Jun Osugi

FAM83B is a novel biomarker for diagnosis and prognosis of lung squamous cell carcinoma

Personalized therapy for non-small cell lung cancer (NSCLC), particularly lung adenocarcinoma, has recently been significantly improved by the discovery of various molecular targets. However, this has not been the case for lung squamous cell carcinoma (SCC). In the present study, we identified the family with sequence similarity 83, member B (FAM83B) as a candidate marker for SCC through a comprehensive gene expression analysis and examined its correlations with various clinicopathological factors. The subjects of this study consisted of 215 patients with NSCLC who underwent complete resection from 2005 to 2011 at the Fukushima Medical University Hospital (Fukushima, Japan). They included 102 patients with adenocarcinoma and 113 with SCC. FAM83B expression was first examined in some of the samples by gene expression analysis and western blotting, and then all clinical specimens were evaluated by immunohistochemistry (IHC). The relationship between the quantitative values for IHC and clinicopathological factors was statistically analyzed. The results showed that FAM83B mRNA expression was significantly higher in SCC than in normal lung or adenocarcinoma (P<0.0001). Immunoblot analysis also confirmed this trend. Specimens containing >10% positive area for FAM83B were judged as ‘positive’; 94.3% (107/113) of SCC and 14.7% (15/102) of adenocarcinoma were positive. Patients were divided into two subgroups according to expression (54 high-expression and 53 low-expression patients); the high-expression group was associated with a better disease-free survival (DFS) rate (P=0.042, log-rank test). In conclusion, FAM83B may be a reliable diagnostic and prognostic biomarker for SCC. Detailed analyses of FAM83B function in lung cancer are required to understand how its expression is associated with better prognosis in SCC.

Prognostic Impact of Hypoxia-Inducible miRNA-210 in Patients with Lung Adenocarcinoma

Objective. The aim of this study was to investigate the prognostic value of MicroRNA-210 (miR-210) expression in patients with non-small-cell lung cancer (NSCLC). Methods. We examined the miR-210 expression of samples of 80 patients, who underwent surgical resection at Fukushima Medical University from 2004 to 2007, by using quantitative RT-PCR. The relationship between miR-210 expression and clinicopathological factors as well as histological subtype was statistically analyzed. Results. miR-210 expression showed an inverse correlation with disease-free and overall survival in patients with NSCLC. Significant correlations were found between miR-210 expression and lymph node metastasis, late disease stages, and poor prognosis in patients with adenocarcinoma. Multivariate Cox analysis indicated that miR-210 expression was an independent prognostic factor for disease-free survival in patients with adenocarcinoma. Conclusions. We showed that miR-210 may be a prognostic biomarker for patients with NSCLC, especially for those with lung adenocarcinoma.

Prognostic impact of the combination of glucose transporter 1 and ATP citrate lyase in node-negative patients with non-small lung cancer

OBJECTIVE Metabolic alternations are deemed a hallmark of cancer cells. Among many metabolic pathways, glycolysis and lipogenesis are essential metabolic processes in cancer cells. In this study, we examined the prognostic impact of the combined expression of glycolysis-related glucose transporter 1 (GLUT1) and ATP-citrate lyase (ACLY), which are important molecules in lipogenesis, in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS GLUT1 and ACLY expression in 134 NSCLC specimens were determined by immunohistochemistry using a tissue microarray (TMA). We examined the overall survival of patients with GLUT1-, ACLY- or GLUT+ACLY-positive expression using Kaplan-Meier analysis. We analyzed the prognostic impact of combined GLUT1 and ACLY expression according to lymph node status using multivariate Cox analysis. RESULTS Patients with GLUT1- or ACLY-positive expression exhibited poorer overall survival compared with GLUT1- or ACLY-negative patients. GLUT1-positive/ACLY-positive expression status was associated with the worst overall survival, in contrast with GLUT1 negative/ACLY-negative expression status, which was correlated with the best overall survival (P=0.003). GLUT1-positive/ACLY-positive expression was significantly correlated with poor prognosis in node-negative but not in node-positive patients. Multivariate Cox analysis indicated combined expression of GLUT1 and ACLY was an independent prognostic factor for overall survival in node-negative patients with NSCLC (P=0.049). CONCLUSION These results suggest that the combined expression of GLUT1 and ACLY could be a more valuable prognostic factor than their individual expression in node-negative patients with NSCLC.

Prognostic impact of the high-sensitivity modified Glasgow prognostic score in patients with resectable non-small cell lung cancer

OBJECTIVE The present study compared the prognostic value of the Glasgow prognostic score (GPS), modified GPS (mGPS), high-sensitivity mGPS (HS-mGPS), neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), prognostic index (PI), and prognostic nutritional index (PNI) in patients with resectable non-small cell lung cancer (NSCLC). MATERIALS AND METHODS This retrospective study included 327 consecutive patients with resectable NSCLC with a follow.-up period. >5. years. Initially, the HS-mGPS was directly compared with the GPS and mGPS in terms of their ability to predict survival in patients with resectable NSCLC. Second, inflammation.-based scores, including the HS-mGPS, NLR, PLR, PI, and PNI, were analyzed preoperatively using multivariate Cox analysis. Clinical characteristics reflecting cancer progression were also analyzed. RESULTS Elevated GPS (P < 0.001), mGPS (P < 0.001), and HS-mGPS (P < 0.001) levels were associated with reduced overall survival. The HS-mGPS (P < 0.001) was superior to the GPS and mGPS (P = 0.884) as a prognostic marker of postoperative outcomes. On multivariate Cox analysis, age (P = 0.026), p-T status (P < 0.001), p-N status (P < 0.001), lymphatic vessel invasion (P = 0.008), and the HS-mGPS (P = 0.016) were independent prognostic factors for survival. CONCLUSION These results suggest that the HS-mGPS might have a greater prognostic impact than the GPS, mGPS, NLR, PLR, PI, or PNI in patients with resectable NSCLC.

