Efficacy and safety of cabozantinib for patients with advanced hepatocellular carcinoma based on albumin-bilirubin grade.

BACKGROUND: Albumin-bilirubin (ALBI) grade is an objective measure of liver function for patients with hepatocellular carcinoma (HCC). The tyrosine kinase inhibitor cabozantinib is approved for patients with advanced HCC who have received prior sorafenib based on the phase 3 CELESTIAL trial (NCT01908426). Cabozantinib improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated HCC. METHODS: Patients were randomised 2:1 to receive cabozantinib 60 mg or placebo orally every day. Clinical outcomes in patients with ALBI grade 1 or 2 at baseline were evaluated in CELESTIAL. ALBI scores were retrospectively calculated based on baseline serum albumin and total bilirubin, with an ALBI grade of 1 defined as ≤ -2.60 score and a grade of 2 as a score of > -2.60 to ≤ -1.39. RESULTS: Cabozantinib improved OS and PFS versus placebo in both ALBI grade 1 (hazard ratio [HR] [95% CI]: 0.63 [0.46-0.86] and 0.42 [0.32-0.56]) and ALBI grade 2 (HR [95% CI]: 0.84 [0.66-1.06] and 0.46 [0.37-0.58]) subgroups. Adverse events were consistent with those in the overall population. Rates of grade 3/4 adverse events associated with hepatic decompensation were generally low and were more common among patients in the ALBI grade 2 subgroup. DISCUSSION: These results provide initial support of cabozantinib in patients with advanced HCC irrespective of ALBI grade 1 or 2. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number, NCT01908426.

Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma.

BACKGROUND: Cabozantinib inhibits tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3, MET, and AXL, which are implicated in the progression of hepatocellular carcinoma and the development of resistance to sorafenib, the standard initial treatment for advanced disease. This randomized, double-blind, phase 3 trial evaluated cabozantinib as compared with placebo in previously treated patients with advanced hepatocellular carcinoma. METHODS: A total of 707 patients were randomly assigned in a 2:1 ratio to receive cabozantinib (60 mg once daily) or matching placebo. Eligible patients had received previous treatment with sorafenib, had disease progression after at least one systemic treatment for hepatocellular carcinoma, and may have received up to two previous systemic regimens for advanced hepatocellular carcinoma. The primary end point was overall survival. Secondary end points were progression-free survival and the objective response rate. RESULTS: At the second planned interim analysis, the trial showed significantly longer overall survival with cabozantinib than with placebo. Median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo (hazard ratio for death, 0.76; 95% confidence interval [CI], 0.63 to 0.92; P=0.005). Median progression-free survival was 5.2 months with cabozantinib and 1.9 months with placebo (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.52; P<0.001), and the objective response rates were 4% and less than 1%, respectively (P=0.009). Grade 3 or 4 adverse events occurred in 68% of patients in the cabozantinib group and in 36% in the placebo group. The most common high-grade events were palmar-plantar erythrodysesthesia (17% with cabozantinib vs. 0% with placebo), hypertension (16% vs. 2%), increased aspartate aminotransferase level (12% vs. 7%), fatigue (10% vs. 4%), and diarrhea (10% vs. 2%). CONCLUSIONS: Among patients with previously treated advanced hepatocellular carcinoma, treatment with cabozantinib resulted in longer overall survival and progression-free survival than placebo. The rate of high-grade adverse events in the cabozantinib group was approximately twice that observed in the placebo group. (Funded by Exelixis; CELESTIAL ClinicalTrials.gov number, NCT01908426 .).

Anti-Platelet Factor 4/Heparin Antibody Plays a Significant Role in Progression of Arterial Stiffness among Hemodialysis Patients.

