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1.  Helicobacter pylori eradication with moxifloxacin-containing therapy following failed first-line therapies in South Korea 
AIM: To investigate moxifloxacin-containing triple therapy as second-line treatment for Helicobacter pylori (H. pylori) infection following failed first-line treatment.
METHODS: The sample included 312 patients for whom first-line treatment failed between January 2008 and May 2013; 27 patients were excluded, and a total of 285 patients received 7- or 14-d moxifloxacin-containing triple therapy as second-line treatment for H. pylori infection. First line regimens included 7-d standard triple (n = 172), 10-d bismuth-containing quadruple (n = 28), 14-d concomitant (n = 37), or 14-d sequential (n = 48) therapy. H. pylori status was evaluated using 13C-urea breath testing 4 wk later, after completion of the treatment. The primary outcome was the H. pylori eradication rate analyzed using intention-to-treat (ITT) and per protocol (PP) analyses. The secondary outcome was the occurrence of serious adverse events. Demographic and clinical factors were analyzed using Student’s t-tests and Pearson’s χ2 tests according to first- and second-line regimens. A P value of less than 0.05 was considered statistically significant.
RESULTS: The eradication rate of moxifloxacin-containing triple therapy was 68.4% (ITT; 95%CI: 62.8-73.5) and 73.9% (PP; 95%CI: 68.3-78.8). The eradication rate was significantly higher with 14 d compared to 7 d of treatment (77.5% vs 62.5%, P = 0.017). Peptic ulcer patients had a higher eradication rate than the patients without ulcers (82.9% vs 70.6%, P = 0.046). The demographic and clinical characteristics were not significantly different between the groups according to first-line therapies. ITT and PP analyses of the moxifloxacin-containing triple therapy indicated the following eradication rates: 70.9% (95%CI: 63.8-77.2) and 77.2% (95%CI: 70.1-83.1) for standard triple; 67.9% (95%CI: 51.5-84.2) and 67.9% (95%CI: 51.5-84.2) for bismuth-containing quadruple; 60.4% (95%CI: 46.3-73.0) and 70.7% (95%CI: 54.0-80.9) for sequential; and 67.6% (95%CI: 51.5-80.4) and 67.6%(95%CI: 51.5-80.4) for concomitant therapy. There were no statistically significant differences in the efficacy of the first-line regimens (P = 0.492). The most common adverse event was diarrhea. There were no serious adverse events and no significant differences in the frequency of side effects between the first- and second-line regimens (28.7% vs 26.1%, respectively).
CONCLUSION: Moxifloxacin-containing triple therapy as second-line treatment resulted in low eradication rates. There were no differences in the efficacy between the first-line regimens in South Korea.
PMCID: PMC4051934  PMID: 24944485
Fluoroquinolones; Helicobacter pylori; Disease eradication; Drug resistance; Second-line
2.  Adenocarcinoma Arising in Gastric Duplication Cyst 
Korean Journal of Pathology  2014;48(2):159-161.
PMCID: PMC4026808  PMID: 24868230
3.  Body Mass Index as a Predictor of Advanced Colorectal Neoplasia 
Journal of Cancer Prevention  2013;18(2):144-148.
Colorectal cancer (CRC) is the third frequent cancer in Korea. There are several risk factors including male sex, older age, smoking and family history of colon cancer. Recently, obesity is thought to be a risk factor for CRC and advanced colon polyps. Therefore, we designed a cross-sectional study to determine the association between BMI and advanced colorectal neoplasia.
A total of 256 patients with advanced colorectal neoplasia who were diagnosed using colonoscopy between May, 2004 and December, 2011 were included in this study. Advanced colorectal neoplasia was defined large (≥1 cm) adenoma or adenocarcinoma. We compared these patients to a control group consisting of 217 subjects with normal colonoscopic findings recruited during the same period.
Of the 256 patients, there were 132 (51.6%) men, and the mean age was 56.4±12.3 years. The rate of males, alcohol drinker and current smokers was significantly higher in the advanced colorectal neoplasia compared to control group. In the subgroup analysis, the mean age and body mass index (BMI, kg/m2) of advanced colorectal neoplasia were higher than control group in the female subjects. However, there were no significant differences between two groups in the male subjects. Multiple logistic regression analysis identified overweight (BMI 23.0–24.9 kg/m2, odds ratios [OR]=2.022) and obesity (BMI≥25 kg/m2, OR=2.383) as independent risk factors for advanced colorectal neoplasia.
We suggest that BMI should be considered as an independent risk factor for advanced colorectal neoplasia, and people with high BMI should be recommended to undergo colonocoscopy screening earlier than scheduled.
PMCID: PMC4189451  PMID: 25337540
Body mass index; Adenomatous polyps; Colorectal neoplasms
4.  Effect of Helicobacter pylori Eradication on Functional Dyspepsia 
This study evaluated the effect of Helicobacter pylori eradication on functional dyspepsia (FD), and the relationship between the changes of histological gastritis and FD symptom responses.
