Naohiro Watanabe

Lung-Dominant Connective Tissue Disease: Clinical, Radiologic, and Histologic Features

BACKGROUND Lung-dominant connective tissue disease (LD-CTD) is a disease concept for interstitial pneumonia; however, it has not been robustly validated. This study was conducted to elucidate the clinical, radiologic, and histologic features of LD-CTD. METHODS We retrospectively reviewed 44 consecutive patients with serologically defined LD-CTD who underwent surgical lung biopsy. Patients were identified as having LD-CTD if they had specific autoantibodies but did not meet the criteria for connective tissue disease. We conducted a multidisciplinary diagnosis and evaluated major histologic patterns according to the current idiopathic interstitial pneumonias (IIPs) classification of 2013. Characteristic histologic features for LD-CTD (eg, prominent plasmacytic infiltration, lymphoid aggregates with germinal centers), high-resolution CT (HRCT) scan patterns, and prognosis were also assessed. RESULTS The major histologic patterns were usual interstitial pneumonia (UIP) in 25 patients and nonspecific interstitial pneumonia (NSIP) in 13 patients. Two or more characteristic histologic features for LD-CTD were observed in 15 patients with histologic UIP (h-UIP) and 11 patients with histologic NSIP (h-NSIP). Fifteen patients with h-UIP (60%) showed an inconsistent UIP pattern on HRCT scan. After multidisciplinary discussion (MDD), 18 patients with h-UIP were labeled as having unclassifiable IIP. The annual change in percent predicted FVC improved significantly in patients with h-NSIP (P = .002), who also had better survival than those with h-UIP (P = .031). In contrast, survival was not associated with HRCT scan pattern (P = .79). CONCLUSIONS The major histologic patterns in LD-CTD were UIP followed by NSIP. Two-thirds of patients had characteristic histologic features for LD-CTD. A majority of patients with h-UIP were considered to have unclassifiable IIP based on MDD. Patients with h-UIP had worse survival than those with h-NSIP.

Efficacy of Chemotherapy for Advanced Non-Small Cell Lung Cancer with Idiopathic Pulmonary Fibrosis

Background: Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonia and is associated with an independent increased risk of lung carcinogenesis. The benefit of chemotherapy for lung cancer in cases of IPF remains unknown. Objectives: This study was conducted to elucidate the efficacy of chemotherapy for advanced non-small cell lung cancer (NSCLC) in patients with IPF. Methods: Advanced (i.e. stage IIIB and IV) NSCLC patients with IPF who received systemic chemotherapy were studied. Response rate, toxicity, overall survival and progression-free survival were investigated. Results: Between January 2000 and December 2009, 21 patients were enrolled in this study and treated with chemotherapy. The overall response rate with the 1st regimen was 42.9%. The median overall survival was 11.4 months, the 1-year survival rate was 28.6% and the median PFS was 5.4 months. Conclusions: This study showed that advanced NSCLC patients with IPF may benefit from chemotherapy; well-controlled studies are still needed to clarify the efficacy.

Crizotinib-induced acute interstitial lung disease in a patient with EML4-ALK positive non-small cell lung cancer and chronic interstitial pneumonia

