Influence of the vascular damaging agents DMXAA and ZD6126 on hypericin distribution and accumulation in RIF-1 tumors

Purpose  

We investigated the influence of two types of vascular damaging agents (VDAs) (DMXAA vs. ZD6126) and sequence of administration (VDA 24 h before HYP vs. HYP 1 h before VDA) to evaluate the effect on hypericin (HYP) accumulation and distribution in necrotic tumors.     

Tumour overexpression of inducible nitric oxide synthase (iNOS) increases angiogenesis and may modulate the anti-tumour effects of the vascular disrupting agent ZD6126

Tumours derived from DLD-1 colon adenocarcinoma cells, transfected to either overexpress inducible nitric oxide synthase (clone iNOS-19) or with empty vector (pBAN2R), were utilised to test the hypothesis that tumour expression of iNOS (a) increases tumour angiogenesis and (b) modulates the anti-tumour activity of the vascular disrupting agent ZD6126. Overexpression of iNOS by clone iNOS-19 cells and murine xenografts was confirmed by the Griess assay and western blot analysis respectively. Clone iNOS-19 tumours grew more rapidly than pBAN2R tumours. Tumour perfusion, assessed by Hoechst 33342 uptake, was significantly greater in the clone iNOS-19 tumours (P < 0.001). A significant reduction in the perfusion of only the pBAN2R tumours, compared with control, was obtained 24 h after treatment with an intermediate dose of 100 mg/kg ZD6126 (P < 0.001), whereas 200 mg/kg significantly reduced the perfusion of both tumour types (P < 0.001). Whilst pBAN2R tumour necrosis increased in a dose-dependent manner, significant at 100 and 200 mg/kg ZD6126 (P < 0.05), intermediate doses did not induce a similar degree of necrosis in clone iNOS-19 tumours. A significant reduction in splenic perfusion was found 24 h after treatment with 100 mg/kg ZD6126, primarily associated with the red pulp. Overexpression of iNOS increases tumour growth, the degree of functionally perfused vasculature and angiogenesis, and also confers resistance to the vascular disrupting agent ZD6126.     

Dependency of the effect of a vascular disrupting agent on sensitivity to tirapazamine and γ-ray irradiation upon the timing of its administration and tumor size,with reference to the effect on intratumor quiescent cells

Purpose The effect of vascular disrupting agent ZD6126 with time on the sensitivity to the hypoxic cytotoxin tirapazamine (TPZ) and γ-rays was examined in large and small solid tumors.Methods Mice bearing SCC VII tumors 1 or 1.5 cm in diameter received 5-bromo-2′-deoxyuridine (BrdU) continuously to label all proliferating (P) cells, followed by injection with or without ZD6126. In the absence of ZD6126, or 1 or 24 h following ZD6126 injection, the response to TPZ or γ-ray irradiation in quiescent (Q) cells was assessed in terms of induced micronucleus (MN) frequency using immunofluorescence staining for BrdU. The MN frequency in the total cell population was determined from the tumors not pretreated with BrdU. Another group of tumor-bearing mice received a series of test doses of γ-rays while alive or after tumor clamping to obtain hypoxic fractions (HFs) in the tumors.Results One hour after ZD6126 injection, both small and large tumors showed lower and higher sensitivity, and 24 h after, higher and lower sensitivity, to γ-rays and TPZ, respectively, than the tumors not treated with ZD6126. Further, they showed larger and smaller HFs 1 and 24 h after ZD6126 injection, respectively. Without ZD6126 and 1 h after injection, small tumors were more sensitive to γ-rays and less sensitive to TPZ than large tumors, probably due to the smaller HFs than large tumors. In contrast, 24 h after the injection, these differences in sensitivity and the HF between small and large tumors were reversed. The changes in sensitivity and the size of the HF were more marked in the total cell population than in Q cells.Conclusions Following ZD6126 treatment, in terms of tumor control, especially large tumors and total tumor cell population, administering TPZ 1 h later and γ-ray irradiation 24 h later were effective. Intratumor physiologic factors such as the size of the HF, depending on the time after ZD6126 injection, have to be taken into account when combining another treatment with ZD6126.     

