Publications by authors named "Shinobu Hosokawa"

66 Publications

The effects of antibiotics on the efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer differ based on PD-L1 expression.

Eur J Cancer 2021 Apr 7;149:73-81. Epub 2021 Apr 7.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Japan.

Background: Immune checkpoint inhibitors (ICIs) are essential for treatment of various malignancies, including non-small-cell lung cancer (NSCLC). Recently, several studies have shown that the gut microbiome plays an important role in ICI treatment of solid cancers, and antibiotic (ATB) use had a negative impact on the outcomes of ICI treatment via dysbiosis in the gut. However, whether this is applicable to NSCLC remains unclear. The impact of ATBs based on PD-L1 expression also remains unclear.

Methods: We retrospectively reviewed the medical records of patients with NSCLC who received ICI monotherapy (anti-PD-1 or anti-PD-L1 antibody) at nine institutions from December 2015 to May 2018. Outcomes with use of ATBs during the 2 months before or a month after initiation of ICI treatment, including progression-free survival (PFS) and overall survival (OS), were investigated using the Kaplan-Meier method. Multivariate analysis was also conducted using a Cox proportional hazards model.

Results: A total of 531 patients were included in this study, among whom 98 (18.5%) received ATBs before or after ICI treatment. ATB use was significantly associated with a shorter median OS (11.7 months in the ATB group vs. 16.1 months in the non-ATB group; p = 0.028), whereas the difference in PFS was not significant (3.5 months in both the groups; p = 0.287). We next investigated the association based on PD-L1 expression in the 265 patients for whom PD-L1 expression was determined. There was no significant difference in the median OS or PFS between patients with NSCLC and PD-L1 expression <50% receiving ATBs and those not receiving ATBs (PFS: 3.3 vs. 2.8 months, p = 0.88; OS: 9.5 vs. 17.1 months, p = 0.24). Conversely, patients with NSCLC and PD-L1 expression ≥50% receiving ATBs showed significantly shorter median PFS and OS (PFS: 4.2 vs. 9.4 months, p = 0.012; OS: 11.9 vs. 28.4 months, p = 0.011). The impact of ATBs in patients with NSCLC and PD-L1 expression ≥50% was more significant than that in the entire cohort.

Conclusions: Our results indicate that the impact of ATB use on the efficacy of ICIs differed based on PD-L1 expression in patients with advanced NSCLC. A negative impact of ATB use was found in patients with NSCLC and PD-L1 expression ≥50% but not in those with PD-L1 expression <50%.
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http://dx.doi.org/10.1016/j.ejca.2021.02.040DOI Listing
April 2021

Significance of PD-L1 expression in the cytological samples of non-small cell lung cancer patients treated with immune checkpoint inhibitors.

J Cancer Res Clin Oncol 2021 Mar 29. Epub 2021 Mar 29.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, Okayama, 700-8558, Japan.

Objectives: The programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) in tumor tissue samples is an established clinical biomarker for non-small cell lung cancer (NSCLC). However, the significance of PD-L1 expression in other types of samples has not been fully investigated.

Patients And Methods: We conducted a multicenter retrospective cohort study of advanced NSCLC patients who received ICI treatment during the clinical course and investigated the effects of ICIs according to PD-L1 expression in cytology samples, including cell block and endobronchial ultrasound-guided (EBUS) transbronchial needle aspiration (TBNA) samples.

Results: A total of 264 patients were included in this study: PD-L1 expression was determined in cell block or TBNA specimens in 55 patients, and in tissue samples in 209 patients. Among the former patients, the median progression-free survival (PFS) of those with a TPS for PD-L1 ≥ 50% was significantly longer compared to that of those with a TPS < 50% (6.5 vs. 1.9 months, respectively, p = 0.008). When the cutoff value was set at 1%, the median PFS was 4.2 months in patients with a TPS ≥ 1% and 1.5 months in patients with a TPS < 1% (p < 0.001).

Conclusion: PD-L1 expression determined using cytology specimens predicts the efficacy of ICIs.
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http://dx.doi.org/10.1007/s00432-021-03615-5DOI Listing
March 2021

Dacomitinib as a retreatment for advanced non-small cell lung cancer patient with an uncommon EGFR mutation.

Thorac Cancer 2021 Apr 2;12(8):1248-1251. Epub 2021 Mar 2.

Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, Okayama, Japan.

In non-small cell lung cancer (NSCLC), uncommon epidermal growth factor receptor (EGFR) mutations are mutations other than Ex19 deletion and Ex21 L858R, which are common mutations highly sensitive to EGFR-tyrosine kinase inhibitors. Afatinib, a second-generation EGFR-tyrosine kinase inhibitor, has been shown to be effective in patients with uncommon mutations. Dacomitinib, another second-generation EGFR-tyrosine kinase inhibitor, has not previously been shown to be effective in patients with uncommon mutations. Here, we report the efficacy of dacomitinib for uncommon EGFR mutations in a 71-year-old woman diagnosed with metastatic lung adenocarcinoma with uncommon EGFR mutation (Ex18 G719A). Afatinib was administered as the first-line treatment, and a remarkable antitumor effect was observed. However, the tumor grew after 14 months. Pemetrexed plus carboplatin followed by pemetrexed, docetaxel, atezolizumab and S-1 were performed in sequence. Although approximately four years had passed since the start of treatment, her physical condition was good. The patient started dacomitinib as the sixth-line treatment. Lesions were markedly reduced and treatment with dacomitinib was continued for 7.8 months. Dacomitinib is a possible treatment option for NSCLC with uncommon mutations.
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http://dx.doi.org/10.1111/1759-7714.13897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046035PMC
April 2021

A randomized trial of sodium alginate prevention of esophagitis in LA-NSCLC receiving chemoradiotherapy: OLCSG1401.

Support Care Cancer 2021 Mar 1. Epub 2021 Mar 1.

Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Background: Radiation esophagitis is a critical adverse event that needs to be appropriately managed while administering thoracic irradiation. This trial aimed to investigate whether sodium alginate has preventative effects on esophagitis in patients with non-small-cell lung cancer (NSCLC) receiving concurrent chemoradiotherapy (CRT).

Methods: Patients with untreated stage III NSCLC who were eligible for concurrent CRT were randomly assigned at a 1:1:1 ratio to receive one of the following treatments: initial or late use of oral sodium alginate (arms A and B) or water as control (arm C). The primary endpoint was the proportion of patients developing G3 or worse esophagitis.

