Hironori Takagi

Efficacy and tolerability of nanoparticle albumin-bound paclitaxel in combination with carboplatin as a late-phase chemotherapy for recurrent and advanced non-small-cell lung cancer: A multi-center study of the Fukushima lung cancer association group of surgeons

The present retrospective multi-center study aimed to evaluate the efficacy and feasibility of nanoparticle albumin-bound (nab)-paclitaxel plus carboplatin as a second or late-phase chemotherapy in patients with non-small cell lung cancer (NSCLC). A total of 25 patients with recurrent or advanced NSCLC who had received previous chemotherapy were treated with nab-paclitaxel (70-100 mg/m2, intravenously) on days 1, 8 and 15 every 28 days with a carboplatin area under the concentration-time curve of 4-6 on day 1. The overall response rate, disease control rate, progression-free survival (PFS), overall survival (OS) and toxicities were statistically evaluated. Of the 25 patients, there were 9 cases of recurrent disease following surgery, 16 cases of advanced disease, 13 cases of adenocarcinoma, 11 cases of squamous cell carcinoma and 1 case of large cell carcinoma. A total of 13 patients received second-line chemotherapy and 12 received fourth-line or later chemotherapy. One patient exhibited a complete response, 7 had a partial response, 10 exhibited stable disease and 7 had progressive disease. The overall response rate was 32.0% and the disease control rate was 72.0%. The median PFS and median OS following nab-paclitaxel treatment were 4.0 and 14.0 months, respectively. Frequent treatment-associated adverse events were myelosuppression, peripheral neuropathy, gastrointestinal symptoms and baldness, the majority of which were grade 1-2. Grade 3-4 neutropenia, thrombocytopenia and anemia occurred in 7 (28.0%), 3 (12.0%) and 2 (8.0%) patients, respectively. No patients experienced grade 3-4 sensory neuropathy and no grade 5 adverse effects were observed. Nab-paclitaxel plus carboplatin as second-phase or later chemotherapy provided a small but significant survival benefit for patients with recurrent or advanced NSCLC, with tolerable adverse effects. To the best of our knowledge, the results of the present study demonstrated for the first time that nab-paclitaxel plus carboplatin is a promising and feasible late-phase chemotherapeutic agent for NSCLC.

Prognostic Impact of Tumor Mutation Burden in Patients with Completely Resected Non-Small Cell Lung Cancer: Brief Report

Introduction: Tumor mutation burden (TMB) is thought to be associated with the amount of neoantigen in the tumor and to have an important role in predicting the effect of immune checkpoint inhibitors. However, the relevance of TMB to prognosis is not yet fully understood. In this study, we investigated the clinical significance of TMB in patients with NSCLC and examined the relationship between TMB and prognosis. Methods: We calculated TMB within individual tumors by whole‐exome sequencing analysis using next‐generation sequencing. We included that there were 90 patients with NSCLC who underwent surgery in the Hospital of Fukushima Medical University from 2013 to 2016. No patients received chemotherapy or immunotherapy before surgery. We assessed the correlation between TMB and prognosis. Results: TMB greater than 62 was associated with worse overall survival (OS) of patients with NSCLC (hazard ratio [HR] = 6.633, p = 0.0003). Multivariate analysis showed poor prognosis with high TMB (HR = 12.31, p = 0.019). In patients with stage I NSCLC, higher TMB was associated with worse prognosis for both OS (HR = 7.582, p = 0.0018) and disease‐free survival (HR = 6.07, p = 0.0072). Conclusions: High TMB in NSCLC is a poor prognostic factor. If high TMB is a predictor of the efficacy of immune checkpoint inhibitors, postoperative adjuvant therapy with immune checkpoint inhibitors may contribute to improvement of recurrence and OS.

Comparison of surgical outcomes after pneumonectomy and pulmonary function-preserving surgery for non-small cell lung cancer

BACKGROUND According to previous reports, lobectomy with bronchoplasty or angioplasty is a more feasible surgery than pneumonectomy for central-type non-small cell lung cancer. However, few studies have compared both the short- and long-term outcomes between pneumonectomy and pulmonary function-preserving surgery. METHODS From January 2004 to December 2015, 18 patients underwent pneumonectomy (Group PN) and 12 patients underwent pulmonary function-preserving surgery (group PS) at Fukushima Medical University Hospital. Clinicopathological factors were statistically compared between the two groups. RESULTS The operation times in Group PN and Group PS were 285.9±27.9 and 271.3±99.2 min, respectively (p=0.613), while the amounts of intraoperative bleeding were 324.8±248.9 and 164.5±116.6 g, respectively (p=0.020). The duration of chest drainage and hospitalization after surgery in both groups were not significantly different but there was a tendency toward shorter periods of these durations in Group PS. The 5-year disease-free survival (DFS) rate in Group PN and PS was 51.4% and 74.1%, respectively, without a significant difference (p=0.298). The 5-year overall survival (OS) rate in Group PN and PS was 52.5% and 56.6%, respectively, also without a significant difference (p=0.748). The 5-year OS rate was inferior to the 5-year DFS rate in Group PS, and the 5-year OS rate was not better than the 5-year DFS rate in Group PN. CONCLUSIONS The short-term results were better in Group PS than PN. However, the long-term results in both groups were similar. Other causes of death influenced OS in both groups; this result might have been affected by the surgical procedures.

