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The aim of the study was to evaluate the response rate and safety of weekly paclitaxel (Taxol((R))) combination chemotherapy with UFT (tegafur, an oral 5-fluorouracil prodrug, and uracil at a 1 : 4 molar ratio) and leucovorin (LV) in patients with advanced gastric cancer. Patients with histologically confirmed, locally advanced or recurrent/metastatic gastric cancer were studied. Paclitaxel 1-h infusion at a dose of 100 mg m(-2) on days 1 and 8 and oral UFT 300 mg m(-2) day(-1) plus LV 90 mg day(-1) were given starting from day 1 for 14 days, followed by a 7-day period without treatment. Treatment was repeated every 21 days. From February 2003 to October 2004, 55 patients were enrolled. The median age was 62 years (range: 32-82). Among the 48 patients evaluated for tumour response, two achieved a complete response and 22 a partial response, with an overall response rate of 50% (95% confidence interval: 35-65%). All 55 patients were evaluated for survival and toxicities. Median time to progression and overall survival were 4.4 and 9.8 months, respectively. Major grade 3-4 toxicities were neutropenia in 25 patients (45%) and diarrhoea in eight patients (15%). Although treatment was discontinued owing to treatment-related toxicities in nine patients (16%), there was no treatment-related mortality. Weekly paclitaxel plus oral UFT/LV is effective, convenient, and well tolerated in treating patients with advanced gastric cancer.

Statins are known to reduce high-sensitivity C-reactive protein (hs-CRP) concentrations and improve endothelial function. However, whether statin withdrawal causes re-elevated concentrations of hs-CRP and von Willebrand Factor (vWF) (a marker of endothelial damage) remains unknown. We hypothesized that the concentrations of hs-CRP and vWF are substantially increased in patients with unstable angina pectoris (UAP) and noticeably decreased following coronary stenting along with atorvastatin therapy. However, re-elevations of these biomarker concentrations occurred once again after withdrawing atorvastatin therapy. We serially examined the plasma concentrations of hs-CRP and vWF in 51 patients with UAP before (day 0) and after (days 21, 90, 180, 270) performing coronary artery stenting. The concentrations of these 2 biomarkers were also measured in 30 healthy control subjects. Patients were treated with atorvastatin (40 mg/day orally) for 180 days, after which the therapy was withdrawn. The hs-CRP and vWF concentrations were significantly higher in the patients than in the healthy control subjects before the procedure (both P values < 0.001). The hs-CRP concentration decreased significantly on day 21 (P < 0.001), and further to a substantially lower level on day 180 (P < 0.0001). However, the hs-CRP level significantly increased again on day 270, as compared with that on day 180 (P < 0.001). The vWF plasma concentration decreased gradually to a significantly lower level on day 180. The concentration of this biomarker did not differ between days 180 and 270. In conclusion, although hs-CRP concentrations decreased markedly following combined stenting and atorvastatin therapy, re-elevation after atorvastatin therapy was withdrawn in UAP patients undergoing coronary stenting was not observed. Conversely, restoration of endothelial function was slow and persistent in these patients.

Increased platelet activity plays a key role in atherothrombotic events. Persistent platelet activity has been reported in patients with atrial fibrillation (AF) following myocardial infarction and in the chronic phase after ischemic stroke. However, platelet activity in patients with AF remains clear. This study investigated platelet reactivity (expressed by CD62p) in patients with chronic nonvalvular (NV) AF. Expression of CD62p was measured by flow cytometry in 62 consecutive patients with chronic NVAF (defined as sustained AF > 6 months) and no previous embolic events. The CD62p expression was also evaluated in 20 healthy subjects. Expression of CD62p was not different between AF patients and healthy subjects (P = 0.970). Additionally, CD62p expression did not differ between patients with and patients without the following atherosclerotic risk factors: hypertension, current smoking, and hypercholesterolemia (all P values > 0.1). Furthermore, CD62p expression did not differ between patients taking and not taking the following medications: warfarin, a statin, or an angiotensin converting enzyme inhibitor/angiotensin II receptor blocker (all P values > 0.2). However, diabetes mellitus (DM) was strongly associated with increased CD62p expression (P < 0.0001). Multiple linear regression analysis demonstrated that only DM independently predicted increased CD62p expression (r2 = 0.509, regression coefficient = 3.044, P < 0.0001). In conclusion, compared to healthy subjects, CD62p expression was not significantly enhanced in chronic NVAF patients. However, CD62p expression was substantially elevated in diabetic patients with chronic NVAF.

Background: Previously, researchers have suggested that Soluble (s) P-selectin mediates the accumulation of leukocytes which in turn promotes fibril deposition. Soluble P-selectin and white blood cell (WBC) counts have been shown to be increased in the systemic circulation after acute myocardial infarction (AMI). However, whether the infarct coronary artery (ICA) and systemic circulation differs with respect to the concentration of sP-selectin and WBC counts following AMI remain unknown. In this study, we investigated whether the concentration of sP-selectin and WBC counts differed between the ICA and the systemic circulation after AMI., Methods: Blood samples for circulating sP-selectin and WBC counts were immediately obtained after vascular puncture in 72 patients with AMI of < 12 h undergoing primary percutaneous coronary intervention (PCI). Additionally, blood samples for ICA sP-selectin and WBC counts were obtained via Export Suction Catheter during PCI. For comparison, blood samples for sP-selectin and WBC counts were obtained once in 30 healthy subjects., Results: The results demonstrated that the circulating sP-selectin [64.7 +/- 18.1 (ng/ml) vs. 29.5 +/- 6.3 (ng/ml), p < 0.0001] and WBC counts [12.1 +/- 3.6 (x 10(3)/ml) vs. 5.0 +/- 1.0 (x 10(3)/ml), p < 0.0001] were significantly higher in our patients than in healthy subjects. Furthermore, the sP-selectin [72.7 +/- 23.3 (ng/ml) vs. 64.7 +/- 18.1 (ng/ml), p < 0.0001] and the WBC counts [16.2 +/- 3.8 (x 10(3/)ml) vs. 12.1 +/- 3.6 (x 10(3)/ml), p < 0.0001] were markedly higher in the ICA than in the systemic circulation for the patients., Conclusions: The plasma level of sP-selectin and WBC counts were more elevated in the ICA than in the systemic circulation of patients with AMI undergoing primary PCI. These findings strengthen the role of sequestration of WBC and sP-selectin in the ICA as crucial in thrombus formation.

We report a patient with disseminated Mycobacterium kansasii infection, but with no underlying disease, presenting with mimicking multiple bone metastases with cancer of unknown primary site. Disseminated M. kansasii infection is rare in HIV-negative patients without underlying diseases. This patient had disseminated M. kansasii infection manifested with vertebral osteomyelitis, sacroiliitis, psoas abscess, bone marrow granuloma, liver granuloma, and possible spleen abscesses. The clinical manifestations are described and discussed in details.

In the past, patients requiring permanent pacing with difficult right ventricular (RV) access were usually subjected to epicardial pacing by a surgical approach. This report describes a young patient with univentricular physiology following repeated palliative surgery for complex congenital heart disease. The patient had symptomatic complete heart block and a dual chamber pacemaker with transvenous atrial and ventricular leads was implanted successfully. The ventricle was paced through the posterolateral cardiac vein with a lead specially designed for cardiac resynchronization therapy. This case illustrates an extended application of the recently developed coronary sinus lead in selected patients, when conventional RV endocardial pacing is impossible.

This case study describes a patient with complete heart block inadvertently paced from the left ventricular posterior wall due to perforation of interventricular septum by a temporary pacing catheter. This is a rare but potentially fatal complication of pacing. The frontal chest radiograph neither identified abnormalities nor could determine the exact site of the catheter tip. The electrocardiogram revealed a right bundle branch block pattern. Echocardiography was performed immediately at bedside and the diagnosis was made. The temporary pacing catheter was removed without complications and, the next day, the patient underwent permanent pacemaker implantation. Given its noninvasiveness and availability, echocardiography is a highly effective means of assessing pacemaker complications such as catheter perforation.

This study investigated whether a regimen that comprised a loading dose of 300 mg of clopidogrel followed by 75 mg/day could significantly suppress circulating levels of soluble CD40 ligand (sCD40L) in patients who had unstable angina and underwent coronary stenting. Study results showed that the clopidogrel loading dose substantially decreased the circulating level of sCD40L at 24 hours after stenting (p <0.0001). Combined with aspirin, 75 mg/day of clopidogrel continuously decreased sCD40L levels after coronary stenting.

