High Microvessel Density Research Articles

1036P - Tumour microvessel density for predicting nintedanib activity: Data from the randomized CHIVA trial (a GINECO study)

BackgroundTumour Microvessel density (MVD) is often used as a surrogate marker for tumoral angiogenic activity. In the randomized phase II neo-adjuvant CHIVA trial, ovarian cancer patients (pts) treated with standard chemotherapy plus Nintedanib (Ni) compared to chemotherapy alone had a reduced rate of complete surgical resection at interval debulking surgery (IDS), worse PFS and OS. To explain these results we assessed the predictive/prognostic value of MVD at baseline and the MVD decrease from baseline to IDS. MethodsPaired tumours from baseline and IDS were available from 79/188 randomized pts. A total of 158 virtual slides of immunostained tumor section with anti-CD31 were analysed. MVD was quantified by an image processing on whole tumor section. MVD high level was defined as MVD > 33.5 vessel/mm² which is the highest Youden index on the ROC curve for PFS. The relationship between MVD at baseline and PFS and OS was evaluated using Kaplan-Meier survival estimates. ResultsMain characteristics of the 79 pts were similar to the overall CHIVA population: mean age (62 years), ECOG performance status = 0 (34%), high-grade serous histology (75%). At baseline, MVD was similar in both arms and was low for 35% and 30% of the pts in the Ni and control arm respectively. The rate of complete resection (CC0) was 56% in the Ni arm versus 70% in the control arm.In the low MVD group median PFS was 13.3 months (95%CI 11 – 22.2) versus 17 months (95%CI 13.7 – 20.5) in the high MVD group (p=0.85). In the low MVD group, PFS in the Ni and control arm were 12.8 (95%CI 10.7-22.2) and 21.3 months (95%CI 12.5-NA) respectively (p=0.08). The corresponding PFS in the high MVD group were 18.0 (95%CI 14.4-21.6) vs 14.5 months (95%CI 12.4-22.5) (p=0.22). No difference was observed for OS. Baseline MVD was not associated with the rate of CC0. There was no significant difference in the decrease of MVD at IDS between the Ni arm (38% of the pts) and the control arm (48%, p=0.4). ConclusionsThe negative impact of Nintedanib in patients with low baseline MVD tumours may be one explanation of the poor PFS rate observed in the Nintedanib arm of the CHIVA trial. Clinical trial identification2011-006288-23. Legal entity responsible for the studyARCAGY-GINECO. FundingHealth ministry grants( PHRC). DisclosureC. Blanc-Fournier: Honoraria (self): Roche. N. Raban: Travel / Accommodation / Expenses: Roche. G. Ferron: Honoraria (self): Olympus Europe; Advisory / Consultancy: AstraZeneca; Travel / Accommodation / Expenses: Roche. A. Floquet: Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Roche. J. Alexandre: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self): PharmaMar; Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen. C. Louvet: Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Servier; Advisory / Consultancy: AstraZeneca. J. Florence: Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy: Astellas; Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: Sanofi; Travel / Accommodation / Expenses: Janssen. All other authors have declared no conflicts of interest.

Increased number of mast cells in the bone marrow of chronic myeloid leukemia may herald the pending myeloid transformation—the mast cell is an indicator of myeloid transformation

Background: Tumor cells are surrounded by many inflammatory cells, including mast cells (MCs), which can secrete several classic proangiogenic factors, resulting in endothelial cell proliferation and angiogenesis. However, the researches of the number of MC and microvessel density (MVD) in the bone marrow in chronic myeloid leukemia (CML) are rare. In this study, we aimed to investigate the relationship between tryptase-positive MCs and MVD in the different phases of CML. Methods: Bone marrow samples of 61 patients with CML and 20 healthy donors were collected from 2007 to 2017. Antibodies against the endothelial cell marker CD34 and against tryptase were used in immunohistochemistry. The diagnosis and counting of tryptase-positive MC and microvessel in bone marrow was at ×400 magnification. Results: MVD in CML group was higher than which in the control group, and the blast phase (BP) group had a higher MVD than which in chronic phase (CP) group (P Conclusions: The number of MCs and MVD might be markers for the outcome of patients with CML in the Chinese population.

