Hirotsugu Ohkubo

Serum Periostin as a Biomarker for Comorbid Chronic Rhinosinusitis in Patients with Asthma

Rationale: Periostin is a matricellular protein that is involved in the pathophysiology of allergic rhinitis, chronic rhinosinusitis, and asthma. Associations of serum periostin with systemic and airway eosinophilic inflammation and comorbid chronic rhinosinusitis in patients with asthma have been demonstrated. Although serum periostin is positioned as a marker of helper T cell 2 immune responses, its implication regarding the presence of comorbid upper airway diseases in patients with asthma remains unclear. Objectives: To investigate the utility of serum periostin as a diagnostic biomarker for upper airway disease in patients with asthma. Methods: We prospectively enrolled 65 patients with stable asthma, 20 without upper airway disease, 22 with rhinitis, and 23 with chronic rhinosinusitis (13 with nasal polyps, 10 without). Serum periostin, eotaxin, total IgE, fractional exhaled nitric oxide, and blood and sputum eosinophil levels were measured and compared between upper airway disease subtypes. We evaluated the utility of each biomarker in detecting upper airway disease, associations among the biomarkers, and severity of upper airway disease as measured by the Lund‐Mackay score for sinus computed tomography. Results: Serum periostin levels were higher in patients with asthma who had chronic rhinosinusitis (109.6 ± 47.4 ng/ml) than in those without upper airway disease (83.2 ± 22.9 ng/ml) (P = 0.04). Serum periostin levels in patients with asthma who had chronic rhinosinusitis and nasal polyps were significantly higher (130.0 ± 46.6 ng/ml) than in those without nasal polyps (87.9 ± 37.7 ng/ml) (P = 0.001). Serum periostin levels were not associated with the presence or the severity of rhinitis. In contrast, receiver operating characteristic curve analyses showed moderate diagnostic accuracy for detecting chronic rhinosinusitis (area under the curve, 0.71; P = 0.01) and high accuracy for chronic rhinosinusitis with nasal polyps (area under the curve, 0.86; P = 0.0002). When we compared patients with asthma who had comorbid chronic rhinosinusitis and nasal polyps with patients with asthma without these comorbidities, we found serum periostin to be the sole biomarker among those tested for detecting the presence of nasal polyps. Serum periostin was also the sole biomarker that significantly correlated with Lund‐Mackay score in patients with chronic rhinosinusitis (r = 0.44; P = 0.04). Conclusions: Serum periostin is useful for detecting chronic rhinosinusitis with nasal polyps and predicting radiological chronic rhinosinusitis severity in patients with asthma. Clinical trial registered with the UMIN Clinical Trials Registry (UMIN000017533).

Involvement of intermediate filament nestin in cell growth of small-cell lung cancer

BACKGROUND Nestin is a class VI intermediate filament protein expressed in stem/progenitor cells during the development of the central nervous system. Nestin is detected in various types of tumors and is involved in malignant processes. This study investigated the expression and function of nestin in small-cell lung cancer (SCLC). METHODS Expression of nestin and achaete-scute homolog 1 (ASH1) was studied in 21 lung cancer cell lines. To assess the function of nestin, a short hairpin RNA (shRNA) targeting nestin was transfected into two SCLC cell lines (DMS53 and SBC3), and cloned cells that showed apparent down-regulation of nestin were obtained. Nestin expression was also studied immunohistochemically in surgically resected SCLC primary tumors and metastatic SCLC tumors obtained from autopsy cases. RESULT Nestin was expressed in nine of 10 SCLC cell lines. The nestin expression level was significantly higher in SCLC cell lines than in NSCLC cell lines (P < 0.01). There was a statistically significant positive correlation between the expression levels of nestin and ASH1 in SCLC cell lines. Nestin knock-down cells created by transfection with shRNA exhibited decreased invasion and cell proliferation capabilities. Furthermore, nestin was detected in SCLC tumor cells and tumor vessels in all clinical tumor specimens. CONCLUSION Nestin is expressed in SCLC in association with neuroendocrine features and participates in malignant phenotypes, including cell growth. Therefore, nestin may be a novel therapeutic target for SCLC.