BACKGROUND: Arterial stiffness is a determinant of cardiovascular disease in end stage renal disease. Hemodialysis patients may develop anti-platelet factor 4/heparin antibody (PF4-H Ab) because of heparin treatment in dialysis. We tested whether PF4-H Ab was associated with progression of arterial stiffness in a 3-year follow-up. METHODS: We enrolled 74 hemodialysis patients and studied their clinical, biochemical and arterial stiffness measurement with brachial-ankle pulse wave velocity (baPWV) over 3 years. Baseline and changes in baPWV after 3 years (ΔbaPWV) were collected and compared with related clinical and biochemical parameters. PF4-H Ab was evaluated by the enzyme-linked immunosorbent assay and titer ≥ 0.4 was defined to have PF4-H Ab. RESULTS: We found a positive PF4-H Ab status in 25 of 74 patients. Mean baPWV was 16.1 ± 3.8 (m/s) at baseline and 17.6 ± 4.0 (m/s) after 3 years. Mean ΔbaPWV was 3.4 ± 2.2 (m/s) in the PF4-H Ab positive group, and 0.6 ± 1.2 (m/s) in the PF4-H Ab negative group. Baseline baPWV was only significantly associated with age (ß = 0.49, p < 0.01). ΔbaPWV was significantly different between the PF4-H Ab positive and negative groups (p < 0.01). In multivariate regression analysis, only PF4-H Ab was positively associated with ΔbaPWV (ß = 0.71, p < 0.01). CONCLUSIONS: Our study concluded that PF4-H Ab was associated with progression of arterial stiffness in hemodialysis patients.

An app to classify a 5-year survival in patients with breast cancer using the convolutional neural networks (CNN) in Microsoft Excel: Development and usability study.

BACKGROUND: Breast cancer (BC) is the most common malignant cancer in women. A predictive model is required to predict the 5-year survival in patients with BC (5YSPBC) and improve the treatment quality by increasing their survival rate. However, no reports in literature about apps developed and designed in medical practice to classify the 5YSPBC. This study aimed to build a model to develop an app for an automatically accurate classification of the 5YSPBC. METHODS: A total of 1810 patients with BC were recruited in a hospital in Taiwan from the secondary data with codes on 53 characteristic variables that were endorsed by professional staff clerks as of December 31, 2019. Five models (i.e., revolution neural network [CNN], artificial neural network, Naïve Bayes, K-nearest Neighbors Algorithm, and Logistic regression) and 3 tasks (i.e., extraction of feature variables, model comparison in accuracy [ACC] and stability, and app development) were performed to achieve the goal of developing an app to predict the 5YSPBC. The sensitivity, specificity, and receiver operating characteristic curve (area under ROC curve) on models across 2 scenarios of training (70%) and testing (30%) sets were compared. An app predicting the 5YSPBC was developed involving the model estimated parameters for a website assessment. RESULTS: We observed that the 15-variable CNN model yields higher ACC rates (0.87 and 0.86) with area under ROC curves of 0.80 and 0.78 (95% confidence interval 0.78-82 and 0.74-81) based on 1357 training and 540 testing cases an available app for patients predicting the 5YSPBC was successfully developed and demonstrated in this study. CONCLUSION: The 15-variable CNN model with 38 parameters estimated using CNN for improving the ACC of the 5YSPBC has been particularly demonstrated in Microsoft Excel. An app developed for helping clinicians assess the 5YSPBC in clinical settings is required for application in the future.

Revealing the Dynamic Nature of Amplitude Modulated Neural Entrainment With Holo-Hilbert Spectral Analysis.

Patterns in external sensory stimuli can rapidly entrain neuronally generated oscillations observed in electrophysiological data. Here, we manipulated the temporal dynamics of visual stimuli with cross-frequency coupling (CFC) characteristics to generate steady-state visual evoked potentials (SSVEPs). Although CFC plays a pivotal role in neural communication, some cases reporting CFC may be false positives due to non-sinusoidal oscillations that can generate artificially inflated coupling values. Additionally, temporal characteristics of dynamic and non-linear neural oscillations cannot be fully derived with conventional Fourier-based analyses mainly due to trade off of temporal resolution for frequency precision. In an attempt to resolve these limitations of linear analytical methods, Holo-Hilbert Spectral Analysis (HHSA) was investigated as a potential approach for examination of non-linear and non-stationary CFC dynamics in this study. Results from both simulation and SSVEPs demonstrated that temporal dynamic and non-linear CFC features can be revealed with HHSA. Specifically, the results of simulation showed that the HHSA is less affected by the non-sinusoidal oscillation and showed possible cross frequency interactions embedded in the simulation without any a priori assumptions. In the SSVEPs, we found that the time-varying cross-frequency interaction and the bidirectional coupling between delta and alpha/beta bands can be observed using HHSA, confirming dynamic physiological signatures of neural entrainment related to cross-frequency coupling. These findings not only validate the efficacy of the HHSA in revealing the natural characteristics of signals, but also shed new light on further applications in analysis of brain electrophysiological data with the aim of understanding the functional roles of neuronal oscillation in various cognitive functions.