Diffusion-weighted magnetic resonance imaging for predicting the response of rectal cancer to neoadjuvant concurrent chemoradiation

AIM:To evaluate the clinical value of diffusion-weighted magnetic resonance imaging(DW-MRI)in predicting the response of rectal cancer to neoadjuvant chemoradiation.METHODS:This prospective study was approved by our institutional review board,and informed consent was obtained from each patient.Fifteen patients(median age 56 years)with locally advanced rectal cancer were treated in our hospital from June 2006 to December 2007.All patients were stageⅢB-C according to the results of MRI and endorectal ultrasound examinations.All patients underwent pelvic irradiation with 45 Gy/25 fx per 35 days.The concurrent chemotherapy regimen consisted of capecitabine 625mg/m2,bid(Monday-Friday),and oxaliplatin 50 mg/m2,weekly.The patients underwent surgery 5-8 wk after the completion of neoadjuvant therapy.T downstaging was defined as the downstaging of the tumor from cT3to ypT0-2 or from cT4 to ypT0-3.Good regression was defined as TRG 3-4,and poor regression was defined as TRG 0-2.Diffusion-weighted magnetic resonance images were obtained prior to and weekly during the course of neoadjuvant chemoradiation,and the apparent diffusion coefficient(ADC)values were calculated from the acquired tumor images.RESULTS:Comparison with the mean pretreatment tumor ADC revealed an increase in the mean tumor ADC during the course of neoadjuvant chemoradiation,especially at the 2ndweek(P=0.004).We found a strong negative correlation between the mean pretreatment tumor ADC and tumor regression after neoadjuvant chemoradiation(P=0.021).In the T downstage and tumor regression groups,we found a significant increase in the mean ADC at the 2ndweek of neoadjuvant therapy(P=0.011;0.004).CONCLUSION:DW-MRI might be a valuable clinical tool to help predict or assess the response of rectal cancer to neoadjuvant chemoradiation at an early timepoint.     

The Correlations Between MRI Perfusion,Diffusion Parameters,and 18F-FDG PET Metabolic Parameters in Primary Head-and-Neck Cancer: A Cross-Sectional Analysis in Single Institute

This study aimed to investigate the relationships among parameters from dynamic contrast-enhanced (DCE) MRI, diffusion-weighted MRI (DWI), and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET in patients with primary head-and-neck squamous cell carcinoma (HNSCC).A total of 34 patients with primary HNSCC underwent DCE-MRI, DWI, and ¹⁸F-FDG PET before treatment. The perfusion parameters (K_trans, K_transmax, K_ep, V_e, V_p, and AUC₆₀) from DCE-MRI and ADC (ADC_mean, ADC_min) values from DWI were calculated within the manually placed ROI around the main tumor. Standardized uptake value (SUV_max, SUV_mean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG = SUV_mean × MTV) were calculated with thresholds of 3.0 SUV. The associations between parameters were evaluated by Pearson correlation analysis.Significant correlations were identified between K_trans and K_ep (r = 0.631), K_trans and V_e (r = 0.603), K_trans and ADC_mean (r = 0.438), K_transmax and K_ep (r = 0.667), K_transmax and V_p (r = 0.351), V_e and AUC₆₀ (r = 0.364), V_e and ADC_mean (r = 0.590), and V_e and ADC_min (r = 0.361). ADC_min was reversely correlated with TLG (r = –0.347). Tumor volume was significantly associated with K_transmax (r = 0.348).The demonstrated relationships among parameters from DCE, DWI, and ¹⁸F-FDG PET suggest complex interactions among tumor biologic characteristics. Each diagnostic technique may provide complementary information for HNSCC.     

Relationship Between the Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) and Lung Adenocarcinoma Patterns: New Possible Insights

IntroductionThis study aimed to evaluate a potential relationship between the diffusing capacity of the lung for carbon monoxide (DLCO) and the aggressiveness of lung adenocarcinoma (ADC).MethodsPatients who underwent radical surgery for lung ADC between 2001 and 2018 were retrospectively reviewed. DLCO values were dichotomized into DLCO_low (<80% of predicted) and DLCO_normal (≥80%). Relationships between DLCO and ADC histopathological features, clinical features, as well as with overall survival (OS), were evaluated.ResultsFour-hundred and sixty patients were enrolled, of which 193 (42%) were included in the DLCO_low group. DLCO_low was associated with smoking status, low FEV₁, micropapillary and solid ADC, tumour grade 3, high tumour lymphoid infiltrate and presence of tumour desmoplasia. In addition, DLCO values were higher in low-grade ADC and progressively decreased in intermediate and high-grade ADC (p = 0.024). After adjusting for clinical variables, at multivariable logistic regression analysis, DLCO_low still showed a significant correlation with high lymphoid infiltrate (p = 0.017), presence of desmoplasia (p = 0.065), tumour grade 3 (p = 0.062), micropapillary and solid ADC subtypes (p = 0.008). To exclude the association between non-smokers and well-differentiated ADC, the relationship between DLCO and histopathological ADC patterns was confirmed in the subset of 377 former and current smokers (p = 0.021). At univariate analysis, gender, DLCO, FEV₁, ADC histotype, tumour grade, stage, pleural invasion, tumour necrosis, tumour desmoplasia, lymphatic and blood invasion were significantly related with OS. At multivariate analysis, only gender (p < 0.001), tumour stage (p < 0.001) and DLCO (p = 0.050) were significantly related with the OS.ConclusionsWe found a relationship between DLCO and ADC patterns as well as with tumour grade, tumour lymphoid infiltrate and desmoplasia, suggesting that lung damage may be associated with tumour aggressiveness.     

