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The presence of tertiary lymphoid structure (TLS) in tumor tissues has been reported to be a factor associated with a good prognosis in several types of cancers. However, the relationship between TLS formation and peripheral blood findings remains unclear. The purposes of the study were to evaluate the effect of the presence of TLS on survival and determine the peripheral blood characteristics associated with TLS formation in non-small cell lung cancer (NSCLC) patients. A total of 147 consecutive NSCLC patients who underwent lung resection at Fukushima Medical University Hospital between 2013 and 2017 were enrolled. TLS expression was evaluated, and the relationships between clinical parameters and outcomes were analyzed. Peripheral blood mononuclear cells (PBMCs) were further analyzed by mass cytometry to characterize the TLS-positive microenvironment. Forty-six patients had high TLS expression, and the remaining 101 patients had low TLS expression. In stage II to IV patients (n = 35), disease-free survival was longer in the high TLS expression group (p = 0.027). A low neutrophil to lymphocyte ratio (NLR)

Objectives Delta-like 1 homolog (DLK1) is a non-canonical Notch ligand known to be expressed in several cancers but whose role in lung cancer is not yet fully understood. We sought to confirm DLK1 expression in small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), and to examine DLK1’s clinical significance. Furthermore, we examined the possible utility of DLK1 as a novel target in radioimmunotherapy (RIT). Methods We retrospectively assessed the correlation between clinical features and DLK1 expression by immunohistochemistry in resected specimens from 112 patients with SCLC and 101 patients with NSCLC. Moreover, we performed cell and animal experiments, and examined the possibility of RIT targeting DLK1 in SCLC using iodine-125 (125I) -labeled anti-DLK1 antibody, knowing that 125I can be replaced with the alpha-particle-emitter astatine-211 (211At). Results In SCLC and NSCLC, 20.5 % (23/112) and 16.8 % (17/101) of patients (respectively) had DLK1-positive tumors. In NSCLC, DLK1 expression was associated with recurrence-free survival (P Conclusion A proportion of SCLC and NSCLC exhibits DLK1 expression. As a clinical feature, DLK1 expression could be a promising prognostic factor for recurrence in patients with resected NSCLC. In addition, DLK1 could serve as a new therapeutic target, including RIT, as suggested by our pilot study using a radiolabeled anti-DLK1 antibody in SCLC.

Background/aim Treatments containing ipilimumab have shown a good outcome in patients with non-small cell lung cancer (NSCLC) regardless of the PD-L1 tumor proportion score (TPS). However, the association between PD-L1 TPS and the expression of CTLA-4 in tumor-infiltrating lymphocytes is unknown. Patients and methods Fifty-five NSCLC patients who underwent surgery in our hospital were included in this study. We measured the proportions of CTLA-4+ regulatory T cells, and CTLA-4+ CD8 T cells, and statistically analyzed their correlations with the PD-L1 TPS. Results Statistical correlations were found neither between the proportion of CTLA-4+ regulatory T cells to CD8 T cells and the PD-L1 TPS (p=0.2859) nor between the proportion of CTLA-4+ cells in CD8 T cells and the PD-L1 TPS (p=0.1919). Conclusion The proportions of CTLA-4+ regulatory T cells to CD8 T cells and CTLA-4+ cells in CD8 T cells were irrelevant to the PD-L1 TPS in NSCLC patients.

β-catenin expression by tumor cells suppressed dendritic cell recruitment to the tumor microenvironment in a melanoma model, resulting in fewer tumor-infiltrating lymphocytes. Immunohistochemistry was used in the present study to examine the association between the expression of β-catenin and tumor infiltrating lymphocytes and CD11c+ cells in 122 patients with non-small cell lung cancer (NSCLC), who underwent radical surgery. β-catenin was positive in 24% of NSCLC tumors compared with 59% of squamous cell carcinomas and 11% of adenocarcinomas. There was no significant association between the expression of β-catenin and the frequency of CD8+ cell infiltration into tumor tissues, including the stroma. Conversely, the infiltration of CD8+ cells into tumor nests was significantly lower in β-catenin-positive cases compared with that in negative β-catenin cases. Similarly, CD11c+ cell infiltration was significantly lower in the β-catenin-positive group. The β-catenin-positive group had shorter overall survival and recurrence-free survival times compared with that in the negative group. Furthermore, β-catenin-positive NSCLC had a high tumor mutation burden, but tended to have a low expression of programmed death-ligand 1. In conclusion, the expression of β-catenin in NSCLC was negatively associated with CD11c+ cells and cytotoxic T cell infiltration at the tumor site and had a tendency towards a poor prognosis.

