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 (ADJ) according to real-world data. Therefore, robust predictive biomarkers for selecting 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 FISH. Statistical analyses to determine whether the status of ACTN4 gene amplification affected recurrence-free survival (RFS) were carried out. Formalin-fixed, paraffin-embedded samples from 1136 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 aged 65 years or older, the ADJ group had better RFS than the OBS group in the ACTN4-positive cohort (hazard ratio [HR], 0.084, 95% confidence interval [CI], 0.009-0.806; P = .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 = .289). Analyses of ACTN4 gene amplification contributed to the decision regarding postoperative ADJ for stage I lung adenocarcinomas, preventing recurrence, improving the quality of medical care, preventing the unnecessary side-effects of ADJ, and saving medical costs.

DOI： 10.1111/cas.15228

PubMed

researchmap

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  

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 (ADJ) according to real-world data. Therefore, robust predictive biomarkers for selecting 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 FISH. Statistical analyses to determine whether the status of ACTN4 gene amplification affected recurrence-free survival (RFS) were carried out. Formalin-fixed, paraffin-embedded samples from 1136 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 aged 65 years or older, the ADJ group had better RFS than the OBS group in the ACTN4-positive cohort (hazard ratio [HR], 0.084, 95% confidence interval [CI], 0.009-0.806; P = .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 = .289). Analyses of ACTN4 gene amplification contributed to the decision regarding postoperative ADJ for stage I lung adenocarcinomas, preventing recurrence, improving the quality of medical care, preventing the unnecessary side-effects of ADJ, and saving medical costs.

DOI： 10.1111/cas.15228

PubMed

researchmap

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 Science and Business Media {LLC}  

<jats:title>Abstract</jats:title><jats:sec>
<jats:title>Background</jats:title>
<jats:p>Osimertinib is effective in patients with T790M mutation-positive advanced non-small-cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its effectiveness and safety in patients with poor performance status (PS) are unknown.</jats:p>
</jats:sec><jats:sec>
<jats:title>Methods</jats:title>
<jats:p>Enrolled patients showed disease progression after treatment with gefitinib, erlotinib, or afatinib; T790M mutation; stage IIIB, IV, or recurrent disease; and PS of 2–4. Osimertinib was orally administered at a dose of 80 mg/day. The primary endpoint of this phase II study (registration, jRCTs061180018) was response rate and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety.</jats:p>
</jats:sec><jats:sec>
<jats:title>Results</jats:title>
<jats:p>Thirty-three patients were enrolled, of which 69.7% and 24.2% had PS of 2 and 3, respectively. One patient was excluded due to protocol violation; in the remaining 32 patients, the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months. The most frequent adverse event of grade 3 or higher severity was lymphopenia (12.1%). Interstitial lung disease (ILD) was observed at all grades and at grades 3–5 in 15.2% (5/33) and 6.1% (2/33) of patients, respectively. Treatment-related death due to ILD occurred in one patient. Patients negative for activating EGFR mutations after osimertinib administration had longer median PFS than those positive for these mutations.</jats:p>
</jats:sec><jats:sec>
<jats:title>Conclusion</jats:title>
<jats:p>Osimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC. Plasma EGFR mutation clearance after TKI treatment could predict the response to EGFR-TKIs.</jats:p>
</jats:sec>

DOI： 10.1007/s10147-021-02043-2

PubMed

researchmap

J-GLOBAL

researchmap

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 Publications  

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

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Acute exacerbation (AEx) of interstitial pneumonia is the most common lethal adverse event related to the pharmacological treatment of patients with lung cancer complicated with interstitial pneumonia. Although small cell lung cancer (SCLC) is linked to poor prognosis, it exhibits good response to chemotherapy. Few previous research studies have investigated the safety and efficacy of treatment for advanced SCLC complicated with idiopathic interstitial pneumonia (IIP). We conducted a single-arm phase II study to evaluate the safety and efficacy of carboplatin plus etoposide for the treatment of patients with SCLC complicated with IIP. METHODS: Chemotherapy-naïve patients with advanced SCLC complicated with IIP were enrolled. Patients received carboplatin every 21-28 days at a dose of area under the curve 4-6 on day 1 and etoposide at a dose of 80-100 mg/m2 on days 1-3. RESULTS: Thirty-one patients were enrolled between December 2009 and December 2022. A median of four cycles of carboplatin plus etoposide were administered. Acute exacerbation of idiopathic interstitial pneumonia was not observed; the rate of AEx was 0% (95% confidence interval [CI]: 0-9.6%, p = 0.038). The objective response rate was 83.9% (95% CI: 82.5-85.2). The median progression-free survival and overall survival were 5.9 (95% CI: 4.7-6.8) months and 14.0 (95% CI: 7.6-27.6) months, respectively. The 1-year survival rate was 61% (95% CI 41-76). CONCLUSIONS: The carboplatin plus etoposide treatment was tolerable and effective in SCLC patients complicated with IIP.

DOI： 10.1186/s12890-024-03459-y

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Chemoresistance to paclitaxel (PTX) significantly ameliorates therapeutic efficacy in patients with non-small cell lung cancer (NSCLC), especially in advanced stages, deteriorating the progression free and overall survival rates. One of the critical mechanisms contributing to drug resistance is the excretion of PTX from target cells via efflux pumps. Ivermectin was developed as a bactericidal agent against parasites; however, it has recently been shown to inhibit the proliferation of human cancer cells. Hence, we aimed to evaluate the therapeutic potential of ivermectin in combination with PTX and investigate the molecular mechanisms by which ivermectin overcomes PTX resistance. MATERIALS AND METHODS: We assessed the antitumor effects of ivermectin in A549 cells treated with or without PTX. We also established PTX-resistant cells using this cell line and explored the underlying mechanisms. Additionally, we evaluated whether ivermectin attenuates PTX-resistance with the retrieval of drug sensitivity. RESULTS: Combined treatment of A549 cells with PTX and ivermectin inhibited cell growth. These cells acquired chemoresistance upon long-term exposure to gradually increasing PTX concentrations, which was accompanied by ABCB1 mRNA up-regulation, and subsequent overproduction of P-glycoprotein (P-gp). Consistent with this, P-gp over-expression resulted in a PTX-resistant phenotype. Notably, the simultaneous ivermectin treatment during the gradual exposure completely abolished P-gp expression, leading to an increased intracellular PTX concentration and sustained PTX sensitivity. Ivermectin was found to regulate P-gp expression via the EGFR/ERK/Akt/NF-[Formula: see text]B pathway. CONCLUSION: Combined treatment of PTX-resistant A549 cells with ivermectin and PTX may circumvent PTX resistance caused by P-gp induction, highlighting a novel therapeutic avenue for drug repurposing.