In vivo videomicroscopy reveals differential effects of the vascular-targeting agent ZD6126 and the anti-angiogenic agent ZD6474 on vascular function in a liver metastasis model

Metastases require a functional blood supply for progressive growth. Thus, therapies that target metastatic vasculature have potential clinical utility. The effects of the vascular-targeting agent (VTA), ZD6126, and the anti-angiogenic agent, ZD6474, on vascular development and function within metastases were compared in an experimental liver metastasis model. Ras-transformed PAP2 fibroblasts were injected into the mesenteric veins of SCID mice to produce a control liver metastasis burden of 40% at 14 days. Mice given a single dose of ZD6126 (200 mg/kg, i.p.) on day 13 were examined 24 h later. Histology revealed a significant reduction in metastatic burden, associated with extensive tumor necrosis, increased tumor cell apoptosis and a reduction in tumor-associated vasculature. In vivo videomicroscopy (IVVM) revealed disrupted, non-functional vascular channels within metastases, with no blood flow. Mice given ZD6474 on days 4 to 10 (50 mg/kg daily, oral gavage) were examined on day 11. Histology revealed a lower metastatic burden, significant reductions in metastasis size and vasculature, and a significant increase in tumor cell apoptosis. IVVM revealed extensive reductions in vascularity and blood flow within metastases. Neither ZD6126 nor ZD6474 treatment affected surrounding normal liver tissue. This study shows that both agents can reduce experimental liver metastasis with no apparent effect on normal vasculature. However, these reductions were attained through distinct effects on the metastatic vasculature. Understanding differences in the modes of action of VTAs and anti-angiogenic agents will be important in optimizing their clinical application and in developing appropriate combination strategies.     

Value of MR diffusion imaging in hepatic fibrosis and its correlations with serum indices

AIM:To compare apparent diffusion coefficient(ADC)values on diffusion-weighted imaging(DWI)of hepatic fibrosis patients with those of healthy controls and to identify their correlations with serum indices of liver fibrosis.METHODS:Hyaluronic acid(HA),laminin(LN),typeⅢprocollagen(PCⅢ),and collagen typeⅣ(Ⅳ-C)were measured in 54 hepatic fibrosis patients and 23normal controls,and ADC values were determined on DWI at different b values(b=300,500,700 s/mm2).Correlations between serum indices and ADC values at different liver fibrosis stages were examined,and each index variation of liver fibrosis in different stages were compared,and correlation analysis of each index and the staging of liver fibrosis carried out,and the correlation of each index performed.RESULTS:With progressive liver fibrosis,HA,PCⅢ,andⅣ-C levels increased(P<0.01).As the b value increased,the ADC value decreased gradually with the hepatic fibrosis stages.In different groups with b values of 500 s/mm2 and 700 s/mm2,the ADC value decreased significantly as liver fibrosis progressed(P<0.01).With b values of 500 s/mm2 and 700 s/mm2,there were negative correlations between ADC and LN,PCⅢ,HA,andⅣ-C.This pattern was observed only for HA andⅣ-C at a b value of 300 s/mm2.CONCLUSION:Serum indices of liver fibrosis and ADC values are useful for diagnosing liver fibrosis,with some correlations among them.     

