log-rank test for trend: p = 0.080; C-index: 0.55, 95%CI: 0.52–0.58). Considering the impact of the probiotics∗antibiotics interaction (p-value 0.0510) on OS, we implemented the drug score by assigning 0 points to concomitant antibiotics and probiotics. With the adapted drug score good, intermediate, and poor risk patients achieved a median OS of 19.6 months, 13.1 months, and 3.7 months, respectively, with a similar diagnostic ability (log-rank test for trend: p = 0.006; C-index: 0.58, 95%CI: 0.54–0.61). However, the diagnostic ability for PFS of the adapted score was improved (log-rank test for trend: p = 0.034; C-index: 0.62, 95%CI: 0.54–0.69). Conclusions: Although we failed to validate the drug score in this independent Japanese cohort, we showed that probiotics may have an antibiotic-dependent impact on its prognostic value. Further investigation looking at the effect of concomitant medications and probiotics across cohorts of different ethnicities is warranted.

DOI： 10.1016/j.ejca.2022.06.002

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記述言語：英語   出版者・発行元：Thoracic Cancer  

Background: In the phase II JO25567 study (JapicCTI-111390), erlotinib plus bevacizumab demonstrated a significant clinical benefit in Japanese patients with epidermal growth factor receptor mutation-positive (EGFR+) non-small cell lung cancer (NSCLC). Here, we present an exploratory analysis investigating the impact of baseline pleural/pericardial effusion (PPE) on patient outcomes. Methods: Patients with stage IIIB/IV or postoperative recurrent EGFR+ NSCLC were randomized 1:1 to receive erlotinib (150 mg/day) plus bevacizumab (15 mg/kg every 3 weeks) or erlotinib monotherapy. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety were evaluated according to the presence or absence of baseline PPE. Results: The population comprised 152 patients, 66 with baseline PPE and 86 without. Median PFS was longer with erlotinib plus bevacizumab than with erlotinib alone, with (hazard ratio [HR] 0.45; 95% confidence interval [CI]: 0.25–0.82) or without (HR 0.62; 95% CI: 0.37–1.04) baseline PPE. Median OS was also prolonged with erlotinib plus bevacizumab relative to erlotinib regardless of the presence (HR 0.82; 95% CI: 0.46–1.47) or absence (HR 0.84; 95% CI: 0.46–1.55) of baseline PPE. ORR was higher with erlotinib plus bevacizumab (70.0%) than with erlotinib (55.6%) in patients with baseline PPE, but similar (68.9% vs. 70.7%) in patients without. Most common grade ≥3 adverse events were hypertension and rash in the erlotinib plus bevacizumab arm, and rash in the erlotinib arm, regardless of baseline PPE status. Conclusions: Erlotinib plus bevacizumab may be a beneficial treatment strategy in patients with EGFR+ NSCLC, especially for those with baseline PPE.

DOI： 10.1111/1759-7714.14541

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記述言語：英語   出版者・発行元：公益社団法人 日本医師会 / 日本医学会  

DOI： 10.31662/jmaj.2021-0227

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CiNii Research

記述言語：英語   出版者・発行元：(公社)日本医師会  

肺癌患者を対象とした前向き研究を実施し、発熱性好中球減少症に対するシタフロキサシン(STFX)の有効性および安全性について検討した。低リスク(MASCCスコア>21)発熱性好中球減少症肺癌患者26例(男性19例、中央値70.0歳)を対象にSTFXを投与した。主要評価項目は奏効率(有害事象を伴わない連続5日間の発熱停止と定義)、副次評価項目は72時間後、7日目、14日目での発熱の有無および安全性とした。その結果、14例(53.85%)で主要評価項目の達成が認められた。STFX以外の抗菌薬投与は2例でのみ認められた。奏効率を微生物変化や重篤な合併症を伴わない発熱性好中球減少症からの回復と定義した場合の奏効率は91.67%であった。72時間後、7日後、14日後に発熱が認められなかった割合は、それぞれ53.84%、86.36%、77.78%であった。有害事象は8例に認められたが、いずれも重篤ではなかった。以上から、STFX投与が肺癌患者における低リスク発熱性好中球減少症に対して有用である可能性が示唆された。

