Hye Sook Min

NKT cells promote antibody-induced joint inflammation by suppressing transforming growth factor β1 production

Although NKT cells has been known to exert protective roles in the development of autoimmune diseases, the functional roles of NKT cells in the downstream events of antibody-induced joint inflammation remain unknown. Thus, we explored the functional roles of NKT cells in antibody-induced arthritis using the K/BxN serum transfer model. NKT cell–deficient mice were resistant to the development of arthritis, and wild-type mice administrated with α-galactosyl ceramide, a potent NKT cell activator, aggravated arthritis. In CD1d−/− mice, transforming growth factor (TGF)-β1 was found to be elevated in joint tissues, and the blockade of TGF-β1 using neutralizing monoclonal antibodies restored arthritis. The administration of recombinant TGF-β1 into C57BL/6 mice reduced joint inflammation. Moreover, the adoptive transfer of NKT cells into CD1d−/− mice restored arthritis and reduced TGF-β1 production. In vitro assay demonstrated that interleukin (IL)-4 and interferon (IFN)-γ were involved in suppressing TGF-β1 production in joint cells. The adoptive transfer of NKT cells from IL-4−/− or IFN-γ−/− mice did not reverse arthritis and TGF-β1 production in CD1d−/− mice. In conclusion, NKT cells producing IL-4 and IFN-γ play a role in immune complex–induced joint inflammation by regulating TGF-β1.

Single-Dose Versus Fractionated Stereotactic Radiotherapy for Brain Metastases

PURPOSE To evaluate the efficacy of stereotactic radiotherapy in patients with brain metastases by comparing two different treatment regimens, single-dose radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT). METHODS AND MATERIALS Between November 2003 and December 2008, 98 patients with brain metastases were included. Fifty-eight patients were treated with SRS, and forty were treated with FSRT. Fractionated stereotactic radiotherapy was used for large lesions or lesions located near critical structures. The median doses were 20 Gy for the SRS group and 36 Gy in 6 fractions for the FSRT group. RESULTS With a median follow-up period of 7 months, the median survival was 7 months for all patients, with a median of 6 months for the SRS group and 8 months for the FSRT group (p = 0.89). Local progression-free survival (LPFS) rates at 6 months and 1 year were 81% and 71%, respectively, for the SRS group and 97% and 69%, respectively, for the FSRT group (p = 0.31). Despite the fact that FSRT was used for large lesions and lesions in adverse locations, LPFS was not inferior to SRS. Toxicity was more frequently observed in the SRS group than in the FSRT group (17% vs. 5%, p = 0.05). CONCLUSIONS Because patients treated with FSRT exhibited similar survival times and LPFS rates with a lower risk of toxicity in comparison to those treated with SRS, despite the fact that FSRT was used for large lesions and lesions in adverse locations, we find that FSRT can particularly be beneficial for patients with large lesions or lesions located near critical structures. Further investigation is warranted to determine the optimal dose/fractionation.

S100A4 expression is associated with lymph node metastasis in papillary microcarcinoma of the thyroid

The detection of papillary microcarcinomas of the thyroid is increasing due to frequent use of ultrasound and fine-needle aspiration biopsy. Although most of the papillary microcarcinomas remain quiescent and follow an indolent clinical course, some behave aggressively and metastasize early, giving rise to clinically significant disease. There have been few studies concerning factors predictive of lymph node metastasis in papillary microcarcinomas. We analyzed the expression of S100A4, cyclin D1, p27 and MUC1, the presence of the BRAFV600E mutation and the clinicopathological features of the tumors, including patient age, tumor size (≥5 vs <5 mm), extrathyroidal extension, multifocality, histological subtype, sclerosis and encapsulation, in a series of 198 papillary microcarcinomas in relation to lymph node metastasis to determine the predictive factors of lymph node metastasis. On univariate analysis, tumor size of 5 mm or more, extrathyroidal extension, multifocality, sclerosis and the expression of S100A4 and cyclin D1 predicted lymph node metastasis, whereas patient age, expression of p27 and MUC1 and the BRAFV600E mutation did not. Moreover, tumor size 5 mm or more, multifocality and expression of S100A4, especially its strong expression in the invasive fronts, were significantly associated with macrometastasis and lateral node metastasis. On multivariate analysis, multifocality and expression of S100A4 were found to be common independent predictive factors of lymph node metastasis, macrometastasis and lateral node metastasis. In conclusion, S100A4 expression in papillary microcarcinomas may indicate the presence of nodal metastasis. Thus, S100A4 immunohistochemistry may be valuable for predicting metastatic potential in papillary microcarcinomas.

Primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer harboring TKI-sensitive EGFR mutations: an exploratory study

BACKGROUND The mechanism of primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC) has not been clearly understood. PATIENTS AND METHODS Eleven patients exhibiting primary resistance (disease progression <3 months) were identified among 197 consecutive NSCLC patients with TKI-sensitive EGFR mutations who received EGFR TKIs at Seoul National University Hospital. Treatment-naïve tumors were examined for concurrent genetic alterations using fluorescence in situ hybridization and targeted deep sequencing of cancer-related genes. Deletion polymorphism of Bcl-2-interacting mediator of cell death (BIM) gene was examined to validate its predictive role for TKI outcome. RESULTS The median progression-free survival (PFS) for patients receiving EGFR TKIs was 11.9 months, and the response rate 78.8%. Among the 11 patients exhibiting primary resistance, a de novo T790M mutation was identified in one patient, and two exhibited mesenchymal-epithelial transition amplification and anaplastic lymphoma kinase fusion. Targeted deep sequencing identified no recurrent, coexistent drivers of NSCLC. Survival analysis revealed that patients with recurrent disease after surgery had a longer PFS than those with initial stage IV disease. However, BIM deletion polymorphism, line of treatment, EGFR genotype, and smoking were not predictive of PFS for EGFR TKIs. CONCLUSIONS We identified coexistent genetic alterations of cancer-related genes that could explain primary resistance in a small proportion of patients. Our result suggests that the mechanism of primary resistance might be heterogeneous.

Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status

Immunotherapies targeting the programmed cell death-1/programmed cell death-ligand 1 pathway have emerged as promising therapeutic strategies for lung cancer. However, the expression pattern and prognostic implications of programmed cell death-ligand 1 and 2 and programmed cell death-1 in comparison with the histology and genetic alterations in pulmonary adenocarcinomas remains unclear and thus were addressed here. Programmed cell death-ligand 1 and 2 expression in tumor cells and the quantities of programmed cell death-1+ and CD8+ tumor-infiltrating lymphocytes were immunohistochemically evaluated in 497 resected pulmonary adenocarcinomas and analyzed according to clinicopathological and genetic statuses. Programmed cell death-ligand 1 and 2 expression were observed in 59% and 64% of pulmonary adenocarcinomas, respectively, and showed a strong positive correlation with each other (P<0.001). Programmed cell death-ligand 1 expression was higher in nodal metastasis cases (P=0.006), smokers (P=0.056), poorly differentiated tumors and histologic subtypes of solid and micropapillary patterns (P<0.001). There was no significant difference in programmed cell death-ligand 1 and 2 expression according to EGFR mutation status. However, programmed cell death-ligand 1 expression was correlated with ALK translocation (P=0.054) and expression of EGFR and MET (P<0.001). Meanwhile, programmed cell death-ligand 2 expression was correlated with ALK translocation (P=0.052), and expression of MET (P<0.001) and ERBB2 (P=0.013). The numbers of CD8+ and programmed cell death-1+ lymphocytes were higher in smokers (P=0.012 and 0.016) and MET-expressing adenocarcinomas (P<0.001). Patients expressing programmed cell death-ligand 1 and/or high ratios of programmed cell death-1+/CD8+ lymphocytes showed shorter disease-free survival (P=0.001). Our study demonstrated that programmed cell death-ligand 1 and 2 expression varied with histology, EGFR, ALK, MET, and ERBB2 statuses, and activation of the programmed cell death-1/programmed cell death-ligand 1 pathway may be a poor prognostic factor in pulmonary adenocarcinomas.

MHC class II-restricted interaction between thymocytes plays an essential role in the production of innate CD8+ T cells.