Increased epicardial adipose tissue (EAT) volume in type 2 diabetes mellitus and association with metabolic syndrome and severity of coronary atherosclerosis.

OBJECTIVE: Epicardial adipose tissue (EAT) is a part of visceral fat deposited around the heart between the pericardium and myocardium along the distribution of coronary arteries. EAT thickness is reported to be associated with coronary atherosclerosis; however, no study has measured EAT volume in patients with type 2 diabetes or investigate its association with coronary artery disease. DESIGN: A hospital-based case control study. PATIENTS: A total of 49 patients with type 2 diabetes mellitus (T2DM) and 78 nondiabetic controls were studied. MEASUREMENTS: Cardiac multislice computed tomography was used to measure EAT volume, Gensini score, coronary artery calcium score and, coronary lesions. The relationships between EAT volume, markers of coronary atherosclerosis and anthropometric and biochemical parameters of metabolic syndrome (MetS) were investigated. RESULTS: EAT volume was significantly higher in patients with T2DM than in nondiabetic subjects (166.1 +/- 60.6 cm(3) vs. 123.4 +/- 41.8 cm(3), P < 0.0001). Logistic regression analysis revealed independent and significant associations between EAT and diabetic status. EAT volume was significantly associated with components of MetS (BMI, waist circumference, fasting serum glucose, total cholesterol, HDL-cholesterol, and triglycerides levels), Gensini score, coronary lesions, coronary disease and coronary calcium scores. Univariate, multivariate and trend analyses confirmed that EAT volume was associated with MetS component clustering and the coronary atherosclerosis index. CONCLUSIONS: The analytical results indicate that EAT volume is increased in T2DM patients and is associated with unfavourable components of MetS and coronary atherosclerosis. The close anatomical relationship between EAT and the coronary arteries, combined with other evidence indicating that EAT is a biologically active adipokine-secreting tissue, suggest that EAT participates in the pathogenesis of diabetic coronary atherosclerosis.

Brachial-ankle pulse wave velocity as an early indicator of left ventricular diastolic function among hypertensive subjects.

While increased arterial stiffness is a known risk of cardiovascular disease, pulse wave velocity (PWV) is a conventionally adopted index of arterial stiffness. However, the relationship between PWV and left ventricular functions are not thoroughly evaluated. This cross-sectional study investigated whether PWV measurement is an early indicator of left ventricular (LV) dysfunction. A noninvasive, volume-plethysmographic apparatus was used to determine blood pressure, electrocardiogram, heart sounds, and PWV in 42 consecutively diagnosed subjects with hypertension, and 42 sex- and age-matched nonhypertension subjects were studied. Arterial stiffness and aortic stiffness were evaluated by brachial-ankle (b-a) PWV, heart-carotid (h-c) PWV, heart-femoral (h-f) PWV, carotid-femoral (c-f) PWV, and femoral-ankle (f-a) PWV. Function of LV was estimated by tissue Doppler imaging (TDI) echocardiography. Hypertension subjects exhibited higher b-a PWV and late diastolic mitral flow velocity values than those of nonhypertensive subjects. Pearson correlation analysis revealed that LV diastolic function (Em(av)) negatively correlated with c-f PWV and b-a PWV. Multiple linear regression analysis indicated that b-a PWV was independently and negatively associated with LV diastolic function (Em(av)). Further analysis by stratified hypertensive status, the b-a PWV were independently and negatively associated with Em(av) in hypertensive subjects (p = 0.004) only. In conclusion, the b-a PWV, but not c-f PWV, h-c PWV, h-f PWV, or f-a PWV, is significantly correlated with LV diastolic function in hypertensive subjects, indicating that b-a PWV involving both central and peripheral components of arterial stiffness may be an early indicator of LV dysfunction.

