Keisuke Tomii

Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids.

BACKGROUND Periostin, an extracellular matrix protein, contributes to subepithelial thickening in asthmatic airways, and its serum levels reflect airway eosinophilic inflammation. However, the relationship between periostin and the development of airflow limitation, a functional consequence of airway remodeling, remains unknown. OBJECTIVE We aimed to determine the relationship between serum periostin levels and pulmonary function decline in asthmatic patients on inhaled corticosteroid (ICS) treatment. METHODS Two hundred twenty-four asthmatic patients (average age, 62.3 years) treated with ICS for at least 4 years were enrolled. Annual changes in FEV1, from at least 1 year after the initiation of ICS treatment to the time of enrollment or later (average, 16.2 measurements over 8 years per individual), were assessed. At enrollment, clinical indices, biomarkers that included serum periostin, and periostin gene polymorphisms were examined. Associations between clinical indices or biomarkers and a decline in FEV1 of 30 mL or greater per year were analyzed. RESULTS High serum periostin levels (≥ 95 ng/mL) at enrollment, the highest treatment step, higher ICS daily doses, a history of admission due to asthma exacerbation, comorbid or a history of sinusitis, and ex-smoking were associated with a decline in FEV1 of 30 mL or greater per year. Multivariate analysis showed that high serum periostin, the highest treatment step, and ex-smoking were independent risk factors for the decline. Polymorphisms of periostin gene were related to higher serum periostin levels (rs3829365) and a decline in FEV1 of 30 mL or greater per year (rs9603226). CONCLUSIONS Serum periostin appears to be a useful biomarker for the development of airflow limitation in asthmatic patients on ICS.

Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: Comparison between T790M mutation-positive and mutation-negative populations.

The secondary epidermal growth factor receptor (EGFR) mutation Thr790Met (T790M) accounts for approximately half of acquired resistances to EGFR‐tyrosine kinase inhibitor (TKI). Recent reports have demonstrated that the emergence of T790M predicts a favorable prognosis and indolent progression. However, rebiopsy to confirm T790M status can be challenging due to limited tissue availability and procedural feasibility, and little is known regarding the differences among patients with or without T790M mutation.

Aleukemic leukemia cutis

A 39-year-old man had multiple nodules on the skin. The appearance of atypical monocytes in a skin biopsy specimen preceded the onset of overt acute monocytic leukemia by 14 months.

Erlotinib after gefitinib failure in relapsed non-small cell lung cancer: Clinical benefit with optimal patient selection

BACKGROUND Recent reports have suggested that erlotinib therapy after gefitinib failure requires optimal patient selection to obtain clinical benefits in relapsed non-small cell lung cancer (NSCLC). However, insufficient evidence exists to determine which clinical factors best identify patients who benefit from erlotinib therapy. METHODS One hundred twenty-five patients with relapsed NSCLC who had received erlotinib therapy after gefitinib failure were retrospectively evaluated between January 2008 and May 2009. RESULTS The response rate (RR), disease control rate (DCR), and median progression-free survival (PFS) for all patients were 9% (95% confidence interval [CI], 5-15%), 44% (95% CI, 35-53%), and 2.0 months (95% CI, 1.4-2.5 months), respectively. The median survival time was estimated to be 11.8 months (95% CI, 6.4-16.0 months). Using multivariate analysis, good performance status (PS), EGFR mutation-positive status, and benefit from prior gefitinib therapy were identified as significant predictive factors for disease control. Using a proportional hazards model, benefit from prior gefitinib therapy, good PS, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies emerged as significant predictive factors for longer PFS. Thirty-two patients with concomitant PS 0/1, benefit from prior gefitinib therapy, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies benefitted more from erlotinib therapy: RR, 25% (95% CI, 12-43%); DCR, 72% (95% CI, 53-86%); and median PFS, 3.4 months (95% CI, 2.4-4.9 months). CONCLUSIONS Higher efficacy of erlotinib after gefitinib failure can be achieved with proper patient selection criteria, including good PS, benefit from prior gefitinib therapy, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies.