Results: Overall, 94 patients were randomly assigned between February 2014 and September 2018. The study was prematurely terminated because of slow accrual. The proportions of patients with G3 or worse esophagitis were 12.5%, 9.8%, and 19.4% in arms A, B, and C, respectively. Patients receiving sodium alginate had fewer onsets of G3 esophagitis; however, differences compared with arm C were not significant (A vs. C: p = 0.46; B vs. C: p = 0.28). The rates of grade 3 or worse non-hematologic toxicities besides esophagitis were 29%, 26%, and 43% in arms A, B, and C, respectively. Interestingly, compared with arm C, a low rate of febrile neutropenia was observed in arm A (3.1% vs. 19.4%: p = 0.04).

Conclusions: Sodium alginate did not show significant preventative effects on radiation-induced esophagitis in patients with NSCLC. The frequency of CRT-induced febrile neutropenia was lower in the early use sodium alginate arm.

Trial Registration: ClinicalTrials.gov Identifier Registry number: UMIN000013133.
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http://dx.doi.org/10.1007/s00520-021-06092-1DOI Listing
March 2021

Crizotinib for recurring non-small-cell lung cancer with EML4-ALK fusion genes previously treated with alectinib: A phase II trial.

Thorac Cancer 2021 03 20;12(5):643-649. Epub 2021 Jan 20.

Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Background: The efficacy of crizotinib treatment for recurring EML4-ALK-positive non-small cell lung cancer (NSCLC) previously treated with alectinib is unclear. Based on our preclinical findings regarding hepatocyte growth factor/mesenchymal epithelial transition (MET) pathway activation as a potential mechanism of acquired resistance to alectinib, we conducted a phase II trial of the anaplastic lymphoma kinase/MET inhibitor, crizotinib, in patients with alectinib-refractory, EML4-ALK-positive NSCLC.

Methods: Patients with ALK-rearranged tumors treated with alectinib immediately before enrolling in the trial received crizotinib monotherapy. The objective response rate was the primary outcome of interest.

Results: Nine (100%) patients achieved a partial response with alectinib therapy with a median treatment duration of 6.7 months. Crizotinib was administered with a median treatment interval of 50 (range, 20-433) days. The overall response rate was 33.3% (90% confidence interval [CI]: 9.8-65.5 and 95% CI: 7.5-70.1), which did not reach the predefined criteria of 50%. Two (22%) patients who achieved a partial response had brain metastases at baseline. Progression-free survival (median, 2.2 months) was not affected by the duration of treatment with alectinib. The median survival time was 24.1 months. The most common adverse events were an increased aspartate transaminase/alanine transaminase (AST/ALT) ratio (44%) and appetite loss (33%); one patient developed transient grade 4 AST/ALT elevation, resulting in treatment discontinuation. Other adverse events were consistent with those previously reported; no treatment-related deaths occurred.

Conclusions: Although the desired response rate was not achieved, crizotinib monotherapy following treatment with alectinib showed efficacy alongside previously described adverse events.
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http://dx.doi.org/10.1111/1759-7714.13825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919114PMC
March 2021

Phase II study of amrubicin plus erlotinib in previously treated, advanced non-small cell lung cancer with wild-type epidermal growth factor receptor (TORG1320).

Invest New Drugs 2021 Apr 7;39(2):530-536. Epub 2020 Nov 7.

Department of Respiratory Medicine, Kitasato University School of Medicine, 1-15-1, Kitasato, Minami-ku, Sagamihara city, Kanagawa, 252-0375, Japan.

Background Amrubicin (AMR) is a completely synthetic 9-aminoanthracycline and clinically active against non-small cell lung cancer (NSCLC). We conducted a phase I study of AMR and erlotinib (ERL) combination therapy in previously treated patients with advanced NSCLC and have already reported the safety and effectiveness. Methods We conducted a multi-center, single-arm phase II trial to evaluate the efficacy of AMR and ERL combination therapy in patients with previously treated, advanced NSCLC harboring wild-type EGFR, PS 0-1 and < 75 years of age. Patients were treated at 3-week intervals with AMR plus ERL. The primary endpoint was the PFS, and the secondary endpoints were the response rate (RR), disease control rate (DCR), overall survival (OS) and toxicity. The trough ERL concentration (C) was measured as an exploratory study to analyze the relationship between the efficacy/safety and pharmacokinetics. Results From June 2013 to July 2016, 25 patients were enrolled in this trial. The PFS according to the central test was 3.6 months (95% confidence interval 2.1-5.1). The RR and DCR were 24.0% and 64.0%, respectively. We had no treatment-related deaths in this study. Conclusions The PFS of AMR and ERL combination therapy was superior to that of AMR monotherapy in the historical setting, but the primary endpoint was not met in this trial. In our study, the pharmacokinetic analysis showed that the C of ERL was elevated with combination therapy. This combination therapy might be a viable treatment for previously treated NSCLC patients without a driver oncogene mutation. Clinical trial information UMIN 000010582.
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http://dx.doi.org/10.1007/s10637-020-01031-zDOI Listing
April 2021

Impact of previous thoracsic radiation therapy on the efficacy of immune checkpoint inhibitors in advanced non-smasll-cell lung cancer.

Jpn J Clin Oncol 2021 Feb;51(2):279-286

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Objectives: Studies investigating the association between radiation therapy and the efficacy of immune checkpoint inhibitors in advanced non-small-cell lung cancer have provided inconsistent results, likely due to relatively small cohort sizes. This study investigated the effect of previous thoracic radiation therapy on the efficacy of immune checkpoint inhibitor therapy in a large non-small-cell lung cancer cohort.

Patients And Methods: We conducted a retrospective cohort study using data from 531 non-small-cell lung cancer patients who received monotherapy with programmed cell death protein 1/programmed death-ligand 1 inhibitors at nine institutions. The effects of thoracic radiation therapy on the efficacy of immune checkpoint inhibitors were investigated.

Results: A total of 531 non-small-cell lung cancer patients treated with immune checkpoint inhibitors were included in this study. The progression-free survival period was significantly longer in patients that had received thoracic radiation therapy before immune checkpoint inhibitor therapy compared to those without previous thoracic radiation therapy (median progression-free survival 5.0 vs. 3.0 months, P = 0.0013). A multivariate analysis showed that thoracic radiation therapy was an independent predictive factor of improved progression-free survival (hazard ratio of progression-free survival: 0.79, P = 0.049). In contrast, extra-thoracic radiation therapy was associated with inferior outcomes (median progression-free survival 3.0 vs. 4.2 months, P = 0.0008).

Conclusion: Previous thoracic radiation therapy, but not prior extra-thoracic radiation therapy, enhanced the efficacy of anti-programmed cell death protein 1/programmed death-ligand 1 therapy in non-small-cell lung cancer patients.
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http://dx.doi.org/10.1093/jjco/hyaa180DOI Listing
February 2021

A Phase 2 Study of Atezolizumab for Pretreated NSCLC With Idiopathic Interstitial Pneumonitis.

J Thorac Oncol 2020 12 25;15(12):1935-1942. Epub 2020 Aug 25.

Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama, Kanagawa, Japan.