Magnetic resonance-based total liver volume and magnetic resonance-diffusion weighted imaging for staging liver fibrosis in mini-pigs

AIM:To determine whether and how magnetic resonance imaging(MRI)-based total liver volume(TLV) and diffusion weighted imaging(DWI) could predict liver fibrosis.METHODS:Sixteen experimental mature mini-pigs(6 males,10 females),weighing between 20.0 and 24.0 kg were prospectively used to model liver fibrosis induced by intraperitoneal injection of 40% CCl4 dissolved in fat emulsion twice a week for 16 wk,and by feeding 40% CCl4 mixed with maize flour twice daily for the subsequent 5 wk.All the survival animals underwent percutaneous liver biopsy and DWI using b = 300,500 and 800 s/mm2 followed by abdominal gadolinium-enhanced MRI at the 0,5th,9th,16th and 21st weekend after beginning of the modeling.TLV was obtained on enhanced MRI,and apparent diffusion coefficient(ADC) was obtained on DWI.Hepatic tissue specimens were stained with hematoxylin and Masson' s trichrome staining for staging liver fibrosis.Pathological specimens were scored using the human METAVIR classification system.Statistical analyses were performed to determine whether and how the TLV and ADC could be used to predict the stage of liver fibrosis.RESULTS:TLV increased from stage 0 to 2 and decreased from stage 3(r = 0.211;P 0.001).There was a difference in TLV between stage 0-1 and 2-4(P = 0.03) whereas no difference between stage 0-2 and 3-4(P = 0.71).TLV could predict stage ≥ 2 [area under receiver operating characteristic curve(AUC) = 0.682].There was a decrease in ADC values with increasing stage of fibrosis for b = 300,500 and 800 s/mm2(r =-0.418,-0.535 and-0.622,respectively;all P 0.001).Differences were found between stage 0-1 and 2-4 in ADC values for b = 300,500 and 800 s/mm2,and between stage 0-2 and 3-4 for b = 500 or 800 s/mm2(all P 0.05).For predicting stage ≥ 2 and ≥ 3,AUC was 0.803 and 0.847 for b = 500 s/mm2,and 0.848 and 0.887 for b = 800 s/mm2,respectively.CONCLUSION:ADC for b = 500 or 800 s/mm2 could be better than TLV and ADC for b = 300 s/mm2 to pre-dict fibrosis stage ≥ 2 or ≥ 3.     

Estimated glomerular filtration rate is associated with both arterial stiffness and N-terminal pro-brain natriuretic peptide in newly diagnosed hypertensive patients

Even a slight decrease in the glomerular filtration rate (GFR) is an independent risk factor for cardiovascular disease. Arterial stiffness, left ventricular hypertrophy and N-terminal pro-brain natriuretic peptide (NT-proBNP) are independent risk factors for cardiovascular disease, which are particularly common in end-stage renal disease. We aimed to evaluate the association between GFR with arterial stiffness, left ventricle mass (LVM) and NT-proBNP in hypertensive subjects with normal to mildly impaired renal function. The study population consisted of 285 newly diagnosed hypertensive patients (mean age; 49.9?±?11.8 years). GFR was estimated (eGFR) by the Modification of Diet in Renal Disease formula. Pulse wave velocity (PWV) and augmentation index (AIx), which reflects arterial stiffness, were calculated using the single-point method via the Mobil-O-Graph® ARCsolver algorithm. LVM was obtained by echocardiography. Plasma NT-proBNP was measured by electrochemiluminescence. The patients were divided into two groups according to the median eGFR value (eGFR_low group?2 and eGFR_high group?≥?101?ml/min/1.73?m²). LVM and NT-proBNP values were higher in eGFR_low group compared with eGFR_high group (p?low group compared with eGFR_high group (p?β?=??0.422, p?β?=??0.404, p?相似文献   

Diffusion-weighted magnetic resonance imaging without bowel preparation for detection of ulcerative colitis

