Purpose: Circulating tumor DNA (ctDNA) is emerging as a valuable non-invasive tool to identify tumor heterogeneity and tumor burden. This study investigated ctDNA dynamics in metastatic colorectal cancer patients treated with regorafenib. Materials and Methods: In this prospective biomarker study, plasma cell-free DNA (cfDNA) samples obtained at baseline, at the first response evaluation after 2 cycles of treatment, and at the time of progressive disease were sequenced using a targeted next-generation sequencing platform which included 106 genes. Results: A total of 285 blood samples from 110 patients were analyzed. Higher baseline cfDNA concentration was associated with worse progression-free survival (PFS) and overall survival (OS). After 2 cycles of treatment, variant allele frequency (VAF) in the majority of ctDNA mutations decreased with a mean relative change of –31.6%. Decreases in the VAF of TP53, APC, TCF7L2, and ROS1 after 2 cycles of regorafenib were associated with longer PFS. We used the sum of VAF at each time point as a surrogate for the overall ctDNA burden. A reduction in sum (VAF) of ≥ 50% after 2 cycles was associated with longer PFS (6.1 vs. 2.7 months, p=0.002), OS (11.3 vs. 5.9 months, p=0.001), and higher disease control rate (86.3% vs. 51.1%, p < 0.001). VAF of the majority of the ctDNA mutations increased at the time of disease progression, and VAF of BRAF increased markedly. Conclusion Reduction in ctDNA burden as estimated by sum (VAF) could be used to predict treatment outcome of regorafenib.

OBJECTIVE: The aim of this study was to evaluate the diagnostic value of integrated 18F-fluoro-2-deoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) for suspected recurrence of epithelial ovarian cancer (EOC) with non-disseminated lesions. METHODS: We retrospectively reviewed the medical records of recurrent EOC patients who underwent secondary cytoreduction from January 2000 to December 2013. A total of 134 patients underwent secondary cytoreduction after imaging with either 18F-FDG-PET/CT or contrast-enhanced computed tomography (CECT). RESULTS: In a patient-based analysis of 134 patients, 124 (92.5%) were confirmed to be positive for malignancy. Among 72 patients with suspected non-disseminated recurrence on 18F-FDG-PET/CT, 65 (89.0%) were confirmed to have recurrence, giving 98.5% sensitivity, 87.7% accuracy, and 88.9% positive predictive value (PPV). In the 65 patients with recurrence, residual tumor remained in 14 patients, giving an accuracy of patient selection for secondary cytoreduction of 69.4% (50/72) and it is higher than that of CECT (64.0%). In 169 lesions removed from patients who underwent preoperative 18F-FDG-PET/CT, 135 (79.9%) were confirmed to be positive for malignancy and 124 were accurately detected by 18F-FDG-PET/CT, giving 91.9% sensitivity, 81.1% accuracy, and 85.5% PPV. Foreign body granuloma was found in 33.3% of 21 lesions with false-positive 18F-FDG-PET/CT findings (7/21). The mean preoperative cancer antigen 125 (CA-125) level in false-positive patients was 28.8 U/mL. CONCLUSION: Compared with CECT, 18F-FDG-PET/CT shows higher sensitivity in lesion-based analysis and better accuracy of patient selection for secondary cytoreduction. However, there is still a need for integration of the results of 18F-FDG-PET/CT, CECT, and CA-125 levels to aid treatment planning.
Cytoreduction Surgical Procedures ; Electrons* ; Granuloma, Foreign-Body ; Humans ; Medical Records ; Neoplasm, Residual ; Ovarian Neoplasms* ; Patient Selection* ; Recurrence ; Retrospective Studies

