Breakthrough bleeding in adult patients with severe hemophilia A receiving low- and intermediate-dose FVIII for tertiary prophylaxis: characteristics and influencing factors / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the characteristics of breakthrough bleeding in adult patients with severe hemophilia A (SHA) receiving low- and intermediate-dose FVIII for tertiary prophylaxis and explore the factors affecting the outcomes of the treatment.</p><p><b>METHODS</b>Forty-nine patients (mean age 31.53∓7.33 years) with SHA receiving tertiary prophylaxis FVIII treatment were divided into low-dose group (n=15) and intermediate-dose group (n=34). The data including clinical bleeding phenotype (Pre?AJBR), 72 h FVIII trough activity, and Functional Independence Score in Hemophilia (FISH) were recorded in all the patients, and Hemophilia Steward APP was used to record the bleeding episode and the treatment data. All the patients were followed up for at least 6 months.</p><p><b>RESULTS</b>In the low-dose and intermediate-dose groups, the number of joint bleeding (AJBR) episodes were 18.79∓13.03 and 9.28∓7.02 per year (P=0.016), and the proportions of spontaneous bleeding were 75.0% and 47.7%, respectively. The proportions of patients with target joint were 80% and 44%, target joint bleeding occurred in 59% and 41%, and cataract bleeding after 0-12 h of prophylactic injection occurred in 4.86% and 5.18% of the patients with a median breakthrough bleeding time of 40.08 h and 46.08 h (P=0.008), respectively. The proportions of patients with 72 h FVIII trough activity <1% were 44.4% and 34.8% in the two groups, respectively. AJBR was negatively correlated with the preventive dose consumed (r=-0.57, P=0.000, n=49) and FISH, but positively correlated with Pre-AJBR in the two groups (P<0.05).</p><p><b>CONCLUSION</b>Tertiary prophylaxis with low- and intermediate-dose FVIII is not sufficient to achieve the goal of preventing progression of joint disease in Chinese adult patients with SHA. Although the prophylactic dose is the most important factor to affect the treatment efficacy, other non-factor approaches may also help to improve the efficacy of the treatment.</p>

Ultrasonic study of deep-vein diameter and blood flow spectrum changes in full-term pregnant women / 南方医科大学学报

<p><b>OBJECTIVE</b>To explore the changes in lower limb deep vein diameters, blood flow velocity and blood biochemistry in full-term pregnant women for early diagnosis and treatment of prothrombotic state.</p><p><b>METHODS</b>One hundred and twenty-eight full-term pregnant women at high risk of thrombosis (Group A), 61 healthy full-term pregnant women (Group B), and 42 healthy non-pregnant women (Group C) underwent high-resolution color Doppler ultrasound (CDU) for examining the deep veins of the lower limbs. The hematological indexes such as D-D, PLT, HGB, HCT, TT, APTT, PT, and FbgC were also observed in these 3 groups.</p><p><b>RESULTS</b>Compared to Group B, the women in group A showed significantly increased diameters of the common femoral veins (CFV) and left superficial femoral vein (SFV), HCT and DD, but with significantly decreased peak blood flow in the bilateral popliteal veins (POPV) (P<0.01) and increased left POPV diameter (P=0.034). Compared to those in group C, the diameters of the bilateral CFVs, SFVs, POPV, and posterior tibial veins (PTVs) were significantly increased, but the peak blood flow in the bilateral CFVs and POPVs were significantly reduced in groups A and B; the PLT, HGB, HCT, DD, TT, APTT, PT, and FbgC also showed significant changes in groups A and B (P<0.01).</p><p><b>CONCLUSION</b>The full-term pregnant women are at higher risk of prothrombotic state than non-pregnant women, and the full-term pregnant women with the high risk factors for thrombosis are more likely to have prothrombotic state than healthy full-term pregnant women. CDU examination of the lower limb deep veins can be of value in the diagnosis of prothrombotic state.</p>