Bcl10 overexpression and nuclear translocation were originally identified in mucosa-associated lymphoid tissue lymphoma with t(1;14)(p32;q32) chromosome translocation. DNA amplification of Bcl10 was also found in other solid tumors. We have recently shown that nuclear translocation of Bcl10 is a specific molecular determinant of Helicobacter pylori-independent mucosa-associated lymphoid tissue lymphoma (Kuo, S.-H., Chen, L. T., Yeh, K.-H., Wu, M. S., Hsu, H. C., Yeh, P. Y., Mao, T. L., Chen, C. L., Doong, S. L., Lin, J. T., and Cheng, A.-L. (2004) J. Clin. Oncol. 22, 3491-3497). However, the molecular mechanism of Bcl10 nuclear translocation remains unknown. In this study, we observed that tumor necrosis factor-alpha (TNFalpha) up-regulates the expression of Bcl10 and induces a fraction of Bcl10 nuclear translocation in human breast carcinoma MCF7 cells. Chromatin immunoprecipitation assays and electrophoretic mobility shift assays indicated that an NF-kappaB-binding site resides in the Bcl10 5 '-untranslated region. This study also demonstrates that Akt1, activated by TNFalpha, phosphorylates Bcl10 at Ser218 and Ser231 and that phosphorylated Bcl10 subsequently complexes with Bcl3 to enter the nucleus. Either inhibition of Akt1 or depletion of Bcl3 blocks Bcl10 nuclear translocation. In summary, these findings characterize a molecular linkage that directs Bcl10 nuclear translocation in response to TNFalpha treatment.

Aim: To determine how glucocorticoids (GCs) may affect the growth and chemosensitivity of common carcinoma cells., Methods: The effect of dexamethasone (DEX) on growth and chemosensitivity was assessed in 14 carcinoma cell lines. The function of GC receptors (GR) was assessed by MMTV reporter assay. Overexpression of GR was done by in vitro transfection and expression of a GR-expressing vector. Immunohistochemical stain of tissues and cells were done by PA1-511A, an anti-GR monoclonal antibody., Results: DEX inhibited cell growth of four (MCF-7, MCF-7/MXR1, MCF-7/TPT300, and HeLa), increased cisplatin cytotoxicity of one (SiHa), and decreased cisplatin cytotoxicity of two (H460 and Hep3B) cell lines. The GR content of the seven cell lines affected by DEX was significantly higher than those of the seven cell lines unaffected by DEX (5.2+/-2.5 x 10(4) sites/cell vs 1.3+/-1.4 x 10(4) sites/cell, P = 0.005). Only two DEX-unresponsive cell lines (NPC-TW01 and NPC-TW04) contained high GR amounts in the range (1.9-8.1 x 10(4) sites/cell) of the seven DEX-responsive cell lines. The GR function of NPC-TW01 and NPC-TW04, however, was found to be impaired. The importance of high cellular amount of GR in mediating DEX susceptibility of the cells was further exemplified by GR dose-dependent drug resistance to cisplatin of AGS, a cell line with low GR content and was unaffected by DEX before transfection of GR-expressing vector. Immunohistochemical studies of human cancer tissues showed that 5 of the 45 (11.1%) breast cancer and 43 of the 85 (50.6%) non-small cell lung cancer had high GR contents at the ranges of the GC-responsive carcinoma cell lines., Conclusion: The growth and chemosensitivity of human carcinomas with high GR contents may be affected by GC. However, in light of the heterogeneous and even contradictive effects of GC on these cells, routine examination of GR contents of human carcinoma tissues may not be clinically useful until other markers that help predict the ultimate effect of GC on individual patients are identified.

Background: The present study tested the hypothesis that high-sensitivity C-reactive protein (hs-CRP) concentrations might show significant serial changes in patients with unstable angina (UAP), and that elevation of hs-CRP might indicate a progressively obstructive lesion, rather than late restenosis in such patients undergoing coronary stenting., Methods and Results: Serum concentrations of hs-CRP in 168 patients with UAP undergoing coronary stenting for a new obstructive lesion were prospectively measured (pre-procedure, and on days 21, 90, and 180 post-procedure). The hs-CRP concentrations were also evaluated in 30 at-risk controls and 50 healthy volunteers. Moderately obstructive lesions of non-culprit vessels (defined as > or =50-69% stenosis) that were not treated by coronary angioplasty were found in 107 (63.7%) patients. The hs-CRP concentration was significantly higher at pre-procedure in the study patients than in the controls and healthy volunteers (all p-values <0.0001) and markedly declined after the procedure (p<0.0001). Pre-procedure (p=0.799) and post-procedure hs-CRP concentrations (all p-values >0.1) did not differ between restenotic and non-restenotic patients. However, at pre-procedure or on day 180, the concentration of hs-CRP was independently associated with progressively obstructive lesions of non-culprit vessels that required coronary angioplasty (both p-values <0.05)., Conclusion: The hs-CRP concentration was significantly higher at pre-procedure and declined substantially thereafter in patients with UAP following coronary stenting. There was no evidence of a positive association between an elevated hs-CRP concentration and late restenosis. However, both the pre-procedure and day 180 concentrations of hs-CRP were strongly associated with the progression of moderately obstructive lesions in non-culprit vessels.

Background: Platelet activation that results from coronary plaque rupture is important in the pathogenesis of acute myocardial infarction (AMI). Soluble p-selectin (sP-selectin) is crucial in modulating leukocyte adhesion to both platelets and endothelial cells during inflammatory response and thrombus formation. We hypothesized that sP-selectin, an index of both platelet activation and acute inflammation, rapidly increases and modulates the recruitment of circulating white blood cells (WBC) in patients following AMI., Methods: We conducted a prospective cohort study of 142 consecutive patients with ST-segment elevated AMI of onset < 12 h who were undergoing primary percutaneous coronary intervention. Blood samples for plasma levels of sP-selectin were obtained in the catheterization laboratory before coronary angiography was performed. The plasma levels of sP-selectin were also measured in 30 risk control subjects and 20 healthy control subjects., Results: The plasma level of sP-selectin and the circulating WBC count were significantly higher in patients with AMI than in either the risk control or healthy subjects (all of p values < 0.0001). Additionally, repeated measures of ANOVA demonstrated that there were no significant differences in plasma levels of sP-selectin (p > 0.10) in three intervals from the start of chest pain to blood sample collection (< 180 min, > or = 180 < 360, and > or = 360 < 720) following AMI. Correlation analysis demonstrated that the increase in the plasma level of sP-selectin was significantly related to the circulating WBC count (r = 0.248, p = 0.003)., Conclusions: sP-selectin was markedly elevated in an early phase of AMI. sP-selectin may be involved in modulating the recruitment of circulating WBC during AMI. These findings raise the need for a prospective investigation of sP-selectin as a potential reliable clinical tool for rapidly diagnosing AMI.

Background: The Cox maze III procedure can effectively restore sinus rhythm in most patients with permanent atrial fibrillation (AF). However, previous studies have shown that the maze procedure results in significant sinus node dysfunction, and, consequently, a considerable number of patients required postoperative pacemaker implantation., Hypothesis: This study investigates the hypothesis that the modification of the Cox III maze procedure, to avoid injuring the sinus node and the atrial physiologic pacemaker complex, will reduce the incidence of sick sinus syndrome following surgery., Methods and Results: This study investigated 71 patients with permanent AF and mitral valve disease who were undergoing concomitant open-heart surgery. Most atrial incisions in the Cox maze III procedure were replaced with radiofrequency ablation, and the intercaval counterablation was moved posterolaterally to avoid injury to the sinus node and atrial pacemaker complex. At a mean (+/- SD) follow-up time of 46.5 +/- 24 months, 59 patients (83.1%) regained sinus rhythm without receiving antiarrhythmic drug therapy or undergoing electrical cardioversion. The transmitral atrial wave was observed in 44 patients (62%), and the transtricuspid atrial wave was also observed in 53 patients (74.6%). Late sinus node dysfunction developed in only two patients (2.8%), who received permanent pacemaker implantation., Conclusion: This modified radiofrequency maze procedure produces few patients with sick sinus syndrome and effectively restores sinus rhythm and atrial transport function in most patients with permanent AF undergoing concomitant open-heart surgery.

Background: Platelet activation is crucial in the development of acute or subacute stent thrombosis following implantation. This study investigated whether a conventional regimen comprising a loading dose of 300 mg of clopidogrel, followed by daily doses of 75 mg, could significantly suppress platelet activation in patients with unstable angina (UA) undergoing coronary stenting., Methods and Results: Platelet activation (expressed by CD62p) was serially examined using flow cytometry in 42 consecutive patients with UA who underwent coronary stenting. CD62p expression was also evaluated in 30 normal control subjects. CD62p expression was markedly higher pre-procedure in the study patients than in the normal control subjects (5.2+/-4.0% vs 1.4+/-0.6%, p<0.0001). CD62p expression in the study patients remained significantly higher at 24 h after the procedure than in the control subjects (3.8+/-2.1% vs 1.4+/-0.6%, p<0.001). Additionally, only 26% of CD62p expression (5.2% vs 3.8%, p=0.026) in the study patients was suppressed at 24 h after the procedure. However, more than 60% of CD62p expression (5.2% vs 2.0%, p<0.0001) was suppressed on day 7 after the procedure., Conclusion: Less than one-third of CD62p expression was suppressed at 24 h by the conventional loading dose (300 mg) of clopidogrel in patients with UA following coronary stenting. This finding indicates the need to evaluate whether an increased loading dose of clopidogrel would be a more efficacious and safe regimen for patients in this clinical setting.

