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Expression of the transcription factor FOXP3 characterizes regulatory T cells (Tregs) that engage in the maintenance of immunological self-tolerance and immune homeostasis. Intra-tumoral accumulation of Tregs is associated with unfavorable prognosis in several kinds of cancers. Recently, expression of FOXP3 and its association with prognosis have also been shown in some cancer cells in clinical studies. For non-small cell lung cancer (NSCLC), however, prognostic significance of tumor FOXP3 expression and its relationship with Tregs remain unknown. FOXP3 expression in cancer cells and tumor-infiltrating lymphocytes was examined by immunohistochemical staining of surgical specimens from 87 patients with NSCLC. Prognostic values of the tumor-infiltrating Treg count and tumor FOXP3 expression status were evaluated retrospectively. FOXP3-positive cancer cells were observed in 27 of 87 (31.0%) patients. There was no significant relationship between Treg count and tumor FOXP3 status. Increased Treg counts were associated with worse overall and relapse-free survival whereas the influence of tumor FOXP3 status on survival was not significant. However, when FOXP3-positive cancer cells were present, the relationship between Treg accumulation and worse prognosis was attenuated. In contrast, patients without tumor FOXP3 expression and high Treg count had significantly worse overall and relapse-free survival (hazard ratio: 3.118 and 3.325, p=0.028 and 0.024, respectively) than other groups. These results suggest that tumor FOXP3 expression has a better prognostic potential in NSCLC and that in combination with tumor-infiltrating Treg count the absence of tumor FOXP3 allows the selection of high-risk patients.

The aim of this study is to clarify the difference of F-18 FDG uptake kinetics between FDG-avid non-small-cell lung cancer (NSCLC) and benign lesions associated with various etiologies on dual-time point PET/CT scan, and to determine the optimal parameter for differentiation.The materials were 76 FDG-avid solitary NSCLC in 76 patients and 57 FDG-avid solitary benign lesions associated with various etiologies in 61 patients. FDG PET/CT scan was performed at 60 and 120 min after intravenous injection of 4.4 MBq/kg F-18 FDG. The maximum standardized uptake value (SUVmax) on early and delayed scans and the percent change of SUVmax (%DeltaSUVmax) between the two time points were measured. The optimal differential parameter was determined by receiver-operating characteristic curve analysis and evaluation of diagnostic accuracy.The mean +/- SD of early SUV max, delayed SUVmax and %DeltaSUVmax were 8.3 +/- 5.2, and 10.2 +/- 6.5, and 21.9% +/- 18.9 in FDG-avid NSCLC, and 3.8 +/- 3.2, 4.0 +/- 3.7, and 11.3% +/- 26.0 in FDG-avid benign lesions, respectively. Delayed SUVmax in NSCLC was significantly higher than early SUVmax (P0.0001); while not different in benign lesions. Percent change of SUVmax in NSCLC was also significantly higher than that in benign lesions (P0.01). The optimal parameter for the differentiation was delayed SUVmax5.5 and yielded sensitivity of 77.6%, specificity of 80.7% and accuracy of 78.9%, which provided better differentiation than the use of %DeltaSUVmax or the traditional parameter of early SUVmax2.5. However, 11 (19.2%) benign lesions were indistinguishable from NSCLC.Although delayed PET/CT scan enhances the difference of FDG uptake between FDG-avid NSCLC and benign lesions, and the use of delayed SUVmax5.5 appears to improve the differentiation of these hypermetabolic lesions compared with an early scan, careful interpretation and management for correct differentiation are still required.

Chlamydiae are obligate intracellular bacteria, causing a variety of diseases, i.e. pneumonia, sexually transmitted disease, conjunctivitis and zoonosis. Tryptophan depletion by interferon-gamma (IFN-gamma) is the most important host defence system against chlamydial infection. Thus chlamydial tryptophan metabolism is thought to play key roles for IFN-gamma resistance, persistent infection and host/tissue tropisms. We tested tryptophan derivatives for activity against chlamydia-infected cells.Rates of chlamydial infection and sizes of the inclusions were evaluated by in vitro infection using three Chlamydiaceae species, Chlamydia trachomatis, Chlamydophila pneumoniae and Chlamydophila felis, which show significant divergence of tryptophan synthesis genes and different susceptibilities to IFN-gamma.Melatonin and serotonin, which are recognized as neural hormones for maintenance of organism homeostasis, reduced chlamydial infection but not other bacterial growth tested here. Unlike IFN-gamma, melatonin limited infection of all three chlamydiae and the effects were not recovered by tryptophan supplementation. Melatonin treatment only of host cells could diminish infection and the infection reduction was neutralized by a pertussis toxin, an inhibitor of G proteins. Ligands of melatonin and serotonin receptors also hampered infection.Inhibition mechanisms of chlamydial infection by melatonin and serotonin appear to be different from those of IFN-gamma and involve specific G-protein-coupled receptors. Melatonin is deemed to inhibit early progression of the chlamydial development cycle, such as establishment of intracellular infection and/or conversion from elementary body to reticulate body. Utilization of melatonin, serotonin or their derivatives may be advantageous for harmless prevention of chlamydial infection.