Women were noninferior to men in cardiovascular outcomes among patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention from Taiwan acute coronary syndrome full-spectrum registry.

This study was conducted to compare the survival rate and the influencing factors between women and men following ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI).A national-wide Acute Coronary Syndrome Full Spectrum Registry conducted by the Taiwan Society of Cardiology was used for data collection between October 2008 and January 2010. Details of 1621 patients with STEMI treated with primary PCI, including 1350 (83%) men and 271 (17%) women, were collected. Composite outcomes included all-cause death, myocardial reinfarction, and an ischemic stroke. Demographic data, comorbidities, clinical presentations, details of treatment received, and outcomes were recorded at 3-month intervals for 1 year.No significant difference was observed between men and women in the composite endpoints after STEMI during their hospital stay (5.5% vs 2.5%, P = .07). However, women showed significantly higher in-hospital and 1-year mortality rates than those of men (4.1% vs 1.8%, P = .008; 11.0% vs 4.1%, P = .000, respectively). Compared with men, women presented with higher age (mean age 68.9 vs 58.9 years, P = .001), less body weight (58.7 vs 70.9 kg, P < .001), more number of risk factors, delayed diagnosis, and more number of inadequate medical treatments. After adjusting for age and cardiovascular risk factors, the difference in mortality ceased to exist between men and women.Although female patients with STEMI-treated primary PCI had higher in-hospital and 1-year mortality rates than those of males in Taiwan, there was no gender difference after adjusting for age and cardiovascular risk factors.

Clinical determinants of sinus conversion by radiofrequency maze procedure for persistent atrial fibrillation in patients undergoing concomitant mitral valvular surgery.

The radiofrequency Maze procedure can effectively restore sinus rhythm in most patients with atrial fibrillation (AF) and mitral valve disease. AF after cardiac surgery is associated with increased morbidity and mortality. However, clinical determinants of long-term postoperative AF after the radiofrequency Maze procedure and concomitant mitral valve surgery are poorly defined. This study comprised 99 consecutive patients with persistent AF and mitral valve disease who underwent radiofrequency Maze procedures and concomitant mitral valvular operations. The predictive values of clinical variables for postoperative AF were examined. After a mean follow-up period of 46.1+/-24.6 months, 83 patients (83.8%) had sinus conversion after the Maze procedure, and 16 patients remained in persistent or paroxysmal AF. Multiple logistic regression analysis determined that predictors of sinus conversion were preoperative left atrial diameter (odds ratio [OR] 1.127 per 1-mm increment in left atrial diameter, 95% confidence interval [CI] 1.045 to 1.215, p<0.002) and the duration of AF (OR 1.022 per 1-month increment in duration of AF, 95% CI 1.009 to 1.035, p<0.001). Discriminant analysis showed that the sinus conversion rate was significantly lower in patients with preoperative left atrial diameters>56.8 mm (p<0.001) or AF duration>66 months (p<0.001) than in patients with preoperative left atrial diameters<56.8 mm or AF duration<66 months. In conclusion, the preoperative left atrial size and duration of AF are primary predictors of sinus conversion by the radiofrequency Maze procedure for patients with persistent AF and mitral valve disease.

Prognostic value of circulating levels of endothelin-1 in patients after acute myocardial infarction undergoing primary coronary angioplasty.