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記述言語：英語   出版者・発行元：Clinical Lung Cancer  

Background: First-line treatment of non–small cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination chemotherapy together with an immune checkpoint inhibitor, regardless of the expression level of the programmed cell death–1 (PD-1) ligand PD-L1 on tumor cells. Moreover, such chemotherapy plus nivolumab (antibody to PD-1) and ipilimumab (antibody to cytotoxic T lymphocyte–associated protein–4) prolonged survival in advanced NSCLC patients compared with chemotherapy alone. We have now designed a randomized, controlled phase III trial (NIPPON, JCOG2007) to confirm that platinum combination chemotherapy plus nivolumab and ipilimumab is superior to such chemotherapy plus pembrolizumab (antibody to PD-1) for treatment-naive patients with advanced NSCLC. Patients and Methods: Chemotherapy-naïve patients aged 20 years or older with a performance status of 0 or 1 are randomly assigned in a 1:1 ratio to receive platinum combination chemotherapy and either pembrolizumab or nivolumab plus ipilimumab. Patients with known genetic driver alterations such as those affecting EGFR or ALK are excluded. Enrollment of 422 patients over 3 years at 55 oncology facilities throughout Japan is planned. The primary endpoint is overall survival. In addition, as ancillary research, metagenomic analysis of the gut microbiota will be performed with fecal samples collected before treatment onset, and the results will be examined for their association to therapeutic effect and adverse events. Conclusion: If the primary endpoint is met, platinum combination chemotherapy together with nivolumab plus ipilimumab will be established as a new, more effective standard treatment for advanced NSCLC.

DOI： 10.1016/j.cllc.2021.10.012

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記述言語：英語   出版者・発行元：BMC Cancer  

Background: Many studies have recently reported the association of concomitant medications with the response and survival in patients with non-small-cell lung cancer (NSCLC) treated with cancer immunotherapy. However, the clinical impact of statin therapy on the outcome of cancer immunotherapy in patients with NSCLC is poorly understood. Methods: In our database, we retrospectively identified and enrolled 390 patients with advanced or recurrent NSCLC who were treated with anti-programmed cell death-1 (PD-1) monotherapy in clinical practice between January 2016 and December 2019 at 3 medical centers in Japan to examine the clinical impact of statin therapy on the survival of patients with NSCLC receiving anti-PD-1 monotherapy. A propensity score-matched analysis was conducted to minimize the bias arising from the patients’ backgrounds. Results: The Kaplan–Meier curves of the propensity score-matched cohort showed that the overall survival (OS), but not the progression-free survival (PFS), was significantly longer in patients receiving statin therapy. However, a Cox regression analysis in the propensity score-matched cohort revealed that statin therapy was not an independent favorable prognostic factor, although it tended to be correlated with a favorable outcome. Conclusions: Statin therapy may be a combination tool for cancer immunotherapy in patients with NSCLC. These findings should be validated in further prospective studies with larger sample sizes.

DOI： 10.1186/s12885-022-09385-8

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記述言語：英語   出版者・発行元：European Journal of Cancer  