A total of 213 FD patients diagnosed by Rome III criteria were consecutively enrolled. H. pylori tests and gastritis grade by the Sydney system were performed before and 1 year after the proton pump based-eradication therapy for 7 days. Serum levels of pepsinogen, and genetic polymorphisms IL-6, IL-8 and IL-10 were investigated.
Total of 91 patients completed the 1 year follow-up. When the response rate of dyspepsia was compared at 1 year between the non-eradicated group (n = 24) and eradicated group (n = 67), each group showed complete response of 62.5% and 62.7%; satisfactory response (≥ 50%) of 0.0% and 19.4%; partial response (< 50%) of 12.5% and 11.9%; and refractory response of 25.0% and 6.0%, respectively (P = 0.015). In addition, the responder group (complete + satisfactory response) at 1 year showed improvement of activity and chronic inflammation in both the antrum and corpus (all P < 0.001). Multivariate analysis showed that H. pylori eradication (OR, 5.81; 95% CI, 1.07-31.59) and symptom improvement at 3 month (OR, 28.90; 95% CI, 5.29-157.82) were associated with the improvement of dyspepsia at 1 year. Among the successfully eradicated FD patients (n = 67), male (P = 0.013) and higher initial BMI (P = 0.016) were associated with the improvement of dyspepsia at 1 year.
H. pylori eradication improved FD symptoms, as well as gastritis at 1 year, suggesting that inflammation mediates FD.
PMCID: PMC3644660  PMID: 23667755
Eradication; Functional dyspepsia; Helicobacter pylori
5.  Cost Effectiveness Associated with Helicobacter pylori Screening and Eradication in Patients Taking Nonsteroidal Anti-Inflammatory Drugs and/or Aspirin 
Gut and Liver  2013;7(2):182-189.
This study was performed to investigate the cost effectiveness of Helicobacter pylori screening/eradication in South Korean patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and/or aspirin.
A decision Markov model was used to estimate the effectiveness and economic impact of an H. pylori screening/eradication strategy compared to a no-screening strategy among patients who were included in the model at the age of 40 years. Utility weights were applied to four of the health status groups to reflect quality-adjusted life years (QALY). The costs of screening, H. pylori eradication, and managing peptic ulcer and ulcer complications were obtained from South Korea-specific data.
The total costs per patient were US $2,454 for the H. pylori screening/eradication and US $3,182 for the no-screening strategy. The QALYs for the two strategies were 16.05 and 15.73, respectively. The results were robust for the analyses of all different cohort groups who entered the model at the age of 30, 50, or 60 years and for NSAIDs-naïve patients. Through the probabilistic sensitivity analysis, the robustness of our study's results was also determined.
The H. pylori screening/eradication strategy was found to be less expensive and more effective compared to the no-screening strategy among South Korean patients taking NSAIDs and/or aspirin.
PMCID: PMC3607772  PMID: 23560154
Cost-benefit analysis; Helicobacter pylori; Mass screening
6.  Clinicopathological Features and Surgical Safety of Gastric Cancer in Elderly Patients 
Journal of Korean Medical Science  2014;29(12):1639-1645.
Gastric cancer is one of the most common cancers, especially among the elderly. However little is known about gastric cancer in elderly patients. This study was designed to evaluate the specific features of gastric cancer in elderly patients. Medical records of 1,107 patients who had radical gastrectomy for gastric cancer between June 2005 and December 2009 were reviewed. They were divided into young (<65 yr, n=676), young-old (65-74 yr, n=332), and old-old age group (≥75 yr, n=99). Increased CA 19-9 (5.6%, 13.4%, 14.6%, P=0.001), advanced diseases (42.5%, 47.0%, and 57.6, P=0.014), and node metastasis (37.6%, 38.9%, 51.5%, P=0.029) were more common in the young-old and old-old age groups. There were no significant differences in Helicobacter pylori status (63.6%, 56.7%, 61.2%, P=0.324) between the three groups. Surgery-related complication rates were similar in the three groups (5.3%, 5.1%, 8.1%, P=0.497). Microsatellite instability (P<0.001) and p53 overexpression (P<0.001) were more common among the elderly. The elderly group had more synchronous tumors (7.5%, 10.2%, 17.2%; P=0.006). Surgery can be applied to elderly gastric cancer without significant risk of complications. However, considering the more advanced disease and synchronous tumors among the elderly, care should be taken while deciding the extent of surgery for elderly gastric cancer.
Graphical Abstract
PMCID: PMC4248584  PMID: 25469063
Aged; Stomach Neoplasms; Pathology; Safety
7.  The Diagnostic Validity of the 13C-Urea Breath Test in the Gastrectomized Patients: Single Tertiary Center Retrospective Cohort Study 
Journal of Cancer Prevention  2014;19(4):309-317.
This study was conducted to evaluate the diagnostic validity of the 13C-urea breath test (13C-UBT) in the remnant stomach after partial gastrectomy for gastric cancer.
