Taro Koba

Phase II study of pemetrexed plus intermittent erlotinib combination therapy for pretreated advanced non-squamous non-small cell lung cancer with documentation of epidermal growth factor receptor mutation status

INTRODUCTION Erlotinib and pemetrexed have been approved for the second-line and maintenance treatment of non-small cell lung cancer (NSCLC). With the recommended doses determined by our previous phase I study, we conducted a phase II study to evaluate the efficacy and safety of combination of the two agents in pretreated non-squamous NSCLC patients. METHODS This study was performed in patients with stage IIIB/IV or post-surgically recurrent non-squamous NSCLC whose disease had progressed on or after receiving first-line chemotherapy. Patients received 500 mg/m(2) of intravenous pemetrexed every 21 days and 150 mg of oral erlotinib on days 2-16 until disease progression, unacceptable toxicity, or withdrawal of consent. The expected response rate and threshold were defined as 33.5% and 10%, respectively. Assuming a one-sided alpha of 5%, a power of 80%, the possible deviation from assessment, 26 patients were necessary. RESULTS A total of 27 patients, 16 males and 11 females were recruited. Patients had the median age of 70 years (range, 48-80 years) and included 21 stage IV diseases, 22 adenocarcinomas. Epidermal growth factor receptor (EGFR) mutations were examined in all patients. One patient had positive EGFR mutation, but the other 26 patients had wild-type EGFR. The median number of treatment courses was 3 (range, 1 to over 19). The best overall response rate and disease control rate were 11.1% and 63.0%, respectively. The median progression-free survival and overall survival were 2.8 months (95% confidence interval (CI); 1.9-7.5 months) and 15.8 months (95% CI; 9.3 months to not available), respectively. Dermal, hepatic, gastrointestinal and hematological disorders were the frequently observed adverse events. One patient experienced grade 3 drug-induced interstitial lung disease. CONCLUSIONS We could not demonstrate the add-on effect of intermittent erlotinib on pemetrexed in a second-line setting for patients with non-squamous NSCLC without EGFR mutations.

Influence of indacaterol on daily physical activity in patients with untreated chronic obstructive pulmonary disease

Background Indacaterol, a once-daily, long-acting β2-agonist, may improve not only respiratory function, dyspnea symptoms, and quality of life, but also physical activity for patients with chronic obstructive pulmonary disease (COPD). This study aimed to evaluate the effect of 12-week indacaterol therapy on daytime physical activity in patients with untreated COPD. Methods The subjects were stable and untreated COPD outpatients with a percent predicted forced expiratory volume in 1 second (%FEV1) below 80%. Baseline assessments included clinical assessment, respiratory function testing, arterial blood gas analysis, the COPD assessment test (CAT™), and the Medical Outcomes Study 36-Item Short-Form Health Survey, Japanese version 2 (SF-36v2®). Patients underwent monitoring by uniaxial accelerometer before and after 12 weeks once-daily inhalation of indacaterol 150 μg/day. Results Eighteen patients were evaluable. Patient characteristics included a mean age of 74.2 years, and three patients were current smokers. Indacaterol improved mean (± standard deviation [SD]) %FEV1 from 55.2% (±17.9%) to 61.0% (±17.3%) (P=0.003), CAT scores from 16.4 (±10.2) points to 12.4 (±8.2) points (P=0.04), some scales of the SF-36v2 (physical component summary, 41.6±9.7 points to 45.1±7.9 points, P=0.03), and number of daily steps (3,311.5±2,103.3 steps/day to 3,841.8±2,096.8 steps/day, P=0.02), but did not affect daily energy expenditure (85.0±77.2 kcal change to 90.9±56.8 kcal, P=0.29) or exercise duration of an intensity of level 1 or more (36.4±23.9 minutes increase to 40.8±21.6 minutes, P=0.12). Conclusion Twelve weeks of indacaterol improved respiratory function and quality of life, but did not significantly affect physical activity in patients with moderate-to-severe COPD.

Rapid intracranial response to osimertinib, without radiotherapy, in nonsmall cell lung cancer patients harboring the EGFR T790M mutation: Two Case Reports

Rationale: Most of nonsmall cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) activating mutations eventually acquire resistance to the first EGFR-tyrosine kinase inhibitors (TKIs) therapy after varying periods of treatment. Of note, approximately one-third of those patients develop brain metastases, which deteriorate their quality of life and survival. The effect of systemic chemotherapy on brain metastases after acquisition of EGFR-TKI resistance is limited, and thus far, whole-brain radiation therapy, which may cause the harmful effect on neurocognitive functions, has been the only established therapeutic option for especially symptomatic brain metastases. Osimertinib is a third-generation oral, potent, and irreversible EGFR-TKI. It can bind to EGFRs with high affinity even when the EGFR T790M mutation exists in addition to the sensitizing mutations. Its clinical efficacy for NSCLC patients harboring the T790M mutation has already been shown; however, the evidence of osimertinib on brain metastases has not been documented well, especially in terms of the appropriate timing for treatment and its response evaluation. Patient concerns, Diagnoses, and Interventions: We experienced 2 NSCLC patients with the EGFR T790M mutation; a 67-year-old woman with symptomatic multiple brain metastases administered osimertinib as seventh-line chemotherapy, and a 76-year old man with an asymptomatic single brain metastasis administered osimertinib as fifth-line chemotherapy. Outcomes: These patients showed great response to osimertinib within 2 weeks without radiation therapy. Lessons: These are the first reports to reveal the rapid response of the brain metastases to osimertinib within 2 weeks. These cases suggest the possibility that preemptive administration of osimertinib may help patients to postpone or avoid radiation exposures. In addition, rapid reassessment of the effect of osimertinib on brain metastases could prevent patients from being too late to receive essential radiotherapy.

