Yoo-Duk Choi

Frequent detection of BRAFV600E mutations in histiocytic and dendritic cell neoplasms

In this study, we examined BRAF mutation in a wide range of histiocytic and dendritic cell neoplasms and compared its detection rate in each disease group.

Association of a common genetic variant in prostate stem‐cell antigen with gastric cancer susceptibility in a Korean population

A recent genome wide association study (GWAS) indentified a significant association between rs2294008 (C > T) polymorphism in prostate stem‐cell antigen (PSCA) and increased risk of gastric cancer in Japanese and Korean populations. The aim of this study was to determine whether rs2294008 polymorphism is associated with risk of gastric cancer in a Korean population. We conducted a large‐scale case–control study of 3,245 gastric cancer patients and 1,700 controls. The frequencies of the CC, CT, and TT genotypes of rs2294008 polymorphism were 17.8%, 49.9%, and 32.3% in the gastric cancer patients; and 24.4%, 48.1%, and 27.5% in the controls, respectively. We found that the CT and TT genotypes were associated with a significantly increased risk of gastric cancer (ORCT = 1.50, 95% confidence intervals, 95% CI: 1.28–1.76; ORTT = 1.71, 95% CI: 1.43–2.04), compared with the CC genotype. Further, stratified by tumor location and histological type, the effect of the rs2294008 T allele was larger in cardia (ORTT = 2.62, 95% CI = 1.42–4.85) than non‐cardia (ORTT = 1.67, 95% CI = 1.40–2.00), in diffuse‐type (ORTT = 2.00, 95% CI: 1.55–2.59) than in intestinal‐type (ORTT = 1.51, 95% CI: 1.22–1.86). Our study showed that rs2294008 in the PSCA gene was associated with increased risks of gastric cancer in a Korean population, suggests that rs2294008 might play an important role in gastric carcinogenesis.

Utility of Napsin A and Thyroid Transcription Factor 1 in Differentiating Metastatic Pulmonary from Non-Pulmonary Adenocarcinoma in Pleural Effusion

Objective: It was our aim to evaluate the usefulness of napsin A and thyroid transcription factor 1 (TTF-1) in the differential diagnosis of metastatic pulmonary and non-pulmonary adenocarcinomas (ACs) in pleural effusion. Study Design: A total of 84 pleural effusion fluid cell blocks were collected from metastatic ACs. There were 53 pulmonary ACs and 31 non-pulmonary ACs. Immunohistochemical staining was performed with antibodies against napsin A and TTF-1. Results: Napsin A was positive in 44/53 (83%) cases of pulmonary ACs, and TTF-1 was positive in 30/53 (57%) cases of pulmonary ACs. All non-pulmonary ACs were negative for napsin A and TTF-1. Napsin A showed a reactivity in >75% of the tumor cells in 36 of the 44 positive cases (82%), whereas TTF-1 showed a reactivity in >75% of the tumor cells only in 6 of the 30 positive cases (20%; p < 0.01). Poorly differentiated pulmonary ACs expressed napsin A (73%) more frequently than TTF-1 (53%), but this was not statistically significant (p = 0.45). Conclusion: We conclude that napsin A is superior to TTF-1 with regard to distinguishing between metastatic pulmonary and non-pulmonary ACs in cell blocks prepared from malignant pleural effusions.

Genetic variations in the PRKAA1 and ZBTB20 genes and gastric cancer susceptibility in a Korean population.

A recent genome‐wide association study (GWAS) identified new susceptibility single‐nucleotide polymorphisms (SNPs) rs13361707 (PRKAA1 and PTGER4 gene on 5p13.1) and rs9841504 (ZBTB20 gene on 3q13.31) that were significantly associated with non‐cardia gastric cancer. The aim of this study was to determine whether rs13361707 and rs9841504 polymorphisms are associated with the risk of gastric cancer in a Korean population. We conducted a large‐scale case–control study of 3245 gastric cancer patients and 1700 controls. The allele frequencies for rs13361707 C and rs9841504 G were 53.5% and 18.3% among gastric cancer cases, compared with 47.1% and 17.2% among controls, respectively. We found that rs13361707 TC and CC genotypes were associated with increased risk for gastric cancer (odds ratios [OR] = 1.29; 95% confidence interval [CI] = 1.11–1.51 for TC vs. TT and 1.68; 1.41–2.01 for CC vs. TT). However, we found no significant association between rs9841504 and gastric cancer risk (OR = 1.11; 0.97–1.28 for CG vs. CC; OR = 1.09; 0.77–1.53 for GG vs. CC). We observed no significant interactions between rs13361707 and rs9841504 polymorphisms and age, gender, smoking habit, alcohol consumption, and clinicopathologic characteristics such as anatomical tumor location and histological type. Our study showed that the rs13361707 polymorphism was associated with increased risk of gastric cancer in a Korean population. This finding provides further evidence that genetic variant of PRKAA1 and PTGER4 genes may contribute to the gastric carcinogenesis. However, we found no association between rs9841504 and gastric cancer risk.