Efficacy of combined corticosteroid and pirfenidone for acute exacerbation of idiopathic pulmonary fibrosis after surgery for lung cancer: A case report

Hirotsugu Ohkubo, MD, PhD, Eiji Kunii, MD, Satoru Moriyama, MD, PhD, Akio Niimi, MD, PhD Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan Department of Oncology, Immunology, and Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan

Organic cation transporter OCT6 mediates cisplatin uptake and resistance to cisplatin in lung cancer

PurposeThe purposes of this study were to determine whether organic cation transporters (OCTs) can mediate platinum uptake, and whether OCT down-regulation confers resistance against cisplatin (CDDP) in cancer cells.MethodsTwo lung cancer cell lines, PC-6 and PC-14, and their CDDP-resistant derivatives, PC-6/CDDP and PC-14/CDDP, were analyzed. OCT expression levels were assayed using quantitative RT-PCR and Western blotting. Additionally, the effect of OCT6 overexpression, induced by transfection of the OCT6 gene SLC22A16 using a forced expression vector, on cellular sensitivity to CDDP and on intracellular platinum accumulation was measured using PC-14/CDDP cells.ResultsBoth gene and protein expression of OCT6 were decreased in both CDDP-resistant cell lines compared with their expression in their respective parental cells. Intracellular accumulation of platinum was decreased in PC-14/CDDP cells compared with the parental cells after CDDP treatment. Furthermore, OCT6 overexpression induced by transfection of the OCT6 gene (SLC22A16) forced expression vector-sensitized PC-14/CDDP cells to CDDP and oxaliplatin (L-OHP) concomitant with increased intracellular concentration of platinum.ConclusionOCT6 is a mediator of platinum uptake in cancer cells, and down-regulation of OCT6 is possibly one of the mechanisms of resistance against cisplatin in lung cancer.

Analgesic effect of switching from oral opioids to a once-a-day fentanyl citrate transdermal patch in patients with lung cancer.

A new once-a-day fentanyl citrate transdermal patch was developed in Japan. We retrospectively investigated analgesic and adverse effects of this drug in 24 patients with lung cancer. All patients were started on this patch by switching from an oral opioid. The mean pain score before switching was 2.45 (0-5); 48 hours after switching, 15 of the 24 patients showed a decreased pain score and the mean score (2.00) was significantly lower than that before switching. Of the 16 patients who had adverse effects of oral opioids, 7 patients showed improvement in their symptoms after switching. Two patients showed adverse effects of the drug but their symptoms were mild, and no patient required dose decrease. This new transdermal patch could be a useful treatment option for cancer pain.

Computer-based quantitative computed tomography image analysis in idiopathic pulmonary fibrosis: A mini review

Idiopathic pulmonary fibrosis (IPF) is the most common type of progressive idiopathic interstitial pneumonia in adults. Many computer-based image analysis methods of chest computed tomography (CT) used in patients with IPF include the mean CT value of the whole lungs, density histogram analysis, density mask technique, and texture classification methods. Most of these methods offer good assessment of pulmonary functions, disease progression, and mortality. Each method has merits that can be used in clinical practice. One of the texture classification methods is reported to be superior to visual CT scoring by radiologist for correlation with pulmonary function and prediction of mortality. In this mini review, we summarize the current literature on computer-based CT image analysis of IPF and discuss its limitations and several future directions.

Dramatic intracranial response to osimertinib in a poor performance status patient with lung adenocarcinoma harboring the epidermal growth factor receptor T790M mutation: A case report

We herein report a case of dramatic intracranial response to osimertinib in a poor performance status patient with lung adenocarcinoma harboring the epidermal growth factor receptor (EGFR) T790M mutation encoded in exon 20. The patient was a 59-year-old woman with EGFR exon 19 deletion-positive lung adenocarcinoma, who relapsed with multiple brain metastases. Computed tomography-guided biopsy of the left pleural tumor revealed adenocarcinoma harboring an EGFR exon 19 deletion and an EGFR T790M mutation encoded in exon 20. The patient was treated with osimertinib, a third-generation EGFR tyrosine kinase inhibitor. Two days after treatment initiation, the patient displayed profound disturbance of consciousness, possibly due to carcinomatous meningitis, and treatment had to be discontinued due to difficulty in taking osimertinib. However, the patient gradually started to recover consciousness and, after 3 days, she was again able to take osimertinib. One month after the initiation of osimertinib treatment, magnetic resonance imaging revealed an apparent reduction in brain metastases. The patient is currently under continued treatment with osimertinib. At the last follow-up (February, 2017) she exhibited partial response to the treatment.