Gastrodia elata (GE) is traditionally used for treatment of various disorders including neurodegenerative diseases such as Alzheimer's disease. To investigate the neuroprotective effect of GE, amyloid-beta peptide (Abeta)-treated PC12 cells were cultured with GE aqueous extract. In vitro assay demonstrated that 50 microM of pre-aggregated Abeta was lethal to about a half portion of PC12 cells and that Abeta aggregate-induced cell death was significantly decreased with GE treatment at < or =10 mg/mL in a dose-dependent manner. To further examine in vivo cognitive-improving effects, an artificial amnesic animal model, scopolamine-injected Sprague-Dawley rats, were orally administered the extract for 6 weeks followed by behavioral tests (the passive avoidance test and Morris water maze test). The results showed that an acute treatment with scopolamine (1 mg/kg of body weight) effectively induced memory impairment in normal rats and that the learning and memory capability of scopolamine-treated rats improved after prolonged administration of GE extract (50, 250 and 500 mg/kg of body weight for 6 weeks). These findings suggest that a GE regimen may potentially ameliorate learning and memory deficits and/or cognitive impairments caused by neuronal cell death.
Administration, Oral* ; Alzheimer Disease ; Animals ; Body Weight ; Cell Death ; Gastrodia* ; Learning* ; Memory Disorders ; Memory* ; Models, Animal ; Neurodegenerative Diseases ; Neurons ; Neuroprotective Agents ; PC12 Cells ; Rats* ; Rats, Sprague-Dawley ; Scopolamine Hydrobromide

Lapatinib, a dual inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinases, has shown promising results as a growth inhibitor of HER2-positive cancer cells in vitro. However, similar to other EGFR-targeting drugs, acquired resistance to lapatinib by HER2-positive cancer cells remains a major clinical challenge. To elucidate resistance mechanisms to EGFR/HER2-targeting agents, we performed a systematic quantitative comparison of the phosphoproteome of lapatinib-resistant (LR) human gastric cancer cells (SNU216-LR) versus parental cells (SNU216) using a titanium dioxide (TiO2) phosphopeptide enrichment method and analysis with a Q-Exactive hybrid quadrupole-Orbitrap mass spectrometer. Biological network analysis of differentially expressed phosphoproteins revealed apparent constitutive activation of the MET-axis phosphatidylinositide 3-kinase (PI3K)/alpha-serine/threonine-protein kinase (AKT) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathways in SNU216-LR. Inhibition of the PI3K/AKT and MAPK/ERK signaling pathways in SNU216-LR also leads to cell cycle arrest, confirming the biological network analysis. Lapatinib sensitivity was restored when cells were treated with several molecular targeting agents in combination with lapatinib. Thus, by integrating phosphoproteomic data, protein networks and effects of signaling pathway modulation on cell proliferation, we found that SNU216-LR maintains constitutive activation of the PI3K/AKT and MAPK/ERK pathways in a MET-dependent manner. These findings suggest that pathway activation is a key compensatory intracellular phospho-signaling event that may govern gastric cancer cell resistance to drug treatment.
Antineoplastic Agents/*pharmacology ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; Humans ; *MAP Kinase Signaling System ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphorylation ; Proteomics ; Proto-Oncogene Proteins c-akt/*metabolism ; Proto-Oncogene Proteins c-met/*metabolism ; Quinazolines/*pharmacology

Caffeine is one of the most widely consumed neuroactive drugs, coming mostly from everyday beverages such as coffee and tea. To investigate whether caffeine induces apoptosis in the central nervous system, 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay, 4,6-diamidino-2-phenylindole (DAPI) staining, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay, flow cytometric analysis, DNA fragmentation assay, and caspase-3 enzyme assay were performed on SK-N-MC human neuroblastoma cells. Cells treated with caffeine at concentrations as high as 10 mM exhibited several characteristics of apoptosis. In addition, caffeine was shown to increase the caspase-3 activity. These results suggest that high-dose of caffeine induces apoptosis in human neuroblastoma cells, probably by increasing the caspase-3 enzyme activity.
Apoptosis/*drug effects ; Caffeine/*toxicity ; Caspase 3 ; Caspases/metabolism ; Cell Cycle/drug effects ; Cell Survival/drug effects ; Central Nervous System/cytology/*drug effects ; DNA Fragmentation ; Humans ; Neuroblastoma/enzymology/pathology ; Tumor Cells, Cultured