The 13C-UBT results after Helicobacter pylori eradication therapy was compared with the results of endoscopic biopsy-based methods in the patients who have received partial gastrectomy for the gastric cancer.
Among the gastrectomized patients who showed the positive 13C-UBT results (≥ 2.5‰, n = 47) and negative 13C-UBT results (< 2.5‰, n = 114) after H. pylori eradication, 26 patients (16.1%) and 4 patients (2.5%) were found to show false positive and false negative results based on biopsy-based methods, respectively. The sensitivity, specificity, false positive rate, and false negative rate for the cut-off value of 2.5‰ were 84.0%, 80.9%, 19.1%, and 16.0%, respectively. The positive and negative predictive values were 44.7% and 96.5%, respectively. In the multivariate analysis, two or more H. pylori eradication therapies (odds ratio = 3.248, 95% confidence interval= 1.088–9.695, P = 0.035) was associated with a false positive result of the 13C-UBT.
After partial gastrectomy, a discordant result was shown in the positive 13C-UBT results compared to the endoscopic biopsy methods for confirming the H. pylori status after eradication. Additional endoscopic biopsy-based H. pylori tests would be helpful to avoid unnecessary treatment for H. pylori eradication in these cases.
PMCID: PMC4285962  PMID: 25574466
Helicobacter pylori; 13C-urea breath test; Eradication; Cut-off value; Subtotal gastrectomy
8.  Human epidermal growth factor receptor 2 testing in gastric cancer: Recommendations of an Asia-Pacific Task Force 
Human epidermal growth factor receptor 2 (HER2) testing in gastric and gastroesophageal junction cancer is an evolving area in clinical practice that has particular relevance to Asia-Pacific countries, which face a high incidence of these diseases. A growing body of evidence demonstrates that HER2-targeted therapy improves survival for patients with HER2-positive advanced disease, and drives the need for high-quality testing procedures to identify patients who will respond to treatment. However, various factors challenge day-to-day testing of gastric specimens in these countries, to a degree greater than that observed for breast specimens. Recommendations for HER2 testing of gastric cancer specimens were published as a result of the Trastuzumab for Gastric Cancer (ToGA) trial. The guidelines proposed in this manuscript build on these recommendations and emphasize local testing environments, particularly in Asia-Pacific countries. A multidisciplinary task force comprising experts from Asia-Pacific who actively work and provide education in the area was convened to assess the applicability of existing recommendations in the Asia-Pacific region. The resulting recommendations reported here highlight and clarify aspects of testing that are of particular relevance to the region, and notably emphasize multidisciplinary collaborations to optimize HER2 testing quality.
PMCID: PMC4241045  PMID: 25227602
gastric cancer; human epidermal growth factor receptor 2; immunohistochemistry; in situ hybridization; quality control
9.  Histologic characteristics of gastric polyps in Korea: Emphasis on discrepancy between endoscopic forceps biopsy and endoscopic mucosal resection specimen 
AIM: To investigate histological characteristics of gastric polyps in the Korean population.
METHODS: We reviewed endoscopic photographs and medical records of patients with gastric polyps who underwent endoscopic mucosal resection from April 1996 through February 2003.
RESULTS: A total of 85 gastric polyps from 74 patients were reviewed. Male-to-female ratio was 1:1.96. Mean age was 59.9 ± 10.8 years. Multiple polyps were observed in 10.8%. Gastric polyps occurred most frequently in the antrum (58.8%). Pathological results on resected specimens were as follows: tubular adenoma 45.9%, hyperplastic polyp 31.8%, inflammatory polyp 9.4%, hamartoma 3.5%, fundic gland polyp 2.4%, tubulovillous adenoma 2.4%, adenocarcinoma 2.4%, dysplasia 1.1%, and mucosal pseudolipomatosis 1.1%. Discrepancy rate between endoscopic biopsy and pathology of resected specimens was 27.1%. There was no relationship between the size of the polyp and concordance rate.
CONCLUSION: There is considerable discrepancy in histologic findings between endoscopic forceps biopsy and resected specimens. Approaches to review of the histology of an entire polyp should be performed, especially when an adenoma is suspected.
PMCID: PMC4087715  PMID: 16810753
Polyp; Gastric; Histology
10.  Polypoid Arteriovenous Malformation Presenting with Jejunojejunal Intussusceptions in an Adult 
Clinical Endoscopy  2014;47(6):575-578.
Jejunal polypoid arteriovenous malformations (AVMs) and jejunojejunal intussusceptions are both rare. Here, we present the case of a 61-year-old woman who suffered intermittent episodes of abdominal pain over the course of 13 years. A computed tomography scan of her abdomen and pelvis revealed a distal jejunojejunal intussusception. A suspected low density mass was observed at the tip of the intussusception. Treatment comprised laparoscopic small bowel resection with end-to-end jejunostomy. The final diagnosis was a polypoid AVM measuring 5×3.5×3 cm. We suggest that polypoid AVM should be considered as a differential diagnosis in patients presenting with small intestinal neoplasms.