Background: Circulating soluble P-selectin (sP-selectin), a biomarker of platelet activation is substantially increased in patients with acute myocardial infarction (AMI). However, the circulating level of sP-selectin in patients in the early (onset of AMI > 12 h but < 7 d) or recent (onset of AMI > 8 d but < 21 d) phase after AMI remains unclear. The purpose of this study was to prospectively evaluate whether the circulating level of sP-selectin remains elevated in these two consecutive phases after an AMI., Methods: Blood samples were collected in the catherization room before coronary angiography to assess the circulating level of sP-selectin. A total of 53 consecutive patients, 34 with early MI (group 1) and 19 with recent MI (group 2), who had had no prior thrombolytic therapy were included. Circulating levels of sP-selectin were also measured in 30 risk control (stable angina) subjects undergoing elective percutaneous coronary intervention and in 20 healthy subjects who comprised the healthy control group., Results: The circulating level of sP-selectin did not differ between patients with early AMI and those with recent MI (p = 0.632). However, the plasma level of sP-selectin was significantly higher in group 1 and 2 patients than in the risk control and healthy control subjects (all p values < 0.0001)., Conclusions: Circulating sP-selectin was elevated in patients 12 hours to 7 days after AMI and the elevation was maintained until 21 days after AMI. Therefore, investigation of longer utilization of anti-platelet and anti-inflammatory agents for patients following AMI might be worthwhile.

The t(11;18)(q21;q21) translocation is a specific marker for Helicobacter pylori-independent status of low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma. However, there are no reliable markers to predict tumor response to H pylori eradication in patients without t(11;18)(q21;q21). Nuclear expression of BCL10 and nuclear factor kappa B (NF-kappaB) was recently found to be closely associated with H pylori-independent status of the high-grade counterpart of gastric MALT lymphoma, which usually lacks t(11;18)(q21;q21). This study examined whether these 2 markers can also predict H pylori-independent status of low-grade gastric MALT lymphomas without t(11; 18)(q21;q21). Sixty patients who underwent successful H pylori eradication for low-grade gastric MALT lymphomas were included. Forty-seven (78.3%) patients were negative for t(11;18)(q21;q21); among them, 36 (76.6%) were H pylori dependent and 11 (23.4%) were H pylori independent. Nuclear expression of BCL10 was significantly higher in H pylori-independent than in H pylori-dependent tumors (8 of 11 [72.7%] vs 3 of 36 [8.3%]; P < .001). Nuclear expression of NF-kappaB was also significantly higher in H pylori-independent than in H pylori-dependent tumors (7 of 11 [63.6%] vs 3 of 36 [8.3%]; P < .001). Further, nuclear translocation of BCL10 and NF-kappaB was observed in 12 of the 13 patients with t(11;18)(q21;q21), and all these 12 patients were H pylori independent. In summary, nuclear expression of BCL10 or NF-kappaB is predictive of H pylori-independent status of low-grade gastric MALT lymphoma with or without t(11;18)(q21; q21).

A 61-year-old never-smoker female suffered from adenocarcinoma of the lung with chest wall invasion and peri-adrenal lymph node metastases. After palliative resection of all clinically detectable primary and metastatic adenocarcinoma, she received cisplatin and gemcitabine combination chemotherapy for a total of 3 cycles. New metastatic lesions were found in spleen and para-aortic lymph nodes. Her tumor tissue was subjected to mutation analysis for epidermal growth factor receptor (EGFR) and had been shown to have a T-->G missense mutation in nucleotide 2819 of EGFR full-length cDNA (accession no. NM&#95;005228.3), within exon 21 of the EGFR gene, resulting in amino acid substitutions from leucine to arginine at codon 858 (L858R) as expected. She received oral gefitinib 250 mg/day after mutation analysis. She had a very good tumor response with more than 90% tumor reduction shown by abdominal computed tomographic scan, normalization of previously elevated carcinoembryonic antigen level, and complete resolution of previous uptake signals in spleen and para-aortic lymph nodes shown by positron emission tomographic scan. She has been kept in clinical complete remission for 11+ months after the initiation of gefitinib treatment. Our patient supports the proposition that somatic mutation L858R in exon 21 of the EGFR gene accounts for complete responsiveness to gefitinib in a Taiwanese female patient with metastatic adenocarcinoma of lung.

Aim: A high percentage of early-stage high-grade gastric mucosa-associated lymphoid tissue (MALT) lymphomas remain Helicobacter pylori (H pylori)-dependent. However, unlike their low-grade counterparts, high-grade gastric MALT lymphomas may progress rapidly if unresponsive to H pylori eradication. It is mandatory to identify markers that may predict the H pylori-dependent status of these tumors. Proliferation of MALT lymphoma cells depends on cognate help and cell-to-cell contact of H pylori-specific intratumoral T-cells. To examine whether the expression of co-stimulatory marker CD86 (B7.2) and the infiltration of CD56 (+) natural killer (NK) cells can be useful markers to predict H pylori-dependent status of high-grade gastric MALT lymphoma., Methods: Lymphoma biopsies from 26 patients who had participated in a prospective study of H pylori-eradication for stage I(E) high-grade gastric MALT lymphomas were evaluated. Tumors that resolved to Wotherspoon grade II or less after H pylori eradication were classified as H pylori-dependent; others were classified as H pylori-independent. The infiltration of NK cells and the expression of CD86 in pre-treatment paraffin-embedded lymphoma tissues were determined by immunohistochemistry., Results: There were 16 H pylori-dependent and 10 H pylori-independent cases. CD86 expression was detected in 11 (68.8%) of 16 H pylori-dependent cases but in none of 10 H pylori-independent cases (P = 0.001). H pylori-dependent high-grade gastric MALT lymphomas contained significantly higher numbers of CD56 (+) NK cells than H pylori-independent cases (2.8+/-1.4% vs 1.1+/-0.8%; P = 0.003). CD86 positive MALT lymphomas also showed significantly increased infiltration of CD56 (+) NK cells compared to CD86-negative cases (2.9+/-1.1% vs 1.4+/-1.3%; P = 0.005)., Conclusion: These results suggest that the expression of co-stimulatory marker CD86 and the increased infiltration of NK cells are associated with H pylori-dependent state of early-stage high-grade gastric MALT lymphomas.

A 46-year-old male patient who had long-term right ventricular (RV) pacing for symptomatic complete heart block, initially by an epicardial, later with an endocardial pacing lead at the RV apex, developed congestive heart failure (CHF) and chronic atrial fibrillation 7 years following the pacemaker implantation and was medically treated. During follow-up, his pacemaker was upgraded to a cardiac resynchronisation therapy (CRT) device, because of uncontrolled CHF symptoms, New York Heart Association (NYHA) functional class IV, while on drugs. The patient's symptomatic status improved to NYHA functional class II with CRT. After 17 months of CRT, the battery became depleted, because of the high capture threshold of the left ventricular lead. The patient was then given dual site RV pacing (RV outflow tract+RV apex) in place of CRT, which showed similar efficacy at 12 weeks follow-up.

Background: Recent data suggest that the pathogenesis of vascular inflammation and thrombosis involves CD40 ligand (CD40L), which is mostly derived from platelets. Previous studies have demonstrated that platelet activation occurs in peripheral blood of patients with rheumatic mitral stenosis (MS). However, in patients with MS, the plasma level of soluble CD40L has never been investigated., Methods and Results: Seventeen patients with symptomatic MS undergoing percutaneous transluminal mitral valvuloplasty were studied (group 1, 11 patients in permanent atrial fibrillation and 6 patients in sinus rhythm). Solid-phase, sandwich enzyme-linked immunosorbent assay determined the plasma levels of soluble CD40L in the femoral vein and artery, and right and left atria before valvuloplasty, and those in the peripheral venous blood obtained 10 min after valvuloplasty, and at the 4-week follow-up after valvuloplasty. The Doppler pressure half-time method was used to calculate the mitral valve area. Additionally, plasma concentrations of soluble CD40L in the peripheral venous blood obtained from 17 control patients were measured (including nine healthy volunteers in sinus rhythm [group 2] and eight patients in permanent lone atrial fibrillation [group 3]). Plasma levels of soluble CD40L were significantly elevated in group 1 patients (437.6 +/- 370.2 pg/mL) [mean +/- SD] compared with group 2 (203.8 +/- 218.0 pg/mL) and group 3 patients (173.5 +/- 105.0 pg/mL) [p < 0.05]. The area of mitral valve increased significantly after valvuloplasty (1.10 +/- 0.20 cm(2) vs 1.47 +/- 0.29 cm(2), p < 0.0001). The mean left atrial pressure fell significantly and immediately after valvuloplasty (22.8 +/- 4.9 mm Hg vs 17.6 +/- 5.5 mm Hg, p = 0.0004). The peripheral venous plasma levels of soluble CD40L obtained before valvuloplasty significantly fell after valvuloplasty (before, 437.6 +/- 370.2 pg/mL; vs 10 min after, 215.4 +/- 113.9 pg/mL; vs 4 weeks after, 217.5 +/- 111.9 pg/mL; p < 0.02)., Conclusions: Patients with moderate-to-severe MS had higher venous plasma levels of soluble CD40L than healthy volunteers or patients with lone atrial fibrillation. Additionally, the elevated venous plasma levels of soluble CD40L fell significantly following valvuloplasty.