Introduction: Interstitial pneumonia (IP) is one of the most common and poor prognostic comorbidities in patients with NSCLC and a known risk factor for pneumonitis. Atezolizumab monotherapy is an established treatment for recurrent NSCLC and reported to have a lower risk of pneumonitis than programmed cell death protein 1 inhibitors. This study aimed to assess the safety and efficacy of atezolizumab monotherapy in patients with pretreated advanced or recurrent NSCLC with idiopathic IP.

Methods: Patients with advanced or recurrent NSCLC with comorbid idiopathic, chronic fibrotic IP with % forced vital capacity of greater than 70% and no history of immune checkpoint inhibitors were enrolled. The patients received atezolizumab (1200 mg) every 3 weeks until the discontinuation criteria were met. The primary end point of this study was the 1-year survival rate. A sample size of 38 patients was set.

Results: This study was terminated early owing to high incidence of pneumonitis. A total of 17 patients were enrolled, with a median age of 70 years. The median % forced vital capacity and % diffusing capacity for carbon monoxide at baseline were 85.4% and 54.4%, respectively. The incidence of pneumonitis was 29.4% (5 of 17) for all grades, 23.5% (4 of 17) for grade greater than or equal to 3, and 5.9% (1 of 17) for grade 5. A total of 57.1% patients (4 of 7) with honeycomb lung developed pneumonitis with a grade greater than or equal to 3, whereas only one patient (10%) without honeycomb lung (n = 10) with grade 1 pneumonitis was found.

Conclusions: Patients with NSCLC with comorbid IP as defined by the selection criteria for this study might have an increased risk of immune checkpoint inhibitor-induced pneumonitis.
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http://dx.doi.org/10.1016/j.jtho.2020.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446731PMC
December 2020

Utility of immune checkpoint inhibitors in non-small-cell lung cancer patients with poor performance status.

Cancer Sci 2020 Oct 26;111(10):3739-3746. Epub 2020 Aug 26.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Most clinical trials of non-small-cell lung cancer (NSCLC) exclude patients with poor ECOG performance status (PS). Thus, the efficacy of immune checkpoint inhibitors (ICIs) in patients with poor PS remains unclear. Herein, we used data from a retrospective cohort to assess the potential clinical benefits of ICIs in NSCLC patients with poor PS. Data from NSCLC patients who received ICI monotherapy at 9 institutions between December 2015 and May 2018 were retrospectively analyzed. After excluding 4 patients who lacked PS data, a total of 527 ICI-treated patients, including 79 patients with PS 2 or higher, were used for our analyses. The progression-free survival (PFS) and overall survival (OS) of patients with PS 2 or higher were significantly shorter compared with those of PS 0-1 patients (median PFS, 4.1 vs 2.0 months; P < .001 and median OS, 17.4 vs 4.0 months; P < .001). Among NSCLC patients with programmed cell death protein-ligand 1 (PD-L1) expression of 50% or higher who were treated with pembrolizumab as first-line therapy, the median PFS times of patients with PS 2 and 0-1 were 7.3 and 8.1 months, respectively. There was no significant difference in PFS between patients with PS 2 and 0-1 (P = .321). Although poor PS was significantly associated with worse outcomes in NSCLC patients treated with ICIs, pembrolizumab as a first-line treatment in NSCLC patients expressing high levels of PD-L1 could provide a clinical benefit, even in patients with PS 2.
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http://dx.doi.org/10.1111/cas.14590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540975PMC
October 2020

Characteristics of patients with EGFR-mutant non-small-cell lung cancer who benefited from immune checkpoint inhibitors.

Cancer Immunol Immunother 2021 Jan 10;70(1):101-106. Epub 2020 Jul 10.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama City, Okayama, 700-8558, Japan.

Objectives: Immune checkpoint inhibitors (ICIs) are less effective in non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. However, a small percentage of patients with EGFR-mutant NSCLC do respond, and the characteristics of these patients are not known. Here, we identify the characteristics of patients who may respond to ICI therapy for EGFR-mutant NSCLC.

Patients And Methods: The medical records of NSCLC patients with EGFR mutations who received PD-1/PD-L1 antibody monotherapy at nine institutions were reviewed.

Results: In total, 58 patients with EGFR-mutant NSCLC were analyzed. Various clinical factors such as smoking history and EGFR mutation type were not associated with progression-free survival (PFS) of ICIs, while the PFS of prior EGFR tyrosine kinase inhibitors (TKIs) was inversely associated with that of ICIs. Patients who responded to prior EGFR TKIs for > 10 months exhibited a significantly shorter response to ICIs compared to those who had responded for ≤ 10 months (PFS of ICI: 1.6 vs. 1.9 months; hazard ratio: 2.54; 95% confidence interval 1.26-5.12; p = 0.009). However, patients who responded to ICIs for > 6 months responded to prior EGFR TKIs for significantly shorter periods compared to those who responded to ICIs for ≤ 6 months (PFS of prior EGFR TKI: 5.3 vs. 12.1 months; log-rank test: p = 0.0025).

Conclusion: The duration of response to prior EGFR TKIs could be a predictive marker of ICI therapy in EGFR-mutant NSCLC patients.
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http://dx.doi.org/10.1007/s00262-020-02662-0DOI Listing
January 2021

Low-Dose Erlotinib Treatment in Elderly or Frail Patients With EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Multicenter Phase 2 Trial.

JAMA Oncol 2020 07 9;6(7):e201250. Epub 2020 Jul 9.

Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.

Importance: Although the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for EGFR gene mutation-positive non-small cell lung cancer is well established, optimal dosing remains to be established, especially in elderly or frail patients.

Objective: To investigate the efficacy and safety of low-dose erlotinib in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer.

Design, Setting, And Participants: Single-arm phase 2 trial with the Southwest Oncology Group (SWOG) 2-stage design that enrolled frail patients from 21 Japanese institutions after meeting the inclusion criteria. Chemotherapy-naive patients with EGFR-activating mutation-positive non-small cell lung cancer who were considered frail based on age, the Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status were eligible for the study.

Interventions: Patients were initially administered 50 mg/d erlotinib for 4 weeks, which was modified based on response or adverse events. Dose increase was permitted for patients with stable disease after 4 weeks.

Main Outcomes And Measures: The primary end point was the independent review committee-confirmed objective response rate (ORR) at the dose of 50 mg/d. The study also evaluated the pharmacokinetics of low-dose erlotinib and influence of ABCB1 gene polymorphisms.