PMCID: PMC4260109  PMID: 25505727
Abdominal pain; Arteriovenous malformations; Jejunum; Intussusception; Polypoid arteriovenous malformation
11.  Discrepancies between primary physician practice and treatment guidelines for Helicobacter pylori infection in Korea 
AIM: To evaluate the attitude of primary care physicians in the diagnosis and treatment of Helicobacter pylori (H pylori) infection.
METHODS: Primary care physicians in the Seoul metropolitan area answered self-administered questionnaire from January to March 2003.
RESULTS: One hundred and eight doctors responded to the questionnaire. The most frequent reasons for testing H pylori infection were gastric and duodenal ulcers (93.5% and 88.9%, respectively). For patients with H pylori positive dyspepsia, 28.7% of doctors always tried to eradicate the worm and 34.4% treated selectively. A large proportion (28.7%) of primary care physicians treated H pylori on a patient’s request basis. Only 9.3% of primary care physicians always conducted follow-up testing after treating H pylori infection. When H pylori was not cleared by the first treatment, 40.7% of doctors reused the same regimen, 16.7% changed to another triple regimen and 25% to a quadruple regimen.
CONCLUSION: It has been well documented that the issuance of guidelines alone has little impact on practice. Communication between primary care physicians and gastroenterologists in the form of continuous medical education is required.
PMCID: PMC4077496  PMID: 16440419
Helicobacter pylori; Guidelines; Primary care
12.  Off-treatment virologic relapse and outcomes of re-treatment in chronic hepatitis B patients who achieved complete viral suppression with oral nucleos(t)ide analogs 
BMC Infectious Diseases  2014;14(1):439.
The durability of off-treatment virologic responses has not been fully elucidated in chronic hepatitis B (CHB) patients who have previously achieved complete virologic suppression with nucleos(t)ide analog (NA) therapy. This study aimed to assess off-treatment virologic relapse rates and to characterize the outcomes of subsequent re-treatment in CHB patients who have discontinued oral NA following complete virologic suppression.
Ninety-five CHB patients who showed complete virologic suppression were withdrawn from NAs: entecavir, lamivudine, and clevudine in 67, 15, and 13 patients, respectively. Consolidation therapy was given for 6 and 12 months for HBeAg-positive and -negative CHB, respectively, before cessation. Virologic relapse was managed with the same NA that had induced complete virologic response before discontinuation.
The cumulative rates of virologic relapse at 12 and 24 months were 73.8% and 87.1%, respectively. The relapse rates were independent of HBeAg positivity, HBeAg seroconversion, and type of oral NA. In a multivariate analysis, duration of oral NA therapy was the only significant predicting factor associated with off-treatment virologic relapse. Although the majority of patients regained complete virologic suppression, some patients did not respond to re-treatment with the initial NA and developed genotypic resistance.
NA consolidation therapy for 6 and 12 months is associated with high off-treatment virologic relapse in HBeAg-positive and -negative CHB patients, respectively. Drugs with high genetic barriers to resistance should be considered as a rescue therapy for off-treatment relapse in CHB.
PMCID: PMC4148928  PMID: 25125320
Chronic hepatitis B; Discontinuation; Nucleos(t)ide analog; Relapse; Sustained response
13.  Expression of CD99 in Multiple Myeloma: A Clinicopathologic and Immunohistochemical Study of 170 Cases 
Korean Journal of Pathology  2014;48(3):209-216.
Multiple myeloma (MM) is a heterogeneous and ultimately fatal disease. Risk stratification using prognostic biomarkers is crucial to individualize treatments. We sought to investigate the role of CD99, a transmembrane protein highly expressed in many hematopoietic cells including subpopulations of normal and neoplastic plasma cells, for MM risk stratification.
CD99 expression was measured in paraffin samples of bone marrow and extramedullary biopsies of 170 patients with MM. Patients were divided into those with high score (moderately and strongly positive) and low score (negative and weakly positive), with all staining being cytoplasmic and/or membranous.
High anti-CD99 immunostaining was observed in 72 of 136 (52.9%) bone marrow biopsies and 24 of 87 (27.6%) extramedullary biopsies in MM. High CD99 expression of extramedullary specimens was associated with significantly longer overall survival (OS; p=.016). High CD99 expression of extramedullary specimens was also associated with better prognosis in the nonautologous stem cell transplantation group of MM patients (p=.044). In multivariate analysis, International Staging System stage was an independent prognostic factor, whereas CD99 expression was no longer statistically significant.
Expression of CD99 in extramedullary specimens was correlated with longer OS, suggesting that CD99 may be a helpful immunohistochemical marker for risk stratification.
PMCID: PMC4087134  PMID: 25013419
CD99; Multiple myeloma; Immunostaining; Autologous stem cell transplantation
14.  Metabolic Signature Genes Associated with Susceptibility to Pyruvate Kinase, Muscle Type 2 Gene Ablation in Cancer Cells 
Molecules and Cells  2013;35(4):335-341.