AIM: To evaluate the accuracy of diffusion-weighted imaging(DWI) without bowel preparation,the optimal b value and the changes in apparent diffusion coefficient(ADC) in detecting ulcerative colitis(UC).METHODS: A total of 20 patients who underwent 3T magnetic resonance imaging(MRI) without bowel preparation and colonoscopy within 24 h were recruited.Biochemical indexes,including C-reactive protein(CRP),erythrocyte sedimentation rate,hemoglobin,leucocytes,platelets,serum iron and albumin,were determined.Biochemical examinations were then performed within 24 h before or after MR colonography was conducted.DWI was performed at various b values(b = 0,400,600,800,and 1000 s/mm2).Two radiologists independently and blindly reviewed conventional- and contrast-enhanced MR images,DWI and ADC maps; these radiologists also determined ADC in each intestinal segment(rectum,sigmoid,left colon,transverse colon,and right colon).Receiver operating characteristic(ROC) analysis was performed to assess the diagnostic performance of DWI hyperintensity from various b factors,ADC values and different radiological signs to detect endoscopic inflammation in the corresponding bowel segment.Optimal ADC threshold was estimated by maximizing the combination of sensitivity and specificity.MRfindings were correlated with endoscopic results and clinical markers; these findings were then estimated by ROC analysis.RESULTS: A total of 100 segments(71 with endoscopic colonic inflammation; 29 normal) were included.The proposed total magnetic resonance score(MR-score-T) was correlated with the total modified Baron score(Baron-T; r = 0.875,P 0.0001); the segmental MR score(MR-score-S) was correlated with the segmental modified Baron score(Baron-S; r = 0.761,P 0.0001).MR-score-T was correlated with clinical and biological markers of disease activity(r = 0.445 to 0.831,P 0.05).MR-score-S 1 corresponded to endoscopic colonic inflammation with a sensitivity of 85.9%,a specificity of 82.8% and an area under the curve(AUC) of 0.929(P 0.0001).The accuracy of DWI hyperintensity was significantly greater at b = 800 than at b = 400,600,or 1000 s/mm2(P 0.05) when endoscopic colonic inflammation was detected.DWI hyperintensity at b = 800 s/mm2 indicated endoscopic colonic inflammation with a sensitivity of 93.0%,a specificity of 79.3% and an AUC of 0.867(P 0.0001).Quantitative analysis results revealed that ADC values at b = 800 s/mm2 differed significantly between endoscopic inflamed segment and normal intestinal segment(1.56 ± 0.58 mm2/s vs 2.63 ± 0.46 mm2/s,P 0.001).The AUC of ADC values was 0.932(95% confidence interval: 0.881-0.983) when endoscopic inflammation was detected.The threshold ADC value of 2.18 × 10-3 mm2/s indicated that endoscopic inflammation differed from normal intestinal segment with a sensitivity of 89.7% and a specificity of 80.3%.CONCLUSION: DWI combined with conventional MRI without bowel preparation provides a quantitative strategy to differentiate actively inflamed intestinal segments from the normal mucosa to detect UC.     

Diffusion-weighted MR imaging of kidneys in patients with systemic lupus erythematosus: initial experience

To evaluate kidney perfusion and diffusion in patients with systemic lupus erythematosus (SLE) and define any correlation between laboratory features of renal involvement and apparent diffusion coefficients (ADCs). We studied 35 patients with SLE and 30 healthy volunteers. Ten of the patients were diagnosed as having lupus nephritis. Transverse diffusion-weighted multisection echo-planar magnetic resonance imaging was created with the following diffusion gradient b values: 0, 111, 222, 333, 444, 556, 667, 778, 889, and 1,000 s/mm². Statistical analyses to compare ADCs of kidneys between patients in the study and control groups were done with the independent sample t test. The Pearson correlation analysis was used to evaluate the relation between the renal function variables and the ADCs. There was statistically significant difference between the ADC_low values and the urine protein levels (P < 0.05) in the patients with SLE. Also, there was a significant correlation between the duration of nephritis and urine protein levels in the patients with SLE (P < 0.01). There was no statistically significant differences regarding ADCs, serum creatinine levels, and GFRs among patients with SLE and controls. Our patients had mild SLE and this might be the reason that no statistically significant differences were found between ADCs, and laboratory features of renal involvement among patients with SLE and controls. Larger series and more diffusion experience may be valuable for future studies.     

Predicting liver metastasis of gastrointestinal tract cancer by diffusion-weighted imaging of apparent diffusion coefficient values