Increased number of mast cells in the bone marrow of chronic myeloid leukemia may herald the pending myeloid transformation-the mast cell is an indicator of myeloid transformation.

BackgroundTumor cells are surrounded by many inflammatory cells, including mast cells (MCs), which can secrete several classic proangiogenic factors, resulting in endothelial cell proliferation and angiogenesis. However, the researches of the number of MC and microvessel density (MVD) in the bone marrow in chronic myeloid leukemia (CML) are rare. In this study, we aimed to investigate the relationship between tryptase-positive MCs and MVD in the different phases of CML.MethodsBone marrow samples of 61 patients with CML and 20 healthy donors were collected from 2007 to 2017. Antibodies against the endothelial cell marker CD34 and against tryptase were used in immunohistochemistry. The diagnosis and counting of tryptase-positive MC and microvessel in bone marrow was at ×400 magnification.ResultsMVD in CML group was higher than which in the control group, and the blast phase (BP) group had a higher MVD than which in chronic phase (CP) group (P<0.05). The number of MCs in three groups of CML was higher than which in control group, and the number of MCs in AMLT group was highest (P<0.05). Patients with a lower grade of tryptase-positive MCs in CP group survived longer OS and PFS (P<0.05).ConclusionsThe number of MCs and MVD might be markers for the outcome of patients with CML in the Chinese population.

Increased tumour angiogenesis in SOX11-positive mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a heterogeneous disease with an aggressive behaviour in most cases, which is associated with expression of sex determining region-Y-box11 (SOX11). Experimental studies have shown that SOX11 expression is associated with an angiogenic switch characterised by increased expression of angiogenic-related signatures and vascularisation of murine tumours. However, the relationship between angiogenesis and SOX11 expression in primary tumours is not well understood. Therefore, the aim of this study was to evaluate the development of microvascular angiogenesis in primary MCL in relation to SOX11 expression and its potential prognostic value. Fifty-six patients diagnosed with MCL, 38 SOX11-positive and 18 SOX11-negative, were studied. The relative intratumoral microvascular area (MVA) and microvessel density (MVD) (number of intratumoral microvessels/μm2 ) were measured on CD34-stained slides using a computerised image analysis system. SOX11-positive MCL showed a significant higher microvascular development than negative tumours (median MVA=14.5×10-3 versus 5.0×10-3 P<0.001; median MVD=18.6/μm2 versus 14.2/μm2 , P=0.021). Analysing the MVA and MVD as continuous variables, a high MVD was associated with shorter overall survival (P=0.004), and a similar tendency was observed for high MVA (P=0.064). The microvascular development was not related to the Ki-67 proliferative index or 17p/TP53, 9p or 11q alterations. These findings suggest that SOX11 promotes an angiogenic phenotype in primary MCL, which may contribute to the more aggressive behaviour of these tumours.

Effect of thalidomide on bone marrow angiogenesis in multiple myeloma patients

BackgroundBone marrow angiogenesis is increased in multiple myeloma (MM) patients, prompting the rationale for using antiangiogenic drugs in the treatment of these patients. ObjectiveTo assess angiogenesis in patients with MM at diagnosis and following treatment with an antiangiogenic drug. Patients and MethodsTwenty-three patients with newly diagnosed MM were treated with thalidomide-based regimens. Bone marrow evaluation was made before and following treatment and included angiogenesis assessment, which was quantified through microvessel density (MVD) determination, by means of anti-CD34 immunohistochemical labeling, and classified either as high MVD or low MVD, according to the mean CD34 count: above or below the median of 12.6. ResultsThe pre-therapy median MVD was 12 (7.5–18.3) versus 8.7 (5.35–18.5) post-therapy, p=0.2114. ConclusionsOur study found no reduction in MVD before and following treatment and, accordingly, we could establish no relationship between MVD and response to therapy in the sample we studied.

Ultrasound-Targeted Microbubble Destruction-Mediated Co-Delivery of Cxcl12 (Sdf-1alpha) and Bmp2 Genes for Myocardial Repair.

