Yoshihiro Kanemitsu

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.

Combined measurements of fractional exhaled nitric oxide and nasal nitric oxide levels for assessing upper airway diseases in asthmatic patients

ABSTRACT Background: Despite the close linkage between rhinitis, chronic rhinosinusitis (CRS) and asthma, relevant biomarkers of both upper and lower airway inflammation are rare. Methods: Patients with asthma (without upper airway disease [UAD; n = 24], with rhinitis [n = 25], CRS [n = 24], and nasal polyps [n = 2]), isolated rhinitis (n = 13), isolated CRS (n = 13), and 10 healthy controls were prospectively recruited. Fractional exhaled nitric oxide (NO) levels at 50 mL/s (FeNO50), nasal NO levels, Lund–Macay-scores of sinus computed tomography and an asthma control questionnaire (ACQ) were evaluated. Results: Asthma was associated with higher FeNO50 levels irrespective of the UAD category. FeNO50 levels were higher in asthmatics with CRS (median: 54.0 ppb) than those with rhinitis (35.2 ppb, p = 0.02) and those without UAD (34.3 ppb, p = 0.002). Nasal NO levels were higher in rhinitis patients than other UAD categories, irrespective of the asthma concomitance. Nasal NO levels were higher in asthmatics with rhinitis (112.8 ppb) than those without UAD (67.2 ppb, p = 0.001) and those with CRS (57.6 ppb, p < 0.0001). A receiver-operating-characteristic curve analysis for detecting comorbid allergic rhinitis (AR) in asthmatics showed a high area under the curve (0.87). Nasal NO levels were positively correlated with FeNO50 levels (ρ = 0.56, p = 0.003) in asthmatics with rhinitis. In contrast, they were negatively correlated with the Lund–Macay (ρ = −0.46, p = 0.03) and ACQ scores (ρ = −0.52, p = 0.009) in asthmatics with CRS. Conclusions: Higher nasal NO levels reflect the presence of AR, irrespective of asthma concomitance. Higher FeNO50 levels reflect the presence of CRS and asthma. These NO measurements are useful for assessing comorbid UAD in asthmatics.

A Rare Case of Isolated Chronic Cough Caused by Pulmonary Lymphangitic Carcinomatosis as a Primary Manifestation of Rectum Carcinoma

A 36-year old man was referred to our hospital due to isolated chronic cough that was refractory to anti-asthma medications, including inhaled corticosteroids/long-acting β2 agonists. Chest X-ray showed diffuse nodular and enhanced vascular shadows with Kerley lines in both lungs. A blood analysis showed elevated serum carcinoembryonic antigen (CEA) and CA19-9 levels. A transbronchial biopsy revealed well to moderately differentiated adenocarcinoma, the origin of which was immunohistochemically suspected to be the gastrointestinal tract. Colonoscopy confirmed the diagnosis of primary rectum carcinoma. Pulmonary lymphangitic carcinomatosis was therefore regarded as the origin of the cough. Lymphangitic carcinomatosis is an uncommon diagnosis but important to consider in patients with persistent cough.

Bronchial Thermoplasty for Severe Asthmatic Cough

Background: Bronchial thermoplasty is a novel treatment for severe asthma that reduces the volume of airway smooth muscles and the number of airway nerves and epithelial neuroendocrine cells (1). These reductions are associated with fewer asthma exacerbations. However, little is known about the efficacy of this therapy on cough. Objective: To describe a patient with severe, cough-predominant asthma whose cough was alleviated by bronchial thermoplasty. Case Report: A 35-year-old woman presented with a 2.5-year history of chronic cough. The patient was diagnosed with asthma 6 months earlier on the basis of wheezing on auscultation and the ability of inhaled salbutamol to increase FEV1 by 13.8% above baseline levels. The cough had worsened and was awakening the patient and disturbing conversation despite treatment with high-dose inhaled corticosteroids, long-acting 2-agonists, and leukotriene-receptor antagonists. A 7-day course of oral prednisolone, 20 mg/d, also had not improved the cough. The patient had a cough visual analogue scale score of 67 mm (range, 0 to 100 mm, with lower scores indicating less frequent cough) and a total Leicester cough questionnaire score of 9.1 (range, 3 to 21, with higher scores indicating better quality of life). These findings documented that the cough was frequent and severe. In addition, the patient had an asthma control test score of 16 (range, 5 to 25, with higher scores reflecting greater asthma control and scores>19 indicating well-controlled asthma). Blood eosinophil counts and levels of exhaled nitric oxide and serum IgE were normal, and we could not detect sensitization to inhaled aeroallergens (data not shown). On capsaicin cough sensitivity testing using the fixed-time inhalation method, an inhalation of the lowest capsaicin concentration (0.61 mcM) evoked 7 coughs (Table). Table. Time Course of the Number of Coughs in Response to Capsaicin* We began treatment with sustained theophylline, tiotropium, and erythromycin, but cough frequency, cough-specific quality of life, asthma control, and the number of capsaicin-induced coughs remained unchanged at 6-month follow-up (Figure). We used bronchial thermoplasty to treat all visible bronchi with heat energy at 65C for 10 seconds during 3 procedures at 3-week intervals for a total of 138 activations. The cough improved immediately after the first procedure. Three months after the final procedure, we documented improvements in cough frequency (cough visual analogue scale score, 36 mm), cough-related quality of life (Leicester cough questionnaire score, 14.6), and asthma control (asthma control test score, 19). The number of capsaicin-induced coughs also decreased, but measures of systemic eosinophilic and airway inflammation and pulmonary function remained unchanged. Figure. Clinical course of cough frequency, cough-specific quality of life, asthma control, and clinical indices. ACT= asthma control test; BT= bronchial thermoplasty; FeNO= fractional exhaled nitric oxide; LCQ= Leicester cough questionnaire; LLL= left lower lobe; LUL= left upper lobe; RLL= right lower lobe; RUL= right upper lobe; VAS= visual analogue scale. * Higher scores indicate better cough-related quality of life. The minimum clinically important difference is1.3. Lower scores indicate less frequent cough. Discussion: Some patients have asthmatic cough that is frequent and severe enough to justify the aggressive treatment that we used in this patient (2). Understanding how this treatment works would be comforting, but we can only speculate about the mechanism. Asthmatic cough is generally induced by bronchoconstriction via A- fibers of the airway smooth muscle (3), and acute bronchoconstriction promotes the capsaicin cough response (4). Airway neuronal dysfunction may therefore be a useful therapeutic target. Patients with stable asthma, particularly women and nonatopic patients, have a more pronounced cough response to capsaicin than healthy persons (5). This patients capsaicin cough response improved after bronchial thermoplasty, which suggests that this therapy may alter the expression of transient receptor potential vanilloid-1, the capsaicin receptor. This receptor is a nonselective cation channel that is activated by temperatures greater than 43C; acidic conditions; capsaicin, which is the irritating compound in hot chili peppers; and allyl isothiocyanate, which is the pungent compound in mustard and wasabi. Decreasing neuronal dysfunction and altering the capsaicin receptor may thus have contributed to this patients improvement. Whatever the explanation, we believe that other clinicians should consider bronchial thermoplasty for patients with severe asthmatic cough who have not responded to more conventional therapies.