AIM: To determine if efficacy of chemotherapy on liver metastasis of gastrointestinal tract cancer can be predicted by apparent diffusion coefficient(ADC) values of diffusion-weighted imaging(DWI). METHODS: In total, 86 patients with liver metastasis of gastrointestinal tract cancer(156 metastatic lesions) diagnosed in our hospital were included in this study. The maximum diameters of these tumors were compared with each other before treatment, 2 wk after treatment, and 12 wk after treatment. Selected patients were classified as the effective group and the ineffective group, depending on the maximum diameter of the tumor after 12 wk of treatment; and the ADC values at different treatment times between the two groups were compared. Spearman rank correlation was used to analyze the relationship between ADC value and tumor diameter. Receiver operating characteristic curve(ROC curve) was used to analyze the ADC values before treatment to predict the patient's sensitivity and specificity degree of efficacy to the chemotherapy. RESULTS: There was no difference in age between the two groups and in maximum tumor diameter before treatment and 2 wk after treatment. However, after 12 wk of treatment, maximum tumor diameter in the effective group was significantly lower than that in the ineffective group(P 0.05). Before treatment, ADC values in the ineffective group were significantly higher than those in the effective group(P 0.05). There was no difference in ADC values between the effective and ineffective groups after 2 and 12 wk of treatment. However, ADC values were significantly higher after 2 and 12 wk of treatment compared to before treatment in the effective group(P 0.05). Spearman rank correlation analysis showed that ADC value before treatment and the reduced percentage of the maximum tumor diameter after 12 wk of treatment were negatively correlated, while the increase in the percentage of the ADC value 12 wk after treatment and the decrease in the percentage of the maximum tumor diameter were significantly positively correlated. The results of the ROC curve showed that ADC value with a chemotherapy ineffective threshold value of 1.14 × 10-3 mm2/s before treatment had a sensitivity and specificity of 94.3% and 76.7%, respectively. CONCLUSION: DWI ADC values can be used to predict the response of patients with liver metastasis of gastrointestinal tract cancer to chemotherapy with high sensitivity and relatively high specificity.     

Diminution of Circulating CD4<Superscript>+</Superscript>CD25<Superscript>high</Superscript> T Cells in Na?ve Crohn’s Disease

Crohn’s disease is considered to be caused either by an excess of T-cell effector functions and/or by a defective regulatory T-cell compartment. The aim of this study was to assess in Crohn’s disease the frequency of circulating CD4⁺CD25^high T cells that possess regulatory T-cell functions and CD4⁺CD25^low T cells that contain activated T cells. Flow cytometry of peripheral blood was used to assess CD4⁺CD25^high and CD4⁺CD25^low T-cell frequencies in a cohort of 66 patients with Crohn’s disease in comparison to 19 patients with ulcerative colitis and 31 healthy individuals enrolled as controls. The CD4⁺CD25^high T-cell frequency was significantly lowered in naïve Crohn’s disease (P = 0.013) and in ulcerative colitis (P = 0.001). CD4⁺CD25^low T-cell frequency was increased in Crohn’s disease (P = 0.0001) and in ulcerative colitis (P = 0.0002). Both CD4⁺CD25^high and CD4⁺CD25^low T-cell frequencies are altered in naïve Crohn’s disease resulting in an imbalance between both populations and a relative contraction of the CD4⁺CD25^high T-cell population.     

The impact of anti-inflammatory cytokines provoked by CD163 positive macrophages on ventricular functional recovery after myocardial infarction

Present study aimed to investigate the impact of anti-inflammatory cytokines provoked by the hemoglobin scavenger receptor, CD163, on left ventricular (LV) functional recovery after successful reperfusion in patients with acute myocardial infarction (AMI). Intraplaque hemorrhage accelerates plaque destabilization. Extracellular hemoglobin is cleared by CD163, a macrophage scavenger receptor. This process provokes secretion of anti-inflammatory atheroprotective cytokine, interleukin (IL)-10. In 40 patients with the first AMI, coronary atherothrombotic debris was retrieved during percutaneous coronary intervention (PCI), stained with antibodies to CD163 and IL-10. LV function was determined by echocardiography before PCI and 6 months after PCI. %CD163 was defined as ratio of CD163 (+)-cells to whole cells. %IL-10 was expressed as the ratio of positively stained areas per total tissue. Patients were divided into two groups depending on the amount of CD163 (+)-cells: CD163 > 10 % (CD_163high, n = 20) and CD163 ≤ 10 % (CD_163low, n = 20). CD_163high group had significantly higher %IL-10. Final thrombolysis in myocardial infarction (TIMI) flow grade was significantly lower in CD_163high group. In subgroups with the final TIMI-3 flow (CD_163high-Reflow, n = 15 and CD_163low-Reflow, n = 20), the time to reperfusion, infarct size, LV dimensions and fractional shortening (%FS) before PCI were similar. Significant correlation was observed between %IL10 and changes in LV dimensions (diastole, r = ?0.49, P = 0.01; systole, r = ?0.65, P < 0.01) or %FS (r = 0.51, P < 0.01) at 6 months after PCI. Plaque with CD163(+)-macrophages could impair distal flow after primary PCI. However, CD163(+)-macrophages enhance the anti-inflammatory cytokine expression that aids in ventricular functional recovery if distal flow can be achieved by successful reperfusion.     