DOI： 10.21873/anticanres.17355

PubMed

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

researchmap

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  

researchmap

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  

researchmap

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  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: A neurotrophic tropomyosin receptor kinase (NTRK)-tyrosine kinase inhibitor (TKI) has shown dramatic efficacy against malignant tumors harboring an NTRK fusion gene. However, almost all tumors eventually acquire resistance to NTRK-TKIs. METHOD: To investigate the mechanism of resistance to NTRK-TKIs, we established cells resistant to three types of NTRK-TKIs (larotrectinib, entrectinib, and selitrectinib) using KM12 colon cancer cells with a TPM3-NTRK1 rearrangement. RESULT: Overexpression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) was observed in three resistant cells (KM12-LR, KM12-ER, and KM12-SR) by microarray analysis. Lower expression of sterol regulatory element-binding protein 2 (SREBP2) and peroxisome proliferator activated receptor α (PPARα) was found in two cells (KM12-ER and KM12-SR) in which HMGCS2 was overexpressed compared to the parental KM12 and KM12-LR cells. In resistant cells, knockdown of HMGCS2 using small interfering RNA improved the sensitivity to NTRK-TKI. Further treatment with mevalonolactone after HMGCS2 knockdown reintroduced the NTRK-TKI resistance. In addition, simvastatin and silibinin had a synergistic effect with NTRK-TKIs in resistant cells, and delayed tolerance was observed after sustained exposure to clinical concentrations of NTRK-TKI and simvastatin in KM12 cells. In xenograft mouse models, combination treatment with entrectinib and simvastatin reduced resistant tumor growth compared with entrectinib alone. CONCLUSION: These results suggest that HMGCS2 overexpression induces resistance to NTRK-TKIs via the mevalonate pathway in colon cancer cells. Statin inhibition of the mevalonate pathway may be useful for overcoming this mechanistic resistance.

DOI： 10.1002/cam4.7393

PubMed

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Osimertinib is a standard treatment for patients with EGFR-mutant NSCLC. Although some osimertinib resistance mechanisms have been identified, nearly 50% of the mechanisms remain to be elucidated. This study was aimed at identifying non-genetic mechanisms underlying osimertinib resistance. METHODS: We established two osimertinib-resistant cell lines from EGFR mutation-positive PC-9 and HCC827 NSCLC cell lines (PC-9OR and HCC827OR, respectively) using a stepwise method. We compared the phosphoproteomic profiles of the osimertinib-resistant and parental cells using mass spectrometry. Upstream kinases were identified using the application Kinase Enrichment Analysis version 3. RESULTS: Phosphoproteomic analysis revealed 80 phosphorylation sites that were mutually up-regulated in PC-9OR and HCC827OR cells. The Kinase Enrichment Analysis version 3 analysis identified focal adhesion kinase (FAK) and proto-oncogene tyrosine-protein kinase Src (Src) as upstream kinases of these up-regulated phosphoproteins. The small-interfering RNA-mediated knockdown of FAK reduced Src phosphorylation and that of Src reduced FAK phosphorylation in both cell lines. Furthermore, FAK- or Src-specific small-interfering RNA treatments restored EGFR phosphorylation in PC-9OR and HCC827OR cells. The combination of FAK and Src inhibitors inhibited PC-9OR and HCC827OR cell proliferation in vitro and suppressed tumor growth in a xenograft mouse model. Immunohistochemistry of tumors from patients with EGFR-mutant NSCLC suggested that phosphorylated FAK and Src are involved in initial and acquired resistance to osimertinib. CONCLUSIONS: Phosphoproteomic analysis may help elucidate the mechanisms of resistance to molecular-targeted therapies in lung cancer. Mutual phosphorylation of FAK and Src is involved in osimertinib resistance. Thus, FAK and Src inhibition may be novel treatment strategies for osimertinib-resistant NSCLC.

DOI： 10.1016/j.jtocrr.2024.100668

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 73-year-old man with lung squamous cell carcinoma was administered carboplatin + nab-paclitaxel + pembrolizumab for four cycles. Subsequently, he presented with multiple purpuras on his extremities, joint swelling on his fingers, abdominal pain, and diarrhea, accompanied by acute kidney injury (AKI), increased proteinuria, hematuria, and elevated C-reactive protein levels. Skin biopsy showed leukocytoclastic vasculitis as well as IgA and C3 deposition in the vessel walls. Based on these findings, the patient was diagnosed with IgA vasculitis as an immune-related adverse event (irAE) induced by carboplatin + nab-paclitaxel + pembrolizumab. After discontinuation of pembrolizumab and glucocorticoids, the symptoms immediately resolved. Regular monitoring of skin, blood tests, and urinalysis are necessary, and the possibility of irAE IgA vasculitis should be considered in cases of purpura and AKI during treatment with immune checkpoint inhibitors.

DOI： 10.3389/fimmu.2024.1370972

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Treatment options for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) after EGFR-tyrosine kinase inhibitor (TKI) treatment failure are limited. An exploratory analysis of 26 patients in the IMpower150 study indicated that treatment with atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) was effective in patients with EGFR-mutated NSCLC. This phase II study was conducted to assess the efficacy of ABCP in EGFR-mutated NSCLC patients after TKI treatment. METHODS: Patients with non-squamous NSCLC harboring sensitizing EGFR mutations were enrolled. ABCP therapy was administered every 3 weeks for four cycles, followed by maintenance therapy with atezolizumab and bevacizumab. The primary endpoint was progression-free survival (PFS) according to extramural review (ER). Key secondary endpoints and preplanned analysis included overall survival (OS), overall response rate (ORR), and differences in the efficacy of ABCP according to prior EGFR-TKI administration, liver metastases, and brain metastases. RESULTS: Sixty patients from 26 centers were enrolled. Median PFS was 7.4 months (95% confidence interval [CI]: 5.7-8.2). The median OS was 23.1 months (95% CI: 13.1-not reached), and the ORR was 55.9%. PFS was significantly shorter in patients who had received osimertinib as a first-line treatment (7.2 months vs. 7.4 months, hazard ratio [HR] 1.932, p = 0.023), those with brain metastases (5.7 months vs. 8 months, HR 1.86, p = 0.032), or those with liver metastases (5.4 months vs. 7.9 months, HR 2.779, p = 0.003). CONCLUSIONS: Although this study did not meet the primary endpoint, ABCP showed clinically meaningful efficacy in EGFR-mutated NSCLC patients.

DOI： 10.1016/j.ejca.2023.113469

PubMed

researchmap

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

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

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

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

記述言語：英語  

Advanced thymic carcinomas have limited treatment options. Recently, lenvatinib was approved for advanced thymic carcinoma treatment. However, the clinical benefit of lenvatinib re-administration in patients with advanced thymic carcinoma who developed prior lenvatinib treatment resistance (lenvatinib rechallenge) remains unclear. Here, we present a case treated with lenvatinib rechallenge for advanced thymic carcinoma who was previously treated with lenvatinib as the second-line treatment followed by multiple cytotoxic agents. Disease control rapidly deteriorated after the eighth line of treatment because of uncontrollable right pleural and pericardial effusion, which required repeated thoracic and pericardial drainage. Shortly after lenvatinib re-administration, rapid pleural and pericardial effusion reduction was observed. Thereafter, the patient achieved sustained clinical response with good pleural and pericardial effusion control for approximately 7 months. Our case might suggest lenvatinib rechallenge as a treatment option for patients with advanced thymic carcinoma, especially those with poor pleural and pericardial effusion control.