Acute myocardial infarction (AMI) is a serious threat to human health. Stem cells can serve as ideal seed cells for myocardial repair and regeneration; however, insufficient homing to the infarcted areas and poor myocardial differentiation limit their further clinical application. Chemokine (C-X-C motif) ligand 12 (CXCL12) is an important stem cell homing factor, and Bone morphogenetic protein-2 (BMP2) is a differentiation-promoting factor. In this study, we designed microbubbleadenovirus complexes and investigated the functional benefit of co-delivery of Cxcl12 and Bmp2 genes in adenoviral vectors by ultrasound-targeted microbubble destruction (UTMD) for myocardial repair in AMI rats. By transfection of rat bone marrow mesenchymal stem cells (BMSCs), high transfection efficiency was achieved under ultrasound irradiation, and successful myocardial differentiation of the transfected BMSCs was induced after ultrasound-mediated-transfection of Bmp2 in vitro. In the AMI rat model, co-delivery of Cxcl12 and Bmp2 at a ratio of 2:1 may result in significantly higher myocardial repair efficacy compared to transfection of Cxcl12 or Bmp2 only. Higher myocardial repairing efficacy was achieved with co-delivery of Cxcl12 and Bmp2 at a ratio of 2:1 than using a ratio of 1:1 or 1:2, as evidenced by smaller infarction size, higher micro-vessel density, and better recovery of cardiac function at 28 days after treatment. Hence, UTMD-mediated co-transfection of Cxcl12 and Bmp2 significantly promoted the repair/regeneration of the infarcted myocardium, thereby providing a promising approach for the repair of cardiac injury.

IL‑17A promotes CXCR2‑dependent angiogenesis in a mouse model of liver cancer.

Serum interleukin (IL)-17A level is associated with higher microvessel density and poor prognosis in liver cancer. However, the specific mechanism underlying the role of IL-17A in liver cancer remains controversial. In the present study, the effect of IL-17A on liver cancer cells was examined. IL-17A had no evident impact on vascular endothelial growth factor A (VEGFA) production in HepG2 and Huh7.5 cells as determined by reverse transcription-quantitative PCR and ELISA, but it did stimulate angiogenic CXC chemokine secretion, including chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2, CXCL3, CXCL5, CXCL6 and CXCL8 in Huh7.5 cells and CXCL2 in HepG2 cells. In addition, the production of angiostatic chemokines such as CXCL10 was not affected. The supernatant of Huh7.5-IL17A cells promoted endothelial cell chemotaxis, which was attenuated by the C-X-C chemokine receptor type 2 (CXCR2) inhibitor SB225002. Although there was no role of IL-17A in promoting in vitro cell proliferation, IL-17A markedly increased the tumor growth of Huh7.5 cells in both subcutaneous and orthotopic xenograft models with increased vascularization. Taken together, these results demonstrated that IL-17A may stimulate chemokine-induced angiogenesis and promote tumor progression, independent of VEGF signaling. The CXCL-CXCR2 axis may be a novel target for the anti-angiogenesis treatment of liver cancer.

From clinic to mechanism: Proteomics-based assessment of angiogenesis in adrenal pheochromocytoma.

Adrenal pheochromocytoma (PCC) is a very rare tumor that stems from chromaffin cells, which can develop into malignant tumor. During the operation, abundant blood vessels were often observed in PCC than other adrenal tumors, which increases the difficulty and risk of the surgery. Therefore, it is important to investigate the mechanism of PCC angiogenesis. Twelve surgical specimens of PCC from Ruijin Hospital, Shanghai Jiaotong University were grouped into high and low microvessel density (MVD) group. They were also divided into rich blood supply and nonenriched blood supply group, according to computed tomography (CT) manifestation. Comparative proteomic analysis based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics analysis revealed that 206 proteins differentially regulated in the high MVD group compared with low MVD group (p < 0.05). Besides, 61 proteins were discovered to be significantly changed when the 12 samples were grouped according to CT manifestation. By intersecting the differentially changed protein from MVD and CT grouping, 25 proteins were filtered out, with pathological function. COX4I2 was verified to be increased gradually with angiogenesis with increasing severity, and PLAT was shown to be decreased with angiogenesis in PCC, by quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. The quantitative proteomics result indicated that the tumor angiogenesis in PCC is associated with hypoxia. COX4I2 and PLAT were highly correlated with blood supply in PCC which contribute to angiogenesis in PCC, which could be used as biomarkers to better indicate tumor angiogenesis, or targets to regress tumor angiogenesis as treatment.