Expression of vascular endothelial growth factor and its receptor Flk-1/KDR in benign and malignant breast neoplasms / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the differences in the expression of angiogenesis-related molecules between benign and malignant breast neoplasms.</p><p><b>METHODS</b>Thirty breast cancer patients (33 foci) and 30 with benign breast neoplasms (34 foci) were examined for CD34, vascular endothelial growth factor (VEGF) and Flk-1/KDR expressions using immunohistochemistry.</p><p><b>RESULTS</b>In patients with breast cancer, the microvessels densely distributed around the cancer nest. The microvessel density (MVD) in the cancer patients was significantly higher than that in patients with benign tumors (34.48+/-8.34 vs 18.65+/-4.69, P<0.05). In the breast cancer patients, strong VEGF expression was found in the epithelial cells and vascular endothelial cells around the breast carcinoma, and Flk-1/KDR was also strongly expressed in the vascular endothelial cells. The expressions of VEGF and Flk-1/KDR were hardly detectable in the benign tumors.</p><p><b>CONCLUSION</b>VEGF is an important regulatory factor in promoting breast tumor angiogenesis.</p>

Evaluation of angiogenesis in the tumorigenesis and progression of breast cancer / 中华外科杂志

<p><b>OBJECTIVES</b>To investigate the expression of CD34, vascular endothelial growth factor (VEGF) and its receptor Flk-1/KDR in precancerous lesion, atypical hyperplasia (AH) and infiltrating carcinoma of breast cancer and to explore the correlation between angiogenesis abnormality and the tumor progression.</p><p><b>METHODS</b>One hundred and sixty cases of resected tissues from breast cancer patients were enrolled in the study and were divided into 5 groups: 30 cases as normal controls, 30 cases with simple hyperplasia, 30 cases with AH, 20 cases with intraductal carcinoma in situ and 50 cases with infiltrating ductal carcinoma. The expression of CD34, VEGF and its receptor, Flk-1/KDR in those tissues were determined with immunohistochemical techniques. The micro vascular density (MVD) in those tissues was determined with the expression of CD34.</p><p><b>RESULTS</b>The expression level of CD34, VEGF and Flk-1/KDR were different among the groups, with the highest expression in the infiltrating ductal carcinoma group. With the progression of breast cancer, the major indexes showed no significant changes in the early stage of progression, but the expression of VEGF and Flk-1/KDR increased significantly from AH stage. Meanwhile, the MVD increased in the same way. There was significant difference between AH and intraductal carcinoma group in the expression of VEGF and Flk-1/KDR (P<0.05), but not in the MVD (P>0.05).</p><p><b>CONCLUSIONS</b>Abnormality in angiogenesis may be an early event in the tumorigenesis of breast cancer. Abnormal expression of VEGF and Flk-1/KDR may be the initiating factor of angiogenesis in the process of breast hyperplasia-AH-breast cancer, it could be the molecular target of early diagnosis and treatment.</p>

Hemodynamic changes in benign and malignant breast tumors and the mechanism / 南方医科大学学报

<p><b>OBJECTIVE</b>To compare the histological morphology, hemodynamics and angiogenesis-related molecules between benign and malignant breast tumor and investigate their variation in different perfusion regions in the same type of tumors.</p><p><b>METHODS</b>Thirty patients with malignant breast carcinoma and 30 with breast fibroadenoma underwent contrast-enhanced ultrasound examination with time-intensity quantitative analysis. The perfusion indices including peak intensity (PI), area under the curve (AUC), time to peak (TTP) and wash-out time (WOT) were measured both inside and on the margin of the foci. The expressions of CD34, vascular endothelial growth factor (VEGF), and Flk-1/KDR in both groups were measured immuhistochemically.</p><p><b>RESULTS</b>The time-intensity curve (TIC) of malignant tumor group was characterized by rapid ascent and slow descent, while that of the benign group presented with slow ascent and rapid descent. The AUC and WOT of the malignant tumor group were significantly higher than those of the benign group, while the PI and TTP showed no significant difference. In malignant tumor group, PI, AUC and WOT on the margin of the foci were significantly higher those of the inside region, while TTP showed a reverse pattern. No significant differences were found in the perfusion parameters between the inside and outside of the foci in the benign group. The distribution of CD34 was heterogeneous in breast carcinoma, and the micro-vessels were densely distributed especially on the margin of the cancer nest. The microvessel density of the malignant group (34.48-/+8.34) was significantly higher than that of the benign group (18.65-/+4.69). Diffuse or focal high VEGF expression was found on the margin of the cancer nest and necrotic tissue, but hardly detected in the benign group. Flk-1/KDR expressed diffusely or focally in breast carcinoma with especial high expression on the margin of the cancer nest and necrotic tissue, but was virtually undetectable in the benign group.</p><p><b>CONCLUSION</b>The perfusion pattern, TIC, mean perfusion parameter and variation of the regional perfusion parameters provide valuable evidence for differential diagnoses between benign and malignant breast tumors. Molecular imaging targeting VEGF and Flk-1/KD shed light on new approaches to early diagnosis of breast carcinoma.</p>