We have recently shown that MHC class II-dependent thymocyte–thymocyte (T–T) interaction successfully generates CD4+ T cells (T–T CD4+ T cells), and that T–T CD4+ T cells expressing promyelocytic leukemia zinc finger protein (PLZF) show an innate property both in mice and humans. In this article, we report that the thymic T–T interaction is essential for the conversion of CD8+ T cells into innate phenotype in the physiological condition. CD8+ T cells developed in the presence of PLZF+ CD4+ T cells showed marked upregulation of eomesodermin (Eomes), activation/memory phenotype, and rapid production of IFN-γ on ex vivo stimulation. Their development was highly dependent on the PLZF expression in T–T CD4+ T cells and the IL-4 secreted by PLZF+ T–T CD4+ T cells. The same events may take place in humans, as a substantial number of Eomes expressing innate CD8+ T cells were found in human fetal thymi and spleens. It suggests that PLZF+ T–T CD4+ T cells in combination with Eomes+ CD8+ T cells might actively participate in the innate immune response against various pathogens, particularly in human perinatal period.

Pathology Reporting of Thyroid Core Needle Biopsy: A Proposal of the Korean Endocrine Pathology Thyroid Core Needle Biopsy Study Group

In recent years throughout Korea, the use of ultrasound-guided core needle biopsy (CNB) has become common for the preoperative diagnosis of thyroid nodules. However, there is no consensus on the pathology reporting system for thyroid CNB. The Korean Endocrine Pathology Thyroid Core Needle Biopsy Study Group held a conference on thyroid CNB pathology and developed guidelines through contributions from the participants. This article discusses the outcome of the discussions that led to a consensus on the pathology reporting of thyroid CNB.

Histogram Analysis of Apparent Diffusion Coefficient Map of Standard and High B-value Diffusion MR Imaging in Head and Neck Squamous Cell Carcinoma: A Correlation Study with Histological Grade

RATIONALE AND OBJECTIVES A histologic grade in head and neck squamous cell carcinoma (HNSCC) is clinically important because of its association with prognosis. The purpose of this study was to investigate the efficacy of histographic analysis of apparent diffusion coefficient (ADC) maps on the basis of the entire tumor volume in differentiating histologic grades in HNSCC at standard (b = 1000 s/mm(2)) and high (b = 2000 s/mm(2)) b values. MATERIALS AND METHODS Fifty-four patients with HNSCC, including well-differentiated (WD; n = 35), moderately differentiated (MD; n = 13) and poorly differentiated (PD; n = 6) carcinomas, were retrospectively evaluated. ADC maps were obtained at two different b values (1000 and 2000 s/mm(2)) in each patient. Tumors were delineated on each slice of ADC maps, and data were collected to obtain a histogram for the entire tumor volume. Histographic parameters were calculated, including mean, standard deviation, kurtosis, skewness, and the ratio of the kurtosis measured at b values of 1000 and 2000 s/mm(2). These parameters were correlated with histologic grades. RESULTS There was no significant correlation between tumor grades and histographic parameters obtained from ADC maps at b = 1000 s/mm(2). However, mean ADC at b = 2000 s/mm(2) was significantly higher in WD HNSCC (881 ± 131 × 10(-6) mm(2)/s) than in MD and PD HNSCC (770 ± 163 and 780 ± 158 × 10(-6) mm(2)/s, respectively) (P < .05). Kurtosis ratio was significantly higher in PD HNSCC (115 ± 10%) compared to WD and MD HNSCC (91 ± 21% and 86 ± 26%, respectively) (P < .05). Diagnostic accuracy was 100%, 76.9%, and 65.8% for PD, MD, and WD HNSCC, respectively. CONCLUSIONS Histographic analysis of ADC maps on the basis of the entire tumor volume can be useful in differentiating histologic grades of HNSCC using mean ADC at b = 2000 s/mm(2) and kurtosis ratio.

In situ induction of dendritic cell–based T cell tolerance in humanized mice and nonhuman primates

Administration of an ICAM-1–specific antibody arrests dendritic cells in a semi-immature state and facilitates antigen-specific T cell tolerance to islet allografts in humanized mice and Rhesus monkeys.

Thyroid follicular neoplasms: Can sonography distinguish between adenomas and carcinomas?

The purpose of this study was to determine whether sonography (US) can usefully differentiate thyroid follicular adenoma (FA) and follicular carcinoma (FC).