Modulation of Lipopolysaccharide-Induced NF-κB Signaling Pathway by 635 nm Irradiation via Heat Shock Protein 27 in Human Gingival Fibroblast Cells

Heat shock protein‐27 (HSP27) is a member of the small HSP family which has been linked to the nuclear factor‐kappa B (NF‐κB) signaling pathway regulating inflammatory responses. Clinical reports have suggested that low‐level light therapy/laser irradiation (LLLT) could be an effective alternative treatment to relieve inflammation during bacterial infection associated with periodontal disease. However, it remains unclear how light irradiation can modulate the NF‐κB signaling pathway. We examined whether or not 635 nm irradiation could lead to a modulation of the NF‐kB signaling pathway in HSP27‐silenced cells and analyzed the functional cross‐talk between these factors in NF‐κB activation. The results showed that 635 nm irradiation led to a decrease in the HSP27 phosphorylation, reactive oxygen species (ROS) generation, I‐κB kinase (IKK)/inhibitor of κB (IκB)/NF‐κB phosphorylation, NF‐κB p65 translocation and a subsequent decrease in the COX‐1/2 expression and prostaglandin (PGE2) release in lipopolysaccharide(LPS)‐induced human gingival fibroblast cells (hGFs). However, in HSP27‐silenced hGFs, no obvious changes were observed in ROS generation, IKK/IκB/NF‐κB phosphorylation, NF‐κB p65 translocation, nor in COX‐1/2 expression, or PGE2 release. This could be a mechanism by which 635 nm irradiation modulates LPS‐induced NF‐κB signaling pathway via HSP27 in inflammation. Thus, HSP27 may play a role in regulating the anti‐inflammatory response of LLLT.

Disease-free survival of patients after surgical resection of non-small cell lung carcinoma and correlation with excision repair cross-complementation group 1 expression and genotype

Background and objective:  Expression of excision repair cross‐complementation group 1 (ERCC1) is recognized as a favourable prognostic marker in patients who have undergone surgical resection of non‐small cell lung cancer (NSCLC). However, in patients treated with adjuvant chemotherapy after surgical resection, ERCC1 correlated with poor prognosis. Class III beta tubulin (TUBB3) is also known to be a predictive marker of the efficacy of treatment with taxanes or vinorelbine.

Expression of matrix metalloproteinases and their inhibitors in different immunohistochemical-based molecular subtypes of breast cancer

BackgroundMetalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) are involved in several key pathways of tumor growth, invasion and metastasis, but little is known about their expression according to different molecular subtypes of breast cancer. The aims of this study were to assess the prevalence and clinical significance of MMP and TIMP expression in invasive breast cancer and to determine its association with immunohistochemical-based molecular classification.MethodsTissue microarray sections were immunostained for estrogen receptor-α (ER-α), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR) and with specific antibodies against MMP-1, 2, 7, 9, 11, 13, and 14 and TIMP-1, 2, and 3. Based on the immunostaining data from five of the markers used (ER-α, PR, HER2, EGFR and CK5/6), three major subtypes (123 luminal A, 31 basal-like, and 17 HER2-overexpressing) were selected.ResultsStatistically significant differences in the expression of MMPs and TIMPs among the three subtypes were found in tumoral MMP7 (P = 0.005), tumoral MMP-9 (P = 0.000), tumoral MMP-13 (P = 0.016) and stromal MMP-13 (P = 0.016). The incidence of tumoral MMP-9 expression in the HER2-overexpressing subtype was significantly higher than in the luminal A subtype (P = 0.021). Tumoral MMP-9 and stromal MMP-13 expression were significantly higher in the HER2-overexpressing subtype than in the basal-like subtype (P = 0.000 and P = 0.016, respectively). Tumoral MMP-7 expression was significantly higher in the basal-like subtype compared to luminal A (P = 0.007) and HER2-overexpressing subtype (P = 0.004). Tumoral MMP-13 showed a higher expression in the basal-like subtype than in the HER2-overexpressing subtype (P = 0.010). In multivariate analysis, stage and stromal MMP-1 expression were significantly related to overall survival. Stage was of independent prognostic significance for disease-free survival.ConclusionWe found some variations in MMP and TIMP expression among the immunohistochemical-based molecular subtypes of breast carcinomas, suggesting differences in their tumor pathophysiology. Additional studies are needed to determine the mechanisms underlying the differences of MMP and TIMP expression in the molecular subtypes for the development of specific therapeutic targets for breast cancer subtypes.