DOI： 10.1111/1759-7714.14699

PubMed

researchmap

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

PubMed

researchmap

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 ({OUP})  

OBJECTIVES: Indications of limited resection, such as segmentectomy, have recently been reported for patients with solid-predominant lung cancers ≤2 cm. This study aims to identify unfavourable prognostic factors using three-dimensional imaging analysis with artificial intelligence (AI) technology. METHODS: A total of 157 patients who had clinical N0 non-small cell lung cancer with a radiological size ≤2 cm, and a consolidation tumour ratio > 0.5, who underwent anatomical lung resection between 2011 and 2017 were enrolled. To evaluate the three-dimensional structure, the ground-glass nodule/Solid Automatic Identification AI software Beta Version (AI software; Fujifilm Corporation, Japan) was used. RESULTS: Maximum standardized uptake value (SUVmax) and solid-part volume measured by AI software (AI-SV) showed significant differences between the 139 patients with adenocarcinoma and the 18 patients with non-adenocarcinoma. Among the adenocarcinoma patients, 42 patients (30.2%) were found to be pathological upstaging. Multivariable analysis demonstrated that high SUVmax, high carcinoembryonic antigen level and high AI-SV were significant prognostic factors for recurrence-free survival (RFS; P < 0.05). The 5-year RFS was compared between patients with tumours showing high SUVmax and those showing low SUVmax (67.7% vs 95.4%, respectively, P < 0.001). The 5-year RFS was 91.0% in patients with small AI-SV and 68.1% in those with high AI-SV (P = 0.001). CONCLUSIONS: High AI-SV, high SUVmax and abnormal carcinoembryonic antigen level were unfavourable prognostic factors of patients with solid-predominant lung adenocarcinoma with a radiological size ≤2 cm. Our results suggest that lobectomy should be preferred to segmentectomy for patients with these prognostic factors.

DOI： 10.1093/ejcts/ezab541

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Indications of limited resection, such as segmentectomy, have recently been reported for patients with solid-predominant lung cancers ≤2 cm. This study aims to identify unfavourable prognostic factors using three-dimensional imaging analysis with artificial intelligence (AI) technology. METHODS: A total of 157 patients who had clinical N0 non-small cell lung cancer with a radiological size ≤2 cm, and a consolidation tumour ratio > 0.5, who underwent anatomical lung resection between 2011 and 2017 were enrolled. To evaluate the three-dimensional structure, the ground-glass nodule/Solid Automatic Identification AI software Beta Version (AI software; Fujifilm Corporation, Japan) was used. RESULTS: Maximum standardized uptake value (SUVmax) and solid-part volume measured by AI software (AI-SV) showed significant differences between the 139 patients with adenocarcinoma and the 18 patients with non-adenocarcinoma. Among the adenocarcinoma patients, 42 patients (30.2%) were found to be pathological upstaging. Multivariable analysis demonstrated that high SUVmax, high carcinoembryonic antigen level and high AI-SV were significant prognostic factors for recurrence-free survival (RFS; P < 0.05). The 5-year RFS was compared between patients with tumours showing high SUVmax and those showing low SUVmax (67.7% vs 95.4%, respectively, P < 0.001). The 5-year RFS was 91.0% in patients with small AI-SV and 68.1% in those with high AI-SV (P = 0.001). CONCLUSIONS: High AI-SV, high SUVmax and abnormal carcinoembryonic antigen level were unfavourable prognostic factors of patients with solid-predominant lung adenocarcinoma with a radiological size ≤2 cm. Our results suggest that lobectomy should be preferred to segmentectomy for patients with these prognostic factors.

DOI： 10.1093/ejcts/ezab541

PubMed

researchmap

記述言語：英語  

DOI： 10.1007/s10147-022-02118-8

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Osimertinib is effective in patients with T790M mutation-positive advanced non-small-cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its effectiveness and safety in patients with poor performance status (PS) are unknown. METHODS: Enrolled patients showed disease progression after treatment with gefitinib, erlotinib, or afatinib; T790M mutation; stage IIIB, IV, or recurrent disease; and PS of 2-4. Osimertinib was orally administered at a dose of 80 mg/day. The primary endpoint of this phase II study (registration, jRCTs061180018) was response rate and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety. RESULTS: Thirty-three patients were enrolled, of which 69.7% and 24.2% had PS of 2 and 3, respectively. One patient was excluded due to protocol violation; in the remaining 32 patients, the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months. The most frequent adverse event of grade 3 or higher severity was lymphopenia (12.1%). Interstitial lung disease (ILD) was observed at all grades and at grades 3-5 in 15.2% (5/33) and 6.1% (2/33) of patients, respectively. Treatment-related death due to ILD occurred in one patient. Patients negative for activating EGFR mutations after osimertinib administration had longer median PFS than those positive for these mutations. CONCLUSION: Osimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC. Plasma EGFR mutation clearance after TKI treatment could predict the response to EGFR-TKIs.

DOI： 10.1007/s10147-021-02043-2

PubMed

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

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 Science and Business Media {LLC}  

<jats:title>Abstract</jats:title><jats:p>PD-L1 expression is the most useful predictive biomarker for immunotherapy efficacy on non-small cell lung cancer (NSCLC), and CD8+ tumor-infiltrating lymphocytes (CD8+ TILs) play an essential role in the clinical activity of immunotherapy. PD-L1 is found on the exosome’s surface, and PD-L1 expressing exosomes can inhibit antitumor immune responses. This study aimed to analyze tumor PD-L1 expression, serum exosomal PD-L1, and CD8+ TILs to investigate anti-PD-1 response and clinicopathological outcomes in NSCLC. One hundred twenty patients with stage I–III NSCLC were enrolled, and serum samples collected during the initial surgery were pooled. The Human CD274/PD-L1 ELISA kit was used to quantify the exosomal PD-L1. Exosomal PD-L1 levels were significantly correlated with tumor PD-L1 levels (p &lt; 0.001) and the number of CD8+ TILs (p = 0.001). Patients with exosomal PD-L1 ≥ 166 pg/mL tended to have a worse RFS than those with &lt; 166 pg/mL in all stage (p = 0.163) and stage I patients (p = 0.116). Seventeen patients exhibited postoperative recurrences and received anti-PD-1 treatment. The disease control rate of patients with exosomal PD-L1 ≥ 166 pg/mL was 100%. The measurement of serum exosomal PD-L1 as a quantitative factor with tumor PD-L1 status may help predict anti-PD-1 response and clinical outcomes in patients with NSCLC.</jats:p>

DOI： 10.1038/s41598-021-87575-3

PubMed

researchmap

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。

researchmap

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

記述言語：英語  

J-GLOBAL

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Patient participation in decisions 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. 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. At discharge, patients' responses to the 'Questionnaire on check sheet and treatment selection' were collected 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, some felt that this activity increased the administrative burden of medical professionals. CONCLUSION: Almost all patients stated that the present check sheet was useful as a decision support tool and facilitated 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