Incremental prognostic value of changes in B-type natriuretic peptide in heart failure

Purpose

B-type natriuretic peptide is one of the most sensitive and specific biohumoral markers of heart failure. We hypothesized that B-type natriuretic peptide changes during treatment of heart failure may provide independent information on disease progression and outcome in patients enrolled in the Val-HeFT trial.

Methods

Patients were divided into four groups according to concentrations of B-type natriuretic peptide at baseline versus 4 months (n = 3740) or 12 months (n = 3343), with respect to the baseline median (97 pg/mL): low→low (stable below median, 44%-46%), high→high (stable above median, 32%-37%), high→low (above to below median, 12%-14%), and low→high (below to above median, 6%-9%). Cox multivariate regression analysis was used to assess the risk of death and morbidity, with adjustment for baseline B-type natriuretic peptide concentrations.

Results

Patients who improved their B-type natriuretic peptide at 4 months (high→low) had a similar risk for mortality (hazard ratio = 1.191, 95% confidence interval [CI] 0.870-1.631, P =.2746) compared with the low→low patients. Conversely, patients who worsened in their B-type natriuretic peptide (low→high) had a risk for mortality (hazard ratio 2.578, CI, 1.861-3.571, P <.0001) higher than patients in the low→low group, and indistinguishable from the high→high group. Worsening of B-type natriuretic peptide (low→high) was associated with 0.03 cm/m² increase in left ventricular end-diastolic diameter, whereas it decreased by 0.10 cm/m² in high→low and low→low groups (P <.001).

Conclusions

Changes in B-type natriuretic peptide over time with respect to a threshold value of 97 pg/mL convey an independent and additional prognostic value compared with a single determination of B-type natriuretic peptide in a large population of patients with chronic symptomatic heart failure and might be helpful in the management of these patients.     

NT-proBNP predicts impaired myocardial function in newly diagnosed hypertensive patients with preserved ejection fraction

N-terminal pro-brain natriuretic peptide (NT-proBNP) is an excellent biomarker to diagnose left ventricular (LV) dysfunction. LV myocardial performance index (MPI-Tei index) is commonly used as a measure of combined systolic and diastolic function. We aimed to investigate the relationship between NT-proBNP and tissue Doppler derived MPI in newly diagnosed hypertensive patients with preserved LV ejection fraction (LVEF). We studied 236 patients with newly diagnosed HT (mean age; 52.9?±?5.2 years). Echocardiographic examination was performed in all patients. LV mass index (LVMI) was calculated. Conventional Doppler indices (E and A waves) were recorded. The MPI value was obtained from the tissue Doppler derived ejection time, isovolumic contraction and relaxation times. The patients were divided into two groups according to the median NT-proBNP value (NT-proBNP_low group <114?pg/ml and NT-proBNP_high group ≥114?pg/ml). Patients with NT-proBNP_high were older and had higher levels of glucose and creatinine, lower E/A ratio and higher LVMI and MPI values than patients with NT-proBNP_low. However, LVEF were similar among the groups. Multiple linear regression analysis showed that NT-proBNP was independently associated with age, LVMI, MPI and E/A ratio. Increased NT-proBNP level was independently associated with impaired myocardial performance index in newly diagnosed hypertensive patients with preserved LVEF.     

Multifunctional human CD56low CD16low natural killer cells are the prominent subset in bone marrow of both healthy pediatric donors and leukemic patients

We phenotypically and functionally characterized a distinct CD56^low natural killer cell subset based on CD16 expression levels in bone marrow and peripheral blood of healthy children and pediatric patients with acute lymphoblastic leukemia. Our findings demonstrate for the first time that CD56^lowCD16^low natural killer cells are more abundant in bone marrow than in peripheral blood and that their frequency is further increased in children with acute lymphoblastic leukemia. Bone marrow and peripheral blood CD56^lowCD16^low natural killer cells compared with CD56^lowCD16^high natural killer cells express lower levels of killer inhibitory receptors, higher levels of CD27, CD127, CD122, CD25, but undetectable levels of CD57, suggesting that they have a higher proliferative and differentiation potential. Moreover, CD56^lowCD16^low natural killer cells display higher levels of CXCR4 and undetectable levels of CX3CR1 and can be consistently and rapidly mobilized in peripheral blood in response to CXCR4 antagonist. Unlike CD56^lowCD16^high, both bone marrow and peripheral blood CD56^lowCD16^low natural killer cells release IFNγ following cytokine stimulation, and represent the major cytotoxic natural killer cell population against K562 or acute lymphoblastic leukemia target cells. All these data suggest that CD56^lowCD16^low natural killer cells are multifunctional cells, and that the presence of hematologic malignancies affects their frequency and functional ability at both tumor site and in the periphery.     

