記述言語：日本語   出版者・発行元：日本医科大学医学会  

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Baseline tumor size (BTS) is one of the prognostic factors of advanced non-small cell lung cancer (NSCLC) treated with immunotherapy. However, its prognostic value in patients with locally advanced NSCLC receiving durvalumab maintenance therapy remains unclear. METHODS: The present study retrospectively reviewed 136 patients with unresectable stage III NSCLC who underwent CRT and durvalumab at two institutions in Japan. The maximum diameter of the target lesion (max BTS) before CRT was measured, the best response to CRT before durvalumab was evaluated, and the impact of the response on durvalumab was explored. Progression-free survival (PFS) and overall survival (OS) were defined as the time from the day of starting durvalumab. RESULTS: Of the total cohort, 133 (97.8%) patients had at least one measurable lesion. The best response to CRT resulting in CR, PR, and SD was seen in 0 (0%), 69 (51.9%), and 64 (48.1%) patients, respectively. PFS was significantly longer in the patients with PR than in those with SD after CRT (median not reached vs. 20.0 months; HR: 0.51; P = 0.023). Moreover, the absence of a massive lesion (max BTS < 50 mm) was associated with a superior CRT response (P < 0.001). CONCLUSION: The best response to induction CRT was associated with better PFS in patients with stage III NSCLC receiving durvalumab following chemoradiotherapy. Although the absence of a massive lesion was associated with a better response to induction CRT in this cohort, this was not translated into PFS and OS benefit.

DOI： 10.1007/s10147-023-02436-5

PubMed

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Pervious studies reported the association of TTF-1 expression with the efficacy of platinum-doublet chemotherapy in combination with immune checkpoint inhibitors in advanced nonsquamous NSCLC. Nevertheless, the predictive value of extent of TTF-1 expression (diffuse or focal TTF-1 positivity) remains unclear. METHODS: The present study retrospectively reviewed 74 patients with TTF-1-positive recurrent or advanced nonsquamous NSCLC receiving first-line chemoimmunotherapy in a single institution in Japan. TTF-1 expression score in pretreatment tumor specimens was evaluated using immunohistochemistry, and the impact of chemoimmunotherapy response was analyzed. RESULTS: In the total cohort, ≥50% of the tumor cells were TTF-1 positive (i.e., diffusely TTF-1 positive) in specimens of 61 patients (82.4%), whereas 10% to 49% of the tumor cells were TTF-1 positive (i.e., focally TTF-1 positive) in specimens of the remaining 13 patients (17.6%). In multivariate analysis, the median progression-free survival and overall survival (OS) were significantly longer in patients with diffusely TTF-1-positive tumors than in those with focally TTF-1-positive tumors (14.2 versus 9.2 mo, p = 0.01 and 30.2 versus 17.3 mo, p = 0.01, respectively). Moreover, the median OS was significantly longer in patients receiving chemoimmunotherapy including pemetrexed than in those receiving chemoimmunotherapy not including pemetrexed among the patients with diffusely TTF-1-positive tumors (not attained versus 23.2 mo, p < 0.01). CONCLUSIONS: The positive extent of diffuse TTF-1 expression associated with patient outcome was an independent predictive factor for better progression-free survival and OS in patients with advanced nonsquamous NSCLC receiving chemoimmunotherapy.

DOI： 10.1016/j.jtocrr.2023.100578

PubMed

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記述言語：日本語   出版者・発行元：(株)総合医学社  

＜最近の研究動向とガイドライン＞●PACIFIC試験の5年フォローアップ解析による全生存期間は47.5ヵ月であり,III期肺癌の予後はついに4年の時代を迎えた.●遺伝子解析,PD-L1発現,微小残存病変(MRD)の把握などが今後重要な指標になると考えられ,バイオマーカーに基づく免疫チェックポイント阻害薬や分子標的薬の選択が今後周術期治療におけるさらなる生存率の改善をもたらすと考えられる.●CheckMate816試験をはじめとした免疫チェックポイント阻害薬を用いた各周術期臨床試験の結果によって,III期切除可能症例に対する治療の選択肢は今後さらに拡がることが予想される.●IMpower010試験の結果により,PD-L1陽性切除例においてプラチナタブレット療法とそれに続く免疫チェックポイント阻害薬が補助療法としての意義を証明し,今後実臨床での症例蓄積が待たれる.●ADAURA試験の結果により,術後補助療法として初めて分子標的薬が保険適用になり,EGFR変異を有する非小細胞肺癌を対象とした術後補助療法としてオシメルチニブは無病生存期間のみならず生存期間の延長をもたらす.●III期非小細胞肺癌の治療目的は「根治」である.今後さらに複雑化する治療方針の決定のためには,集学的治療チームによるディスカッション,特に呼吸器外科・内科・放射線治療科の連携の充実が望まれる.(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Glycan structure is often modulated in disease or predisease states, suggesting that such changes might serve as biomarkers. Here, we generated a monoclonal antibody (mAb) against the core fucose of the N-glycan in human IgG. Notably, this mAb can be used in Western blotting and ELISA. ELISA using this mAb revealed a low level of the core fucose of the N-glycan in IgG, suggesting that the level of acore fucosylated (noncore fucosylated) IgG was increased in the sera of the patients with lung cancer, chronic obstructive pulmonary disease, and interstitial pneumonia compared to healthy subjects. In a coculture analysis using human lung adenocarcinoma A549 cells and antibody-secreting B cells, the downregulation of the FUT8 (α1,6 fucosyltransferase) gene and a low level of core fucose of the N-glycan in IgG in antibody-secreting B cells were observed after coculture. A dramatic alteration in gene expression profiles for cytokines, chemokines, and their receptors were also observed after coculturing, and we found that the identified C-C motif chemokine 2 was partially involved in the downregulation of the FUT8 gene and the low level of core fucose of the N-glycan in IgG in antibody-secreting B cells. We also developed a latex turbidimetric immunoassay using this mAb. These results suggest that communication with C-C motif chemokine 2 between lung cells and antibody-secreting B cells downregulate the level of core fucose of the N-glycan in IgG, i.e., the increased level of acore fucosylated (noncore fucosylated) IgG, which would be a novel biomarker for the diagnosis of patients with pulmonary diseases.

DOI： 10.1016/j.jbc.2023.105365

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Vascular endothelial growth factor (VEGF) inhibitors are widely used in chemotherapy for non-small lung cancer (NSCLC). The purpose of the current study was to examine the impact of background cardiovascular risk factors on VEGF inhibitor-related adverse vascular events (VEGF-related AVEs) in patients with NSCLC who also had comorbidities. METHODS: We conducted a retrospective study of 118 NSCLC patients treated with bevacizumab or ramucirumab from April 2010 to December 2022. We compared baseline cardiovascular risk factors with VEGF-related AVEs. RESULTS: VEGF-related AVEs and discontinuation due to VEGF-related AVEs were reported in 54 patients and 21 patients, respectively. VEGF-related AVEs were significantly more common with male sex, smoking history, history of hypertension, dyslipidemia, diabetes mellitus, or cardiovascular disease. Discontinuation due to VEGF-related AVEs was significantly more common in patients with history of hypertension or chronic kidney disease. VEGF-related AVEs were significantly more common in patients with ≥ 3 cardiovascular risk factors than patients with < 3. Discontinuation due to VEGF-related AVEs was significantly more common in patients with ≥ 4 cardiovascular risk factors than patients with < 4. Multivariate analysis demonstrated that male sex, hypertension, and ≥ 6 cycles of VEGF inhibitors were each associated with VEGF-related AVEs and hypertension was associated with discontinuation due to VEGF-related AVEs. CONCLUSION: Our study demonstrated that history of hypertension was independently associated with increased risk of both VEGF-related AVEs and discontinuation due to VEGF-related AVEs. In conclusion, we need to be aware of VEGF-related AVEs when using VEGF inhibitors for patients with ≥ 3 cardiovascular risk factors.

DOI： 10.1007/s00432-023-05092-4

PubMed

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記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Thyroid transcription factor-1 (TTF-1) is expressed in approximately 70% of lung adenocarcinomas and is one of the most reliable makers to distinguish primary lung adenocarcinoma from metastatic disease. TTF-1-negative status is a poor prognostic factor, and TTF-1-negative lung adenocarcinoma is associated with poor efficacy of immune checkpoint inhibitor (ICI) monotherapy. However, the relationship between TTF-1 expression and the efficacy of ICI plus chemotherapy is still unclear. METHODS: We performed a retrospective analysis of 129 consecutive patients with advanced non-squamous non-small cell lung cancer (NS-NSCLC) treated with ICI monotherapy or ICI plus chemotherapy between January 2016 and December 2021. The expression of programmed death ligand-1 (PD-L1) and TTF-1 was also determined in cases for which no previous data were available. We then evaluated the association between TTF-1 expression status and treatment efficacy. RESULTS: Of the 129 cases, 33 were TTF-1-negative and 96 were positive. In the ICI monotherapy group (N=70), progression-free survival (PFS) was not significantly different between TTF-1-positive and negative patients (median 3.6 vs. 3.8 months, P=0.27); however, in patients with wild-type epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), a trend for worse PFS was observed in TTF-1-negative cases compared with those that were TTF-1-positive (median 3.8 vs. 4.5 months, P=0.088). Moreover, long-term efficacy of ICI monotherapy (>2 years) was not observed in the TTF-1-negative group. TTF-1-negative patients tended to have worse overall survival (OS) than TTF-1-positive patients (median 15.6 vs. 19.5 months, P=0.13). In the ICI plus chemotherapy group (N=59), TTF-1-negative patients tended to have better PFS and similar OS compared with TTF-1-positive patients (median 9.9 vs. 9.6 months, P=0.14; median 32.3 vs. 18.9 months, P=0.78). Long-term efficacy was generally observed in TTF-1-negative patients treated with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) (median PFS 22.5 months, median OS not reached). CONCLUSIONS: ICI monotherapy is generally less efficacious in TTF-1-negative NS-NSCLC patients, and clinicians should consider ICI plus chemotherapy in these cases. Our study suggests that ABCP is an optimal regimen for TTF-1-negative NS-NSCLC.

DOI： 10.21037/tlcr-23-331

PubMed

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The epidermal growth factor receptor (EGFR) mutation is a risk factor associated with brain metastases (BMs) in patients with non-small cell lung cancer (NSCLC). This study aimed to evaluate the impact of osimertinib early dose reduction on BM worsening. METHODS: We retrospectively analyzed EGFR-mutant NSCLC patients treated with osimertinib as first-line treatment between August 2018 and October 2021. To evaluate the impact of osimertinib early dose reduction, we performed a landmark analysis of patients who achieved disease control at 4 months. Patients were divided into two groups according to whether the osimertinib dose was reduced or not, within 4 months after the start of treatment. We evaluated the time to BMs onset or progression, progression-free survival, and overall survival. RESULTS: In total, 62 NSCLC patients with EGFR mutations were analyzed. Thirteen patients experienced early dose reduction of osimertinib treatment. Seven patients received osimertinib 40 mg daily, and six received 80 mg every other day. The most common reason for dose reduction was gastrointestinal toxicity (n = 4), followed by skin rashes (n = 3). The time to BMs onset or progression was significantly shorter in patients who experienced early dose reduction than in those who continued regular treatment (Hazard ratio 4.47, 95% confidence interval, 1.52-13.11). The 1-year cumulative incidence of BM onset or progression was 23.1% in the reduced-dose group and 5.0% in the standard dose group. The risk of worsening BMs with early dose reduction of osimertinib treatment was higher in patients who had BMs before treatment and in younger patients. CONCLUSION: Early dose reduction of osimertinib was a risk factor for the worsening of BMs. A higher risk was associated with younger patients and those presenting BMs before treatment.

DOI： 10.1002/cam4.6393

PubMed

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The mechanisms of fibrosis onset and development remain to be elucidated. However, it has been reported that mechanical stretch promotes fibrosis in various organs and cells, and may be involved in the pathogenesis of pulmonary fibrosis. We demonstrated that ventilator-induced lung hyperextension stimulation in mice increased the expression of connective tissue growth factor (CTGF), a profibrotic cytokine, in lung tissue. Increased CTGF expression induced by cyclic mechanical stretch (CMS) was also observed in vitro using A549 human alveolar epithelial cells. Pathway analysis revealed that the induction of CTGF expression by CMS involved MEK phosphorylation. Furthermore, early growth response 1 (Egr-1) was identified as a transcription factor associated with CTGF expression. Finally, the antifibrotic drug pirfenidone significantly reduced CTGF expression, MEK phosphorylation, and Egr-1 levels induced by CMS. Thus, our results demonstrated that profibrotic cytokine CTGF induced by CMS may be a therapeutic target of pirfenidone.

DOI： 10.1016/j.resp.2023.104142

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Long-term maintenance steroid therapy (MST) is frequently required for repeated relapses of cryptogenic organizing pneumonia (COP); however, the optimal minimal dose has not been clarified. Therefore, this study evaluated the minimal MST dose required to prevent repeated relapses and identify relapse predictors. METHODS: We retrospectively reviewed the medical records of patients with steroid-treated COP and compared background factors between the non-relapse and relapse groups. We also reviewed the treatment course in the relapse group and determined the minimal effective steroid dose based on the MST dose at relapse events and the current relapse prevention dose. RESULTS: In total, 48 patients were identified, including 27 (56%) in the non-relapse group and 21 (44%) in the relapse group. Receiver operating characteristic curve analysis identified prednisolone at 5 mg/day as the optimal cut-off value in the relapse group. Relapse-free time in patients with relapsed COP was significantly longer in the MST dose ≥5 mg/day group than in the <5 mg/day group (log-rank P = 0.003; hazard ratio, 0.19; 95% confidence interval [CI], 0.04-0.60). Multivariate logistic regression analysis demonstrated that a high eosinophil percentage and CD4/CD8 ratio in bronchoalveolar lavage fluid (BALF) were predictors of relapse (odds ratio [OR], 1.12; 95% CI, 1.02-1.23; P = 0.008 and OR, 3.87; 95% CI, 1.29-11.6; P = 0.008, respectively). CONCLUSIONS: Our results indicate that 5 mg/day of prednisolone may be the minimal effective dose for preventing repeated relapses, and a high BALF eosinophil percentage and CD4/CD8 ratio are independent predictors of relapse.

DOI： 10.1016/j.rmed.2023.107390

PubMed

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Amrubicin (AMR) is one of the most active agents for small-cell lung cancer (SCLC). However, hematologic toxicity and infection at a commonly used dose (40 mg/m2) is problematic; the optimal dose remains undetermined. PATIENTS AND METHODS: To evaluate the optimal dose of AMR in terms of efficacy and safety, we reviewed consecutive data on patients with relapsed SCLC who received AMR at doses of 40, 35, and 30 mg/m2 (on days 1-3) at Nippon Medical School Hospital between October 2010 and November 2021. RESULTS: We reviewed the data of 86 patients (20, 45, 27 who received AMR doses of 40, 35, 30 mg/m2, respectively) according to our study criteria. For patients  ≥ 75 years, the proportion who received second-line treatment tended to be higher in the 30-35 mg/m2 group. Objective response rates were 37/46/35%, median progression-free survival (PFS) were 3.0/4.7/3.2 months, and median overall survival (OS) were 7.8/16.3/8.0 months, respectively. Grade 4 neutropenia occurred in 58/39/31% of patients, which was higher for the 40 mg/m2 group. The incidence of febrile neutropenia did not differ between groups. Multivariate analysis identified the AMR dose was not associated with longer PFS and OS. CONCLUSION: Treatment with AMR between 30 and 35 mg/m2 showed relatively mild hematologic toxicity compared with AMR at 40 mg/m2, without any significant difference in efficacy. Lower dose of AMR for relapsed SCLC could be a promising treatment option.

DOI： 10.1007/s10147-023-02343-9

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Rechallenge with platinum-combination chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) after disease progression on platinum-combination chemotherapy occasionally leads to a favorable response. The efficacy and safety of platinum-combination chemotherapy with or without immune-checkpoint inhibitor (ICI) for patients with recurrent NSCLC after surgery followed by adjuvant platinum-doublet chemotherapy remains uncertain. METHODS: Patients who relapsed after surgery plus adjuvant platinum-doublet chemotherapy and received platinum-combination chemotherapy with or without ICI between April 2011 and March 2021 at four Nippon Medical School hospitals were retrospectively analyzed. RESULTS: Among 177 patients who received adjuvant platinum-doublet chemotherapy after surgery, a total of 30 patients who received platinum-combination rechemotherapy with or without ICI after relapse were included in this study. Seven patients received ICI-combined chemotherapy. The median disease-free survival (DFS) after surgery was 13.6 months. The objective response rate and disease-control rate were 46.7% and 80.0%, respectively. The median progression-free survival and overall survival were 10.2 and 37.5 months, respectively. Patients with longer DFS (≥12 months) had a better prognosis than others. The most common grade ≥3 toxicity associated with this treatment was neutropenia (33%). Grade ≥3 immune-related adverse events were pneumonitis (14%) and colitis (14%). Treatment-related deaths did not occur in this study. CONCLUSION: Platinum-combination chemotherapy with or without ICI for patients with postoperative recurrent NSCLC who previously received adjuvant platinum-doublet chemotherapy was effective and safe. In particular, this therapy may be promising for patients with longer DFS.

DOI： 10.1111/1759-7714.14992

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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：AME PUBLISHING COMPANY  

Background: Primary pulmonary choriocarcinoma (PPC) is a rare malignancy, and only 41 PPC cases have been reported in males up to 2021. Due to its rarity, no standardized treatments for PPC have been established. Cytotoxic chemotherapy has limited efficacy, and the prognosis of advanced PPC is notably poor. Immune checkpoint inhibitors (ICIs) are expected to provide long-term survival for PPC patients, but only a few cases have been reported. The optimal treatment for PPC has not been determined.Case Description: Here, we report a 72-year-old male with post-surgery relapsed PPC, presenting with multiple pulmonary nodules and an intracardiac mass. The OncomineTM Dx target test showed no mutation of cancer-relevant genes, and programmed death-ligand 1 (PD-L1) expression was negative (0%) in the 22C3 assay. He received a combination of carboplatin, paclitaxel, nivolumab, and ipilimumab which is widely used as a first-line treatment for advanced non-small-cell lung cancer (NSCLC). Two months after treatment began, computed tomography (CT) showed multiple lung nodules and an intracardiac mass reduction, which has been sustained for 12 months. Grade 3 febrile neutropenia and grade 2 rash were observed, however, these adverse events were manageable. Conclusions: This is the first case of postoperative relapse PPC that has been successfully treated with the combination of chemotherapy, nivolumab, and ipilimumab. This therapy may be a promising option for advanced PPC.

DOI： 10.21037/tcr-23-221

Web of Science

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Ferroptosis is an iron-dependent programmed cell death mode induced by the toxic buildup of phospholipid peroxidation. Although it is known to affect the initiation and growth of tumors, the association between ferroptosis-related genes (FRGs) and small cell lung cancer (SCLC) has yet to be established. METHODS: We used the gene expression omnibus (GEO) and ferroptosis database (FerrDb) to acquire information on SCLC and its associated FRGs. Marker genes were subsequently identified using Least Absolute Shrinkage and Selection Operator (LASSO) and support vector machine recursive feature eilmination (SVM-RFE) algorithms and analyzed for single-gene function and pathway enrichment. Using the drug-gene interaction database (DGIdb), we identified forty drugs targeting six marker genes. The competing endogenous RNA (ceRNA) network revealed the regulation pattern for long non-coding RNA (LncRNA)-microRNA (miRNA)-messenger RNA (mRNA) based on marker genes. RESULTS: Six differentially expressed FRGs (ATG3, MUC1, RRM2, IDH2, PARP1, and EZH2) were identified as marker genes with accurate diagnostic capabilities. According to single-gene function and pathway enrichment analyses, these marker genes may be involved in immunomodulation and the cell cycle, as well as numerous pathways connected to tumorigenesis, including the JAK-STAT and PPAR signal pathways. In addition, CIBERSORT analysis showed that MUC1 and PARP1 expression may affect the immune microenvironment in SCLC. CONCLUSIONS: We confirmed the accuracy of marker genes for the diagnosis of SCLC using a logistic regression model, thus providing further opportunities to study SCLC-related mechanisms. The accuracy of these results for the diagnosis of SCLC must now be confirmed by further research prior to clinical application.

DOI： 10.31083/j.fbl2806125

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Soluble interleukin-2 receptor (sIL-2R) suppresses effector T-cells. Few studies have assessed serum sIL-2R in patients receiving immunotherapy. We evaluated the association between serum sIL-2R levels and the efficacy of anti-programmed cell death 1/ programmed death-ligand 1 (anti-PD-1/PD-L1) antibody combined with chemotherapy in non-small cell lung cancer (NSCLC) patients. We prospectively enrolled NSCLC patients who received anti-PD-1/PD-L1 antibody combined with platinum-based chemotherapy between 8/2019 and 8/2020 and measured their serum sIL-2R. The patients were divided into high and low sIL-2R groups based on the median of sIL-2R levels at pretreatment. Progression-free survival (PFS) and overall survival (OS) of patients in the high and low sIL-2R groups were compared. The Kaplan-Meier curves of PFS and OS were evaluated using the log-rank test. The multivariate analysis of PFS and OS was performed using the Cox proportional hazard models. Among 54 patients (median age 65, range 34-84), 39 were male and 43 had non-squamous cell carcinoma. The sIL-2R cut-off value was 533 U/mL. Median PFS was 5.1 months (95% CI, 1.8-7.5 months) and 10.1 months (95% CI, 8.3-not reached [NR] months) in the high and low sIL-2R groups (P = 0.007), respectively. Median OS was 10.3 months (95% CI, 4.0-NR months) and NR (95% CI, 10.3-NR months) in the high and low sIL-2R groups (P = 0.005), respectively. Multivariate Cox regression analysis showed that high sIL-2R was significantly associated with shorter PFS and OS. SIL-2R may be a biomarker for the poor efficacy of anti-PD-1/PD-L1 antibody combined with chemotherapy.

DOI： 10.1007/s10637-023-01358-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Platinum-based combination therapy plus a programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitor is a standard treatment for patients with stage IV non-small cell lung cancer. However, necitumumab is used with gemcitabine and cisplatin as a first-line treatment option for squamous cell lung cancer (SqCLC). Furthermore, the combination of necitumumab with immune checkpoint inhibitors has the potential to enhance tumor immunity and improve the therapeutic effect. Thus, we planned and initiated this phase I/II study to evaluate the safety and efficacy of necitumumab plus pembrolizumab, nanoparticle albumin-bound (nab)-paclitaxel), and carboplatin therapy for patients with previously untreated SqCLC. PATIENTS AND METHODS: In phase I, the primary endpoint is the tolerability and recommended dose of necitumumab combined with pembrolizumab plus nab-paclitaxel and carboplatin. In phase II, the primary endpoint is the overall response rate. Secondary endpoints are disease control rate, progression-free survival, overall survival, and safety. Forty-two patients will be enrolled in phase II. CONCLUSION: This is the first study to investigate the efficacy and safety of necitumumab plus pembrolizumab combined with platinum-based chemotherapy in patients with previously untreated SqCLC.

DOI： 10.1016/j.cllc.2023.01.008

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: The efficacy and safety of atezolizumab in previously treated patients with NSCLC have been established in the registrational phase 3 OAK trial. In this study, we evaluated the effectiveness and safety of atezolizumab monotherapy in a large real-world cohort to confirm the reproducibility of the results of the registrational trial. METHODS: This was a multicenter, prospective, single-arm observational study. Consecutive patients with previously treated NSCLC scheduled to receive atezolizumab monotherapy were enrolled. The primary end point was the 18-month overall survival (OS) rate. The incidence of adverse events (AEs) and immune-related AEs was evaluated. RESULTS: Overall, 1002 patients were included in the safety analysis set and 1000 in the full analysis set. Median follow-up was 11.5 months. Of the full analysis set, 62% were ineligible for the OAK trial (OAK-unlike subpopulation). The 18-month OS rate was 41.1%, with a median OS of 13.0 months (95% confidence interval: 12.2-15.1). The 18-month OS rate was 49.4% and 36.1% in OAK-like and OAK-unlike subpopulations, respectively; that in patients with Eastern Cooperative Oncology Group performance status greater than or equal to 2 was 14.3%. The incidence of AEs overall, in the OAK-like, and OAK-unlike subpopulations was 43.9%, 46.2%, and 42.5%; that of immune-related AEs was 19.0%, 20.1%, and 18.3%, respectively. CONCLUSIONS: The findings suggest that atezolizumab may be effective and safe for previously treated patients with NSCLC in real-world settings; however, atezolizumab administration should be considered carefully regarding the benefit-risk balance for the OAK-unlike subpopulation, especially in patients with Eastern Cooperative Oncology Group performance status greater than or equal to 2.

DOI： 10.1016/j.jtocrr.2023.100484

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Nab-paclitaxel (nab-PTX) has better transfer to tumor tissue than cremophor-based paclitaxel. It suggests that the optimum dose of nab-PTX might be lower than the dose and schedule that is widely used. We designed a randomized phase II trial to examine the clinical utility and safety of nab-PTX in patients with previously treated advanced non-small cell lung cancer (NSCLC). METHODS: Patients were randomly allocated (1:1) to receive nab-PTX monotherapy at 100 mg/m2 (group A) or 70 mg/m2 (group B). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: Finally, 81 patients were randomized. Similar results were observed in both groups for PFS (3.75 vs. 3.71 months), OS (13.50 vs. 16.13 months), or ORR (20.5% vs. 23.1%). The incidences of grade 3 or worse AEs were 57.5% in group A and 41.5% in group B. The proportion of serious side effects was 10.0% in group A and 4.9% in group B. CONCLUSION: Both standard dose and low dose of nab-PTX monotherapy are active for previously treated NSCLC patients with better safety profile. Therefore, nab-PTX 70 mg/m2 dose and schedule in the trial would be a reasonable option.

DOI： 10.1002/cam4.5652

PubMed

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担当区分：最終著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Adenoid cystic carcinoma (ACC) is a rare type of malignant tracheal tumor originating from the secretory glands. Complete surgical resection is the current standard of care for tracheal ACC. However, there have been few case reports of chemoradiotherapy for unresectable tracheal ACC. We herein report a 28-year-old man with unresectable tracheal ACC who received concurrent chemoradiotherapy (CCRT) followed by maintenance therapy with durvalumab. CCRT was completed with a good response and safety, and the patient is currently receiving durvalumab as maintenance therapy. Durvalumab after CCRT can be a treatment option for patients with unresectable tracheal ACC.

DOI： 10.2169/internalmedicine.1142-22

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The anticancer function of superoxide dismutases (SODs) is still controversial. Removing superoxide and/or producing oxygen and hydrogen peroxide exhibits both pro- and anti-tumor effects. SOD3 is an extracellular superoxide dismutase and contains a single N-glycan chain. Although we reported previously that the N-glycosylation of SOD3 was essential for its secretion, the role played by the N-glycosylation of SOD3, as it relates to lung cancer, is poorly understood. We report herein that the fucose structure of the N-glycan in SOD3 was increased in the sera of patients with lung cancer. In cell lines of non-small lung cancer cell (NSCLC), we also found a high level of the core fucose structure in the N-glycan of SOD3, as determined by lectin blotting and mass spectrometry analysis. To address the roles of the core fucose structure of SOD3, we generated FUT8 (α1,6-fucosyltransferase) gene knockout A549 cells. Using these cells, we found that the core fucose structure of SOD3 was required for its secretion and enzymatic activity, which contributes to the suppression of cell growth of NSCLC cells. These data demonstrate that N-glycans, especially those with core fucose structures, regulate the anti-tumor functions of SOD3 against NSCLC.