Clinical significance of expanded Foxp3+ Helios- regulatory T cells in patients with non-small cell lung cancer

The functions of different regulatory T cell (Treg) types in cancer progression are unclear. Recently, expression of the transcription factor Helios was proposed as a marker for natural (non-induced) Tregs. The present study investigated the clinical significance of Helios expression in patients with non-small cell lung cancer (NSCLC). We enrolled 64 patients with NSCLC, of whom 45 were treated surgically and 19 received chemotherapy because of advanced/recurrent disease. Their peripheral blood mononuclear cells were examined by flow cytometry. From the 45 surgery patients, we matched 9 patients with recurrent disease with 9 stage-matched patients without recurrence (n=18), compared their specimens immunohistochemically for tumor infiltrating lymphocytes (TILs) and analyzed these data against clinicopathological factors. Helios expression in Foxp3+ Tregs was 47.5±13.3% in peripheral blood and 18.1±13.4% in tumor specimens. Percentage of Helios− Tregs among CD4+ T cells were significantly higher in the cancer patients (2.4%), especially those with stage IA disease (2.6%) than in healthy donors (1.5%; P<0.001). Patients with low levels of Helios expression in Tregs among their TILs had significantly poorer survival (P=0.038). Helios− Tregs may affect immune suppression, even in early stage NSCLC; they could also be a useful prognostic biomarker in patients with NSCLC, and possibly a novel cancer immunotherapy target.

Epidermal growth factor receptor gene mutation as risk factor for recurrence in patients with surgically resected lung adenocarcinoma: a matched-pair analysis

OBJECTIVES Epidermal growth factor receptor (EGFR) mutation is a robust prognostic factor in patients with lung adenocarcinoma (ADC). However, the role of EGFR mutation status as a recurrence-risk factor remains unknown because the presence of such mutations is associated with other background characteristics. We therefore conducted a matched-pair analysis to compare recurrence-free survival (RFS) in matched cohorts of patients with lung ADC. METHODS We enrolled 379 patients who underwent surgical resection for lung ADC between 2005 and 2012. We determined the EGFR mutation status of each tumour. Matching their age, gender, smoking history and pathological stage (pStage), we compared RFS between matched cohorts with and without EGFR mutation (n = 86 each). RESULTS The median age was 67 years, there were 39 (45%) men, 39 (45%) ex- or current smokers and pStage I: 71 (83%), II: 5 (6%), III: 8 (9%), IV: 2 (2%) in each group. The 3- and 5-year RFS rates in patients with mutant and wild-type EGFR were 85 and 78%, and 74 and 60%, respectively, with significant differences between the groups (P = 0.040). Multivariate analysis identified vascular invasion and lymphatic permeation, but not EGFR mutation status, as independent risk factors for recurrence. CONCLUSIONS EGFR-gene mutation might be a favourable recurrence-risk factor in patients with surgically resected lung ADC, but further studies in larger cohorts are needed to verify this hypothesis.

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.

Epidermal growth factor receptor mutation status is strongly associated with smoking status in patients undergoing surgical resection for lung adenocarcinoma

OBJECTIVES The purpose of this analysis was to examine the relationship between epidermal growth factor receptor (EGFR) mutation status and clinicopathological factors in a cohort of patients who underwent surgical resections for lung adenocarcinoma. METHODS From the patients who underwent surgical resections for primary lung cancers between 2005 and 2012, 371 consecutive adenocarcinoma patients were enrolled in this study, and their tumours were analysed for EGFR mutations. We examined the clinicopathological factors of all enrolled patients, including age, sex, pathological stage and smoking status and tested for associations with EGFR mutation status. RESULTS Among the 371 enrolled patients, 195 (52%) patients had EGFR mutations. There were significantly more women, never smokers and tumours of lower grade histology in the EGFR mutation group than in the wild-type group (P < 0.001 each). However, other factors, such as pathological stage and World Health Organization classification, were not significantly associated with mutation status. Multivariable analysis showed that age, smoking history and histological grade were independently associated with EGFR mutations (P = 0.026, P < 0.001 and P < 0.001, respectively), but sex was not. Regarding smoking status, especially, frequency of EGFR mutation decreased, as smoking index increased. On the other hand, sex and smoking cessation (whether the patients were former or current smokers) were not significantly associated with EGFR mutation status. CONCLUSIONS In our cohort of patients who underwent surgical resection for lung adenocarcinoma, EGFR mutation status was strongly associated with smoking status, especially smoking index.

Successful Management of Crizotinib-Induced Neutropenia in a Patient with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Case Report.

Crizotinib, the first clinically available inhibitor of anaplastic lymphoma kinase (ALK) gene rearrangement, is generally well tolerated. In contrast, neutropenia induced by crizotinib is a commonly reported grade 3 or 4 adverse event. In such cases, interruption and dose reduction of crizotinib might be necessary for some patients with severe neutropenia. However, information concerning clinical experience and management of severe neutropenia is currently limited. In this report, the successful management of crizotinib-induced neutropenia by dose reduction of crizotinib in a patient with ALK-positive non-small cell lung cancer is described.

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.