Surgical Treatment of Local Recurrence After Stereotactic Body Radiotherapy for Primary and Metastatic Lung Cancers

Introduction: Stereotactic body radiotherapy (SBRT) has been proposed as an alternative to surgery for the treatment of lung cancer. The treatment of local recurrence that occurs after SBRT has not been reported. We present surgical outcomes for local recurrence following SBRT for primary and metastatic lung cancers. Methods: Seven of the patients who received SBRT between 2002 and 2008 underwent salvage surgery for local recurrence. These seven patients (two with stage I non-small cell lung cancer and five with metastatic tumors) were operable, although they refused surgery and chose SBRT for the first treatment as a less invasive procedure. Results: Six of the seven patients underwent lobectomy, and the other patient underwent segmentectomy. None of the seven patients had direct pleural adhesion resulting from SBRT, although, in general, radiation fibrosis occurs after radiotherapy and induces pleural adhesion that makes surgery difficult. Conclusions: Our study suggests that SBRT may not be the cause of difficulties encountered during the surgical process, and surgery is a good alternative treatment for local recurrence after SBRT. During follow-up after SBRT, the appearance of tumor regrowth on lung images resembled that of inflammatory changes such as radiation pneumonitis. We suggest that close follow-ups should be mandatory after SBRT.

Frequency of EGFR and KRAS Mutations in Japanese Patients with Lung Adenocarcinoma with Features of the Mucinous Subtype of Bronchioloalveolar Carcinoma

Introduction: Adenocarcinoma of the lung, especially bronchioloalveolar carcinoma (BAC) and adenocarcinoma with BAC features (AWBF), is potentially sensitive to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs); however, the efficacy seems to differ between the histologic subtypes. Mucinous BAC and AWBF (MBAC/AWBF) are not particularly responsive to EGFR-TKIs compared with nonmucinous BAC/AWBF (N-MBAC/AWBF). This may be due to the rarity of EGFR mutations and high frequency of KRAS mutations in MBAC/AWBF in contrast to N-MBAC/AWBF. Methods: One hundred ninety-one patients with adenocarcinoma of the lung underwent surgery at our institution. There were 59 patients (30%) diagnosed with BAC/AWBF; 20 had MBAC/AWBF (10%) and 39 had N-MBAC/AWBF (20%). We isolated 44 tissue specimens from these patients (20 consecutive cases of MBAC/AWBFs and 24 randomly chosen cases of N-MBAC/AWBFs as the control group), and we analyzed them for EGFR and KRAS mutations. We used the peptide nucleic acid-locked nucleic acid polymerase chain reaction clump method to detect EGFR mutations and conventional DNA sequencing to identify KRAS mutations. Results: EGFR mutations were found in three of the 20 MBAC/AWBFs (15%) and in 14 of the 24 N-MBAC/AWBFs (58%) (p = 0.005). In addition, there were 14 KRAS mutations identified in the 20 MBAC/AWBFs (70%) and seven in the 24 N-MBAC/AWBFs (29%) (p = 0.0144). Conclusions: The incidence of EGFR mutation is low and that of KRAS mutation is frequent in MBAC/AWBFs. Conversely, the incidence of EGFR mutation is high and KRAS mutation is low in N-MBAC/AWBFs. Based on these findings, EGFR-TKIs may not be effective in patients with MBAC/AWBF.

Clinical Features and Outcome of Acute Exacerbation of Interstitial Pneumonia: Collagen Vascular Diseases-Related versus Idiopathic