Heterogeneity of angioarchitecture and their hemodynamic changes in benign and malignant breast tumors / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To explore the differences between the angioarchitecture, hemodynamics, ultrastructure of neovasculr endothelial cells, and vascular distribution in different perfusion regions in benign and malignant breast tumors.</p><p><b>METHODS</b>30 cases of breast carcinoma (33 lesions) and 30 cases of breast fibroadenoma (34 lesions) were examined by contrast enhanced microvascular imaging (MVI), and perfusion indexes were collected both inside and at the margin of each focus according to time-intensity quantitative analysis, including peak intensity (PI), area under the curve (AUC), time to peak (TTP) and wash-out time (WOT). The ultrastructure of neovascular endothelial cells was examined by transmission electron microscopy. The expression of CD34, VEGF, Flk-1/KDR in both two groups were detected by immuhistochemistry.</p><p><b>RESULTS</b>Significant differences were found between the two groups characterized with filling defect, vascular distortion, dilatation and uneven enhancement. Most of the curves of malignant group (87.9%, 29/33) ascended rapidly and dropped slowly while those of the benign group (79.4%, 27/34) ascended slowly and dropped rapidly. The AUC and WOT of malignant tumor group were significantly higher than those of benign group, while the PI and TTP had statistically no significant difference. In the malignant tumor group, PI, AUC and WOT collected from the margin of foci were significantly different from those collected inside the foci, however, there was no significant difference in the benign group. The margin of foci was characterized with dilated and distorted vessels, and the center of the foci was occupied by narrow or occluded blood vessels, sometimes with contracted endothelial cells and pericytes. Abundant microvascular areas located at the margin of foci. The ultrastructure of endothelial cells in the newly formed blood vessels of malignant group showed strong ability to divide, which was different from normal endothelium cells.</p><p><b>CONCLUSION</b>The perfusion pattern, mode of time-intensity curve, mean perfusion parameter and variation of regional perfusion parameters provide a valuable diagnostic basis in distinguishing benign and malignant breast tumors. The density, morphology, distribution, structure and function of newly formed microvessels in tumor foci are also crucial factors when tumors are assessed by imaging examination.</p>

Lower limb deep vein ultrasonography and blood biochemistry in women after full-term delivery / 南方医科大学学报

<p><b>OBJECTIVE</b>To observe the postpartum changes in lower limb deep vein ultrasonography and blood biochemistry in women 2-5 days after full-term delivery.</p><p><b>METHODS</b>A total of 212 women at high risk of thrombosis underwent high-resolution color Doppler ultrasound (CDU) of the lower limb deep veins 2-5 days after full-term delivery (Group A). Sixty-one healthy women 2-5 days after full-term delivery (Group B) and 42 healthy non-pregnant women (Group C) were recruited as the controls. The hematological indexes including the D-dimers (D-D), platelet (PLT), hemoglobin (HGB), hematocrit (HCT), thrombin time (TT), activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrinogen (Fbg) were also determined in these 3 groups.</p><p><b>RESULTS</b>Compared to Group B, the women in group A showed significantly increased diameters and D-D value of the common femoral veins (FV), common superficial femoral veins (SFV) and common popliteal veins (POV) (P<0.01), with decreased peak blood flow in the bilateral POVs (P<0.05). Compared to those in Groups C, the diameters of the bilateral FVs, SFVs, POVs, and posterior tibial veins (PTVs) were significantly increased, but the peak blood flow in the bilateral FVs, SFVs, and POVs were significantly reduced in groups A and B; the PLT, HGB, HCT, DD, TT, APTT, PT, and Fbg also showed significant changes in groups A and B (P<0.01).</p><p><b>CONCLUSIONS</b>The women 2-5 days after full-term delivery are at high risk of prethrombotic state in comparison with non-pregnant women, and the presence of high-risk factors for thrombosis increases the likeliness of prothrombotic state in these postpartum women. CDU examination of the lower limb deep veins can be of value in the diagnosis of prethrombotic state.</p>

The prognostic value of angiogenic activity evaluation with contrast enhanced power doppler imaging in axillary-node-negative breast carcinoma / 中华外科杂志