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Medical Association of Nippon Medical School  

BACKGROUND: Patient participation in decisions 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. 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. At discharge, patients' responses to the 'Questionnaire on check sheet and treatment selection' were collected 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, some felt that this activity increased the administrative burden of medical professionals. CONCLUSION: Almost all patients stated that the present check sheet was useful as a decision support tool and facilitated 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

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

PD-L1 expression is the most useful predictive biomarker for immunotherapy efficacy on non-small cell lung cancer (NSCLC), and CD8+ tumor-infiltrating lymphocytes (CD8+ TILs) play an essential role in the clinical activity of immunotherapy. PD-L1 is found on the exosome's surface, and PD-L1 expressing exosomes can inhibit antitumor immune responses. This study aimed to analyze tumor PD-L1 expression, serum exosomal PD-L1, and CD8+ TILs to investigate anti-PD-1 response and clinicopathological outcomes in NSCLC. One hundred twenty patients with stage I-III NSCLC were enrolled, and serum samples collected during the initial surgery were pooled. The Human CD274/PD-L1 ELISA kit was used to quantify the exosomal PD-L1. Exosomal PD-L1 levels were significantly correlated with tumor PD-L1 levels (p < 0.001) and the number of CD8+ TILs (p = 0.001). Patients with exosomal PD-L1 ≥ 166 pg/mL tended to have a worse RFS than those with < 166 pg/mL in all stage (p = 0.163) and stage I patients (p = 0.116). Seventeen patients exhibited postoperative recurrences and received anti-PD-1 treatment. The disease control rate of patients with exosomal PD-L1 ≥ 166 pg/mL was 100%. The measurement of serum exosomal PD-L1 as a quantitative factor with tumor PD-L1 status may help predict anti-PD-1 response and clinical outcomes in patients with NSCLC.

DOI： 10.1038/s41598-021-87575-3

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

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  

DOI： 10.21037/jtd.2020.04.29

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：英語  

DOI： 10.21037/jtd.2020.04.29

PubMed

researchmap

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  

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

PubMed

researchmap

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

PubMed

researchmap

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 Science and Business Media {LLC}  

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

PubMed

researchmap

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

PubMed

researchmap

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

researchmap

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

PubMed

researchmap

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 ({OUP})  

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

PubMed

researchmap

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

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Anticancer Research {USA} Inc.  

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

PubMed

researchmap

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

PubMed

researchmap

J-GLOBAL

researchmap

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 Science and Business Media {LLC}  

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

PubMed

researchmap

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

PubMed

researchmap

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

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jacep.2018.03.008

PubMed

researchmap

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

PubMed

researchmap

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

PubMed

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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.

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The development of formulations and the assessment of oral drug absorption for Biopharmaceutical Classification System (BCS) class IIb drugs is often a difficult issue due to the potential for supersaturation and precipitation in the gastrointestinal (GI) tract. The physiological environment in the GI tract largely influences in vivo drug dissolution rates of those drugs. Thus, those physiological factors should be incorporated into the in vitro system to better assess in vivo performance of BCS class IIb drugs. In order to predict oral bioperformance, an in vitro dissolution system with multiple compartments incorporating physiologically relevant factors would be expected to more accurately predict in vivo phenomena than a one-compartment dissolution system like USP Apparatus 2 because, for example, the pH change occurring in the human GI tract can be better replicated in a multi-compartmental platform. The Gastrointestinal Simulator (GIS) consists of three compartments, the gastric, duodenal and jejunal chambers, and is a practical in vitro dissolution apparatus to predict in vivo dissolution for oral dosage forms. This system can demonstrate supersaturation and precipitation and, therefore, has the potential to predict in vivo bioperformance of oral dosage forms where this phenomenon may occur. In this report, in vitro studies were performed with dipyridamole and ketoconazole to evaluate the precipitation rates and the relationship between the supersaturation levels and oral absorption of BCS class II weak base drugs. To evaluate the impact of observed supersaturation levels on oral absorption, a study utilizing the GIS in combination with mouse intestinal infusion was conducted. Supersaturation levels observed in the GIS enhanced dipyridamole and ketoconazole absorption in mouse, and a good correlation between their supersaturation levels and their concentration in plasma was observed. The GIS, therefore, appears to represent in vivo dissolution phenomena and demonstrate supersaturation and precipitation of dipyridamole and ketoconazole. We therefore conclude that the GIS has been shown to be a good biopredictive tool to predict in vivo bioperformance of BCS class IIb drugs that can be used to optimize oral formulations.

DOI： 10.1016/j.ejps.2017.02.042

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Weakly basic drugs exhibit a pH-dependent dissolution profile in the gastrointestinal (GI) tract, which makes it difficult to predict their oral absorption profile. The aim of this study was to investigate the utility of the gastrointestinal simulator (GIS), a novel in vivo predictive dissolution (iPD) methodology, in predicting the in vivo behavior of the weakly basic drug dipyridamole when coupled with in silico analysis. The GIS is a multicompartmental dissolution apparatus, which represents physiological gastric emptying in the fasted state. Kinetic parameters for drug dissolution and precipitation were optimized by fitting a curve to the dissolved drug amount-time profiles in the United States Pharmacopeia apparatus II and GIS. Optimized parameters were incorporated into mathematical equations to describe the mass transport kinetics of dipyridamole in the GI tract. By using this in silico model, intraluminal drug concentration-time profile was simulated. The predicted profile of dipyridamole in the duodenal compartment adequately captured observed data. In addition, the plasma concentration-time profile was also predicted using pharmacokinetic parameters following intravenous administration. On the basis of the comparison with observed data, the in silico approach coupled with the GIS successfully predicted in vivo pharmacokinetic profiles. Although further investigations are still required to generalize, these results indicated that incorporating GIS data into mathematical equations improves the predictability of in vivo behavior of weakly basic drugs like dipyridamole.

DOI： 10.1021/acs.molpharmaceut.6b01063

PubMed

researchmap

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We report a case of ruptured mycotic thoracic aortic aneurysm treated with a pedicled latissimus dorsi flap after stent-graft implantation. The patient was a 64-year-old woman with diabetes mellitus that had developed septicemia as a result of pyelonephritis and a perinephric abscess. The patient required emergency stent-graft implantation due to rupture of an infected thoracic aortic aneurysm on hospital day 10. On hospital day 19, the abscess cavity was debrided and irrigated, and a pedicled latissimus dorsi flap was created. No recurrence of the inflammatory reaction was observed at 1 year postoperatively.