There have been many reports on the association between tumor infiltrating lymphocytes and cancer prognosis. It is known that tumor infiltrating lymphocytes contain not only cytotoxic T lymphocytes but also bystander lymphocytes and immunosuppressive cells. In most of previous reports, tumor infiltrating lymphocytes were defined as CD3 or CD8 T cells. It is generally thought that patients with cancer rich in tumor infiltrating lymphocytes have a good prognosis. Most tumor infiltrating lymphocytes are thought to be cytotoxic T lymphocytes. It is also reported that cancer rich in tumor infiltrating lymphocytes is responsive to immune checkpoint inhibitors. In recent years, several reports revealed clonal replacement in tumor infiltrating lymphocytes after administration of immune checkpoint inhibitors. This change was also detectable in peripheral blood. From the viewpoint of lung cancer treatment, combination of immune checkpoint inhibitors and chemotherapy became the standard therapy. We need to understand the tumor immune microenvironment in order to select the best treatment regimen for each patient. However, it is often difficult to obtain an adequate amount of tissue biopsy sample in standard of care. It is hoped that we can understand the tumor immune microenvironment using the peripheral blood. Thus, studying the association between treatment response, tumor infiltrating lymphocytes, and peripheral blood is considered to be important to research and develop peripheral blood biomarkers in lung cancer.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are an approved first-line therapy against unresectable or advanced non-small cell lung cancer (NSCLC) harboring EGFR gene activating mutations. However, the majority of tumors develop acquired resistance against EGFR-TKIs and some tumors exhibit natural resistance. A number of resistance mechanisms against the latest third-generation EGFR-TKIs have been reported, including tertiary EGFR C797S mutation and several gene alterations activating EGFR or other signaling pathways. The current study aimed to identify the frequency of natural EGFR-TKI resistance in pretreatment NSCLC and to predict the therapeutic effect of EGFR-TKIs. A total of 246 EGFR-TKI-naïve NSCLC patients harboring known EGFR gene mutations were identified. The presence of EGFR C797S and T790M mutations were determined using the peptide nucleic acid-locked nucleic acid PCR clamp method. ERBB2, MET, EGFR, ALK, BRAF, FGFR1, MYC, RET, CCND1, CCND2, CDK4, CDK6, MDM2 and MDM4 gene amplification, which can lead to resistance against any generation EGFR-TKIs, was determined using the multiplex ligation-dependent probe amplification assay. No concurrent C797S mutation with known EGFR mutations were identified. T790M mutation was identified in 12 patients (4.9%). ERBB2 or MET gene amplification was found in some patients (0.0–0.4%). MDM2 gene amplification was associated with tumor recurrence and shorter progression-free survival (PFS) for first- or second-generation EGFR-TKIs. De novo EGFR C797S mutation was not identified. Other resistance mechanisms against EGFR-TKIs were indicated in some patients with EGFR-TKI-naïve NSCLC. MDM2 gene amplification, which can lead to altered cell cycle, was associated with tumor recurrence and shorter PFS in EGFR-TKI therapy.

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.