Results: Eighty patients were enrolled, with a median (range) age of 80 (49-90) years; 54 (68%) were men. An independent review committee confirmed a significant ORR of 60.0% (90% CI, 50.2%-69.2%). The disease control rate was 90.0% (90% CI, 82.7%-94.9%), median progression-free survival was 9.3 months (95% CI, 7.2-11.4 months), and median overall survival was 26.2 months (95% CI, 21.9-30.4 months). Mild adverse events were observed in some participants, with few patients exhibiting grade 3 or greater adverse events. Low-dose erlotinib treatment was temporarily suspended for 10 patients owing to adverse events. Five of 80 patients (6%) had their erlotinib dose reduced to 25 mg because of oral mucositis, paronychia, erythema multiforme, diarrhea, and anorexia. Two patients discontinued treatment because of adverse events (cutaneous ulcer and bone infection, and oral mucositis, respectively). There were no cases of interstitial lung disease or treatment-related deaths. The median (range) erlotinib plasma concentration was measured at 685 (153-1950) ng/mL. Seventy-three patients discontinued study treatment owing to disease progression (n = 60), death (n = 3), AEs (n = 4), and patient requests (n = 6). No clear association was observed between the pharmacokinetics of low-dose erlotinib and the treatment outcome.

Conclusions And Relevance: Low-dose erlotinib appears to be safe and effective in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer and can be a valid treatment option.

Trial Registration: UMIN-CTR Identifier: UMIN000015949.
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http://dx.doi.org/10.1001/jamaoncol.2020.1250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226294PMC
July 2020

Paradoxical Embolism of Stroke-Related Patent Foramen Ovale in a Nonagenarian Woman.

J Cardiovasc Echogr 2019 Oct-Dec;29(4):172-174

Department of Cardiology, Tokushima Red Cross Hospital, Tokushima, Japan.

There are few clinical reports of elderly patients with paradoxical embolism in the current literature. Herein, we describe the case of a nonagenarian patient with paradoxical embolism of stroke-related patent foramen ovale (PFO). A 95-year-old woman was admitted to our hospital because of dysarthria. Her medical history included cerebral infarction, hypertension, and dyslipidemia. Magnetic resonance imaging performed in the emergency room revealed cerebral infarction of the left temporal lobe. After hospitalization in the neurosurgery department, we performed further clinical investigations to diagnose the type of stroke. There was no significant stenosis with plaque of the carotid and cerebral arteries, and there were no sources of cardiac embolism or an episode of atrial arrhythmia. Transesophageal echocardiography (TEE) showed PFO with separation and the Eustachian valve. In addition, spontaneous bidirectional shunt flow through the PFO was detected by TEE with the patient at rest. Ultrasonography of the leg vein revealed a thrombus in the deep vein. Therefore, she was diagnosed as having paradoxical embolism of stroke-related PFO and prescribed a direct oral anticoagulant (DOAC). This very rare case in which stroke-related PFO was diagnosed in a nonagenarian patient demonstrates that PFO is the cause of paradoxical embolism of stroke regardless of age.
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http://dx.doi.org/10.4103/jcecho.jcecho_35_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011487PMC
February 2020

The impact of body mass index on the efficacy of anti-PD-1/PD-L1 antibodies in patients with non-small cell lung cancer.

Lung Cancer 2020 01 18;139:140-145. Epub 2019 Nov 18.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Objectives: Body mass index (BMI) is reported to be associated with the efficacy of immune checkpoint inhibitors (ICIs) in solid tumors such as melanomas. However, it remains unclear whether such a relationship exists in non-small cell lung cancer (NSCLC) treated with programmed cell death protein 1 (PD-1)/ programmed death-ligand 1(PD-L1) inhibitors. The purpose of this study was to investigate the relationship between BMI and the efficacy of ICI treatment in patients with advanced NSCLC.

Materials And Methods: The medical records of NSCLC patients who received PD-1/PD-L1 antibody monotherapy at nine institutions between December 2015 and May 2018 were reviewed retrospectively. The effect of BMI was investigated in two cohorts. Cohort 1 included patients with NSCLCs with high PD-L1 expression (≥ 50 %) treated with pembrolizumab as first-line therapy, and cohort 2 included patients with NSCLCs treated with nivolumab/pembrolizumab/atezolizumab as second- or later-line treatment.

Results: A total of 513 from nine institutions were analyzed (84 in cohort 1, 429 in cohort 2). Using a BMI cut-off value of 22 kg/m2, which is an ideal BMI in our country (high BMI:22.0 and low BMI:22.0), there was no significant difference in the PFS or OS between the high and low BMI patients in cohort 1. However, in cohort 2, survival was significantly longer in patients with a high versus low BMI (PFS: 3.7 vs. 2.8 months, p = 0.036; OS: 15.4 vs. 13.5 months, p = 0.021).

Conclusion: BMI was significantly associated with the efficacy of ICIs in patients with NSCLC treated with second- or later-line PD-1/PD-L1 inhibitors in our cohort.
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http://dx.doi.org/10.1016/j.lungcan.2019.11.011DOI Listing
January 2020

Updated Survival Data for a Phase I/II Study of Carboplatin plus Nab-Paclitaxel and Concurrent Radiotherapy in Patients with Locally Advanced Non-Small Cell Lung Cancer.

Oncologist 2020 06 24;25(6):475-e891. Epub 2019 Oct 24.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Lessons Learned: Updated survival data for a phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy were collected. In the group of 58 patients who were enrolled at 14 institutions in Japan, the median overall survival was not reached and the 2-year overall survival rate was 66.1% (95% confidence interval, 52.1%-76.8%). Results reveal encouraging feasibility and activity for this regimen.

Background: We report the updated survival data for a phase I/II study of carboplatin plus nab-paclitaxel (nab-P/C) and concurrent radiotherapy (CRT) in patients with locally advanced non-small cell lung cancer (NSCLC).

Methods: Individuals between 20 and 74 years of age with unresectable NSCLC of stage IIIA or IIIB and a performance status of 0 or 1 were eligible for the study. Patients received weekly nab-paclitaxel at 50 mg/m for 6 weeks together with weekly carboplatin at an area under the curve (AUC) of 2 mg/ml/min and concurrent radiotherapy with 60 Gy in 30 fractions. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel (100 mg/m on days 1, 8, and 15) plus carboplatin (AUC of 6 on day 1). After the treatment, patients were observed off therapy. The primary endpoint of the phase II part of the study was progression-free survival (PFS).

Results: Between October 2014 and November 2016, 58 patients were enrolled at 14 institutions in Japan, with 56 of these individuals being evaluable for treatment efficacy and safety. At the median follow-up time of 26.0 months (range, 4.0-49.6 months), the median overall survival (OS) was not reached (95% confidence interval [CI], 25.3 months to not reached) and the 2-year OS rate was 66.1% (95% CI, 52.1%-76.8%). The median PFS was 11.8 months (95% CI, 8.2-21.0 months), and the 2-year PFS rate was 35.9% (95% CI, 23.1%-48.9%). Subgroup analysis according to tumor histology or patient age revealed no differences in median PFS or OS. Long-term follow-up of toxicities did not identify new safety signals, and no treatment-related deaths occurred during the study period.