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The aim of the present study was to clarify the characteristics of Japanese critical limb ischemia (CLI) patients and analyze the rates of real-world mortality and amputation-free survival (AFS) in all patients with Fontaine stage IV CLI who were treated with/without revascularization therapy by an intra-hospital multidisciplinary care team. All consecutive patients who presented with CLI at Showa University Fujigaoka Hospital between April 2008 and March 2014 were prospectively registered. The intra-hospital committee consisted of cardiologists, plastic surgeons, dermatologists, diabetologists, nephrologists, cardiovascular surgeons, and vascular technologists. The primary endpoint of this study was all-cause mortality and AFS during the follow-up period. The present study included 145 patients with Fontaine stage IV CLI. The mean age was 76.5 ± 10.2 years. The all-cause mortality rate during the follow-up period (15.5 ± 16.1 months) was 21.4 %. The AFS rate during the follow-up period (14.1 ± 16.4 months) was 58.6 %. A multivariate Cox proportional hazards regression analysis found that age >75 years and hemodialysis were significantly associated with all-cause mortality; and that age >75 years, Rutherford 6, and wound infection were significantly associated with AFS. A multidisciplinary approach and comprehensive care may improve the outcomes and optimize the collaborative treatment of CLI patients. However, all-cause mortality remained high in patients with Fontaine stage IV CLI and early referral to a hospital that can provide specialized treatment for CLI, before the occurrence of major tissue loss or infection, is necessary to avoid primary amputation.

DOI： 10.1007/s00380-016-0840-z

PubMed

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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-naïve 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

PubMed

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

In this study, the data of 113 human bioequivalence (BE) studies of immediate release (IR) formulations of 74 active pharmaceutical ingredients (APIs) conducted at Sawai Pharmaceutical Co., Ltd., was analyzed to understand the factors affecting intra- and intersubject variabilities in oral drug absorption. The ANOVA CV (%) calculated from area under the time-concentration curve (AUC) in each BE study was used as an index of intrasubject variability (Vintra), and the relative standard deviation (%) in AUC was used as that of intersubject variability (Vinter). Although no significant correlation was observed between Vintra and Vinter of all drugs, Vintra of class 3 drugs was found to increase in association with a decrease in drug permeability (P(eff)). Since the absorption of class 3 drugs was rate-limited by the permeability, it was suggested that, for such drugs, the low P(eff) might be a risk factor to cause a large intrasubject variability. To consider the impact of poor water solubility on the variability in BE study, a parameter of P(eff)/Do (Do; dose number) was defined to discriminate the solubility-limited and dissolution-rate-limited absorption of class 2 drugs. It was found that the class 2 drugs with a solubility-limited absorption (P(eff)/Do < 0.149 × 10(-4) cm/s) showed high intrasubject variability. Furthermore, as a reason for high intra- or intersubject variability in AUC for class 1 drugs, effects of drug metabolizing enzymes were investigated. It was demonstrated that intrasubject variability was high for drugs metabolized by CYP3A4 while intersubject variability was high for drugs metabolized by CYP2D6. For CYP3A4 substrate drugs, the Km value showed the significant relation with Vintra, indicating that the affinity to the enzyme can be a parameter to predict the risk of high intrasubject variability. In conclusion, by analyzing the in house data of human BE study, low permeability, solubility-limited absorption, and high affinity to CYP3A4 are identified as risk factors for high intrasubject variability in oral drug absorption. This information is of importance to design the human BE study for oral drug products containing APIs with a risk of large intrasubject variability in oral absorption.

DOI： 10.1021/acs.molpharmaceut.5b00602

PubMed

researchmap

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 Science and Business Media {LLC}  

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

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

USP apparatus I and II are gold standard methodologies for determining the in vitro dissolution profiles of test drugs. However, it is difficult to use in vitro dissolution results to predict in vivo dissolution, particularly the pH-dependent solubility of weak acid and base drugs, because the USP apparatus contains one vessel with a fixed pH for the test drug, limiting insight into in vivo drug dissolution of weak acid and weak base drugs. This discrepancy underscores the need to develop new in vitro dissolution methodology that better predicts in vivo response to assure the therapeutic efficacy and safety of oral drug products. Thus, the development of the in vivo predictive dissolution (IPD) methodology is necessitated. The major goals of in vitro dissolution are to ensure the performance of oral drug products and the support of drug formulation design, including bioequivalence (BE). Orally administered anticancer drugs, such as dasatinib and erlotinib (tyrosine kinase inhibitors), are used to treat various types of cancer. These drugs are weak bases that exhibit pH-dependent and high solubility in the acidic stomach and low solubility in the small intestine (>pH 6.0). Therefore, these drugs supersaturate and/or precipitate when they move from the stomach to the small intestine. Also of importance, gastric acidity for cancer patients may be altered with aging (reduction of gastric fluid secretion) and/or co-administration of acid-reducing agents. These may result in changes to the dissolution profiles of weak base and the reduction of drug absorption and efficacy. In vitro dissolution methodologies that assess the impact of these physiological changes in the GI condition are expected to better predict in vivo dissolution of oral medications for patients and, hence, better assess efficacy, toxicity and safety concerns. The objective of this present study is to determine the initial conditions for a mini-Gastrointestinal Simulator (mGIS) to assess in vivo dissolution of BCS class IIb drugs, dasatinib as a model drug, including the different gastric condition. The maximum dissolution of dasatinib with USP dissolution apparatus II was less than 1% in pH 6.5 SIF, while the one with mGIS (pH 1.2 SGF/pH 6.5 SIF) reached almost 100%. The supersaturation and precipitation of dasatinib were observed in the in vitro dissolution studies with mGIS but not with USP apparatus II. Additionally, dasatinib dissolution with mGIS was reduced to less than 10% when the gastric pH was elevated, suggesting the co-administration of acid reducing agents will decrease the oral bioavailability of dasatinib. Accurate prediction of in vivo drug dissolution would be beneficial for assuring product safety and efficacy for patients. To this end, we have created a new in vitro dissolution system, mGIS, to predict the in vivo dissolution phenomena of a weak base drug, dasatinib. The experimental results when combined with in silico simulation suggest that the mGIS predicted the in vivo dissolution well due to the elevation of gastric pH. Thus, mGIS might be suitable to predict in vivo dissolution of weak basic drugs. This mGIS methodology is expected to significantly advance the prediction of in vivo drug dissolution. It is also expected to assist in optimizing product development and drug formulation design in support of Quality by Design (QbD) initiatives.

DOI： 10.1016/j.ejps.2015.05.013

PubMed

researchmap

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

DOI： 10.1158/1538-7445.AM2015-756

Web of Science

researchmap

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

DOI： 10.1158/1538-7445.AM2015-184

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

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  

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 MESO1 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 MESO1 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

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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 MESO1 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 MESO1 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

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

In vitro dissolution tests are performed for new formulations to evaluate in vivo performance, which is affected by the change of gastrointestinal (GI) physiology, in the GI tract. Thus, those environmental changes should be introduced to an in vitro dissolution test. Many studies have successfully shown the improvement of in vitro-in vivo correlations (IVIVC) by introducing those physiological changes into dissolution tests. The gastrointestinal simulator (GIS), a multicompartment in vitro dissolution apparatus, was developed to evaluate in vivo drug dissolution. A gastric-emptying rate along with transit rate are key factors to evaluate in vivo drug dissolution and, hence, drug absorption. Dissolution tests with the GIS were performed with Biopharmaceutical Classification System class I drugs at five different gastric-emptying rates in the fasted state. Computational models were used to determine in vivo gastric-emptying time for propranolol and metoprolol based on the GIS dissolution results. Those were compared with published clinical data to determine the gastric half-emptying time. In conclusion, the GIS is a practical tool to assess dissolution properties and can improve IVIVC.