Background: Now that immunotherapy plus chemotherapy (CT) is one standard option in first-line treatment of advanced non-small cell lung cancer (NSCLC), there exists a medical need to assess the efficacy of second-line treatments (2LT) with antiangiogenics (AA). We performed an individual patient data meta-analysis to validate the efficacy of these combinations as 2LT. Methods: Randomised trials of AA plus standard 2LT compared to 2LT alone that ended accrual before 2015 were eligible. Fixed-effect models were used to compute pooled hazard ratios (HRs) for overall survival (OS, main end-point), progression-free survival (PFS) and subgroup analyses. Results: Sixteen trials were available (8,629 patients, 64% adenocarcinoma). AA significantly prolonged OS (HR = 0.93 [95% confidence interval {CI}: 0.89; 0.98], p = 0.005) and PFS (0.80 [0.77; 0.84], p < 0.0001) compared with 2LT alone. Absolute 1-year OS and PFS benefit for AA were +1.8% [−0.4; +4.0] and +3.5% [+1.9; +5.1], respectively. The OS benefit of AA was higher in younger patients (HR = 0.87 [95% CI: 0.76; 1.00], 0.89 [0.81; 0.97], 0.94 [0.87; 1.02] and 1,04 [0.93; 1.17] for patients <50, 50–59, 60–69 and ≥ 70 years old, respectively; trend test: p = 0.02) and in patients who started AA within 9 months after starting the first-line therapy (0.88 [0.82; 0.99]) than in patients who started AA later (0.99 [0.91; 1.08]) (interaction: p = 0.03). Results were similar for PFS. AA increased the risk of hypertension (p < 0.0001), but not the risk of pulmonary thromboembolic events (p = 0.21). Conclusions: In the 2LT of advanced NSCLC, adding AA significantly prolongs OS and PFS, but the benefit is clinically limited, mainly observed in younger patients and after shorter time since the start of first-line therapy.

DOI： 10.1016/j.ejca.2022.02.002

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DOI： 10.1016/j.annonc.2022.02.022

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DOI： 10.1016/j.annonc.2022.02.071

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記述言語：英語   出版者・発行元：BMC Cancer  

Background: Platinum-based chemoradiotherapy is the standard treatment for unresectable stage III non-small-cell lung cancer (NSCLC). However, few studies have evaluated the efficacy of subsequent chemotherapy for relapsed NSCLC following platinum-based chemoradiotherapy. This study aimed to evaluate the efficacy of platinum-doublet chemotherapy as a second-line treatment for patients with unresectable stage III NSCLC. Methods: We retrospectively evaluated patients with unresectable stage III NSCLC treated with cytotoxic chemotherapy following platinum-based chemoradiotherapy who were registered in a nationwide registry NSCLC database. Patients were divided into the platinum-doublet chemotherapy (platinum) group and single-agent chemotherapy (non-platinum) group based on the type of second-line chemotherapy. Results: The platinum group (n = 119) showed significantly better overall survival (OS) than the non-platinum group (n = 201) (median OS: 21.5 vs. 10.5 months, hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.40–0.73, p < 0.001). OS from the beginning of chemoradiotherapy was also significantly better in the platinum group than in the non-platinum group (median OS: 34.9 vs. 21.8 months, HR: 0.58, 95% CI: 0.43–0.79, p = 0.001). In the multivariate analysis, platinum-doublet chemotherapy as second-line therapy, female sex, clinical stage IIIA, and duration of ≥ 8.6 months from the beginning of first-line therapy to the beginning of second-line therapy were associated with significantly better OS. Conclusion: Platinum-doublet chemotherapy as a second-line therapy may prolong survival in unresectable stage III NSCLC patients following platinum-based chemoradiotherapy. Thus, re-administration of platinum agents may be a promising treatment for unresectable stage III NSCLC treated with platinum-based chemoradiotherapy.

DOI： 10.1186/s12885-022-09441-3

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PubMed

記述言語：日本語   出版者・発行元：福岡医学会  

日本人の死因第1位を占める『がん』．なかでも肺がんは癌の死因の第1位であり，わが国においては年間7万人を超える患者が亡くなる．肺がん健診により早期発見の努力がなされてはいるが，診断時にその半数以上が遠隔転移を伴う手術不能の進行肺癌であり，全身状態が保たれていれば抗がん剤による薬物療法の適応となる．進行肺癌に対する薬物療法の治療成績は，20年前は平均生存期間が12〜15か月と極めて厳しいものであった．しかし近年，遺伝子異常に基づく分子標的治療の導入により治療成績は著しく改善し，5年以上に渡り日常生活を維持できている症例も多く経験するようになっている．この肺癌治療の長足の進歩は優れた分子生物学的基礎研究の成果が礎となっていることは言うまでもな いが，質の高い医師主導臨床研究の積み重ねが治療成績向上に繋がったことは，この疾患領域においては特筆すべきことである．本稿においては，肺癌薬物治療が如何にして進歩してきたのか，その中で医師主導臨床研究がどのような役割を果たしてきたのかを，我々の研究の一端を含め紹介する．

