Faculty Profiles - YONESHIMA YASUTO (2024)

Language：English Publisher：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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DOI：10.1016/j.clc.2024.06.010

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Language：English

DOI：10.7759/cureus.61470

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Language：English Publisher：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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Language：English Publisher：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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Language：English Publisher：Japanese Journal of Clinical Oncology

Objective: As first-line treatment for stage IV or recurrent non-small cell lung cancer, combination immunotherapy with nivolumab and ipilimumab, with or without chemotherapy, had demonstrated survival benefits over chemotherapy; however, data on Japanese patients are limited. Methods: LIGHT-NING was a multicenter, observational study and retrospectively collected data. In this interim analysis, we analyzed patients who received combination immunotherapy between 27 November 2020 and 31 August 2021 for the treatment status, safety objectives (treatment-related adverse events and immune-related adverse events incidences), and effectiveness objectives (objective response rate and progression-free survival) to determine the characteristics and early safety information. Results: We analyzed 353 patients, with a median follow-up of 7.1 (interquartile range, 5.0–9.7) months. Overall, 60.1 and 39.9% received nivolumab plus ipilimumab with and without chemotherapy, respectively. In these cohorts, the median age was 67 and 72 years; 10.8 and 35.5% were aged ≥75 years; 80.2 and 79.4% were male; 5.2 and 13.5% had a performance score ≥ 2; 32.1 and 27.0% developed grade 3–4 immune-related adverse events; treatment-related deaths were observed in 6 (2.8%) and 5 (3.5%) patients, respectively. Grade 3–4 immune-related adverse event incidence was the highest within the first month of treatment in both cohorts, although the immune-related adverse event risk persisted throughout. No new safety signals were observed at this interim analysis. The median progression-free survival was 6.0 (95% confidence interval, 5.2–7.6) and 5.8 (4.3–7.0) months in nivolumab plus ipilimumab with and without chemotherapy cohorts, respectively. Conclusions: LIGHT-NING offers valuable insights into combination immunotherapy for untreated patients with stage IV or recurrent non-small cell lung cancer in Japanese real-world settings.

DOI：10.1093/jjco/hyad195

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

DOI：10.1007/s12325-023-02648-1.

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

DOI：10.1016/j.lungcan.2023.107264.

Language：English Publisher：Annals of the American Thoracic Society

Rationale: A fatal acute exacerbation (AE) occasionally develops during chemotherapy for small cell lung cancer (SCLC) with comorbid idiopathic pulmonary fibrosis (IPF).Objectives: This study aimed to assess the safety and efficacy of carboplatin, etoposide, and nintedanib combination therapy for unresectable SCLC with comorbid IPF.Methods: The NEXT-SHIP study is a multicenter, single-arm, phase 2 trial for unresectable SCLC with IPF (Japan Registry of Clinical Trials registry number jRCTs031190119). The patients received carboplatin, etoposide, and nintedanib (150 mg twice daily). The primary endpoint was the incidence of IPF-AE at 28 days after the last administration of cytotoxic chemotherapy, and the sample size was set at 33 (5.0% expected, 20.0% threshold).Results: A total of 33 patients were registered; 87.9% were male, the median age was 73 years, the median percentage forced vital capacity was 85.2%, and 51.5% had honeycomb lungs. The median observation period was 10.5 months. The incidence of IPF-AE at 28 days after the last administration of cytotoxic chemotherapy was 3.0% (90% confidence interval [CI], 0.2-13.6). The objective response rate was 68.8% (95% CI, 50.0-83.9). The median progression-free survival and overall survival times were 4.2 months (95% CI, 4.2-5.5) and 13.4 months (95% CI, 8.1-21.6), respectively. The most common adverse event of grade 3 or higher was neutropenia (81.8%), followed by leukopenia (39.4%) and thrombocytopenia (30.3%).Conclusions: This study met its primary endpoint regarding the incidence of IPF-AEs with promising results for efficacy. Carboplatin, etoposide, and nintedanib combination therapy may be one of the standard treatment options for SCLC with comorbid IPF.Clinical trial registered with the Japan Registry of Clinical Trials (jRCTs031190119).

DOI：10.1513/AnnalsATS.202311-941OC

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Language：English Publisher：Oxford University Press

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

DOI：10.1038/s41698-024-00557-2.

Language：English Publisher：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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Language：English Publisher：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

CiNii Research

Language：English Publisher：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

CiNii Research

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

DOI：10.1016/j.bbrc.2023.09.067.

Language：English Publisher：(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。

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

DOI：10.1111/cas.15921.

Language：English Publisher：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。

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

DOI：10.1111/1759-7714.15014.

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

DOI：10.1016/j.jtho.2023.06.012.

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

DOI：10.1016/j.lungcan.2023.107195.

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

DOI：10.2217/fon-2023-0230.

Language：English Publisher：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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DOI：10.1200/JCO.2023.41.17_suppl.LBA9009

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DOI：10.3389/fimmu.2023.1192861.