BACKGROUND: The link between increased circulating level of endothelin (ET)-1 and adverse clinical outcomes after acute myocardial infarction (AMI) has been established. Current studies demonstrate that reperfusion therapy by either thrombolysis or primary percutaneous coronary intervention (PCI) can salvage myocardium, improving survival of AMI patients. However, whether reperfusion therapy by primary PCI can prevent the adverse effect of ET-1 on clinical outcomes in patients after AMI remains unclear. Therefore, this study examined the predictive value of circulating ET-1 levels on 30-day outcomes in ST-segment elevated AMI treated with primary PCI. METHODS AND RESULTS: We conducted a prospective cohort study of 186 consecutive patients with ST-segment elevated AMI of onset < 12 h who underwent primary PCI. Blood samples for plasma concentration of ET-1 were collected in the catheterization laboratory following vascular puncture. Patients were classified into a high group (group 1, ET-1 level >or= 0.632 pg/mL, n = 93) and a low group (group 2, ET-1 level < 0.632 pg/mL, n = 93) according to the median value of ET-1 after AMI. Univariate analysis demonstrated that the 30-day composite major adverse clinical outcomes (MACO) [advanced Killip score >or= 3], severe congestive heart failure (CHF) [New York Heart Association functional class 4], and 30-day mortality were strongly associated with high ET-1 level (>or= 0.632 pg/mL; p < 0.0001), unsuccessful reperfusion (final Thrombolysis in Myocardial Infarction flow

Risk of Developing Coronary Artery Disease in Patients with Type 2 Diabetes Receiving Traditional Chinese Medicine Therapy.

OBJECTIVES: To compare risk of developing coronary artery disease (CAD) between diabetic patients receiving Traditional Chinese Medicine (TCM) therapy and those treated by Western medicine (WM). METHODS: This prospective cohort study included 13,655 diabetic patients receiving solely TCM and 435,165 patients treated exclusively by WM. Study patients were identified from Taiwan's National Health Insurance (NHI) ambulatory claims in 2000-2001. These patients were then linked to the 2000-2008 NHI inpatient claims, searching for possible new onset of hospitalization for CAD. A Cox proportional hazard model and logistic regression model were used to assess the hazard ratio of CAD admission and odds ratio (OR) of higher rates of admission for CAD in relation to TCM. RESULTS: During 9 years of follow-up, 2607 diabetic patients with TCM were hospitalized for CAD, representing a cumulative incidence rate of 19.1% and an incidence density of 50.5 per 1000 person-years. The corresponding figures for patients treated by WM were 24.1% and 72.7 per 1000 person-years. Compared with the patients treated by WM, those treated by TCM were associated with a slightly reduced, but insignificantly, adjusted OR of CAD admission (0.96; 95% confidence interval, 0.92-1.01). Moreover, the adjusted OR for a higher rate (≥0.212 admission per person-year) of CAD admission for the patients with TCM was also insignificantly decreased at 0.97. CONCLUSIONS: After adjustment for prior co-morbidity score, risk or rate of CAD admission did not significantly differ between diabetic patients receiving TCM therapy and those treated by WM, suggesting that TCM is as efficacious as WM in preventing diabetes from being complicated with CAD.

Anti-platelet factor 4/heparin antibody is associated with progression of peripheral arterial disease in hemodialysis patients.

BACKGROUND: Heparin therapy may induce anti-platelet factor 4/heparin antibody (PF4-H Ab). Hemodialysis patients receive scheduled heparin and are at a risk of developing PF4-H Ab. Hemodialysis patients are also at a high risk of peripheral arterial disease (PAD). This study examines whether chronic PF4-H Ab exposure contributes to the progression of PAD measured by ankle brachial index (ABI) in hemodialysis patients. MATERIALS AND METHODS: A total of 71 hemodialysis patients were enrolled, and the association between clinical, biochemical parameters and ABI after 3 years was studied. PF4-H Ab was evaluated by ELISA, and patients with titer ≥ 0.4 were taken as having PF4-H Ab. RESULTS: Mean ABI was 1.04 ± 0.18 at baseline and 1.01 ± 0.17 after 3 years. Mean ΔABI (change in ABI after 3 years) was -0.04 ± 0.13. PF4-H Ab was positive in 26 patients. PF4-H Ab was not related to hemodialysis duration, DM history, smoking and age. Platelet count showed no correlation with PF4-H Ab. However, there was significance in ΔABI between PF4-H Ab-positive and PF4-H Ab-negative patients (p = 0.002). ΔABI was negatively correlated with PF4-H Ab and 3-year averaged serum Ca × P only (ß = -0.378, p = 0.001; ß = -0.263, p = 0.018, respectively). However, in PF4-H Ab-positive patients, the extent of ΔABI did not correlate with PF4-H Ab titers (r = -0.021, p = 0.921). CONCLUSIONS: PF4-H Ab positivity, along with high levels of serum Ca × P, played a potential role in the progression of PAD over time.