A pretreatment CT model predicts survival following chemolipiodolization in patients with hepatocellular carcinoma.

e14509 Background: This study aimed to establish a computed tomography-based prognostic model for patients with hepatocellular carcinoma treated with transarterial chemoembolization. Methods: Using prospectively collected data from 195 consecutive patients with hepatocellular carcinoma who underwent chemolipiodolization at the Eastern Hepatobiliary Surgery Hospital between 2013 and 2016, we established a prognostic model based on hepatocellular carcinoma enhancement patterns on computed tomography scans to predict the outcome of transarterial chemoembolization. Furthermore, a histopathology analysis was performed on 108 different patients undergoing resection between 2014 and 2016 to identify whether there was a correlation between enhancement pattern and microvessel density. Results: The prognostic model classified hepatocellular carcinoma into 3 types: Type I, which reached peak enhancement during the arterial phase and had a high mean microvessel density (101.5 vessels/0.74 mm2); Type II, which reached peak enhancement during the portal venous or delayed phase and had an intermediate microvessel density (53.6 vessels/0.74 mm2); and Type III, in which the tumor was insignificantly enhanced and had a low microvessel density (21.1 vessels/0.74 mm2). For type I, II, and III hepatocellular carcinoma, the post-transarterial chemoembolization 1-year tumor complete necrosis rates were 13.7%, 36.5%, and 0%, respectively (p &lt; 0.001) and the 3-year overall survival rates were 14.1%, 38.6%, and 0%, respectively (p &lt; 0 .001). Conclusions: Our results indicate that hepatocellular carcinoma type is an independent predictor of complete necrosis and overall survival.

18F-FDG-PET Can Predict Microvessel Density in Head and Neck Squamous Cell Carcinoma.

Aim: Positron emission tomography (PET) with 18F-fluordeoxyglucose (18F-FDG) plays an essential role in the staging and tumor monitoring of head and neck squamous cell carcinoma (HNSCC). Microvessel density (MVD) is one of the clinically important histopathological features in HNSCC. The purpose of this study was to analyze possible associations between 18F-FDG-PET findings and MVD parameters in HNSCC. Materials and Methods: Overall, 22 patients with a mean age of 55.2 ± 11.0 and with different HNSCC were acquired. In all cases, whole-body 18F-FDG-PET was performed. For each tumor, the maximum and mean standardized uptake values (SUVmax; SUVmean) were determined. The MVD, including stained vessel area and total number of vessels, was estimated on CD105 stained specimens. All specimens were digitalized and analyzed by using ImageJ software 1.48v. Spearman’s correlation coefficient (r) was used to analyze associations between investigated parameters. p-values of <0.05 were taken to indicate statistical significance. Results: SUVmax correlated with vessel area (r = 0.532, p = 0.011) and vessel count (r = 0.434, p = 0.043). Receiver operating characteristic analysis identified a threshold SUVmax of 15 to predict tumors with high MVD with a sensitivity of 72.7% and specificity of 81.8%, with an area under the curve of 82.6%. Conclusion: 8F-FDG-PET parameters correlate statistically significantly with MVD in HNSCC. SUVmax may be used for discrimination of tumors with high tumor-related MVD.

Enhancement of the Marginal Area in Colorectal Cancer Liver Metastasis on Computed Tomography Correlates With Microvessel Density and Clinicopathological Factors.