Inflammation plays an important pathogenic role in the initiation and progression of atherosclerotic plaque lesions. C-reactive protein (CRP), which directly participates in plaque inflammation, induces vascular cell adhesion molecule-1 (VCAM-1) expression in endothelial cells. However, the levels and values of high-sensitivity (hs)-CRP, white blood cell (WBC) count, and VCAM-1 in both stable and unstable angina pectoris (AP) have not been fully investigated. This study examines the levels and values of these inflammatory markers in patients with stable or unstable AP. From March 2003 to December 2003, a prospective cohort study was conducted in 128 consecutive patients, including unstable AP patients (class I: n = 59; combined class II and III: n = 16) and stable AP patients (n = 53) undergoing elective coronary stenting. Blood samples for hs-CRP, WBC count, and VCAM-1 were obtained in the catheterization laboratory before coronary angiography. The circulating levels of hs-CRP and VCAM-1 were also evaluated in 40 healthy volunteers. The circulating levels of these three inflammatory markers were substantially higher in patients than in healthy volunteers (all P values < 0.0001). Additionally, circulating levels of hs-CRP and the WBC count were significantly higher in patients with unstable AP than in patients with stable AP (all P value < 0.0001). However, only those patients with class II and III unstable AP had significantly higher circulating levels of VCAM-1 than patients with stable AP (P < 0.0001). On the other hand, the circulating levels of VCAM-1 did not differ between patients with class I unstable AP and patients with stable AP (P = 0.782). Multiple stepwise logistic regression analysis showed that only hs-CRP level was independently associated with unstable AP (P = 0.0002). In conclusion, circulating levels of hs-CRP, WBC count, and VCAM-1 were significantly increased in patients with AP. The circulating level of hs-CRP was strongly associated with the clinical setting of unstable AP.

Ventricular tachycardia originating from the right ventricular septum is very uncommon. In a 54-year-old male patient with right ventricular tachycardia, the focus of the ventricular tachycardia was localized to the subtricuspid septum of the right ventricle, which could be successfully eliminated with radiofrequency catheter ablation. The patient's echocardiogram and coronary angiogram were normal. The available literature on idiopathic right ventricular tachycardia is reviewed.

We describe two patients who presented with a history of recurrent palpitations on swallowing of solid food. The event-recorder and Holter monitoring documented episodic supraventricular tachycardia (SVT) initiated by atrial premature contractions (APCs). During electrophysiological study (EPS), swallowing of solid food consistently induced APCs and their activation sequence, morphology of P wave were suggestive of their right atrial origin in them. Drug challenge did not affect the APC onset during the swallowing. During EPS, slow-fast variety of atrioventricular nodal reentrant tachycardia (AVNRT) was induced and successful radiofrequency (RF) catheter ablation of slow pathway resulted in total relief of their symptoms.

We prospectively investigated the efficacy and safety of combining weekly vinorelbine (VNB) with weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (LV) in the treatment of patients with advanced breast cancer (ABC). Vinorelbine 25 mg m(-2) 30-min intravenous infusion, and high-dose 5-FU 2600 mg m(-2) plus LV 300 mg m(-2) 24-h intravenous infusion (HDFL regimen) were given on days 1 and 8 every 3 weeks. Between June 1999 and April 2003, 40 patients with histologically confirmed recurrent or metastatic breast cancer were enrolled with a median age of 49 years (range: 36-68). A total of 25 patients had recurrent ABC, and 15 patients had primary metastatic diseases. The overall response rate for the intent-to-treat group was 70.0% (95% CI: 54-84%) with eight complete responses and 20 partial responses. All 40 patients were evaluated for survival and toxicities. Among a total of 316 cycles of VNB-HDFL given (average: 7.9: range: 4-14 cycles per patient), the main toxicity was Gr3/4 leucopenia and Gr3/4 neutropenia in 57 (18.0%) and 120 (38.0%) cycles, respectively. Gr1/2 infection and Gr1/2 stomatitis were noted in five (1.6%) and 59 (18.7%) cycles, respectively. None of the patients developed Gr3/4 stomatitis or Gr3/4 infection. Gr2/3 and Gr1 hand-foot syndrome was noted in two (5.0%) and 23 (57.5%) patients, respectively. Gr1 sensory neuropathy developed in three patients. The median time to progression was 8.0 months (range: 3-25.5 months), and the median overall survival was 25.0 months with a follow-up of 5.5 to 45+ months. This VNB-HDFL regimen is a highly active yet well-tolerated first-line treatment for ABC.

A diagnostic triad characterizes Brugada syndrome. It consists of a right bundle branch block, ST-segment elevation in leads V1-V3 and sudden cardiac death (SCD). Approximately 50% of patients with Brugada syndrome noted to have familial occurrence, this suggests a genetic component of the disease. Mutations in gene SCN5A, an encoder for human cardiac sodium channel on chromosome 3p21, causes Brugada syndrome. Before considering the diagnosis of Brugada syndrome, exclude precordial ST-segment elevation secondary to acute coronary syndrome, electrolyte imbalance, myocarditis, drug over dosage (cocaine, tricyclic antidepressants), and arrhythmogenic right ventricular cardiomyopathy/dysplasia. Intravenous administration of ajmaline, flecainide, and procainamide may exaggerate the ST-segment elevation, or unmask it when it is initially absent in patients with suspected Brugada syndrome. Programmed electrical stimulation (PES) may help in risk stratification, and in some cases, establish the diagnosis. However, the accuracy of PES in predicting outcome is debatable, especially in patients showing an asymptomatic Brugada ECG, and reporting no family history of SCD. Treatment with an implantable cardioverter-defibrillator (ICD) is the only established effective therapy for the disease. With ICD therapy, the mortality rate at a 10 year follow-up was 0%. Supporting data for long-term pharmacological therapy with quinidine, or isoproterenol for prevention of SCD, in these patients, is uncomplete. Future advances in understanding the molecular mechanisms of Brugada syndrome may provide answers to many of the controversial issues in the management of this disease.

Objective: High-dose epirubicin was shown to be effective in the treatment of inoperable non-small cell lung cancer (NSCLC). Paclitaxel is synergistic to a conventional dose of anthracyclines in the treatment of advanced cancer. A phase II study was designed to test the effectiveness of combining paclitaxel with a conventional dose of epirubicin in inoperable NSCLC patients., Methods: Eligibility criteria included inoperable stage IIIB or IV NSCLC patients, Eastern Cooperative Oncology Group performance status of 0-2, measurable or evaluable disease and adequate organ function. Epirubicin 70 mg/m2 intravenous infusion for 15 min was given on day 1. Paclitaxel 175 mg/m2 intravenous infusion for 3 h was given on day 2. Cycles were repeated every 21 days. Tumor response was evaluated every two cycles. Patients received treatment until disease progression, unacceptable toxicity or stable disease after cycle 6., Results: Thirty-eight patients received a total of 185 cycles (median 6 cycles). Seventeen patients responded to treatment (response rate 44.7%). Twenty-six (68%) patients received second-line chemotherapy. All patients were followed until their death. Median survival was 11.9 months (95% confidence interval 9.0-14.9 months). Median time-to-treatment-failure was 4.6 months., Conclusion: Conventional dose epirubicin plus paclitaxel is effective as a first-line treatment for inoperable NSCLC patients., ((c) 2004 S. Karger AG, Basel.)

Unlabelled: Accessory pathways (APs) that can only be ablated from the coronary sinus are likely to be located subepicardially. The electrocardiographic (ECG) and electrophysiological characteristics as well as the immediate radiofrequency ablation success rate and the recurrence rate were compared in 15 patients (11 posteroseptal and 4 left free-wall) with subepicardial APs and in 31 control patients with posteroseptal (15) and left free-wall (16) APs matched with age, sex, and AP location during the same study period in whom APs were successfully ablated from the endocardial approach. Patients with posteroseptal subepicardial APs had a longer tachycardia cycle length (355 +/- 32 vs 286 +/- 49 milliseconds, P < .05), a lower success rate (9 /11 vs 15/15, P = .09), and a higher recurrence rate (3/9 vs 0/15, P < .05) as compared with control patients. A negative delta wave with QS or QR pattern in lead II was present in all 4 patients with a manifest posteroseptal subepicardial AP located in the middle cardiac vein as compared with none of the 5 control patients with posteroseptal APs located in the proximal coronary sinus and 1 of the 9 control patients (P < .01). A positive delta wave in lead I along with an R/S of less than 1 in lead V 1 , and a negative delta wave in lead II, was noted in 1 of the 2 patients with left free-wall subepicardial APs and none of the 7 controls (P = .047). The local activation time is significantly shorter in the 4 patients with left free-wall subepicardial AP than in the 16 control patients (31 +/- 9 vs 89 +/- milliseconds, P = .044)., Conclusions: Some ECG characteristics are suggestive of APs located in the middle cardiac vein and left free-wall subepicardial site, while a longer local activation time is characteristic of left free-wall APs. The success rate is lower and the recurrence rate higher with radiofrequency ablation in patients with subepicardial AP.