Involvement of p38 MAPK in the Anticancer Activity of Cultivated Cordyceps militaris.

Cordyceps militaris is a traditional Chinese medicine frequently used for tonic and therapeutic purposes. Reports from our laboratory and others have demonstrated that extracts of the cultivated fruiting bodies of C. militaris (CM) exhibit a potent cytotoxic effect against many cancer cell lines, especially human leukemia cells. Here, we further investigated the underlying mechanism through which CM is cytotoxic to cancer cells. The CM-mediated induction of PARP cleavage and its related DNA damage signal (γH2AX) was diminished by caspase inhibitor I. In contrast, a ROS scavenger failed to prevent CM-mediated leukemia cell death. Moreover, two signaling molecules, AKT and p38 MAPK, were activated during the course of apoptosis induction. Employing MTT analysis, we found that a p38 MAPK inhibitor but not an AKT inhibitor could rescue cells from CM-mediated cell death, as well as inhibit the cleavage of PARP, formation of apoptotic bodies and up-regulation of the γH2AX signal. These results suggest that CM-mediated leukemia cell death occurs through the activation of the p38 MAPK pathway, indicating its potential therapeutic effects against human leukemia.

Mechanism of reducing platelet activity by percutaneous transluminal mitral valvuloplasty in patients with rheumatic mitral stenosis.

BACKGROUND: Previous studies have demonstrated that platelet activity significantly decreased after optimal percutaneous transluminal mitral valvuloplasty (PTMV) in patients with rheumatic mitral stenosis (MS). However, the mechanism of reducing platelet activity by valvuloplasty remains unclear. METHODS AND RESULTS: We studied 19 patients with symptomatic MS who were undergoing PTMV. The fractions of unstimulated platelets expressing P-selectin in the venous blood obtained before, and at the 1-week and 4-week follow-ups after PTMV were determined by flow cytometry. The mitral valve areas, measured before and at the 1-week follow-up after PTMV, were calculated by means of the Doppler pressure half-time method. The mean (+/- SD) area of the mitral valve increased significantly after PTMV (1.05 +/- 0.17 vs 1.44 +/- 0.27 cm2, respectively; p < 0.0001). The mean left atrial area was reduced in size significantly after PTMV (36.6 +/- 11.4 vs 33.9 +/- 13.4 cm2, respectively; p < 0.05). The mean left atrial pressure (23.3 +/- 5.1 vs 18.0 +/- 5.8 mm Hg, respectively; p < 0.0001) and the mean pulmonary arterial pressure (31.4 +/- 7.8 vs 26.1 +/- 7.7 mm Hg, respectively; p < 0.0001) fell significantly after PTMV. The fraction of platelets expressing P-selectin in the venous blood fell significantly after PTMV (before PTMV, 4.7 +/- 2.4%; 1 week after PTMV, 2.2 +/- 2.1%; 4 weeks after PTMV, 2.0 +/- 1.7%; p < 0.0001). Correlation analysis demonstrated that there was a significantly direct relationship between the magnitude of increase in mitral valve area and the magnitude of decrease in the fraction of platelets expressing P-selectin in the venous blood 4 weeks after PTMV (p = 0.0013; r = 0.682). However, there was no significant correlation between the magnitude of decrease in the fraction of platelets expressing P-selectin in the venous blood and the magnitude of decrease in the left atrial area, the decrease in left atrial pressure, or the decrease in the pulmonary artery pressure after PTMV. CONCLUSIONS: In patients with moderate-to-severe MS, increased platelet activation fell significantly after PTMV. It was the increase in mitral valve area by PTMV, instead of hemodynamic and echocardiographic factors, that accounted for the decrease in the fraction of venous platelets expressing P-selectin after PTMV.