Systemic Air Embolism Following Diagnostic Bronchoscopy

A 51-year-old man was admitted to have a nodule evaluated using chest computed tomography (CT). Shortly after curetting and transbronchial biopsies via bronchoscopy, hypotension, bradycardia, unconsciousness, and left hemiplegia appeared and resolved within one hour. Head CT showed cerebral air embolism. The following day, lower left quadrant pain developed. Pneumatosis intestinalis on abdominal CT and elevation of creatine kinase and troponin T levels indicated air embolism in the mesenteric and coronary arteries. Some reports have documented cerebral air embolism alone after bronchoscopy; however, we should consider systemic air embolism, even when encountering a patient without specific symptoms related to any organ.

Efficacy and safety of transbronchial lung biopsy for the diagnosis of lymphangioleiomyomatosis: A report of 24 consecutive patients

Lymphangioleiomyomatosis (LAM) is a diffuse cystic lung disease that occurs in women of childbearing age. LAM can be diagnosed on a clinical basis in patients with typical high‐resolution computed tomography (HRCT) patterns and at least one other corroborating disease feature, such as chylothorax, angiomyolipoma, tuberous sclerosis complex or elevated serum vascular endothelial growth factor (VEGF)‐D. However, patients who do not meet these criteria require tissue confirmation for a definitive diagnosis, and the utility of methods that are less invasive than surgical lung biopsy, such as transbronchial lung biopsy (TBLB), are not well studied. We retrospectively studied the efficacy and safety of TBLB for the diagnosis of LAM.

Double deletion of tetraspanins CD9 and CD81 in mice leads to a syndrome resembling accelerated aging

Chronic obstructive pulmonary disease (COPD) has been recently characterized as a disease of accelerated lung aging, but the mechanism remains unclear. Tetraspanins have emerged as key players in malignancy and inflammatory diseases. Here, we found that CD9/CD81 double knockout (DKO) mice with a COPD-like phenotype progressively developed a syndrome resembling human aging, including cataracts, hair loss, and atrophy of various organs, including thymus, muscle, and testis, resulting in shorter survival than wild-type (WT) mice. Consistent with this, DNA microarray analysis of DKO mouse lungs revealed differential expression of genes involved in cell death, inflammation, and the sirtuin-1 (SIRT1) pathway. Accordingly, expression of SIRT1 was reduced in DKO mouse lungs. Importantly, siRNA knockdown of CD9 and CD81 in lung epithelial cells additively decreased SIRT1 and Foxo3a expression, but reciprocally upregulated the expression of p21 and p53, leading to reduced cell proliferation and elevated apoptosis. Furthermore, deletion of these tetraspanins increased the expression of pro-inflammatory genes and IL-8. Hence, CD9 and CD81 might coordinately prevent senescence and inflammation, partly by maintaining SIRT1 expression. Altogether, CD9/CD81 DKO mice represent a novel model for both COPD and accelerated senescence.

Lysosomal Protein Lamtor1 Controls Innate Immune Responses via Nuclear Translocation of Transcription Factor EB

Amino acid metabolism plays important roles in innate immune cells, including macrophages. Recently, we reported that a lysosomal adaptor protein, Lamtor1, which serves as the scaffold for amino acid–activated mechanistic target of rapamycin complex 1 (mTORC1), is critical for the polarization of M2 macrophages. However, little is known about how Lamtor1 affects the inflammatory responses that are triggered by the stimuli for TLRs. In this article, we show that Lamtor1 controls innate immune responses by regulating the phosphorylation and nuclear translocation of transcription factor EB (TFEB), which has been known as the master regulator for lysosome and autophagosome biogenesis. Furthermore, we show that nuclear translocation of TFEB occurs in alveolar macrophages of myeloid-specific Lamtor1 conditional knockout mice and that these mice are hypersensitive to intratracheal administration of LPS and bleomycin. Our observation clarified that the amino acid–sensing pathway consisting of Lamtor1, mTORC1, and TFEB is involved in the regulation of innate immune responses.