DOI： 10.1002/jps.24112

PubMed

researchmap

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

DOI： 10.1158/1538-7445.AM2014-784

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

This study sought to understand the reasons for the bioinequivalence of a newly developed generic product of pioglitazone hydrochloride and to improve its formulation so that it is equivalent to that of the reference listed drug (RLD). In this clinical study, despite a similar in vitro dissolution profile, the new oral product exhibited a lower plasma concentration of pioglitazone compared to the RLD. The strong pH-dependency of pioglitazone solubility as a weak base indicates that pioglitazone would precipitate in the small intestine after being dissolved in the stomach. Thus, in vitro experiments were performed to investigate the effect of excipients on the particle size distribution of precipitated pioglitazone. Then, the impact of particle size on in vivo absorption was discussed. The precipitated pioglitazone from the RLD showed a peak for small particles (less than 1 μm), which was not observed in the precipitate from the new product. As an excipient, hydroxypropyl cellulose (HPC) influenced the particle size of precipitated pioglitazone, and the amount of HPC in the formulation was increased to the same level as that in the RLD. The precipitate from this improved product showed approximately the same particle size distribution as that of the RLD and successfully demonstrated bioequivalence in the clinical study. In conclusion, for drugs with low solubility, this type of analysis of the particle size distribution of precipitated drugs, in addition to the dissolution test, may help to obtain a better in vitro-in vivo correlation for oral absorption and to develop a bioequivalent product.

DOI： 10.1208/s12248-014-9646-z

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

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

DOI： 10.1158/1538-7445.AM2013-3541

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

UNLABELLED: In the revised WHO classification of lung cancer, published in 1999, large cell neuroendocrine carcinoma (LCNEC) was employed as a new histological entity. LCNEC is generally considered a high-grade malignant lung cancer, and appropriate treatment remains to be determined. Before its new classification, LCNEC had long been classified into several entities. Advancing the review of previous cases in Nippon Medical School Hospital, we noticed that some LCNEC patients were formally diagnosed as having small cell lung cancer (SCLC), and they showed long-term survival. MATERIAL AND METHODS: All histological specimens of surgically resected SCLC in Nippon Medical School Hospital were reclassified according to the 1999 WHO classification manual. Their neuroendocrine differentiations were confirmed by the use of immunostainings with chromogranin A and synaptophysin. RESULTS: Fourteen cases satisfied the qualifications for both histological and clinical reevaluation. Among them, 6 patients were reclassified as LCNEC, and their stage distribution was as follow: IA; 1, IB; 2, IIIA; 2, and IIIB; 1. Their survival term ranged from 33.8 to 78.0 months; 5 were still alive, and 1 (IIIB) died 57.6 months after surgery. DISCUSSION: According to this study, all the LCNEC patients who were treated as SCLC patients showed more favorable prognoses than patients described in published studies, even overall lung cancer. Therefore, it is suggested that multimodality therapy for SCLC may improve the prognoses of patients with LCNEC.

PubMed

researchmap

記述言語：日本語  

抗癌剤による心毒性は、1970年代にanthracycline系薬剤のdoxorubicinが登場、普及して以来認識されるようになった。集学的治療や高用量・多剤併用化学療法、そして分子標的治療の発展を背景に心毒性の危険因子は増加し、心毒性はより日常的な副作用として認識されるべき時代となった。分子標的薬の有害事象としての心毒性(trastuzumabに代表される)は、発現した場合、不可逆的な心機能障害に陥る可能性がある。心毒性の発生機序はいずれの薬剤においても十分に解明されておらず、現段階では治療前の心機能の評価、投与期間における心機能のモニタリングを行いつつ、化学療法を実施・中止していくことが実際的な戦術となる。分子標的薬による浮腫(imatinibに代表される)も比較的新しい有害事象の一つである。浮腫の迅速かつ的確な鑑別診断は必須で、適切な対応が求められる。しかし、現段階では対症療法に努める他なく、今後、分子標的薬による心毒性・浮腫のメカニズムの解明、対処法の新たな構築が求められる。(著者抄録)

researchmap

その他リンク： https://search.jamas.or.jp/default/link?pub_year=2008&ichushi_jid=J00296&link_issn=&doc_id=20081020420004&doc_link_id=1573668925859003904&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1573668925859003904&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

記述言語：英語  

INTRODUCTION: A neurotrophic tropomyosin receptor kinase (NTRK)-tyrosine kinase inhibitor (TKI) has shown dramatic efficacy against malignant tumors harboring an NTRK fusion gene. However, almost all tumors eventually acquire resistance to NTRK-TKIs. METHOD: To investigate the mechanism of resistance to NTRK-TKIs, we established cells resistant to three types of NTRK-TKIs (larotrectinib, entrectinib, and selitrectinib) using KM12 colon cancer cells with a TPM3-NTRK1 rearrangement. RESULT: Overexpression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) was observed in three resistant cells (KM12-LR, KM12-ER, and KM12-SR) by microarray analysis. Lower expression of sterol regulatory element-binding protein 2 (SREBP2) and peroxisome proliferator activated receptor α (PPARα) was found in two cells (KM12-ER and KM12-SR) in which HMGCS2 was overexpressed compared to the parental KM12 and KM12-LR cells. In resistant cells, knockdown of HMGCS2 using small interfering RNA improved the sensitivity to NTRK-TKI. Further treatment with mevalonolactone after HMGCS2 knockdown reintroduced the NTRK-TKI resistance. In addition, simvastatin and silibinin had a synergistic effect with NTRK-TKIs in resistant cells, and delayed tolerance was observed after sustained exposure to clinical concentrations of NTRK-TKI and simvastatin in KM12 cells. In xenograft mouse models, combination treatment with entrectinib and simvastatin reduced resistant tumor growth compared with entrectinib alone. CONCLUSION: These results suggest that HMGCS2 overexpression induces resistance to NTRK-TKIs via the mevalonate pathway in colon cancer cells. Statin inhibition of the mevalonate pathway may be useful for overcoming this mechanistic resistance.

