PURPOSE: Lapatinib is a candidate drug for treatment of trastuzumab-resistant, human epidermal growth factor receptor 2 (HER2)–positive gastric cancer (GC). Unfortunately, lapatinib resistance renders this drug ineffective. The present study investigated the implication of forkhead box O1 (FOXO1) signaling in the acquired lapatinib resistance in HER2-positive GC cells. MATERIALS AND METHODS: Lapatinib-resistant GC cell lines (SNU-216 LR2-8) were generated in vitro by chronic exposure of lapatinib-sensitive, HER2-positive SNU-216 cells to lapatinib. SNU-216 LR cells with FOXO1 overexpression were generated by stable transfection of a constitutively active FOXO1 mutant (FOXO1A3). HER2 and MET in SNU-216 LR cells were downregulated using RNA interference. The sensitivity of GC cells to lapatinib and/or cisplatin was determined by crystal violet assay. In addition, Western blot analysis, luciferase reporter assay and reverse transcription–polymerase chain reaction were performed. RESULTS: SNU-216 LR cells showed upregulations of HER2 and MET, but downregulation of FOXO1 compared to parental SNU-216 cells. FOXO1 overexpression in SNU-216 LR cells significantly suppressed resistance to lapatinib and/or cisplatin. In addition, FOXO1 negatively controlled HER2 and MET at the transcriptional level and was negatively controlled by these molecules at the post-transcriptional level. A positive crosstalk was shown between HER2 and MET, each of which increased resistance to lapatinib and/or cisplatin. CONCLUSION: FOXO1 serves as an important linker between HER2 and MET signaling pathways through negative crosstalks and is a key regulator of the acquired lapatinib resistance in HER2-positive GC cells. These findings provide a rationale for establishing a novel treatment strategy to overcome lapatinib resistance in a subtype of GC patients.
Blotting, Western ; Cell Line ; Cisplatin ; Down-Regulation ; Drug Resistance ; Gentian Violet ; Humans ; In Vitro Techniques ; Luciferases ; Parents ; Receptor, Epidermal Growth Factor ; Receptor, ErbB-2 ; RNA Interference ; Stomach Neoplasms ; Transfection ; Up-Regulation

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by the proliferation of one or more myeloid lineages. The current study demonstrates that three driver mutations were detected in 82.6% of 407 MPNs with a mutation distribution of JAK2 in 275 (67.6%), CALR in 55 (13.5%) and MPL in 6 (1.5%). The mutations were mutually exclusive in principle except in one patient with both CALR and MPL mutations. The driver mutation directed the pathologic features of MPNs, including lineage hyperplasia, laboratory findings and clinical presentation. JAK2-mutated MPN showed erythroid, granulocytic and/or megakaryocytic hyperplasia whereas CALR- and MPL-mutated MPNs displayed granulocytic and/or megakaryocytic hyperplasia. The lineage hyperplasia was closely associated with a higher mutant allele burden and peripheral cytosis. These findings corroborated that the lineage hyperplasia consisted of clonal proliferation of each hematopoietic lineage acquiring driver mutations. Our study has also demonstrated that bone marrow (BM) fibrosis was associated with disease progression. Patients with overt fibrosis (grade ⩾2) presented an increased mutant allele burden (P<0.001), an increase in chromosomal abnormalities (P<0.001) and a poor prognosis (P<0.001). Moreover, among patients with overt fibrosis, all patients with wild-type JAK2/CALR/MPL (triple-negative) showed genomic alterations by genome-wide microarray study and revealed the poorest overall survival, followed by JAK2-mutated MPNs. The genetic–pathologic characteristics provided the information for understanding disease pathogenesis and the progression of MPNs. The prognostic significance of the driver mutation and BM fibrosis suggests the necessity of a prospective therapeutic strategy to improve the clinical outcome.
Alleles ; Bone Marrow ; Chromosome Aberrations ; Disease Progression ; Fibrosis ; Hematopoietic Stem Cells ; Humans ; Hyperplasia ; Prognosis ; Prospective Studies

BACKGROUND/AIMS: Colorectal cancer (CRC) develops from colonic adenomas. Type 2 diabetes mellitus (DM) is associated with a higher risk of CRC and metformin decreases CRC risk. However, it is not certain if metformin affects the development of colorectal polyps and adenomas. This study aimed to elucidate if metforminaffects the incidence of colonic polyps and adenomas in patients with type 2 DM. METHODS: Of 12,186 patients with type 2 DM, 3,775 underwent colonoscopy between May 2001 and March 2013. This study enrolled 3,105 of these patients, and divided them in two groups: 912 patients with metformin use and 2,193 patients without metformin use. Patient clinical characteristics, polyp and adenoma detection rate in the two groups were analyzed retrospectively. RESULTS: The Colorectal polyp detection rate was lower in the metformin group than in the non-meformin group (39.4% vs. 62.4%, P<0.01). Colorectal adenoma detection rate was significantly lower in the metformin group than in the non-metformin group (15.2% vs. 20.5%, P<0.01). Fewer advanced adenomas were detected in the metformin group than in the non-metformin group (12.2% vs. 22%, P<0.01). Multivariate analysis identified age, sex, Body mass index and metformin use as factors associated with polyp incidence, whereas only metforminwas independently associated with decreased adenoma incidence (Odd ratio=0.738, 95% CI=0.554-0.983, P=0.03). CONCLUSIONS: In patients with type 2 DM, metformin reduced the incidence of adenomas that may transform into CRC. Therefore, metformin may be useful for the prevention of CRC in patients with type 2 DM.
Adenoma* ; Body Mass Index ; Colon ; Colonic Polyps* ; Colonoscopy ; Colorectal Neoplasms ; Diabetes Mellitus, Type 2* ; Humans ; Incidence* ; Metformin* ; Multivariate Analysis ; Polyps ; Retrospective Studies

