Purpose: Epidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare and poorly understood oncogenic mutation in non–small cell lung cancer (NSCLC). We aimed to investigate the acquired resistance mechanism of EGFR-KDD against EGFR-TKIs. Materials and Methods: We identified EGFR-KDD in tumor tissue obtained from a patient with stage IV lung adenocarcinoma and established the patient-derived cell line SNU-4784. We also established several EGFR-KDD Ba/F3 cell lines: EGFR-KDD wild type (EGFR-KDDWT), EGFR-KDD domain 1 T790M (EGFR-KDDD1T), EGFR-KDD domain 2 T790M (EGFR-KDDD2T), and EGFR-KDD both domain T790M (EGFR-KDDBDT). We treated the cells with EGFR tyrosine kinase inhibitors (TKIs) and performed cell viability assays, immunoblot assays, and ENU (N-ethyl-N-nitrosourea) mutagenesis screening. Results: In cell viability assays, SNU-4784 cells and EGFR-KDDWT Ba/F3 cells were sensitive to 2nd generation and 3rd generation EGFR TKIs. In contrast, the T790M-positive EGFR-KDD Ba/F3 cell lines (EGFR-KDDT790M) were only sensitive to 3rd generation EGFR TKIs. In ENU mutagenesis screening, we identified the C797S mutation in kinase domain 2 of EGFR-KDDBDT Ba/F3 cells. Based on this finding, we established an EGFR-KDD domain 1 T790M/domain 2 cis-T790M+C797S (EGFR-KDDT/T+C) Ba/F3 model, which was resistant to EGFR TKIs and anti-EGFR monoclonal antibody combined with EGFR TKIs. Conclusion Our study reveals that the T790M mutation in EGFR-KDD confers resistance to 1st and 2nd generation EGFR TKIs, but is sensitive to 3rd generation EGFR TKIs. In addition, we identified that the C797S mutation in kinase domain 2 of EGFR-KDDT790M mediates a resistance mechanism against 3rd generation EGFR TKIs.

BACKGROUND: We aimed to investigate the effectiveness and safety of adding basal insulin to initiating dipeptidyl peptidase-4 (DPP-4) inhibitor and metformin and/or sulfonylurea (SU) in achieving the target glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM). METHODS: This was a single-arm, multicenter, 24-week, open-label, phase 4 study in patients with inadequately controlled (HbA1c ≥7.5%) T2DM despite the use of DPP-4 inhibitor and metformin. A total of 108 patients received insulin glargine while continuing oral antidiabetic drugs (OADs). The primary efficacy endpoint was the percentage of subjects achieving HbA1c ≤7.0%. Other glycemic profiles were also evaluated, and the safety endpoints were adverse events (AEs) and hypoglycemia. RESULTS: The median HbA1c at baseline (8.9%; range, 7.5% to 11.1%) decreased to 7.6% (5.5% to 11.7%) at 24 weeks. Overall, 31.7% subjects (n=33) achieved the target HbA1c level of ≤7.0%. The mean differences in body weight and fasting plasma glucose were 1.2±3.4 kg and 56.0±49.8 mg/dL, respectively. Hypoglycemia was reported in 36 subjects (33.3%, 112 episodes), all of which were fully recovered. There was no serious AE attributed to insulin glargine. Body weight change was significantly different between SU users and nonusers (1.5±2.5 kg vs. −0.9±6.0 kg, P=0.011). CONCLUSION: The combination add-on therapy of insulin glargine, on metformin and DPP-4 inhibitors with or without SU was safe and efficient in reducing HbA1c levels and thus, is a preferable option in managing T2DM patients exhibiting dysglycemia despite the use of OADs.
Blood Glucose ; Body Weight ; Body Weight Changes ; Diabetes Mellitus, Type 2 ; Fasting ; Hemoglobin A, Glycosylated ; Humans ; Hypoglycemia ; Hypoglycemic Agents ; Insulin Glargine ; Insulin ; Metformin ; Morinda