DOI： 10.15017/4795993

CiNii Research

DOI： 10.1371/journal.pone.026324

Web of Science

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

【Background】“Cancer genomic medicine” for development of an innovative medicines based on the analysis of information about genomics and clinical records is now ongoing in Japan. It is expected that introduction of the comprehensive genomic analysis and screening of cancer-related gene are going to be carried on a full-scale operation in the near future. Although HER2 gene mutations are one of the driver mutations and have been identified in 2-4% of non-small cell lung cancer (NSCLC), no effective targeted therapy has been developed for NSCLC with such mutations. Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate of trastuzumab and derivative of maytansine (DM1), which has been approved for metastatic breast cancer positive for overexpression of HER2 protein but not for NSCLC. It has recently been reported that T-DM1 demonstrated a marked ORR of 44% (8 of 18 patients) in a phase II study abroad. Moreover, the ORR was 55% (6 of 11 patients) when focused on the exon 20 insertion mutation including exon 20 A775_G776insYVMA, which accounts for most (50-96%) of HER2 mutations. Several retrospective studies have shown that ORR in treatment with combination therapy of trastuzumab and chemotherapy for patients with NSCLC positive for HER2 exon 20 insertion mutations was 50-60%. Together with the basic studies demonstrating that HER2 exon 20 insertion mutations have functions as a driver mutation, such mutations should be a good target for treatment with an anti-HER antibody.

【Method】We have planned to conduct a phase II study to evaluate the efficacy of T-DM1 for NSCLC positive for HER2 exon 20 insertion mutations (target sample size: 20), with ORR being a primary endpoint and with progression free survival, overall survival and safety being secondary endpoints. NSCLC with such mutations will be screened based on a next generation sequencing based comprehensive genomic profiling assay of FoundationOne CDxTM, LC-SCRUM-Japan or NCC Oncopanel. The purpose of our study is to have T-DM1 approved in expanded use for NSCLC positive for HER2 exon 20 insertion mutations, which confer an appropriate molecular targeted therapy to patients harboring such disease who have only received a treatment based on cytotoxic drugs.

【Results】Between February 2019 and July 2020, 22 patients were enrolled in the study. A775_G776insYVMA was the most frequent HER2 exon-20 insertion mutation, accounting for 19 (86.4%) of the 22 patients. The ORR was 38.1% (90% confidence interval, 23.0-55.9%), and the disease control rate was 52.4%. The median duration of response was 3.5 months, and the median progression-free survival and median overall survival were 2.8 and 8.1 months, respectively. Toxicity was mild, with the frequency of adverse events of grade 3 or more being low.

【Conclusion and significance】Although these findings did not result in an approval of T-DM1 for NSCLC with HER2 exon-20 insertion mutations in Japan, our study demonstrated the similar effectiveness to that observed in the previous study, confirming the treatment strategy of anti-HER2 antibody-drug conjugate for such disease.

記述言語：英語   出版者・発行元：ESMO Open  

Introduction: The albumin-bilirubin (ALBI) grade is a novel indicator of the liver function. Some studies showed that the ALBI grade was a prognostic and predictive biomarker for the efficacy of chemotherapy in cancer patients. The association between the ALBI grade and outcomes in patients with non-small-cell lung cancer (NSCLC) treated with cancer immunotherapy, however, is poorly understood. Methods: We retrospectively enrolled 452 patients with advanced or recurrent NSCLC who received anti-programmed cell death protein 1 (PD-1)-based therapy between 2016 and 2019 at three medical centers in Japan. The ALBI score was calculated from albumin and bilirubin measured at the time of treatment initiation and was stratified into three categories, ALBI grade 1-3, with reference to previous reports. We examined the clinical impact of the ALBI grade on the outcomes of NSCLC patients receiving anti-PD-1-based therapy using Kaplan–Meier survival curve analysis with log-rank test and Cox proportional hazards regression analysis. Results: The classifications of the 452 patients were as follows: grade 1, n = 158 (35.0%); grade 2, n = 271 (60.0%); and grade 3, n = 23 (5.0%). Kaplan–Meier survival curve analysis showed that the ALBI grade was significantly associated with progression-free survival and overall survival. Moreover, Cox regression analysis revealed that the ALBI grade was an independent prognostic factor for progression-free survival and overall survival. Conclusion: The ALBI grade was an independent prognostic factor for survival in patients with advanced or recurrent NSCLC who receive anti-PD-1-based therapy. These findings should be validated in a prospective study with a larger sample size.