Previously, we aimed to predict the effect of bevacizumab in liver metastasis using the ratio of the computed tomography (CT) value for hepatic metastatic lesions in the arterial phase in contrast-enhanced (CE) CT to that on plain CT. However, there is no report on the relation between the CT contrast effect and microvessel density (MVD) in liver metastasis. Thirty-two patients who underwent liver resection for metastasis from colorectal cancer (excluding neoadjuvant chemotherapy cases) between April 2006 and October 2011 at our Department were analyzed retrospectively. The relation between the CE ratios obtained from the whole tumor or tumor margin and the MVD using the liver metastatic lesion of colorectal cancer were analyzed. It was also examined whether the CE ratios and MVD were related to the clinicopathological factors of the primary tumor. There was a significant correlation between the CE ratios obtained from assessment using the entire tumor and the tumor margin as regions of interest (ROI). Furthermore, there was a significant correlation between the MVD and CE ratios. Cases with lymphatic invasion, N2, N3 nodal status and grade B and C were significantly more often observed in the group with high MVD. In contrast, in the group with high CE using the whole tumor as ROI, cases with grade B or C were significantly fewer. However, the number of hepatic metastasis was significantly higher and the diameter was significantly larger in the group with high CE using the tumor margin as ROI. Moreover, cases with grade B or C were recognized significantly more often. The CE ratio correlated with the MVD. The CE ratio using the tumor margin was similar to the MVD in relation to the clinicopathological factors. Taken together, these findings suggest that the CE ratio using the tumor margin as ROI may reflect MVD.

Clinical significance of cancer‐associated fibroblasts and their correlation with microvessel and lymphatic vessel density in lung adenocarcinoma

BackgroundTo determine whether cancer‐associated fibroblasts (CAFs) are associated with microvessel density (MVD) and lymphatic vessel density (LVD) in lung adenocarcinoma (ADC) or are not prognostic.MethodsNinety‐three lung adenocarcinoma patients without adjuvant therapy between January 2010 and June 2011 were enrolled. CAFs, MVD, and LVD were identified by α‐smooth muscle actin (α‐SMA), CD34 and D2‐40 staining via immunohistochemistry. Staining intensities were assessed and quantified. For statistics, Pearson's chi‐square test, logistic regression, Kaplan‐Meier, and log‐rank tests were applied. In addition, the Cox proportional hazards model was used for multifactor analysis to predict survival.ResultsCAFs abundance in lung adenocarcinoma is associated with higher MVD and LVD. In addition, a correlation was demonstrated between MVD and LVD (P < 0.05). CAFs, MVD, and LVD are significantly correlating with age, tumor size, differentiation grade, clinical stage, and lymph node metastasis (P < 0.05), but not influenced by gender, tumor location, and smoking history. Three‐year overall survival in the CAFs‐poor group is 64.5%, which is significant higher than that in the CAFs‐rich cohort (41.9%). Further, we found that age, clinical stage, α‐SMA, CD34, D2‐40 positivity, tumor size, differentiation grade, and lymph node metastasis significantly correlate with overall survival of patients with lung adenocarcinoma. However, sex, smoking history, and tumor location have no association with 3‐year survival. The clinical stage is an independent prognostic factor in overall survival (P < 0.05).ConclusionsThe density of CAFs identified by α‐SMA staining is associated with progression and metastasis of lung adenocarcinoma and affects the patient's disease outcome.

Allogenic endothelial progenitor cell transplantation increases flap survival through an upregulation of eNOs and VEGF on venous flap survival in rabbits

Endothelial progenitor cells (EPCs) are one type of bone marrow hematopoietic stromal cells which play a vital role in neovascularization and tissue repair. In this study, we investigated whether EPCs promote flap survival in a rabbit venous model. EPCs were customized from CHI Scientific, Inc, China. Thirty-six rabbits were randomly assigned to either the sham group (n = 12), the control group (n = 12) or the EPC transplantation group (n = 12). A 10 × 6cm venous flap was created on the rabbit abdomen. Both the EPC transplantation and control groups had the same volume of EPCs-PBS (phosphate buffered saline) and PBS on postoperative day 1. Flap survival, blood flow, histopathology, expression of endothelial nitric oxide synthase (eNOs) and Vascular Endothelial Growth Factor (VEGF) were detected on postoperative day 10. Cellular immunofluorescence assay positively confirmed that the EPCs were undergoing differentiation. The survival rate of the flap in the EPC transplantation group was 58.4±7.1%, which was significantly higher than that of the control group (4.8±3.4%) (p<0.01). Histological examination revealed that the EPC transplantation group had higher microvessel density, fewer inflammatory cells, and a higher expression of eNOs and VEGF. Significantly increased blood flow perfusion was seen in the EPC transplantation group using laser Doppler imaging. The Western Blot technique revealed that the expression of eNOs and VEGF in the EPC transplantation group were both significantly higher than those in the control group. This study demonstrated that EPC transplantation improved venous flap survival in rabbits. The present findings may provide insight into the promotion of venous flap survival in clinical practice in the future.