OBJECTIVE: While the prognostic factors of survival for patients with hepatocellular carcinoma (HCC) who underwent transarterial chemoembolization (TACE) are well known, the clinical significance of performing selective TACE for HCC patients has not been clearly documented. We tried to analyze the potential factors of disease-free survival for these patients, including the performance of selective TACE. MATERIALS AND METHODS: A total of 151 patients with HCC who underwent TACE were retrospectively analyzed for their disease-free survival (a median follow-up of 23 months, range: 1-88 months). Univariate and multivariate analyses were performed for 20 potential factors by using the Cox proportional hazard model, including 19 baseline factors and one procedure-related factor (conventional versus selective TACE). The parameters that proved to be significant on the univariate analysis were subsequently tested with the multivariate model. RESULTS: Conventional or selective TACE was performed for 40 and 111 patients, respectively. Univariate and multivariate analyses revealed that tumor multiplicity, venous tumor thrombosis and selective TACE were the only three independent significant prognostic factors of disease-free survival (p = 0.002, 0.015 and 0.019, respectively). CONCLUSION: In our study, selective TACE was a favorable prognostic factor for the disease-free survival of patients with HCC who underwent TACE.
Adult ; Aged ; Antibiotics, Antineoplastic/administration & dosage ; Carcinoma, Hepatocellular/mortality/*therapy ; *Chemoembolization, Therapeutic ; Contrast Media/administration & dosage ; Disease-Free Survival ; Doxorubicin/administration & dosage ; Female ; Humans ; Iodized Oil/administration & dosage ; Liver Neoplasms/mortality/*therapy ; Male ; Middle Aged ; Prognosis

Self-expanding metallic stent insertion has been widely applied for the palliative treatment of malignant esophageal strictures. Although it is known as an easy, safe, and effective procedure, complications are well known and include things such as stent migration and esophageal stent occlusion caused by tumor ingrowth. However, metallic stent fractures have been rarely reported in the esophagus, especially for nitinol stents. We report a case of a stent fracture associated with migration in a patient with a malignant esophageal stricture near the gastroesophageal junction. It is highly probable that the stent fracture was due to chemical erosion of the stent caused by gastric juice.
Alloys ; Constriction, Pathologic ; Esophageal Stenosis ; Esophagogastric Junction ; Esophagus ; Gastric Juice ; Humans ; Palliative Care ; Stents

The absence of the inferior vena cava is an uncommon congenital anomaly that has recently been identified as an important risk factor contributing to the development of deep venous thrombosis. Congenital agenesis of the right hepatic lobe is a rare anomaly which is found incidentally in radiologic examinations. We present a case of a congenital absence of the infrarenal inferior vena cava, combined with agenesis of the right hepatic lobe in a 62-year-old man presented with symptoms of deep venous thrombosis.
Humans ; Liver/*abnormalities/radiography ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Tomography, X-Ray Computed ; Vena Cava, Inferior/*abnormalities/radiography ; Venous Thrombosis/etiology

Elastofibroma dorsi is a rare, slow-growing, ill defined soft tissue tumor that's typically found between the inferior scapula and chest wall. The characteristic findings on ultrasonography, MRI and CT usually allow the correct diagnosis and so prevent unnecessary surgical procedure. We experienced a case of bilateral elastofibroma dorsi in an 87-year-old man, and we report on this case along with a review of the literature.
Aged, 80 and over ; Diagnosis ; Humans ; Magnetic Resonance Imaging ; Scapula ; Thoracic Wall ; Ultrasonography

BACKGROUND: Secondary spinal cord injury (SCI) that follows an initial mechanical insult can exacerbate the overall damage, limit the restorative processes and eventually lead to an in- creased neurological deficit. We hypothesized that selective inhibition of cyclooxygenase-2 (COX-2) may decrease the delayed cell death, and so this will contribute to decreased level of the secondary injury. METHODS: The dorsal surface of the cord at the T9 level was subjected to weight drop impact using a 10 g rod. To block COX-2 activation, a selective COX-2 inhibitor (NS-398) was administered (5 mg/kg, i.p.) 15 min prior to SCI. The COX-1, COX-2, Caspase-3 and PGE2 expressions were measured by real time quantitative RT-PCR and fluorescence immunostaining. RESULTS: Many activated caspase-3 positive cells were observed at 6 h and they increased until 72 h after SCI. The expression of COX-2 peaked at 6 h after SCI, while the COX-1 expression was unaffected. The principal cells that showed a COX-2 expression were the neurons and microglia. Pretreatment with NS-398 caused a significant decrease in the expression of prostaglandin E2 and activated caspase-3 positive cells after SCI. CONCLUSION: These data suggest that COX-2 is one of the main factors related with the pathologic deficits from secondary SCI.
Animals ; Caspase 3 ; Cell Death ; Contusions* ; Cyclooxygenase 2 Inhibitors ; Cyclooxygenase 2* ; Dinoprostone ; Fluorescence ; Microglia ; Neurons ; Rats* ; Spinal Cord Injuries ; Spinal Cord*