Conclusion: Concurrent chemoradiation with nab-P/C was safe and provided a long-term survival benefit for patients with locally advanced NSCLC.
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http://dx.doi.org/10.1634/theoncologist.2019-0746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288639PMC
June 2020

A Prospective Cohort Study to Define the Clinical Features and Outcome of Lung Cancers Harboring HER2 Aberration in Japan (HER2-CS STUDY).

Chest 2019 08 6;156(2):357-366. Epub 2019 May 6.

Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Background: Human epidermal growth factor 2 (HER2) is a potential driver oncogene. Although HER2-targeted precision therapy has been tested in non-small cell lung cancer (NSCLC), the demographic characteristics of HER2-positive NSCLC have not been systematically defined.

Methods: Patients with pathologically confirmed stage IIIB/IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, were prospectively registered. HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays were performed to screen patients. HER2 mutations were identified by using direct gene sequencing. The aim of this study was to clarify the frequency, characteristics, and outcome of HER2-positive NSCLC. HER2 was defined as positive if the tumor harbored IHC3+, IHC2+/FISH+, or exon 20 insertion mutations.

Results: Of the 1,126 tumors screened, 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 epidermal growth factor receptor wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775-G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female patients had HER2-mutant tumors more frequently, whereas both IHC3+ and IHC2+/FISH+ tumors were detected more often in male subjects and smokers. Patients with an HER2-aberrant tumor had a significantly worse prognosis than those with epidermal growth factor receptor-positive and anaplastic lymphoma kinase-positive tumors, possibly due to the low proportion that received HER2-targeted therapies (n = 15 [26%]) and low response rates of 0% and 14% in patients with HER2-overexpressing and HER2-mutant tumors, respectively.

Conclusions: This prospective large-scale cohort study is the first to show comprehensively the frequency and clinical demographic characteristics of those with HER2-positive advanced lung tumors in detail, providing critical historical data for future drug development against HER2-positive NSCLC. Future treatment strategies would be developed stratified according to the types of HER2 aberrations.

Trial Registry: UMIN Registration No. 000017003; URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000019691.
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http://dx.doi.org/10.1016/j.chest.2019.01.011DOI Listing
August 2019

Correction to: Percutaneous transcatheter closure of high-risk patent foramen ovale in the elderly.

Heart Vessels 2019 10;34(10):1663-1664

Department of Cardiology, Tokushima Red Cross Hospital, 103 Irinokuchi, Komatsushima-cho, Komatsushima, Tokushima, 773-8502, Japan.

In the original publication of the article, the below sentence were garbled.
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http://dx.doi.org/10.1007/s00380-019-01408-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732151PMC
October 2019

Percutaneous closure for iatrogenic atrial septal defect composed of a hole with slit fenestration and patent foramen ovale after pulmonary vein isolation.

Cardiovasc Interv Ther 2020 01 8;35(1):101-103. Epub 2019 Apr 8.

Department of Cardiology, Tokushima Red Cross Hospital, 103 Irinokuchi, Komatsushima-cho, Komatsushima, Tokushima, 773-8502, Japan.

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http://dx.doi.org/10.1007/s12928-019-00584-yDOI Listing
January 2020

A phase I/II trial of weekly nab-paclitaxel for pretreated non-small-cell lung cancer patients without epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangement.

Asia Pac J Clin Oncol 2019 Aug 1;15(4):250-256. Epub 2019 Apr 1.

Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Aim: We investigated the efficacy, safety and optimal schedule of nanoparticle albumin-bound paclitaxel monotherapy as second- or third-line treatment for non-small-cell lung cancer patients without epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement.

Methods: Patients with pretreated advanced non-small-cell lung cancer without epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement were included. The patients were administered 100 mg/m of nanoparticle albumin-bound paclitaxel on days 1, 8, 15 and 22 (level 0) or on days 1, 8 and 15 (level -1) every 4 weeks during phase I of the trial. The primary endpoint was objective response rate. The estimated objective response rate was 15% and the threshold was 5% with an α error of 0.05 and β error of 0.2 in phase II.

Results: The recommended schedule was determined as level -1 in phase I. The characteristics of the 55 patients enrolled in phase II were as follows: median age = 66 years, male/female = 40/15, second/third line = 34/21 and adenocarcinoma/squamous cell carcinoma/large cell carcinoma/others = 34/17/2/2. Objective response rate was 7.3% (95% confidence interval, 2.0-17.6%). Median progression-free survival was 3.4 months. Treatment-related grade 3 or 4 toxicities were neutropenia (36.4%), febrile neutropenia (5.5%) and pulmonary infection (3.6%). Three patients had grade 2 pneumonitis and one treatment-related death occurred due to adult respiratory distress syndrome.

Conclusion: This study failed to meet predefined primary endpoints for pretreated patients with advanced non-small-cell lung cancer without epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement.
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http://dx.doi.org/10.1111/ajco.13147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849786PMC
August 2019

Percutaneous transcatheter closure of high-risk patent foramen ovale in the elderly.

Heart Vessels 2019 Oct 13;34(10):1657-1662. Epub 2019 Mar 13.

Department of Cardiology, Tokushima Red Cross Hospital, 103 Irinokuchi, Komatsushima-cho, Komatsushima, Tokushima, 773-8502, Japan.

The efficacy of percutaneous transcatheter closure for preventing recurrent cerebrovascular events in elderly patients with high-risk patent foramen ovale (PFO) remains unclear, whereas in young patients, it has been shown to effectively prevent the recurrence of embolic stroke. The aim of this study was to investigate the safety and efficacy of percutaneous PFO closure in elderly patients with high-risk PFO. Between September 2012 and October 2018, 14 patients ≥ 60 years old with high-risk PFO underwent percutaneous closure to prevent recurrence of cerebrovascular events. The primary end point was recurrence of cerebrovascular events after closure in elderly patients with high-risk PFO, and the secondary end points were occurrence of device-related complications, cerebral hemorrhage, and new-onset atrial fibrillation (AF). The mean patient age and number of cerebrovascular events before closure were 75.2 ± 6.5 years and 1.7 ± 0.7, respectively. All procedures were successfully performed under general anesthesia by transesophageal echocardiography and using a 25-mm Amplatzer Cribriform device. No procedure-related complications occurred. Patients were followed up for a mean 2.6 ± 1.8 years. No patients experienced device-related complications or recurrent cerebrovascular events. However, one patient had AF-related device closure complications at 1 month postoperatively. In addition, other patient had a cerebral hemorrhage with unknown relationship to PFO closure 3 years postoperatively. Percutaneous closure of high-risk PFO in elderly patients may be as effective and safe as in younger patients. It is crucial to evaluate PFO morphology regardless of age in cases of paradoxical embolism.
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http://dx.doi.org/10.1007/s00380-019-01379-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732153PMC
October 2019

Efficacy and safety of percutaneous transcatheter aortic valvuloplasty prior to non-cardiac surgery in Japanese patients with severe aortic stenosis.