Background: Relatively little is known about acute exacerbation (AE) of interstitial pneumonia associated with collagen vascular diseases (CVD-IPs). Objectives: This study was aimed at clarifying clinical characteristics and outcome in AE of CVD-IPs, compared with those of idiopathic interstitial pneumonias (IIPs). Methods: We retrospectively reviewed 112 admission cases with suspected AE of CVD-IPs or IIPs during 2003–2009. IIPs were diagnosed with idiopathic pulmonary fibrosis (IPF) or non-IPF, mostly based on radiologic findings. Of these, 15 AEs of CVD-IPs (6 rheumatoid arthritis, 6 dermatomyositis and 3 systemic sclerosis) and 47 AEs of IIPs (13 IPF and 34 non-IPF) were included. Results: The clinical characteristics in AE of CVD-IPs were similar to those of IIPs, except for younger age (63.3 ± 6.8 vs. 73.8 ± 9.1 years; p = 0.0001) and higher PaO2/FiO2 at the onset of AE (205 ± 81.2 vs. 145 ± 53.8 mm Hg; p = 0.002) in the former. Dermatomyositis-related interstitial pneumonia (IP) showed a relatively indolent onset and was often associated with worsening control of the underlying disease, whereas AE of other CVD-IPs resembled that of IIPs. 90-day mortality of 33% in AE of CVD-IPs was similar to that of IIPs (44%; p = 0.44) or non-IPF (34%; p = 0.94), but was significantly better than that of IPF (69%; p = 0.04). Conclusion: Clinical features and outcome in AE of CVD-IPs were similar, if not identical, to those of IIPs, having a significant impact on the clinical course. AE of advanced IPF with typical radiologic features seems to have higher mortality compared with other forms of IP.

Using Exhaled Nitric Oxide and Serum Periostin as a Composite Marker to Identify Severe/Steroid-Insensitive Asthma

At present, exhaled nitric oxide (FENO) is a clinically useful biomarker of eosinophilic airway inflammation (1); its levels increase during exacerbation and decrease with inhaled corticosteroid (ICS) treatment (2). Evidence has demonstrated that high FENO levels (>35 ppb) indicate the presence of a highly reactive phenotype among patients with asthma (3), which is useful for the management of patients. Nonetheless, additional markers are required for better characterization of patients with asthma with elevated FENO (>25 ppb), particularly to identify patients who may have steroid resistance (2). Serum periostin is a biomarker of helper T type 2/eosinophilic airway inflammation in asthma (4, 5) distinct from FENO (6). Periostin is a matricellular protein actively involved in airway remodeling (4, 7, 8), with partial steroid resistance (9), although steroid-sensitive aspects were initially highlighted (10). Indeed, high serum periostin levels are associated with refractory eosinophilic inflammation (5) and accelerated decline in pulmonary function in patients with asthma under ICS treatment (11, 12). Importantly, serum periostin levels are relatively stable and less variable than FENO (5, 6), which is advantageous for long-term monitoring of patients with asthma. Therefore, we hypothesized that high serum periostin could be used as a biomarker to efficiently identify ICS-insensitive patients among patients with elevated FENO. In the present study, we demonstrated the reliability of comeasurement of FENO and serum periostin to identify ICS-insensitive patients; they were defined as those with an accelerated decline in FEV1 of at least 30 ml/year (11) or a risk of asthma exacerbations requiring systemic corticosteroid bursts despite adequate ICS treatments in this study. This is a substudy of the Kinki Hokuriku Airway Disease Conference (KiHAC) study that investigated genobiological factors associated with pulmonary function decline in adults with asthma receiving ICS treatment; the patients had undergone 16.26 13.9 FEV1 measurements over 8.06 4.5 years (11). The study protocol (UMIN000002414) was approved by the ethics committee of each participating institution. The present study included the patients who agreed to FENO measurements with a chemiluminescence analyzer (NOA 280; Sievers, Boulder, CO) at enrollment. All patients underwent baseline examination, including a selfcompleted questionnaire, the asthma control test, spirometry, and blood tests at enrollment, as described previously (11). FENO levels were determined at an expiratory flow rate of 50 ml/second, according to the present guidelines (13, 14). The frequency of asthma exacerbation, requiring systemic corticosteroid bursts, was documented for 2 years after enrollment, except for one patient who was lost to follow-up 1 year after enrollment. Serum periostin levels were determined using an enzyme-linked immunosorbent assay at Shino-Test (Kanagawa, Japan), and a cutoff point of 95 ng/ml was used to define high serum periostin (11). Follow-up FENO and serum periostin measurements were not obligatory, but they were measured in several patients on various occasions during the subsequent 2 years (see the online supplement). Statistical analysis was performed with JMP version 9.0 software (SAS Institute Inc., Tokyo, Japan). FENO and serum periostin levels were log-transformed to achieve normal distribution. Pearson correlation coefficients were used to identify relationships between the parameters. Two data sets were compared, using the unpaired t test or Wilcoxon rank-sum test for numerical data and the x test or Fisher exact test for nominal data, as deemed appropriate. The comparison between high and low serum periostin groups or FENO groups regarding an accelerated decline in FEV1 was performed after adjustment for sex, height, age at enrollment, and FEV1 at the first measurement. Logistic regression analysis was performed to estimate the risk of subsequent asthma exacerbations (see the online supplement). Data are presented as means6 SD or percentage. P< 0.05 was considered statistically significant. The FENO levels, determined in 121 patients, were weakly associated with serum periostin levels (Figure 1). This relationship between FENO and serum periostin was stronger when the analysis was confined to patients undergoing treatment step 4 or 5 as