Ovarian cancer cell-secreted exosomal miR-205 promotes metastasis by inducing angiogenesis.

Background: By providing oxygen, nutrients and metastatic conduits, tumour angiogenesis is essential for cancer metastasis. Cancer cell-secreted microRNAs can be packaged into exosomes and are implicated in different aspects of tumour angiogenesis. However, the underlying mechanisms are incompletely understood.Methods: The GEPIA database and in situ hybridization assay were used to analyse expression of miR-205 in ovarian tissues. Immunohistochemistry was performed to examine the relationship between miR-205 and microvessel density. Expression of circulating miR-205 was evaluated by RT-PCR and GEO database analysis. Co-culture and exosome labelling experiments were performed to assess exosomal miR-205 transfer from ovarian cancer (OC) cells to endothelial cells ECs. Exosome uptake assays were employed to define the cellular pathways associated with the endocytic uptake of exosomal miR-205. The role of exosomal miR-205 in angiogenesis was further investigated in vivo and in vitro. Western blotting and rescue experiments were applied to detect regulation of the PTEN-AKT pathway by exosomal miR-205 in ECs.Results: miR-205 was up-regulated in OC tissues, and high expression of miR-205 was associated with metastatic progression in OC patients. Moreover, miR-205 was highly enriched in cancer-adjacent ECs, and up-regulation of miR-205 correlated positively with high microvessel density in OC patients. Importantly, miR-205 was markedly enriched in the serum of OC patients, and a high level of miR-205 in circulating exosomes was associated with OC metastasis. In addition, OC-derived miR-205 was secreted into the extracellular space and efficiently transferred to adjacent ECs in an exosome-dependent manner, and the lipid raft-associated pathway plays an important role in regulating uptake of exosomal miR-205. Exosomal miR-205 from OC cells significantly promoted in vitro angiogenesis and accelerated angiogenesis and tumour growth in a mouse model. Furthermore, we found that exosomal miR-205 induces angiogenesis via the PTEN-AKT pathway.Conclusion: These findings demonstrate an exosome-dependent mechanism by which miR-205 derived from cancer cells regulates tumour angiogenesis and implicate exosomal miR-205 as a potential therapeutic target for OC.

A Pretreatment CT Model Predicts Survival Following Chemolipiodolization in Patients With Hepatocellular Carcinoma.

Purpose:To establish a computed tomography–based prognostic model for patients with hepatocellular carcinoma treated with transarterial chemoembolization.Materials and Methods:Using prospectively collected data from 195 consecutive patients with hepatocellular carcinoma who underwent chemolipiodolization at the Eastern Hepatobiliary Surgery Hospital between 2013 and 2016, we established a prognostic model based on hepatocellular carcinoma enhancement patterns on computed tomography scans to predict the outcome of transarterial chemoembolization. Furthermore, a histopathology analysis was performed on 108 different patients undergoing resection between 2014 and 2016 to identify whether there was a correlation between enhancement pattern and microvessel density.Results:The prognostic model classified hepatocellular carcinoma into 3 types: type I, which reached peak enhancement during the arterial phase and had a high mean microvessel density (101.5 vessels/0.74 mm2); type II, which reached peak enhancement during the portal venous or delayed phase and had an intermediate microvessel density (53.6 vessels/0.74 mm2); and type III, in which the tumor was insignificantly enhanced and had a low microvessel density (21.1 vessels/0.74 mm2). For type I, II, and III hepatocellular carcinoma, the post-transarterial chemoembolization 1-year tumor complete necrosis rates were 13.7%, 36.5%, and 0%, respectively (P < .001), and the 3-year overall survival rates were 14.1%, 38.6%, and 0%, respectively (P < .001).Conclusion:Our results indicate that hepatocellular carcinoma type is an independent predictor of complete necrosis and overall survival