Comparison of baseline characteristics, clinical features, angiographic results, and early outcomes in men vs women with acute myocardial infarction undergoing primary coronary intervention.

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.

Synergistic property of cordycepin in cultivated Cordyceps militaris-mediated apoptosis in human leukemia cells.

Cordyceps militaris is a well-known Chinese traditional medicinal mushroom frequently used for tonics and recently of a potential interest for cancer intervention. Here, we explored the cancer cell killing activity of the hot water extracts of C. militaris cultured mycelia (CM(MY)) and cultivated fruiting bodies (CM(FB)). We found that CM(FB) exhibited a greater cytotoxic effect against various cancer cells over CM(MY). Apoptotic phenotypes including apoptotic body formation, DNA laddering, caspase 3 activation and cleavage of PARP proteins were induced by CM(FB) treatment but only slightly induced by same concentration of CM(MY) treatment in human HL-60 leukemia cells. Cordycepin in CM(FB) (10.47 mg/g) is significantly higher (∼ 15.2 times) than that of CM(MY) (0.69 mg/g). Using isobolographic analysis, the synergy of cytotoxicity was observed across different combined concentrations of CM(MY) and cordycepin. By complementing cordycepin into CM(MY) to the level comparable with CM(FB), we observed that CM(MY) (500 µg/ml) with cordycepin (4.8 µg/ml) induced apoptosis to a level similar to that induced by CM(FB) (500 µg/ml). Together, our results suggest that cordycepin possesses a synergistic cytotoxic effect with Cordyceps militaris-mediated apoptosis in human leukemia cells and therefore explaining a better anti-proliferating activity of CM(FB) over CM(MY).

Therapy-related acute lymphoblastic leukemia with t(4;11)(q21;q23) masqueraded as marrow lymphocytosis in a patient with breast cancer.

Therapy-related acute leukemia develops in patients after chemotherapy and/or radiotherapy for a prior cancer, and most cases are acute myeloid leukemia with a much lower frequency of acute lymphoblastic leukemia (ALL). One unique feature of these therapy-related ALL (t-ALL) is an increased incidence of chromosome band 11q23 aberrations as compared with de novo ALL. In adult female patients, breast cancer is the most common primary cancer. Herein, we report the case of a 49-year-old Taiwanese lady who developed t-ALL with t(4;11)(q21;q23) 16 months after cyclophosphamide, epirubicin, and 5-fluorouracil chemotherapy for her breast cancer. The unusual feature is that the t-ALL was heralded 4 months ago by marrow lymphocytosis comprising atypical small lymphocytes with condensed chromatin mimicking a B-cell chronic lymphoproliferative disorder. Retrospective studies using additional antibodies for immunophenotyping and PCR-based clonality study for immunoglobulin gene rearrangement showed that these atypical small lymphocytes shared similar features with the leukemic blasts at the frank leukemic stage. Our results suggest that these atypical small lymphocytes are lymphoblasts in disguise and that the clinicopathological correlations with ancillary pathological studies are important to reach a definitive diagnosis of such an unusual case.

Percutaneous coronary intervention for iatrogenic left main coronary artery dissection.

BACKGROUND: Although catheter-induced left main coronary artery (LMCA) dissection is a rare complication of coronary catheterization, it is a common cause of periprocedural mortality. Emergent coronary artery bypass surgery (CABG) is the mainstay for managing this acute complication. However, hemodynamic deterioration may progress while patients await emergent CABG; consequently, a high postoperative mortality rate has been reported. Although the number of cases was small, prompt bail-out stenting for iatrogenic LMCA dissection had reportedly reversed this complication with favorable clinical outcomes. METHODS: This study included 13 cases of attempted stenting for iatrogenic LMCA dissection classified as grades C-F based on the National Heart, Lung and Blood Institute (NHLBI) classification system. Angiographic success, in-hospital mortality and long-term outcomes were analyzed. RESULTS: The incidence of iatrogenic LM dissection was 0.071%. Most of the patients were initially asymptomatic. Angiographic success was achieved in 11 of 13 patients (84.6%). Including one patient who underwent emergent CABG after a failed wiring attempt, two mortalities occurred in this series. Mean follow-up duration of the ten patients discharged was 30.1+/-11.8 months, and no cardiac deaths occurred. Follow-up angiogram of eight patients with a mean interval of 5.2+/-2.3 months after initial event demonstrated restenosis in three patients occurring either at the ostiums of the left anterior descending artery or left circumflex artery. Revascularization was performed on two patients. CONCLUSIONS: Successful bail-out stenting resulted in good long-term survival and should be considered for initial management of iatrogenic LMCA dissection.