Chest radiography in a 59-year-old woman with recurrent pneumonia showed infiltrates in her left upper lung field. Fiberoptic bronchoscopy and chest computed tomography revealed severe constriction in the upper bronchus and a nodule in the left upper lobe. After lobectomy, adenocarcinoma was confirmed, with multiple non-caseating granulomas in the lung parenchyma and lymph nodes. Bronchial constriction was thought to be due to a sarcoid-like reaction secondary to lung cancer, leading to granuloma formation.

e17517 Background: Survival benefits of induction therapy followed by surgery for advanced non-small cell lung cancer (NSCLC) have been shown. Anti-cancer agents are suggested to mediate cytotoxic effect not only directly on tumor cells but also through the immune system. We investigated the relationship between the status of T-cell differentiation in tumor stroma and pathologic responses to induction therapy in patients with advanced NSCLC. Methods: A total of 69 patients with c-stage IIA to IIIB NSCLC who underwent induction therapy followed by R0 surgery between January 2002 and July 2011 were enrolled. Tumor-infiltrating T cells expressing CD8 or FOXP3 were detected by immunohistochemical staining from biopsy and surgically removed specimens using anti-CD8 antibody and anti-FOXP3 antibody. Staining-positive T cells were counted in 10 fields at 200× magnification of digital images, and then FOXP3+/CD8+ T cell ratio was determined based on the average counts. Results: The mean values of FOXP3+/CD8+ T cell ratio in operative specimens were 1.11 for the patients with pathological no change (p-NC), 0.32 for those with pathological partial response (p-PR), and 0.21 for those with pathological complete response (p-CR) (p = 0.002). There was no association of FOXP3+/CD8+ T cell ratio with gender, histologic types of tumor, or clinical stages. Patients with p-CR showed better relapse-free survival, though statistically no-significant (p = 0.323). Pre-treatment TBLB specimens were available in 12 patients (3 p-NCs, 7 p-PRs, and 2 p-CRs). FOXP3+/CD8+ T cell ratios in operative specimens after induction therapies were elevated compared with that of biopsy specimens in p-NC patients (p = 0.105), whereas the ratios were decreased in p-PR and p-CR patients (p = 0.021). Conclusions: The status of tumor-infiltrating T cell differentiation indicated by FOXP3+/CD8+ T cell ratio was correlated with pathologic response in patients treated with induction therapy followed by surgery for NSCLC. FOXP3+/CD8+ T cell ratio can be a marker for effectiveness of induction treatment.

10040 Background: Malignant mesothelioma is a highly aggressive tumor arising from serosal membranes, most commonly the pleura. Worldwide incidence is increasing because of widespread exposure to asbestos, the major causal agent. Incidence of this disease also is increasing dramatically in Japan. Association of simian virus 40 (SV40) with malignant mesothelioma has been reported, suggesting that SV40 plays an important role in the origin of a subset of these tumors. Most recently, evidence against any role for SV40 in this disease has been also reported. The role of SV40 in malignant mesothelioma remains still controversial. In addition, it has been argued that differences in the reported frequency of SV40 detection in malignant mesothelioma may be related to geographic variation in populations exposed to the virus. Whether SV40 is associated with malignant mesothelioma in Japan therefore is an important issue. However, no study concerning SV40 in malignant mesothelioma has been reported from Japan. Methods: To address this, we studied 35 malignant mesotheliomas including 32 men and 3 women with a median age of 61 years (ranges 34 to 85) and examined the presence of SV40 large T antigen DNA with real time PCR based on TaqMan technology using primers that PCR amplified a specific 156-bp region of the large Tag of SV40 as well as its expression with immnohistological methods using anti-SV40 large T antigen antibody (pAb101, Santa Cruz Biotechnology, Inc., CA). Results: Two of 35 mesotheliomas were considered positive for the presence of SV40 large T antigen DNA, showing ratios of 36.0 and 4.9. The ratio in the positive control was 199.0. The two positive cases consisted of one epithelioid tumor and one biphasic tumor. In addition, none of 35 malignant mesothelioma specimens were positve for staining with SV40 large T antigen antibody; in contrast, diffuse staining for SV40 large T antigen was observed in the cytoplasm and on the cell membranes in the positive control. Conclusions: Taken together, these findings strongly argue against any role of SV40 in the etiology of the majority of malignant mesothelioma in Japan. No significant financial relationships to disclose.