DOI： 10.1089/ars.2022.0010

PubMed

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Versatile biomarkers for immune checkpoint inhibitors (ICI) efficacy in patients with cancer remain to be identified. Liquid biopsy using serum-derived exosomal microRNAs (miRNAs) are widely investigated as diagnostic and therapeutic outcome predictors in patients with cancer. However, exosomal miRNAs linked to the response to ICI in patients with non-small cell lung cancer (NSCLC) remain elusive thus far. METHODS: The value of serum-derived exosomal miRNAs in predicting the effect of anti-programmed cell death-1 (PD-1)/anti-programmed cell death-ligand 1 (PD-L1) monotherapy in 41 patients with advanced NSCLC was assessed. We performed functional analysis of candidate miRNAs using NSCLC cell lines. RESULTS: Exosomal miR-125a-3p was associated with response to treatment with ICI. Exosomal miR-125a-3p was more useful in predicting response to ICI versus tumoral PD-L1 in patients with low PD-L1 expression (≤50%). Moreover, high expression of miR-125a-3p was associated with worse progression-free and overall survival. In H1975 and H441 cells, induction of miR-125a-3p regulated PD-L1 expression via suppression of neuregulin 1 (NRG1). CONCLUSIONS: Exosomal miR-125a-3p is a potential predictor of response to anti-PD-1/PD-L1 therapy in advanced NSCLC patients with low PD-L1 expression.

DOI： 10.1016/j.gene.2023.147177

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Eosinophilic bronchiolitis is a disease concept reported in Japan in 2001, that presents with bronchiolitis accompanied by eosinophilia in the blood and lungs. In 2013, hypereosinophilic obliterative bronchiolitis, as a group of disease presenting with eosinophilic bronchiolitis, was proposed in France. The relationship between eosinophilic bronchiolitis and other eosinophil-related diseases has not been clarified. Herein, we report the case of a 56-year-old female patient with eosinophilic bronchiolitis without asthma, which developed into eosinophilic pneumonia. Treatment with oral prednisone improved the respiratory function. According to the clinicopathological findings in this case, eosinophilic bronchiolitis may be a different disease from asthma.

DOI： 10.1016/j.rmcr.2023.101901

Scopus

PubMed

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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担当区分：最終著者   記述言語：英語  

Alectinib is a selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor as standard therapy for ALK-rearranged non-small cell lung cancer (NSCLC). Hemolytic anemia is considered as a rare but significant adverse event with alectinib. Here, we report a case of a 73-year-old female with lung adenocarcinoma, harbouring an ALK fusion gene, who received alectinib as second-line therapy and developed gradually progressive grade 4 (6.4 g/dL) drug-induced hemolytic anemia (DIHA) after complete response. We discontinued alectinib and performed a blood transfusion for the severe anemia. The anemia improved with no recurrence of lung adenocarcinoma over 10 months. Regular hematologic monitoring and the possibility of DIHA should be considered in case of progressive hemolytic anemia during alectinib treatment.

DOI： 10.2147/OTT.S398375

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Sarcoidosis is a multisystem disease with an unknown etiology and is characterized by the formation of noncaseating granulomas in the affected organs. We present the case of a 69-year-old male Japanese patient with bilateral hilar lymphadenopathy on chest radiographs for more than 10 years, left without further investigation. The patient reported no clinical symptoms. Chest computed tomography revealed ground-glass opacities and reticular shadows in both lungs, along with bilateral hilar and mediastinal lymphadenopathy. Lymphocytosis was observed in bronchoalveolar lavage fluid. Pathological examination of transbronchial lung biopsy revealed noncaseating, epithelioid granulomas congruous with sarcoidosis, together with other findings. There were no abnormalities on electrocardiogram, echocardiogram, and ophthalmic examination.For progressive dyspnea on exertion, systemic corticosteroid therapy with oral prednisolone (25 mg/day) was initiated in 2017 and gradually tapered. Despite this intervention, the decline in forced vital capacity (FVC) was accelerated. Three years later, the patient noticed swelling in his right wrist. Further investigation revealed elevated anti-cyclic citrullinated peptide antibodies and absence of noncaseating epithelioid granuloma on surgical biopsy, leading to the diagnosis of rheumatoid arthritis (RA). Thereafter, the anti-fibrotic agent nintedanib was initiated, because interstitial lung disease (ILD) was considered to have converted into a progressive fibrosing phenotype (PF-ILD) with overlapping RA-associated lung involvement. With treatment, the progression of decline in FVC was slowed, although home oxygen therapy was introduced.

DOI： 10.1177/17534666231158279

PubMed

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記述言語：英語  

Anaplastic lymphoma kinase-positive (ALK-positive) lung adenocarcinoma with multiple liver metastases accounts for a relatively small number of cases of non-small cell lung cancer. Several ALK-tyrosine kinase inhibitors (ALK-TKIs) are available for the treatment of lung cancer. However, there is limited evidence on the treatment of multiple liver metastases in patients with lung cancer that are refractory to ALK-TKIs. We report the case of a 42-year-old male patient with ALK-positive lung adenocarcinoma who experienced rapid progression to multiple liver metastases while receiving treatment with alectinib. Biopsy of the liver metastases revealed echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) fusion and tumor protein p53 (TP53) mutation; notably, ALK secondary mutations were not detected. Despite the sequential administration of third-generation ALK-TKIs, the liver metastases did not respond, the serum levels of total bilirubin and biliary enzymes continued to increase, and the patient's general appearance worsened. Finally, the patient exhibited a remarkable clinical response to treatment with a combination of atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP). ABCP is one of the optimal options for ALK-positive lung cancer with liver metastasis that is refractory to ALK-TKIs therapy.

DOI： 10.2147/OTT.S404035

PubMed

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記述言語：英語  

We present a case of a drug-induced sarcoidosis-like reaction (DISR) in a 34-year-old female patient who had been receiving dupilumab for eosinophilic rhinosinusitis, for seven months. Computerized tomography scans revealed multiple lymphadenopathies, and biopsies performed on the lung and skin lesions showed the presence of non-caseating granulomas. The patient's serum levels of soluble interleukin-2 receptor and angiotensin-converting enzyme were elevated. There were no findings of Mycobacterium spp, or any other bacterial infections. Based on these findings, it was suspected that the sarcoidosis-like reaction observed in this patient was caused by dupilumab. Switching the patient's treatment from dupilumab to mepolizumab improved the DISR.

DOI： 10.1016/j.rmcr.2023.101883

PubMed

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記述言語：英語  

Pulmonary involvement associated with inflammatory bowel disease (IBD) are a rare extraintestinal manifestation (EIM) of inflammatory bowel disease (IBD), we herein presented two cases. Case 1: 53-year-old man with Crohn's disease treated with mesalazine and azathioprine. Pulmonary nodular shadows were incidentally detected on chest imaging, and revealed granulomas through transbronchial lung biopsy. Case 2: 68-year-old man with ulcerative colitis treated with mesalazine. He presented with fever and respiratory symptoms, and chest imaging showed multiple nodular infiltrates. He was diagnosed with organizing pneumonia by lung biopsy. Both cases were diagnosed to have pulmonary involvement associated with inflammatory bowel disease (IBD) according to multidisciplinary examination including positron emission tomography-computed tomography (FDG-PET) and pathological test. Pulmonary manifestations with IBD may not always require discontinuation of drugs or additional use of steroids or immunosuppressants.

DOI： 10.1016/j.rmcr.2023.101914

PubMed

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: Pembrolizumab is a programmed death-ligand 1 inhibitor that was initially indicated for monotherapy in patients with advanced lung cancer. The Japanese Lung Cancer Society conducted an observational study on pembrolizumab using confirmative data obtained through postmarketing all-case surveillance (PMACS), which was performed by a pharmaceutical company under the Japanese law in 2017. Methods: This multicenter observational study was conducted by the Japanese Lung Cancer Society using PMACS data with the newly created central registration system regarding patients with NSCLC who received pembrolizumab monotherapy between February 1, 2017 and June 30, 2017; a new database was created by adding the clinical information regarding prognosis for 3 years after therapy to the existing data collected by PMACS. Results: A total of 300 patients from 43 facilities were enrolled in this study. The median overall survival and progression-free survival after pembrolizumab initiation were 558 and 188 days, respectively. Moreover, the 1- and 3-year survival rates were 58.9% and 33.7%, respectively. Results of multivariate analysis revealed performance status (p < 0.0001), histology (p = 0.0118), previous chemotherapy (p = 0.0007), programmed death-ligand 1 expression status (p = 0.0195), and previous steroid use (p = 0.0460) as significant factors that affected overall survival. The toxicity profile was similar to that previously reported. Conclusions: In this first attempt to use PMACS data, we successfully collected clinical information and found the real-world efficacy and safety of pembrolizumab.

DOI： 10.1016/j.jtocrr.2022.100404

PubMed

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(公社)日本生化学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：特定非営利活動法人 日本肺癌学会  

背景．免疫チェックポイント阻害薬によるpseudo-progressionは非小細胞肺癌患者の約5%にみられるが，免疫チェックポイント阻害薬単剤における報告がほとんどである．今回，ニボルマブ＋イピリムマブ併用療法後に胸膜炎様のpseudo-progressionを認めた肺腺癌の1例を経験した．症例．70歳，男性．胸膜播種を伴う肺腺癌pT3N0M1a stage IVAに対し1次治療としてカルボプラチン＋ペメトレキセド＋ニボルマブ＋イピリムマブを投与した．投与後から発熱，呼吸困難，CRPの上昇，患側胸水の増加を認めた．胸水ドレナージを行い，セルブロック標本でCD4陽性T細胞を主体とした豊富なリンパ球の滲出を認めた．その後症状が軽快し，化学療法継続下で胸水の再貯留を認めていないことから，免疫関連有害事象ではなく，pseudo-progressionと診断した．結論．本症例はニボルマブ＋イピリムマブ併用療法後に胸膜炎様のpseudo-progressionを認めた肺癌における初めての報告である．免疫関連有害事象による胸膜炎との鑑別が重要である．

DOI： 10.2482/haigan.62.400

CiNii Research

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：日本サルコイドーシス  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

RATIONALE: Black pleural effusion is a rare medical condition and a diagnostic marker. Pancreaticopleural fistula is one of the causes of black pleural effusion. Thus far, black pleural effusions caused by pancreaticopleural fistulae have mostly been reported in patients with alcohol-induced chronic pancreatitis. In this report, we present a case of black pleural effusion caused by a pancreaticopleural fistula associated with autoimmune pancreatitis. PATIENT CONCERNS AND DIAGNOSIS: A 59-year-old female without a history of alcohol drinking presented to our hospital with a chief complaint of dyspnea, as well as chest and back discomfort. She had left pleural effusion, and thoracentesis showed black pleural effusion. Computed tomography revealed the presence of encapsulated fluid from the pancreatic tail to the left pleural cavity, which was diagnosed as a pancreaticopleural fistula. It also showed diffuse pancreatic swelling. Serum testing showed a high IgG4 level (363 mg/dL). These findings led to the diagnosis of autoimmune pancreatitis. INTERVENTIONS AND OUTCOME: The patient underwent endoscopic pancreatic sphincterotomy and pancreatic duct stent placement and received treatment with steroids. After treatment, there was no further accumulation of pleural effusion observed. CONCLUSION: This is the first report of black pleural effusion due to a pancreaticopleural fistula associated with autoimmune pancreatitis. The characteristic appearance of black pleural effusion may assist diagnosis. We report this case to emphasize that autoimmune pancreatitis can be a cause of black pleural effusion.

DOI： 10.1097/MD.0000000000030322

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Surgical treatment is the best curative treatment option for patients with non-small cell lung cancer (NSCLC), but some patients have recurrence beyond the surgical margin even after receiving curative surgery. Therefore, therapies with anti-cancer agents also play an important role perioperatively. In this paper, we review the current status of adjuvant chemotherapy in NSCLC and describe promising perioperative therapies, including molecularly targeted therapies and immune checkpoint inhibitors. Previously reported biomarkers of adjuvant chemotherapy for NSCLC are discussed along with their limitations. Adjuvant chemotherapy after resective surgery was most effective in patients with metastatic lesions located just outside the surgical margin; in addition, these metastatic lesions were the most sensitive to adjuvant chemotherapy. Thus, the first step in predicting patients who have sensitivity to adjuvant therapies is to perform a qualified evaluation of metastatic ability using markers such as actinin-4 (ACTN4). In this review, we discuss the potential use of biomarkers in patient stratification for effective adjuvant chemotherapy and, in particular, the use of ACTN4 as a possible biomarker for NSCLC.

DOI： 10.3390/cancers14184363

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection.

DOI： 10.1038/s41467-022-32276-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: The addition of cytotoxic chemotherapy to immune checkpoint inhibitor (ICI) may enhance anti-tumor effects. We conducted an open-label randomized phase II/III study to evaluate nivolumab + docetaxel combination therapy in comparison to nivolumab monotherapy for previously treated ICI-naïve non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: The primary endpoint of the phase III study was overall survival (OS), and the secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and toxicity. Since ICI and platinum-doublet combination chemotherapy was approved in the first-line setting during this study, patient accrual was discontinued. RESULTS: One hundred twenty-eight patients (each arm, n=64) were included in the full analysis set (FAS). The median OS in the nivolumab (arm A) and nivolumab+docetaxel (arm B) was 14.7 months (95%CI, 11.4-18.7) and 23.1 months (95%CI, 16.7-NR). The HR for OS was 0.63 (90%CI, 0.42-0.95; p=0.0310). The median PFS in the arm A and arm B was 3.1 months (95%CI, 2.0-3.9) and 6.7 months (95%CI, 3.8-9.4). The HR for progression was 0.58 (95%CI, 0.39-0.88; p=0.0095). The ORR was 14.0% (95%CI, 6.3-25.8) in arm A, and 41.8% (95%CI, 28.7-55.9) in arm B. Hematotoxicity and gastrointestinal adverse events were more common in arm B than in arm A. Two treatment-related deaths were observed, including one patient in arm A who died of pneumonitis, and one in arm B who died of myocarditis. CONCLUSIONS: Despite the slightly elevated toxicity, the addition of docetaxel to nivolumab has significantly prolonged the OS and PFS of patients with previously treated ICI-naïve NSCLC.

DOI： 10.1158/1078-0432.CCR-22-1687

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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 coprimary 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.In a randomized, open-label, phase III NEJ009 study, gefitinib plus chemotherapy significantly improved progression-free survival (PFS) and overall survival (OS) compared with gefitinib-alone in patients with untreated non-small-cell lung cancer harboring mutations in epidermal growth factor receptor. Herein, we report the updated survival outcome and long-term tolerability. Patients were randomly assigned to gefitinib (gefitinib 250 mg orally, once daily) and gefitinib combined with carboplatin plus pemetrexed (GCP in a 3-week cycle for six cycles followed by concurrent gefitinib and pemetrexed maintenance) groups. At the data cutoff (May 22, 2020), GCP demonstrated significantly better PFS2 (hazard ratio, 0.77; 95% CI, 0.62 to 0.97; P = .027) than gefitinib. However, the updated median OS was 38.5 months (95% CI, 31.1 to 47.1) and 49.0 months (95% CI, 41.8 to 56.7) in the gefitinib and GCP groups, respectively (hazard ratio, 0.82; 95% CI, 0.64 to 1.06; P = .127). The OS in both groups was similar for the overall patient population. No severe adverse events occurred since the first report. This updated analysis revealed that the GCP regimen improved PFS and PFS2 with an acceptable safety profile compared with gefitinib-alone. GCP is more efficient than gefitinib monotherapy as a first-line treatment for non-small-cell lung cancer with epidermal growth factor receptor mutations.

DOI： 10.1200/JCO.21.02911

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Identifying the factors underlying severe COVID-19 in the host genetics is an emerging issue1-5. We conducted a genome-wide association study (GWAS) involving 2,393 Japanese COVID-19 cases collected in initial pandemic waves with 3,289 controls, which identified a variant on 5q35 (rs60200309-A) near DOCK2 associated with severe COVID-19 in younger (<65 ages) patients (nCase=440, odds ratio=2.01, P=1.2×10-8). This risk allele was prevalent in East Asians but rare in Europeans, showing a value of non-European GWAS. RNA-seq of 473 bulk peripheral blood identified decreasing effect of the risk allele on DOCK2 expression in younger patients. DOCK2 expression was suppressed in severe forms of COVID-19. Single cell RNA-seq analysis (n=61) identified cell type-specific downregulation of DOCK2 and COVID-19-specific decreasing effects of the risk allele on DOCK2 in non-classical monocytes. Immunohistochemistry of lung specimens from severe COVID-19 pneumonia showed suppressed DOCK2. Moreover, inhibition of DOCK2 function using CPYPP induced much more severe pneumonia in a Syrian hamster model of SARS-CoV-2 infection characterized as weight loss, lung edema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 plays an important role in the host immune response to SARS-CoV-2 infection and development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.

DOI： 10.1038/s41586-022-05163-5

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担当区分：最終著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Malignant tumors are the major cause of death in hemodialysis patients. Management of these patients remains challenging as there is no evidence that chemotherapy is beneficial, and a lack of information about actual clinical practice. METHODS: This multicenter retrospective study included hemodialysis patients who were diagnosed with lung cancer from January 2002 to June 2018. We reviewed their clinical information including patient characteristics associated with lung cancer and end-stage renal disease, regimen, efficacy and safety of chemotherapy, and outcomes. RESULTS: A total of 162 patients from 22 institutions in Japan were registered. Of 158 eligible patients, 91 received chemotherapy (80 as palliative chemotherapy and 11 as chemoradiotherapy) and 67 received best supportive care only regardless of cancer stage. In small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) patients who received cytotoxic chemotherapy, the objective response rates (ORR) and median overall survival (OS) were 68.1 %, 12.3 months and 37.0 %, 8.5 months, respectively. The ORR and median OS in patients with EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors (TKI) were 44.4 % and 38.6 months. The treatment-related adverse events (Grade 3 or higher) induced by cytotoxic chemotherapy were myelosuppression and febrile neutropenia; treatment-related death (TRD) was observed in one patient. TRD occurred in 3 of 18 patients who received EGFR-TKI. CONCLUSION: Chemotherapy should be considered for hemodialysis patients with EGFR-mutant NSCLC and SCLC. However, the survival benefits of chemotherapy for NSCLC patients with EGFR-wild type are unclear; physicians should carefully consider whether to offer chemotherapy to this patient subset.

DOI： 10.1016/j.lungcan.2022.07.009

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

症例は23歳女性。シェーグレン症候群に対して免疫抑制薬を長期内服中であった。2ヵ月前から倦怠感、発熱、腰痛を認め、全身精査で肺野に活動性病変を認めず、全身リンパ節、骨、皮下、腹膜、腸管に多彩な病変を認めた。インターフェロンγ遊離試験(interferon gamma release assay:IGRA)は陰性であった。縦隔リンパ節生検から結核菌が培養され、播種性結核と診断した。免疫抑制宿主において、複数の病変を認める際は、IGRAが陰性で活動性肺病変を認めない場合でも、播種性結核を念頭におく必要がある。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

症例は23歳女性。シェーグレン症候群に対して免疫抑制薬を長期内服中であった。2ヵ月前から倦怠感、発熱、腰痛を認め、全身精査で肺野に活動性病変を認めず、全身リンパ節、骨、皮下、腹膜、腸管に多彩な病変を認めた。インターフェロンγ遊離試験(interferon gamma release assay:IGRA)は陰性であった。縦隔リンパ節生検から結核菌が培養され、播種性結核と診断した。免疫抑制宿主において、複数の病変を認める際は、IGRAが陰性で活動性肺病変を認めない場合でも、播種性結核を念頭におく必要がある。(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Some of the most common causes of chronic cough include cough variant asthma (CVA), bronchial asthma (BA), and asthma-COPD overlap (ACO). Although there is some overlap in the etiology of these diseases, it is clinically important to attempt an early differential diagnosis due to treatment strategies and prognoses. Spirometry and impulse oscillometry (IOS) before and after bronchodilator inhalation were analyzed for clinically diagnosed CVA (cCVA, n = 203), BA (cBA, n = 222), and ACO (cACO, n = 61).A significant difference in ΔFEV1 was observed between cBA and cCVA (ΔFEV1 improvement of 122.5 mL/5.4% and 65.7mL/2.2%, respectively), but no difference was observed in ΔPEF, ΔV50, or ΔV25. Except for R20 (resistance at 20 Hz), significant differences between the three groups were observed in IOS. In IOS, cCVA and cBA showed comparable peripheral airway response to bronchodilator which was thought to be commensurate with changes in V50 and V25. cACO improved ΔFEV1 improvement of 81.0 mL/6.2% and was distinguished by a downward Xrs (respiratory system reactance) waveform with a limited bronchodilator response. FEV1/FVC, %FEV1, and %V25 had relatively strong correlations with the three IOS parameters, X5 (reactance at 5 Hz), Fres (resonant frequency), and ALX (low-frequency reactance area), in the correlation between IOS and spirometers.Changes in IOS parameters were more sensitive in this study than changes in FEV1 or the flow-volume curve. Considering the benefits and relevance of the two different tests, simultaneous IOS and spirometry testing were useful in the diagnosis of asthmatic cough.

DOI： 10.1080/02770903.2022.2094803

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Small cell lung cancer (SCLC) is a highly aggressive disease with a poor prognosis. Although most patients initially respond to topoisomerase inhibitors, resistance rapidly emerges. The aim, therefore, is to overcome resistance to topoisomerase I (irinotecan) or II (etoposide) inhibitors in SCLCs. METHODS: To identify key factors in the chemoresistance of SCLCs, we established four cell lines resistant to etoposide or an active metabolite of irinotecan, SN-38, from SCLC cell lines and evaluated RNA profiles using parental and newly established cell lines. RESULTS: We found that the drug efflux protein, ATP-binding cassette sub-family B member 1 (ABCB1), was associated with resistance to etoposide, and ATP-binding cassette sub-family G member 2 (ABCG2) was associated with resistance to SN-38 by RNA sequencing. The inhibition of ABCB1 or ABCG2 in each resistant cell line induced synergistic apoptotic activity and promoted drug sensitivity in resistant SCLC cells. The ABC transporter inhibitors, elacridar and tariquidar, restored sensitivity to etoposide or SN-38 in in vitro and in vivo studies, and promoted apoptotic activity and G2-M arrest in resistant SCLC cells. CONCLUSIONS: ABC transporter inhibitors may be a promising therapeutic strategy for the purpose of overcoming resistance to topoisomerase inhibitors in patients with SCLC.

DOI： 10.1111/1759-7714.14527

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記述言語：日本語   出版者・発行元：東邦大学医学会  

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記述言語：日本語   出版者・発行元：東邦大学医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Following COVID-19 vaccination, ipsilateral axillary and cervical lymphadenopathy may occur, called vaccine-related hypermetabolic lymphadenopathy, which is considered reactive lymphadenopathy. We report here a case of Kikuchi-Fujimoto disease, which occurred three months after vaccination with COVID-19 vaccine. The patient had cervical and axillary lymph node enlargement and a short-term fever that resolved spontaneously after the first and second vaccines. On the 90th day after the first vaccination, the patient developed a high fever and pathologically diagnosed necrotizing lymphadenitis in the axilla, which was diagnosed as Kikuchi-Fujimoto disease. Gallium scintigraphy showed localized swelling and strong uptake in the ipsilateral axilla. It implies the possibility of Kikuchi-Fujimoto Disease in axillary drainage lymph nodes in association with COVID-19 vaccine. Although only a few cases have been reported so far, this case is novel because of its later onset and diagnosis based on pathological and gallium scintigraphy imaging findings.

DOI： 10.1080/21645515.2022.2071080

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Research has shown that some microbiomes are linked to cancer. Hence, we hypothesize that alterations in the respiratory microbiome might be associated with lung cancer. METHODS: Through droplet digital polymerase chain reaction analysis, we investigated the abundance of Acidovorax in surgically resected primary tumors and corresponding nontumor lung tissues obtained from 50 Japanese patients with non-small cell lung cancer. RESULTS: The rate of positivity for Acidovorax in tumor and nontumor tissues was 44 and 26%, respectively. The abundance of Acidovorax in tumor tissues was significantly higher in patients with nonsquamous cell carcinoma complicated by chronic obstructive pulmonary disease (COPD) and those who relapsed after surgical resection (p < 0.05). In tumor tissues, the results of the univariate and multivariate analyses revealed that only COPD exerted a direct effect on the abundance of Acidovorax (p < 0.05). Furthermore, the presence of Acidovorax was high in lung cancer patients with COPD comorbidity (65%) and TP53 gene mutation; only one of the nontumor tissues was positive for Acidovorax. In patients with lung cancer complicated by COPD, Acidovorax tended to be present in both the tumor and nontumor areas. CONCLUSIONS: This study identified novel microbiota involved in lung cancer with COPD comorbidity. The results suggested that Acidovorax may be a useful biomarker in the screening for lung cancer. Further studies are warranted to validate the clinical significance of the microbiome in a larger independent patient cohort.

DOI： 10.1111/1759-7714.14463

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器内視鏡学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although corticosteroids are expected to be a candidate therapy for coronavirus disease 2019 (COVID-19) through the suppression of cytokine production, the efficacy in non-severe patients who do not require supplemental oxygen remains controversial. The aim of this study was to investigate the efficacy of corticosteroid therapy for non-severe patients. METHODS: We performed a retrospective observational study for 10 patients with non-severe COVID-19 who received corticosteroid therapy at our institute between July 1, 2020, and January 31, 2021. RESULTS: The median age of the 10 patients was 60 years, and nine patients were male. Nine of the 10 patients had multiple comorbid conditions (e.g., hypertension, diabetes and obesity). Although blood oxygen saturation was maintained above 95%, all patients showed persistent fever and deterioration of their chest imaging findings. Thus, we decided to initiate corticosteroid treatment. The median duration from the onset of symptoms to the initiation of corticosteroid therapy was eight days. All patients used dexamethasone (6 mg/day) as corticosteroid therapy, and the median period was 7.5 days. After the start of corticosteroid therapy, all patients showed a rapid clinical improvement, and no patients showed severe progression. CONCLUSION: The latest World Health Organization guidance recommends against corticosteroid treatment for non-severe patients. In this report, we showed that the early administration of corticosteroids during the non-critical phase, when oxygen supplementation is not required, was useful for the early improvement and prevention of severe disease in patients with risk factors for severe COVID-19 and worsening clinical symptoms.

DOI： 10.1272/jnms.JNMS.2022_89-409

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記述言語：英語  

Superior mesenteric artery (SMA) syndrome is a rare disease, characterized by the narrowing of the third portion of the duodenum between the aorta and SMA. The cause of the stenosis is a decrease in retroperitoneal fat between the aorta and SMA. In this report, we present two cases of SMA syndrome that occurred during chemotherapy for lung cancer. The first case was a 61-year-old male treated with nanoparticle albumin-bound-paclitaxel (nab-PTX) for lung adenocarcinoma. On day 23 of the first course of nab-PTX, he was admitted to our hospital due to vomiting and weight loss of 15.6 kg in 10 months. He was diagnosed with SMA syndrome through computed tomography, and drainage was performed using a nasogastric tube. Conservative treatment was successful, and the patient was able to continue therapy with nab-PTX. The second case was a 70-year-old male with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer. He was admitted to our hospital due to vomiting and dizziness while receiving treatment with pembrolizumab, as well as weight loss of 14.6 kg in 6 months. He was diagnosed with SMA syndrome using computed tomography. Conservative treatment using a nasogastric tube led to improvement, and the patient was able to continue treatment with pembrolizumab after discharge. This is the first report of SMA syndrome in patients with lung cancer undergoing chemotherapy with nab-PTX or pembrolizumab. Late diagnosis and treatment render SMA syndrome a potentially fatal disease. Vomiting and weight loss during chemotherapy are known treatment-related side effects; in patients developing these adverse effects, the presence of SMA syndrome should be suspected and managed appropriately.

DOI： 10.1007/s13691-022-00534-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Thymic carcinoma is a relatively rare type of malignant tumor. The present retrospective study evaluated the efficacy and safety of carboplatin plus nanoparticle albumin-bound paclitaxel for the treatment of advanced thymic carcinoma. The study included data from 12 patients with advanced thymic carcinoma treated in the Nippon Medical School Hospital (Tokyo, Japan). Response to treatment, patient survival and treatment safety were assessed. The objective response rate was 66.7% (8/12 patients). Disease control was achieved in 11 patients (91.7%). At the median follow-up time of 27.6 months (range, 6.2-75.1 months), the median progression-free survival and median first-line overall survival times were 16.7 months [95% confidence interval (CI), 13.2-37.7] and 14.3 months (95% CI, 4.7-54.6), respectively. There was no occurrence of febrile neutropenia or treatment-related death. The results of the present study showed that carboplatin plus nanoparticle albumin-bound paclitaxel was effective and safe. Therefore, it is a promising chemotherapy regimen for the treatment of advanced thymic carcinoma.