DOI： 10.1016/j.esmoop.2021.100348

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：European Journal of Cancer  

Background: Human epidermal growth factor receptor 2 (HER2) mutations are present in ∼3% of patients with non–small cell lung cancer (NSCLC), with exon-20 insertions accounting for ∼90% of such HER2 mutations and having been identified as driver oncogenic alterations. Antibody–cytotoxic drug conjugates including trastuzumab deruxtecan have shown an excellent efficacy for NSCLC with HER2 mutations. We have now performed a phase II study to evaluate the efficacy of ado-trastuzumab emtansine (T-DM1) for NSCLC positive for HER2 exon-20 insertion mutations. Patients and methods: Eligible patients with HER2 exon-20 insertion mutations confirmed by next-generation sequencing or multiplex polymerase chain reaction platforms and a history of one or two lines of chemotherapy received T-DM1 (3.6 mg/kg) intravenously every 21 days. The primary end-point of the study was the objective response rate (ORR). Results: Between February 2019 and July 2020, 22 patients were enrolled in the study. A775_G776insYVMA was the most frequent HER2 exon-20 insertion mutation, accounting for 19 (86.4%) of the 22 patients. The ORR was 38.1% (90% confidence interval, 23.0–55.9%), and the disease control rate was 52.4%. The median duration of response was 3.5 months, and the median progression-free survival and median overall survival were 2.8 and 8.1 months, respectively. Toxicity was mild, with the frequency of adverse events of grade ≥3 being low. Conclusion: T-DM1 is a potential treatment option for patients with NSCLC with HER2 exon-20 insertion mutations. Further investigation of biomarkers for T-DM1 is warranted to improve its efficacy for NSCLC with such mutations. Clinical trial number: JapicCTI-194620

DOI： 10.1016/j.ejca.2021.11.021

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：PLoS ONE  

A recent study suggested that proton pump inhibitor (PPI) use in patients with advanced non-small-cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICIs) was associated with poor clinical outcomes. However, the clinical impact of PPI use on the outcome of patients receiving ICIs for postoperative recurrent NSCLC is unknown. The outcomes of 95 patients with postoperative recurrence of NSCLC receiving ICIs at 3 medical centers in Japan were analyzed. We conducted adjusted Kaplan–Meier survival analyses with the log-rank test, a Cox proportional hazards regression analysis, and a logistic regression analysis using inverse probability of treatment weighting (IPTW) to minimize the bias arising from the patients’ backgrounds. The IPTW-adjusted Kaplan–Meier curves revealed that the progression-free survival (PFS), but not the overall survival (OS), was significantly longer in patients who did not receive PPIs than in those who did receive them. The IPTW-adjusted Cox regression analysis revealed that PPI use was an independent poor prognostic factor for the PFS and OS. Furthermore, in the IPTW-adjusted logistic regression analysis, PPI non-use was an independent predictor of disease control. In this multicenter and retrospective study, PPI use was associated with poor clinical outcomes in patients with postoperative recurrence of NSCLC who were receiving ICIs. PPIs should not be prescribed indiscriminately to patients with postoperative recurrence of NSCLC who intend to receive ICIs. These findings should be validated in a future prospective study.