DOI： 10.1002/cam4.7393

PubMed

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：英語  

INTRODUCTION: Osimertinib is a standard treatment for patients with EGFR-mutant NSCLC. Although some osimertinib resistance mechanisms have been identified, nearly 50% of the mechanisms remain to be elucidated. This study was aimed at identifying non-genetic mechanisms underlying osimertinib resistance. METHODS: We established two osimertinib-resistant cell lines from EGFR mutation-positive PC-9 and HCC827 NSCLC cell lines (PC-9OR and HCC827OR, respectively) using a stepwise method. We compared the phosphoproteomic profiles of the osimertinib-resistant and parental cells using mass spectrometry. Upstream kinases were identified using the application Kinase Enrichment Analysis version 3. RESULTS: Phosphoproteomic analysis revealed 80 phosphorylation sites that were mutually up-regulated in PC-9OR and HCC827OR cells. The Kinase Enrichment Analysis version 3 analysis identified focal adhesion kinase (FAK) and proto-oncogene tyrosine-protein kinase Src (Src) as upstream kinases of these up-regulated phosphoproteins. The small-interfering RNA-mediated knockdown of FAK reduced Src phosphorylation and that of Src reduced FAK phosphorylation in both cell lines. Furthermore, FAK- or Src-specific small-interfering RNA treatments restored EGFR phosphorylation in PC-9OR and HCC827OR cells. The combination of FAK and Src inhibitors inhibited PC-9OR and HCC827OR cell proliferation in vitro and suppressed tumor growth in a xenograft mouse model. Immunohistochemistry of tumors from patients with EGFR-mutant NSCLC suggested that phosphorylated FAK and Src are involved in initial and acquired resistance to osimertinib. CONCLUSIONS: Phosphoproteomic analysis may help elucidate the mechanisms of resistance to molecular-targeted therapies in lung cancer. Mutual phosphorylation of FAK and Src is involved in osimertinib resistance. Thus, FAK and Src inhibition may be novel treatment strategies for osimertinib-resistant NSCLC.

DOI： 10.1016/j.jtocrr.2024.100668

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：英語  

INTRODUCTION: Treatment options for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) after EGFR-tyrosine kinase inhibitor (TKI) treatment failure are limited. An exploratory analysis of 26 patients in the IMpower150 study indicated that treatment with atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) was effective in patients with EGFR-mutated NSCLC. This phase II study was conducted to assess the efficacy of ABCP in EGFR-mutated NSCLC patients after TKI treatment. METHODS: Patients with non-squamous NSCLC harboring sensitizing EGFR mutations were enrolled. ABCP therapy was administered every 3 weeks for four cycles, followed by maintenance therapy with atezolizumab and bevacizumab. The primary endpoint was progression-free survival (PFS) according to extramural review (ER). Key secondary endpoints and preplanned analysis included overall survival (OS), overall response rate (ORR), and differences in the efficacy of ABCP according to prior EGFR-TKI administration, liver metastases, and brain metastases. RESULTS: Sixty patients from 26 centers were enrolled. Median PFS was 7.4 months (95% confidence interval [CI]: 5.7-8.2). The median OS was 23.1 months (95% CI: 13.1-not reached), and the ORR was 55.9%. PFS was significantly shorter in patients who had received osimertinib as a first-line treatment (7.2 months vs. 7.4 months, hazard ratio [HR] 1.932, p = 0.023), those with brain metastases (5.7 months vs. 8 months, HR 1.86, p = 0.032), or those with liver metastases (5.4 months vs. 7.9 months, HR 2.779, p = 0.003). CONCLUSIONS: Although this study did not meet the primary endpoint, ABCP showed clinically meaningful efficacy in EGFR-mutated NSCLC patients.

DOI： 10.1016/j.ejca.2023.113469

PubMed

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：日本医科大学医学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：日本医科大学医学会  

researchmap

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)

J-GLOBAL

researchmap

記述言語：英語  

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

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

researchmap

記述言語：英語  

J-GLOBAL

researchmap

記述言語：英語  

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

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：英語  

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

researchmap

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  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

担当区分：責任著者   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  

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(株)日本臨床社  

researchmap

記述言語：日本語   出版者・発行元：(株)日本臨床社  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本胸部外科学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本胸部外科学会  

researchmap

担当区分：責任著者   記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本胸部外科学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：日本臨床外科学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：日本臨床外科学会  

J-GLOBAL

researchmap

担当区分：責任著者   記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：日本語   出版者・発行元：日本胸部外科学会-関東甲信越地方会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：日本語   出版者・発行元：日本臨床外科学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器外科学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器外科学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器外科学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器外科学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器外科学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

J-GLOBAL

researchmap

記述言語：英語  

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

PubMed

researchmap

記述言語：英語  

DOI： 10.1007/s10147-022-02118-8

PubMed

researchmap

記述言語：英語  

OBJECTIVES: Indications of limited resection, such as segmentectomy, have recently been reported for patients with solid-predominant lung cancers ≤2 cm. This study aims to identify unfavourable prognostic factors using three-dimensional imaging analysis with artificial intelligence (AI) technology. METHODS: A total of 157 patients who had clinical N0 non-small cell lung cancer with a radiological size ≤2 cm, and a consolidation tumour ratio > 0.5, who underwent anatomical lung resection between 2011 and 2017 were enrolled. To evaluate the three-dimensional structure, the ground-glass nodule/Solid Automatic Identification AI software Beta Version (AI software; Fujifilm Corporation, Japan) was used. RESULTS: Maximum standardized uptake value (SUVmax) and solid-part volume measured by AI software (AI-SV) showed significant differences between the 139 patients with adenocarcinoma and the 18 patients with non-adenocarcinoma. Among the adenocarcinoma patients, 42 patients (30.2%) were found to be pathological upstaging. Multivariable analysis demonstrated that high SUVmax, high carcinoembryonic antigen level and high AI-SV were significant prognostic factors for recurrence-free survival (RFS; P < 0.05). The 5-year RFS was compared between patients with tumours showing high SUVmax and those showing low SUVmax (67.7% vs 95.4%, respectively, P < 0.001). The 5-year RFS was 91.0% in patients with small AI-SV and 68.1% in those with high AI-SV (P = 0.001). CONCLUSIONS: High AI-SV, high SUVmax and abnormal carcinoembryonic antigen level were unfavourable prognostic factors of patients with solid-predominant lung adenocarcinoma with a radiological size ≤2 cm. Our results suggest that lobectomy should be preferred to segmentectomy for patients with these prognostic factors.

DOI： 10.1093/ejcts/ezab541

PubMed

researchmap

記述言語：日本語   出版者・発行元：日本臨床外科学会  

researchmap

記述言語：日本語   出版者・発行元：日本胸部外科学会-関東甲信越地方会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(株)文光堂  

J-GLOBAL

researchmap

記述言語：英語  

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 (ADJ) according to real-world data. Therefore, robust predictive biomarkers for selecting 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 FISH. Statistical analyses to determine whether the status of ACTN4 gene amplification affected recurrence-free survival (RFS) were carried out. Formalin-fixed, paraffin-embedded samples from 1136 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 aged 65 years or older, the ADJ group had better RFS than the OBS group in the ACTN4-positive cohort (hazard ratio [HR], 0.084, 95% confidence interval [CI], 0.009-0.806; P = .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 = .289). Analyses of ACTN4 gene amplification contributed to the decision regarding postoperative ADJ for stage I lung adenocarcinomas, preventing recurrence, improving the quality of medical care, preventing the unnecessary side-effects of ADJ, and saving medical costs.