DOI： 10.3892/mco.2022.2520

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Synergistic effects of epidermal growth factor receptor tyrosine kinase inhibitors and chemotherapy have been reported. Here, we evaluated the therapeutic potential of combining osimertinib with pemetrexed and investigated the molecular mechanisms. MATERIALS AND METHODS: We analyzed the antitumor effects of osimertinib± pemetrexed in PC-9 and H1975 cells. Gene expression on exposure to osimertinib±pemetrexed was assessed in these cultured cells. Cell lines resistant to osimertinib±pemetrexed were established to explore mechanisms of resistance. RESULTS: Osimertinib+pemetrexed treatment delayed the emergence of resistance relative to monotherapy in vitro and in vivo. Expression of the anti-apoptotic gene PLK1 was down-regulated in PC-9 and H1975 exposed to osimertinib+ pemetrexed, whereas it was up-regulated in resistant cells. Furthermore, inhibition of PLK1 induced apoptosis and inhibited proliferation of resistant cells. CONCLUSION: Blocking PLK1 contributes to mediating the synergistic anti-proliferative effect of osimertinib+pemetrexed. PLK1 over-expression may be a critical mechanism for acquired resistance to osimertinib+pemetrexed.

DOI： 10.21873/anticanres.15529

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2022&ichushi_jid=J04260&link_issn=&doc_id=20220307420008&doc_link_id=10.1272%2Fmanms.18.47&url=https%3A%2F%2Fdoi.org%2F10.1272%2Fmanms.18.47&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Patients with uncommon EGFR-mutated non-small-cell lung cancer (NSCLC) demonstrated lower clinical efficacy of first-generation EGFR-tyrosine kinase inhibitors compared with patients harboring common EGFR-mutated NSCLC. The US FDA has approved afatinib for uncommon EGFR mutation positive NSCLC based on the pooled analysis in the first- or second-line setting. Osimertinib has limited evidence in the small sample sizes of phase 2 studies in any-line settings. The aim of the present single-arm, multicenter, phase 2 study is to evaluate the efficacy of osimertinib for previously untreated NSCLC. The primary end point is to assess the overall response to osimertinib. The secondary end points include disease control rate, progression-free survival, duration of time-to-treatment failure, overall survival and safety. Clinical trial registration: jRCTs071200002.

DOI： 10.2217/fon-2021-0892

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記述言語：英語  

Pembrolizumab is an immune checkpoint inhibitor (ICI) that targets programmed death-1. Although ICIs have shown efficacy in the treatment of lung cancer, they have also been reported to cause a variety of immune-related adverse events (irAEs). Hepatotoxicity is a known irAEs, but currently, there is not enough information on its pathological characteristics and treatment. We report the case of a 70-year-old man with advanced squamous-cell lung cancer who developed severe grade 4 hepatitis on day 8 after receiving carboplatin, nab-paclitaxel, and pembrolizumab as fourth-line therapy. We treated him with steroid therapy the day after a liver biopsy was performed to investigate his pathological features, which led to a rapid and remarkable improvement. Confirmation of immune-related hepatotoxicity by pathological findings allowed the early tapering and discontinuation of steroid therapy. Performing a liver biopsy and verifying histological characteristics are needed for successful treatment with short-term steroids when drug-induced hepatitis caused by anti-cancer therapy including pembrolizumab is considered.

DOI： 10.2147/OTT.S361467

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記述言語：英語  

A 59-year-old woman complaining of wet cough, hemoptysis, slight fever, anorexia, and malaise was admitted to hospital with suspected lobar pneumonia. She received treatment for myocardial infarction and deep venous thrombosis caused by familial protein C deficiency. Rapid deterioration due to respiratory failure occurred despite intensive care with broad-spectrum antibiotics. At a later date, sputum examination revealed the presence of Aspergillus niger. Based on clinical and autopsy findings, she was diagnosed with acute respiratory failure due to pulmonary aspergillosis with acute fibrinous and organizing pneumonia. This is the first reported case of pulmonary aspergillosis with acute fibrinous and organizing pneumonia complicated by calcium oxalate resulting from Aspergillus niger infection, leading to severe inflammation and tissue injury in the lungs.

DOI： 10.1016/j.rmcr.2022.101641

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To investigate histologic features of immunological components in the primary tumor site of patients with cancer-associated myositis (CAM) by focusing on tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs), which play major roles in antitumor immunity. METHODS: Cancer-associated myositis patients were selected from the single-center idiopathic inflammatory myopathy cohort based on the availability of primary tumor specimens obtained before the introduction of immunomodulatory agents. Control cancer subjects without CAM were selected from the cancer tissue repository at a ratio of 1:2 matched for demographics and cancer characteristics of CAM cases. A series of immunohistochemical analyses was conducted using sequential tumor sections. TLS was defined as an ectopic lymphoid-like structure composed of DC-LAMP+ mature dendritic cells, CD23+ follicular dendritic cells (FDCs) and PNAd+ high endothelial venules. TLS distribution was classified into the tumor center, invasive margin, and peritumoral area. RESULTS: Six CAM patients and 12 matched non-CAM controls were eligible for the study. There was no apparent difference in the density or distribution of TILs between the groups. TLSs were found in 3 CAM patients (50%) and 4 non-CAM controls (33%). TLSs were exclusively located at the tumor center or invasive margin in CAM cases but were mainly found in the peritumoral area in non-CAM controls. FDCs and class-switched B cells colocalized with follicular helper T cells were abundantly found in the germinal center-like area of TLSs from CAM patients compared with those from non-CAM controls. CONCLUSION: The adaptive immune response within TLSs in the primary tumor site might contribute to the pathogenic process of CAM.

DOI： 10.3389/fmed.2022.1066858

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: To evaluate the actual treatment patterns with respective outcomes and the patient characteristics of stage III non-small cell lung cancer (NSCLC) in Japan. MATERIALS AND METHODS: Patients (aged ≥20 years at diagnosis) who were diagnosed with stage III NSCLC between January 2013 and December 2014 and underwent surgery, chemoradiotherapy (CRT), chemotherapy (CT), or radiotherapy (RT) at 11 institutions in Japan were consecutively registered in this retrospective, observational study (SOLUTION; UMIN000031385). Study measures included patient characteristics, first-line treatments, overall survival (OS), progression-free survival, objective response rate, and incidence of radiation-related adverse events. RESULTS: The study population comprised 744 patients. The tumors were classified as stage IIIA and IIIB in 58.9% and 41.1% of patients, respectively. The tumors were considered resectable at diagnosis in 25.0% of patients. First-line treatments were surgery (20.0%), CRT (46.1%), CT (22.2%), and RT (11.7%). The median OS (mOS) in the overall population was 25.4 months and the 3-year OS rate was 38.7%. Among the four first-line treatment cohorts, OS most favored the surgery cohort: mOS was 43.4 months and the 3-year OS rate was 53.8%. Prognostic factors for OS in each treatment modality were analyzed using multivariable analysis and included the following: age, performance status, and histological type for the surgery cohort; sex, histological type, and primary lesion location (lower lobe) for the CRT cohort; and performance status and clinical stage for the RT cohort. The timing of peak incidence of pneumonitis from the start of first-line treatment was 18-20 and 12-14 weeks in the CRT and RT cohorts, respectively. CONCLUSION: Patients with clinical stage III NSCLC received a variety of treatments selected to the clinical background and tumor status, and we clarified the outcome and prognostic factors. These findings will be a useful reference for future studies evaluating newly introduced treatments for stage III NSCLC.

DOI： 10.1016/j.lungcan.2021.12.005

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/s2666-7568(21)00255-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although adjuvant tegafur/uracil (UFT) is recommended for patients with completely resected stage I non-small cell lung cancer (NSCLC) in Japan, only one-third of cases has received adjuvant chemotherapy according to real-world data. Therefore, robust predictive biomarkers for selecting adjuvant chemotherapy (ADJ) or observation (OBS) without ADJ are needed. Patients who underwent complete resection of stage I lung adenocarcinoma with or without adjuvant UFT were enrolled. The status of ACTN4 gene amplification was analyzed by fluorescence in situ hybridization (FISH). Statistical analyses to determine whether the status of ACTN4 gene amplification affected recurrence-free survival (RFS) were performed. Formalin-fixed, paraffin-embedded (FFPE) samples from 1,136 lung adenocarcinomas were submitted for analysis of ACTN4 gene amplification. Ninety-nine (8.9%) of 1114 cases were positive for ACTN4 gene amplification. In the subgroup analysis of patients ≥ 65 years, the ADJ group had better RFS than the OBS group in the ACTN4-positive cohort (HR: 0.084, 95% CI: 0.009, 0.806; P = 0.032). The difference in RFS between the ADJ group and the OBS group was not significant in ACTN4-negative cases (all ages, HR: 1.214, 95% CI: 0.848, 1.738; P = 0.289). Analyses of ACTN4 gene amplification contributed to the decision regarding postoperative adjuvant chemotherapy for stage I lung adenocarcinomas, preventing recurrence, improving the quality of medical care, preventing the unnecessary side effects of adjuvant chemotherapy, and saving medical costs.

DOI： 10.1111/cas.15228

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記述言語：日本語   出版者・発行元：金原出版(株)  

＜文献概要＞81歳,男性。肺腺癌の術後再発のため,上皮成長因子受容体に対するチロシンキナーゼ阻害薬であるアファチニブマレイン酸塩を投与されていた。投与開始3年後より四肢に紅斑を生じ,次第に両下腿に浮腫,多量の滲出液,潰瘍を生じるようになった。浮腫の原因となる心機能低下はなく,アファチニブマレイン酸塩による薬剤性浮腫による下腿潰瘍が考えられた。アファチニブマレイン酸塩を中止し,潰瘍治療および局所圧迫により下腿潰瘍は改善した。アファチニブマレイン酸塩内服中に難治性皮膚潰瘍をきたした場合は休薬を考慮する必要がある。

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01266&link_issn=&doc_id=20211122060025&doc_link_id=10.18888%2Fhi.0000002945&url=https%3A%2F%2Fdoi.org%2F10.18888%2Fhi.0000002945&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: To investigate the genomic profiles of patients with lung cancer with idiopathic pulmonary fibrosis (IPF-LC), mechanism of carcinogenesis, and potential therapeutic targets. Methods: We analyzed 29 matched, surgically resected, cancerous and noncancerous lung tissues (19 IPF-LC and 10 non-IPF-LC) by whole-exome sequencing and bioinformatics analysis and established a medical-engineering collaboration with the Department of Engineering of the Tokyo University of Science. Results: In IPF-LC, CADM1 and SPC25 were mutated at a frequency of 47% (9 of 19) and 53% (10 of 19), respectively. Approximately one-third of the IPF-LC cases (7 of 19; 36%) had both mutations. Pathway analysis revealed that these two genes are involved in transforming growth factor-β1 signaling. CADM1 and SPC25 gene mutations decreased the expression of CADM1 and increased that of SPC25 revealing transforming growth factor-β1-induced epithelial-to-mesenchymal transition and cell proliferation in lung cancer cells. Furthermore, treatment with paclitaxel and DNMT1 inhibitor suppressed SPC25 expression. Conclusions: CADM1 and SPC25 gene mutations may be novel diagnostic markers and therapeutic targets for IPF-LC.

DOI： 10.1016/j.jtocrr.2021.100232

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：日本医科大学医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background The role of inhaled corticosteroid (ICS) in chronic obstructive pulmonary disease (COPD) is unclear. Hence, this study aimed to evaluate the efficacy of ICS as an add-on to long-acting muscarinic antagonist (LAMA)/long-acting beta 2 agonist (LABA), which was assessed using the impulse oscillation system (IOS), in patients with COPD. Methodology We included patients with COPD whose treatment was changed from LAMA/LABA (≥four weeks) to ICS/LAMA/LABA between April 2019 and March 2021. To gain insight into the effect and safety of ICS-containing triple therapy for COPD, pulmonary function; Short-Form 36, St. George's Respiratory Questionnaire, COPD Assessment Test, and modified Medical Research Council scores; and airway resistance assessed using the IOS from one week before LAMA/LABA was switched to ICS/LAMA/LABA therapy until more than eight but less than twelve weeks after switching were evaluated. Results In total, 46 patients with COPD (mean age: 72.28 ± 7.81 years) were included in the study. None of the pulmonary function test parameters significantly changed from baseline values (mean difference in forced expiratory volume in one second [FEV1.0]: +0.032, P = 0.12; percentage FEV1.0 [FEV1.0%]/forced vital capacity [FVC]: -0.58, P = 0.42; and FVC: +0.087, P = 0.058). Meanwhile, the IOS showed that resonant frequency (mean difference from baseline: -2.12, P < 0.0001) and bodily pain scores in the St. George's Respiratory Questionnaire (mean difference: -7.03, P = 0.031) significantly decreased. Conclusions Switching from LAMA/LABA to ICS/LAMA/LABA therapy reduces airway elasticity-to-inertial resistance ratios, which may lead to structural airway improvements in patients with COPD.

DOI： 10.7759/cureus.19168

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The coronavirus disease (COVID-19) poses an urgent threat to global public health and is characterized by rapid disease progression even in mild cases. In this study, we investigated whether machine learning can be used to predict which patients will have a deteriorated condition and require oxygenation in asymptomatic or mild cases of COVID-19. METHODS: This single-center, retrospective, observational study included COVID-19 patients admitted to the hospital from February 1, 2020, to May 31, 2020, and who were either asymptomatic or presented with mild symptoms and did not require oxygen support on admission. Data on patient characteristics and vital signs were collected upon admission. We used seven machine learning algorithms, assessed their capability to predict exacerbation, and analyzed important influencing features using the best algorithm. RESULTS: In total, 210 patients were included in the study. Among them, 43 (19%) required oxygen therapy. Of all the models, the logistic regression model had the highest accuracy and precision. Logistic regression analysis showed that the model had an accuracy of 0.900, precision of 0.893, and recall of 0.605. The most important parameter for predictive capability was SpO2, followed by age, respiratory rate, and systolic blood pressure. CONCLUSION: In this study, we developed a machine learning model that can be used as a triage tool by clinicians to detect high-risk patients and disease progression earlier. Prospective validation studies are needed to verify the application of the tool in clinical practice.

DOI： 10.1272/jnms.JNMS.2022_89-210

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記述言語：日本語   出版者・発行元：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Bevacizumab is a promising candidate for combination treatment with epidermal growth factor receptor tyrosine-kinase inhibitors (eg, erlotinib), which could improve outcomes for patients with metastatic EGFR-mutant non-small-cell lung cancer (NSCLC). We have previously shown in NEJ026, a phase 3 trial, that the combination of bevacizumab plus erlotinib significantly prolonged progression-free survival compared with erlotinib alone in these patients. In further analyses, we aimed to examine the effects of bevacizumab-erlotinib on overall survival, time from enrolment to progressive disease during second-line treatment or death, and quality of life. METHODS: This open-label, randomised, multicentre, phase 3 trial (NEJ026) was done in 69 hospitals and medical, community-based centres across Japan. Eligible patients had stage IIIB, stage IV, or postoperative recurrent, EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg point mutation) NSCLC, had not previously received systemic chemotherapy, and were randomly assigned (1:1) by a computer-generated randomisation sequence and minimisation to receive either 150 mg oral erlotinib once daily plus 15 mg/kg intravenous bevacizumab once every 21 days, or 150 mg oral erlotinib once daily, until disease progression or intolerable toxicity. Randomisation was stratified according to sex, smoking status, EGFR mutation subtype, and clinical disease stage. All participants, investigators, and study personnel (including those assessing outcomes) were unmasked to treatment allocation. We report the secondary outcomes of overall survival and quality of life (the period from enrolment to confirmation of a minimally important difference on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-C30), and the exploratory outcome of time from enrolment to progressive disease during second-line treatment or death. Overall survival and the exploratory outcome were analysed in the modified intention-to-treat population, which comprised all randomly assigned patients who received at least one dose of the study drug and had response evaluations. Quality of life was analysed in patients in the modified intention-to-treat population who had completed the quality of life questionnaires. The trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, UMIN000017069, and the Japan Registry of Clinical Trials, jRCTs031180056, and is currently closed. FINDINGS: Between June 3, 2015, and Aug 31, 2016, 228 patients were enrolled. 112 patients who received bevacizumab-erlotinib and 112 who received erlotinib only were included in the modified intention-to-treat population. At data cutoff (Nov 30, 2019) and a median follow-up of 39·2 months (IQR 23·9-43·5), the median overall survival was 50·7 months (95% CI 37·3-not estimable [NE]) in the bevacizumab-erlotinib group and 46·2 months (38·2-NE) in the erlotinib-only group (hazard ratio [HR] 1·007, 95% CI 0·681-1·490; p=0·97). In analysis of the exploratory outcome, after a median follow-up of 23·9 months (IQR 14·2-39·1), the median time from enrolment to progressive disease during second-line treatment or death was 28·6 months (95% CI 22·1-35·9) in the bevacizumab-erlotinib group and 24·3 months (20·4-29·1) in the erlotinib-only group (HR 0·773, 95% CI 0·562-1·065). The median time between enrolment and confirmation of a minimally important difference on the EORTC QLQ-C30 was 6·0 months (95% CI 5·2-11·3) in the bevacizumab-erlotinib group and 8·3 months (5·7-13·9) in the erlotinib-only group (p=0·47). INTERPRETATION: The addition of bevacizumab to erlotinib did not prolong survival in patients with metastatic EGFR-mutant NSCLC, but both treatment groups had relatively long survival durations. Why the addition of bevacizumab to erlotinib did not affect overall survival is unclear, but it is possible that the beneficial effects of combination therapy were not seen because overall survival was influenced by treatment regimens used after disease progression. FUNDING: Chugai Pharmaceutical.

DOI： 10.1016/S2213-2600(21)00166-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Combination therapy, consisting of immune checkpoint inhibitors and traditional chemotherapeutic agents, has significantly improved the clinical outcomes of non-small cell lung cancer. Therefore, it will be a promising first-line therapy, whereas, there is a prospect that associated kidney injury may increase during treatment. We presented four patients, diagnosed with advanced non-small cell lung cancer, who received combination therapy, consisting of pembrolizumab, cisplatin, and pemetrexed as first-line treatment. All of them had been referred to nephrologists and had undergone renal biopsy. We observed that three of four patients presented a very rapid time course for acute kidney injury development. Notably, the three patients received only one or two cycles of the combined chemotherapy. In a renal biopsy, one patient showed severe acute tubular injury rather than interstitial nephritis. Another patient presented focal segmental glomerular sclerosis concomitant with tubulointerstitial nephritis. However, it was challenging to distinguish which agent was primarily responsible for kidney injury. Regarding the treatment, all the patients discontinued pembrolizumab and received corticosteroid treatment. We adjusted the dose and duration of corticosteroid according to the pathological results and patient conditions. The current cases provide a further understanding of clinical features and appropriate management in patients treated with combination therapy including pembrolizumab.

DOI： 10.1007/s13730-021-00636-4

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, the mechanisms of acquired drug resistance to osimertinib have not as yet been clarified. Exosomes and microRNAs (miRNAs) are involved in carcinogenesis and drug resistance in human cancers. METHODS: We used previously established osimertinib-resistant HCC827 (HCC827-OR) and PC-9 (PC-9-OR) cells. We evaluated the profiles of exosomal miRNA associated with resistance to osimertinib in EGFR-mutant NSCLC cells. RESULTS: Epithelial-mesenchymal transition (EMT) phenomenon was observed in HCC827-OR and PC-9-OR cells. Microarray and quantitative reverse transcription-polymerase chain reaction analysis revealed that miR-210-3p was co-upregulated in exosomes isolated from HCC827-OR and PC-9-OR cells compared with those isolated from parental HCC827 and PC-9 cells. HCC827-OR cell-derived exosomes induced EMT changes and resistance to osimertinib in HCC827 cells. Subsequently, the induction of miR-210-3p directly promoted the EMT phenomenon and resistance to osimertinib in HCC827 cells. CONCLUSIONS: Exosomal miR-210-3p may play a crucial role in resistance to osimertinib in the tumor microenvironment of EGFR-mutant NSCLC.

DOI： 10.1111/1759-7714.13943

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Pulmonary pleomorphic carcinoma (PPC) is a rare and aggressive tumor that is resistant to treatment. The expression and prognostic value of programmed cell death-ligand 1 (PD-L1) and its association with epithelial-mesenchymal transition (EMT) in PPC remains unclear. PATIENTS AND METHODS: The expression of PD-L1 and EMT markers, such as E-cadherin, vimentin, zinc finger E-box-binding homeobox 1 (ZEB-1), and cellular mesenchymal-epithelial transition (c-Met) was evaluated by immuno - histochemistry in 16 patients with PPC who underwent surgical resection. RESULTS: The expression of PD-L1 varied between carcinomatous and sarcomatous areas. Positive correlations between PD-L1 and vimentin expression in carcinomatous areas (r=0.668, p=0.005) and PD-L1 and ZEB-1 expression in sarcomatous areas (r=0.562, p=0.023) were found. High PD-L1 and ZEB-1 expression in sarcomatous areas predicted poor survival (p=0.045 and p=0.012, respectively). CONCLUSION: PD-L1 expression associated with ZEB1 expression in the sarcomatoid component of patients with PPC may be useful for predicting patient prognosis.

DOI： 10.21873/anticanres.15028

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

(1) Background: Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is an intractable problem for many clinical oncologists. The mechanisms of resistance to EGFR-TKIs are complex. Long non-coding RNAs (lncRNAs) may play an important role in cancer development and metastasis. However, the biological process between lncRNAs and drug resistance to EGFR-mutated lung cancer remains largely unknown. (2) Methods: Osimertinib- and afatinib-resistant EGFR-mutated lung cancer cells were established using a stepwise method. A microarray analysis of non-coding and coding RNAs was performed using parental and resistant EGFR-mutant non-small cell lung cancer (NSCLC) cells and evaluated by bioinformatics analysis through medical-industrial collaboration. (3) Results: Colorectal neoplasia differentially expressed (CRNDE) and DiGeorge syndrome critical region gene 5 (DGCR5) lncRNAs were highly expressed in EGFR-TKI-resistant cells by microarray analysis. RNA-protein binding analysis revealed eukaryotic translation initiation factor 4A3 (eIF4A3) bound in an overlapping manner to CRNDE and DGCR5. The CRNDE downregulates the expression of eIF4A3, mucin 1 (MUC1), and phospho-EGFR. Inhibition of CRNDE activated the eIF4A3/MUC1/EGFR signaling pathway and apoptotic activity, and restored sensitivity to EGFR-TKIs. (4) Conclusions: The results showed that CRNDE is associated with the development of resistance to EGFR-TKIs. CRNDE may be a novel therapeutic target to conquer EGFR-mutant NSCLC.

DOI： 10.3390/ijms22084005

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: The Renin-Angiotensin system (RAS) induces immunosuppression in the tumor microenvironment, and RAS inhibitors (RASi) improve the tumor immune microenvironment. We evaluated the impact of RASi on the efficacy anti-programmed cell death-1/Ligand-1 (anti-PD-1/PD-L1) antibodies. PATIENTS AND METHODS: This retrospective study analyzed non-small cell lung cancer (NSCLC) patients who received anti-PD-1/PD-L1 antibodies monotherapy as second- or later-line treatment. We classified patients into those with or without use of RASi. RESULTS: A total of 256 NSCLC patients were included and 37 patients used RASi. The median PFS of patients treated with RASi was significantly longer than that of patients treated without (HR=0.59, 95%CI=0.40-0.88). The median OS of patients treated with RASi tended to be longer than that of patients treated without (HR=0.71, 95%CI=0.45-1.11). CONCLUSION: The use of RASi was associated with a significantly longer PFS in NSCLC patients treated with anti-PD-1/PD-L1 antibodies. RASi use may enhance the efficacy of anti-PD-1/PD-L1 antibodies.

DOI： 10.21873/anticanres.14980

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein EML4-ALK in non-small cell lung cancer (NSCLC). The understanding of EML4-ALK function can be improved by a functional study using normal human cells. METHODS: Here we for the first time conduct such study to examine the effects of EML4-ALK on cell proliferation, cellular senescence, DNA damage, gene expression profiles and transformed phenotypes. RESULTS: The lentiviral expression of EML4-ALK in mortal, normal human fibroblasts caused, through its constitutive ALK kinase activity, an early induction of cellular senescence with accumulated DNA damage, upregulation of p16INK4A and p21WAF1, and senescence-associated β-galactosidase (SA-β-gal) activity. In contrast, when EML4-ALK was expressed in normal human fibroblasts transduced with telomerase reverse transcriptase (hTERT), which is activated in the vast majority of NSCLC, the cells showed accelerated proliferation and acquired anchorage-independent growth ability in soft-agar medium, without accumulated DNA damage, chromosome aberration, nor p53 mutation. EML4-ALK induced the phosphorylation of STAT3 in both mortal and hTERT-transduced cells, but RNA sequencing analysis suggested that the different signaling pathways contributed to the different phenotypic outcomes in these cells. While EML4-ALK also induced anchorage-independent growth in hTERT-immortalized human bronchial epithelial cells in vitro, the expression of EML4-ALK alone did not cause detectable in vivo tumorigenicity in immunodeficient mice. CONCLUSIONS: Our data indicate that the expression of hTERT is critical for EML4-ALK to manifest its in vitro transforming activity in human cells. This study provides the isogenic pairs of human cells with and without EML4-ALK expression.

DOI： 10.1186/s12885-021-07905-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: MET exon 14 skipping mutation, observed in 3-4% of non-small cell lung cancer (NSCLC), is emerging as a targetable alteration. In recent years, immune checkpoint inhibitors (ICI) have been effective in treating several NSCLCs. Our research aimed to investigate the characteristics of patients with NSCLCs harboring MET exon 14 mutations and their response to ICI in Japan. METHODS: Among the 1954 consecutive NSCLCs diagnosed at Saitama Cancer Center between 2010 and 2019, MET exon 14 skipping mutations were detected in 68 (3.5%) NSCLCs. We evaluated their characteristics such as programmed cell death ligand 1 (PD-L1) expression. RESULTS: Median age of patients with NSCLCs harboring MET exon 14 skipping mutations was 73 years. PD-L1 was highly expressed in 17 (70.8%) of the 24 patients examined. Seven patients received ICI monotherapy, and three out of seven had a remarkable treatment response, resulted in objective response rate (ORR) of 42.9% and progression-free survival of 24.7 months. Three patients with donor splice-site mutations showed a long-term treatment response, despite the fact that two with acceptor splice-site mutations demonstrated no response and experienced early disease progression with ICI monotherapy. CONCLUSION: Our results indicated that patients with NSCLCs harboring MET exon 14 mutations presented with a high rate of positive PD-L1 expression. ICI treatment showed a high ORR and long-term efficacy for NSCLCs harboring MET exon 14 mutations. Variants of MET exon 14 splice-site mutations may be associated with ICI response.

DOI： 10.1007/s10147-021-01893-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Pleural mesothelioma, a devastating asbestos-associated malignancy, urgently requires a novel effective therapy. Heat shock protein 70 (HSP70), which is synthesized in the cell response to protein damage, is expected to be a new target for antitumor treatment. In addition to its well-known protein refolding function, HSP70 regulates cell proliferation through different pathways, including PI3K/AKT/mTOR, and autophagy in malignant cells. In this study, we attempted to clarify the effects of VER-155008, an HSP70 inhibitor, on pleural mesothelioma. METHODS: Human pleural mesothelioma cell lines 211H, H2452 and H28 were cultured with VER-155008, and protein expression, cell proliferation, colony formation, cell cycle, synergistic effect with cisplatin, and autophagy induction were analyzed. RESULTS: In mesothelioma cell lines, VER-155008 (5.0 μM or more) inhibited cell growth and colony formation, accompanied by G1 cell cycle arrest. According to western blot analysis, VER-155008 reduced p-AKT expression. However, VER-155008 failed to show a synergistic effect with cisplatin on cell growth. Mesothelioma cells transfected with the novel plasmid pMRX-IP-GFP-LC3-RFP-LC3ΔG, which was developed for the quantitative and statistical estimation of macroautophagy, showed enhanced macroautophagy upon treatment with VER-155008 and gefitinib which is an EGFR-tyrosine kinase inhibitor. In addition, fetal bovine serum deprivation induced macroautophagy was further enhanced by VER-155008. CONCLUSIONS: On the basis of these results, functional HSP70 inhibition by VER-155008 suppressed cell growth in pleural mesothelioma cells, accompanied by enhanced macroautophagy. HSP70 inhibition is thus expected to become a new strategy for treating mesothelioma. KEY POINTS: Significant findings of the study In pleural mesothelioma cells, inhibition of HSP70 function by VER-155008 suppressed cell proliferation accompanied by induction of autophagy which was synergistically enhanced under the starvation condition, whereas gefitinib, an EGFR-TKI, did not show the same synergistic effect in autophagy. What this study adds The inhibition of HSP70 induced autophagy and suppressed cell proliferation in mesothelioma cells.