Publisher：Current Problems in Cancer: Case Reports

DOI：10.1016/j.cpccr.2023.100236

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Publisher：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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Language：English Publisher：eClinicalMedicine

Background: Approximately 3–4% of patients with non-small-cell lung cancer (NSCLC) have MET exon 14 (METex14) skipping mutations. We report primary results from the phase 2 stage of a phase 1b/2 study of gumarontinib, a selective, potent, oral MET inhibitor, in patients with METex14 skipping mutation-positive (METex14-positive) NSCLC. Methods: The single-arm, multicentre, open-label, phase 2 stage of the GLORY study was conducted at 42 centres across China and Japan. Adults with locally advanced or metastatic METex14-positive NSCLC received oral gumarontinib 300 mg once daily in continuous 21-day cycles until disease progression, intolerable toxicity, or withdrawal of consent. Eligible patients had failed one or two prior lines of therapy (not including a MET inhibitor), were ineligible for/refused chemotherapy, and had no genetic alterations targetable with standard therapies. The primary endpoint was objective response rate in patients with a valid baseline tumour assessment, by blinded independent review. The study was registered at ClinicalTrials.gov (NCT04270591). Findings: Between Aug 2, 2019 and Apr 28, 2021, 84 patients were enrolled and received gumarontinib (median follow-up 13.5 months [IQR 8.7–17.1]), at data cut-off (Apr 28, 2022) five patients whose METex14 status could not be confirmed by a central laboratory were excluded from the efficacy analysis. The objective response rate was 66% (95% CI 54–76) overall (n = 79), 71% (95% CI 55–83) in treatment-naïve patients (n = 44), and 60% (95% CI 42–76) in previously-treated patients (n = 35). The most common treatment-related adverse events (any grade) were oedema (67/84 patients, 80%) and hypoalbuminuria (32/84, 38%). Grade ≥3 treatment-emergent adverse events occurred in 45 (54%) patients. Treatment-related adverse events leading to permanent discontinuation occurred in 8% (7/84) of patients. Interpretation: Gumarontinib monotherapy had durable antitumour activity with manageable toxicity in patients with locally advanced or metastatic METex14-positive NSCLC when used in first line or later. Funding: Haihe Biopharma Co., Ltd. Supported in part by grants from the National Science and Technology Major Project of China for “Clinical Research of Gumarontinib, a highly selective MET inhibitor” (2018ZX09711002-011-003); the National Natural Science Foundation of China (82030045 to S.L. and 82172633 to YF.Y); Shanghai Municipal Science & Technology Commission Research Project (19411950500 to S.L.); Shanghai Shenkang Action Plan (16CR3005A to S.L.) and Shanghai Chest Hospital Project of Collaborative Innovation (YJXT20190105 to S.L.).

DOI：10.1016/j.eclinm.2023.101952

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

DOI：10.1016/j.eclinm.2023.101952.

Language：English

DOI：10.1111/cas.15645

Language：English Publisher：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。

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

DOI：10.1016/S0140-6736(23)00221-0

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Web of Science

Web of Science

Language：English Publisher：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

Scopus

PubMed

Language：English Publisher：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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Scopus

PubMed

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

DOI：10.1016/j.cllc.2022.08.011

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

DOI：10.21037/tlcr-22-393

Web of Science

Language：English Publisher：Journal of Thoracic Oncology

Introduction: To evaluate the efficacy and safety of osimertinib plus bevacizumab for previously untreated patients with advanced nonsquamous NSCLC harboring EGFR-sensitizing mutations. Methods: We conducted a randomized, open-label, phase 2 study at 21 institutions in Japan. Previously untreated patients with advanced nonsquamous NSCLC harboring EGFR-sensitizing mutations received either osimertinib (80 mg, daily) plus bevacizumab (15 mg/kg, every 3 wk) or osimertinib monotherapy, and were stratified according to sex, stage, and EGFR mutation status. The primary end point was progression-free survival (PFS) in the intention-to-treat population, assessed by means of blinded, independent central radiologic review. Results: Between January 2018 and September 2018, a total of 122 patients were enrolled (osimertinib + bevacizumab arm, 61 patients; osimertinib monotherapy arm, 61 patients). At a median follow-up duration of 19.8 months, the median PFS was 22.1 months for osimertinib plus bevacizumab and 20.2 months for osimertinib monotherapy, with a hazard ratio of 0.862 (60% confidence interval: 0.700–1.060, 95% confidence interval: 0.531–1.397, one-sided stratified log-rank p = 0.213). Adverse events of grade 3 or worse were observed in 34 patients (56%) in the osimertinib plus bevacizumab arm and 29 (48%) in the osimertinib monotherapy arm. In addition, two (3%) and 11 patients (18%) experienced any grade pneumonitis, respectively, and grade 3 pneumonitis was observed in one patient (2%) in each arm. Conclusions: This study failed to exhibit the efficacy of osimertinib plus bevacizumab for improving the PFS among patients with nonsquamous NSCLC harboring EGFR mutations as first-line treatment.