Background Cisplatin is a key drug in lung cancer therapy. However, cisplatin is also well known to induce gastrointestinal disorders, such as chemotherapy-induced nausea and vomiting, anorexia, and weight loss. These symptoms sometimes affect patients’ quality of life and make continuation of chemotherapy difficult. Anorexia is a cause of concern for patients with cancer because a persistent loss of appetite progresses to cancer cachexia. Although evidence-based management for chemotherapy has recently been established, there is room for improvement. Methods/design This placebo-controlled, double-blind, randomized trial will aim to determine the efficacy of the traditional Japanese Kampo medicine rikkunshito (TJ-43) for preventing anorexia caused by cisplatin-including chemotherapy in patients with lung cancer. Patients with lung cancer who plan to receive cisplatin-including chemotherapy will be recruited. Patients who provide written consent will be randomly allocated to receive either TJ-43 (arm A) or placebo (arm B) for one course of chemotherapy (21 or 28 consecutive days). Investigators and patients will be masked to the treatment assignment throughout the trial. The primary endpoint will be evaluated as the change in dietary intake from day 0 (the day before the start of chemotherapy) to day 7 of cisplatin-including chemotherapy. The two arms of the trial will comprise 30 patients each. From November 2014, a total of 60 patients will be recruited, and recruitment for the study is planned to be complete by October 2017. Discussion This trial is designed to examine the efficacy of rikkunshito (TJ-43) for reducing anorexia and maintaining food intake caused by cisplatin-including chemotherapy in patients with lung cancer. Trial registration Japan Pharmaceutical Information Center Clinical Trials Information (JAPIC CTI), trial registration: JAPIC CTI-142747. Registered on 15 December 2014; the RICH trial. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2227-6) contains supplementary material, which is available to authorized users.

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.

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.

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.

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 (P10% 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.

Therapeutic cancer peptide vaccination is an immunotherapy designed to elicit cytotoxic T-lymphocyte (CTL) responses in patients. A number of therapeutic vaccination trials have been performed, nevertheless there are only a few reports that have analyzed the T-cell receptors (TCRs) expressed on tumor antigen-specific CTLs. Here, we use next-generation sequencing (NGS) to analyze TCRs of vaccine-induced CTL clones and the TCR repertoire of bulk T cells in peripheral blood mononuclear cells (PBMCs) from two lung cancer patients over the course of long-term vaccine therapy. In both patients, vaccination with two epitope peptides derived from cancer/testis antigens (upregulated lung cancer 10 (URLC10) and cell division associated 1 (CDCA1)) induced specific CTLs expressing various TCRs. All URLC10-specific CTL clones tested showed Ca2+ influx, IFN-γ production, and cytotoxicity when co-cultured with URLC10-pulsed tumor cells. Moreover, in CTL clones that were not stained with the URLC10/MHC-multimer, the CD3 ζ chain was not phosphorylated. NGS of the TCR repertoire of bulk PBMCs demonstrated that the frequency of vaccine peptide-specific CTL clones was near the minimum detectable threshold level. These results demonstrate that vaccination induces antigen-specific CTLs expressing various TCRs at different time points in cancer patients, and that some CTL clones are maintained in PBMCs during long-term treatment, including some with TCRs that do not bind peptide/MHC-multimer.

Background/aim Reportedly, hypertension tends to be associated with response to bevacizumab therapy, because bevacizumab suppresses vascular nitric oxide production. In this study we examined the predictive value of nitric oxide in bevacizumab-treated non-small cell lung cancer (NSCLC) patients. Patients and methods Fifteen patients with advanced or recurrent NSCLC treated with bevacizumab-based regimens were evaluated retrospectively. Serum NOx (NO2-/NO3-) was assayed by the Griess method. Results Serum nitric oxide levels were decreased after two courses of bevacizumab treatment in our responder group (p=0.02). According to the change in nitric oxide levels after the second course of treatment, median progression-free survival was 11.0 months in the group with decreased serum nitric oxide and 7.6 months in the group with increased serum nitric oxide (p=0.08). Conclusion Serum nitric oxide levels could be a predictive biomarker for response to bevacizumab in NSCLC patients.