DOI： 10.1371/journal.pone.0263247

Scopus

PubMed

記述言語：英語   出版者・発行元：Journal for ImmunoTherapy of Cancer  

Background PD-L1 expression on tumor cells is a marker of PD-1/PD-L1 antibody treatment efficacy for advanced non-small cell lung cancer (NSCLC). PD-L1 antibody (atezolizumab) prolongs overall survival (OS) compared with platinum doublet as first-line treatment for NSCLC with high PD-L1 expression. Bevacizumab enhanced cytotoxic agent and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor efficacy in non-squamous (NS)-NSCLC, and PD-1/PD-L1 antibodies in preclinical models. Methods This single-arm phase II study investigated clinical benefits of adding bevacizumab 15 mg/kg to atezolizumab 1200 mg fixed dose in a first-line setting for advanced NS-NSCLC patients with PD-L1 expression ≥50% without EGFR/ALK/ROS1 alterations. Primary endpoint was objective response rate (ORR) assessed by central review committee. Secondary endpoints were progression-free survival (PFS), duration of response (DOR), OS, and safety. Results Of 39 enrolled patients, 33 (84.6%) had stage IV NSCLC and 36 (92.3%) had smoking history. As of March 31, 2020, no patient had a complete response and 25 patients had a partial response (ORR=64.1%, 95% CI 47.18 to 78.80). Twelve-month PFS and OS rates were 54.9% (35.65 to 70.60) and 70.6% (50.53 to 83.74), respectively. The median DOR in 25 responders was 10.4 months (4.63-not reached). The median treatment cycle was 12 (1 to 27). Nineteen patients discontinued study treatment because of disease progression (N=17) or immune-related adverse events (AEs) (N=2) (sclerosing cholangitis or encephalopathy). There were 23 serious AEs in 12 patients, but no grade 4/5 toxicity. Conclusions Atezolizumab with bevacizumab is a potential treatment for NS-NSCLC with high PD-L1 expression. Trial registration number JapicCTI-184038.

DOI： 10.1136/jitc-2021-004025

Web of Science

Scopus

PubMed

Web of Science

記述言語：英語   出版者・発行元：Journal of Clinical Oncology  

PURPOSE To investigate the efficacy of gefitinib as an adjuvant therapy for non–small-cell lung cancer patients with EGFR mutation. PATIENTS AND METHODS IMPACT (WJOG6410L; University Hospital Medical Information Network Clinical Trials Registry: UMIN000006252), a randomized, open-label, phase III study, included patients with completely resected pathologic stage II-III non–small-cell lung cancer harboring EGFR mutations (exon 19 deletion or L858R) during September 2011 to December 2015. Patients were randomly assigned to receive gefitinib (250 mg once daily) for 24 months or cisplatin (80 mg/m2 on day 1) plus vinorelbine (25 mg/m2 on days 1 and 8; cis/vin) once every 3 weeks for four cycles. The primary end point was disease-free survival (DFS). RESULTS Overall, 234 patients were randomly assigned. Among 232 eligible patients (116 each; excluding two who withdrew consent), the median DFS was 35.9 and 25.1 months in the gefitinib and cis/vin groups, respectively. However, Kaplan-Meier curves crossed around 4 years after surgery with no statistically significant difference (stratified log-rank P =.63; hazard ratio by stratified Cox proportional hazards model = 0.92; 95% CI, 0.67 to 1.28). Overall survival (OS) was also not different (stratified log-rank P =.89; hazard ratio = 1.03; 95% CI, 0.65 to 1.65), with the 5-year OS rates being 78.0% and 74.6% in the gefitinib and cis/vin groups, respectively. Treatment-related deaths occurred in 0 and three patients in the gefitinib and cis/vin groups, respectively. CONCLUSION Although adjuvant gefitinib appeared to prevent early relapse, it did not prolong DFS or OS. However, similar DFS and OS may justify adjuvant gefitinib in the selected patient subsets, especially those deemed ineligible for platinum-doublet adjuvant therapy; however, this was not a noninferiority trial.