DOI： 10.1111/cas.15228

PubMed

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

J-GLOBAL

researchmap

記述言語：英語  

BACKGROUND: Osimertinib is effective in patients with T790M mutation-positive advanced non-small-cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its effectiveness and safety in patients with poor performance status (PS) are unknown. METHODS: Enrolled patients showed disease progression after treatment with gefitinib, erlotinib, or afatinib; T790M mutation; stage IIIB, IV, or recurrent disease; and PS of 2-4. Osimertinib was orally administered at a dose of 80 mg/day. The primary endpoint of this phase II study (registration, jRCTs061180018) was response rate and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety. RESULTS: Thirty-three patients were enrolled, of which 69.7% and 24.2% had PS of 2 and 3, respectively. One patient was excluded due to protocol violation; in the remaining 32 patients, the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months. The most frequent adverse event of grade 3 or higher severity was lymphopenia (12.1%). Interstitial lung disease (ILD) was observed at all grades and at grades 3-5 in 15.2% (5/33) and 6.1% (2/33) of patients, respectively. Treatment-related death due to ILD occurred in one patient. Patients negative for activating EGFR mutations after osimertinib administration had longer median PFS than those positive for these mutations. CONCLUSION: Osimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC. Plasma EGFR mutation clearance after TKI treatment could predict the response to EGFR-TKIs.

DOI： 10.1007/s10147-021-02043-2

PubMed

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：日本語   出版者・発行元：日本胸部外科学会-関東甲信越地方会  

researchmap

記述言語：日本語   出版者・発行元：日本臨床外科学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本胸部外科学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本胸部外科学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：日本臨床外科学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：日本臨床外科学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

researchmap

記述言語：英語  

BACKGROUND: Patient participation in decisions 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. 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. At discharge, patients' responses to the 'Questionnaire on check sheet and treatment selection' were collected 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, some felt that this activity increased the administrative burden of medical professionals. CONCLUSION: Almost all patients stated that the present check sheet was useful as a decision support tool and facilitated 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

PubMed

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：日本胸部外科学会-関東甲信越地方会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：日本外科系連合学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(株)篠原出版新社  

近年の分子標的治療薬および免疫チェックポイント阻害薬の導入によって、胸膜播種・悪性胸水陽性非小細胞肺癌を含めた肺癌非切除例の成績は飛躍的に向上している。胸膜播種・悪性胸水は全身性の病態と位置づけられており、原則的には切除の適応外であるが、術中にこれらが初めて発見された場合には、試験開胸にて手術を終了するか、あるいは肺切除を行うかについて議論が分かれる。今回、当院で2008～2018年に胸膜播種・悪性胸水陽性非小細胞肺癌に対し腫瘍減量目的で肺切除を施行した16例の長期成績を調査し、同期間に同肺癌に対して全身治療が行われた非切除群(75例)の成績と比較検討した。結果、肺切除群は非切除群に比べて5年OS(全生存)割合、5年PFS(無増悪生存)割合とも有意に高かった。肺切除例のうち術後に全身治療を受けた群(10例)は全身治療を受けなかった群に比べてOS・PFSとも高く、特に免疫チェックポイント阻害薬を投与された4例ではいずれも肺切除後の生存期間が5年を超えていた。

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

J-GLOBAL

researchmap

記述言語：英語  

PD-L1 expression is the most useful predictive biomarker for immunotherapy efficacy on non-small cell lung cancer (NSCLC), and CD8+ tumor-infiltrating lymphocytes (CD8+ TILs) play an essential role in the clinical activity of immunotherapy. PD-L1 is found on the exosome's surface, and PD-L1 expressing exosomes can inhibit antitumor immune responses. This study aimed to analyze tumor PD-L1 expression, serum exosomal PD-L1, and CD8+ TILs to investigate anti-PD-1 response and clinicopathological outcomes in NSCLC. One hundred twenty patients with stage I-III NSCLC were enrolled, and serum samples collected during the initial surgery were pooled. The Human CD274/PD-L1 ELISA kit was used to quantify the exosomal PD-L1. Exosomal PD-L1 levels were significantly correlated with tumor PD-L1 levels (p < 0.001) and the number of CD8+ TILs (p = 0.001). Patients with exosomal PD-L1 ≥ 166 pg/mL tended to have a worse RFS than those with < 166 pg/mL in all stage (p = 0.163) and stage I patients (p = 0.116). Seventeen patients exhibited postoperative recurrences and received anti-PD-1 treatment. The disease control rate of patients with exosomal PD-L1 ≥ 166 pg/mL was 100%. The measurement of serum exosomal PD-L1 as a quantitative factor with tumor PD-L1 status may help predict anti-PD-1 response and clinical outcomes in patients with NSCLC.

DOI： 10.1038/s41598-021-87575-3

PubMed

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：東京医科大学医学会  

がんゲノム医療連携病院である東京医科大学病院において、2019年10月1日より保険診療下での「がん遺伝子パネル検査」を導入してから1年が経過した。2019年10月から「NCCオンコパネル」、2020年4月から「FoundationOne CDx」を導入し、2019年10月から2020年9月までの1年間のがん遺伝子パネル検査の出検総数は33件であった。検査の対象となった標準治療実施後の症例33件に対し、実際にプロファイリングデータが取得できた症例は32/33例であり、actionable geneが31/32例(97%)、druggable geneが18/32例(56%)検出されたが、その中で治療の選択に繋がった症例はわずか5/32例(16%)であった。今後の「個別化がん医療」の促進において、院内でのがんゲノム医療の環境・体制構築の現状をがん診療に携わるすべてのスタッフが把握することで、「より多くの患者が恩恵を受けることのできるがんゲノム医療」の推進に向けた課題対応が期待される。(著者抄録)

J-GLOBAL

researchmap

その他リンク： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J00877&link_issn=&doc_id=20210924440003&doc_link_id=%2Fcr4tokyo%2F2021%2F007902%2F004%2F0141-0151%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcr4tokyo%2F2021%2F007902%2F004%2F0141-0151%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：日本胸部外科学会-関東甲信越地方会  

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本胸部外科学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

researchmap

記述言語：英語  

DOI： 10.21037/jtd.2020.04.29

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器外科学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：東京医科大学医学会  

researchmap

その他リンク： https://search.jamas.or.jp/default/link?pub_year=2020&ichushi_jid=J00877&link_issn=&doc_id=20201113360016&doc_link_id=%2Fcr4tokyo%2F2020%2Fs07803%2F008%2F0280-0280%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcr4tokyo%2F2020%2Fs07803%2F008%2F0280-0280%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：東京医科大学医学会  

researchmap

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  

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：英語  

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

PubMed

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

記述言語：英語  

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

PubMed

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

researchmap

記述言語：英語  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：英語  

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

PubMed

researchmap

記述言語：英語  

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

PubMed

researchmap

記述言語：英語  

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

PubMed

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

記述言語：英語  

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

PubMed

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

researchmap