BACKGROUND: Genistein and daidzein are two major soybean isoflavones. They have received increasing attention because of their possible roles for cancer prevention. However, their mechanisms of action and molecular targets on the human colon cancer cells are not fully understood. METHODS: Human colon cancer HCT-116 cells were treated with genistein and daidzein to investigate their effects on the cell growth and this was analyzed with MTT assay. TUNEL assay and Hoechst33342 stain were carried out to identify apotosis. RESULTS: Daidzein was able to inhibit cell proliferation and induce apoptosis of the HCT-116 cells, but genistein didn't affect the cell growth. The ER antagonist ICI182780 didn't attenuate the antiproliferative and proapoptotic effects of daidzein: this means the effect of daidzein on the HCT-116 cells may not be dependent on the ER pathway. The other soybean isoflavone, genistein, attenuated the effects of daidzein on the HCT-116 cells and its mechanism should be elucidated. CONCLUSIONS: These data suggest that daidzein may act as a preventive agent on human colon cancer, and its mechanism of action doesn't involve the ER-dependent pathway.
Apoptosis ; Cell Proliferation ; Colon* ; Colonic Neoplasms* ; Genistein* ; HCT116 Cells* ; Humans* ; In Situ Nick-End Labeling ; Isoflavones ; Soybeans

Acute spinal cord injury (SCI) is two-step process that first involves the primary mechanical injury and then the secondary injury is induced by various biochemical reactions. Apoptosis is one of secondary SCI mechanisms and it is thought to play an important role for the delayed neuronal injury. The enhanced formation of nitric oxide (NO) via inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of apoptosis in SCI. The level of .iNOS mRNA peaked at 6 hr after SCI and it declined until 72 hr after SCI in a rat model. Double-immunofluorescence staining revealed that iNOS positive cells were stained for ED-1, synaptophysin, GFAP, and oligodendrocyte marker. The terminal deoxynucleotidyl-transferase-mediated dUDP-biotin nick end-labeling (TUNEL) positive cell count was higher for the 72 hr post-SCI group than for the 24 hr post-SCI group. This cell count was also higher going in the caudal direction than in the rostral direction from the epicenter, and especially for the 72 hr group. Treatment with a selective iNOS inhibitor resulted in the reduction of TUNEL-positive cells at the lesion site. These findings suggest that nitric oxide generated by the iNOS of macrophages, neurons, oligodentrocytes, and astrocytes plays an important role for the acute secondary SCI that results from apoptotic cell death.
Analysis of Variance ; Animals ; Apoptosis ; Comparative Study ; Glial Fibrillary Acidic Protein/analysis ; In Situ Nick-End Labeling ; Microscopy, Fluorescence ; RNA, Messenger/genetics/metabolism ; Rats ; Rats, Sprague-Dawley ; Research Support, Non-U.S. Gov't ; Reverse Transcriptase Polymerase Chain Reaction ; Spinal Cord/chemistry/enzymology/pathology ; Spinal Cord Injuries/*enzymology/pathology/physiopathology ; Time Factors

OBJECTIVES: Apoptosis may play a major role in determining the growth and progression of the tumors. Certain oncogenes and tumor supressor genes are known to modulate apoptosis. The aim of study was to investigate whether apoptosis is related to the degree of differentiation, MIB-1 indicies, and expression of mutated p53 and bcl-2 in cervical neoplasms. MATERIALS AND METHODS: We examined 57 samples of normal, premalignant(i.e. mild, moderate and severe dysplasia and carcinoma in situ), malignant cervical tissue to evaluate whether differences in the apoptotic activity. Apoptotic cells and bodies were visualized by 3' end labelling. Simultaneously, quantitative immunostaining was performed for bcl-2 and p53, two known regulators of apoptosis. RESULTS: The cell proliferation index as determined by MIB-1 immunohistochemistry increased with progression from normal to cervical intraepithelial neoplasm and invasive cancer. The apoptotic index(AI) also increased with grade of lesion and was significantly associated with cell proliferation. However, the extent of apoptosis did not correlate with the expression of p53 and bcl-2. CONCLUSIONS: These results suggest that the elevation of AI in cervical neoplasm is associated with cell proliferation activity but is independent of the expression of p53 and bcl-2. It is likely that the effects on apoptosis of bcl-2 and p53 are countered by those of other oncogene products and/or additional factors that regulate apoptosis in vivo.
Apoptosis* ; Cell Proliferation ; Cervical Intraepithelial Neoplasia* ; Immunohistochemistry ; Oncogene Proteins ; Oncogenes ; Uterine Cervical Neoplasms