DOI： 10.1200/JCO.21.01729

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Journal of Clinical Oncology  

PURPOSE We evaluated the efficacy and safety of fosnetupitant (FosNTP) versus fosaprepitant (FosAPR) for preventing highly emetogenic chemotherapy-induced nausea and vomiting. This phase III study was the first head-to-head comparison between two different neurokinin-1 receptor antagonists in combination with palonosetron and dexamethasone. PATIENTS AND METHODS Patients scheduled to receive cisplatin-based chemotherapy were randomly assigned 1:1 to FosNTP 235 mg or FosAPR 150 mg in combination with palonosetron 0.75 mg and dexamethasone. The primary end point was overall (0-120 hours) complete response (CR; no emetic event and no rescue medication) rate, stratified by sex and age category, to show the noninferiority of FosNTP to FosAPR (noninferiority margin, –10% for the difference in the overall CR rate). RESULTS Overall, 795 patients were randomly assigned, of whom 785 received the study drug (FosNTP [N = 392] v FosAPR [N = 393]) and were evaluated for efficacy and safety. The overall CR rate was 75.2% versus 71.0%, respectively (Mantel-Haenszel common risk difference, 4.1%; 95% CI, –2.1% to 10.3%), demonstrating noninferiority of FosNTP to FosAPR. The CR rates in the acute (0-24 hours), delayed (24-120 hours), and beyond delayed (120-168 hours) phases, and at 0-168 hours were 93.9% versus 92.6%, 76.8% versus 72.8%, 86.5% versus 81.4%, and 73.2% versus 66.9%, respectively. The incidence rates of treatment-related adverse events with FosNTP versus FosAPR were 22.2% versus 25.4%, whereas adverse events or treatment-related adverse events relevant to injection site reactions were 11.0% versus 20.6% (P <.001) and 0.3% versus 3.6% (P <.001), respectively. CONCLUSION FosNTP demonstrated noninferiority to FosAPR, with a favorable safety profile and lower risk for injection site reactions. Thus, FosNTP is valuable in the prophylaxis of acute, delayed, and beyond delayed chemotherapy-induced nausea and vomiting.

DOI： 10.1200/JCO.21.01315

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Cancer Management and Research  

Background: The standard of care for extensive-stage small cell lung cancer (ES-SCLC) is an immune checkpoint inhibitor (ICI) combined with platinum-etoposide (PE) chemotherapy. At initial diagnosis, about 25% of ES-SCLC patients have brain metastases, which are associated with a poor prognosis. The decision as to whether to treat brain metastases with local therapies such as surgery or radiotherapy before initiation of systemic chemoimmunotherapy is based on symptoms due to the brain lesions and the general condition of the patient. Subset analysis of the CASPIAN study showed that combination therapy with PE plus durvalumab (MEDI4736) is promising for ES-SCLC with brain metastases. However, data required in daily clinical practice, such as intracranial response rate and duration of intracranial response, are insufficient for such patients. Patients and Methods: We have designed a single-arm phase II trial of durvalumab plus PE for patients aged ≥20 years with chemotherapy-naïve ES-SCLC and at least one brain metastasis ≥5 mm in size that has not been previously treated. Patients receive durvalumab intravenously combined with four cycles of PE. Enrollment of 50 patients over 2 years at 25 oncology facilities in Japan is planned. The primary endpoint is intracranial response rate. Conclusion: This is the first prospective study to evaluate the effects of an ICI with PE specifically in ES-SCLC patients with brain metastases. If it demonstrates intracranial efficacy, this regimen will be a potential treatment option for such individuals, and radiation therapy or surgery for brain metastases can be avoided or postponed.

DOI： 10.2147/CMAR.S391220

Web of Science

Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

担当ページ：p105-106   記述言語：日本語   著書種別：一般書・啓蒙書

担当ページ：p294-298   記述言語：日本語   著書種別：一般書・啓蒙書

担当ページ：第71巻増刊号6, p130-134   記述言語：日本語   著書種別：一般書・啓蒙書

担当ページ：p200-201   記述言語：日本語   著書種別：一般書・啓蒙書

担当ページ：第71巻増刊号6, p35-39   記述言語：日本語   著書種別：一般書・啓蒙書

担当ページ：p416-419   記述言語：日本語   著書種別：一般書・啓蒙書

担当ページ：p351-359   記述言語：日本語   著書種別：一般書・啓蒙書

担当ページ：p351-359   記述言語：日本語   著書種別：一般書・啓蒙書

担当ページ：p351-359   記述言語：日本語   著書種別：一般書・啓蒙書