BACKGROUND: Sixty five cases with congenitally corrected transposition of the great arteries (CCTGA) indicated for biventricular repair were operated on between 1984 and september 1998. Comparison between the results of the conventional(classic) connection(LV-PA) and the anatomic repair was done. MATERIAL AND METHOD: Retrospective review was carried out based on the medical records of the patients. Operative procedures, complications and the long-term results accoding to the combining anomalies were analysed. RESULT: Mean age was 5.5+/-4.8 years(range, 2 months to 18years). Thirty nine were male and 26 were female. Situs solitus {S,L,L} was in 53 and situs inversus{I,D,D} in 12. There was no left ventricular outflow tract obstruction(LVOTO) in 13(20%) cases. The LVOTO was resulted from pulmonary stenosis(PS) in 26(40%)patients and from pulmonary atresia(PA) in 26(40%) patients. Twenty-five(38.5%) patients had tricuspid valve regurgitation(TR) greater than the mild degree that was present preoperatively. Twenty two patients previously underwent 24 systemic- pulmonary shunts previously. In the 13 patients without LVOTO, 7 simple closure of VSD or ASD, 3 tricuspid valve replacements(TVR), and 3 anatomic corrections(3 double switch operations: 1 Senning+ Rastelli, 1 Senning+REV-type, and 1 Senning+Arterial switch opera tion) were performed. As to the 26 patients with CCTGA+VSD or ASD+LVOTO(PS), 24 classic repairs and 2 double switch operations(1 Senning+Rastelli, 1 Mustard+REV-type) were done. In the 26 cases with CCTGA+VSD+LVOTO(PA), 19 classic repairs(18 Rastelli, 1 REV-type), and 7 double switch operations(7 Senning+Rastelli) were done. The degree of tricuspid regurgitation increased during the follow-up periods from 1.3+/-1.4 to 2.2+/-1.0 in the classic repair group(p<0.05), but not in the double switch group. Two patients had complete AV block preoperatively, and additional 7(10.8%) had newly developed complete AV block after the operation. Other complications were recurrent LVOTO(10), thromboembolism(4), persistent chest tube drainage over 2 weeks(4), chylothorax(3), bleeding(3), acute renal failure(2), and mediastinitis(2). Mean follow-up was 54+/-49 months(0-177 months). Thirteen patients died after the operation(operative mortality rate: 20.0%(13/65)), and there were 3 additional deaths during the follow up period(overall mortality: 24.6%(16/65)). The operative mortality in patients underwent anatomic repair was 33.3%(4/12). The actuarial survival rates at 1, 5, and 10 years were 75.0+/-5.6%, 75.0+/-5.6%, and 69.2+/-7.6%. Common causes of death were low cardiac output syndrome(8) and heart failure from TR(5). CONCLUSION: Although our study could not demonstrate the superiority of each classic or anatomic repair, we found that the anatomic repair has a merit of preventing the deterioration of tricuspid valve regurgitations. Meticulous selection of the patients and longer follow-up terms are mandatory to establish the selective advantages of both strategies.
Arteries* ; Atrioventricular Block ; Cardiac Output, Low ; Cause of Death ; Chest Tubes ; Drainage ; Female ; Follow-Up Studies ; Heart Failure ; Humans ; Male ; Medical Records ; Mortality ; Retrospective Studies ; Surgical Procedures, Operative ; Survival Rate ; Tricuspid Valve ; Tricuspid Valve Insufficiency