Left ventricular (LV) dysfunction due to frequent isolated premature ventricular contractions (PVCs) has been rarely reported. LV dysfunction and concealed mechanical bradycardia resolved in a patient with idiopathic dilated cardiomyopathy after the focal source of PVCs in the LV was eliminated by radiofrequency ablation (RFA). The patient remained free from PVCs and maintained normal LV function over 36-month follow-up. In a subset of patients with idiopathic dilated cardiomyopathy with frequent isolated PVCs, RFA of the arrhythmic focus restores normal LV function that can be long lasting.

To investigate the efficacy and safety of combining weekly paclitaxel with weekly 24-hour infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (LV, folinic acid) in the treatment of patients with advanced gastric cancer. Patients with histologically confirmed recurrent or metastatic gastric cancer were studied. Paclitaxel 80 mg/m2 3-hour intravenous infusion was given on days 1, 8, and 15, and high-dose 5-FU 2,600 mg/m2 plus LV 300 mg/m2 24-hour intravenous infusion (HDFL) was given on days 2, 9, and 16, repeated every 4 weeks. Between August 1997 and August 2003, 30 patients were enrolled. The median age was 58 years (range: 37-70). Eighteen patients (60.0%) had recurrent or metastatic disease and 12 patients had de novo metastatic disease. Among the 27 patients evaluable for tumor response, 2 achieved complete response and 9 achieved partial response, with an overall response rate of 40.7% (95% confidence interval, CI: 22-61%). Eleven of the 21 patients without prior exposure to HDFL-containing regimens responded (response rate: 52.4%, 95% CI: 29-74%), while none of the 6 patients who had previously failed HDFL-containing regimens responded (p value = 0.054 by Fisher's exact test). All 30 patients were evaluated for survival and toxicities. Median time to progression and overall survival were 6 and 10 months, respectively. Major grade 3-4 toxicities were neutropenia in 12 patients (40.0%), diarrhea in 10 patients (33.3%), and stomatitis in 3 patients (10.0%). Grade 1-2 and 3-4 paclitaxel-related neuropathy developed in 16 (53.3%) and 2 (6.7%) patients, respectively. None of the patients discontinued protocol treatment because of paclitaxel-related neuropathy or developed HDFL-related hyperammonemic encephalopathy. This paclitaxel-HDFL regimen is effective and well tolerated in the treatment of advanced gastric cancer.

Background: C-reactive protein (CRP), which has been suggested to directly enhance inflammation in plaques, is rapidly synthesized and secreted in the liver 6 h after an acute inflammatory stimulus. Therefore, serum levels of CRP within 6 h after the onset of acute myocardial infarction (AMI) merely reflect a chronic and persistent inflammatory process and are not due to acute myocardial damage. We hypothesized that the serum CRP level, which would abnormally elevate thereafter, is followed by a plaque rupture in the clinical setting of AMI., Methods and Results: CRP was prospectively measured by high-sensitivity CRP assay (hs-CRP) in 157 consecutive patients (106 patients within 6 h, and 51 patients >/= 6 h but < 12 h after the onset of AMI) with ST-segment elevation AMI undergoing primary percutaneous coronary intervention (PCI). Serum levels of hs-CRP were also measured in 30 patients with stable angina undergoing elective PCI and in 30 healthy control subjects. The serum level of hs-CRP was significantly higher in patients with an onset of AMI < 6 h than in patients with angina pectoris (2.7 +/- 2.3 mg/L vs 1.4 +/- 0.7 mg/L, p < 0.0001 [mean +/- SD]) and in healthy subjects (2.7 +/- 2.3 mg/L vs 1.0 +/- 0.6 mg/L, p < 0.0001). There were no significant differences in serum levels of hs-CRP in patients with an onset of AMI 3 h but < 6 h (2.7 +/- 2.5 mg/L vs 2.7 +/- 2.2 mg/L, p = 0.87). However, the serum level of hs-CRP was significantly higher in patients with an onset >/= 6 h than in patients with an onset < 6 h (14.1 +/- 16.5 mg/L vs 2.7 +/- 2.3 mg/L, p < 0.0001)., Conclusions: Serum levels of hs-CRP were significantly higher in patients with an onset of AMI < 6 h than in healthy subjects and in patients with angina pectoris undergoing PCI. The inflammatory process has been proved as one of the mechanisms causing plaque rupture. Elevated serum hs-CRP levels in patients with AMI < 6 h may portend vulnerable plaque rupture.

The long-term performance of two high impedance, steroid-eluting, passive-fixation ventricular leads, porous platinum iridium electrode CPI Selute Picotip 4035 (131 patients), and platinized platinum electrode Medtronic Capsure Z 5034 (57 patients), was compared with one conventional 8.0-mm2 porous platinum iridium electrode CPI Selute 4285 (38 patients). The mean follow-up period was 28 +/- 14 months. Capture threshold, R wave amplitude, and pacing impedance were measured at the time of implantation, immediately after implantation, 1 week, 1, 3, and 6 months after implantation and then every 6 months thereafter. The two high impedance leads revealed a higher sensing slew rate than the conventional lead, the R wave amplitude was similar among the three groups, but the voltage threshold at 0.5-ms pulse width was significantly higher in porous platinum iridium groups at the time of implantation. During follow-up, the conventional lead revealed a significantly higher R wave amplitude within the first 3 months, however, this pattern disappeared after 3 months. Pacing impedance was significantly higher in the high impedance porous platinum iridium electrode groups. Voltage threshold at 0.5-ms pulse width was similar among the three groups in the first 3 months, however, it increased gradually and was significantly higher in porous platinum iridium electrode groups subsequently. The energy threshold at 0.5 ms was significantly lower in the two high impedance groups than the conventional group, but no difference was found in the two high impedance groups. Lead related complications were similar among the three groups. In conclusion, high impedance electrodes with different design and materials had different properties; platinized platinum electrode showed a lower pacing impedance but had a more stable long-term capture threshold as compared to the porous platinum iridium electrode. Further studies are mandatory for the development of an ideal pacing lead.

Purpose: A high percentage of early-stage, high-grade gastric mucosa-associated lymphoid tissue (MALT) lymphomas remain Helicobacter pylori dependent. t(11;18)(q21;q21), a genetic aberration highly predictive of H. pylori-independent status in low-grade gastric MALT lymphoma, is rarely detected in its high-grade counterpart. This study examined whether nuclear expression of BCL10 or nuclear factor kappa B (NF-kappaB) is useful in predicting H. pylori-independent status in patients with stage IE high-grade gastric MALT lymphomas., Patients and Methods: Twenty-two patients who had participated in a prospective study of H. pylori eradication for stage IE high-grade gastric MALT lymphomas were studied. The expression of BCL10 and NF-kappaB in pretreatment paraffin-embedded lymphoma tissues was evaluated by immunohistochemistry and confocal immunofluorescence microscopy. The presence of t(11;18)(q21;q21) was identified by a multiplex reverse transcriptase polymerase chain reaction of the API2-MALT1 chimeric transcript., Results: Aberrant nuclear expression of BCL10 was detected in seven (87.5%) of eight H. pylori-independent and in none of 14 H. pylori-dependent high-grade gastric MALT lymphomas (P <.001). All seven patients with nuclear BCL10 expression had nuclear expression of NF-kappaB, compared with only two of 15 patients without nuclear BCL10 expression (P =.002). As a single variable, the frequency of nuclear expression of NF-kappaB was also significantly higher in H. pylori-independent tumors than in H. pylori-dependent tumors (seven of eight [87.5%] v two of 15 [12.3%]; P =.002). The API2-MALT1 fusion transcript was detected in only one (12.5%) of eight H. pylori-independent lymphomas., Conclusion: Nuclear expression of BCL10 or NF-kappaB is highly predictive of H. pylori-independent status in high-grade gastric MALT lymphoma, and coexpression of these two markers in the nuclei is frequent.