Pyruvate kinase, muscle type 2 (PKM2), is a key factor in the aerobic glycolysis of cancer cells. In our experiments, liver cancer cell lines exhibited a range of sensitivity to PKM2 knockdown-mediated growth inhibition. We speculated that this differential sensitivity is attributable to the variable dependency on glycolysis for the growth of different cell lines. Transcriptome data revealed overexpression of a glucose transporter (GLUT3) and a lactate transporter (MCT4) genes in PKM2 knockdown-sensitive cells. PKM2 knockdown-resistant cells expressed high levels of the lactate dehydrogenase B (LDHB) and glycine decarboxylase (GLDC) genes. Concordant with the gene expression results, PKM2 knockdown-sensitive cells generated high levels of lactate. In addition, ATP production was significantly reduced in the PKM2 knockdown-sensitive cells treated with a glucose analog, indicative of dependency of their cellular energetics on lactate-producing glycolysis. The PKM2 knockdown-resistant cells were further subdivided into less glycolytic and more (glycolysis branch pathway-dependent) glycolytic groups. Our findings collectively support the utility of PKM2 as a therapeutic target for high lactate-producing glycolytic hepatocellular carcinoma (HCC).
PMCID: PMC3887894  PMID: 23515579
glycolysis; glycolysis-dependent; lactate; PKM2; SLC16A3
15.  Helicobacter pylori and Molecular Markers as Prognostic Indicators for Gastric Cancer in Korea 
Journal of Cancer Prevention  2014;19(1):56-67.
The prognosis of H. pylori infection-negative gastric cancer (HPIN-GC) has been rarely investigated. Applying a strict definition of H. pylori status, the prognosis and molecular prognostic markers in HPIN-GC were evaluated.
A combination of multiple methods was carried out to strictly evaluate H. pylori infection in gastric cancer (GC) patients between June 2003 and October 2012 at Seoul National University Bundang Hospital. H. pylori infection was defined as negative if histology, a rapid urease test, culturing, serology and history of H. pylori eradication were all negative. Patients with severe gastric atrophy by the serum pepsinogen test or histology were assumed to have had a previous H. pylori infection. Epstein-Barr virus (EBV) in situ hybridization, PCR-based microsatellite instability (MSI) testing, and p53 immunohistochemistry were performed.
Compared to 509 H. pylori infection-positive gastric cancer (HPIN-PC) patients, 24 HPIN-GC patients showed a significantly higher frequency of cardia location (P=0.013), and the depth of invasion in HPIN-GC was more advanced, although there was no statistical significance (pT3-pT4, 37.5% for HPIN-GC vs. 28.5% for HPIP-GC, P=0.341). In multivariate analysis, depth of invasion and lymph node metastasis were identified as the most important prognostic factors for relapse-free survival and overall survival (P<0.001). However, the status of H. pylori infection was not an independent prognostic factor for relapse-free survival and overall survival. The positivity of EBV in both groups was low, and the survivals according to MSI and p53 status in HPIN-GC patients were not significantly different.
The status of H. pylori infection was not a prognostic factor for survival in GC patients when applying the strict definition of H. pylori infection. The prognostic implication of MSI and p53 on survival in HPIN-GC patients was not clear.
PMCID: PMC4189474  PMID: 25337573
Helicobacter pylori; Gastric cancer; Prognosis; p53; Microsatellite instability
16.  Correlations Among Endoscopic, Histologic and Serologic Diagnoses for the Assessment of Atrophic Gastritis 
Journal of Cancer Prevention  2014;19(1):47-55.
Atrophic gastritis is a precancerous condition, which can be diagnosed by several methods. However, there is no consensus for the standard method. The aim of this study was to evaluate the correlations among endoscopic, histologic, and serologic findings for the diagnosis of atrophic gastritis.
From March 2003 to August 2013, a total of 2,558 subjects were enrolled. Endoscopic atrophic gastritis was graded by Kimura-Takemoto classification and histological atrophic gastritis was assessed by updated Sydney system. Serological assessment of atrophic gastritis was based on serum pepsinogen test.
The serum pepsinogen I/II ratio showed a significant decreasing nature when the extent of atrophy increased (R2=0.837, P<0.001) and the cut-off value for distinguishing between presence and absence of endoscopic atrophic gastritis was 3.2. The serum pepsinogen I and pepsinogen I/II ratio were significantly lower when the histological atrophic gastritis progressed and the cut-off value was 3.0 for a diagnosis of histological atrophic gastritis. A significant correlation between endoscopic and histological atrophic gastritis was noted and the sensitivity and specificity of endoscopic diagnosis were 65.9% and 58.0% for antrum, 71.3% and 53.7% for corpus, respectively.
The endoscopic, histological, and serological atrophic gastritis showed relatively good correlations. However, as these three methods have a limitation, a multifactorial assessment might be needed to ameliorate the diagnostic accuracy of atrophic gastritis.