Osimertinib‑induced interstitial lung disease in a patient with non‑small cell lung cancer pretreated with nivolumab: A case report

Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for EGFR-T790M-positive non-small cell lung cancer. A high incidence of interstitial lung disease (ILD) during combination treatment with osimertinib and anti-programmed cell death-ligand 1 (PD-L1) inhibitor has been reported. The current study presents a case of ILD development during osimertinib treatment following nivolumab (an anti-PD-1 antibody) treatment. The 59-year-old female was diagnosed with stage IV lung adenocarcinoma harboring a deletion in exon 19 of the EGFR gene. Following nivolumab as a sixth-line treatment, an EGFR-T790M-encoding mutation in EGFR exon 20 was identified by re-biopsy. Osimertinib was therefore initiated as a seventh-line treatment. A partial response was subsequently noted; however, 63 days after initiation of the treatment the patient presented with dyspnea with decreased oxygenation in the absence of fever and sputum. A computed tomography scan revealed the emergence of ground-glass opacities with bronchiectasis in both lungs, and a diagnosis of ILD due to osimertinib was made. Following steroid pulse therapy with discontinuation of osimertinib, the patients chest findings and respiratory condition improved. Therefore, it is considered that anti-PD-1 therapies may be associated with a risk of ILD during subsequent osimertinib treatment.

A folylpoly-γ-glutamate synthase single nucleotide polymorphism associated with response to pemetrexed treatment combined with platinum for non-small cell lung cancer.

OBJECTIVES In this study, we investigated whether single nucleotide polymorphisms (SNPs) in folylpoly-γ-glutamate synthase (FPGS), which catalyzes the polyglutamation of pemetrexed (PEM), is related to FPGS expression and the response to PEM in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS We first examined FPGS protein expressions according to FPGS SNPs genotype groups in 15 lung adenocarcinoma cell lines. Next, 101 non-squamous NSCLC patients treated with PEM and platinum drugs were classified into FPGS SNP genotype groups to investigate the relation between FPGS SNP genotypes and treatment outcome. RESULTS When the 15 adenocarcinoma cell lines were classified into FPGS SNP 2572C>T genotype groups, we found that the FPGS protein expression was significantly higher in the CC genotype group than in the TT+CT genotype group (p=0.0022). In contrast, there was no significant difference in FPGS expression when another FPGS SNP was analyzed. We also examined the FPGS SNP 2572C>T genotype in 101 non-squamous NSCLC patients treated with PEM and platinum drugs. Among these 101 patients, response rate was significantly higher in the CC genotype group than in the TT+CT genotype group (p=0.0034). When we examined the patients treated with PEM, platinum drugs and Bev, almost all (29/33) were classified into the TT+CT genotype group. The response rate, progression-free survival, and over-all survival were all significantly better in the patients of the TT+CT genotype group who also received Bev than in those who did not receive Bev (p=0.034, 0.021, 0.018, respectively). CONCLUSION FPGS SNP 2572C>T is a predictive marker of the efficacy of PEM and platinum drugs for NSCLC.

Prevention of hypoxemia during endobronchial ultrasound-guided transbronchial needle aspiration: Usefulness of high-flow nasal cannula

BACKGROUND Hypoxemia during endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is often encountered even in patients without respiratory impairment before the procedure. The aim of this study was to evaluate the efficacy of a high-flow nasal cannula (HFNC) in preventing hypoxemia during EBUS-TBNA. METHODS The present investigation was designed as a prospective pilot study. Eligible subjects were adults who could undergo EBUS-TBNA under intravenous midazolam sedation. The main exclusion criteria were as follows: age > 80 years with impaired oxygenation and peripheral oxygen saturation (SpO2) < 95% at room air. The primary outcome was the oxygenation level during the procedure. Cutaneous carbon dioxide tension (PcCO2) and complications were evaluated as secondary outcomes. HFNC use was started at an inspired O2 fraction of 30% and was titrated to maintain SpO2 over 90%. The lowest SpO2 values during EBUS-TBNA were retrospectively compared between patients who underwent HFNC and those were given a conventional nasal cannula as a historical control group. RESULTS Twelve patients received HFNCs. The mean lowest SpO2 during the procedure was 93%. Although the mean SpO2 tended to decrease in the early stages, it remained over 90% throughout the procedure. The mean highest PcCO2 was 39 mmHg (range, 30-46 mmHg). There were no major complications. In patients who underwent EBUS-TBNA using a conventional nasal cannula, the mean lowest SpO2 was 88%, which was significantly lower than that in the HFNC cases (p = 0.005). CONCLUSION HFNC could be an effective and safe device for prevention of hypoxemia during EBUS-TBNA.