DOI： 10.1111/1759-7714.13784

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Idiopathic pulmonary fibrosis (IPF), a progressive disorder of unknown etiology, is characterized by pathological lung fibroblast activation and proliferation resulting in abnormal deposition of extracellular matrix proteins within the lung parenchyma. The pathophysiological roles of exosomal microRNAs in pulmonary fibrosis remain unclear; therefore, we aimed to identify and characterize fibrosis-responsive exosomal microRNAs. We used microRNA array analysis and profiled the expression of exosome-derived miRNA in sera of C57BL/6 mice exhibiting bleomycin-induced pulmonary fibrosis. The effect of microRNAs potentially involved in fibrosis was then evaluated in vivo and in vitro. The expression of exosomal microRNA-16 was increased by up to 8.0-fold on day 14 in bleomycin-treated mice, compared to vehicle-treated mice. MicroRNA-16 mimic administration on day 14 after bleomycin challenge ameliorated pulmonary fibrosis and suppressed lung and serum expression of secreted protein acidic and rich in cysteine (SPARC). Pretreatment of human lung fibroblasts with the microRNA-16 mimic decreased the expression of rapamycin-insensitive companion of mTOR (Rictor) and TGF-β1-induced expression of SPARC. This is the first study reporting the anti-fibrotic properties of microRNA-16 and demonstrating that these effects occur via the mTORC2 pathway. These findings support that microRNA-16 may be a promising therapeutic target for IPF.

DOI： 10.1016/j.yexcr.2020.112416

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記述言語：英語  

Antibody-drug conjugate (ADC) was novel type of anticancer drugs. Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2) targeting ADC, can be a novel treatment option for HER2 alternation (mutation, expression, amplification) advanced-stage non-small-cell lung cancer (NSCLC) from DESTINY-Lung01 result. Herein, we report a successful treatment with T-DXd for NSCLC harboring HER2 exon 20 insertion mutation in a patient with poor performance status (PS). We presented a case of a 52-year-old heavily pretreated female patient diagnosed with lung adenocarcinoma (cT1bN3M0, stage IIIB). After fifth-line pretreatment of systemic chemotherapy, primary tumor recurrence, pleural effusion, and miliary lung metastases were observed. The patient presented with hypoxia requiring oxygen therapy via nasal cannula at a flow rate of 4 L per minute, cancer pain, and cachexia requiring opioid treatment. Her Eastern Cooperative Oncology Group PS score was assessed 3. Comprehensive genomic profiling revealed HER2 exon 20 insertion mutation. After treatment with T-DXd was approved by the ethical review committee of Nippon Medical School Hospital, treatment was started. The tumor size decreased significantly, and her PS score decreased from 3 to 1, with improvement of hypoxia, cancer pain, and cachexia. The patient is still receiving treatment, without disease progression 6 months after starting treatment with T-DXd. Despite cases of poor PS, NGS should be performed and target therapy including ADCs should be considered.

DOI： 10.2147/OTT.S341290

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Metastasis is the primary cause of death in cancer patients, and its management is still a major challenge. Epithelial to mesenchymal transition (EMT) has been implicated in the process of cancer metastasis, and its pharmacological interference holds therapeutic promise. METHODS: Traf2- and Nck-interacting kinase (TNIK) functions as a transcriptional coregulator of Wnt target genes. Given the convergence of Wnt and transforming growth factor-β (TGFβ) signalling, we examined the effects of a small-molecule TNIK inhibitor (named NCB-0846) on the TGFβ1-induced EMT of lung cancer cells. RESULTS: NCB-0846 inhibited the TGFβ1-induced EMT of A549 cells. This inhibition was associated with inhibition of Sma- and Mad-Related Protein-2/3 (SMAD2/3) phosphorylation and nuclear translocation. NCB-0846 abolished the lung metastasis of TGFβ1-treated A549 cells injected into the tail veins of immunodeficient mice. The inhibition of EMT was mediated by suppression of the TGFβ receptor type-I (TGFBR1) gene, at least partly through the induction of microRNAs targeting the TGFBR1 transcript [miR-320 (a, b and d) and miR-186]. CONCLUSIONS: NCB-0846 pharmacologically blocks the TGFβ/SMAD signalling and EMT induction of lung cancer cells by transcriptionally downregulating TGFBRI expression, representing a potentially promising approach for prevention of metastasis in lung cancer patients.

DOI： 10.1038/s41416-020-01162-3

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記述言語：日本語   出版者・発行元：(一社)日本救急医学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is now a standard treatment of previously untreated EGFR-mutated advanced non-small-cell lung cancer (NSCLC). However, disease progression occurs within 19 months of treatment. In the NEJ009 study, gefitinib plus carboplatin plus pemetrexed demonstrated significantly better progression-free and overall survival compared with gefitinib monotherapy. Furthermore, the Lung Oncology Group in Kyushu and North East Japan Study Group, major clinical trial groups in Japan, conducted a randomized phase II study to evaluate the efficacy and safety of second-line osimertinib plus carboplatin plus pemetrexed versus osimertinib monotherapy for patients with disease progression during first-line EGFR tyrosine kinase inhibitor therapy and the EGFR T790M resistance mutation (TAKUMI trial; trial registration no., jRCTs071180062). In the first treatment course for the initial 24 patients, no safety issues were reported in the combination arm. Thus, we have planned this phase II study to evaluate the safety and preliminary efficacy of osimertinib plus cisplatin/carboplatin plus pemetrexed therapy for patients with previously untreated EGFR-mutated NSCLC. PATIENTS AND METHODS: A total of 66 patients will be enrolled, because this sample size will be adequate for assessing treatment safety and efficacy. The co-primary endpoints include safety and the objective response rate, and the secondary endpoints include the complete response rate, disease control rate, and progression-free survival. CONCLUSIONS: This is the first study to explore the efficacy and safety of osimertinib combined with platinum-based chemotherapy in previously untreated NSCLC patients with EGFR-sensitizing mutations. Our findings could provide valuable information for phase III studies such as FLAURA2 and for developing treatment strategies for EGFR-mutated NSCLC.

DOI： 10.1016/j.cllc.2020.09.023

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Measuring lung compliance is useful for evaluating interstitial lung disease (ILD) progression because reduced lung compliance by fibrosis progression is the main primary cause of decreased vital capacity. However, because of the invasiveness of the method, requiring the insertion of a balloon into the esophagus, lung compliance is rarely measured. A recently developed, possible method estimates intrathoracic pressure using fingertip photoplethysmography. This method non-invasively measures the lung dynamic compliance (Cdyn) by simultaneously measuring tidal volume. We evaluated the efficacy of this method in assessing ILD. METHODS: We conducted a single-center, observational cross-sectional study to evaluate the efficacy of this method in subjects with ILD as compared with that in healthy control subjects. The main outcome was the estimated Cdyn (eCdyn) determined using this method. We also evaluated potential confounding factors of eCdyn in the baseline characteristics. RESULTS: In the ILD group (n = 14) the median eCdyn was significantly lower than that in the control group (n = 49) (0.122 vs. 0.183; P = 0.011). In univariate regression analysis, eCdyn was significantly correlated with height, weight, forced vital capacity, forced expiratory volume in one second, diffusing capacity for carbon monoxide, and usual interstitial pneumonia (UIP). In multivariate regression analysis, both weight (β = 0.49, P = 0.011) and UIP (β = 0.52, P = 0.007) were significantly associated with eCdyn. CONCLUSIONS: We demonstrated a significant reduction in Cdyn in subjects with ILD using photoplethysmography. This non-invasive method might be a novel, promising tool for evaluating fibrosis progression in ILD.

DOI： 10.1272/jnms.JNMS.2021_88-411

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Osimertinib is the standard treatment for epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer. However, drug-induced interstitial lung disease (ILD) is recognized as a serious adverse event associated with EGFR-tyrosine kinase inhibitors (TKIs). We herein report a 78-year-old woman with stage IV lung adenocarcinoma harboring an EGFR L858R mutation on exon 21 who received rechallenge treatment with afatinib after osimertinib-induced ILD with an organizing pneumonia pattern. This is the first report of successful rechallenge with afatinib after osimertinib-induced ILD. Treatment with other EGFR-TKIs after osimertinib-induced ILD may be an option for subsequent therapy.

DOI： 10.2169/internalmedicine.5435-20

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The efficacy of anti-programmed cell death-1/ligand 1 antibody monotherapy (anti-PD-1/PD-L1 monotherapy) in patients with active brain metastases (BMs) is not established. Here, we aimed to evaluate the efficacy of anti-PD-1/PD-L1 monotherapy in non-small cell lung cancer (NSCLC) patients with active BMs. METHODS: This retrospective study included NSCLC patients treated with second-line or later-line anti-PD-1/PD-L1 monotherapy between December 2015 and August 2019. Patients were classified into those with or without active BMs, including symptomatic BMs requiring systemic steroids and untreated BMs. The progression-free survival (PFS) and overall survival (OS) of the patients with and without active BMs were compared. Intracranial and extracranial tumor responses were evaluated in patients with active BMs. RESULTS: We analyzed 197 patients who had received anti-PD-1/PD-L1 monotherapy. Among them, 24 had active BMs. Among those without active BMs, 145 had no BMs and 28 had treated asymptomatic BMs. The PFS and OS of patients with active BMs were significantly shorter than those of patients without active BMs (1.3 vs. 2.7 months; P < 0.001, and 4.5 vs. 16.3 months; P = 0.001 respectively). For patients with active BMs, the intracranial and extracranial response rates were 13.3% and 26.7%, respectively. On multivariate analysis, active BMs, poor performance status (PS), and EGFR/ALK positivity were significant factors associated with shorter PFS. Active BMs and poor PS were significant factors associated with shorter OS. CONCLUSIONS: This study suggested that anti-PD-1/PD-L1 monotherapy was not effective for NSCLC patients with active BMs. Further studies on immunotherapy are needed for patients with active BMs. KEY POINTS: Significant findings of the study: The present study showed that anti-PD-1/PD-L1 antibody monotherapy was not effective for non-small cell lung cancer patients with active brain metastases. Intracranial and extracranial response rates were 13.3% and 26.7%, respectively. WHAT THIS STUDY ADDS: Further studies on immunotherapy are needed for patients with active BMs.

DOI： 10.1111/1759-7714.13557

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

There are limited real-world data on the treatment practices, outcomes, and safety of chemoradiotherapy (CRT) alone in potential candidates for immune checkpoint inhibitors (ICI) for unresectable non-small cell lung cancer (NSCLC). In this study, we analyzed the safety and efficacy of CRT in patients who underwent CRT and would satisfy the key eligibility criteria for maintenance therapy with durvalumab (eg, no progression after CRT) in real-world settings (m-sub) for unresectable Stage III NSCLC between 1 January 2013 and 31 December 2015 at 12 sites in Japan. The m-sub comprised 214 patients with a median follow-up of 31.6 months (range 1.9-65.8 months). Median overall survival (OS) and progression-free survival (PFS) from completing CRT were 36.4 months (95% confidence interval [CI] 28.1 months to not reached) and 9.5 months (95% CI 7.7-11.7 months), respectively. Consolidation chemotherapy did not influence OS or PFS. Median PFS was 16.9 vs 9.1 months in patients with vs without epidermal growth factor receptor (EGFR) mutations, with PFS rates of ~20% at 3-4 years. Pneumonitis was the most common adverse event (according to MedDRA version 21.0J), and about half of events were grade 1. Pneumonitis mostly occurred 10-24 weeks after starting CRT, peaking at 18-20 weeks. Esophagitis and dermatitis generally occurred from 0 to 4 weeks, peaking at 2-4 weeks after starting CRT. Pericarditis was rare and occurred sporadically. In conclusion, the results of the m-sub provide real-world insight into the outcomes of CRT, and will be useful for future evaluations of ICI maintenance therapy after CRT.

DOI： 10.1002/cam4.3306

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01244&link_issn=&doc_id=20200914250001&doc_link_id=130007896391&url=http%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F130007896391&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

記述言語：日本語   出版者・発行元：(一社)日本呼吸器外科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although aberrant proliferation and activation of lung fibroblasts are implicated in the initiation and progression of idiopathic pulmonary fibrosis (IPF), the underlying mechanisms are not well characterized. Numerous microRNAs (miRNAs) have been implicated in this process; however, miRNAs derived from exosomes and the relevance of such miRNAs to fibroblast-to-myofibroblast differentiation are not well understood. In this study, we attempted to identify exosome-derived miRNAs relevant to fibrosis development. METHODS: Using miRNA array analysis, we profiled exosome-derived miRNA expression in sera of C57BL/6 mice exhibiting bleomycin-induced pulmonary fibrosis. After validating a selected miRNA by quantitative reverse-transcription polymerase chain reaction, its effect on fibroblast-to-myofibroblast differentiation was investigated in human lung fibroblasts. Furthermore, we determined the role of the selected miRNA in an in vivo model of pulmonary fibrosis. RESULTS: MiRNA array analysis revealed that miR-22 expression was increased by up to 2 fold on day 7 after bleomycin treatment compared with that in vehicle-treated mice. In vitro, miR-22 transfection suppressed TGF-β1-induced α-SMA expression. This was mediated via inhibition of the ERK1/2 pathway. Baseline α-SMA expression was increased upon miR-22 inhibitor transfection. Furthermore, miR-22 negatively regulated connective tissue growth factor expression in the presence of TGF-β1. In vivo, administration of a miR-22 mimic on day 10 after bleomycin challenge ameliorated pulmonary fibrosis lesions accompanied by decreased α-SMA expression in the model mice. CONCLUSIONS: Exosomal miR-22 modulates fibroblast-to-myofibroblast differentiation. The present findings warrant further study, which could shed light on miR-22 as a novel therapeutic target in IPF.

DOI： 10.1272/jnms.JNMS.2020_87-302

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Pleurodesis is the standard of care for non-small cell lung cancer (NSCLC) patients with symptomatic malignant pleural effusion (MPE). However, there is no standard management for MPE uncontrolled by pleurodesis. Most patients with unsuccessful MPE control are unable to receive effective chemotherapy. Vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of MPE. This multicenter, phase II study investigated the effects of bevacizumab plus chemotherapy in nonsquamous NSCLC patients with unsuccessful management of MPE. METHODS: Nonsquamous NSCLC patients with MPE following unsuccessful tube drainage or pleurodesis received bevacizumab (15 mg/kg) plus chemotherapy every three weeks. The primary endpoint was pleural effusion control rate (PECR), defined as the percentage of patients without reaccumulation of MPE at eight weeks. Secondary endpoints included pleural progression-free survival (PPFS), safety, and quality of life (QoL). RESULTS: A total of 20 patients (median age: 69 years; 14 males; 20 adenocarcinomas; six epidermal growth factor receptor mutations) were enrolled in nine centers. The PECR was 80% and the primary end point was met. The PPFS and the overall survival (OS) were 16.6 months and 19.6 months, respectively. Patients with high levels of VEGF in the MPE had shorter PPFS (P = 0.010) and OS (P = 0.002). Toxicities of grade ≥ 3 included neutropenia (50%), thrombocytopenia (10%), proteinuria (10%), and hypertension (2%). The cognitive QoL score improved after treatment. CONCLUSIONS: Bevacizumab plus chemotherapy is highly effective with acceptable toxicities in nonsquamous NSCLC patients with uncontrolled MPE, and should be considered as a standard therapy in this setting. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Bevacizumab plus chemotherapy is highly effective with acceptable toxicities in nonsquamous NSCLC patients with uncontrolled MPE. WHAT THIS STUDY ADDS: Bevacizumab plus chemotherapy should be considered as a standard treatment option for patients with uncontrolled MPE. CLINICAL TRIAL REGISTRATION: UMIN000006868 was a phase II study of efficacy of bevacizumab plus chemotherapy for the management of malignant pleural effusion (MPE) in nonsquamous non-small cell lung cancer patients with MPE unsuccessfully controlled by tube drainage or pleurodesis (North East Japan Study Group Trial NEJ-013B) (http://umin.sc.jp/ctr/).

DOI： 10.1111/1759-7714.13472

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: The majority of pulmonary carcinoid (PC) tumors can be cured by surgical resection alone, but a significant proportion of patients experience recurrence. As PC is insensitive to conventional chemotherapy, further clarification of the molecular mechanisms of metastasis is needed in order to develop targeted therapeutics. METHODS: We performed comprehensive whole-exome sequencing (WES) of primary tumors and corresponding normal lung tissues from 14 PC patients (including 4 patients who developed postsurgical distant metastasis) and RNA sequencing of primary tumors from 6 PC patients (including 4 patients who developed postsurgical distant metastasis). Exon array-based gene expression analysis was performed in 25 cases of PC. RESULTS: We identified a total of 139 alterations in 136 genes. MUC6 and SPTA1 were recurrently mutated at a frequency of 21% (3/14) and 14% (2/14), respectively. Mucin protein family genes including MUC2, MUC4 and MUC6 were mutated in a mutually exclusive manner in 36% (5/14). Pathway analysis of the mutated genes revealed enrichment of genes involved in mitogen-activated protein kinase (MAPK) signaling, regulation of the actin cytoskeleton and focal adhesion, and transforming growth factor (TGF)-β signaling. RNA sequencing revealed a total of 8 novel fusion transcripts including one derived from a chromosomal translocation between the TRIB2 and PRKCE genes. All of the 8 fusion genes were detected in primary PCs that had developed metastasis after surgical resection. We identified 14 genes (DENND1B, GRID1, CLMN, DENND1B, NRP1, SEL1L3, C5orf13, TNFRSF21, TES, STK39, MTHFD2, OPN3, MET, and HIST1H3C) up-regulated in 5 PCs that had relapsed after surgical resection. CONCLUSIONS: In this study we identified novel somatic mutations and chromosomal rearrangements in PC by examining clinically aggressive cases that had developed postsurgical metastasis. It will be essential to validate the clinical significance of these genetic changes in a larger independent patient cohort.

DOI： 10.1016/j.lungcan.2020.03.027

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The participation of patients in the decision-making process related to their treatment is strongly recommended. This study was conducted to develop and evaluate a support tool that can help patients make decisions related to their own treatment. METHODS: Twenty cancer patients who were hospitalized for first line treatment were enrolled on the study. Before hospitalization, a 'Check sheet on treatment selection', which contained 14 questions, was distributed to patients and/or their families. After hospitalization, the attending physician explained the treatment while referring to the written check sheet. Also, at the time of discharge, the patients's responses to the 'Questionnaire on check sheet and treatment selection' were collected in order to evaluate the utility of the check sheet. Finally, the 'Questionnaire of the check sheet' was handed to the attending physician to evaluate. RESULTS: Of the fourteen patients who responded to the questionnaire, all indicated that the check sheets were helpful for decision-making, and that using the sheets empowered them to ask their doctors questions. Only one person felt uncomfortable with compiling the check sheet.Physicians stated that the check sheet facilitated patient decision-making and improved communication with patients. However, there was an opinion that this activity increased the administrative burden of medical professionals. CONCLUSION: Almost all patients stated that the check sheet used in this study was useful as a decision support tool, and also facilitated the communication between doctors and patients. Before incorporation into general clinical practice, this increased benefit should be weighed against the potential extra administrative workload imposed on clinicians.

DOI： 10.1272/jnms.JNMS.2021_88-401

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Docetaxel (DTX) efficacy increases in patients with non-small cell lung cancer (NSCLC) who had received anti-programmed cell death-1/ligand 1 (anti-PD-1/L1) therapy. However, the effect of ramucirumab (Ram) on DTX efficacy following anti-PD-1/L1 therapy is unknown. Here, we aimed to evaluate the effect of Ram on DTX efficacy following anti-PD-1/L1 therapy. MATERIALS AND METHODS: This retrospective study included 99 patients with NSCLC, who were divided into those who had (pre-ICI group) or had not (no-ICI group) received anti-PD-1/L1 antibody before DTX. Both groups were then treated with DTX or DTX plus Ram (DTX/Ram). Patient characteristics were compared between the DTX and DTX/Ram groups and adjusted with inverse probability of treatment weighting using propensity scores and the following confounding variables: age, sex, performance status, smoking status, histology, driver mutation, and line of treatment. We compared DTX/Ram and DTX in terms of efficacy in both the pre-ICI and no-ICI groups. RESULTS: In the pre-ICI group, 18 and 21 patients received DTX and DTX/Ram, respectively. In the no-ICI group, 35 and 25 patients received DTX and DTX/Ram. In the no-ICI group, progression-free survival (PFS) and overall survival (OS) were not significantly different between DTX/Ram- and DTX-treated patients (median PFS, 2.6 versus 1.6 months; p = 0.30, median OS; 8.2 versus 8.0 months; p = 0.30). In the pre-ICI group, PFS was significantly longer in DTX/Ram-treated than in DTX-treated patients (median, 5.9 versus 2.8 months; p = 0.03). Hazard ratio for disease progression or death was 0.75 (95% confidence interval, 0.20-0.96). The OS of DTX/Ram-treated patients tended to be longer than that of DTX-treated patients (median, 19.8 versus 8.6 months; p = 0.10). CONCLUSIONS: DTX efficacy following anti-PD-1/L1 therapy may be enhanced by Ram. Further studies are needed to validate the efficacy of inhibiting the vascular endothelial growth factor pathway following anti-PD-1/L1 therapy.

DOI： 10.1016/j.lungcan.2020.04.021

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Combination carboplatin and S-1 is active in the treatment of non-small cell lung cancer (NSCLC). However, data on this combination for elderly patients with NSCLC are insufficient. METHODS: Eligibility criteria were no prior chemotherapy, Stage IIIB or IV NSCLC, performance status 0-1, age ≥ 75 years, and adequate hematological, hepatic, and renal functions. Carboplatin was administered on day 1 and S-1 was administered orally, twice a day, between days 1 and 14, repeated every 3 weeks. In phase I, the primary purpose was determination of the recommended dose. Starting doses of carboplatin and S-1 were area under the curve (AUC) of 4 and 80 mg/m2/day, respectively. In the extension study, the effects and tolerability of this combination therapy of recommended dose were confirmed. RESULTS: A total of 10 patients were entered into phase I and 14 patients were entered into the extension study. The recommended doses for this drug combination are AUC 5 for carboplatin and 80 mg/m2/day every 3 weeks for S-1. With carboplatin and S-1 combination therapy at the recommended dose, the response rate was 30.0% [95% confidence interval (CI) 12-54%] and the disease control rate was 90.0% (95% CI 68-99%). Thrombocytopenia and neutropenia were major adverse events. CONCLUSIONS: The recommended doses for this combination therapy are carboplatin AUC 5 and S-1 80 mg/m2/day every 3 weeks, and this combination is effective with tolerable toxicities for advanced NSCLC patients ≥ 75 years old.

DOI： 10.1007/s10147-020-01629-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

LESSONS LEARNED: Alectinib confers a pronounced survival benefit in patients with ALK rearrangement-positive non-small cell lung cancer and a poor performance status. Survival benefit of alectinib for patients with a poor performance status was consistent regardless of the presence of central nervous system metastases. BACKGROUND: We previously reported a marked objective response rate (ORR) and safety for alectinib treatment in patients with ALK rearrangement-positive non-small cell lung cancer (NSCLC) and a poor performance status (PS) in the Lung Oncology Group in Kyushu (LOGiK) 1401 study. It remained unclear, however, whether alectinib might also confer a long-term survival benefit in such patients. METHODS: Eighteen patients with ALK rearrangement-positive advanced NSCLC and a PS of 2, 3, or 4 (n = 12, 5, and 1, respectively) were enrolled in LOGiK1401 between September 2014 and December 2015 and received alectinib. We have now updated the survival data for the study. RESULTS: The median follow-up time for all patients was 27.3 months. The median progression-free survival (PFS) was 16.2 months (95% confidence interval [CI], 7.1-30.8 months), and the median survival time (MST) and the 3-year overall survival rate were 30.3 months (95% CI, 11.5 months to not reached) and 43.8% (95% CI, 20.8-64.7%), respectively. This survival benefit was similarly manifest in patients with a PS of 2 (MST, 20.5 months) and those with a PS of ≥3 (MST, not reached). PFS did not differ between patients with or without central nervous system (CNS) metastases at baseline (median of 17.5 and 16.2 months, respectively, p = .886). CONCLUSION: Alectinib showed a pronounced survival benefit for patients with ALK rearrangement-positive NSCLC and a poor PS regardless of the presence of CNS metastases, a patient population for which chemotherapy is not indicated.

DOI： 10.1634/theoncologist.2019-0728

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Interstitial lung disease (ILD) induced by immune checkpoint inhibitors (ICIs) is a potentially life-threatening adverse event. The purpose of this study was to evaluate whether the development of immune-related adverse events (irAEs), especially ILD, was associated with treatment efficacy and to research the features and risk factors of ILD in advanced non-small cell lung cancer (NSCLC). METHODS: Between December 2015 and November 2018, 130 advanced NSCLC patients were treated with nivolumab, pembrolizumab or atezolizumab. The patients were categorized into two groups (irAEs group or non-irAEs group). Subsequently, we divided the irAEs group into two groups based on the incidence of ILD (ILD group and irAEs-non-ILD group). Treatment efficacy and the characteristics of ILD were evaluated. RESULTS: A total of 39 (30%) patients developed irAEs. ILD was observed in 16 (12%) patients. Patients with ILD had a higher objective response rate (ORR) compared with irAEs-non-ILD patients and non-irAEs patients (63%, 43% and 22%, respectively). Median progression-free survival (mPFS) was 15.9 months in ILD patients, 5.4 months in irAEs-non-ILD patients and 3.3 months in non-irAEs patients (log-rank test, P = 0.033). Pre-existing interstitial pneumonia (IP) was an independent risk factor for ILD-induced ICIs (odds ratio [OR] 14.7; 95% confidence interval [CI]: 2.16-99.6, P = 0.006). CONCLUSIONS: ORR and PFS were significantly better in ILD patients than in irAEs-non-ILD and non-irAEs patients. Pre-existing history of IP was an independent risk factor for ILD-induced ICIs.

DOI： 10.1111/1759-7714.13364

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Dissociated responses (DR) are phenomena in which some tumors shrink, whereas others progress during treatment of patients with cancer. The purpose of the present study was to evaluate the frequency and prognosis of DR in non-small cell lung cancer (NSCLC) patients treated with anti-programmed cell death-1/ligand 1 (anti-PD-1/L1) inhibitors. METHODS: This retrospective study included NSCLC patients who received anti-PD-1/L1 inhibitor as second- or later-line treatment. We excluded patients without radiological evaluation. In patients who showed progressive disease (PD) according to the RECIST 1.1 at the initial CT evaluation, we evaluated all measurable lesions in each organ to identify DR independently of RECIST 1.1. We defined DR as a disease with some shrinking lesions as well as growing or emerging new lesions. Cases not classified as DR were defined as 'true PD'. Overall survival was compared between patients with DR and those with true PD using Cox proportional hazards models. RESULTS: The present study included 62 NSCLC patients aged 27-82 years (median: 65 years). DR and true PD were observed in 11 and 51 patients, respectively. The frequency of DR in NSCLC patients who showed PD to anti-PD-1/L1 was 17.7%. Median overall survival was significantly longer in patients with DR versus true PD (14.0 vs. 6.6 months, respectively; hazard ratio for death: 0.40; 95% confidence interval: 0.17-0.94). CONCLUSIONS: Patients with DR exhibited a relatively favorable prognosis.