Shi L , Sun X , Zhang J , Zhao C , Li H , Liu Z , et al . Gab2 [1] expression in glioma and its implications for tumor invasion . Acta Oncol 2013 ; 52 : 1739 – 50 . Daly RJ , Binder MD , Sutherland RL . Overexpression of the [2] Grb2 gene in human breast cancer cell lines . Oncogene 1994 ; 9 : 2723 – 7 . Mendoza-Gamboa E , Siwak DR , Tari AM . The HER2/Grb2/ [3] Akt pathway regulates the DNA binding activity of AP-1 in breast cancer cells . Oncol Rep 2004 ; 12 : 903 – 8 . Dankort D , Maslikowski B , Warner N . Grb2 and Shc [4] adapter proteins play distinct roles in Neu (ErbB-2)-induced mammary tumorigenesis: Implications for human breast cancer . Mol Cell Biol 2001 ; 21 : 1540 – 51 . Lim SJ , Lopez-Berestein G , Hung MC , Lupu R , Tari AM . [5] Grb2 downregulation leads to Akt inactivation in heregulinstimulated and ErbB2-overexpressing breast cancer cells . Oncogene 2000 ; 19 : 6271 – 6 . Yip SS , Crew AJ , Gee JM . Up-regulation of the protein tyro[6] sine phosphatase SHP-1 in human breast cancer and correlation with GRB2 expression . Int J Cancer 2000 ; 88 : 363 – 8 . Zang XP , Siwak DR , Nguyen TX , Tari AM , Pento JT . [7] KGF-induced motility of breast cancer cells is dependent on Grb2 and Erk1,2 . Clin Exp Metastasis 2004 ; 21 : 437 – 43 . Xu XL , Wang X , Chen ZL . Overexpression of Grb2[8] associated binder 2 in human lung cancer . Int J Biol Sci 2011 ; 7 : 496 – 504 . Park D , Choi YB , Han MK , Kim UH , Shin J , Yun Y . Adaptor [9] protein Lad relays PDGF signal to Grb2 in lung cells: A tissue-specifi c PDGF signal transduction . Biochem Biophys Res Commun 2001 ; 284 : 275 – 81 . Yu GZ , Chen Y , Wang JJ . Overexpression of Grb2/HER2 [10] signaling in Chinese gastric cancer: Their rela tionship with clinicopathological parameters and prog nostic signifi cance . J Cancer Res Clin Oncol 2009 ; 135 : 1331 – 9 . mediates its modulatory role by accentuating Ets-2dependent transcription within the breast cancer cells [3]. In addition, it also increases activation of the Akt signaling pathway. Besides this, it may also up-regulate the activity of the protein tyrosine phosphatase SHP-1 [4]. Augmentation of the intratumoral levels of “ Grb2 and the hSos-1 Ras GDPGTP ” complexes is typically seen following up-regulation of Grb2 levels [5]. Grb2 along with Shc also has an activating impact on extracellular signal-regulated kinases within the breast tumor [6]. These changes have been confi rmed recently in MCF-7 breast cancer cell lines [7]. Similar up-regulation of Grb2 has been noted in pulmonary malignancies. For instance, only 12% of benign lung tissue stains positive for Grb2 in contrast to nearly 62% of all squamous cell lung carcinomas [8]. Interestingly, the PSGF signal to Grb2 is mediated by Lad and results in accentuated AP-1 activation within the tumor cells [9]. Similar accentuation of Grb2 expression is seen in gastrointestinal malignancies such as gastric carcinomas. For instance, up-regulated Grb2 levels are seen in nearly 48% of all gastric malignancies [10]. Malignant gastric tumors in the gastric cardia tend to express higher levels of Grb2. Also higher levels have been noted in gastric carcinoma patients over the age of 60 years. Not surprisingly, decreased overall survival is seen in patients with up-regulated Grb2 expression. The above examples clearly illustrate the signifi cant role of Grb2 in tumor progression in a number of systemic malignancies and the need for further large scale studies to fully explore and understand its role in tumor evolution and growth. 158 N. Watanabe et al.

Clinical Predictors of Response to EGFR Tyrosine Kinase Inhibitors in Patients with EGFR-Mutant Non-Small Cell Lung Cancer

Background: The presence of EGFR (epidermal growth factor receptor) mutations is a robust predictor of EGFR tyrosine kinase inhibitor (TKI) responsiveness. Predictors of EGFR-TKI responsiveness in EGFR-mutant non-small cell lung cancer (NSCLC) patients, however, have not been well investigated. The purpose of this study is to examine predictors of EGFR-TKI responsiveness in EGFR-mutant NSCLC patients. Patients and Methods: Seventy EGFR-mutant NSCLC patients who received EGFR-TKIs in our institution between April 2007 and March 2013 were analyzed retrospectively. Results: The objective response rate was 50.0% (95% confidence interval, CI, 38.6-61.4%) and the disease control rate was 91.4% (95% CI, 82.5-96.0%). The median progression-free survival (PFS) and overall survival were 9.0 (95% CI, 3.92-14.08) and 20.8 months (95% CI, 14.56-27.04), respectively. In multivariate analysis, adenocarcinoma (hazard ratio, HR, 12.25; 95% CI, 37.7-41.10; p < 0.001) and major mutations (deletions in exon 19 and L858R point mutation in exon 21; HR, 2.46; 95% CI, 1.14-5.28; p = 0.022) were significant predictors of longer PFS. Conclusion: Major mutations and adenocarcinoma histology were independent predictors of better treatment outcome in EGFR-mutant NSCLC patients who received EGFR-TKIs. Further well-controlled prospective studies are warranted to confirm our findings.