磁共振扩散加权成像对经皮酒精注射术治疗兔VX2肝移植瘤后残余肿瘤微血管生成情况的评价

目的研究磁共振扩散加权成像(DWI)评价兔VX2肝移植瘤模型经皮酒精注射术(PEI)疗效及PEI对残余肿瘤微血管生成的影响。方法将26只接种成功的兔VX2肝移植瘤模型随机分为实验组和对照组,每组各13只。实验组CT引导下行PEI,对照组不予处理,术后1周行DWI检查,比较实验组肿瘤活性区及坏死区表观弥散系数(ADC)的差异、2组活性肿瘤区ADCperf和微血管密度(MVD)计数的差异,并分析ADCperf与MVD计数的相关性。正态性分析采用Shapiro-Wilk检验,计量资料组间比较采用Wilcoxon秩和检验,ADCperf与MVD计数的相关性比较采用Pearson相关分析。结果实验组坏死区与活性肿瘤区ADCtotal值分别为[1.674(1.340~2.571)]×10-3mm2/s、[1.296(1.120~1.972)]×10-3mm2/s,差异有统计学意义(Z=2.052,P=0.040);实验组与对照组活性肿瘤区ADCperf值分别为[0.568(0.381~1.873)]×10-3mm2/s、[0.947(0.518~1.476)]×10-3mm2/s,MVD计数分别为(23.641±6.138)、(23.487±3.466),2组比较差异均无统计学意义(Z值分别为0.487、-0.128,P值分别为0.626、0.898);2组肿瘤活性区ADCperf与MVD计数均呈正相关(r值分别为0.583、0.593,P值分别为0.037、0.033)。结论 DWI可准确评价兔VX2肝移植瘤PEI的疗效并在一定程度上反映其微血管生成情况,PEI术后1周对残余肿瘤微血管生成无明显影响。     

The MI SYNTAX score for risk stratification in patients undergoing primary percutaneous coronary intervention for treatment of acute myocardial infarction: A substudy of the COMFORTABLE AMI trial

Background

To investigate the performance of the MI Sxscore in a multicentre randomised trial of patients undergoing primary percutaneous coronary intervention (PPCI).

Methods and results

The MI Sxscore was prospectively determined among 1132 STEMI patients enrolled into the COMFORTABLE AMI trial, which randomised patients to treatment with bare-metal (BMS) or biolimus-eluting (BES) stents. Patient- (death, myocardial infarction, any revascularisation) and device-oriented (cardiac death, target-vessel MI, target lesion revascularisation) major adverse cardiac events (MACEs) were compared across MI Sxscore tertiles and according to stent type.The median MI SXscore was 14 (IQR: 9–21). Patients were divided into tertiles of Sxscore_low (≤ 10), Sxscore_intermediate (11–18) and Sxscore_high (≥ 19). At 1 year, patient-oriented MACE occurred in 15% of the Sxscore_high, 9% of the Sxscore_intermediate and 5% of the Sxscore_low tertiles (p < 0.001), whereas device-oriented MACE occurred in 8% of the Sxscore_high, 6% of the Sxscore_intermediate and 4% of the Sxscore_low tertiles (p = 0.03). Addition of the MI Sxscore to the TIMI risk score improved prediction of patient- (c-statistic value increase from 0.63 to 0.69) and device-oriented MACEs (c-statistic value increase from 0.65 to 0.70). Differences in the risk for device-oriented MACE between BMS and BES were evident among Sxscore_high (13% vs. 4% HR 0.33 (0.15–0.74), p = 0.007 rather than those in Sxscore_low: 4% vs. 3% HR 0.68 (0.24–1.97), p = 0.48) tertiles.

Conclusions

The MI Sxscore allows risk stratification of patient- and device-oriented MACEs among patients undergoing PPCI. The addition of the MI Sxscore to the TIMI risk score is of incremental prognostic value among patients undergoing PPCI for treatment of STEMI.