BACKGROUND: This study has proven the effect of modified ultrafiltration(MUF) performed after the cessation of cardiopulmonary bypass in pediatric patients who underwent open heart surgery. MATERIAL AND METHOD: From Jan. to Dec. 1997, modified ultrafiltration was performed after cardiopulmonary bypass in 50 infants with cyanotic heart disease and the results were compared to the control group of 50 patients with cyanotic heart disease in whom modified ultrafiltration was not used. Changes of hematocrit, central venous pressure, systolic and diastolic pressure, heart rate and body weight were compared. RESULT: Age and body weight were not different(p=0.38, p=0.46). Disease categories were similar. Average filtering volume was 60.0+/-29.2cc/kg for 7.0+/-2.4minutes of filtration. Mean hematocrit after filtration(MUF=36.1%, control=26.4%, p=0.001) was higher in the MUF group. Systolic (p=0.0001) and diastolic blood pressure(p=0.0001) were observed to increase more and the central venous pressure(p=0.02) and the heart rate(p=0.02) were lower after filtration in the MUF group. CONCLUSION: This study demonstrated that modified ultrafiltration after cardiopulmonary bypass was a technically feasible option to improve the post-surgical course through the effective hemoconcentration, hemodynamic improvements, and body water control.
Blood Pressure ; Body Water ; Body Weight ; Cardiopulmonary Bypass ; Central Venous Pressure ; Filtration ; Heart Diseases ; Heart Rate ; Heart* ; Hematocrit ; Hemodynamics ; Humans ; Infant ; Thoracic Surgery* ; Ultrafiltration*

BACKGROUND: To evaluate the risk factor and long-term result of arterial switch operation , a retrospective study was done. MATERIAL AND METHOD: A retrospective analysis was done to evaluate the early and long-term results on 58 patients who underwent an arterial switch operation(ASO) for transposition of the great arteries(TGA) with intact ventricular septum, between January 1988 and December 1996. Beforesurgery, 36 patients(62.1%) underwent balloon atrial septostomy, 32 patients(51.7%) received PGE1 infusion, and preparatory banding of pulmonary artery was performed on 6 patients(mean LV/RV pressure ratio 0.53+/-0.11). RESULT: The age at operation ranged from 1 to 137 days(mean 24+/-26 days) and the weights ranged from 1.8 to 6.8 kg (mean 3.5+/-0.8 kg). There were 14 early deaths(24.1%), but of the last 24 patients operated on since 1994, there were only 2 early deaths(8.3%). In the risk factor analysis, the date of operation was the only risk factor for early death(p-value <0.01). Eight of the 14 early deaths were due to acute myocardial failure(mainly inadequate coronary blood flow). The length of follow-up ranged from 2 months to 8 years, average of 36+/-27 months. The follow-up included sequential noninvasive evaluations and 21 catheterizations and angiographic studies performed 5 to 32 months postoperatively with particular attention to the great vessel and coronary anastomosis, ventricular function, valvular competence, and cardiac rhythm. There were 5 late deaths(11.4%), one of thesedeaths was related to the late coronary problems, two to aspiration, one to uncontrolled chronic mediastinitis, and one to progressive aortic insufficiency and heart failure. The most frequent postoperative hemodynamic abnormality was supravalvular stenosis and the degree of pulmonary or aortic obstruction had slowly progressed in some cases, however there were no children who had to undergo a reoperation for supravalvular pulmonary or aortic stenosis. Aortic regurgitation was identified in 9 patients, which was mild in 7 and moderate in 2 and had progressed in some cases. Two patients who had an unremarkable perioperative course were identified as having coronary artery obstructions. The other late survivors were in good condition, were in sinus rhythm, and had normal LV functions. Actuarial survival rate at 8 years was 68.8%. CONCLUSION: We concluded that anatomic correction will be established as the optimal approach to the TGA with intact ventricular septum, though further long-term evaluations are needed.
Alprostadil ; Aortic Valve Insufficiency ; Aortic Valve Stenosis ; Arteries* ; Catheterization ; Catheters ; Child ; Constriction, Pathologic ; Coronary Vessels ; Follow-Up Studies ; Heart Failure ; Hemodynamics ; Humans ; Mediastinitis ; Mental Competency ; Pulmonary Artery ; Reoperation ; Retrospective Studies ; Risk Factors* ; Survival Rate ; Survivors ; Transposition of Great Vessels ; Ventricular Function ; Ventricular Septum* ; Weights and Measures