Efficacy of combined therapy with cyclosporin and low-dose prednisolone in interstitial pneumonia associated with connective tissue disease.

Background: The optimal treatment method for interstitial pneumonia (IP) with connective tissue disease (CTD) remains controversial. In addition, a clinically meaningful end point to judge drug efficacy has not been fully investigated. Objectives: The aim of this study was to evaluate, from various aspects, the therapeutic benefit and tolerability of combined therapy with cyclosporin A (CsA) and low-dose prednisolone (PSL) for chronic fibrosing CTD-IP patients. Methods: A total of 26 CTD-IP patients diagnosed by surgical lung biopsy and subsequently treated with the above combination therapy were retrospectively reviewed. The therapeutic regimen comprised methylprednisolone induction therapy for 2-4 weeks, followed by a combined therapy of CsA with low-dose PSL for 1 year. Evaluation of the therapeutic benefit was based on not only pulmonary function but also exercise capacity, health-related quality of life and dyspnea. Results: After 1 year of therapy, clinically significant improvements in forced vital capacity (≥10%), carbon monoxide diffusing capacity of the lung (≥15%), 6-min walk distance (≥28 m), and St. Georges Respiratory Questionnaire (≤-7) were observed in 61.5, 69.2, 61.5 and 69.2% of the patients, respectively. All measurements showed statistically significant improvements compared with baseline values. The 1-year treatment did not need to be discontinued in any patients due to unacceptable toxicity, and no deaths occurred. Conclusions: Combined therapy with CsA and low-dose PSL for CTD-IP patients was well-tolerated and patients displayed a noteworthy response.

Broader criteria of undifferentiated connective tissue disease in idiopathic interstitial pneumonias

BACKGROUND Kinder et al. proposed a broader definition of undifferentiated connective tissue disease (UCTD) and reported that the entity of nonspecific interstitial pneumonia (NSIP) is a lung manifestation of this more broadly defined UCTD. However, a retrospective study did not support their findings and its clinical significance remains unclear. METHODS We prospectively evaluated the significance of this broadly defined UCTD in idiopathic interstitial pneumonias (IIPs) in consecutive patients with surgical lung biopsy. Patients were evaluated with a symptoms check list and underwent comprehensive serologic testing as screening for UCTD. Clinical characteristics, high-resolution CT images, lung biopsy specimens, serial FVC change, and survival were analyzed. RESULTS Among 76 patients with IIPs, 24 patients (32%) fulfilled the UCTD criteria. Diagnosis of 24 patients with UCTD was usual interstitial pneumonia in 12 (50%), NSIP in 7 (29%), and unclassifiable interstitial lung disease (ILD) in 5 (21%). The diagnosis of 52 patients who did not have UCTD was idiopathic pulmonary fibrosis in 27 (52%), NSIP in 11 (21%), unclassifiable ILD in 13 (25%) and cryptogenic organizing pneumonia in 1 (2%). One-year and two-year FVC changes showed no significant difference between UCTD and non-UCTD, however, significant differences in FVC change were observed among histopathological diagnoses both in UCTD and in non-UCTD. In multivariate survival analysis, %FVC and histopathological UIP pattern were independent predictors for survival but UCTD diagnosis was not. CONCLUSIONS A diagnosis of UCTD was not useful in discriminating NSIP or in predicting disease progression and prognosis in our cohort of IIPs. Histopathological UIP pattern was an independent predictor for mortality irrespective of a diagnosis of UCTD.

Significance of pulmonary arterial pressure as a prognostic indicator in lung-dominant connective tissue disease.