Cardiovasc Interv Ther 2019 Oct 7;34(4):352-357. Epub 2019 Mar 7.

Department of Cardiology, Tokushima Red Cross Hospital, 103 Irinokuchi, Komatsushima-cho, Komatsushima, Tokushima, 773-8502, Japan.

This study aimed to investigate the efficacy of percutaneous transcatheter aortic valvuloplasty (PTAV) performed prior to non-cardiac surgery and the safety of non-cardiac surgery after PTAV in elderly Japanese patients. Between March 2012 and August 2018, 14 patients who underwent PTAVs prior to non-cardiac surgery were enrolled. The mean age was 82.2 ± 7.0 years. A total of 9 patients (64.3%) were women. A retrograde approach was selected for 57.1% of the patients. More than 75% of the procedures were performed using echocardiographic imaging. Echocardiographic data including the aortic valve area (AVA), peak aortic valve blood velocity flow (AVF), peak aortic valve pressure gradient (AVPG), and mean AVPG significantly improved after PTAV (AVA; from 0.54 ± 0.11 to 0.80 ± 0.13 cm, peak AVF; from 4.6 ± 0.8 to 3.8 ± 0.7 m/s, peak AVG; from 87.9 ± 28.0 to 62.2 ± 19.9 mmHg, mean AVG; from 49.8 ± 18.9 to 35.7 ± 11.6 mmHg; p < 0.001, p < 0.001, p < 0.001, p = 0.0012, respectively). Neither complications related to the PTAV procedure nor procedural mortality were noted. Non-cardiac surgery after PTAV was safely performed; there were no significant adverse events during non-cardiac surgery and no in-hospital mortality occurred after non-cardiac surgery. PTAV prior to non-cardiac surgery in elderly Japanese patients with severe aortic stenosis is safe and effective. In addition, non-cardiac surgery after PTAV can be safety performed without adverse events.
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http://dx.doi.org/10.1007/s12928-019-00581-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754350PMC
October 2019

Phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy for patients with locally advanced non-small cell lung cancer.

Lung Cancer 2018 11 18;125:136-141. Epub 2018 Sep 18.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. Electronic address:

Objectives: Chemoradiation regimens of greater efficacy are needed for patients with locally advanced non-small cell lung cancer (NSCLC).

Patients And Methods: In a phase I study, escalating doses of weekly nab-paclitaxel (40 or 50 mg/m) were administered along with weekly carboplatin at an area under the curve (AUC) of 2 mg mL min and concurrent radiotherapy with 60 Gy in 30 fractions to patients with locally advanced NSCLC. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel plus carboplatin. In a phase II study, nab-paclitaxel was administered at the recommended dose (RD) together with carboplatin and radiation.

Results: In the phase I study, one of six patients experienced dose-limiting toxicity (leukopenia of grade 3 requiring a second consecutive skip in the administration of weekly chemotherapy) with nab-paclitaxel at 50 mg/m, which was therefore determined to be the RD. Fifty-six patients treated at the RD were evaluable for safety and efficacy. Common toxicities of grade 3 or 4 in the concurrent phase included leukopenia (60.7%) and neutropenia (28.6%). No treatment-related deaths occurred during the study period. The objective response rate was 76.8% (95% confidence interval [CI], 64.2-85.9%), median progression-free survival was 11.8 months (60% CI, 10.6-16.2 months; 95% CI, 8.2-20.8 months), and median overall survival was not reached.

Conclusion: Our results reveal encouraging feasibility and activity for concurrent chemoradiation with nab-paclitaxel at 50 mg/m and carboplatin at an AUC of 2 in patients with locally advanced NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2018.09.014DOI Listing
November 2018

Statistical analysis of F-fluorodeoxyglucose positron-emission tomography/computed tomography ground-glass nodule findings.

Mol Clin Oncol 2018 Sep 16;9(3):279-282. Epub 2018 Jul 16.

Okayama Diagnostic Imaging Center, Okayama, Okayama 700-0913, Japan.

F-fluorodeoxyglucose positron-emission tomography/computed tomography (F-FDG-PET/CT) is important in lung cancer diagnosis; false negatives are often caused by ground-glass nodules (GGNs). PET/CT utility in GGN diagnosis is unknown. The associations between GGN CT findings (size, properties), the pathological diagnosis and maximum standardized uptake value (SUV) were explored. Sixty-six patients with pathological stage IA1-IIA lung adenocarcinoma underwent surgical resection and PET/CT between January 2010 and December 2014. Clinical characteristics, CT findings, pathological diagnoses and PET/CT findings were retrospectively examined. The age range was 47-86 years (median, 69 years), the female/male ratio was 38:28 and the pathological stage was IA1, IA2, IA3, IB and IIA in 5, 30, 21, 9 and 1, respectively. Total and solid-part lesion diameters ranged from 7.00-41.13 mm (median, 19.43 mm) and 0.00-23.23 mm (median, 4.55 mm), respectively; the solid-part ratio (solid-part diameter/total diameter) was 0-77% (median, 20%). SUV ranged from a value too low for evaluation to 3.9 (median, 1.0). Pathological diagnoses were adenocarcinoma (AIS), minimally invasive adenocarcinoma (MIA), lepidic-predominant adenocarcinoma (LPA) and papillary predominant adenocarcinoma (PPA) in 17, 15, 32 and 2, respectively. Correlation coefficients for each factor and SUV for total and solid-part diameters were 0.513 (p<0.0001) and 0.461 (p<0.0001), respectively. All pure GGNs showed clinically unimportant SUV<2.5, even though some large GGNs were included (maximum, 40.0 mm). A total diameter ≥20 mm was significantly associated with FDG uptake (p<0.0001). SUV were <2.5 when the solid-part diameter was <4.55 mm. The AIS-MIA group showed significantly lower SUV than the LPA-PPA group (p=0.0008). There was no clinically important SUV with diagnostic value for pure or small part-solid GGNs. There were medium correlations for GGN total diameter, solid-part diameter, and SUV. We should note PET/CT's limitations in GGN diagnosis.
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http://dx.doi.org/10.3892/mco.2018.1670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109674PMC
September 2018

Percutaneous closure of patent foramen ovale for paradoxical embolism in acute limb ischemia.

Cardiovasc Interv Ther 2019 07 14;34(3):282-284. Epub 2018 Aug 14.

Department of Cardiology, Tokushima Red Cross Hospital, 103 Irinokuchi, Komatsushima-cho, Komatsushima, Tokushima, 773-8502, Japan.