DOI： 10.1186/s12885-020-6704-z

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担当区分：責任著者   記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

背景.末梢肺病変に対するガイドシース併用気管支腔内超音波断層法(endobronchial ultrasonography with a guide sheath:EBUS-GS)を用いた肺生検(EBUS-GS-TBB)の有用性が示されているが、診断に影響を与える因子は明らかになっていない。目的.EBUS-GS-TBBの診断に影響を与える因子を明らかにすることを目的とした。方法.日本医科大学付属病院において2016年7月から2018年4月までにEBUS-GSを用いて肺生検が施行された118例の中で、最終的に確定診断が得られた101例を後方視的に検討した。EBUSのプローブの位置によって、エコー所見を'within'、'outside'、'broadly adjacent to'、'narrowly adjacent to'の4つに分類した。Adjacent toの中でプローブ周囲の180度以上360度未満の範囲に病変が描出されたものをbroadly adjacent toと新たに定義し、それ以外をnarrowly adjacent toと新たに定義した。結果.EBUS-GSによる確定診断率は78.2%であった。多変量解析にて、エコー所見がwithinまたはbroadly adjacent toの患者は診断率が有意に高かった(オッズ比4.25、P<0.01)。肺気腫を合併する患者では有意に診断率が低かった(オッズ比0.29、P=0.02)。検査前のthin-section CTにおけるbronchus sign陽性は診断に寄与する有意な因子であった(オッズ比6.86、P=0.03)。結論.EBUS-GS-TBBでは、エコー所見がbroadly adjacent toの場合でも診断率は高く、withinが得られない症例でもよりよいエコー描出を目指すべきである。肺気腫合併例は診断率が低い可能性があり、検査前の背景肺の評価も重要である。(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Vascular endothelial growth factor-A (VEGF-A) plays important roles in tumor immune suppression and thus correlates with the efficacy of anti-programmed cell death-1/ligand 1 (anti-PD-1/PD-L1) antibodies. We aimed to determine the association between change in plasma VEGF-A levels and the efficacy of chemotherapy combined with anti-PD-1/PD-L1 antibodies (chemo-PD1) in non-small cell lung cancer (NSCLC) patients. METHODS: We included NSCLC patients treated with chemo-PD1. Plasma VEGF-A levels were measured at baseline (Pre) and days 7 (D7) and 14 (D14) after the initiation of chemo-PD1. Continuous VEGF-A decrease was determined by comparing Pre with the median value of maximum change rate of posttreatment VEGF-A as cutoff. Patients whose change rates of VEGF-A at both D7 and D14 were consistently lower than the cutoff value were classified into the VEGF-A decrease group, whereas those whose VEGF-A at D7 or D14 were higher than the cutoff level were classified into the VEGF-A no-decrease group. The primary outcome was progression-free survival (PFS). RESULTS: A total of 32 patients were evaluated. The median Pre VEGF-A levels was 49 (range, 13-257). The median change rate of VEGF-A at D7 and D14 was -25.6% (range, -77.5-376.9) and -42.3% (range, -100-138.5) respectively. The cutoff value of posttreatment VEGF-A change rate was -9.3%. The PFS was significantly longer in the VEGF-A decrease group than that in the VEGF-A no-decrease group (median, not reached vs 2.4 months; p = 0.017). CONCLUSIONS: Continuous decrease of plasma VEGF-A levels during treatment may be associated with the efficacy of chemo-PD1.

DOI： 10.1016/j.ctarc.2020.100249

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記述言語：英語  

We report a case of pneumonitis with alveolar hemorrhage induced by herbal medicines in a 73-year-old woman who was admitted to our hospital because of dyspnea and an abnormal shadow on a chest radiograph. She had received treatment with numerous drugs, including the herbal medicines Seisin-renshi-in, Chotosan, Rikkunshi-to, and Shakuyakukannzo-to. Chest radiography revealed diffuse ground-glass shadows in both lungs, and bronchoalveolar lavage fluid was progressively hemorrhagic. A culture of the fluid showed no evidence of microorganisms. Moreover, there were no findings suggestive of rheumatic disease or vasculitides. On the basis of this evidence, we suspected drug-induced diffuse alveolar hemorrhage. She discontinued all medicines and started treatment with corticosteroids. Her respiratory condition and chest radiographic findings improved. The timing of administration and rechallenge with other drugs suggested that the herbal medicines were the causative drugs. The primary concern was Seisin-renshi-in, because it contains Ougon (skullcap; a known cause of pneumonitis) and because a drug lymphocyte stimulation test was positive for Seisin-renshi-in. This is the first report indicating that Seisin-renshi-in may cause diffuse alveolar hemorrhage. Diffuse alveolar hemorrhage due to herbal medicines is a rare but emergent disorder. Therefore, treating physicians should be aware that it may be caused by herbal medicines, including Seisin-renshi-in.

DOI： 10.1272/jnms.JNMS.2019_86-504

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Idiopathic interstitial pneumonias (IIPs) are associated with increased risk of lung cancer. In Japan, acute exaberation of IIPs induced by anticancer treatment is a critical issue. For this reason, there is limited available evidence regarding the optimal treatment approach for lung cancer patients complicated with IIPs. Our previous prospective pilot study demonstrated the safety and efficacy of weekly paclitaxel in combination with carboplatin for advanced non-small-cell lung cancer (NSCLC) with IIPs. The current study was conducted to confirm the results of the same combination therapy used in a larger patient population. METHODS: Chemotherapy-naïve patients with advanced stage or post-operative recurrent NSCLC patients complicated by IIPs were enrolled. Patients received paclitaxel (100 mg/m2) on days 1, 8, and 15, and carboplatin (AUC 5.0) once every 4 weeks. RESULTS: Thirty-three of 35 enrolled patients were evaluable for analysis and received a median of four treatment cycles (range 1-6). Four patients (12.1%; 95% confidence interval 3.4-28.2%) had acute exacerbation (AEx)-related IIPs to the study treatment. However, no fatalities due to AEx were observed. The overall response was 69.7%. The median progression-free survival, median survival time, and 1-year survival were 6.3 months, 19.8 months, and 55.4%, respectively. CONCLUSIONS: The efficacy of carboplatin plus weekly paclitaxel treatment for advanced NSCLC patients with IIPs was comparable to that of conventional chemotherapy in advanced NSCLC patients without IIPs. Moreover, the primary endpoint was set to the frequency of treatment-related acute exacerbation, and the primary endpoint was met. These results suggest that patients with advanced NSCLC complicated by IIPs may benefit from this combination chemotherapy.

DOI： 10.1007/s10147-019-01516-9

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語  

LESSONS LEARNED: Alectinib confers a pronounced survival benefit in patients with ALK rearrangement-positive non-small cell lung cancer and a poor performance status.Survival benefit of alectinib for patients with a poor performance status was consistent regardless of the presence of central nervous system metastases. BACKGROUND: We previously reported a marked objective response rate (ORR) and safety for alectinib treatment in patients with ALK rearrangement-positive non-small cell lung cancer (NSCLC) and a poor performance status (PS) in the Lung Oncology Group in Kyushu (LOGiK) 1401 study. It remained unclear, however, whether alectinib might also confer a long-term survival benefit in such patients. METHODS: Eighteen patients with ALK rearrangement-positive advanced NSCLC and a PS of 2, 3, or 4 (n = 12, 5, and 1, respectively) were enrolled in LOGiK1401 between September 2014 and December 2015 and received alectinib. We have now updated the survival data for the study. RESULTS: The median follow-up time for all patients was 27.3 months. The median progression-free survival (PFS) was 16.2 months (95% confidence interval [CI], 7.1-30.8 months), and the median survival time (MST) and the 3-year overall survival rate were 30.3 months (95% CI, 11.5 months to not reached) and 43.8% (95% CI, 20.8-64.7%), respectively. This survival benefit was similarly manifest in patients with a PS of 2 (MST, 20.5 months) and those with a PS of ≥3 (MST, not reached). PFS did not differ between patients with or without central nervous system (CNS) metastases at baseline (median of 17.5 and 16.2 months, respectively, p = .886). CONCLUSION: Alectinib showed a pronounced survival benefit for patients with ALK rearrangement-positive NSCLC and a poor PS regardless of the presence of CNS metastases, a patient population for which chemotherapy is not indicated.

DOI： 10.1634/theoncologist.2019-0728

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Osimertinib exhibits good efficacy in patients with T790M-positive non-small cell lung cancer (NSCLC) and acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Compared with the clinical trials, in real-world clinical practice, osimertinib must be administered to older patients and those with poor Eastern Cooperative Oncology Group performance status (ECOG-PS). Therefore, we investigated the association between osimertinib efficacy/safety and PS score, age, and other clinical features in patients with T790M-positive NSCLC. Methods: We reviewed all patients with T790M-positive NSCLC and acquired resistance to initial EGFR-TKIs who were administered osimertinib between March 2016 and January 2018 at the Tokyo Metropolitan Cancer and Infectious Diseases Center in Komagome Hospital, Japan. Results: In total, 31 patients, including 8 young (<65 years) and 23 elderly (≥65 years) patients, were included in the study. Of these, 10 (32.3%) patients had poor PS scores. The progression-free survival (PFS) was significantly shorter in young patients was than elderly patients [3.5 vs. 6.4 months, P=0.041; hazard ratio (HR), 2.41]. The overall survival (OS) of the young patients tended to be shorter than that of the elderly patients (5.3 vs. 19.4 months, P=0.067; HR, 2.58). The PFS (9.1 vs. 5.5 months; P=0.071; HR, 0.38) and the OS (not reached vs. 6.6 months, P=0.061; HR, 0.39) were shorter in patients with poor ECOG-PS than those with good ECOG-PS. The toxic effects of osimertinib were manageable. By multivariate analysis, both age and ECOG-PS were independent predictors of osimertinib efficacy. Conclusions: Poor ECOG-PS and younger age were associated with lower efficacy of osimertinib in T790M-positive NSCLC.

DOI： 10.21037/jtd.2019.06.03

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：英語  

We report a case of pneumonitis with alveolar hemorrhage induced by herbal medicines. A 73-year-old female was admitted to our hospital due to dyspnea and the presence of an abnormal shadow on the chest roentgenogram. She had received treatment with numerous drugs, including the following herbal medicines: Seisin-renshi-in, Chotosan, Rikkunshi-to, and Shakuyakukannzo-to. Chest radiography revealed diffuse ground-glass shadows in both lungs. The bronchoalveolar lavage fluid was progressively bloody. In addition, culture did not show the presence of microorganisms in the fluid. Moreover, there were no findings suggestive of rheumatic disease or vasculitides. Based on this evidence, we suspected drug-induced diffuse alveolar hemorrhage. She discontinued the use of all previous agents, and received treatment with corticosteroids. Her respiratory condition and the chest roentgenogram improved. According to the timing of administration and rechallenge with other drugs, the herbal medicines were suspected to be the causative drugs. Among those, Seisin-renshi-in was the most suspicious. Firstly, Seisin-renshi-in contains Ougon (skullcap), which is known to cause pneumonitis. Secondly, a dr

DOI： 10.1272/jnms.JNMS.2019_86-504

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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.ajic.2019.04.009

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Pembrolizumab, an anti-programmed cell death-1 protein monoclonal antibody, is effective for patients with advanced non-small-cell lung cancer. However, immune checkpoint inhibitors such as pembrolizumab induce various immune-related adverse events, involving the lung, liver, gastrointestinal, endocrine system, and skin. Intralymphatic histiocytosis (ILH) is a rare, chronic cutaneous disorder with a reactive inflammatory component, which often occurs in patients with rheumatoid arthritis. CASE PRESENTATION: We present a 67-year-old man with lung adenocarcinoma who developed ILH associated with pembrolizumab treatment. He was treated with palliative thoracic radiotherapy for superior vena cava syndrome. Subsequently, he received four cycles of pembrolizumab. Approximately 2.5 months after the initiation of pembrolizumab, he developed erythema on the trunk of his body. Based on findings of skin biopsies, he was diagnosed with pembrolizumab-induced ILH. Moreover, the upregulation of tumor necrosis factor-α was observed during pembrolizumab therapy. CONCLUSIONS: This is the first report of ILH induced by pembrolizumab in a patient with lung adenocarcinoma.

DOI： 10.1186/s40425-019-0534-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Nanoparticle albumin-bound paclitaxel is indicated for the treatment of patients with lung cancer. It can induce interstitial lung disease, but the incidence of nanoparticle albumin-bound paclitaxel-associated interstitial lung disease in clinical practice has not been determined. We investigated the incidence of interstitial lung disease in patients with lung cancer who had received nanoparticle albumin-bound paclitaxel therapy at our institution. Methods: We reviewed clinical data for patients with advanced lung cancer who received nanoparticle albumin-bound paclitaxel with or without carboplatin or bevacizumab therapy at the Nippon Medical School Main Hospital between April 2013 and September 2017. Interstitial lung disease was diagnosed based on clinical symptoms, radiographic findings and exclusion of other diseases. Results: A total of 110 advanced lung cancer patients received nanoparticle albumin-bound paclitaxel, and nine of them (8.2%) developed interstitial lung disease. Of those who developed interstitial lung disease, eight were treated with corticosteroids and three received cyclophosphamide pulse therapy. High-resolution computed tomography images demonstrated diffuse alveolar damage pattern pneumonitis in seven patients and organized pneumonia pattern pneumonitis in two patients. Six of the patients with diffuse alveolar damage pattern pneumonitis died from respiratory failure. The two patients with organized pneumonia pattern pneumonitis recovered. The incidence of interstitial lung disease was 19.0% (8/42) among patients with preexisting interstitial pneumonia and 1.5% (1/68) among those without preexisting interstitial pneumonia. Six patients with preexisting interstitial pneumonia met the criteria for acute exacerbation of interstitial pneumonia (14.3%). Conclusion: Nanoparticle albumin-bound paclitaxel-associated interstitial lung disease was a severe and potentially fatal adverse event. We found it demonstrated diffuse alveolar damage or organized pneumonia pattern pneumonitis, and preexisting interstitial pneumonia was associated with higher rate of nanoparticle albumin-bound paclitaxel-associated interstitial lung disease.

DOI： 10.1093/jjco/hyy180

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Malignant mesothelioma (MM) is an aggressive tumor with poor prognosis. The establishment of a new diagnostic and therapeutic approach for MM is expected. This study investigated the diagnostic significance of tenascin XB (TNXB) for MM. MATERIALS AND METHODS: TNXB gene expression was found to be significantly higher in MM tumor tissues compared to paired normal tissues, as assessed by the Gene Expression Omnibus database. The inhibition of TNXB using small interfering RNAs suppressed the proliferation and colony formation of MM cells. Expression of TNXB and calretinin, a current diagnostic marker of MM, was evaluated by immunohistochemistry. RESULTS: The sensitivity and specificity of TNXB for MM were 80.0% and 69.5%, respectively. When the detection of TNXB was combined with that of calretinin, 83.3% of MM cases were detected. CONCLUSION: These findings suggest that TNXB is a novel diagnostic biomarker for MM. A combination of detecting TNXB and calretinin may be useful for the differential diagnosis of MM from lung adenocarcinoma.

DOI： 10.21873/anticanres.13156

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記述言語：英語  

DOI： 10.1111/ajd.12868

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The prevalence of chronic obstructive pulmonary disease (COPD) is 8.6% in Japan and 10% worldwide. Unfortunately, many patients with COPD are not correctly identified and appropriately educated regarding the condition. In this paper, we demonstrate that some citizens of Ebina City with symptoms suspicious for COPD, such as cough, sputum production, and shortness of breath, have undiagnosed COPD. We describe our activities to raise awareness of COPD through a 10-year campaign. METHODS: From 2006 to 2015, we developed activities to raise awareness of COPD, including public lectures, utilization of pulmonary function tests, and questionnaires on subjective symptoms and knowledge of COPD. RESULTS: Among 1,206 participants aged>40 years, COPD was suspected in 5.6%, as indicated by airway obstruction (i.e. forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio (FVC) <0.70). However, most of these participants were not diagnosed with COPD. Furthermore, half of these participants had not consulted a medical institution despite demonstrating symptoms. Results of the COPD awareness questionnaire, which was administered to 1,055 people, indicated that 65% of survey respondents were unaware of COPD. CONCLUSIONS: There are individuals with symptoms suspicious for COPD who are unaware of the disease at the Plaza in Ebina City. Clinicians have a responsibility to raise public awareness of COPD and to reduce the prevalence of COPD and its associated mortality.

DOI： 10.1272/jnms.JNMS.2019_86-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Acute exacerbation of pre-existing interstitial lung disease (ILD) associated with systemic anticancer therapy is recognized as a life-threatening adverse event of lung cancer treatment. Programmed cell death 1 (PD-1) checkpoint inhibitors, such as nivolumab, often induce pneumonitis in patients with cancer; however, the tolerance and safety of nivolumab for advanced lung cancer with ILD are unclear. We report a 72-year-old patient with lung cancer with pathologically proven idiopathic pulmonary fibrosis who was treated with nivolumab. She demonstrated pneumonitis with an organized pneumonia (OP) pattern, but no acute exacerbation of ILD featuring a diffuse alveolar damage (DAD) pattern. She was successfully treated with corticosteroid therapy, and maintained good disease control after the discontinuation of nivolumab. She also showed pseudoprogression of the primary tumor, implying infiltration of T-cells into the lung. These findings suggest that T-cell activation by nivolumab treatment might not be directly associated with acute ILD exacerbation, and that treatable OP might be a major pulmonary complication of nivolumab in patients with pre-existing ILD, similar to patients without underlying ILD.

DOI： 10.1272/jnms.JNMS.2019_86-8

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DOI： 10.1016/j.rmcr.2019.01.012

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DOI： 10.1016/j.rmcr.2019.01.021

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担当区分：責任著者   記述言語：英語  

An 82-year-old man with a recurrence of pulmonary pleomorphic carcinoma was treated with pembrolizumab. He achieved partial response after three cycles of pembrolizumab. However, he developed febrile neutropenia. A bone marrow aspiration sample revealed a decrease of mature neutrophils, and anti-neutrophil antibody was detected in blood. Computed tomography scans revealed consolidation in the right lung. Pathological findings in lung biopsy tissue revealed organizing pneumonia. Pembrolizumab-induced agranulocytosis and interstitial lung disease (ILD) were diagnosed. We initiated antibacterial therapy and granulocyte colony-stimulating factor (G-CSF). The neutrophil count immediately increased, and the fever decreased. The improvement of ILD was achieved without using systemic steroids. Moreover, the patient developed ocular myasthenia gravis induced by pembrolizumab. This is the first case report of pembrolizumab-induced agranulocytosis. Agranulocytosis was improved by administration of G-CSF without using systemic steroids. However, further studies are needed to determine the optimal treatment for patients with anti-neutrophil antibody whose tumor has progressed.

DOI： 10.1093/omcr/omy094

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is critical in combating EGFR-mutant non-small cell lung cancer (NSCLC). We tried to construct a novel therapeutic strategy to conquer the resistance to second-and third-generation EGFR-TKIs in EGFR-positive NSCLC patients. We established afatinib- and osimertinib-resistant lung adenocarcinoma cell lines. Exome sequencing, cDNA array and miRNA microarray were performed using the established cell lines to discover novel therapeutic targets associated with the resistance to second-and third-generation EGFR-TKIs. We found that ANKRD1 which is associated with the epithelial-mesenchymal transition (EMT) phenomenon and anti-apoptosis, was overexpressed in the second-and third-generation EGFR-TKIs-resistant cells at the mRNA and protein expression levels. When ANKRD1 was silenced in the EGFR-TKIs-resistant cell lines, afatinib and osimertinib could induce apoptosis of the cell lines. Imatinib could inhibit ANKRD1 expression, resulting in restoration of the sensitivity to afatinib and osimertinib of EGFR-TKI-resistant cells. In EGFR-mutant NSCLC patients, ANKRD1 was overexpressed in the tumor after the failure of EGFR-TKI therapy, especially after long-duration EGFR-TKI treatments. ANKRD1 overexpression which was associated with EMT features and anti-apoptosis, was commonly involved in resistance to second-and third-generation EGFR-TKIs. ANKRD1 inhibition could be a promising therapeutic strategy in EGFR-mutant NSCLC patients.

DOI： 10.1038/s41598-018-33190-8

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記述言語：英語  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) induce a dramatic response in non-small cell lung cancer (NSCLC) patients with the ALK fusion gene. However, acquired resistance to ALK-TKIs remains an inevitable problem. In this study, we aimed to discover novel therapeutic targets to conquer ALK-positive lung cancer. We established three types of ALK-TKI (crizotinib, alectinib and ceritinib)-resistant H2228 NSCLC cell lines by high exposure and stepwise methods. We found these cells showed a loss of ALK signaling, overexpressed AXL with epithelial-mesenchymal transition (EMT), and had cancer stem cell-like (CSC) properties, suggesting drug-tolerant cancer cell subpopulations. Similarly, we demonstrated that TGF-β1 treated H2228 cells also showed AXL overexpression with EMT features and ALK-TKI resistance. The AXL inhibitor, R428, or HSP90 inhibitor, ganetespib, were effective in reversing ALK-TKI resistance and EMT changes in both ALK-TKI-resistant and TGF-β1-exposed H2228 cells. Tumor volumes of xenograft mice implanted with established H2228-ceritinib-resistant (H2228-CER) cells were significantly reduced after treatment with ganetespib, or ganetespib in combination with ceritinib. Some ALK-positive NSCLC patients with AXL overexpression showed a poorer response to crizotinib therapy than patients with a low expression of AXL. ALK signaling-independent AXL overexpressed in drug-tolerant cancer cell subpopulations with EMT and CSC features may be commonly involved commonly involved in intrinsic and acquired resistance to ALK-TKIs. This suggests AXL and HSP90 inhibitors may be promising therapeutic drugs to overcome drug-tolerant cancer cell subpopulations in ALK-positive NSCLC patients for the reason that ALK-positive NSCLC cells do not live through ALK-TKI therapy.

DOI： 10.18632/oncotarget.25531

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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：Oxford University Press  

Elotuzumab, a humanized immunoglobulin G1 monoclonal antibody targeted against signaling lymphocytic activation molecule F7 (SLAMF7), has recently been used in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma. The clinical characteristics of drug-induced interstitial lung disease (ILD) due to elotuzumab have not been clarified. In this report, we describe a patient with refractory multiple myeloma who received elotuzumab in combination with lenalidomide and dexamethasone in whom fatigue, fever and diffuse pulmonary infiltration developed. The patient had a history of long-term therapy with lenalidomide without pulmonary toxicity. Bronchoscopy with bronchoalveolar lavage was negative for infection, and transbronchial lung biopsies showed active alveolitis with lymphocytic infiltration and myxomatous change of the thick alveolar wall. After the discontinuation of elotuzumab and lenalidomide, the patient's clinical symptoms gradually improved, and spontaneous remission of the pulmonary infiltration was observed. Based on the chest CT and lung pathology findings, the exclusion of infection and pulmonary edema, and according to the clinical course, we established a diagnosis of drug-induced ILD due to elotuzumab. Clinicians should bear in mind the potential for pulmonary toxicity in patients receiving elotuzumab-containing therapy.

DOI： 10.1093/jjco/hyy049

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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：International Institute of Anticancer Research  

Background/Aim: Programmed cell death ligand 1 (PD-L1) expression is a predictive marker for immunotherapy effects in advanced non-small cell lung cancer (NSCLC), but its association with patient characteristics or specimens is controversial. We aimed to retrospectively analyze the association of PD-L1 expression with clinicopathological features of NSCLC patients. Materials and Methods: The PD-L1 expression and clinicopathological features of NSCLC patients were assessed from January 2017 to June 2017 in the Tokyo Metropolitan Cancer and Infectious Diseases Centre, Komagome Hospital were reviewed (n=108). Results: For PD-L1 expressions of 0% and &gt
1%, multivariate analysis showed that lymph node sample results were associated with positive PD-L1 expression. Archival samples and high serum carcinoembryonic antigen (CEA) levels were associated with negative PD-L1 expression. Sample preservation time and CEA levels correlated with PD-L1 expression. Conclusion: Nodal metastasis, sample preservation time and CEA levels were associated with PD-L1 expression in NSCLC.

DOI： 10.21873/anticanres.12326

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Recent clinical trials have shown that immune checkpoint blockades that target either PD-1 or PD-L1 yield remarkable responses in a subgroup of patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We retrospectively examined, by immunohistochemical analysis, 211 NSCLC samples. Using 32 independent samples, we also evaluated PD-L1 expression in NSCLC patients with EGFR gene mutations treated by EGFR-TKIs. RESULTS: Overall survival of PD-L1-positive stages I-III NSCLC and stage I NSCLC and stages I-III squamous cell carcinoma (SQ) were significantly shorter than those of PD-L1-negative NSCLC (p<0.01 and p=0.02 and p=0.01, respectively). In stage I NSCLC and stages I-III SQ, PD-L1 expression was found to be independent predictor of death after multivariate analysis. Response to EGFR-TKIs was not significantly different between PD-L1-positive and PD-L1-negative NSCLC patients with EGFR mutations. CONCLUSION: PD-L1 expression was a significant independent predictor of poor outcome in NSCLC patients.

DOI： 10.21873/anticanres.12281

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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：Spandidos Publications  

It was previously revealed that Wnt signaling is activated in mesothelioma cells. Although epidermal growth factor receptor (EGFR) is expressed in mesothelioma cells, EGFR‑tyrosine kinase inhibitors (TKIs) are not effective for mesothelioma treatment. However, in non‑small cell lung cancer, the blocking of Wnt signaling has been identified to enhance the anticancer effect of EGFR‑TKIs. To confirm the anticancer effect of blocking Wnt signaling in combination with EGFR‑TKI treatment in mesothelioma, the present study evaluated the effect of simultaneous suppression of human dishevelled‑3 (Dvl‑3) expression with Dvl‑3 small interfering RNA (siRNA) and of EGFR inhibition with gefitinib on mesothelioma cell viability. Mesothelioma cell lines with and without β‑catenin gene expression were transfected with Dvl‑3 siRNA and were cultured with gefitinib, and cell viability, colony formation and cell cycle analyses were performed. Dvl‑3 siRNA downregulated the expression of Dvl‑3 in mesothelioma cells. The combination of Dvl‑3 siRNA with gefitinib acted synergistically to induce concomitant suppression of cell viability and colony formation, suggesting that inhibition of Wnt signaling by downregulating Dvl‑3 with siRNA and inhibiting EGFR with gefitinib leads to significant antitumor effects.

DOI： 10.3892/ol.2017.7382

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The aim of this trial was to evaluate the safety and efficacy of oral hydration as a substitute for intravenous hydration after cisplatin (CDDP) administration. Methods: The major eligibility criteria included patients with lung cancer, indications for a CDDP-based regimen at a dose of 60 mg/m2 or higher, an age of between 20 and 74 years and adequate renal function. Antiemetic prophylaxis consisted of an appropriate dose of palonosetron, aprepitant, dexamethasone and magnesium sulfate (8 mEq). Five hundred millilitres of commercially available oral hydration solution (OS-1: Otsuka Pharmaceutical Factory, Tokushima, Japan) was used as a substitute for intravenous posthydration. The planned sample size was 46 to reject a proportion of 70% under an expectation of 88% with a power of 90% and an alpha error of 5%. Results: Between May and November 2013, 31 men and 15 women with a median (range) age of 65 (33-74) years were enrolled from three institutions. Of these, five received adjuvant chemotherapy, 17 received definitive chemoradiotherapy and 24 received chemotherapy for advanced diseases. The median (range) number of chemotherapy cycles was 4 (1-5). After the first cycle of CDDP administration, none of the patients experienced a creatinine elevation of grade 2 or higher, thereby meeting the primary endpoint. Of the 46 patients, 45 (97.8%, 95% CI 88.2 to 99.9) completed the CDDP-based chemotherapy without grade 2 or higher renal dysfunction. Conclusion: Oral hydration can be used as a safe and convenient substitute for intravenous posthydration for CDDP administration at the standard dose. Trial registration number: UMIN000010201.