Neovascularization and Intraplaque Hemorrhage in Atherosclerotic Plaque Destabilization-A Mathematical Model

Observational studies have identified angiogenesis from the adventitial vasa vasorum and intraplaque hemorrhage (IPH) as critical factors in atherosclerotic plaque progression and destabilization. Here we propose a mathematical model incorporating intraplaque neo vascularization and hemodynamic calculation for the quantitative evaluation of atherosclerotic plaque hemorrhage. An angiogenic microvasculature based on histology of a patient’s carotid plaque is generated by two - dimensional nine - point model of endothelial cell migration. Three key cells (endothelial cells, smooth muscle cells and macrophages) and three key chemicals (vascular endothelial growth factors, extracellular matrix and matrix metalloproteinase) are involved in the intraplaque angiogenesis model, and described by the reaction - diffusion partial equations. The hemodynamic calculation of the microcirculation on the generated microvessel network is carried out by coupling the intravascular, interstitial and transvascular flow. The plasma concentration in the interstitial domain is defined as the description of IPH area according to the diffusion and convection with the interstitial fluid flow, as well as the extravascular movement across the leaky vessel wall. The simulation results demonstrate a series of pathophysiological phenomena during the progression of an atherosclerotic plaq ue, including the high microvessel density (MVD) region at the shoulder areas, the transvascular flow through the capillary wall and the intraplaque hemorrhage. The hemodynamic results show significant consistency with both the histology data and the MR im aging data in quality and quantity. In addition, the sensitivity analysis of IPH to model parameters reveals that the decreased MVD and the vessel permeability may reduce the IPH area dramatically.

Prognostic implications of peritumoral vasculature in head and neck cancer.

BackgroundThere is conflicting evidence regarding the role of peritumoral lymphatic vessel density (LVD) and blood microvessel density (MVD) in the metastasis and prognosis of head and neck squamous cell carcinoma (HNSCC). Existing studies are limited to one or two head and neck subsites and/or small sample sizes. A larger study incorporating multiple sub‐sites is needed to address the role of peritumoral LVD and MVD in HNSCC metastasis and prognosis.MethodsTissue samples from 200 HNSCC cases were stained simultaneously using immunohistochemistry (IHC) for markers of peritumoral LVD (lymphatic vessel marker D240) and MVD (blood vessel marker CD31). Of the stained slides, 166 and 167 were evaluable for LVD and MVD, respectively. The results were then correlated with clinicopathologic features and patient outcomes.ResultsPatients with metastatic disease were more likely to have high peritumoral MVD. Through multivariable analyses, MVD was not significantly related to DFS and OS, while low LVD was related to higher risk of disease progression and poor survival.ConclusionsPeritumoral MVD was found to be positively associated with metastasis, while LVD was found to be inversely related to both metastasis and progression of HNSCC. These findings may suggest a prognostic role of both peritumoral LVD and MVD in patients with HNSCC.

Expression and clinical significance of oxido-reductase containing WW structure domain in tissue of children with osteosarcoma

Objective To explore the expression levels and the relationship between the expression of oxido-reductase containing WW structure domain(WWOX) gene and clinicopathological features in children with osteosarcoma. Methods A total of 153 children with osteosarcoma who were diagnosed and treated in the Xinxiang First People′s Hospital from January 2013 to September 2017 were selected by retrospectively method.Biopsy specimens before treatment were collected.The clinical stage of all patients was T2N0M0.The expression of WWOX was analyzed by using immunohistochemistry.The relationship between WWOX expression and other clinicopathological features, such as gender, age, primary site of tumor, response to chemotherapy and so on were analyzed.Cox regression was used to screen out single and multiple risk factors of disease-free survival(DFS) of preadolescent patients with osteosarcoma. Results Among the 153 cases, there were 91 males and 62 females with an average age of 13.9 years old.The sensitivity to chemotherapy in children with high WWOX expression was better (P=0.027). The expression of WWOX in specimens of osteosarcoma in children was negatively correlated with microvessel density(MVD) (r=-0.185, P=0.022), and the WWOX expression was negatively correlated with runt related gene 2(RUNX2) and VEGF expressions (r=0.182, 0.176, all P<0.05). Children with osteosarcoma DFS risk factors included low WWOX expression, high VEGF expression, limbs tumors and MVD (all P<0.05); the children with osteosarcoma DFS independent risk factors included low WWOX expression and high vascular endothelial growth factor(VEGF) expression (all P<0.05). Conclusions Expression deletion of WWOX in children patients with osteosarcoma is a risk factor independent of clinicopathological features such as gender, age, primary site of tumor of DFS and it may become a useful prognostic marker in the response to neoadjuvant chemotherapy.WWOX may play a role in angiogenesis in children with osteosarcoma. Key words: Osteosarcoma; Oxido-reductase containing WW structure domain; Prognosis; Child