DOI：10.1016/j.jtho.2022.05.006

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Scopus

PubMed

DOI：10.1016/j.annonc.2022.07.1110

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DOI：10.1016/j.annonc.2022.05.276

Web of Science

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

DOI：10.1016/j.lungcan.2021.05.023.

Language：English

DOI：10.1186/s12885-022-09385-8.

Language：English

DOI：10.1186/s12885-022-09385-8.

Language：English Publisher：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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PubMed

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

DOI：10.1016/j.jtho.2022.05.006.

Language：English Publisher：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

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Scopus

PubMed

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

DOI：10.1016/j.jtho.2021.03.027.

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

DOI：10.1002/ijc.33557.

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

DOI：10.1111/cas.14536.

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

DOI：10.1038/s41598-021-92098-y.

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

DOI：10.1007/s00262-020-02783-6.

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

DOI：10.21037/tlcr-21-92

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

DOI：10.1016/j.lungcan.2021.03.018.

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

DOI：10.1016/j.lungcan.2020.11.026.

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

DOI：10.1172/jci.insight.140229.

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

DOI：10.1016/j.cllc.2019.09.001

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

Objectives: To examine the possible effects of antinuclear antibodies (ANA) on the safety and efficacy of programmed cell death–1 (PD-1) inhibitors in patients with advanced non–small cell lung cancer (NSCLC). Patients and methods: Clinical data including ANA status were reviewed retrospectively for patients with advanced NSCLC who received monotherapy with a PD-1 inhibitor. Results: Of the 83 patients analyzed, 18 (21.7%) were positive for ANA. The incidence of immune-related adverse events (irAEs) did not differ significantly between patients with ANA (6/18, 33.3%) and those negative for ANA (21/65, 32.3%), although it tended to increase as the ANA titer increased. Progression-free survival (2.9 versus 3.8 months, p = 0.03) and overall survival (11.6 versus 15.8 months, p = 0.03) were significantly shorter in patients positive for ANA than in those without ANA. Conclusion: PD-1 inhibitors can be administered safely in advanced NSCLC patients positive for ANA without obvious exacerbation of autoimmune disease, although patients with a high titer of such antibodies may warrant close monitoring. However, the presence of ANA might be associated with a poor outcome of such treatment.

DOI：10.1016/j.lungcan.2019.01.014

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

DOI：10.1016/j.lungcan.2018.11.002

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

DOI：10.1016/j.lungcan.2018.01.024

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

DOI：10.1016/j.suronc.2018.01.002

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

DOI：10.1093/annonc/mdx497

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

DOI：10.1016/j.lungcan.2017.07.020

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

Background Nanoparticle albumin-bound (nab) paclitaxel is a promising new therapeutic agent for all histologic types of non–small-cell lung cancer (NSCLC). We recently performed a phase 2 study of weekly nab-paclitaxel in patients with previously treated advanced NSCLC, finding promising activity and acceptable toxicity for this regimen. We have now designed a randomized phase 3 intergroup study (J-AXEL, UMIN000017487) to examine the clinical benefit and safety of nab-paclitaxel compared to docetaxel in patients with previously treated advanced NSCLC. Patients and Methods Patients are randomized to receive either docetaxel (60 mg/m² on day 1 every 3 weeks, control arm) or nab-paclitaxel (100 mg/m² on days 1, 8, and 15 every 3 weeks, experimental arm), with each drug being administered until disease progression or unacceptable toxicity. The study will evaluate the noninferiority of nab-paclitaxel relative to docetaxel for the primary end point of overall survival. Conclusion If the primary objective is achieved, this study will provide evidence for a new alternative treatment option for patients with previously treated advanced NSCLC.

DOI：10.1016/j.cllc.2016.08.003

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

DOI：10.1038/srep32849

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

DOI：10.1016/j.lungcan.2015.03.012

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

DOI：10.1007/s10637-014-0195-1

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

DOI：10.2169/internalmedicine.51.7599

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

Fosfomycin exerts anti-inflammatory effects through inhibiting the production of proinflammatory cytokines. Transcription of the genes for these proinflammatory cytokines is regulated by NF-κB. We tested the hypothesis that fosfomycin inhibits the activation of NF-κB induced by tumor necrosis factor-α (TNF-α) in human monocytic U-937 cells, and a T cell line (Jurkat). Western blot analysis demonstrated that fosfomycin inhibits NF-κB activation in both cells. Flow cytometry revealed that fosfomycin suppresses NF-κB activation in both cells in a dose-related manner. These findings are consistent with the idea that fosfomycin suppresses the production of proinflammatory cytokines via inhibition of NF-κB activation.

DOI：10.1016/S0924-8579(03)00054-2