DOI： 10.1136/esmoopen-2017-000288

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担当区分：責任著者   記述言語：英語  

Immuno-checkpoint inhibitors (ICI) have become an effective treatment option for non-small-cell lung cancer patients. However, ICI therapy was reported to be less effective in patients with epidermal growth factor receptor (EGFR) mutations than in those with wild-type EGFR. We report here that an non-small-cell lung cancer patient with the EGFR mutant T790M showed a programmed cell death ligand 1 (PD-L1) expression level that increased from <25% to >90% after eighth-line osimertinib therapy. He was treated with pembrolizumab as a ninth-line treatment, and attained stable disease. After the pembrolizumab therapy, he was treated with gemcitabine, which produced a good response despite being the 10th-line treatment. We should consider administering ICI and chemotherapy even to EGFR mutant patients after failure of EGFR tyrosine kinase inhibitor, especially in cases with high PD-LI expression.

DOI： 10.2147/OTT.S168598

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担当区分：責任著者   記述言語：英語  

We herein describe the case of a 67-year-old woman with advanced lung adenocarcinoma who developed interstitial lung disease (ILD) with alveolar hemorrhage induced by pembrolizumab. She received four courses of pembrolizumab therapy and achieved a partial response. She had no respiratory symptoms; however, chest radiography and computed tomography (CT) revealed ground-glass opacities (GGOs) and crazy-paving pattern. Based on findings of bloody bronchoalveolar lavage fluid and transbronchial lung biopsy samples, pembrolizumab-induced ILD with alveolar hemorrhage was diagnosed. Corticosteroid therapy rapidly improved alveolar hemorrhage and regressed GGOs on CT scan. This is the first report on ILD with alveolar hemorrhage induced by pembrolizumab.

DOI： 10.2147/OTT.S169321

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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.jtho.2017.02.012

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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：SPANDIDOS PUBL LTD  

Cancer stem cell (CSC) properties have been recently proposed to explain tumor carcinogenesis and multi drug resistance in several human cancers, including non-small cell lung cancer (NSCLC). The present study examined the protein expression of three CSC-associated markers, namely ATP binding cassette subfamily B member 1 (ABCB1), aldehyde dehydrogenase 1 family member Al (ALDH1A1) and cluster of differentiation (CD) 44, by immunohistochemistry in 194 NSCLC patients who underwent complete resection of NSCLC tumors. The association between the expression of these proteins and patient prognosis was evaluated to clarify the prognostic significance of CSC-associated markers in NSCLC patients. Positive staining for ABCB1 demonstrated a trend toward worse survival compared with negative staining in stage I-III NSCLC. Negative staining for ALDH1 or CD/44 exhibited a trend toward worse survival compared with positive staining in stage I-III NSCLC. It was observed that patients with stage I lung adenocarcinoma (ADC) showing positivity for ABCB1 expression had significantly poorer survival than those with negative ABCB1 staining (P=0.03). Furthermore, stage I ADC patients with wild-type epidermal growth factor receptor (EGFR) who exhibited positive staining for ABCB1 had significantly shorter disease-free survival (DFS) compared with patients with negative staining for ABCB1 (P&lt;0.01). Analyses by univariate and multivariate Cox proportional hazards models revealed that ABCB1-positive staining was significantly associated with DFS and was an independent prognostic factor (hazard ratio, 3.49; P&lt;0.05) in these patients. These results suggest that ABCB1 protein expression is useful for predicting prognosis and selecting patients for post-operative therapy in stage I lung ADC patients, particularly those harboring wild-type EGFR.

DOI： 10.3892/ol.2017.6145

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記述言語：英語  

Nivolumab, a monoclonal antibody targeting the PD-1, has recently been used as a standard treatment for lung cancer, melanoma and renal cell carcinoma. We herein report the case of a patient undergoing treatment for non-small cell lung cancer (NSCLC) who developed interstitial pneumonia which featured nivolumab-induced granuloma formation. An 82-year-old male patient with NSCLC was initially treated with radiation therapy and chemotherapy. Five years later, however, he developed metastatic carcinoma in a hilar lymph node accompanied by ground glass opacity (GGO), suggesting tumor cell invasion. Treatment with nivolumab was initiated. At 21 days after the first dose of nivolumab, he complained of cough and dyspnea. Chest computed tomography scans demonstrated tumor progression and newly formed GGO in the area surrounding the primary tumor. Fibrosing active alveolitis with granuloma formation and organizing pneumonia findings were observed in the pathological examination of a transbronchial lung biopsy (TBLB) specimen. No malignant cells were found in TBLB. A bacteriological analysis of cultures, a PCR, and special staining did not reveal any infections. The patient's pneumonitis improved after treatment with systemic corticosteroids. Granuloma-forming interstitial pneumonia may be a feature of nivolumab-associated pneumonitis.

DOI： 10.1007/s13691-017-0291-0

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：INT INST ANTICANCER RESEARCH  

Background/Aim: We evaluated the usefulness of reverse transcription-polymerase chain reaction (RT-PCR) for detecting anaplastic lymphoma kinase (ALK) translocations using cytology samples from lung cancer patients. Materials and Methods: We analyzed ALK translocations by RT-PCR in cytology samples from lung cancer patients diagnosed at the Nippon Medical School Hospital between 2013 and 2015. Immunochemistry (IHC) and break-apart fluorescence in situ hybridization (FISH) were also performed on available tissue samples. Results: A total of 155 cytology samples were analyzed in our study. We obtained 115 (68%) samples from bronchial lavage. We were able to determine 153 (99%) results by RT-PCR with 4 (3%) positive samples. The four samples positive by RT-PCR were also positive by IHC and FISH performed on the tissue samples collected simultaneously. Conclusion: RT-PCR is a suitable method for detecting ALK translocations using cytology samples from patients with primary lung cancer, especially when tissue samples are not available.

DOI： 10.21873/anticanres.11696

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

AXL, a receptor tyrosine kinase implicated in cell survival, proliferation, and migration, is also associated with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor therapy. However, its prognostic significance in lung adenocarcinoma (AD) remains unclear. We therefore evaluated the prognostic significance of the expression of AXL and/or its ligand, growth arrest specific 6 (GAS6), in completely resected lung AD. We evaluated the relationship between AXL, GAS6, and vimentin expression, as determined by immunohistochemistry (IHC) analysis, with overall survival and disease-free survival in 113 patients with stages I-III lung AD. Protein expression was also assayed using western blot analysis in 10 lung AD cell lines. AXL-positive (AXL(+)), GAS6-positive (GAS6(+)), or AXL(+)/GAS6(+) staining was significantly associated with vimentin-positive (vimentin) expression. AXL(+)/GAS6(+) and vimentin showed a negative tendency toward an association with EGFR mutation. AXL(+), GAS6(+), or AXL(+)/GAS6(+) status significantly correlated with poor overall survival. In stage I cases, AXL(+)/VGAS6(+) status significantly correlated with poor overall survival and disease-free survival, especially in cases with wild-type EGFR. In multivariate analysis, AXL/GAS6 classifications in stage I as well as in stages I-III lung AD were found to be independent factors for poor patient outcomes. Unlike lung AD cell lines with mutant EGFR, almost all cells with wild-type EGFR showed AXL and vimentin co-expression as determined by western blotting. AXL(+) and GAS6(+) expression is relevant to a poor prognosis in resected lung AD patients at stage I. AXL/GAS6 might serve as crucial predictive and prognostic biomarkers and targets to identify individuals at high risk of post-operative death.

DOI： 10.3892/or.2017.5594

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記述言語：英語   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/JCO.2017.35.15_suppl.e21660

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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：ELSEVIER SCIENCE INC  

Introduction: There are no validated molecular methods that prospectively identify patients with surgically resected lung squamous cell carcinoma (SCC) at high risk for recurrence. By focusing on the expression of genes with known functions in development of lung SCC and prognosis, we sought to develop a robust prognostic classifier of early stage lung SCC.
Methods: The expression of 253 genes selected by literature search was evaluated in microarrays from 107 stage I/II tumors. Associations with survival were evaluated by Cox regression and Kaplan-Meier survival analyses in two independent cohorts of 121 and 91 patients with SCC, respectively. A classifier score based on multivariable Cox regression was derived and exam fined in six additional publicly available data sets of stage I/II lung SCC expression profiles (n = 358). The prognostic value of this classifier was evaluated in meta analysis of patients with stage I/II (n = 479) and stage I (n = 326) lung SCC.
Results: Dual specificity phosphatase 6 gene (DUSP6) and actinin alpha 4 gene (ACTN4) were associated with prognostic outcome in two independent patient cohorts. Their expression values were utilized to develop a classifier that identified patients with stage I/II lung SCC at high risk for recurrence (hazard ratio [HR] = 4.7, p = 0.018) or cancer-specific mortality (HR = 3.5, p = 0.016). This classifier also identified patients at high risk for recurrence (HR = 2.7, p = 0.008) or death (HR = 2.2, p = 0.001) in publicly available data sets of stage I/II and in meta analysis of stage I patients.
Conclusions: We have established and validated a prognostic classifier to inform clinical management of patients with lung SCC after surgical resection. Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer.

DOI： 10.1016/j.jtho.2016.08.141

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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：SPRINGER INTERNATIONAL PUBLISHING AG  

Background: Chemotherapy-induced nausea and vomiting (CINV) is a major adverse toxicity of cancer chemotherapy. Recommended treatments for prevention of CINV vary among published guidelines, and optimal care for CINV caused by moderately emetogenic chemotherapy has not been established. This study assessed the efficacy and safety of triple antiemetic therapy comprising palonosetron, dexamethasone and aprepitant for carboplatin-based chemotherapy. Chemotherapy-naive patients with lung cancer scheduled for a first course of a carboplatin-containing regimen formed the study cohort. Patients were pretreated with antiemetic therapy comprising palonosetron (0.75 mg, i.v.) and dexamethasone (9.9 mg, i.v.) on day 1, and aprepitant (125 mg, p.o.) on day 1 followed by 80 mg on days 2 and 3. Primary endpoint was the proportion of patients who did not experience vomiting and did not require rescue medication [complete response (CR)] in the acute phase (0-24 h), late phase (24-168 h) and overall. Secondary endpoint was the proportion of patients who experienced no vomiting episodes and no more than mild nausea without the need for rescue medication [complete control (CC)].
Results: Prevalence of a CR during the acute phase, delayed phase, and overall was 100, 91.9 and 91.9%, whereas that of CC was 100, 84.4 and 84.4%, respectively. The most common adverse event was mild constipation; severe adverse events related to antiemetic treatment were not observed.
Conclusion: Triple antiemetic therapy comprising palonosetron, dexamethasone and aprepitant shows excellent effects in the prevention of CINV in patients receiving a carboplatin-containing regimen.

DOI： 10.1186/s40064-016-3769-x

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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：OXFORD UNIV PRESS  

Objective: Amrubicin, which is used as a chemotherapeutic agent for lung cancer, can induce interstitial lung disease. There is insufficient evidence on the incidence of amrubicin-associated interstitial lung disease under practical use settings. We therefore investigated the occurrence of interstitial lung disease in the patients with lung cancer who received amrubicin in our institution.
Methods: We reviewed the data of all patients with lung cancer who received amrubicin at the Nippon Medical School Hospital from March 2002 to April 2015. Interstitial lung disease was diagnosed based on clinical symptoms, radiographic findings and the exclusion of other diseases.
Results: We reviewed 92 consecutive patients with lung cancer. Amrubicin-associated interstitial lung disease occurred in 3 of the 92 patients (3.3%): 2 were definite interstitial lung disease and 1 was possible interstitial lung disease. The severity of interstitial lung disease was mild to moderate, and interstitial lung disease improved with or without corticosteroid therapy in all cases. The findings in a computed tomography image analysis showed preexisting pulmonary fibrosis (n = 13), including interstitial pneumonitis (n = 10) and radiation fibrosis (n = 3). No patients showed the presence of honeycomb lung. Among the 13 patients, 1 (7.7%) developed interstitial lung disease after amrubicin chemotherapy.
Conclusion: Interstitial lung disease occurred in 3.3% of the patients in our study; this appeared to be less frequent than the rates in previous reports. Preexisting pulmonary fibrosis may be a risk factor for interstitial lung disease; however, no fatal cases were found among the patients with asymptomatic pulmonary fibrosis without honeycomb lung. It is thus considered to be necessary to carefully assess the possibility of preexisting pulmonary fibrosis and clarify the presence or absence of honeycomb lung before starting amrubicin chemotherapy.

DOI： 10.1093/jjco/hyw043

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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：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Cisplatin is a highly effective anticancer drug for treatment of various tumors including non-small-cell lung cancer (NSCLC), and is especially useful in cases nonresponsive to molecular-targeted drugs. Accumulating evidence has shown that cisplatin activates the p53-dependent apoptotic pathway, but it also induces apoptosis in p53-mutated cancer cells. Here we demonstrated that DNA-damage inducible proapoptotic BH3 (Bcl-2 homology region 3)-only Bcl-2 family members, Noxa, Puma, Bim and Bid, are not involved in cisplatin-induced apoptosis in human NSCLC cell lines. In contrast, the expression of proapoptotic multidomain Bcl-2-family members, Bak and Bax, was induced by cisplatin in p53 dependent and-independent manners, respectively. Moreover, in wild-type p53-expressing cells, cisplatin mainly used the Bak-dependent apoptotic pathway, but this apoptotic pathway shifted to the Bax-dependent pathway by loss-of-function of p53. Furthermore, both Bak- and Bax-induced apoptosis was enhanced by the antiapoptotic Bcl-2 family member, Bcl-X-L knockdown, but not by Mcl-1 knockdown. From this result, we tested the effect of ABT-263 (Navitoclax), the specific inhibitor of Bcl-2 and Bcl-XL, but not Mcl-1, and found that ABT-263 synergistically enhanced cisplatin-induced apoptosis in NSCLC cells in the presence or absence of p53. These results indicate a novel regulatory system in cisplatin-induced NSCLC cell apoptosis, and a candidate efficient combination chemotherapy method against lung cancers. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2016.03.053

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

Nintedanib (BIBF1120) is a multi-targeted angiokinase inhibitor and has been evaluated in idiopathic pulmonary fibrosis and advanced non-small cell lung cancer (NSCLC) patients in clinical studies. In the present study, we evaluated the antitumor effects of nintedanib in 16 NSCLC cell lines and tried to identify microRNA (miRNA) associated with sensitivity to nintedanib. No correlations between FGFR, PDGFR and VEGFR family activation and sensitivity to nintedanib were found. The difference in miRNA expression profiles between 5 nintedanib-sensitive and 5 nintedanib-resistant cell lines was evaluated by miRNA array and quantitative RT-PCR analysis (qRT-PCR). Expression of miR-200b, miR-200a and miR-141 belonging to the miR-200 family which contributes to epithelial-mesenchymal transition (EMT), was significantly lower in 5 nintedanib-resistant than in 5 nintedanib-sensitive cell lines. We examined the protein expression of EMT markers in these 10 NSCLC cell lines. E-cadherin expression was lower, and vimentin and ZEB1 expression were higher in 5 nintedanib-resistant cell lines. PC-1 was the most sensitive of the NSCLC cell lines to nintedanib. We established nintedanib-resistant PC-1 cells (PC-1R) by the stepwise method. PC-1R cells also showed decreased expression of miR-200b, miR-141 and miR-429 and increased expression of ZEB1 and ZEB2. We confirmed that induction of miR-200b or miR-141 enhanced sensitivity to nintedanib in nintedanib-resistant A549 and PC1-R cells. In addition, we evaluated the response to gefitinib in combination with nintedanib after TGF-beta 1 exposure of A549 cells. Nintedanib was able to reverse TGF-beta 1-induced EMT and resistance to gefitinib caused by miR-200b and miR-141 upregulation and ZEB1 downregulation. These results suggested that the miR-200/ZEB axis might be predictive biomarkers for sensitivity to nintedanib in NSCLC cells. Furthermore, nintedanib combined with gefitinib might be a novel therapeutic strategy for NSCLC cells with EMT phenotype and resistance to gefitinib.

DOI： 10.3892/ijo.2016.3331

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

To date, a number of potential biomarkers for lung squamous cell cancer (SCC) have been identified; however, sensitive biomarkers are currently lacking to detect early stage SCC due to low sensitivity and specificity. In the present study, we compared the 7 serum proteomic profiles of 11 SCC patients, 7 chronic obstructive pulmonary disease (COPD) patients and 7 healthy smokers as controls to identify potential serum biomarkers associated with SCC and COPD. Two-dimensional difference gel electrophoresis (2D-DIGE) and mass-spectrometric analysis (MS) using an affinity column revealed two candidate proteins, haptoglobin (HP) and apolipoprotein 4, as biomarkers of SCC, and alpha-1-antichymotrypsin as a marker of COPD. The iTRAQ technique was also used to identify SCC-specific peptides. HP protein expression was significantly higher in SCC patients than in COPD patients. Furthermore, two HP protein peptides showed significantly higher serum levels in SCC patients than in COPD patients. We established novel polyclonal antibodies for the two HP peptides and subsequently a sandwich enzyme-linked immunosorbent assay (ELISA) for the quantification of these specific peptides in patient and control sera. The sensitivity of detection by ELISA of one HP peptide (HP216) was 70% of SCC patients, 40% of COPDs patients and 13% of healthy controls. We also measured CYFRA, a cytokeratin fragment clinically used as an SCC tumor marker, in all the 28 cases and found CYFRA was detected in only seven SCC cases. However, when the measurement of HP216 was combined with that of CYFRA, 100% (10 of 10 patients) of SCC cases were detected. Our proteomic profiling demonstrates that the SCC-specific HP peptide HP216 may potentially be used as a diagnostic biomarker for SCC.

DOI： 10.3892/ijo.2016.3330

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

Patients with non-small cell lung cancer (NSCLC) EGFR mutations have shown a dramatic response to EGFR inhibitors (EGFR-TKI). EGFR T790M mutation and MET amplification have been recognized as major mechanisms of acquired resistance to EGFR-TKI. Therefore, MET inhibitors have recently been used in NSCLC patients in clinical trials. In this study, we tried to identify the mechanism of acquired resistance to MET inhibitors. We analyzed the antitumor effects of two MET inhibitors, PHA-665752 and crizotinib, in 10 NSCLC cell lines. EBC-1 cells with MET amplification were the only cells that were sensitive to both MET inhibitors. We established PHA-665752-resistant EBC-1 cells, namely EBC-1R cells. Activation of KRAS, EGFR, and FGFR2 signaling was observed in EBC-1R cells by FISH and receptor tyrosine kinase phosphorylation antibody arrays. EBC-1R cells also showed overexpression of ATP-binding cassette subfamily B member 1 (ABCB1) as well as phosphorylation of MET. EBC-1R cells grew as cell spheres that exhibited cancer stem cell-like (CSC) properties and epithelial-mesenchymal transition (EMT). The level of miR138 that targeted ABCB1 was decreased in EBC-1R cells. ABCB1 siRNA and the ABCB1 inhibitor elacridar could reduce sphere numbers and suppress EMT. Elacridar could also reverse resistance to PHA-665752 in EBC-1R cells. Our study demonstrated that ABCB1 overexpression, which was associated with CSC properties and EMT, was involved in the acquired resistance to MET inhibitors. Inhibition of ABCB1 might be a novel therapeutic strategy for NSCLC patients with acquired resistance to MET inhibitors. (C) 2015 AACR.

DOI： 10.1158/1535-7163.MCT-15-0050

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記述言語：英語  

DOI： 10.1007/s13691-014-0205-3

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Mammalian target of rapamycin (mTOR) inhibitors have anti-tumor effects against renal cell carcinoma, pancreatic neuroendocrine cancer and breast cancer. In this study, we analyzed the antitumor effects of mTOR inhibitors in small cell lung cancer (SCLC) cells and sought to clarify the mechanism of resistance to mTOR inhibitors.
Methods: We analyzed the antitumor effects of three mTOR inhibitors including everolimus in 7 SCLC cell lines by MTS assay. Gene-chip analysis, receptor tyrosine kinases (RTK) array and Western blotting analysis were performed to identify molecules associated with resistance to everolimus.
Results: Only SBC5 cells showed sensitivity to everolimus by MTS assay. We established two everolimus resistant-SBC5 cell lines (SBC5 R1 and SBC5 R10) by continuous exposure to increasing concentrations of everolimus stepwise. SPP1 and MYC were overexpressed in both SBC5 R1 and SBC5 R10 by gene-chip analysis. High expression levels of eukaryotic translation initiation factor 4E (eIF4E) were observed in 5 everolimus-resistant SCLC cells and SBC5 R10 cells by Western blotting. MYC siRNA reduced eIF4E phosphorylation in SBC5 cells, suggesting that MYC directly activates eIF4E by an mTOR-independent bypass pathway. Importantly, after reduction of MYC or eIF4E by siRNAs, the SBC5 parent and two SBC5-resistant cells displayed increased sensitivity to everolimus relative to the siRNA controls.
Conclusion: These findings suggest that eIF4E has been shown to be an important factor in the resistance to everolimus in SCLC cells. Furthermore, a link between MYC and mTOR-independent eIF4E contribute to the resistance to everolimus in SCLC cells. Control of the MYC-eIF4E axis may be a novel therapeutic strategy for everolimus action in SCLC.

DOI： 10.1186/s12885-015-1202-4

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Lung adenocarcinoma patients with EGFR gene mutations have shown a dramatic response to gefitinib. However, drug resistance eventually emerges which limits the mean duration of response. With that in view, we examined the correlations between MET gene status as assessed by fluorescence in situ hybridization (FISH) with overall survival (OS) and progression-free survival (PFS) in adenocarcinoma patients with EGFR gene mutations who had received gefitinib therapy.
Methods: We evaluated 35 lung cancer samples with EGFR mutation from adenocarcinoma patients who had received gefitinib. Gene copy numbers (GCNs) and amplification of MET gene before gefitinib therapy was examined by FISH. MET protein expression was also evaluated by immunohistochemistry (IHC).
Results: FISH assessment showed that of the 35 adenocarcinoma samples, 10 patients (29%) exhibited high polysomy (5 copies. mean MET per cell) and 1 patient (3%) exhibited amplification (2 &lt;= MET gene (red)/CEP7q (green) per cell). IHC evaluation of MET protein expression could not confirm MET high polysomy status. The Eleven patients with MET FISH positivity had significantly shorter progression-free survival (PFS) and overall survival (OS) than the 24 patients who were MET FISH-negative (PFS: p = 0.001 and OS: p = 0.03). Median PFS and OS with MET FISH-positivity were 7.6 months and 16.8 months, respectively, whereas PFS and OS with MET FISH-negativity were 15.9 months and 33.0 months, respectively. Univariate analysis revealed that MET FISH-positivity was the most significant independent factor associated with a high risk of progression and death (hazard ratio, 3.83 (p = 0.0008) and 2.25 (p = 0.03), respectively).
Conclusions: Using FISH analysis to detect high polysomy and amplification of MET gene may be useful in predicting shortened PFS and OS after Gefitinib treatment in lung adenocarcinoma. The correlation between MET gene status and clinical outcomes for EGFR-TKI should be further evaluated using large scale samples.

DOI： 10.1186/s12885-015-1019-1

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

The recent development of human genome studies has demonstrated the possibility of alteration of several genes as oncogenic driver mutations of lung squamous cell carcinoma (SQCC). FGFR1, PIK3CA and SOX2 genes have been recognized as candidate driver genes of SQCC. The aim of the present study was to evaluate FGFR1, PIK3CA and SOX2 protein expression in SQCC and determine whether the expression of these can be used as prognostic biomarkers. We evaluated the relationships between FGFR1, PIK3CA and SOX2 expression by immunohistochemical analysis and overall survival in lung SQCC patients with stage I-Ill that originated from China, United States and Japan. FGFR1-positive, PIK3CA-negative and SOX2-positive staining each showed trends toward better survival, although the differences were not statistically significant in a Chinese cohort of 57 patients. Patients with PIK3CA-negative and SOX2-positive staining (PIK3CA/SOX2(+)) showed better prognosis compared with those with PIK3CA-positive or SOX2-negative staining in the Chinese cohort (P=0.04). The robustness of PIK3CAT/SOX2(+) classification as having prognostic significance was validated in an independent set of 66 Japanese cohort patients (P=0.007). Japanese SQCC patients with stage I were evaluated separately and PIK3CA(-)/SOX2(+) cases had significantly better survival than the group with PIK3CA-positive or SOX2-negative status (P=0.03). In univariate and multivariable Cox proportional hazards models of Asian stage I patients, the PIK3CA(-)/SOX2(+) classification was statistically significantly associated with survival and was an independent prognostic factor. Classification by PIK3CA and SOX2 protein expression is useful for predicting the prognosis of Asian patients with lung SQCC with stage I.

DOI： 10.3892/ijo.2014.2742

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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：SPANDIDOS PUBL LTD  

Malignant pleural mesothelioma (MPM) is a rapidly fatal malignancy that is increasing in incidence in Japan. In this study, we performed gene and microRNA (miRNA) expression profiling to identify novel therapeutic targets in MPM cells. Based on relative sensitivities to pemetrexed (PEM) and the histone deacetylase (HDAC) inhibitor, vorinostat (SAHA), 211H cells were determined to be the only sensitive MPM cell line out of the 6 tested. On the same series of cell lines, we performed whole genome transcriptomic profiling via DNA microarrays and pathway analysis of the derived data. Of particular note, IL-18 gene expression levels were significantly higher in the cell lines that were either drug resistant or displayed intermediate sensitivity, compared to the sensitive 211H cell line. Pathway analysis revealed IL-18 as an important gene associated with drug sensitivity of MPM cells. A relationship between IL-18 overexpression and drug resistance was also observed following targeted assessment of 10 cytokine genes using quantitative RT-PCR. miRNA expression profiles were evaluated in the MPM cell line panel in order to discern the mechanism of IL-18 induction in the drug-resistant lines. We found that miR-379 and miR-411 belonged to the same cluster of miRNAs located on chromosome 14q32 that commonly target the IL-18 gene. Luciferase reporter assays revealed that miR-379 and miR-411 directly target the IL-18 gene. Introduction of miR-379 plus miR-411, as well as IL-18 silencing, significantly suppressed the invasive capacity of MES01 cells in vitro. Furthermore, the use of either PEM or SAHA together with miR-379 plus miR-411 mimics mediated increased sensitivity to these drugs in MES01 cells. These results suggest that the miR-379/411 cluster may provide new therapeutic opportunities for advanced MPM patients, depending on the nature of IL-18 gene expression.

DOI： 10.3892/or.2014.3481

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DOI： 10.1158/1538-7445.AM2014-5206

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記述言語：英語   出版者・発行元：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2014-4062

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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：ELSEVIER IRELAND LTD  

Background: Combined pulmonary fibrosis and emphysema (CPFE) patients may be at significantly increased risk of lung cancer compared with either isolated emphysema or pulmonary fibrosis patients. Acute exacerbation (AE) of interstitial lung disease caused by anticancer treatment is the most common lethal complication in Japanese lung cancer patients. Nevertheless, the clinical significance of CPFE compared with isolated idiopathic interstitial pneumonias (IIPs) in patients with lung cancer is not well understood.
Methods: A total of 1536 patients with lung cancer at Nippon Medical School Hospital between March 1998 and October 2011 were retrospectively reviewed. Patients with IIPs were categorized into two groups: (i) CPFE; IIP patients with definite emphysema and (ii) non-CPFE; isolated IIP patients without definite emphysema. The clinical features, anti-cancer treatments and outcomes of the CPFE group were compared with those of the non-CPFE group.
Results: CPFE and isolated IIPs were identified in 88 (5.7%) and 63 (4.1%) patients respectively, with lung cancer. AE associated with initial treatment occurred in 22 (25.0%) patients in the CPFE group and in 8 (12.7%) patients in the non-CPFE group, irrespective of treatment modality. Median overall survival (OS) of the CPFE group was 23.7 months and that of the non-CPFE group was 20.3 months (P = 0.627). Chemotherapy was performed in a total of 83 patients. AE associated with chemotherapy for advanced lung cancer occurred in 6 (13.6%) patients in the CPFE group and 5 (12.8%) patients in the non-CPFE group. Median OS of the CPFE group was 14.9 months and that of the non-CPFE group was 21.6 months (P = 0.679).
Conclusion: CPFE was not an independent risk factor for AE and was not an independent prognosis factor in lung cancer patients with IIPs. Therefore, great care must be exercised with CPFE as well as IIP patients when performing anticancer treatment for patients with lung cancer. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2014.05.016

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

Pemetrexed (PEM) is currently recommended as one of the standard anticancer drugs for malignant pleural mesothelioma (MPM). However, the mechanism of the sensitivity of MPM to PEM remains unclear. We analyzed the antitumor effects of PEM in six MPM cell lines by MTS assay. To identify genes associated with drug sensitivity, we conducted gene expression profiling on the same set of cell lines using GeneChips and pathway analysis. Three cell lines were sensitive to PEM. A total fo 18 transcripts and 14 genes identified by GeneChips were significantly correlated with sensitivity to PEM. Pathway analysis revealed that osteopontin (SPP1/OPN) was an important target in PEM sensitivity. Overexpression of SPP1/OPN was observed in the sensitive cells by quantitative PCR and western blot analysis. Introduction of SPP1/OPN by lentiviral vector significantly enhanced the invasion activities of MPM cells. PEM treatment with SPP1/OPN knockdown inhibited the PEM-induced cell growth-inhibitory effect in PEM-sensitive cells. Expression of SPP1/OPN and AKT phosphorylation significantly decreased after PEM treatment of the PEM-sensitive cells. High immunohistochemical expression of SPP1/OPN was observed in two of three MPM patients who had a partial response to PEM-based chemotherapy. PEM has antitumor effects in MPM cells dependent on SPP1/OPN overexpression resulting in AKT activation. Our results suggest that SPP1 may be used as a single predictive biomarker of the effectiveness of PEM treatment in MPM.