PMCID: PMC4189476  PMID: 25337572
Atrophic gastritis; Histology; Endoscopy; Pepsinogen
17.  Mechanisms of acquired resistance to EGFR-tyrosine kinase inhibitor in Korean patients with lung cancer 
BMC Cancer  2013;13:606.
Despite an initial good response to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), resistance to treatment eventually develops. Although several resistance mechanisms have been discovered, little data exist regarding Asian patient populations.
Among patients at a tertiary referral hospital in Korea who initially responded well to gefitinib and later acquired resistance to treatment, we selected those with enough tissues obtained before EGFR-TKI treatment and after the onset of resistance to examine mutations by mass spectrometric genotyping technology (Asan-Panel), MET amplification by fluorescence in situ hybridization (FISH), and analysis of AXL status, epithelial-to-mesenchymal transition (EMT) and neuroendocrine markers by immunohistochemistry.
Twenty-six patients were enrolled, all of whom were diagnosed with adenocarcinoma with EGFR mutations (19del: 16, L858R: 10) except one (squamous cell carcinoma with 19del). Secondary T790M mutation was detected in 11 subjects (42.3%) and four of these patients had other co-existing resistance mechanisms; increased AXL expression was observed in 5/26 patients (19.2%), MET gene amplification was noted in 3/26 (11.5%), and one patient acquired a mutation in the phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) gene. None of the patients exhibited EMT; however, increased CD56 expression suggesting neuroendocrine differentiation was observed in two patients. Interestingly, conversion from L858R-mutant to wild-type EGFR occurred in one patient. Seven patients (26.9%) did not exhibit any known resistance mechanisms. Patients with a T790M mutation showed a more favorable prognosis.
The mechanisms and frequency of acquired EGFR-TKI resistance in Koreans are comparable to those observed in Western populations; however, more data regarding the mechanisms that drive EGFR-TKI resistance are necessary.
PMCID: PMC3877961  PMID: 24369725
Non-small cell lung carcinoma; Epidermal growth factor receptor mutation; EGFR tyrosine kinase inhibitor; Acquired resistance; Resistant mechanism; Mass spectrometric genotyping
18.  Inhibition of 15-hydroxyprostaglandin dehydrogenase by Helicobacter pylori in Human Gastric Carcinogenesis 
Helicobacter pylori (H pylori) infection induces a chronic inflammatory response, which promotes gastric carcinogenesis. 15-hydroxyprostaglandin dehydrogenase (15–PGDH) plays a key role as a tumor suppressor in gastrointestinal cancers. The aim of this study was to elucidate the role of 15-PGDH in gastric carcinogenesis associated with H pylori. 15-PGDH expression in gastric biopsies from H pylori-infected (n=25) and non-infected (n=15) subjects was analyzed by quantitative real-time PCR, western blot analysis, and immunohistochemisty. 15-PGDH DNA methylation was evaluated by methylation specific PCR and pyrosequencing. The expression of 15-PGDH, Snail, ERK1/2, TLR4 and MyD88 in response to H pylori infection was assessed by immunoblot analysis. Compared to negative specimens, H pylori positive specimens had 2-fold lower 15-PGDH mRNA levels and significantly less 15-PGDH protein. In four H pylori infected subjects with longitudinal follow-up, the suppression of 15-PGDH expression was reversed by H pylori eradication therapy. In parallel with suppressing 15-PGDH expression, H pylori infection activated expression of TLR4 and MyD88 expression, increased levels of phospho-ERK1/2, and increased expression of epidermal growth factor receptor (EGFR)-Snail. Inhibition of Snail and MyD88 reversed suppression of 15-PGDH expression and small interfering Myd88 reduced phosphorylated ERK1/2. Similarly, treatment with an ERK1/2 and EGFR inhibitor also restored 15-PGDH expression. Heliocobacter pylori appeared to promote gastric carcinogenesis by suppressing15-PGDH. This process is mediated by the TLR4/MyD88 pathway via ERK1/2 or EGFR - Snail transcriptional regulation. 15-PGDH may be a useful marker and a potential therapeutic target in H pylori-induced gastric carcinogenesis.
PMCID: PMC3796116  PMID: 23430757
Gastric cancer; Helicobacter pylori; 15-prostaglandin dehydrogenase
19.  2-(3-Fluoro-4-methylsulfonylaminophenyl) Propanamides as Potent Transient Receptor Potential Vanilloid 1 (TRPV1) Antagonists: Structure Activity Relationships of 2-Amino Derivatives in the N-(6-trifluoromethyl-pyridin-3-ylmethyl) C-region 
Journal of medicinal chemistry  2012;55(19):8392-8408.