Several types of immunosuppressive mechanisms in cancer patients have been reported to date. Regulatory T cells (Tregs), which express the master control transcription factor forkhead box P3 (FoxP3), are considered to play a major role in hampering antitumor immune response. However, the clinical significance of Tregs in patients with lung cancer has not been fully elucidated. The aim of this study was to investigate the clinical significance of Tregs in the peripheral blood and in resected cancer tissue specimens. We analyzed peripheral blood mononuclear cells (PBMCs) collected prior to surgery and resected specimens obtained from 67 patients with non-small-cell lung cancer (NSCLC). Peripheral Tregs (pTregs) were detected as CD4+ and FoxP3+ cells by flow cytometry. Immunohistochemical staining for CD4, CD8 and FoxP3 expression was also performed quantitatively by analyzing three randomly selected fields from central regions (cCD4, cCD8 and cFoxP3) and interstitial regions of the tumors (iCD4, iCD8 and iFoxP3). The associations between the expression frequencies in selected cells and clinicopathological parameters were statistically analyzed. The frequency of pTregs was found to be significantly higher in patients with pleural invasion (P=0.0049), vessel invasion (P=0.0009), lymphatic vessel invasion (P=0.0053) and recurrent disease (P=0.0112). Patients with T1 exhibited a significantly higher frequency of cCD4 (P=0.0199) and cCD8 (P=0.0058), although cFoxP3 expression was not significant (P=0.0935). Patients with low levels of cFoxP3/iFoxP3 exhibited a significantly higher frequency of pTregs (P=0.0338) and patients with a high frequency of pTregs exhibited significantly poorer recurrence-free survival (P=0.0071). The multivariate analysis identified pTreg frequency as an independent prognostic factor (P=0.0458). Although the pathological analysis remains controversial, the frequency of pTregs in NSCLC patients may be a useful prognostic biomarker.

Purpose This retrospective study evaluated whether the maximum standardized uptake value (SUVmax) on 18F-deoxyglucose (FDG)-positron emission tomography (PET) could be used to predict the prognosis of patients with pathological stage I adenocarcinoma. Methods We analyzed 138 consecutive patients with pathological stage IA or IB lung adenocarcinoma except pure bronchioloalveolar carcinoma (BAC) who underwent preoperative FDG-PET imaging and curative resection from January 2005 to October 2010. We analyzed associations between disease-free survival (DFS) and clinicopathological factors. Results The 5-year DFS rate was 77.7%. Twenty two patients (15.9%) developed recurrence after surgery. Multivariate analysis identified SUVmax and lymphovascular (ly) involvement as the independent prognostic factors for recurrence (p = 0.0255 and p = 0.0333, respectively). We divided the patients into groups according to SUVmax and ly involvement. The 5-year DFS rate was 97.0% in patients with SUVmax ≤2.5 and without ly involvement, 100% with both SUVmax ≤2.5 and ly involvement, 70.2% with SUVmax >2.5 and without ly involvement, and 53.1% with both SUVmax >2.5 and ly involvement. Conclusions The results of this study suggest that SUVmax and ly involvement could be used to predict the prognosis of patients with pathological stage I adenocarcinoma. The combination of these prognostic factors could also identify high risk groups of recurrence.

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

症例は80歳，男性．2003年9月に左肺原発の腺扁平上皮癌の診断にて左下葉切除術を施行した（p-stage IB）．2004年10月の胸部CTにて右S2およびS6に結節影を認め，増大傾向にあった．FDG-PETにて病変部に集積を認め再発肺癌と診断した．他病変を認めなかったが，高齢，低肺機能であったため，肺野の2病変に対し2期的に経皮的ラジオ波焼灼術（radiofrequency ablation: RFA）を施行した．術後のCTでは，2病変とも空洞を伴う腫瘤影が残存し治療効果判定が困難であったが，FDG-PETを再検したところ2病変ともFDGの集積は消失しており，腫瘍細胞のviabilityの消失が示された．現在，新たな病変の出現なく経過観察中である．今後，経時的な変化を観察していく必要があるが，RFAは低侵襲で比較的安全に施行可能であり，再発症例を含む手術不能肺癌症例に対する有効な局所療法となることが期待される．また，本例では治療効果判定にFDG-PETは有用であると考えられた．

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

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

症例は７７歳，男性．風邪様症状あり近医受診．縦隔腫瘍を指摘され当院紹介となった．CT下針生検を施行し，胸腺カルチノイドと診断した．術前施行したFDG-PETにて局所に一致したFDGの集積を認めた．他に集積はなかった．腫瘍および胸腺摘出術を施行した．病理診断は非定型的カルチノイドであり，術前診断通りリンパ節転移は認めなかった．術後放射線治療を追加し，現在無再発生存中である．胸腺カルチノイドは，内分泌細胞群から発生する腫瘍と定義され，胸腺腫とは異なる疾患概念であり，発生頻度も比較的稀である．FDG-PETは，肺癌を中心に汎用されているが，胸腺カルチノイドに対しFDG-PETを行った報告はほとんどない．今後，悪性腫瘍である胸腺カルチノイドに対する局在診断や病期診断におけるFDG-PETの有用性が期待される．