<p><b>OBJECTIVE</b>To determine the value of contrast ultrasound on evaluating tumor angiogenic activity and its prognostic value in axillary-node-negative breast carcinoma (ANNBC).</p><p><b>METHODS</b>Power doppler imaging (PDI) was used to observe intratumoral vascularization before and post contrast agents injection. Intratumoral blood flow signals were measured and intratumoral vessel positive total areas (VPTA) were analyzed with computer-assisted quantitative assessment. Sections of malignant tumors were analyzed for the intratumoral microvessel density (MVD) by immunohistochemistry using monoclonal antibody to factor VIII-related antigen. The relationships within VPTA, MVD and prognosis were the main outcome measures.</p><p><b>RESULTS</b>There was no significant correlation between VPTA and MVD before contrast agents used while there was a positive correlation between them after that. However, VPTA and MVD had significant correlation with histology grade and tumor recurrence and metastasis while had no correlation with the general clinic pathologic factors. VPTA and MVD were significantly higher in postoperative cases with recurrence or metastasis than those in cases with tumor-free. Total survival rate and tumor-free survival rate of high-VPTA or high-MVD group were significantly lower than those of low-VPTA or low-MVD group.</p><p><b>CONCLUSIONS</b>The value of VPTA by contrast enhanced PDI was a beneficial prognostic indicator. High VPTA in ANNBC patients may has worse prognosis and antiangiogenic therapy is strongly suggested on them.</p>

Effects of anti-VEGF antibody on angiogenesis and proliferation and apoptosis of human osteosarcoma cell line OS-732 / 第三军医大学学报

Objective　To investigate the effects of anti-VEGF antibody on angiogenesis and on the proliferation and apoptosis of the osteosarcoma OS-732 cells and the vascular endothelial cells. Methods　The effects of polyclonal antibody against VEGF on OS-732 induced angiogenesis were observed by a stero-microscope and light microscope in a tumor model of the chick embryo chorioallantoic membrane (CAM). Furtheremore, the proliferation and apoptosis of tumor cells and vascular endothelial cells were examined by TdT-mediated dUTP nick and labelling (TUNEL) and immunohistochemical staining by using monoclonal antibody for proliferating cell nuclear antigen (PCNA). Results　The number of both the newly formed vessels in the tumor and the tumor population were significantly decreased in the anti-VEGF antibody group as compared with that of the PBS control group. The apoptotic index for tumor cell was higher in the anti-VEGF antibody treated group than that in the negative control group, but the proliferation index was not significantly different between them. At the same time, increased apoptotic cells and decreased proliferation in vascular endothelial cells were also noted. Conclusion　VEGF antibody can inhibit the neovascularization of OS-732, probabaly by the mechanism of inhibi-ting the proliferation and promoting the apoptosis of vascular endothelial cells, further, might be contributive to the apoptosis of tumor cells and result in suppression of tumor growth.

Effects of anti-VEGF antibody on angiogenesis and proliferation and apoptosis of human osteosarcoma cell line OS-732 / 第三军医大学学报

Objective　To investigate the effects of anti-VEGF antibody on angiogenesis and on the proliferation and apoptosis of the osteosarcoma OS-732 cells and the vascular endothelial cells. Methods　The effects of polyclonal antibody against VEGF on OS-732 induced angiogenesis were observed by a stero-microscope and light microscope in a tumor model of the chick embryo chorioallantoic membrane (CAM). Furtheremore, the proliferation and apoptosis of tumor cells and vascular endothelial cells were examined by TdT-mediated dUTP nick and labelling (TUNEL) and immunohistochemical staining by using monoclonal antibody for proliferating cell nuclear antigen (PCNA). Results　The number of both the newly formed vessels in the tumor and the tumor population were significantly decreased in the anti-VEGF antibody group as compared with that of the PBS control group. The apoptotic index for tumor cell was higher in the anti-VEGF antibody treated group than that in the negative control group, but the proliferation index was not significantly different between them. At the same time, increased apoptotic cells and decreased proliferation in vascular endothelial cells were also noted. Conclusion　VEGF antibody can inhibit the neovascularization of OS-732, probabaly by the mechanism of inhibi-ting the proliferation and promoting the apoptosis of vascular endothelial cells, further, might be contributive to the apoptosis of tumor cells and result in suppression of tumor growth.