A series of N-(2-amino-6-trifluoromethyl-pyridin-3-ylmethyl) 2-(3-fluoro-4-methylsulfonylaminophenyl) propanamides were designed combining previously identified pharmacophoric elements and evaluated as hTRPV1 antagonists. The SAR analysis indicated that specific hydrophobic interactions of the 2-amino substituents in the C-region of the ligand were critical for high hTRPV1binding potency. In particular, compound 49S was an excellent TRPV1 antagonist (Ki(CAP) = 0.2 nM; IC50(pH) = 6.3 nM) and was thus ca. 100- and 20-fold more potent, respectively, than the parent compounds 2 and 3 for capsaicin antagonism. Furthermore, it demonstrated strong analgesic activity in the rat neuropathic model superior to 2 with almost no side effects. Compound 49S antagonized capsaicin induced hypothermia in mice, but showed TRPV1-related hyperthermia. The basis for the high potency of 49S compared to 2 is suggested by docking analysis with our hTRPV1 homology model in which the 4-methylpiperidinyl group in the C-region of 49S made additional hydrophobic interactions with the hydrophobic region.
PMCID: PMC3469757  PMID: 22957803
20.  Clinical Characteristics and Treatment Outcomes of 3 Subtypes of Achalasia According to the Chicago Classification in a Tertiary Institute in Korea 
Achalasia is classified into 3 types according to the Chicago classification. The aim of this study was to investigate characteristics and treatment outcomes of 3 achalasia subtypes in Korean patients.
Fifty-five patients diagnosed with achalasia based on conventional or high-resolution esophageal manometry were consecutively enrolled. Their clinical characteristics, manometric, endoscopic and esophagographic findings and treatment responses were analyzed among the 3 subtypes of achalasia.
Of 55 patients, 21 (38.2%) patients had type I, 28 (50.9%) patients had type II and 6 (10.9%) patients had type III. The median follow-up period was 22.4 (interquartile range, 3.6-67.4) months. Type III patients were older than type I and II patients (70.0 vs. 46.2 and 47.6 years, P = 0.023). The width of the esophagus in type I patients was wider with more frequent bird's beak appearance on esophagogram than the other 2 types (P = 0.010 and 0.006, respectively). Of the 50 patients who received the evaluation for treatment response at 3 months, 7 patients (36.8% vs. 26.9%) were treated with pneumatic dilatation and 4 patients (21.1% vs. 15.4%) with laparoscopic Heller's myotomy in type I and II groups, respectively. The treatment responses of pneumatic dilatation and Heller's myotomy in type I group were 71.4 and 50.0% and in type II were 85.7 and 75.0%, respectively, and all 5 patients in type III group showed good response to medical therapy.
Clinical characteristics of 3 achalasia subtypes in Korean patients are consistent with other studies. Treatment outcomes are variable among 3 subtypes.
PMCID: PMC3816183  PMID: 24199009
Esophageal achalasia; Esophageal motility disorders; Manometry
21.  Long-term follow up Helicobacter Pylori reinfection rate after second-line treatment: bismuth-containing quadruple therapy versus moxifloxacin-based triple therapy 
BMC Gastroenterology  2013;13:138.
The increasing trend of antibiotic resistance requires effective second-line Helicobacter pylori (H. pylori) treatment in high prevalence area of H. pylori. The aim of our study was to evaluate the reinfection rate of H. pylori after second-line treatment that would determine the long-term follow up effect of the rescue therapy.
A total of 648 patients who had failed previous H. pylori eradication on standard triple therapy were randomized into two regimens: 1, esomeprazole (20 mg b.i.d), tripotassium dicitrate bismuthate (300 mg q.i.d), metronidazole (500 mg t.i.d), and tetracycline (500 mg q.i.d) (EBMT) or 2, moxifloxacin (400 mg q.d.), esomeprazole (20 mg b.i.d), and amoxicillin (1000 mg b.i.d.) (MEA). At four weeks after completion of eradication therapy, H. pylori tests were performed with 13C urea breath test or invasive tests. In patients who maintained continuous H. pylori negativity for the first year after eradication therapy, H. pylori status was assessed every year. For the evaluation of risk factors of reinfection, gender, age, clinical diagnosis, histological atrophic gastritis or intestinal metaplasia were analyzed.
The recrudescence rate of the EBMT was 1.7% and of the MEA group 3.3% (p = 0.67). The annual reinfection rate of H. pylori of EBMT was found to be 4.45% and the MEA group 6.46%. Univariate analysis (Log-rank test) showed no association with any clinical risk factor for reinfection.
The long-term reinfection rate of H. pylori stayed low in both of bismuth-containing quadruple therapy and moxifloxacin-based triple therapy; thus reinfection cannot affect the choice of second-line treatment.
Trial registration
Clinical Trial Registration Number NCT01792700
PMCID: PMC3848835  PMID: 24050512
Helicobacter pylori; Reinfection; Quadruple; Moxifloxacin; Second-line
23.  CD49fhigh Cells Retain Sphere-Forming and Tumor-Initiating Activities in Human Gastric Tumors 
PLoS ONE  2013;8(8):e72438.