To investigate the efficacy and safety of combining weekly oxaliplatin with weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) and folinic acid (FA) in treatment of patients with advanced gastric cancer. Patients with histologically confirmed, locally advanced or recurrent/metastatic gastric cancer were studied. Oxaliplatin 65 mg m(-2) 2-h intravenous infusion, and 5-FU 2600 mg m(-2) plus FA 300 mg m(-2) 24-h intravenous infusion, were given on days 1 and 8, repeated every 3 weeks. Between January 2001 through January 2002, 55 patients were enrolled. The median age was 64 years (range: 22-75). In all, 52 patients (94.5%) had recurrent or metastatic disease and three patients had locally advanced disease. Among 50 patients evaluable for tumour response, 28 patients achieved partial response, with an overall response rate of 56% (95% confidence interval (CI): 41.8-70.3%). All 55 patients were evaluated for survival and toxicities. Median time to progression and overall survival were 5.2 and 10.0 months, respectively, during median follow-up time of 24.0 months. Major grades 3-4 toxicities were neutropenia in 23 cycles (7.1%) and thrombocytopenia in 16 cycles (5.0%). Treatment was discontinued for treatment-related toxicities in nine patients (16.4%), of whom eight were due to oxaliplatin-related neurotoxicity. One patient (1.8%) died of neutropenic sepsis. This oxaliplatin-containing regimen is effective in the treatment of advanced gastric cancer. Except for neurotoxicity that often develops after prolonged use of oxaliplatin, the regimen is well tolerated.

Background: Women have had a higher early mortality rate than men after acute myocardial infarction (AMI) in the prethrombolytic and thrombolytic eras. Primary percutaneous coronary intervention (PCI) has been shown to significantly improve survival of patients with AMI, and to be superior to thrombolytic therapy in terms of immediate restoration of normal flow in the infarct-related artery and reduction of recurrent ischemic events. However, the effect of primary PCI on early outcomes of women vs men remains unknown. Therefore, we examined whether there was any difference in term of 30-day mortality between women and men after primary PCI., Methods and Results: Between May 1993 and April 2002, primary PCI was performed in 1,032 consecutive patients (15.3% women and 84.7% men) with AMI. The overall successful reperfusion (final Thrombolysis in Myocardial Infarction grade 3 flow) and 30-day morality rates were 84.0% and 8.5%, respectively. The rate of successful reperfusion did not differ between women and men (84.8% vs 83.9%, p = 0.77). However, mortality at 30 days was significantly higher in women than in men (14.6% vs 7.4%, p = 0.003). In comparison with men, women were older; had significantly higher incidences of hypertension, diabetes mellitus, complete atrioventricular block, and right ventricular infarction; and had longer times of reperfusion (all p values < 0.05). During hospitalization, advanced congestive heart failure (New York Heart Association class 3 or greater), free wall rupture, and major bleeding complications were more likely to occur in women than in men (all p values < 0.05). Compared with men, the unadjusted odds ratio for 30-day death among women was 2.12 (95% confidence interval [CI], 1.27 to 3.53). After adjusting for age, the odds ratio was substantially reduced to 1.66 (95% CI, 0.98 to 2.79). Further adjustment for age and other variables further reduced the odds ratio to 1.06 (95% CI, 0.53 to 2.14)., Conclusions: A gender gap of 30-day mortality existed between women and men with AMI that could not be altered by primary PCI. However, this gap was only an apparent one, and was not truly related to gender alone. In comparison with men, women were older, had significantly higher incidences of comorbidities and major untoward clinical events, and had longer times of reperfusion, which could help explain why the 30-day mortality rate was higher in women than in men.

We previously reported that suppression of the MEK/ERK pathway increases drug resistance of SiHa cells. In this study, we further characterized the underlying mechanism of this phenomenon. Pretreatment of SiHa cells with MEK/ERK inhibitor enhanced cisplatin-induced NF-kappaB activation. However, results of immunoblotting analysis showed that neither cisplatin nor MEK/ERK inhibitors induced marked IkappaBalpha degradation, suggesting that suppression of the MEK/ERK signaling pathway may enhance cisplatin-induced NF-kappaB activation via mechanisms other than the conventional pathway. Previous findings that protein phosphatase 4 (PP4), a nuclear serine/threonine phosphatase, directly interacts with and activates NF-kappaB led us to examine the phosphorylation status of NF-kappaB p65. Coincident with activation of NF-kappaB, cisplatin induced Ser phosphorylation but decreased Thr phosphorylation of NF-kappaB p65. Suppression of the MEK/ERK pathway further enhanced cisplatin-induced Thr dephosphorylation but did not affect cisplatin-induced Ser phosphorylation of NF-kappaB p65. Further, in parallel with Thr dephosphorylation, the protein level of nuclear PP4 was increased in cisplatin-treated cells and was further increased by suppression of the MEK/ERK pathway. SiHa cells were then transfected by a sense or an antisense PP4 gene. PP4-overexpressing cells showed a decrease in Thr phosphorylation of NF-kappaB p65 to nearly undetectable levels, and both basal and cisplatin-induced NF-kappaB activities were higher than those in parental cells. By contrast, cisplatin, either alone or with MEK/ERK inhibitors, induced little NF-kappaB activation in antisense PP4-transfected cells. Coprecipitated complex kinase assay revealed a fragment of NF-kappaB p65 (amino acids 279-444) to contain potential phosphorylation sites that directly interact with PP4. Further studies by site-directed mutagenesis suggested that Thr(435) was the major phosphorylation site.

Both gemcitabine and weekly 24-h infusion of high-dose 5-fluorouracil/leucovorin (HDFL) have shown promising antitumour activity for patients with locally advanced or metastatic carcinoma of the biliary tract (CBT). From April 1999 through December 2002, 30 patients with inoperable CBT were treated with gemcitabine 800 mg m(-2), intravenous infusion for 30 min, followed by 5-FU, 2000 mg m(-2) and leucovorin, 300 mg m(-2), intravenous infusion for 24 h, on day 1, 8 and 15, every 4 weeks. A total of 166 cycles were given (median of four cycles per patient, range 1-24 cycles). Response was evaluable in 28 patients and toxicity in 29 patients. Partial response was obtained in six patients, stable disease in 13, while progressive disease occurred in nine. The objective response rate was 21.4% (95% CI: 5.2-37.6%). The most common grade 3 or 4 toxicity was infection (nine patients). Other types of grade 3 or 4 toxicity included leucopenia (four patients), thrombocytopenia (three patients), anaemia (three patients), nausea/vomiting (two patients) and elevation of liver transaminases (three patients). As of 30 September 2003, the median progression-free survival was 3.7 months (95% CI: 2.8-4.6 months) and the median overall survival was 4.7 months (95% CI: 0.8-8.6 months). Our data suggest that weekly gemcitabine plus HDFL is modestly active with acceptable treatment-related toxicity for patients with advanced CBT.

Background: Recent data suggest that the risk of acquired ventricular septal defect (VSD), a complication of acute myocardial infarction (AMI), could be reduced using thrombolytic therapy. There are, however, still no available data regarding the potential impact of primary percutaneous coronary intervention (PCI) on AMI-related VSD in a clinical setting. The purposes of this study were to delineate the incidence and the potential risk factors of AMI-related VSD in the Chinese population, and to determine whether primary PCI could reduce such risk., Methods and Results: From May 1993 through March 2003, a total of 1,321 patients with AMI (for < 12 h) underwent primary PCI in our hospital. Of these 1,321 patients, 3 patients (0.23%) developed VSD after undergoing a primary PCI, with a mean (+/- SD) time of occurrence of 25.3 +/- 12.2 h. During the same period, a total of 616 consecutive, unselected patients with early AMI [ie, > 12 h and < or = 7 days] or recent myocardial infarction (MI) [ie, > or = 8 days and < 30 days] who had not received thrombolytic therapy underwent elective PCI. Of these 616 patients, 18 (2.9%) had VSD either on presentation or during hospitalization, with a mean time of occurrence of 71.1 +/- 64.2 h. Clinical variables were utilized to statistically analyze the potential risk factors. Univariate analysis demonstrated that the enrollment variables strongly related to this complication were advanced age, hypertension, nonsmokers, anterior infarction, female gender, and lower body mass index (BMI) [all p < 0.005]. Using multiple stepwise logistic regression analysis, the only variables independently related to VSD were advanced age, female gender, anterior infarction, and low BMI (all p < 0.05). The in-hospital mortality rate was significantly higher in patients with this complication than in patients without this complication (47.6% vs 8.0%; p < 0.0001). The incidence of this complication was significantly lower in patients with AMI who underwent primary PCI than in those with early or recent MI who underwent elective PCI (3.0% vs 0.23%, respectively; p = 0.0001)., Conclusion: Primary PCI had a striking impact on reducing the incidence of VSD after AMI compared to elective PCI in patients who did not receive thrombolytic therapy. Advanced age, female gender, anterior infarction, and low BMI had potentially increased the risk of this catastrophic complication after AMI in this Chinese population.