Oncological and genetic factors impacting PDX model construction with NSG mice in pancreatic cancer.

A patient-derived xenograft (PDX) approach, which relies on direct transplantation of tumor specimens into an immunocompromised animal, is a commonly used method for investigating tumor therapy predictions in vivo. This study evaluated influencing factors, including clinical, oncological, and genetic variables, for a pancreatic PDX model in mice. Tumor specimens were obtained from 121 patients with pancreatic ductal adenocarcinoma who underwent surgical resection at the Changhai Pancreatic Surgery Medical Center (Shanghai, China) between April 2016 and February 2017. Pancreatic cancer (PC) samples <3 mm3 were subcutaneously implanted into the NOD/Shi-scid/IL-2Rγnull (NSG) mice. Once the xenograft reached 300-500 mm3 or reached 180 d after cell inoculation, the tumor was excised. Part of the tumor was subsequently transplanted to next-generation mice, and another part was analyzed by using immunohistochemistry. Among the 121 patients with PC, tumor xenograft was successfully generated in 86 patients (71.1%). Primary tumor >3.5 cm in size was independently associated with xenograft formation rate. In addition, several enriched mutated genes within the VEGF pathway and higher microvessel density were found in the positive group (with xenograft) compared with the negative group (without xenograft). We concluded that tumor size and mutated VEGF pathway in PC are important factors affecting PDX model construction with NSG mice.-Guo, S., Gao, S., Liu, R., Shen, J., Shi, X., Bai, S., Wang, H., Zheng, K., Shao, Z., Liang, C., Peng, S., Jin, G. Oncological and genetic factors impacting PDX model construction with NSG mice in pancreatic cancer.

Overexpression of S100A13 protein is associated with tumor angiogenesis and poor survival in patients with early-stage non-small cell lung cancer.

BackgroundS100A13 plays a key role in tumor growth and metastasis. The purpose of this study was to investigate the prognostic significance of S100A13 expression, microvessel density (MVD), and survival in early stage non‐small cell lung cancer (NSCLC).MethodsIn silico analysis was performed to determine the associations between S100A13 and NSCLC. The data of 82 patients with early‐stage NSCLC who underwent radical resection were evaluated. Paraffin‐embedded tumor specimens were stained with S100A13 and CD31 (a specific endothelial marker) using immunohistochemical methods. Prognostic significance was assessed by univariate and multivariate analyses.ResultsS100A13 messenger RNA was overexpressed in NSCLC, especially in advanced stage. Of the 82 NSCLC specimens examined, 37 (45.1%) cases exhibited S100A13 overexpression and 31 (37.8%) showed high MVD. Univariate analysis indicated that gender, age, smoking status, histology type, tumor differentiation, and T stage were not significantly associated with prognosis. However, the overall and disease‐free survival rates of patients with S100A13 overexpression and high MVD were significantly lower than in the remaining cases. Multivariate analysis demonstrated that only S100A13 overexpression was an independent factor for poor prognosis in early‐stage NSCLC. Statistical analysis demonstrated that the MVD was significantly higher in tumors with high (67.6%, 25/37) compared to low S100A13 expression (13.3%, 6/45) (P < 0.01).ConclusionsHigh S100A13 expression is closely associated with high intratumoral angiogenesis and poor prognosis in patients with stage I NSCLC. Immunohistochemical evaluation of S100A13 expression, along with an examination of the perioperative extent of angiolymphatic invasion, has value for predicting prognosis.