Enteropathy-type T-cell lymphoma (ETL) or enteropathy-associated T-cell lymphoma is a very rare malignant intestinal tumor. ETL is usually diagnosed by surgery. Endoscopic findings of ETL are not well known, and there are few reports of findings from endoscopy that has been performed only using white light. Additionally, there are no definite treatment guidelines for ETL. Therefore, we report a case of ETL diagnosed by enteroscopy with imaging-enhanced endoscopy and also review recently developed treatment options.
Endoscopy ; Enteropathy-Associated T-Cell Lymphoma ; Humans ; Light ; Lymphoma, T-Cell ; T-Lymphocytes

OBJECTIVE: To ascertain the etiology of non-traumatic plexopathy and clarify the clinical, electrophysiological characteristics according to its etiology. METHOD: We performed a retrospective analysis of 63 non-traumatic plexopathy patients that had been diagnosed by nerve conduction studies (NCS) and needle electromyography (EMG). Clinical, electrophysiological, imaging findings were obtained from medical records. RESULTS: We identified 36 cases with brachial plexopathy (BP) and 27 cases with lumbosacral plexopathy (LSP). The causes of plexopathy were neoplastic (36.1%), thoracic outlet syndrome (TOS) (25.0%), radiation induced (16.7%), neuralgic amyotrophy (8.3%), perioperative (5.6%), unknown (8.3%) in BP, while neoplastic (59.3%), radiation induced (22.2%), neuralgic amyotrophy (7.4%), psoas muscle abscess (3.7%), and unknown (7.4%) in LSP. In neoplastic plexopathy, pain presented as the first symptom in most patients (82.8%), with the lower trunk of the brachial plexus predominantly involved. In radiation induced plexopathy (RIP), pain was a common initial symptom, but the proportion was smaller (50%), and predominant involvements of bilateral lumbosacral plexus and whole trunk of brachial or lumbosacral plexus were characteristic. Myokymic discharges were noted in 41.7% patients with RIP. Abnormal NCS finding in the medial antebrachial cutaneous nerve was the most sensitive to diagnose TOS. Neuralgic amyotrophy of the brachial plexus showed upper trunk involvement in all cases. CONCLUSION: By integrating anatomic, pathophysiologic knowledge with detailed clinical assessment and the results of ancillary studies, physicians can make an accurate diagnosis and prognosis.
Abscess ; Adult ; Brachial Plexus ; Brachial Plexus Neuritis ; Brachial Plexus Neuropathies ; Electromyography ; Electrophysiology ; Humans ; Lumbosacral Plexus ; Needles ; Neural Conduction ; Prognosis ; Psoas Muscles ; Retrospective Studies ; Thoracic Outlet Syndrome

Enteropathy-associated T-cell lymphoma (EATL) is an unusual primary gastrointestinal lymphoma, and it is particularly associated with celiac sprue. These patients typically suffer from abdominal pain, diarrhea and/or weight loss. Primary intestinal T-cell lymphoma without celiac sprue is known to be rare. We report here on a case of EATL that presented with persistent abdominal pain and diarrhea, but this patient was without celiac sprue.
Abdominal Pain* ; Celiac Disease ; Diarrhea* ; Enteropathy-Associated T-Cell Lymphoma ; Humans ; Intestines ; Lymphoma ; Lymphoma, T-Cell* ; T-Lymphocytes* ; Weight Loss

Enteropathy-associated T-cell lymphoma (EATL) is an unusual primary gastrointestinal lymphoma, and it is particularly associated with celiac sprue. These patients typically suffer from abdominal pain, diarrhea and/or weight loss. Primary intestinal T-cell lymphoma without celiac sprue is known to be rare. We report here on a case of EATL that presented with persistent abdominal pain and diarrhea, but this patient was without celiac sprue.
Abdominal Pain* ; Celiac Disease ; Diarrhea* ; Enteropathy-Associated T-Cell Lymphoma ; Humans ; Intestines ; Lymphoma ; Lymphoma, T-Cell* ; T-Lymphocytes* ; Weight Loss