Background/aims: Our previous studies showed that high-dose tamoxifen may improve the therapeutic efficacy of doxorubicin (HTD regimen) in hepatocellular carcinoma. Interferon-alpha, either as a single-agent treatment or as a biochemical modulator, has also been reported to be effective in the treatment of hepatocellular carcinoma. In this study, we sought to clarify if the addition of Interferon-alpha2b to HTD regimen could further improve the control of advanced hepatocellular carcinoma., Methodology: Eligible patients had unresectable and non-embolizable hepatocellular carcinoma, objectively measurable tumors, adequate hemogram and major organ function, age > or = 75 year, and a Karnofsky performance status > or = 60%. The treatment included oral tamoxifen 40 mg/m2, q.i.d., Day 1-7; interferon-alpha2b subcutaneous injection, 5 MU/m2, q.d. (Day 3-5) and 3 MU/m2, q.o.d. (Day 6-21); and intravenous doxorubicin 60 mg/m2, Day 4, repeated every 4 weeks., Results: From May 1997 through July 2002, a total of 30 patients were enrolled, 25 of whom were eligible for assessment of response and toxicity. These included 20 men and 5 women, with a median age of 45 years. They received an average of 3.5 (range: 1-8) courses of chemotherapy. Grade 3-4 leukopenia and Grade 3-4 thrombocytopenia developed in 46.7% and 51.0% of treatment courses, respectively. Gastrointestinal toxicity was generally mild. One patient achieved a complete remission and remained disease-free at this report, with a progression-free survival of 49 months at last follow-up in September 2002. Five patients achieved a partial remission, with a median progression-free survival of 7 months. The total response rate was 24% (95% confidence interval 9.4-45.1%). Median survival for all 25 patients was 6.0 months and the 1-year survival rate was 16%., Conclusions: Combination of interferon-alpha2b, high-dose tamoxifen, and doxorubicin is an effective treatment for advanced hepatocellular carcinoma. However, the data does not support that addition of interferon-alpha2b is superior to HTD regimen alone.

We recently reported that exposure of human cervical carcinoma cells to doxorubicin results in extracellular signal-regulated kinase (ERK)2 activation, which in turn phosphorylates p53 on a previously uncharacterized site, Thr55. This study sought to clarify the biological significance of doxorubicin-induced Thr55 phosphorylation. In breast carcinoma MCF7 cells, doxorubicin (300 nM) activated ERK2 and induced phosphorylation of p53 on Thr55 residues. Pretreatment of MCF7 cells with an ERK2 chemical inhibitor, PD98059 or U0126, blocked doxorubicin-induced p53 activation and suppressed phosphorylation of p53Thr55. MCF55a cells were established by transfection of full-length p53 carrying Thr55 mutation (Thr to Ala) into MCF7 cells. Doxorubicin (500 nM) could not induce p53 activation in MCF55a cells, which showed significantly increased drug resistance toward doxorubicin. While the expression of the apoptotic protein, Bax, showed no difference between MCF7 and MCF55a cells, Bcl-2, an antiapoptotic protein, was constitutively expressed in MCF55a cells. The increase of Bcl-2 protein and/or Bcl-2/Bax ratio might at least partly contribute to the drug resistance of MCF55a cells. In summary, our results suggest that phosphorylation of p53Thr55 by ERK2 is important for doxorubicin-induced p53 activation and cell death.

We studied 196 consecutive patients with posterior paraseptal accessory pathway (AP); 124 showed manifest preexcitation and 72 were concealed AP. Successful ablation was obtained from left-sided approach in 134 patients (left posterior pasaseptal [LPS] group) and from right sided approach in 62 patients (right posterior paraseptal [RPS] group). A ventriculo-atrial (VA) interval of <50 ms recorded at LPS region (VA(LPS)) during right ventricular pacing identified 95 of the 134 patients (71%) with LPS AP with 100% specificity and positive predictive value. In the 101 patients with VA(LPS) >/=50 ms, a difference in VA interval of <20 ms recorded at the His bundle region and LPS region, DeltaVA(H-LPS), during right ventricular pacing predicted RPS AP with a sensitivity of 97%, a specificity of 85% and a positive predictive value of 91%. When these 2 parameters were used together for prediction of LPS or RPS AP, the sensitivity, specificity, and positive predictive value were 96%, 97%, and 98% for LPS AP, and 97%, 96%, and 91% for RPS AP, respectively. This simple new algorithm using VA(LPS) and DeltaVA (H-LPS) during right ventricular pacing successfully discriminates LPS and RPS AP with high sensitivity, specificity, and positive predictive value and could facilitate radiofrequency ablation in patients with posterior paraseptal AP.

Recently, evidence has accumulated that weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) with leucovorin (LV, folinic acid) biochemical modulation may improve the response rates compared with the bolus 5-FU regimens in colorectal cancer (CRC). Combining the infusional 5-FU/LV (iFL) regimens with oxaliplatin or irinotecan is widely adopted to further improve treatment efficacy. Either oxaliplatin-iFL or irinotecan-iFL may achieve an overall response rate of more than 50% in the first-line treatment. Intriguingly, in the salvage treatment for metastatic CRC patients who had failed iFL, only oxaliplatin-iFL may achieve a response rate of about 13-25%. In contrast, oxaliplatin alone or irinotecan-iFL had a very low response rate of 5% or less. To test if the oxaliplatin may reverse the iFL-related 5-FU resistance in CRC, we used DLD-1 colon adenocarcinoma cells as the in vitro study model. First, we revealed that oxaliplatin and 5-FU act synergistically on DLD-1 cells by MTT cytotoxicity assay and median drug effect analysis. Second, we treated the DLD-1 cells with serial concentrations of oxaliplatin (0.1-10 microM). Oxaliplatin treatment results in down-regulation of free thymidylate synthase (TS) protein expression by Western blotting. Further, we analyzed the TS mRNA level by reverse transcription and real-time quantitative polymerase chain reaction assay. Oxaliplatin treatment results in down-regulation of the TS mRNA level up to 40% (mean +/- SD of ratio to reference control = 0.60 +/- 0.21, range 0.42-0.84). In this study, our data provide important information explaining the reason why the combination of oxaliplatin and 5-FU results in a better objective response in 5-FU-resistant patients than oxaliplatin alone does. Our data also suggest that TS down-regulation happens at the transcriptional level. TS modulation and down-regulation had, thus, shed light on the useful potential strategy to achieve objective responses in 5-FU-resistant CRC patients.

Gastric cancer is the fourth leading cause of death from cancer in Taiwan. Complete surgical resection is the only potentially curative treatment for gastric cancer. Randomized trials have failed to show the superiority of D2 over D1 dissection, and comparisons showing higher survival rates following more extensive surgery in Japan may have been influenced at least in part by the fact that D1 dissection underestimates disease stage in Western populations. No studies have shown convincing evidence of a survival benefit from adjuvant chemotherapy. A regimen of postoperative 5-fluorouracil (5-FU)-based chemoradiotherapy can improve disease-free and overall survival compared with surgery alone. Inadequate lymph node dissection for local control is a major concern. For advanced disease, HDFL (weekly 24-hour infusion of high-dose 5-FU and leucovorin)-based 'doublet' chemotherapy forms a cornerstone of combination chemotherapy in gastric cancer, but the effect on prolonged median survival is minimal. A 'sequential' non-cross-resistant strategy may be useful to prolong overall survival in patients with advanced gastric cancer. There are indications that preoperative neoadjuvant chemotherapy or chemoradiotherapy may increase the resectability of tumors and reduce the risk of postoperative recurrence. In the future, substantial improvements of treatment outcome will likely depend on the integration of novel, molecularly targeted agents into multimodality treatment strategies for all stages of gastric cancer. Further clinical research is mandatory to develop optimal therapies for gastric cancer.

Background: Changes in the circulating volume associated with hemodialysis (HD) resulted in alternations of left ventricular (LV) filling. However, previous studies offered conflicting findings. This study thus evaluated the impact of HD on LV diastolic filling indices and hemodynamics., Materials and Methods: Forty patients with end-stage renal disease were studied by Doppler echocardiography immediately before and after HD. The cardiac size, volume and mass were determined by M-mode and two-dimensional echocardiography. LV diastolic filling parameters and hemodynamics were assessed from mitral inflow using Doppler echocardiography., Results: Left atrial and LV dimension, LV volume, and LV mass decreased significantly after HD (p<0.001). Cardiac output declined from 5.74+/-1.37 to 4.98+/-1.27 L/min (p<0.001), whereas, the ejection fraction remained unchanged. HD elicited marked changes in the early diastolic E (95.1+/-20.5 to 70.3+/-18.2 cm/s, p<0.001) and late atrial filling A velocities (104.3+/-20.9 to 88.9+/-16.9 cm/s, p<0.001). In addition, correction of the deceleration time of E and isovolumic relaxation time prolonged significantly (p=0.011 and p<0.001, respectively)., Conclusions: Findings in this study indicate that HD altering the loading condition significantly influenced the LV diastolic function and hemodynamics. Moreover, Doppler echocardiography provides an effective means of assessing the effects on LV diastolic filling and hemodynamics during HD.