DOI： 10.3892/ijo.2014.2370

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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：SPANDIDOS PUBL LTD  

Lung cancer is the most common cancer and the most common cause of cancer-related death in the world. Nestin, a class VI intermediate filament, is known to be a cancer stem cell (CSC) marker as well as a neuroepithelial stem cell marker. High expression levels of nestin are reported in several types of cancers including lung, pancreatic and prostate cancers. Nestin is thought to regulate tumor cell proliferation, migration, invasion and CSC properties. Here, we confirmed nestin expression in non-small cell lung cancer (NSCLC): Immunohistochemical analysis in surgical specimens detected nestin protein expression in the cytoplasm of 20 of 48 adenocarcinoma (AD) cases (41.7%) and 25 of 47 squamous cell carcinoma cases (53.2%). Nestin immunore-activity significantly correlated with not only tumor size and lymph node metastasis in NSCLC, but also poor survival in surgical patients with AD. High and moderate expression levels of nestin were confirmed in several lung AD cell lines including H1975 and PC-3. Nestin inhibition by shRNA decreased proliferation, migration, invasion and sphere formation in AD cells. Correspondingly, nestin upregulation by nestin gene transfection resulted in the opposite changes. Moreover, Akt inhibitor IV effectively decreased nestin expression via SRY-box containing protein 2 (Sox2) down-regulation and overcame the enhanced sphere formation induced by nestin upregulation. Overall, our results show that nestin correlates with the aggressiveness and stemness of AD. Regulation of nestin via Akt/Sox2 is, thus, a promising candidate for novel therapeutic approaches to eradicate CSCs in lung AD.

DOI： 10.3892/ijo.2014.2278

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1158/1535-7163.MCT-13-0448

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担当区分：筆頭著者   記述言語：英語  

DOI： 10.1007/s13691-0123-9

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担当区分：筆頭著者   記述言語：英語   掲載種別：論文集(書籍)内論文   出版者・発行元：Pan Stanford Publishing Pte. Ltd.  

DOI： 10.4032/9789814316989

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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：BIOMED CENTRAL LTD  

Background: The EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) fusion oncogene represents a novel molecular target in a small subset of non-small-cell lung cancers (NSCLCs). The EML4-ALK fusion gene occurs generally in NSCLC without mutations in epidermal growth factor receptor (EGFR) and KRAS.
Case presentation: We report that a case of EML4-ALK-positive NSCLC with EGFR mutation had a response of stable disease to both an EGFR tyrosine kinase inhibitor (EGFR-TKI) and ALK inhibitor.
Conclusions: We described the first clinical report of a patient with EML4-ALK-positive NSCLC with EGFR mutation that had a response of stable disease to both single-agent EGFR-TKI and ALK inhibitor. EML4-ALK translocation may be associated with resistance to EGFR-TKI, and EGFR signaling may contribute to resistance to ALK inhibitor in EML4-ALK-positive NSCLC.

DOI： 10.1186/1471-2407-13-262

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: A phase II study was conducted in order to determine the tumor efficacy and tolerance of alternating chemotherapy for extensive-stage small cell lung cancer (ED-SCLC). PATIENTS AND METHODS: Twenty patients with previously-untreated ED-SCLC were enrolled in the study. At least four courses of chemotherapy consisting of alternation of two drug combinations were given: alternating cycles of amrubicin and cisplatin with weekly administration of irinotecan and cisplatin at 3- or 4-week intervals. RESULTS: The overall response rate was 85.0% (17/20). The median duration of overall survival and progression-free survival were 359 days and 227 days, respectively. Hematological toxicity was the main adverse event. Grade 3 or 4 neutropenia, thrombocytopenia and anemia were observed in 20 (100%), 4 (20%) and 6 (30%) patients, respectively. With regard to non-hematological adverse events, grade 3 or 4 anorexia, diarrhea, febrile neutropenia and infection were observed in 5 (25%), 2 (10%), 2 (10%) and 2 (10%) patients, respectively. No treatment-related death occurred during either regimen. CONCLUSION: The novel alternating non-cross-resistant chemotherapy was probably active against ED-SCLC and had acceptable toxicities. Further evaluation of this treatment for ED-SCLC in randomized phase III trials is warranted.

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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：SPRINGER  

The presence of malignant pleural effusion (MPE) indicates a poorer prognosis for patients with non-small-cell lung cancer (NSCLC) and impairs their quality of life. Because vascular endothelial growth factor (VEGF) is the key mediator MPE production, we evaluated the efficacy and safety of chemotherapy plus bevacizumab, an anti-VEGF antibody, in non-squamous NSCLC patients with MPE, especially regarding the control of pleural effusions.
From November 1, 2009 to September 30, 2011, medical charts of 13 consecutive patients with MPE who received bevacizumab plus chemotherapy as the initial or secondary treatment were retrospectively analyzed.
Of the 13 patients, 6 did not undergo pleurodesis, 3 were unsuccessfully treated by pleurodesis, 2 had encapsulated pleural effusion, and 2 had no re-expansion of the lung. Twelve patients (92.3 %) achieved MPE control lasting &gt; 8 weeks following bevacizumab plus chemotherapy. Five of 10 patients with measurable lesions had confirmed partial responses. Of 3 patients without measurable lesions, one had confirmed CR. Median progression-free survival time without re-accumulation of MPE was 312 days. Grade 3 or 4 neutropenia, thrombocytopenia, hypertension, or proteinuria was observed in 2, 2, 1, or 1 patient, respectively.
This is the first study to report that bevacizumab plus chemotherapy is highly effective for the management of MPE in non-squamous NSCLC patients. Prospective clinical trials are warranted to investigate the efficacy of bevacizumab for MPE.

DOI： 10.1007/s00280-012-2026-4

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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：JAPAN SOC INTERNAL MEDICINE  

Histiocytic sarcoma (HS) is a rare malignancy of soft tissues with an unknown etiology. The CHOP (cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride and prednisolone) regimen is often adopted as first-line chemotherapy; however, its therapeutic efficacy against HS is usually low. We herein first present the case of a patient with HS who was infected with human immunodeficiency virus-1 (HIV) in whom treatment with a combination of CHOP and antiretroviral therapy (ART) was successful. The patient has been in complete remission for 12 months following the discontinuation of chemotherapy under continuous ART. This case report may help to promote further investigation of both HS and HIV-related malignancy.

DOI： 10.2169/internalmedicine.52.0523

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記述言語：英語  

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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：INT INST ANTICANCER RESEARCH  

Background: A phase II study was conducted to determine the tumor efficacy and tolerance of alternating chemotherapy in extensive-stage small-cell lung cancer (ED-SCLC). Patients and Methods: Thirty-six patients with previously untreated ED-SCLC were enrolled in the study. At least four courses of chemotherapy consisting of alternation of two drug combinations were given: alternating cycles of etoposide and carboplatin (EC) with weekly administration of irinotecan and cisplatin (IP) at 3- or 4-week intervals. Results: The overall response rate was 81.8%. The median duration of survival and progression-free survival were 314 days and 144 days, respectively. Hematological toxicity was the main adverse event. Grade 3 or 4 neutropenia, thrombocytopenia and anemia were observed in 69.2, 25.6 and 23.1% of the patients, respectively. Severe diarrhea (10.8%) was remarkable during the IP regimen. Conclusion: This novel alternating chemotherapy for patients with ED-SCLC showed moderate tumor efficacy and an acceptable safety profile.

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3892/ijo.2012.1535

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記述言語：日本語   出版者・発行元：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

Non-small cell lung cancer (NSCLC) patients with activating mutations of the epidermal growth factor receptor (EGFR) gene have shown a dramatic response to EGFR tyrosine kinase inhibitors (EGFR-TKI) such as gefitinib and erlotinib. EGFR-activating mutations including exon 19 deletion and exon 21 L858R are recognized as markers of the sensitivity to EGFR-TKI therapy in NSCLC. However, the emergence of acquired resistance is virtually inevitable, thus limiting improvement in patient outcomes. Several acquired-resistance mechanisms and candidates, including exon 20 T790M secondary mutation, MET amplification, a high-level of HGF expression, PTEN downregulation, FAS-NF-κB pathway activation, epithelial-mesenchymal transition, and conversion to small cell lung cancer, have been identified. Understanding the mechanisms of acquired resistance to EGFR-TKI, followed by the development of molecular targeted drugs that can overcome the resistance, could serve as an important advance for targeting EGFR, which is activated in NSCLC. Further studies should be performed to clarify other mechanisms associated with the acquired resistance to EGFR-TKI. In this review, we summarize recent advances in the therapeutic biomarkers to EGFR-TKI.

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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：LIPPINCOTT WILLIAMS & WILKINS  

Background: Idiopathic interstitial pneumonias (IIPs) are among the most common complications in patients with lung cancer. In such patients with cancer, the most serious expression of toxicity in Japan is acute exacerbation of IIPs caused by anticancer treatment. Nevertheless, there has been no consensus and no evidence presented, regarding optimal treatment for advanced lung cancer with IIP.
Patients and Methods: Chemotherapy-naive patients with advanced small cell lung cancer (SCLC) with IIP who were ineligible for curative radiotherapy were enrolled. Patients received carboplatin every 21 days at a dose of area under the curve 6.0 on day 1 and etoposide at a dose of 100 mg/m(2) on days 1 to 3.
Results: Between July 2002 and October 2008, 17 patients with SCLC with IIP, including 14 men, eight of whom were diagnosed with idiopathic pulmonary fibrosis, were enrolled and treated for a mean of 3.5 cycles of carboplatin plus etoposide. One patient (5.9%; 95% confidence interval, 0-18.4%) with clinically confirmed idiopathic pulmonary fibrosis had acute exacerbation of IIPs associated with the treatment. The overall response rate was 88.2%. The median progression-free survival, median survival time, and 1-year survival rate were 5.5 months, 8.7 months, and 29.4%, respectively.
Conclusion: This is the first report indicating that patients with advanced SCLC with IIPs may benefit from chemotherapy. Patients with advanced SCLC with IIP treated with etoposide and carboplatin combination chemotherapy gain benefits, with safety equivalent to that seen in patients without IIP. The results from this study would support, on ethical grounds, the conduct of a large-scale study to evaluate this regimen.

DOI： 10.1097/JTO.0b013e3182103d3c

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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：ELSEVIER IRELAND LTD  

Background: Idiopathic interstitial pneumonias (IIPs) are one of the most common complications in patients with lung cancer. In lung cancer patients with IIP, the most serious toxicity is acute exacerbation of IIP caused by anticancer treatment in Japan. However, there has been no consensus and no evidence presented, regarding optimal treatment for advanced lung cancer with IIP.
Patients and methods: Chemotherapy-naive patients of inoperable stage, or post-operative recurrent non-small cell lung cancer (NSCLC) with IIPs were enrolled. Patients received paclitaxel at a dose of 100 mg/m(2) on Days 1, 8, 15, and carboplatin every 28 days at a target dose of area under the curve (AUC) 5.0 on Day 1.
Results: Between May 2004 and October 2008, 18 patients, including 6 with idiopathic pulmonary fibrosis (IPF), were enrolled and treated for a median of four cycles (range, 1-6). One patient (5.6%; 95% confidence interval (Cl). 0-17%) with histologically confirmed IPF had acute exacerbation of IIPs associated with the treatment. The overall response rate was 61% (95% Cl, 36-86%). The median progression-free survival, median survival time, and 1-year survival rate were 5.3 months, 10.6 months, and 22%, respectively.
Conclusion: This is the first report indicating that advanced NSCLC patients with IIP may benefit from chemotherapy. Weekly paclitaxel and carboplatin combination chemotherapy was as effective as conventional regimens in advanced NSCLC patients without IIP and was safer than previously reported for NSCLC patients with IIP. The results from this study would support, on ethical grounds, the conduct of a large-scale study to confirm the feasibility of this regimen. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2010.04.014

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記述言語：英語   出版者・発行元：The Medical Association of Nippon Medical School  

DOI： 10.1272/jnms.78.46

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記述言語：日本語   出版者・発行元：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.33.Special_S299_3

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

Epithelial to mesenchymal transition (EMT) is induced by transforming growth factor-beta 1 (TGF-beta 1) and is a crucial event for cancer cells to acquire invasive and metastatic phenotypes. However, the signals that induce EMT in cancer cells have yet to be adequately defined. In this study, a proteomic investigation was performed to understand the signaling pathway of the EMT of lung cancer using two-dimensional difference gel electrophoresis (2D-DIGE) and mass spectrometry. The protein expression profiles of A549 were compared to those of A549 cells treated with TGF-beta 1. Of more than 2,000 protein spots shown by 2D-DIGE, 53 were found to be up- or down-regulated upon induction with TGF-beta 1. In the 53 protein. spots, the protein level of heat shock protein (HSP) 27 was found to increase significantly. HSP27 protein was higher in two different lung cancer cell lines, demonstrating the EMT phenomenon with TGF-beta 1. Notably, the silencing of HSP27 enhanced. spindle integration, resulting in an additive effect with TGF-beta 1-induced EMT. Furthermore, the TGF-beta 1-induced HSP27 increase was not affected by the suppression of Smad2 and Smad3 in A549 cells. These results suggest that HSP27 was involved in TGF-beta 1-induced EMT in a Smad-independent manner in lung cancer cells and may provide an effective clinical strategy in lung cancer patients whose tumors are dependent on TGF-beta 1-induced EMT.

DOI： 10.3892/ol.2010.190

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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：WILEY-BLACKWELL  

It is desirable to find more appropriate therapeutic opportunities in non-small-cell lung cancer (NSCLC) due to the current poor prognosis of affected patients. Recently, several histone deacetylase (HDAC) inhibitors, including suberoylanilide hydroxamic acid (SAHA), have been reported to exhibit antitumor activities against NSCLC. S-1, a novel oral fluorouracil anticancer drug, has been developed for clinical use in the treatment of NSCLC in Japan. Using an MTT assay, we analyzed the growth-inhibitory effect of 5-fluorouracil (5-FU), S-1, and SAHA against three NSCLC cell lines, as well as the breast cancer cell line MCF7 which is known to be highly sensitive to 5-FU. Combined treatment with low-dose SAHA enhanced 5-FU- and S-1-mediated cytotoxicity and resulted in synergistic effects, especially in 5-FU-resistant cells. Both the mRNA and protein expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and orotate phosphoribosyltransferase (OPRT), which are associated with 5-FU sensitivity/response, were analyzed in the cells undergoing treatment. 5-Fluorouracil-resistant lung cancer cells displayed high expression of TS mRNA and protein. Suberoylanilide hydroxamic acid down-regulated TS mRNA and protein expression, as well as repressed the rapid induction of this factor during 5-FU treatment, in all examined cell types. We also examined the status of the Rb-E2F1 pathway, with SAHA up-regulating p21waf1/cip1 expression via promoter histone acetylation; this, in turn, blocked the Rb-E2F1 pathway. We conclude that combination therapy with SAHA and S-1 in lung cancer may be promising due to its potential to overcome S-1 resistance via modulation of 5-FU/S-1 sensitivity-associated biomarker (TS) by HDAC inhibitor. (Cancer Sci 2010).

DOI： 10.1111/j.1349-7006.2010.01559.x

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記述言語：英語  

Small interfering RNAs (siRNAs) and microRNAs (miRNAs) are functional RNA molecules that have recently emerged as important regulators of gene expression at the posttranscriptional or translational level. The RNA interference effects of siRNA on gene expression make it a valuable research tool for knocking down the expression of genes in mammalian cells in vitro and in vivo enabling the elucidation of molecular mechanisms underlying human diseases. Endogenous miRNAs are involved in a variety of physiological and pathological processes in humans. In this mini-review we first address the synthesis, mechanisms of action, and functions of siRNAs. Then, we focus on recent advances and technologies in miRNA and protein research of the human placenta. Next, we discuss the clinical applications of miRNA in lung cancer. We also touch on "long" noncoding RNAs from intergenic regions of the human genome. This review article is based on a presentation given at a symposium entitled Basic and Clinical Studies on Functional RNA Molecules for Advanced Medical Technologies held at Nippon Medical School in Tokyo, Japan, on November 7, 2009.

DOI： 10.1272/jnms.77.71

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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：SPANDIDOS PUBL LTD  

Previously, we performed a molecular pharmacological study that applied a combination of DNA microarray-based gene expression profiling and drug sensitivity tests in vitro with a view to designing an improved chemotherapeutic strategy for advanced lung cancer Utilizing recent key technological advances in proteomics, particularly antibody array-based methodologies, the current study aimed to examine the benefit of protein expression profiling in an analogous molecular pharmacological context We performed protein expression analysis in a panel of lung cancer cell lines via an antibody array approach Using a modified NCI program, we related cell line-specific proteomic profiles to the previously determined cytotoxic activity of a selection of commonly used anticancer agents, namely docetaxel, paclitaxel, gemcitabine, vinorelbine, 5-fluorouracil (5-FU), SN38, cisplatin (CDDP) and carboplatin (CBDCA) In addition, we compared these results with those obtained from our prior DNA microarray-based transcriptomic study In our expression-drug correlation analysis using antibody array, gemcitabine consistently belonged to an isolated cluster Docetaxel, paclitaxel, 5-FU, SN38, CBDCA and CDDP were gathered together into one large cluster These results coincided with those generated by the prior transcriptomic study Various genes were commonly listed that differentiated gemcitabine from the others The identified factors associated with drug sensitivities were different between both analyses Our proteomic profiling data provided confirmation of the previous transcript expression-drug sensitivity correlation analysis These results suggest that chemotherapy regimens that include gemcitabine should be evaluated in second-line chemotherapy in cases where the first-line chemotherapy did not include this drug Protein expression-drug sensitivity correlations in lung cancer cells in vitro may provide useful information in determining the most appropriate therapeutic options for lung cancer patients

DOI： 10.3892/etm_00000007

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記述言語：日本語   出版者・発行元：日本プロテオーム学会（日本ヒトプロテオーム機構）  

DOI： 10.14889/jhupo.2010.0.75.1

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Epithelial to mesenchymal transition (EMT) is a process by which cells undergo a morphological switch from the epithelial polarized phenotype to the mesenchymal fibroblastoid phenotype and which can be elicited by transforming growth factor-β1 (TGF-β1). EMT has been recognized to play pivotal roles in several diverse processes during embryonic development, chronic inflammation and fibrosis, and the progression of solid tumors, including lung cancer. EMT is a crucial event for lung cancer cells to acquire invasive and metastatic phenotypes. These findings suggest that EMT is a potential target for the chemoprevention and treatment of lung cancer.

DOI： 10.1272/jnms.76.181

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATL ACAD SCIENCES  

Fifteen percent of lung cancer cases occur in never-smokers and show characteristics that are molecularly and clinically distinct from those in smokers. Epidermal growth factor receptor (EGFR) gene mutations, which are correlated with sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs), are more frequent in never-smoker lung cancers. In this study, microRNA (miRNA) expression profiling of 28 cases of never-smoker lung cancer identified aberrantly expressed miRNAs, which were much fewer than in lung cancers of smokers and included miRNAs previously identified (e. g., up-regulated miR-21) and unidentified (e. g., down-regulated miR-138) in those smoker cases. The changes in expression of some of these miRNAs, including miR-21, were more remarkable in cases with EGFR mutations than in those without these mutations. A significant correlation between phosphorylated-EGFR (p-EGFR) and miR-21 levels in lung carcinoma cell lines and the suppression of miR-21 by an EGFR-TKI, AG1478, suggest that the EGFR signaling is a pathway positively regulating miR-21 expression. In the never-smoker-derived lung adenocarcinoma cell line H3255 with mutant EGFR and high levels of p-EGFR and miR-21, antisense inhibition of miR-21 enhanced AG1478-induced apoptosis. In a never-smoker-derived adenocarcinoma cell line H441 with wildtype EGFR, the antisense miR-21 not only showed the additive effect with AG1478 but also induced apoptosis by itself. These results suggest that aberrantly increased expression of miR-21, which is enhanced further by the activated EGFR signaling pathway, plays a significant role in lung carcinogenesis in never-smokers, as well as in smokers, and is a potential therapeutic target in both EGFR-mutant and wild-type cases.

DOI： 10.1073/pnas.0905234106

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）  

DOI： 10.1272/jnms.76.44

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担当区分：筆頭著者   記述言語：英語   出版者・発行元：The Medical Association of Nippon Medical School  

Lung cancer is the leading cause of cancer death and the most common cause of smoking-related mortality both in the United States and worldwide. However, approximately 25% of cases of lung cancer are not attributable to smoking. Molecular and clinical characteristics of lung cancers in never-smokers are extremely different from those in smokers. For example, G to T transversions of the p53 gene and K-ras mutations occur more frequently in lung adenocarcinomas from smokers than in lung carcinomas from never-smokers. In contrast, mutations of the epidermal growth factor receptor (EGFR) gene are frequently observed in adenocarcinomas from never-smokers. Striking differences in response rates to EGFR tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, have been observed between lung cancers in never-smokers and those in smokers. Further understanding of the biological differences between lung cancers in never-smokers and those in smokers is necessary for the treatment strategies of lung cancer in never-smokers.<br> MicroRNAs (miRNAs) are small noncoding RNA molecules comprising 18 to 25 nucleotides which are frequently located at previously reported regions for genetic alterations in cancers, suggesting that miRNAs are a new class of genes involved in human tumorigenesis. Expression levels of miRNAs are altered in most human cancers, including lung cancers. Recently, miRNAs have also been demonstrated to be prognostic biomarkers, including for the response to therapy, in leukemia, lung cancer, and colon cancer. These findings suggest that miRNA could serve as a novel diagnostic marker and a therapeutic target in human cancers, including lung cancer. We have previously analyzed the miRNA profiles of 104 lung cancers and found that high miR-155 expression and low let7a expression, as independent risk factors, have a negative prognostic impact in patients with lung adenocarcinoma. The altered miRNA profiles were reflected primarily by the profiles of lung cancers in smokers.<br> In this study of 28 lung cancers in never-smokers, we found high expression levels of unique miRNAs in tumor tissues with a further statistically significant increase in cases with EGFR mutations by miRNA microarray analyses. In addition, the level of miR-21 was high in the lung adenocarcinoma cell line H3255, which contains an EGFR mutation and is hypersensitive to AG1478, an EGFR-TKI. After treatment with AG1478, expression levels of miR-21 were significantly decreased in H3255 cells with and without epidermal growth factor stimulation. Furthermore, inhibition of the miR-21 by antisense oligonucleotide-enhanced AG1478 induced apoptotic activities in lung cancer cells, which showed intermediate sensitivity to AG1478. These results suggest that aberrant expression of miR-21 contributes to the development of lung cancers in never-smokers through the activation of the EGFR signaling pathway. Our findings support the possibility of developing a treatment combining an EGFR-TKI with the inhibition of miR-21 in lung cancers from never-smokers.<br>

DOI： 10.1272/jnms.76.275

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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：AMER ASSOC CANCER RESEARCH  

To ascertain the potential for histone deacetylase (HDAC) inhibitor-based treatment in non-small cell lung cancer (NSCLC), we analyzed the antitumor effects of trichostatin A (TSA) and suberoylanilide hydroxamic acid (vorinostat) in a panel of 16 NSCLC cell lines via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. TSA and vorinostat both displayed strong antitumor activities in 50% of NSCLC cell lines, suggesting the need for the use of predictive markers to select patients receiving this treatment. There was a strong correlation between the responsiveness to TSA and vorinostat (P &lt; 0.0001). To identify a molecular model of sensitivity to HDAC inhibitor treatment in NSCLC, we conducted a gene expression profiling study using cDNA arrays on the same set of cell lines and related the cytotoxic activity of TSA to corresponding gene expression pattern using a modified National Cancer Institute program. In addition, pathway analysis was done with Pathway Architect software. We used nine genes, which were identified by gene-drug sensitivity correlation and pathway analysis, to build a support vector machine algorithm model by which sensitive cell lines were distinguished from resistant cell lines. The prediction performance of the support vector machine model was validated by an additional nine cell lines, resulting in a prediction value of 100% with respect to determining response to TSA and vorinostat. Our results suggested that (a) HDAC inhibitors may be promising anticancer drugs to NSCLC and (b) the nine-gene classifier is useful in predicting drug sensitivity to HDAC inhibitors and may contribute to achieving individualized therapy for NSCLC patients.

DOI： 10.1158/1535-7163.MCT-07-2140

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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：PROFESSOR D A SPANDIDOS  

To understand the mechanisms of PTEN inactivation, which is reported to be involved in tumor progression and drug resistance in lung cancer, we analyzed the expression levels of PTEN at mRNA and protein levels, along with the genetic and epigenetic status of the PTEN gene, in a panel of lung cancer cell lines. Western blot analysis showed that six out of 25 (24%) cell lines displayed low expression of PTEN protein. The level of PTEN mRNA correlated well with corresponding protein expression in each of these six cell lines. In two of the six cell lines genomic analysis revealed homozygous deletions of the PTEN gene. Another two of the six cell lines displayed hypermethylation of the PTEN gene promoter assessed by methylation-specific PCR. The levels of PTEN mRNA and protein expression in PC9/f9 and PC9/f14 cells, which are gefitinib-resistant derivatives of the gefitinib-sensitive cell line, PC9, were reduced compared to the parental line. After treatment with the demethylating agent 5-aza-2'deoxycytidine (5-AZA) and the histone deacetyl-transferase (HDAC) inhibitor Trichostatin A (TSA), the expression levels of PTEN mRNA and protein in these four cell lines (PC9/f9, PC9/f14, PC10 and PC14) were actually restored. In summary, reduction in PTEN protein expression was regulated by histone deacetylation and hypermethylation of the gene promoter, as well as homozygous deletion. In addition, we demonstrated that the combination treatment of gefitinib and TSA induced significant growth inhibition in gefitinib-resistant PC9/f9 and PC9/f14 cells. These findings suggest that the combination of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib with the demethylating agent 5-AZA and the HDAC inhibitor TSA may be a useful strategy for the treatment of some lung cancers,

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS INC  

Background A 17-cytokine gene expression signature in noncancerous hepatic tissue from patients with metastatic hepatocellular carcinoma (HCC) was recently found to predict HCC metastasis and recurrence. We examined whether the cytokine gene expression profile of noncancerous lung tissue could predict the metastatic capability of adjacent lung adenocarcinoma.
Methods We analyzed a 15-cytokine gene expression profile in noncancerous lung tissue and corresponding lung tumor tissue from 80 US lung adenocarcinorna patients using real-time quantitative reverse transcription-polymerase chain reaction. We then used unsupervised hierarchical clustering and Prediction Analysis of Microarray classification to test the prognostic ability of the 15-cytokine gene profile in the US patients and in an independent validation set comprising 50 Japanese patients with stage I disease. Survival was analyzed by the Kaplan-Meier method using the log-rank test, and univariate and multivariable Cox proportional hazards modeling were used to analyze the association of clinical variables with patient survival. All statistical tests were two-sided.
Results A 15-cytokine gene signature in noncancerous lung tissue primarily reflected the lymph node status of 80 long adenocarcinoma patients, whereas the gene signature of the corresponding lung tumor tissue was associated with prognosis independent of lymph node status. Cytokine Lung Adenocarcinoma Survival Signature of 11 genes (CLASS-11), a refined 11-gene signature, accurately classified patients, including those with stage I disease, according to risk of death from adenocarcinoma. CLASS-1 1 prognostic classification was statistically significantly associated with survival and was an independent prognostic factor for stage I patients (hazard ratio for death in the high-risk CLASS-11 group compared with the low-risk CLASS-1 1 reference group = 7.46, 95% confidence interval = 2.14 to 26.05; P = .002). CLASS-11 also classified patients in the validation set according to risk of recurrence.
Conclusion CLASS-11, which consists of genes for pro- and anti-inflammatory cytokines, identifies stage I lung adenocarcinoma patients who have a poor prognosis.