Clinical implications of monitoring nivolumab immunokinetics in non–small cell lung cancer patients

BACKGROUND. The PD-1–blocking antibody nivolumab persists in patients several weeks after the last infusion. However, no study has systematically evaluated the maximum duration that the antibody persists on T cells or the association between this duration and residual therapeutic efficacy or potential adverse events. METHODS. To define the duration of binding and residual efficacy of nivolumab after discontinuation, we developed a simplified strategy for T cell monitoring and used it to analyze T cells from peripheral blood from 11 non–small cell lung cancer patients previously treated with nivolumab. To determine the suitability of our method for other applications, we compared transcriptome profiles between nivolumab-bound and nivolumab-unbound CD8 T cells. We also applied T cell monitoring in 2 nivolumab-treated patients who developed progressive lung tumors during long-term follow-up. RESULTS. Prolonged nivolumab binding was detected more than 20 weeks after the last infusion, regardless of the total number of nivolumab infusions (2–15 doses) or type of subsequent treatment, in 9 of the 11 cases in which long-term monitoring was possible. Ki-67 positivity, a proliferation marker, in T cells decreased in patients with progressive disease. Transcriptome profiling identified the signals regulating activation of nivolumab-bound T cells, which may contribute to nivolumab resistance. In 2 patients who restarted nivolumab, T cell proliferation markers exhibited the opposite trend and correlated with clinical response. CONCLUSIONS. Although only a few samples were analyzed, our strategy of monitoring both nivolumab binding and Ki-67 in T cells might help determine residual efficacy under various types of concurrent or subsequent treatment. TRIAL REGISTRATION. University Hospital Medical Information Network Clinical Trials Registry, UMIN000024623. FUNDING. This work was supported by Japan Society for the Promotion of Science KAKENHI (JP17K16045, JP18H05282, and JP15K09220), Japan Agency for Medical Research and Development (JP17cm0106310, JP18cm0106335 and JP18cm059042), and Core Research for Evolutional Science and Technology (JPMJCR16G2).

Combination of virtual bronchoscopic navigation, endobronchial ultrasound, and rapid on-site evaluation for diagnosing small peripheral pulmonary lesions: a prospective phase II study.

BACKGROUND The diagnostic yield of peripheral pulmonary lesions (PPLs) by flexible bronchoscopy (FB) is still insufficient. To improve the diagnostic yield of bronchoscopy, several techniques such as endobronchial ultrasound (EBUS), virtual bronchoscopic navigation (VBN), and rapid on-site evaluation (ROSE) have been examined. The primary purpose of the present study was to evaluate the usefulness of combining EBUS, VBN, and ROSE for diagnosing small PPLs. METHODS Patients with PPLs 30 mm or less on chest computed tomography (CT) were prospectively enrolled. We determined the responsible bronchus for the target lesions using VBN before bronchoscopy was performed. EBUS and ROSE were performed during the examination to determine whether the bronchus and specimen were adequate. On the basis of previous studies, we assumed that the diagnostic yield of 85% among eligible patients would indicate potential usefulness, whereas, the diagnostic yield of 75% would indicate the lower limit of interest. The required number of patients was estimated as 45 for a one-sided α value of 0.2 and a β value of 0.8. The primary study endpoint was the diagnostic yield. RESULTS Between June 2014 and July 2015, we enrolled 50 patients in the present study, and we excluded 5 patients. The total diagnostic yield of 45 PPLs was 77.7%. In cases of lung cancer, the diagnostic yield was 84.2%. The sensitivity, specificity, positive predictive value, and negative predictive value of ROSE were 90.6%, 92.3%, 96.7%, and 80.0%, respectively. The diagnostic yield of PPLs from 20 to 30 mm was 87.5%, and the diagnostic yield of PPLs less than 20 mm was 66.7%. PPLs for which the probe was located within the lesion had the highest diagnostic yield. CONCLUSIONS We could not demonstrate usefulness for diagnosing small PPLs by combining EBUS, VBN, and ROSE. However, combining these techniques may be useful for diagnosing lung cancer.

An Abscopal Response to Radiation Therapy in a Patient with MetastaticNon-Small Cell Lung Cancer: A Case Report

Introduction: The Abscopal effect refers to radiotherapy-induced tumor regression in lesions distant from a targeted site, and is a rare phenomenon in patients receiving local radiotherapy. This report is the first to describe an Abscopal response in a chemotherapy-naive non-small cell lung cancer (NSCLC) patient following whole-brain radiotherapy as well as palliative radiotherapy. Case presentation: A 63-years-old man who was a current-smoker (with 86 pack years) with metastatic NSCLC underwent whole brain radiotherapy (WBRT) plus boost radiotherapy to total dose of 45 Gy in 15 fractions because the metastatic brain tumor with cerebral oedema from the left temporal lobe to the occipital lobe rapidly progressed after the enucleation of the brain tumor. The patient also received palliative radiation (30 Gy in 10 fractions) for the third lumbar vertebral metastasis. The tumor in the left upper lobe of the lung and his mediastinal lymph nodes had regressed in size upon reviewing his follow-up CT results seven weeks post-radiotherapy. Conclusion: The Abscopal effect in metastatic NSCLC patients can occur after the irradiation of metastatic lesions without chemotherapeutic or immunotherapeutic interventions.