Two cases of clear cell sarcoma with different clinical and genetic features: cutaneous type with BRAF mutation and subcutaneous type with KIT mutation

Clear cell sarcoma (CCS), also known as malignant melanoma of soft parts, is a rare malignancy constituting approximately 1% of all soft‐tissue sarcomas. It occurs predominantly in the lower extremities of young adults, manifesting as a deep, painless, slow‐growing mass. CCS is sometimes confused with other types of melanoma because of its melanocytic differentiation. Although BRAF and KIT mutations are well‐known melanocytic tumour‐promoting mutations frequently found in cutaneous melanoma, they are rare or absent in CCS. We present two cases of CCS with different clinical and genetic features. Both female patients, aged 25 and 20 years, presented with a palpable nodule on a lower extremity. Biopsies of both tumours revealed features diagnostic of CCS. Each tumour cell was positive for S100 protein and HMB‐45. However, one patients tumour was localized to the dermis, with many multinucleated giant cells, whereas the other was located in the deep subcutaneous fat layer near bone. Fluorescence in situ hybridization demonstrated the presence of a characteristic Ewing sarcoma RNA‐binding protein (EWSR)1 gene rearrangement in both cases. Reverse‐transcription polymerase chain reaction (PCR) and sequencing of the PCR product revealed an EWSR1–activating transcription factor 1 type 1 fusion transcript in both cases. In addition, we detected BRAF mutation in the dermal type and KIT mutation in the subcutaneous type. It is of interest that the BRAF and KIT mutations are known to be very rare in CCS. On the basis of our observations, we suggest that mutation inhibitors may be useful in selected patients with mutated CCS lineages.

The Role of Radiotherapy in the Treatment of Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

Purpose To assess radiotherapy for patients with early stage gastric mucosa-associated lymphoid tissue (MALT) lymphoma with respect to survival, treatment response, and complications. Materials and Methods Enrolled into this study were 48 patients diagnosed with gastric MALT lymphoma from January 2000 to September 2012. Forty-one patients had low grade and seven had mixed component with high grade. Helicobacter pylori eradication was performed in 33 patients. Thirty-four patients received radiotherapy alone. Ten patients received chemotherapy before radiotherapy, and three patients underwent surgery followed by chemotherapy and radiotherapy. One patient received surgery followed by radiotherapy. All patients received radiotherapy of median dose of 30.6 Gy. Results The duration of follow-up ranged from 6 to 158 months (median, 48 months). Five-year overall survival and cause-specific survival rates were 90.3% and 100%. All patients treated with radiotherapy alone achieved pathologic complete remission (pCR) in 31 of the low-grade and in three of the mixed-grade patients. All patients treated with chemotherapy and/or surgery prior to radiotherapy achieved pCR except one patient who received chemotherapy before radiotherapy. During the follow-up period, three patients developed diffuse large B-cell lymphoma in the stomach, and one developed gastric adenocarcinoma after radiotherapy. No grade 3 or higher acute or late complications developed. One patient, who initially exhibited gastroptosis, developed mild atrophy of left kidney. Conclusion These findings indicate that a modest dose of radiotherapy alone can achieve a high cure rate for low-grade and even mixed-grade gastric MALT lymphoma without serious toxicity. Patients should be carefully observed after radiotherapy to screen for secondary malignancies.

Histological transformation from non-small cell to small cell lung carcinoma after treatment with epidermal growth factor receptor-tyrosine kinase inhibitor.

Several cases of acquired resistance in patients with activating epidermal growth factor receptor (EGFR) mutation have been reported. However, rare clinical cases exist of a transformation to small cell lung cancer (SCLC) following treatment with EGFR‐tyrosine kinase inhibitors (TKIs). We report a case of non‐small cell lung cancer (NSCLC) with L858R mutation at the time of diagnosis. After failure of EGFR‐TKI therapy, we performed additional histopathologic examinations. We confirmed that the patient had a histological transformation from NSCLC to SCLC. We performed chemotherapy with etoposide and cisplatin against the SCLC and radiologic findings were improved.