DOI： 10.1093/jnci/djm083

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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：BIOMED CENTRAL LTD  

Background: Phase III trials evaluating the efficacy of gefitinib (IRESSA) in non-small cell lung cancer (NSCLC) lend support to the need for improved patient selection in terms of gefitinib use. Mutation of the epidermal growth factor receptor (EGFR) gene is reported to be associated with clinical responsiveness to gefitinib. However, gefitinib-sensitive and prolonged stable-disease-defined tumors without EGFR gene mutation have also been reported.
Methods: To identify other key factors involved in gefitinib sensitivity, we analyzed the protein expression of molecules within the EGFR family, PI3K-Akt and Ras/MEK/Erk pathways and examined the sensitivity to gefitinib using the MTT cell proliferation assay in 23 lung cancer cell lines.
Results: We identified one highly sensitive cell line (PC9), eight cell lines displaying intermediate-sensitivity, and 14 resistant cell lines. Only PC9 and PC14 (intermediate-sensitivity) displayed an EGFR gene mutation including amplification. Eight out of the nine cell lines showing sensitivity had Akt phosphorylation without ligand stimulation, while only three out of the 14 resistant lines displayed this characteristic (P = 0.0059). Furthermore, the ratio of phosphor-Akt/total Akt in sensitive cells was higher than that observed in resistant cells (P = 0.0016). Akt phosphorylation was partially inhibited by gefitinib in all sensitive cell lines.
Conclusion: These results suggest that Akt phosphorylation without ligand stimulation may play a key signaling role in gefitinib sensitivity, especially intermediate-sensitivity. In addition, expression analyses of the EGFR family, EGFR gene mutation, and FISH (fluorescence in situ hybridization) analyses showed that the phosphorylated state of EGFR and Akt might be a useful clinical marker of Akt activation without ligand stimulation, in addition to EGFR gene mutation and amplification, particularly in adenocarcinomas.

DOI： 10.1186/1471-2407-6-277

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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：INT INST ANTICANCER RESEARCH  

A gene-drug correlation analysis was previously performed in lung cancer cell lines using the NC160 program. On the basis of this work, a phase I/II pilot study of weekly paclitaxel and carboplatin (CBDCA) was subsequently planned for refractory or recurrent non-small cell lung cancer (NSCLC). Safety and antitumor effects were evaluable in all 30 patients registered for this study. Seven patients were stage IIIB and 23 were stage IV. At level 5 (paclitaxel 100 mg/m(2) and CBDCA AUC5), toxicities were not dose-limiting factors, but three out of the initial six cases had infusion skips. Our recommended dose was paclitaxel 100 mg/m(2) and CBDCA AUC5. The response rate was 50% (9118)(95% CI: 27-73%) in step 5. The median survival time was 12 months. This combination showed a promising clinical activity with mild toxicity and should be selected for the investigational arm of phase III trials to be compared with either docetaxel or pemetrexed.

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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：BIOMED CENTRAL LTD  

background: The effect of current therapies in improving the survival of lung cancer patients remains far from satisfactory. It is consequently desirable to find more appropriate therapeutic opportunities based on informed insights. A molecular pharmacological analysis was undertaken to design an improved chemotherapeutic strategy for advanced lung cancer.
Methods: We related the cytotoxic activity of each of commonly used anti-cancer agents ( docetaxel, paclitaxel, gemcitabine, vinorelbine, 5-FU, SN38, cisplatin ( CDDP), and carboplatin ( CBDCA)) to corresponding expression pattern in each of the cell lines using a modified NCI program.
Results: We performed gene expression analysis in lung cancer cell lines using cDNA filter and high-density oligonucleotide arrays. We also examined the sensitivity of these cell lines to these drugs via MTT assay. To obtain our reproducible gene-drug sensitivity correlation data, we separately analyzed two sets of lung cancer cell lines, namely 10 and 19. In our gene-drug correlation analyses, gemcitabine consistently belonged to an isolated cluster in a reproducible fashion. On the other hand, docetaxel, paclitaxel, 5-FU, SN-38, CBDCA and CDDP were gathered together into one large cluster.
Conclusion: These results suggest that chemotherapy regimens including gemcitabine should be evaluated in second-line chemotherapy in cases where the first-line chemotherapy did not include this drug. Gene expression-drug sensitivity correlations, as provided by the NCI program, may yield improved therapeutic options for treatment of specific tumor types.

DOI： 10.1186/1471-2407-6-174

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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：CELL PRESS  

MicroRNA (miRNA) expression profiles for lung cancers were examined to investigate miRNA's involvement in lung carcinogenesis. miRNA microarray analysis identified statistical unique profiles, which could discriminate lung cancers from noncancerous lung tissues as well as molecular signatures that differ in tumor histology. miRNA expression profiles correlated with survival of lung adenocarcinomas, including those classified as disease stage 1. High hsa-mir-155 and low hsa-let-7a-2 expression correlated with poor survival by univariate analysis as well as multivariate analysis for hsa-mir-155. The miRNA expression signature on outcome was confirmed by real-time RT-PCR analysis of precursor miRNAs and crossvalidated with an independent set of adenocarcinomas. These results indicate that miRNA expression profiles are diagnostic and prognostic markers of lung cancer.

DOI： 10.1016/j.ccr.2006.01.025

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-V C H VERLAG GMBH  

We performed proteomic studies on lung cancer cells to elucidate the mechanisms that determine histological phenotype. Thirty lung cancer cell lines with three different histological backgrounds (squamous cell carcinoma, small cell lung carcinoma and adenocarcinoma) were subjected to two-dimensional difference gel electrophoresis (2-D DIGE) and grouped by multivariate analyses on the basis of their protein expression profiles. 2-D DIGE achieves more accurate quantification of protein expression by using highly sensitive fluorescence dyes to label the cysteine residues of proteins prior to two-dimensional polyacrylamide gel electrophoresis. We found that hierarchical clustering analysis and principal component analysis divided the cell lines according to their original histology. Spot ranking analysis using a support vector machine algorithm and unsupervised classification methods identified 32 protein spots essential for the classification. The proteins corresponding to the spots were identified by mass spectrometry. Next, lung cancer cells isolated from tumor tissue by laser microdissection were classified on the basis of the expression pattern of these 32 protein spots. Based on the expression profile of the 32 spots, the isolated cancer cells were categorized into three histological groups: the squamous cell carcinoma group, the adenocarcinoma group, and a group of carcinomas with other histological types. In conclusion, our results demonstrate the utility of quantitative proteomic analysis for molecular diagnosis and classification of lung cancer cells.

DOI： 10.1002/pmic.200401166

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-V C H VERLAG GMBH  

We assessed proteomic profiles as biomarkers for monitoring cell phenotypes. Protein expression profiles were obtained by fluorescence two-dimensional difference gel electrophoresis (2-D-DIGE), in which quantitative ability is improved by labeling proteins with fluorescent dyes prior to electrophoresis. Integrated protein spot intensities were analyzed by a statistical approach. The proteomic data of two groups of cell lines: (1) adenocarcinoma (AC) cell lines derived from lung, pancreas and colon tissues and (2) lung cancer cell lines with different histological backgrounds, including AC, squamous cell carcinoma and small cell carcinoma, were assessed on the basis of prior biological information. Hierarchical clustering analysis and principal component analysis were used to divide the cell lines into subgroups on the basis of similarities between their protein expression profiles. The majority of cell lines were grouped according to their organ of origin or histological background. A machine-learning algorithm selected 32 protein spots that were responsible for the classification. The results indicate that proteomic data generated by 2-D-DIGE can provide a signature of essential cell phenotypes, suggesting that it might be possible to apply this technique to developing tumor markers that could identify the organ of origin of metastatic tumors and contribute to the differential diagnosis of lung cancer.

DOI： 10.1002/pmic.200300795

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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：NATURE PUBLISHING GROUP  

Tumor-associated alternative RNA splicing has gained considerable attention. We identified a novel alternative splice variant RNA of actinin-4 in human small cell lung caner (SCLC). Expression of the splice variant was highly specific to SCLC cell lines (10/10), biopsies (3/3), and testis. The variant encoded a peptide with a three amino-acid change in exon 8, where the germline missense mutation takes place in familial focal segmental glomerulosclerosis (FSGS). The variant protein showed high affinity to filamentous actin polymers and was not localized with cortical actin. Alternatively spliced actinin-4 may be a new diagnostic marker of SCLC and a candidate target for selective therapy.

DOI： 10.1038/sj.onc.1207652

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Allelic deletion at chromosome 8p21-25 is an early and frequent event in the carcinogenesis and development of various cancers. To facilitate investigation of alterations of the macrophage scavenger receptor 1 (MSR1), which is located on 8p22, and to determine the role of this gene in human carcinogenesis and tumor progression, we determined intronic primers designed to amplify the coding region. Since frequent deletion of 8p21-23 has been previously reported in lung cancer, we searched for mutations throughout the coding sequence of the MSR1 gene within a panel of genomic DNA samples obtained from 30 primary lung cancers. Our approach, which involved polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and direct DNA sequencing, revealed nucleotide variants of the MSR1 gene in only one of the 30 cases examined, with this sample displaying both a 6 bp deletion and a thymine-to-cytosine substitution, the latter occurring within intron 7. The 6 bp deletion was located at a DNA microsatellite region and the thymine-to-cytosine substitution seemed to be a polymorphism. These results suggest that the MSR1 gene is not commonly mutated in lung cancer and not important in susceptibility to lung cancer. Further studies may focus on alternative mechanisms through which the MSR1 gene might be inactivated, such as aberrant DNA methylation, and/or pursue analyses of other genes on 8p21-23 for mutational events. Nevertheless, the panel of intronic PCR primer pair sequences presented here will facilitate future studies to determine the full spectrum and frequency of genetic events that may affect expression/activity of the MSR1 gene in human tumors.

DOI： 10.1272/jnms.71.99

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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.lungcan.2003.10.003

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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：WILEY-LISS  

Reduced expression of the retinoblastoma gene (RB)2/p130 protein, as well as mutation of exons 19, 20, 21, and 22 of the same gene, has been reported in primary lung cancer. However, it has been suggested by other investigators that mutational inactivation and loss of the RB2/p130 gene and protein, respectively, are rare events in lung cancer. In order to determine the contribution and mechanisms of RB2/p130 gene inactivation to lung cancer development and progression, we quantified RB2/p130 mRNA expression levels in a range of human lung cancer cell lines (n=13) by real-time reverse transcription (RT)-polymerase chain reaction (PCR) analysis. In comparison to normal lung tissue, reduced transcription of the RB2/p130 gene was found in all small cell lung cancer cell lines examined, along with six out of the eight nonsmall cell lung cancers tested, most of which had inactivation of RB/p16 pathway. On the basis of Western blot analysis, the expression of RB2/p130 protein was consistent with RNA expression levels in all lung cancer cell lines examined. In addition, the mutational status of the RB2/p130 gene (specifically, exons 19, 20, 21, and 22) was determined in 30 primary lung cancers (from patients with distant metastasis) and 30 lung cancer cell lines by PCR-single strand conformation polymorphism (SSCP) analysis and direct DNA sequencing. There was no evidence of somatic mutations within the RB2/p130 gene in the 60 lung cancer samples (both cell lines and tumors) assessed, including the 11 lung cancer cell lines that displayed reduced expression of the gene. Furthermore, hypermethylation of the RB2/p130 promoter was not found in any of the above-mentioned 11 cell lines, as determined by a DNA methylation assay, combined bisulfite restriction analysis (COBRA). The results of the present study suggest that the reduced RB2/p130 expression seen in lung cancer may be in part transcriptionally mediated, albeit not likely via a mechanism involving hypermethylation of the RB2/p130 promoter. The observed reduction in RB2/p130 gene expression may be due to histone deacetylation, altered mRNA stability, and/or other forms of transcriptional regulation. (C) 2003 Wiley-Liss, Inc.

DOI： 10.1002/mc.10152

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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：WILEY-V C H VERLAG GMBH  

The combination of laser microdissection and two-dimensional gel electrophoresis. (2-D PAGE) has been developed to perform proteomic analysis on specific populations of cells in cancer tissues. However, as conventional low sensitivity silver staining was used for spot detection, the microdissection required to obtain an adequate amount of protein for 2-D PAGE is laborious and only a restricted number of protein spots could be visualized. As a consequence, this technology was impractical for direct clinical applications and had a limited impact on cancer studies. To solve these problems, we developed an application in which fluorescent dyes label the proteins extracted from microdissected tissues prior to 2-D PAGE separation. In this application, a small amount of protein, less than 6.6 mug, was enough to generate a 2-D profile with approximately 1500 protein spots. This technique was applied to compare the proteome of normal intestinal epithelium with that of adenoma in Min mice. Thirty-seven protein spots reproducibly showed significant differences in intensities. Mass spectrometric analysis and Western blotting identified eight of them, including prohibitin, 14-3-3zeta, tropomyosin 3 and Hsp84. these results indicate that fluorescence labeling of proteins from microdissected tissues prior to 2-D PAGE is a powerful cancer proteomic study tool.

DOI： 10.1002/pmic.200300531

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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：AMER ASSOC CANCER RESEARCH  

Aberrant accumulation of beta-catenin protein because of mutation of either the beta-catenin or adenomatous polyposis coli gene plays an essential role in the development of colorectal carcinoma. We established previously a stable clone of the rat small intestinal epithelial cell line IEC6, which is capable of inducing stabilized beta-catenin protein lacking NH2-terminal glycogen synthase kinase-3beta phosphorylation site under a strict control of the tetracycline-regulatory system. This clone, IEC6-TetOFF-beta-catenin DeltaN89, shows in vitro polypoid growth on the removal of doxycycline and seems to be an appropriate model for analyzing the molecular mechanisms of early intestinal carcinogenesis. Of &gt;2000 protein spots displayed by newly developed two-dimensional difference gel electrophoresis, 22 were found to be up- or down-regulated on the induction of stabilized beta-catenin. The majority of these proteins fell into two categories: (a) redox-status regulatory proteins and (b) cytoskeleton-associated proteins. Representatively, a key redox-status regulatory protein, manganese superoxide dismutase, up-regulated in IEC6 cells expressing stabilized beta-catenin protein, was overexpressed in adenoma and adenocarcinoma cells of familial adenomatous polyposis patients in parallel with the accumulation of beta-catenin. These results suggest that aberrant accumulation of beta-catenin might contribute to colorectal carcinogenesis by affecting redox status in the mitochondria of intestinal epithelial cells.

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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：WILEY-LISS  

Patients with lung cancer have a poor prognosis because of the high metastatic potential of the neoplasm. Therefore, identifying new molecular targets for anti-metastatic therapy is very important. To identify novel key factors of tumor metastasis in lung cancer, we established the gene expression profiles of two adenocarcinoma cell line variants, PC9/f9 and PC9/f14, by use of genome-wide human cDNA microarray analysis and comparing these profiles with that of the parental cell line, PC9. The PC9/f9 and PC9/f14 cell lines were selected for analysis because of their high metastatic potential. We identified five genes in the highly metastatic cell lines that showed a significantly enhanced or reduced expression and that had not been reported to be involved in metastasis of lung cancer. One of the overexpressed genes that was identified encoded the beta-galactoside-binding protein LGALS3 (Galectin 3). LGALS3 has been reported to be overexpressed in a variety of human cancers, but not in lung cancer, and to be involved in tumor metastasis. We examined the expression of LGALS3 by use of real-time quantitative reverse transcription-polymerase chain reaction in 38 lung cancer cell lines and in tumor tissue obtained by thoracoscopic biopsy. A population (10130) of the non-small-cell lung cancers examined was found to overexpress the LGALS3 gene at levels three times higher than those of normal epithelial cells. In contrast, all small-cell lung cancers either failed to express the gene or expressed it at a very low level. The mean of the relative expression of the LGALS3 gene in nonsmall-cell lung cancer (3.065 +/- 3.976) was significantly higher than those of small-cell lung cancer (0.02 +/- 0.03) (P &lt; 0.025). This is the first report of alterations of LGALS3 gene expression in lung cancer. These results, together with the previous reports on Galectin 3 function, suggest that Galectin 3 may play a role in the process of metastasis in non-small-cell lung cancer that overexpresses Galectin 3, but not in small-cell cancer. Accordingly, LGALS3 may be a phenotypic marker that excludes small-cell lung cancer and may represent a novel target molecule in non-small-cell lung cancer therapy. (C) 2003 Wiley-Liss, Inc.

DOI： 10.1002/gcc.10205

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記述言語：日本語   出版者・発行元：日本プロテオーム学会（日本ヒトプロテオーム機構）  

DOI： 10.14889/jhupo.2003.0.29.0

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記述言語：日本語   出版者・発行元：日本プロテオーム学会（日本ヒトプロテオーム機構）  

DOI： 10.14889/jhupo.2003.0.30.0

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担当区分：筆頭著者  

DOI： 10.1016/S0169-5002(02)00218-0

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DOI： 10.1016/S0959-8049(01)00154-X

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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：ELSEVIER SCI IRELAND LTD  

Some of the many human cancers that exhibit chromosomal instability also carry mutations in mitotic checkpoint genes and/or reveal reduced expression of some of those genes, such as hMAD2. To facilitate investigation of alterations of hMAD2, we determined its genomic structure and intronic primers designed to amplify the entire coding region. Since general impairment of the mitotic checkpoint is frequently reported in lung cancers, and reduced expression of hMAD2 has been reported in breast cancers as well. we searched for mutations throughout the coding sequence of this gene in the genomic DNA of 30 primary lung tumors, 30 lung-cancer cell lines and 48 primary breast cancers. Our approach, which involved polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and direct sequencing, revealed nucleotide variants in only two of the 108 specimens. One was a cytosine-to-adenine substitution 3 bp upstream of exon 4 that occurred in one lung cancer cell line and one primary breast tumor, a change that did not alter transcriptional sequence. The other was an adenine-to-guanine substitution within er;on 4, of the same lung cell line: this change already had been reported as a polymorphism. The results suggested that the hMAD2 gene is not commonly mutated in either lung nor breast cancers. Further studies should focus on other mechanisms that might account for reduced expression of the hMAD2 gene, and/or pursue analyses of other mitotic checkpoint genes for mutations in human cancer. Nevertheless, the genomic structure, the intronic primer sequences. and polymorphisms of the hMAD2 gene presented here will facilitate future studies to determine the Full spectrum and frequency of the genetic events that can affect expression of the hMAD2 gene in human tumors. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

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掲載種別：研究論文（学術雑誌）  

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担当区分：筆頭著者   記述言語：英語   掲載種別：学位論文（博士）  

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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：ELSEVIER SCI IRELAND LTD  

The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) is involved in activating the transforming growth factor beta (1) (TGF-beta (1)), an inhibitor of the cell proliferation, and limiting the insulin-like growth factor 2 mediated-growth stimulation. The M6P/IGF2R gene has been reported to be mutated and deleted in various cancers, and is a candidate tumor suppressor gene. We studied the genomic structure of the M6P/IGF2R gene and designed the intron primers to detect mutations in the M6P/IGF2R gene of genomic DNA samples. The M6P/IGF2R gene consists of 48 exons. The previously reported 23 mutations of the M6P/IGF2R gene in human cancers, liver, breast, and gastrointestinal tumors, are located in five exons, exon 27, 28, 31, 40, 48. Using the intron primers designed in this study, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis, and direct sequencing, we performed an initial analysis of the complete coding sequences of the M6P/IGF2R gene in 21 human cell lines resistant to growth inhibition by TGF-beta (1). An adenine-to-guanine transition, resulting in an asparagine-to-serine amino acid substitution, was found in one lung adenocarcinoma cell line at exon 40 where the mutation has been previously reported in human cancers. This is the first report of a mutation of the M6P/IGF2R gene in lung tumor. These results indicated that the mutation in M6P/IGF2R may be involved in human lung cancinogenesis. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

Mutations in mitotic checkpoint genes have been detected in several human cancers, and these cancers exhibit chromosomal instability. Aneuploid stem cells seem to result from chromosomal instability and have been reported in many lung cancers. To determine whether alteration of mitotic checkpoint regulators is involved in carcinogenesis and tumor progression in primary lung cancer, we screened the genomic DNA sequence of 30 human lung cancer cell lines and 30 primary lung cancer tumors for a mutation in the hBUB1 mitotic checkpoint gene. First, we designed 26 sets of intron-based primers to amplify each of the 25 exons of the hBUB1 gene to examine the entire coding region of the hBUB1 gene. Using these primers, we performed polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis as well as direct sequencing in the mutation analysis of the hBUB1 gene. Three different nucleotide substitutions were detected in the coding region of the hBUB1 gene in some of the cancer cell lines and primary tumors as follows. The hBUB1 gene of one adenocarcinoma tumor contained a somatic missense mutation, a cytosine-to-guanine substitution in codon 51 of exon 5 that resulted in a histidine-to-aspartic acid amino acid substitution. The hBUB1 gene of three lung cancer cell lines contained a thymine-to-cytosine substitution in codon 430 of exon 12, which did not result in an amino-acid substitution. We were unable to determine whether the nucleotide substitution in exon 12 was a polymorphism or a silent mutation because matched normal tissue was not available. A polymorphism in codon 93 of exon 4, a guanine-to-thymine substitution, in hBUB1 was found in one lung cancer cell line and one primary lung tumor. This is the first report of a somatic missense mutation of a gene involved in a mitotic checkpoint in primary lung cancer. The presence of a point mutation in the hBUB1 gene is consistent with the hypothesis that alteration of mitotic checkpoint genes is involved in the development of primary lung cancers. Because the frequency of hBUB1 gene mutations was low, future studies should focus on other mechanisms of inactivation of the hBUB1 gene as well as mutation analysis of other mitotic checkpoint genes in lung cancers. (C) 2000 Wiley-Liss, Inc.

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

67歳男.アルミニウムの研磨業に2ヵ月従事し,約10年前より会社健診にて胸部X線上じん肺と診断されていた.経過中に発熱,労作時呼吸困難,四肢の痺れ,胸部X線上,新たに両側下肺野にスリガラス影が出現した.経気管支肺生検(TBLB)で,じん肺の所見に相当する線維化所見と,元素分析でアルミニウムの存在を証明し,アルミニウム肺と診断した.腎生検にて半月体形成性糸球体腎炎,小動脈の血管炎の所見を認め,血清の抗好中球細胞質抗体(P-ANCA)が陽性で,Microscopic-polyangiitis(MPA)と診断した.活動性の間質性肺炎の所見があり,MPAによる間質性肺炎がじん肺に加わった所見と判断した

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記述言語：日本語   出版者・発行元：特定非営利活動法人 日本呼吸器内視鏡学会  

末梢型小型肺腺癌のCT画像の特徴と, 発見から確定診断に至る経緯について検討した。1995年より, 当院にて手術が施行された長径15mm以下の肺癌14例を対象とした。男性4例, 女性10例, 平均年齢58歳。10例は検診発見(うち5例はCT検診), 3例が他疾患経過観察中, 1例が咳嗽精査中であった。2例は経気管支肺生検, 2例はCTガイド下肺生検で診断されたが, 10例は胸腔鏡下肺生検等の侵襲的検査を必要とした。診断までに要した期間は4.4ヵ月(1&acd;20ヵ月)であった。全例I期腺癌で, 治癒切除が行われ, 平均腫瘍径は12.4mmであった。病理学的には野口分類のtype Aが4例, Bが3例, Cが5例, Dが1例, Fが1例であった。CT画像上, 血管の関与が肺腺癌共通の特徴と思われ, 非癌性病変との鑑別の一助となることが示唆された。今後, 更なる症例の集積が必要と考えられる。

DOI： 10.18907/jjsre.21.6_381

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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：ELSEVIER SCI IRELAND LTD  

The PTEN/MMAC1 gene located at 10q23, has been proposed to be a tumor suppressor gene. To determine the involvement of alteration of the PTEN/MMAC1 gene in carcinogenesis and the progression of primary lung cancers, we analyzed tumor samples of primary and distant metastatic sites and normal lung tissue samples of 30 patients with advanced lung cancer with distant metastasis. The tissues were analyzed for allelic deletion and mutational inactivation of PTEN/MMAC1 by loss of heterozygosity (LOH) analysis, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), and direct sequence analysis. LOH of the PTEN/MMAC1 locus was common in each histologic type of primary lung cancer. In this study, the overall allelic deletion rate was 33.3% (7/21). Allelic loss at the primary site and that at the metastatic site of each patient, were identical; in most cases, it seemed that the allelic loss had occurred before metastasis. Sequence analysis of the PTEN/MMAC1 gene revealed a G to C substitution located 8 bp upstream of the coding region of exon 1 and which seems to be a polymorphism, in 4 of the 30 cases. Somatic mutations of the PTEN/MMAC1 gene were not identified in any of the tumors at the primary and metastatic sites. These data indicate that point mutations in the PTEN/MMAC1 gene are probably not an important factor in tumorigenesis and the progression of a major subset of lung cancers. Due to frequent allelic loss at the PTEN/MMAC1 locus occurring at a stage earlier than the metastatic process, alternative mechanisms in which the remaining allele is inactivated such as methylation or homozygous deletion of a small region of the gene that can not be detected by the usual analysis, or alteration of other important tumor suppressor genes lying close to the PTEN/MMAC1 gene on 10q23, may be involved in the tumorigenesis of lung cancers of all histologic subtypes. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：(株)癌と化学療法社  

非小細胞肺癌の進行,再発例及び高用量のcisplatin(CDDP)投与困難な症例15例に対し,少量のCDDP(5mg/body,day1〜5,4週間),UFT(400〜600mg/body,day1〜5,4週間)の連日併用療法を施行した.骨髄抑制,消化器毒性等の副作用は軽微でQOLの低下はなく,奏効率も20.0%と既存の標準的治療と比べても遜色なかった

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記述言語：日本語   出版者・発行元：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.20.3_265_4

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

56歳女.54歳より胸部X線上,肺間質影指摘.55歳より労作時息切れ,咳嗽が出現.眼瞼及び口腔粘膜の乾燥感も加わった為,来院.眼科的に涙液分泌減少症,点状表層角膜炎を認め,シェーグレン症候群と診断された.画像上は,両肺野にび漫性の線状網状影と含気量の低下,更に肺門・縦隔リンパ節腫大を認めた.経気管支肺生検では確診に至らず,開胸肺生検でリンパ球性間質性肺炎(LIP)と診断し得た.病理組織学,免疫組織学のみならず,遺伝子解析を用いて,多クローン性増殖を証明した報告は少なく,肺悪性リンパ腫との鑑別に有用と考えられた.ステロイド剤と免疫抑制剤の併用により異常蛋白血症を含め,自他覚症状は改善した

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：克誠堂出版(株)  

62歳女.発熱,全身倦怠感,体重減少,関節痛,筋肉痛を主訴に入院.その後,肺胞出血と腎不全併発.腎生検で,半月体形成性糸球体腎炎,右腓腹筋生検で,小動脈の血管炎の所見を認めた.血清の抗MPO-ANCAが陽性でmicroscopic polyangiitisによる肺胞出血,腎不全と診断した.ステロイド剤,免疫抑制剤で軽快し,現在経過観察中である

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