***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Blood vessels in solid tumors are not r and omly distributed , but are clustered in angiogenic hotspots . Tumor microvessel density ( MVD ) within these hotspots correlates with patient survival and is widely used both in diagnostic routine and in clinical trials . Still , these hotspots are usually subjectively defined . There is no unbiased , continuous and explicit representation of tumor vessel distribution in histological whole slide images . This shortcoming distorts angiogenesis measurements and may account for ambiguous results in the literature . In the present study , we describe and evaluate a new method that eliminates this bias and makes angiogenesis quantification more objective and more efficient . Our approach involves automatic slide scanning , automatic image analysis and spatial statistical analysis . By comparing a continuous MVD function of the actual sample to r and om point patterns , we introduce an objective criterion for hotspot detection : An angiogenic hotspot is defined as a clustering of blood vessels that is very unlikely to occur r and omly . We evaluate the proposed method in N=11 images of human colorectal carcinoma sample s and compare the results to a blinded human observer . For the first time , we demonstrate the existence of statistically significant hotspots in tumor images and provide a tool to accurately detect these hotspots OBJECTIVES To determine whether markers of tumor angiogenesis were associated with progression-free survival ( PFS ) and overall survival ( OS ) in women with high-risk , early-stage cervical cancer treated on a phase III trial . METHODS One hundred seventy-three tumor specimens were analyzed by semi-quantitative immunohistochemical ( IHC ) staining for vascular endothelial growth factor ( VEGF , pro-angiogenesis factor ) , thrombospondin-1 ( TSP-1 , anti-angiogenesis factor ) , CD31 ( non-specific endothelial marker ) , and CD105 ( tumor-specific endothelial marker ) . Tumoral histoscores ( HS ) were calculated for VEGF using the formula : [ % cells positivex(intensity+1 ) ] . TSP-1 specimens were categorized as negative or positive . CD31 and CD105 microvessel density ( MVD ) " hotspots " were counted in three 20x high-power fields . Associations between angiogenesis markers and survival were evaluated . RESULTS TSP-1 expression was observed in 65 % of cases while 66 % expressed high VEGF ( > or=200 ) , 34 % exhibited high CD31 ( CD31>or=110 ) and 66 % displayed high CD105 ( CD105>or=28 ) . In univariate analyses CD31 MVD , but not tumor TSP-1 , was associated with improved PFS ( HR=0.37 ; 95 % CI=0.18 - 0.76 ; p=0.007 ) and OS ( HR=0.37 ; 95 % CI=0.17 - 0.79 ; p=0.010 ) . After adjusting for prognostic clinical covariates , high CD31 MVD , but not TSP-1 , VEGF or CD105 MVD , was an independent prognostic factor for PFS ( HR=0.36 ; 95 % CI=0.17 - 0.75 ; p=0.006 ) and OS ( HR=0.36 ; 95 % CI=0.17 - 0.79 ; p=0.010 ) . CONCLUSIONS Tumor angiogenesis measured by CD31 MVD is an independent prognostic factor for both PFS and OS in high-risk , early-stage cervical cancer . We hypothesize that this finding may be explained by improved treatment response in well-vascularized , well-oxygenated tumors 
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Furthermore , subgroup analysis revealed that the association between the overexpression of ENG in tumor microvessels and the outcome endpoints ( OS or DFS ) were also significant in the Asians and Caucasians patients with different cancer types .
Conclusions ENG of tumor microvessels is a predictor of poor OS , DFS and CSS and may be a prognostic marker of patients with cancer