Family with sequence similarity 83, member B is a predictor of poor prognosis and a potential therapeutic target for lung adenocarcinoma expressing wild‑type epidermal growth factor receptor

Lung adenocarcinoma (ADC) patients with tumors that harbor no targetable driver gene mutation, such as epidermal growth factor receptor (EGFR) gene mutations, have unfavorable prognosis, and thus, novel therapeutic targets are required. Family with sequence similarity 83, member B (FAM83B) is a biomarker for squamous cell lung cancer. FAM83B has also recently been shown to serve an important role in the EGFR signaling pathway. In the present study, the molecular and clinical impact of FAM83B in lung ADC was investigated. Matched tumor and adjacent normal tissue samples were obtained from 216 patients who underwent complete lung resection for primary lung ADC and were examined for FAM83B expression using cDNA microarray analysis. The associations between FAM83B expression and clinicopathological parameters, including patient survival, were examined. FAM83B was highly expressed in tumors from males, smokers and in tumors with wild-type EGFR. Multivariate analyses further confirmed that wild-type EGFR tumors were significantly positively associated with FAM83B expression. In survival analysis, FAM83B expression was associated with poor outcomes in disease-free survival and overall survival, particularly when stratified against tumors with wild-type EGFR. Furthermore, FAM83B knockdown was performed to investigate its phenotypic effect on lung ADC cell lines. Gene silencing by FAM83B RNA interference induced growth suppression in the HLC-1 and H1975 lung ADC cell lines. FAM83B may be involved in lung ADC tumor proliferation and can be a predictor of poor survival. FAM83B is also a potential novel therapeutic target for ADC with wild-type EGFR.

Abstract 5307: Analysis of volatile organic compounds for the diagnosis of lung cancer

Background: Lung cancer is the leading cause of cancer-related deaths in the world. The prognosis of lung cancer depends on disease detection at an early stage. Recently, effectiveness of lung cancer screening by using low dose computed tomography scanning have been showing. However, it still has problems such as cost of screening and radiation exposure. Thus, less invasive and cost beneficial lung cancer screening procedure would be needed. In this context, several study to understand the efficacy of molecules from expiration of patients as a lung cancer screening were showing, but it was still controversial. In this study, we investigated to determine whether volatile organic compounds (VOC) from patients could be used for the detection for lung cancer by using novel small and unique absorbent material named MonoTrap . Method: The subjects’ gas was collected from skin and exhaled breath in a MonoTrap (GL sciences), and the VOCs were analyzed by gas chromatography/ mass spectrometry (GC/MS). First of all, we preliminary analyzed for both sample from skin and exhaled breath for 12 patients and 11 healthy volunteers to clarify which samples were more sensitive to diagnose lung cancer. Subsequently, each VOC was determined in detail for 7 healthy individuals and 4 lung cancer patients and these values were statistically analyzed. Results: By preliminary study, characteristics of VOC derived from skin were significantly correlated with cancer condition as compared with healthy volunteer by using comprehensive multivariate analysis. Therefore, we performed further quantitative analysis by targeting unique individual molecules derived from skin. In VOCs from skin, Mann-Whitney U test showed that 4-hydroxy-4-methyl-2-pentanone, hexadecane, and acetamide were significantly higher in lung cancer patients (p=0.036, p=0.006, p=0.036, respectively). Conclusion: In this study, we found that 3 kinds of VOCs could be a potential diagnostic biomarkers of lung cancer. Further prospective study is now planning to validate these data using large number samples. Citation Format: Takuya Inoue, Hironori Takagi, Yuki Owada, Yuzuru Watanabe, Mitsuro Fukuhara, Takumi Yamaura, Satoshi Muto, Naoyuki Okabe, Yuki Matsumura, Takeo Hasegawa, Takeda Manami, Atsushi Sato, Hiroyuki Suzuki. Analysis of volatile organic compounds for the diagnosis of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5307. doi:10.1158/1538-7445.AM2017-5307

Abstract 422: Functional analysis of family with sequence similarity 83, member B in lung adenocarcinoma

Background: We have reported the usefulness of Family with sequence similarity 83, member B (FAM83B) as a novel biomarker for diagnosis and prognosis of lung squamous cell carcinoma. FAM83B expresses not only in lung cancer but also in several types of solid cancer such as breast, esophageal, and so on. More recently, novel finding showing FAM83B involve to the resistance of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in breast cancer cell lines has been shown. EGFR signaling pathway also plays an important role in lung adenocarcinoma, therefore we hypothesize that FAM83B associates to the tumor proliferation in lung adenocarcinoma, and its results in the resistance to EGFR TKI and in a novel therapeutic target in lung adenocarcinoma. Materials and methods: Sixty-four paired tumor and corresponding normal tissue samples obtained from patients with lung adenocarcinoma who underwent surgical resection since 2008 to 2011 were subjected. FAM83B mRNA expression were examined and analyzed relationship between the level of FAM83B and clinicopathological variables. Then, FAM83B knock down study was performed in several types of cancer cell lines (PC-14, H820, H1650, H1975, HLC-1, H2347) to understand whether FAM83B involve to cell proliferation. Results: Multivariate analysis show that smaller cancer(≦3cm vs >3cm, p = 0.044), and wild type EGFR(wild type vs. mutant, p = 0.004) tend to express higher FAM83B mRNA. There is no significant difference between FAM83B expression and progression-free survival. FAM83B knock down results in suppression of proliferation in HLC-1, H1650, which express high level of FAM83B protein. Conclusions: FAM83B could involve to tumor proliferation of lung adenocarcinoma in part, and could be the novel therapeutic target. Citation Format: Takumi Yamaura, Naoyuki Okabe, Hironori Takagi, Yuki Owada, Takuya Inoue, Yuzuru Watanabe, Mitsuro Fukuhara, Satoshi Muto, Yuki Matsumura, Takeo Hasegawa, Atsushi Yonechi, Mika Hoshino, Jun Osugi, Yutaka Shio, Mitsunori Higuchi, Junji Ezaki, Satoshi Waguri, Mitsukazu Gotoh, Hiroyuki Suzuki. Functional analysis of family with sequence similarity 83, member B in lung adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 422.