Complex Mutations in the Epidermal Growth Factor Receptor Gene in Non-small Cell Lung Cancer

Introduction: Mutation of the epidermal growth factor receptor (EGFR) gene can predict the efficacy of EGFR-tyrosine kinase inhibitors. Different mutations have been shown to co-occur in a single tumor. However, the frequency of these so-called “complex mutations” and the efficacy of gefitinib in treating patients with these mutations are unclear. Methods: We investigated the frequency of complex mutations in 783 patients with non-small cell lung cancer seen at our institutes between April 2006 and May 2009. Mutational analysis was performed using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method. Gefitinib efficacy was evaluated in patients found to have complex mutations. Results: EGFR mutations were detected in 318 (41%) patients, with 21 (6.6%) of these individuals having complex mutations. Sixteen of these 21 patients received gefitinib. The response rate (RR) was 67% (95% confidence interval [CI], 35–90%) and median progression-free survival was 12.2 months (95% CI, 1.3 months to undeterminable). Analysis of RR according to mutation type revealed that patients with deletional mutation in exon 19 (Del-19) and a point mutation in exon 21 (L858R) had a better RR (86%, 6 of 7) than those with other complex mutation patterns such as a point mutation in exon 18 (G719S) + L858R (40%, 2 of 5) (p = 0.2222). The median progression-free survival was also longer in these patients (16.5 months; 95% CI, 1.1 months to undeterminable versus 3.8 months; 95% CI, 0.7–10.0 months) (p = 0.0459). Conclusions: Complex EGFR mutations are not rare. Gefitinib has different efficacy according to the type of complex EGFR mutations. Patients with Del-19 and L858R mutations may benefit more from gefitinib than other types of complex mutations.

How Sensitive Are Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitors for Squamous Cell Carcinoma of the Lung Harboring EGFR Gene–Sensitive Mutations?

Introduction: Epidermal growth factor receptor (EGFR) mutations are found mostly in adenocarcinoma, and rarely in squamous cell carcinoma (SQC). Little is known about SQC harboring EGFR mutations. Methods: Between April 2006 and October 2010, we investigated the incidence of EGFR activating mutations in SQC of the lung using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method. The efficacy of EGFR-tyrosine kinase inhibitors (TKIs) was retrospectively evaluated in patients with EGFR-mutated SQC. Further pathologic analyses were performed using immunohistochemistry. Results: Thirty-three of 249 patients with SQC (13.3%) had EGFR mutations, including exon 19 deletion (19 of 33 patients, 58%), L858R point mutation in exon 21 (12 of 33, 36%), and G719S point mutation in exon 18 (2 of 33, 6%). Twenty of these 33 patients received EGFR-TKI therapy, and five of these 20 responded to EGFR-TKIs with a response rate of 25.0% (95% confidence interval [CI], 8.7%–49.1%). The patients’ median progression-free survival and median overall survival were 1.4 months (95% CI, 0.7–5.8 months) and 14.6 months (95% CI, 2.9–undeterminable months), respectively. Approximately one third of the EGFR-mutated SQC patients achieved progression-free survival for longer than 6 months. Some of these patients had high carcinoembryonic antigen levels or a history of never smoking, or were positive for thyroid transcription factor-1. Conclusions: Although EGFR-TKIs seem to be generally less effective in EGFR-mutated SQC than in EGFR-mutated adenocarcinoma, some EGFR-mutated SQC patients can obtain clinical benefit from EGFR-TKIs. To better identify these patients, not only EGFR mutation status, but also clinical factors and pathologic findings should be taken into consideration.