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http://dx.doi.org/10.1007/s12928-018-0542-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561983PMC
July 2019

Successful Long-term Management of Two Cases of Moderate Hemoptysis Due to Chronic Cavitary Pulmonary Aspergillosis with Bronchial Occlusion Using Silicone Spigots.

Intern Med 2018 Aug 30;57(16):2389-2393. Epub 2018 Mar 30.

Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, Japan.

Chronic pulmonary aspergillosis is a major cause of life-threatening hemoptysis. In symptomatic patients with simple aspergillomas, surgery is the main therapeutic method for preventing or treating life-threatening hemoptysis. However, the risks of both death and complications are higher in chronic cavitary pulmonary aspergillosis than in simple aspergilloma. We herein report two patients with persistent moderate hemoptysis due to chronic cavitary pulmonary aspergillosis who were not indicated for surgery, but were able to undergo successful long-term management with bronchial occlusion using silicone spigots. In diseases with a high recurrence rate of hemoptysis, the continuous placement of silicone spigots might therefore be effective to prevent rebleeding.
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http://dx.doi.org/10.2169/internalmedicine.0553-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148162PMC
August 2018

Predictors of early restenosis after intracardiac echocardiography guided antegrade balloon aortic valvuloplasty in high-risk or inoperable patients.

Cardiovasc Interv Ther 2018 Apr 20;33(2):109-115. Epub 2017 Jan 20.

Division of Cardiology, Tokushima Red Cross Hospital, Irinokuchi103, Komatsushima-cho, Komatsushima, 773-8502, Japan.

Antegrade balloon aortic valvuloplasty (BAV) may be more effective than retrograde BAV. However, early restenosis is found inconstantly within three months after BAV. To evaluate the factor of ER after intracardiac echocardiogram (ICE) guided Antegrade BAV, fifty patients with severe aortic stenosis (AS) underwent BAV procedures with ICE. ER was defined as mean aortic valve pressure gradient (PG) >40 mmHg. During one-year follow-up period, 6 patients died and 2 patients underwent aortic valve replacement. ER was present in 13 patients (26%) at three months after BAV. Procedural, clinical, and hemodynamic data were collected. The mean age of the patient population was 85.4 ± 7.6 years; the mean STS score and EuroSCORE were 7.8 ± 1.1 and 14.6 ± 4.1, respectively. The mean aortic valve PG decreased from 63.4 ± 19.8 to 28.5 ± 10.1 mmHg (p < 0.0001). Baseline characteristics were similar between the two groups. There is no significant difference of mean aortic valve PG immediate after BAV(ER; 29 ± 8.8 mmHg, nonER; 21 ± 6.1 mmHg, p = ns). Univariate analysis showed patients with ER group had significantly higher rate of left ventricular hypertrophy, pulmonary hypertension, and high mean aortic valve PG at admission. Multivariate analysis revealed high mean aortic valve PG at admission as independent predictors of ER. Antegrade BAV may be effective for severe AS. Left ventricular hypertrophy, pulmonary hypertension and high mean PG were predictor of early restenosis. Early intervention should be considered for these patients.
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http://dx.doi.org/10.1007/s12928-016-0451-8DOI Listing
April 2018

A phase II study of topotecan and cisplatin with sequential thoracic radiotherapy in elderly patients with small-cell lung cancer: Okayama Lung Cancer Study Group 0102.

Cancer Chemother Pharmacol 2016 Oct 20;78(4):769-74. Epub 2016 Aug 20.

Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Purpose: The treatment outcome in elderly patients with limited-disease small-cell lung cancer (LD-SCLC) remains poor. We carried out a phase II trial of split topotecan and cisplatin (TP) therapy and sequential thoracic radiotherapy for elderly LD-SCLC patients as a follow-up to our previous phase I trial.

Methods: In total, 30 patients aged 76 years or older, with untreated LD-SCLC were enrolled. Four courses of topotecan (1.0 mg/m(2), days 1-3) and cisplatin (20 mg/m(2), days 1-3) were administered, followed by thoracic radiotherapy (1.8 Gy/day, total of 45 Gy). The primary end point was the overall response rate (ORR).

Results: The trial was terminated early with 22 patients because of slow accrual. Their median age was 79 years. The median number of courses of chemotherapy administered was three, and the actual completion rate of the entire treatment course was 41 %. The ORR was 68 % with a 95 % confidence interval of 47-89 % (15/22 cases). The median progression-free survival and overall survival were 9.1 and 22.2 months, respectively. The main toxicity was myelosuppression, with grades 3-4 neutropenia (96 %), thrombocytopenia (50 %), and febrile neutropenia (32 %).

Conclusions: This regimen produced a favorable survival outcome, despite moderate-to-severe toxicity profiles. Further efforts are necessary to define an optimal regimen for elderly patients with limited SCLC.
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http://dx.doi.org/10.1007/s00280-016-3135-2DOI Listing
October 2016

Non-Small Cell Lung Cancer Cells Acquire Resistance to the ALK Inhibitor Alectinib by Activating Alternative Receptor Tyrosine Kinases.

Cancer Res 2016 Mar 30;76(6):1506-16. Epub 2015 Dec 30.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama City, Okayama, Japan.

Crizotinib is the standard of care for advanced non-small cell lung cancer (NSCLC) patients harboring the anaplastic lymphoma kinase (ALK) fusion gene, but resistance invariably develops. Unlike crizotinib, alectinib is a selective ALK tyrosine kinase inhibitor (TKI) with more potent antitumor effects and a favorable toxicity profile, even in crizotinib-resistant cases. However, acquired resistance to alectinib, as for other TKIs, remains a limitation of its efficacy. Therefore, we investigated the mechanisms by which human NSCLC cells acquire resistance to alectinib. We established two alectinib-resistant cell lines that did not harbor the secondary ALK mutations frequently occurring in crizotinib-resistant cells. One cell line lost the EML4-ALK fusion gene, but exhibited increased activation of insulin-like growth factor-1 receptor (IGF1R) and human epidermal growth factor receptor 3 (HER3), and overexpressed the HER3 ligand neuregulin 1. Accordingly, pharmacologic inhibition of IGF1R and HER3 signaling overcame resistance to alectinib in this cell line. The second alectinib-resistant cell line displayed stimulated HGF autocrine signaling that promoted MET activation and remained sensitive to crizotinib treatment. Taken together, our findings reveal two novel mechanisms underlying alectinib resistance that are caused by the activation of alternative tyrosine kinase receptors rather than by secondary ALK mutations. These studies may guide the development of comprehensive treatment strategies that take into consideration the various approaches ALK-positive lung tumors use to withstand therapeutic insult.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-1010DOI Listing
March 2016

Phase II trial of gefitinib in combination with bevacizumab as first-line therapy for advanced non-small cell lung cancer with activating EGFR gene mutations: the Okayama Lung Cancer Study Group Trial 1001.