BACKGROUND: We analysed differences in operative methods and postoperative outcome according to the severity of preoperative cyanosis in adult ToF (Tetralogy of Fallot) patients. MATERIAL AND METHOD: From August 1989 to June 2001, thirty three adult patients, 18 females and 15 males, underwent total correction for ToF. Their age ranged from 15 years to 54 years (median: 34). Patients were divided into 2 groups by preoperative SaO2 (arterial oxygen saturation): group I (n=cyanotic, SaO2 < or =94%) and group II (acyanotic, SaO2 > or =95%). Preoperative median hemoglobin level was higher in group I compared to group II (17.5 g/dl vs 15 g/dl). Postoperative follow-up duration ranged from 1 to 94 months (670 patient-month, median: 14 months), and 63 two-dimensional echocardiographic examinations were done during this period. RESULT: There were no early or late mortality. With regard to RVOT (right ventricular outflow tract) reconstruction, trans-annular patch and RV-PA extracardiac conduit were used in 7 and 3 patients respectively, and all of them belonged to group I. In group I, cardiopulmonary bypass time, aortic cross-clamping time, ICU day, hospital day were significantly longer than in group II, and postoperative inotropic support was significantly greater than in group II. There was no ventricular arrhythmia in both groups, and one patient in group I suffered from atrial arrhythmia, which was resolved spontaneously after tricuspid and pulmonary valve replacement. During follow-up periods, functional class, residual RVOT stenosis and pulmonary regurgitation, tricuspid regurgitation, occurrence of ventricular and atrial arrhythmias were comparable between two groups. CONCLUSION: In adult ToF patients with severe preoperative cyanosis, more aggressive RVOT reconstruction and careful postoperative care are mandatory. However intermediate-term outcome of this group of patients is comparable to the patients with minimal or no preoperative cyanosis.
Adult ; Arrhythmias, Cardiac ; Cardiopulmonary Bypass ; Constriction, Pathologic ; Cyanosis* ; Echocardiography ; Female ; Follow-Up Studies ; Humans ; Male ; Mortality ; Oxygen ; Postoperative Care ; Pulmonary Valve ; Pulmonary Valve Insufficiency ; Tetralogy of Fallot* ; Tricuspid Valve Insufficiency

BACKGROUND: We assessed the intermediate-term result of tricuspid annuloplasty (TAP) for tricuspid valve regurgitation (TR) associated with congenital heart disease in adults. Risk factors for residual TR were also analysed. MATERIAL AND METHOD: From August 1989 to June 2001, seventy three adult patients, 51 females and 22 males, underwent TAP for TR associated with various congenital heart disease. Their age ranged from 16 years to 73 years (mean:43). Associated heart anomalies were atrial septal defect (55), ventricular septal defect (6), partial anomalous pulmonary venous return (4) and others (8). Preoperative and postoperative TR velocities were 3.25 m/sec and 2.56 m/sec respectively, and the types of TAP were De Vega in 43, Kay in 18 and Ring annuloplasty in 12. Postoperative follow-up duration was 2,347 patient-month (mean: 32.6 months), and 134 two-dimensional echocardiographic examinations were done during this period. Residual TR greater than III/IV was considered as TAP failure. RESULT: TAP failure was observed in 7 patients (9.6%), and one patient among them underwent tricuspid valve replacement. Risk factors for TAP failure were diagnosis other than atrial septal defect (p=0.001), preoperative (p=0.038) and postoperative (p=0.028) high TR velocity. There was no statistical significance in terms of TAP methods. CONCLUSION:Careful evaluation of valve morphology and aggressive surgical intervention are mandatory for the repair of TR with preoperative or residual RV pressure overload.
Adult* ; Diagnosis ; Echocardiography ; Female ; Follow-Up Studies ; Heart ; Heart Defects, Congenital* ; Heart Septal Defects, Atrial ; Heart Septal Defects, Ventricular ; Heart Valve Diseases ; Humans ; Male ; Risk Factors ; Scimitar Syndrome ; Tricuspid Valve ; Tricuspid Valve Insufficiency*

OBJECTIVES: The present study explored the reliability and the validity of our newly constructed job stress scale, the Korean version of the Occupational Stress Inventory (K-OSI) METHODS: Through preliminary item-analysis, we constructed 140 items of the Korean version of Occupational Stress Inventory (K-OSI) K-OSI consists of three subscales measuring three sections, 'ORQ'(Occupational Role Questionnaire) 'PSQ'(Personal Strain Questionnaire) and 'PRQ'(Personal Resource Questionnaire) respectively. The normative group consisted of 805 adult workers who represented six major job classes in Korea. RESULTS: The internal consistency coefficients of 'ORQ', 'PSQ', and 'PRQ' ranged from .89 to .92, and of those 14 subscales ranged from .70 to .88. The test-retest reliability coefficients of 8 week duration ranged from .62 to . 79, and bilingual's consistency coefficient ranged from .82 to . 96. The validity of the K-OSI was investigated by factor-analysis, yielding 3 factors of overall job stress and its responses, personal stress coping, psychological, physical, and behavioral responses of job stress. CONCLUSION: The present results indicate that the K-OSI is a reliable and valid measure of job stress.
Adult ; Humans ; Korea ; Reproducibility of Results*