e23136 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. More recently, novel finding showing FAM83B involve to tumor growth, oncogenesis, and 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 with tumor proliferation in lung adenocarcinoma (ADC), results in resistance to EGFR-TKI and in a novel therapeutic target in a part of lung ADC. Here we show that correlation between FAM83B expression and clinicopathological features. Methods: This study was conducted with approval of ethics committee in our institute, and informed consent was obtained from all the participants. We identified 216 participants underwent for primary lung ADC between 2008 and 2015. Paired tumor and corresponding normal tissue samples obtained from patients were subjected. FAM83B mRNA expression were examined by cDNA microarray, and analyzed relationship between the level of FAM83B and clinicopathological variables including survival analysis. Further, FAM83B knock down study was performed in several types of cancer cell lines (H1975, HLC-1, H2347) to validate whether FAM83B involve to cell proliferation. Results: FAM83B highly expressed in male (p = 0.007), or smoker (p = 0.007), or EGFR wild type tumor (p

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.

Several types of immunosuppressive mechanisms in cancer patients have been reported to date. Regulatory T cells (Tregs), which express the master control transcription factor forkhead box P3 (FoxP3), are considered to play a major role in hampering antitumor immune response. However, the clinical significance of Tregs in patients with lung cancer has not been fully elucidated. The aim of this study was to investigate the clinical significance of Tregs in the peripheral blood and in resected cancer tissue specimens. We analyzed peripheral blood mononuclear cells (PBMCs) collected prior to surgery and resected specimens obtained from 67 patients with non-small-cell lung cancer (NSCLC). Peripheral Tregs (pTregs) were detected as CD4+ and FoxP3+ cells by flow cytometry. Immunohistochemical staining for CD4, CD8 and FoxP3 expression was also performed quantitatively by analyzing three randomly selected fields from central regions (cCD4, cCD8 and cFoxP3) and interstitial regions of the tumors (iCD4, iCD8 and iFoxP3). The associations between the expression frequencies in selected cells and clinicopathological parameters were statistically analyzed. The frequency of pTregs was found to be significantly higher in patients with pleural invasion (P=0.0049), vessel invasion (P=0.0009), lymphatic vessel invasion (P=0.0053) and recurrent disease (P=0.0112). Patients with T1 exhibited a significantly higher frequency of cCD4 (P=0.0199) and cCD8 (P=0.0058), although cFoxP3 expression was not significant (P=0.0935). Patients with low levels of cFoxP3/iFoxP3 exhibited a significantly higher frequency of pTregs (P=0.0338) and patients with a high frequency of pTregs exhibited significantly poorer recurrence-free survival (P=0.0071). The multivariate analysis identified pTreg frequency as an independent prognostic factor (P=0.0458). Although the pathological analysis remains controversial, the frequency of pTregs in NSCLC patients may be a useful prognostic biomarker.

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.

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Introduction Foxp3+ regulatory T cells (Tregs) have been thought to have at least two subsets: natural Tregs (nTregs) and induced Tregs (iTregs). Recently, expression of the transcription factor Helios, a member of the Ikaros gene family, has been expected to be a molecular marker of nTregs, but this is still controversial. To date, several in vitro studies and animal model studies regarding Helios have been reported, but there has been no examination of the clinical impact of Helios expression on Tregs in patients with lung cancer to date. Methods A total of 45 non-small cell lung cancer (NSCLC) patients who underwent surgical resection and 19 advanced/recurrent NSCLC patients was evaluated. Peripheral blood mononuclear cells (PBMCs) taken from these patients were examined by flow-cytometry. Of these 45 patients, 18 who were evaluable for tumor tissue underwent immunohistochemical investigation for tumor-infiltrating lymphocytes. Results Helios-negative Tregs of CD4+ T cells were significantly higher not only in all cancer patients (2.4%), but also in stage IA patients (2.6%) as compared with normal controls (1.5%, p