BACKGROUND: Supravalvular aortic stenosis is a rare form of congenital cardiac anomaly involving ascending aorta distal to coronary orifice. MATERIALS AND METHODS: We operated 12 cases of supravalvular aortic stenosis between July 1986 and March 1997. Age ranged from 4 to 17 (mean 10.2) years and 11 of them were male. Nine patients had clinical features of Williams syndrome. We experienced two types of supravalvular aortic stenosis, including 10 hour glass type and 2 diffuse type. RESULTS: Preoperative transaortic pressure gradient ranged from 40 to 180 (mean 92) mmHg by cardiac catheterization. Pulmonary stenosis was associated in 5 and 2 of them required angioplasty. Operative techniques included 6 standard aortoplasty with elliptical patch, 4 extended aortoplasty with inverted Y shaped patch, and 2 modified Brom's repair. There were no operative deaths. Postoperative echocardiographic evaluation was done at a mean interval of 12 months. Grade I or II aortic regurgitation was found in 3 cases. Postoperative cardiac catheterization revealed a mean transaortic pressure gradient of 26 (range 0 to 75) mmHg. A mean pressure drop was 78 (range 30 to 114) mmHg. All patients were followed up for a mean of 40 (range 1 to 67) months with uneventful clinical course. CONCLUSIONS: Our data proved the low mortality and excellent hemodynamic improvement after surgical relief of supravalvular aortic stenosis in children.
Angioplasty ; Aorta ; Aortic Stenosis, Supravalvular* ; Aortic Valve Insufficiency ; Aortic Valve Stenosis ; Cardiac Catheterization ; Cardiac Catheters ; Child ; Echocardiography ; Glass ; Hemodynamics ; Humans ; Male ; Mortality ; Pulmonary Valve Stenosis ; Williams Syndrome

BACKGROUND: This study is to evaluate the effectiveness and application of Lecompte procedure as a treatment for various complex cardiac anomalies with pulmonary outflow tract obstruction. Methods: Between July 1988 and December 1997, 44 patients underwent Lecompte procedure in Seoul National University Children's Hospital. The male to female ratio was 24 to 20 and the mean age was 29.2 months (range, 3 to 83). Of these patients, 28 (63.6%) had transposition of great arteries with ventricular septal defect and pulmonary stenosis (or pulmonary atresia), 14 (31.8%) had double outlet right ventricle with pulmonary stenosis (or pulmonary atresia), and so on. The principles of the technique are 1) extension of the ventricular septal defect or conal resection, 2) construction of a intracardiac tunnel connecting the left ventricle to the aorta, and 3) direct connection, without a prosthetic conduit, of the pulmonary trunk to the right ventricle. RESULTS: There were 3 in-hospital deaths and their causes were sustained hypoxia, myocardial failure, and sepsis, respectively. There was 1 late death due to sepsis. Reoperations were performed in 6 patients who had pulmonary outflow tract obstructions (4 cases), residual muscular ventricular septal defect (1 case), and recurrent septic vegetation (1 case). The cumulative survival rates by the Kaplan-Meier method were 92.7%, 92.7%, and 92.7% at 1, 2, and over 4 years. The reoperation free survival rates were 92.7%, 92.7%, and 70.2% at 1, 3, and over 5 years. Among the risk factors for the operative death, aortic cross clamping time had statistical significance (p<0.05) and all the risk factors for the recurrent pulmonary stenosis such as age, pulmonary artery index, and materials used for the pulmonary outflow tract reconstruction had no statistical significance (p>0.05). CONCLUSIONS: Our review suggests that Lecompte procedure is an effective treatment modality for various complex cardiac anomalies with pulmonary outflow tract obstruction. Repair in early age is possible and the rates of mortality and morbidity are also acceptable.
Anoxia ; Aorta ; Constriction ; Double Outlet Right Ventricle ; Female ; Heart Diseases* ; Heart Failure ; Heart Septal Defects, Ventricular ; Heart Ventricles ; Heart* ; Humans ; Male ; Mortality ; Pulmonary Artery ; Pulmonary Valve Stenosis ; Reoperation ; Risk Factors ; Seoul ; Sepsis ; Survival Rate ; Transposition of Great Vessels