Background Lung-dominant connective tissue disease (LD-CTD) is a new concept for classifying the subset of patients with interstitial pneumonia who have clinical features suggesting an associated CTD, but whose features fall short of a clear diagnosis of CTD under the current rheumatologic classification systems. The impact of mean pulmonary arterial pressure (MPAP) in LD-CTD has not been sufficiently elucidated. Objectives To evaluate the survival impact of MPAP measured during the initial evaluation in patients with LD-CTD. Methods We retrospectively analyzed the initial evaluation data of 100 LD-CTD patients undergoing pulmonary function test, 6-min walk test (6MWT), and right heart catheterization (RHC). Results The mean MPAP was 16.2±4.4 mm Hg, and 18 patients had MPAP≥20 mm Hg. A univariate Cox proportional hazard model showed that MPAP and several variables have a statistically significant impact on survival. With stepwise, multivariate Cox proportional analysis, MPAP (HR  = 1.293; 95% CI 1.130–1.480; p<0.001) and mean forced vital capacity (FVC) % predicted (HR = 0.958; 95% CI 0.930–0.986; p = 0.004) were shown to be independent determinants of survival. Conclusions Higher MPAP and lower %FVC at the initial evaluation were significant independent prognostic factors of LD-CTD. MPAP evaluation provides additional information of disease status and will help physicians to predict mortality in LD-CTD.

Prognosis in Patients with Non-Small Cell Lung Cancer Who Received Erlotinib Treatment and Subsequent Dose Reduction due to Skin Rash

Background: Severe skin rash as toxicity of erlotinib has been reported in relation to better response and survival. However, some patients require dose reduction due to skin toxicities, and their prognosis remains uncertain. We retrospectively evaluated the clinical course of non-small cell lung cancer patients receiving erlotinib at a reduced dose because of skin rash. Patients and Methods: Among 76 patients treated with erlotinib, 55 patients who developed skin rash severer than grade 2 were divided into 2 groups: 24 patients treated with erlotinib with dose reduction because of skin rash (dose reduction group) and 31 patients without any dose reduction (non-dose reduction group). Results: The median progression-free survival in the dose reduction and non-dose reduction groups was 341 and 70 days, respectively, and the median overall survival was 566 and 202 days, respectively (p < 0.001). In the dose reduction group, no smoking history, female sex, epidermal growth factor receptor gene mutation, and grade 3 skin rash were significant baseline factors. Conclusions: Patients who received erlotinib at a reduced dose following skin rash showed better survival than those without reduction. In cases of intolerable skin rash, patients may benefit from continuous treatment with a reduced dose of erlotinib.

Soluble thrombomodulin in bronchoalveolar lavage fluid is an independent predictor of severe drug‐induced lung injury

Drug‐induced lung injury (DLI) can result from a vast number of agents, and sometimes presents findings similar to those of acute respiratory distress syndrome (ARDS). Previous studies have reported that circulating levels of soluble thrombomodulin (TM) reflect endothelial injuries, which play key roles in the development of ARDS. We hypothesized that endothelial injuries are an important aspect of pathogenesis in severe DLI. The primary aim of this study was to examine the associations between soluble TM and disease severity in DLI patients.

Efficacy and Safety Data of Osimertinib in Elderly Patients with NSCLC Who Harbor the EGFR T790M Mutation After Failure of Initial EGFR-TKI Treatment

Background/Aim: The aim of this study was to evaluate the safety and efficacy of osimertinib for elderly patients, since the data remain limited. Patients and Methods: A total of 77 patients with advanced non-small cell lung cancer (NSCLC) harboring the epidermal growth factor receptor (EGFR) T790M mutation and treated with osimertinib were reviewed. Efficacy and safety indicators, such as EGFR-tyrosine kinase inhibitor (TKI)-related adverse events (AEs) and osimertinib-associated hematotoxicity, were evaluated in elderly patients (elderly group, EG; age, ≥75 years) by comparing them with younger patients (non-EG; aged <75 years). The frequency of AEs associated with osimertinib was compared with the initial EGFR-TKI treatment before osimertinib administration in the same patient cohort. Results: Of the total 77 patients, 18 (23%) were assigned to the EG, whereas 59 (77%) were assigned to the non-EG. There were no significant differences in overall response rate and progression-free survival between the two groups. Regarding the safety of osimertinib, the EG had significantly more grade ≥2 paronychia than the non-EG (16.6% vs. 1.6%, p=0.04). Additionally, the maximum grade of EGFR-TKI-related AEs associated with osimertinib in the EG was significantly lower than that of the initial EGFR-TKI treatment (p=0.03). Conclusion: Osimertinib is a safe and effective treatment option for elderly patients with advanced NSCLC who harbor the EGFR mutation.