Impact of PercuSurge GuardWire device on prevention and reduction of recovery time from complete heart block in patients with acute inferior myocardial infarction undergoing primary percutaneous coronary intervention.

Second-degree heart block or complete heart block (CHB) is a relatively frequent complication of acute inferior wall myocardial infarction (AIWMI). This study investigated whether the PercuSurge device can prevent procedure-related CHB or can shorten CHB recovery time in patients with AIWMI undergoing primary percutaneous coronary intervention (PCI). Between May 2002 and April 2005, a PercuSurge device was utilized in 113 patients (study population, group 1) with AIWMI due to obstruction of the right coronary artery (RCA) with a reference lumen diameter (RLD) > or = 3.5 mm. The control subjects (group 2) consisted of 119 patients who experienced AIWMI due to RCA obstruction with a RLD > or = 3.5 mm from May 2000 to April 2002. The combined incidence of new onset of CHB following the interventional procedure was significantly higher in group 2 than in group 1. Additionally, recovery time from CHB to first-degree heart block or normal sinus rhythm was remarkably longer in group 2 than in group 1. Furthermore, the duration of hospitalization in group 2 was significantly longer than in group 1. Multiple stepwise analyses demonstrated that the PercuSurge device was the only independent predictor of preventing new onset of CHB during the procedure. Additionally, this mechanical device along with final TIMI-3 flow and final myocardial blush grade > or = 2 was independently associated with reducing recovery time from CHB. In conclusion, the PercuSurge device can prevent procedure-related CHB and shorten the recovery time for CHB in patients with AIWMI undergoing primary PCI.

Intensity of C-reactive protein immunohistochemical staining of atherosclerotic plaque macrophages and extracellular tissue of patients with angina pectoris undergoing directional coronary atherectomy.

BACKGROUND: An elevated C-reactive protein (CRP) level plays a crucial role in cell biology of atherosclerosis and unstable plaque formation. However, direct evidence of CRP involvement in atherosclerotic plaque development and vulnerability is still limited. We hypothesized that CRP is present in the vulnerable plaques and that CRP staining intensity is stronger in vulnerable plaques compared to stable plaques. METHODS: Directional coronary atherectomy (DCA) was performed on 58 patients with stable angina (group 1) and 40 patients with unstable angina (group 2). White blood cell (WBC) counts were measured prior to DCA. Immunohistochemical staining (IHCS) was performed to localize CRP in the atheroma. Staining intensity in macrophages and extracellular tissue was graded as: 0, no staining; 1+, < 30%; 2+, 30%-60%; 3+, > 60%. RESULTS: The IHCS demonstrated that CRP staining - 1+ intensity in macrophages and extracellular tissue were significantly higher in group 1 than in group 2 patients (all p values < 0.0001). However, IHCS demonstrated that CRP staining a 2+ intensity in macrophages and extracellular tissue were significantly higher in group 2 than in group 1 patients (all p values < 0.0001). By multiple analysis, only stable angina was independently associated with CRP staining : 1+ intensity in both macrophages and extracellular tissue (p < 0.0001), whereas unstable angina and WBC counts were independent predictors of CRP staining > or = 2+ intensity in both macrophages and extracellular tissue (p < 0.0001). CONCLUSION: CRP was frequently found in atherosclerotic plaques of patients with unstable angina. This analytical finding suggests that CRP directly mediates an inflammatory process in the atherosclerotic plaque.