Identification of gastric tumor-initiating cells (TICs) is essential to explore new therapies for gastric cancer patients. There are reports that gastric TICs can be identified using the cell surface marker CD44 and that they form floating spheres in culture, but we could not obtain consistent results with our patient-derived tumor xenograft (PDTX) cells. We thus searched for another marker for gastric TICs, and found that CD49fhigh cells from newly-dissected gastric cancers formed tumors with histological features of parental ones while CD49flow cells did not when subcutaneously injected into immunodeficient mice. These results indicate that CD49f, a subunit of laminin receptors, is a promising marker for human gastric TICs. We established a primary culture system for PDTX cells where only CD49fhigh cells could grow on extracellular matrix (ECM) to form ECM-attaching spheres. When injected into immunodeficient mice, these CD49fhigh sphere cells formed tumors with histological features of parental ones, indicating that only TICs could grow in the culture system. Using this system, we found that some sphere-forming TICs were more resistant than gastric tumor cell lines to chemotherapeutic agents, including doxorubicin, 5-fluorouracil and doxifluridine. There was a patient-dependent difference in the tumorigenicity of sphere-forming TICs and their response to anti-tumor drugs. These results suggest that ECM plays an essential role for the growth of TICs, and that this culture system will be useful to find new drugs targeting gastric TICs.
PMCID: PMC3756075  PMID: 24015244
24.  Type-Specific Diagnosis and Evaluation of Longitudinal Tumor Extent of Borrmann Type IV Gastric Cancer: CT versus Gastroscopy 
Korean Journal of Radiology  2013;14(4):597-606.
To compare the accuracy of computed tomography (CT) with that of gastroscopy for the extent of evaluation of longitudinal tumor and type-specific diagnosis of Borrmann type IV gastric cancer.
Materials and Methods
Fifty-nine patients (35 men with mean age of 60 years and 24 women with mean age of 55 years) who underwent surgical resection of Borrmann type IV gastric cancer were included in this study. Histopathological analysis data was used as a reference standard to confirm the clinical interpretations of gastroscopy and CT for the diagnosis of Borrmann type IV and evaluation of longitudinal tumor extent. For the evaluation of longitudinal extent, gastroscopic and CT results were classified as underestimated, accurate, or overestimated. The McNemar test was used to identify statistically significant differences in the accuracy between gastroscopy and CT.
For the diagnosis of Borrmann type IV gastric cancer, the accuracy of CT was significantly higher than that of gastroscopy (74.6% [44/59] vs. 44.1% [26/59], p < 0.001). CT was significantly more accurate in assessing the overall tumor extent than gastroscopy (61.4% [35/57] vs. 28.1% [16/57], p < 0.001). The proximal (75.4% [43/57] vs. 50.9% [29/57], p = 0.003) and distal tumor extent (71.9% [41/57] vs. 43.9% [25/57], p < 0.05) were more accurately predicted by CT compared with gastroscopy. The underestimation of tumor extent was a major source of error in both examinations.
CT was found to be more predictive than gastroscopy in type-specific diagnosis and the evaluation of longitudinal tumor extent in patients with Borrmann type IV gastric cancer.
PMCID: PMC3725354  PMID: 23901317
Stomach; Cancer; CT; Gastroscopy; Borrmann type IV; Linitis plastica
25.  Risk Factors of Atrophic Gastritis and Intestinal Metaplasia in First-Degree Relatives of Gastric Cancer Patients Compared with Age-Sex Matched Controls 
Journal of Cancer Prevention  2013;18(2):149-160.
To identify whether first-degree relatives (FDRs) of gastric cancer (GC) patients have increased risk for atrophic gastritis (AG) and intestinal metaplasia (IM) in relation to other risk factors of GC.
The study cohort consisted of 224 pairs of age-sex matched controls and FDRs. AG and IM in the gastric mucosa were scored histologically using the updated Sydney classification. Risk of having AG and IM was studied by comparing FDRs to controls. Impacts of age, H. pylori infection, smoking, dietary and socioeconomic factors on the presence of AG and IM were studied.
In multivariate regression analysis, FDRs had adjusted OR of 2.69 (95% CI 1.06–6.80, P=0.037) for antral IM in male population. Adjusted OR for antral AG and IM were 9.28 (95% CI 4.73–18.18, P<0.001) and 7.81 (95% CI 3.72–16.40, P<0.001) for the H. pylori infected subjects in total population. Getting old by 5 years increased the ORs of having AG and IM by approximately 1.25 fold (P<0.001). Spicy food increased the OR of antral IM by 2.28 fold (95% CI 1.36–3.84, P=0.002).
Family history of GC was an independent risk factor for antral IM in male in our study, which could be one reason for the increase of gastric cancer in the family member of gastric cancer. It could be an evidence for the necessity of frequent endoscopy in the presence of family history of GC compared to general population in male.
PMCID: PMC4189453  PMID: 25337541
Stomach neoplasms; Helicobacter pylori; Atrophic gastritis; Metaplasia

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