The benefit of primary percutaneous coronary intervention is limited by a 5% to 20% incidence of suboptimal epicardial coronary blood (< or = TIMI-2 flow). Recently, data has demonstrated that when administered in conjunction with primary stenting for the treatment of acute myocardial infarction (AMI), abciximab improves the success rate of the stenting procedure and provides additional clinical benefits. But data on a combination of tirofiban and primary stenting for treatment of ST-segment elevated (ST-se) AMI is unknown. Between May 1999 and September 2000, primary stenting without adjunctive tirofiban therapy was performed in 136 consecutive patients (control group) with ST-se AMI. Between January 2001 and May 2002, we routinely administered tirofiban to 133 consecutive patients (study group) with ST-se AMI before they underwent primary stenting. The angiographic and clinical outcomes of both groups were compared in a chronologically consecutive manner. The overall mortality rate was significantly higher in patients with failed (< or = TIMI-2 flow) than in patients with successful (TIMI-3) reperfusion (20.0% vs 3.5%, P < 0.0001). Univariate analysis demonstrated that there were no significant differences in the successful reperfusion (85.7% vs 84.6%, P = 0.84) or 30-day combined end points - death, recurrent ischemia or reinfarction (8.3% vs 11.0%, P = 0.59) between study and control group patients. Clinical variables were used to statistically analyze potential risk factors for unsuccessful reperfusion (< or = TIMI-2 flow) in the study group patients. Multiple stepwise logistic regression analysis demonstrated that the reference lumen diameter (RLD) of the infarct-related artery (IRA) > or = 3.5 mm (P = 0.0004) and the lesion length of the obstruction > or = 20.0 mm (P = 0.018) were the significant independent predictors of failed normalized coronary blood flow. There were no significant differences in the restenotic rate of IRA (29.2% vs 30.8%, P = 0.9) or mortality rate (1.6% vs 1.6%, P = 1.0) at six-month follow-up. In conclusion, our study demonstrates that primary stenting with adjunctive tirofiban therapy in ST-se AMI did not provide additional benefits in short-term and intermediate-term angiographic and clinical outcomes compared to conventional primary stenting.

A 46-year-old female patient suffered from uterine malignant leiomyosarcoma. Ten months after abdominal subtotal hysterectomy, multiple lung, bone and spine metastases developed. She received 3 cycles of infusional ADI chemotherapy (adriamycin 60 mg/m2, 96-hour i.v. infusion, dacarbazine 500 mg/m2, 96-hour i.v. infusion and ifosfamide 5,000 mg/m2, 72-hour i.v. infusion, repeated every 3 weeks), but the metastatic tumors progressed. An empirical ADI-TAM chemotherapy which incorporated high-dose tamoxifen (TAM) (150 mg/m2/day, in 4 divided doses) into the original ADI regimen was applied from the fourth cycle. High-dose tamoxifen consisted of 240 mg/day for 4 days during chemotherapy and 40 mg/day between cycles. Good partial response with nearly total tumor reduction was achieved after 3 cycles of ADI-TAM therapy. The excellent tumor response by simple addition of high-dose tamoxifen into a previously inactive ADI regimen advocates further investigation for the development of chemotherapy in metastatic uterine leiomyosarcoma.

Administration of suboptimal doses of anticancer drugs not only fails to control tumor but often results in increased drug resistance of tumor cells. However, little is known about the effects of transient exposure to a minimally cytotoxic dose of chemotherapy on the development of drug resistance of the tumors. Previous studies have shown that upregulation of drug-exporter proteins (ATP-binding-cassette proteins) may be one of the key mechanisms involved in inducible drug resistance. In this study, we demonstrated that upregulation of NF-kappa B is another possible mechanism. SiHa cells were exposed to low-dose doxorubicin (100 nM; IC(30)) for 3 hr, and then were continuously cultured in drug-free culture media (designated as SiHa/DR cells). SiHa/DR cells at up to 9 passages showed increased resistance to doxorubicin and cross-resistance to cisplatin. Results of quantitative real-time PCR and flow cytometry assay indicated that the increased drug-resistance in SiHa/DR cells was not due to upregulation of drug-exporter proteins or to the decrease of intracellular concentration of anticancer drugs. Both the basal and drug-induced NF-kappa B activity were shown to be increased in SiHa/DR cells by EMSA and NF-kappa B-driven luciferase reporter gene assay. Suppression of NF-kappa B activation by transfection of a dominant negative I kappa B alpha prevented the development of drug resistance, indicating that the upregulated NF-kappa B activity was positively correlated with the low-dose doxorubicin-induced drug resistance. These results suggest that even a transient exposure to a small dose of anticancer drugs may induce drug resistance in some cancer cells via upregulation of NF-kappa B activity.

Background: Simultaneous ST-segment elevation in the precordial and inferior leads is a rare ECG finding in patients with acute myocardial infarction (AMI) and its clinical implications rarely have been reported. The purpose of this study was to evaluate the clinical features of this distinctive ECG manifestation and its impact on clinical outcome., Methods and Results: Between May 1993 and July 2001 in our hospital, direct percutaneous coronary intervention (dPCI) was performed in 924 patients with AMI. Of these 924 consecutive patients, 37 patients (4.0%) who had simultaneous ST-segment elevation (> or = 1 mm) in the precordial and inferior leads were retrospectively analyzed. Eight of these 37 patients who had a wrapped left anterior descending artery (LADA) occlusion were placed into group 1 (ie, wrapped LADA). Twenty-nine of the 37 patients who had anatomic lesions other than a wrapped LADA in the coronary arteries were placed into group 2 (ie, "nonwrapped" LADA). Group 2 patients had significantly higher incidences of cardiogenic shock (58.6% vs 0%, respectively; p = 0.004), pulmonary edema (43.8% vs 0%, respectively; p = 0.02), and sustained sudden cardiac death due to malignant ventricular tachyarrhythmias (44.8% vs 0%, respectively; p = 0.03) than did group 1 patients. Group 1 patients usually had ST-segment elevations of < 2 mm the inferior leads. However, group 2 patients always had ST-segment elevations of > or = 2 mm in the inferior leads. Univariate analysis demonstrated that the mean (+/- SD) ST-segment elevation in the inferior leads was significantly higher in group 2 patients than in group 1 patients (11.08 +/- 4.18 vs 2.95 +/- 0.92 mm, respectively; p = 0.0001). Coronary angiography demonstrated that the incidence of multivessel disease (93.1% vs 37.5%, respectively; p = 0.002) and the incidence of severe obstructive two-vessel disease (ie, stenosis of > 85%) [93.1% vs 0%, respectively; p = 0.0001] were significantly higher in group 2 than in group 1 patients. Although there was no significant difference in the rate of unsuccessful reperfusion (24% vs 13%, respectively; p = 0.38) between group 2 and group 1 patients, the 30-day mortality rate was significantly higher in group 2 patients than in group 1 patients (48.3% vs 0%, respectively; p = 0.015)., Conclusions: AMI with ECG manifestation of simultaneous ST-segment elevation in precordial and inferior leads can be caused by either a wrapped LADA occlusion or a nonwrapped LADA occlusion. While patients with wrapped LADA occlusions usually have favorable clinical outcomes, patients with nonwrapped LADA occlusions usually have serious clinical presentations and unfavorable clinical outcomes. Specific clinical and ECG features identifying high-risk patients in this clinical setting would be extremely important for early, aggressive, and appropriate management.

There is a lack of consensus among cardiologists regarding the length of time patients should be hospitalized after an uncomplicated acute myocardial infarction (AMI) and successful direct percutaneous coronary intervention (d-PCI). The purpose of this study was to evaluate the feasibility and safety of early discharge (discharge <4 days after the procedure) for low risk patients with AMI who underwent successful d-PCI. From May 1996 through December 2001, d-PCI was performed in 898 consecutive patients with AMI. Of these 898 patients, 463 (51.6%) were stratified to be at low risk. Lower risk was defined as: (1) Killip classification < or = 2 on admission; (2) the infarct-related artery achieved normal blood flow without recurrent ischemia or reinfarction in the first 24 hours; (3) no mechanical or electrical complications after d-PCI. (4) no acute renal failure, acute stroke, or major bleeding complication; (5) no advanced congestive heart failure (defined as > or = New York Heart Association functional class 3); and (6) no sepsis. Patients who were discharged <4 days after undergoing the procedure were enrolled in group 1 (n = 266). Patients who were discharged > or = 4 days after undergoing the procedure were enrolled in group 2 (n = 197). Univariate analysis demonstrated that group 2 patients had a significantly longer hospital stay (P = 0.0001) than group 1 patients. At the first 30-day follow-up examination, there were no significant differences in the combined major cardiac events (death, recurrent isehemia, reinfarction, revascularization. or advanced congestive heart failure) between the group 1 and group 2 patients (1.50% vs 1.52%, P = 0.92). There were also no significant differences in the combined major noncardiac complications (acute stroke, acute renal failure, bleeding complications requiring blood transfusion, vascular sequelae, or sepsis) between the group 1 and group 2 patients (1.13% vs 0.51%. P = 0.89). Early discharge was feasible in a majority of the patients who experienced AMI and were at lower risk 24 hours after successful d-PCI. Thus, the patients had a shortened hospital stay and no increased risk.