J Thorac Oncol 2015 Mar;10(3):486-91

*Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan; †Department of Hematology/Oncology, Vanderbilt Vanderbilt University Medical Center, Nashville, TN; ‡Department of Respiratory Medicine, NHO Shikoku Cancer Center, Matsuyama, Japan; §Department of Respiratory Medicine, NHO Iwakuni Clinical Center, Iwakuni, Japan; ‖Department of Medical Oncology, NHO Yamaguchi-Ube Medical Center, Ube, Japan; ¶Department of Respiratory Internal Medicine, Japanese Red Cross Kobe Hospital, Kobe, Japan; #Division of Clinical Oncology, Sumitomo Besshi Hospital, Niihama, Japan; **Department of Clinical Research, NHO Yamaguchi-Ube Medical Center, Ube, Japan; ††Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, Okayama, Japan; ‡‡Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan; and §§Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan.

Purpose: Whether bevacizumab enhances the effect of the epidermal growth factor receptor (EGFR) inhibitor gefitinib on EGFR mutant non-small cell lung cancers (NSCLCs) remains unknown. We conducted a phase II trial to investigate the efficacy and safety of gefitinib when combined with bevacizumab as first-line therapy in patients with advanced NSCLC harboring EGFR gene mutations.

Methods: In this trial, 42 patients with a performance status of 0 to 2 received gefitinib (250 mg/d) and bevacizumab (15 mg/kg, every 3 weeks). The primary end point of this study was the 1-year progression-free survival (PFS) rate. We assumed that a 1-year PFS rate of 55% would indicate potential usefulness and that a 1-year PFS rate of 40% would constitute the lower limit of interest.

Results: Forty-two patients were enrolled in the study with a median age of 73 (range 42-86) years. Activating EGFR gene mutations included exon 19 deletion (57%) and L858R point mutations in exon 21 (38%). The objective response rate was 73.8% and included two complete responses. The 1-year PFS rate and median PFS time were 56.7% (95% confidence interval [CI] 39.9-70.5) and 14.4 months (95% CI 10.1-19.2), respectively. The median PFS differed significantly between EGFR exon 19 deletion and the L858R point mutation (18.0 versus 9.4 months, respectively; p = 0.006). The median overall survival had not yet been reached. Severe adverse events included grade 3 skin rash (15%), hypertension (17%), aspartate transaminase/alanine aminotransferase elevation (17%), proteinuria (7%), intracranial hemorrhage (2%), and grade 4 perforation of the digestive tract (2%). There were no treatment-related deaths.

Conclusion: Gefitinib in combination with bevacizumab as first-line therapy seems to be a favorable and well-tolerated treatment for patients with advanced NSCLC with activating EGFR gene mutations, especially those with EGFR exon 19 deletion mutations, although the primary end point was not met because the lower limit of the CI was less than 40%.
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http://dx.doi.org/10.1097/JTO.0000000000000434DOI Listing
March 2015

A phase II study of cisplatin plus S-1 with concurrent thoracic radiotherapy for locally advanced non-small-cell lung cancer: the Okayama Lung Cancer Study Group Trial 0501.

Lung Cancer 2015 Feb 8;87(2):141-7. Epub 2014 Nov 8.

Department of Thoracic oncology, Okayama University Hospital, Okayama, Japan.

Background: Although cisplatin-based chemotherapy combined with thoracic irradiation (TRT) is a standard treatment for unresectable, locally advanced non-small cell lung cancer (NSCLC), this treatment outcome has remained unsatisfactory. We had previously conducted a phase I trial of cisplatin plus S-1, an oral 5-fluorouracil derivative, and TRT, which were safe and effective.

Methods: In this phase II trial, 48 patients with stage III NSCLC received cisplatin (40mg/m(2) on days 1, 8, 29 and 36) and S-1 (80mg/m(2) on days 1-14 and 29-42) and TRT (60Gy). The primary endpoint was the response rate.

Results: A partial response was observed in 37 patients (77%; 95% confidence interval: 63-88%). At a median follow up of 54 months, the median progression-free survival and median survival time were 9.3 and 31.3 months, respectively. No difference in efficacy was observed when the patients were stratified by histology. Toxicities were generally mild except for grade 3 or worse febrile neutropenia and pneumonitis of 8% and 4%, respectively. No patient developed severe esophagitis. At the time of this analysis, 35 (73%) of the 48 patients recurred; 15 (31%) showed distant metastasis, 17 (35%) had loco-regional disease, and 2 (4%) showed both loco-regional disease and distant metastasis.

Conclusions: This chemoradiotherapy regimen yielded a relatively favorable efficacy with mild toxicities in patients with locally advanced NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2014.11.001DOI Listing
February 2015

Cerebral venous sinus thrombosis concomitant with leptomeningeal carcinomatosis, in a patient with epidermal growth factor receptor-mutated lung cancer.

Oncol Lett 2014 Dec 10;8(6):2489-2492. Epub 2014 Oct 10.

Department of Pulmonary Disease, Japanese Red Cross Okayama Hospital, Okayama 700-8607, Japan.

A 64-year-old woman presented with dizziness, after two weeks of experiencing symptoms. Chest computed tomography revealed a peripheral nodule in her left upper lobe, and brain magnetic resonance imaging (MRI) demonstrated the presence of multiple brain masses. The patient underwent whole-brain radiotherapy based on a tentative diagnosis of lung cancer with multiple brain metastases. The diagnosis was confirmed by endobronchial biopsy as T4N3M1b, stage IV lung adenocarcinoma with an epidermal growth factor receptor mutation. On the 31st day of hospitalization, the patient developed severe headache. Subsequent magnetic resonance venography revealed defects in the superior sagittal, right sigmoid, and right transverse venous sinuses and the right internal jugular vein. Anticoagulation therapy with unfractionated heparin and warfarin was immediately administered following diagnosis of cerebral venous sinus thrombosis (CVST). Brain MRI demonstrated leptomeningeal gadolinium enhancement in front of the pons and medulla. Positive cerebrospinal fluid tumor cytology confirmed the diagnosis of leptomeningeal carcinomatosis. Following four weeks of antithrombotic therapy, complete thrombolysis was confirmed by magnetic resonance venography. Effective treatment with gefitinib was administered, and the patient survived for 10 months after the diagnosis of CVST and leptomeningeal carcinomatosis. Adequate early diagnosis and treatment of CVST enabled an excellent survival rate for the patient, despite leptomeningeal carcinomatosis. Following the development of headaches in patients with lung cancer, CVST, although rare, should be considered. Furthermore, following a diagnosis of CVST, leptomeningeal carcinomatosis should be investigated as an underlying cause.
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http://dx.doi.org/10.3892/ol.2014.2603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214432PMC
December 2014