Study of prognostic significance of marrow angiogenesis assessment in patients with de novo acute leukemia.

BACKGROUND: Angiogenesis is the highly ordered formation of new blood vessels from pre-existing vessels. It is seen throughout growth, in wound healing, menses, and is important in cancer, where pro- and antiangiogenic signals can be released by cancer cells, endothelial cells, stromal cells, blood, and the extracellular matrix. Aim of the study is to use standardized method for counting blood vessels to verify the significance and prognostic value of assessing marrow angiogenesis at diagnosis of de novo acute leukemia. SUBJECTS AND METHODS: The study included 70 newly diagnosed acute leukemia cases and a control group composed of 35 bone marrow biopsy sections obtained from breast cancer patients. Examination of CD34 immunohistochemically stained sections for the assessment of marrow angiogenesis by quantification of its microvessel density (MVD). RESULTS: MVD was significantly increased in acute leukemia patients in comparison to control group (P-value <0.001). Increased MVD was associated with unfavorable outcome. CONCLUSION: The study demonstrated an evidence of increased angiogenesis in acute leukemia detected by high bone marrow MVD which may play a significant role in leukemic process. Understanding its role may help in designing new therapeutic strategies for acute leukemia.

Assessment of tumor angiogenesis as a prognostic factor of survival in patients with oligodendroglioma.

According to World Health Organization (WHO) and Daumas-Duport grading systems, progression of oligodendrogliomas (ODGs) to a higher grade (WHO grade III, grade B) is associated with increased angiogenesis. Based on multivariate assessment of molecular, pathological, and radiological parameters, we further assessed the influence of tumor angiogenesis on tumor progression and patient survival. Patients with a diagnosis of ODG, consecutively treated in a single institution, were reviewed and reclassified according to WHO and Daumas-Duport grading systems. MRI scans were reviewed to assess contrast enhancement and necrosis. Tissue sections were used for pathology review and to evaluate immunostaining of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGF-R), Ki-67, and CD34. Multivariate analysis was performed to assess the impact of tumor angiogenesis-related pathological and radiological factors on patient survival. One hundred thirty-four patients with pure ODG were included in this study. Multivariate analysis identified four independent poor prognostic factors: necrosis, absence of seizure, increased vascularization, and age >55 years. A subgroup of patients with tumor necrosis, increased vascularization, and absence of seizures had a significantly worse outcome than predicted, with a median overall survival of 14.2 months. VEGF expression was significantly higher in this subgroup and correlated with disease progression regardless of histologic grade. Based on the presence of radiological or pathological necrosis, contrast enhancement or endothelial hyperplasia, and absence of seizures, a high risk group of ODG can be identified with significantly worse overall survival. Also, VEGF over-expression in ODG constitutes an early marker for predicting tumor progression.

Antiangiogenic therapy for high-grade gliomas.

BACKGROUND: Gliomas and in particular high-grade gliomas (HGG) demonstrate when compared to other non-neural solid cancers amongst the highest levels of tumor angiogenesis (the formation of new blood vessels from pre-existing vasculature). METHODS: Angiogenesis is a common theme in cancer biology and reflects the requirement of a vascular network to support continued uncontrolled cancer growth. Early recognition of this paradigm suggested a potential and novel cancer treatment target that led to the discovery and implementation of antiangiogenic therapies. Two basic strategies of cancer antiangiogenic therapy have emerged, one targeting vascular endothelial growth factor, VEGF (growth factor ligand-based antagonists) and the second targeting the vascular endothelial growth factor receptor, VEGFR (receptor-based antagonists, small molecule tyrosine kinase inhibitors). Emerging literature suggests efficacy of antiangiogenic therapy for recurrent HGG. RESULTS: Notwithstanding the limited literature regarding the treatment of recurrent HGG with antiangiogenic therapy (predominantly ligand-based and administered in conjunction with cytotoxic chemotherapy), this therapy has become the de facto standard of care for many. Response rates vary from 30-60% and 6-month progression free survival varies from 25-50%. Problematic however are new antiangiogenic class side effects (hypertension, fatigue, proteinuria, intratumoral hemorrhage, arterial thrombosis and wound dehiscence), timing in relationship to surgery, measurements of response, lack of established dose response relationships and pharmacoeconomics and a possible change in tumor biology. CONCLUSIONS: Ligand-based antiangiogenic therapy (in particular bevacizumab) is a compelling new targeted therapy for HGG and will continue to emerge as an important novel anti-glioma therapy. Further studies are required to define the population of patients with HGG in whom this therapy is of benefit, identify the optimal dose and schedule, better characterize the value of co-administered (cytotoxic and targeted) therapies and establish validated response measures.

Computed tomographic assessment of vascular invasion and resectability of mediastinal masses in dogs and a cat.

AIMS: To assess the sensitivity of non-angiographic contrast-enhanced computed tomography (CT) to determine the presence of vascular invasion of cranial mediastinal masses in dogs and a cat, and to evaluate the association between vascular invasion and peri-operative mortality. METHODS: A retrospective study was conducted on 25 dogs and one cat. CT scans were completed with slices ranging from 2 to 10 mm. CT images were evaluated by a board-certified radiologist blinded to previous diagnoses and surgical findings. Each CT study was evaluated for vascular invasion, defined as disruption of the vessel wall and extension of the mass into the vessel lumen. Data retrieved from the surgery reports included surgical approach, whether vascular invasion was present, the surgeon's decision on operability, and post-operative complications. RESULTS: Computed tomographic evaluation revealed 25/26 masses had no evidence of vascular invasion. During surgical exploration, 10/26 masses were found to invade major regional vasculature; the cranial vena cava (CVC) was the vessel most commonly invaded (7/10 animals), and 4/7 (57%) patients with invasion of the CVC were euthanised or died in the peri-operative period, from surgical or disease-related problems, which was significantly higher than patients without vascular invasion (p=0.045). CONCLUSIONS: Non-angiographic contrast-enhanced CT was significantly less sensitive for detecting vascular invasion of cranial mediastinal masses when compared with surgical evaluation. If the CVC was invaded by a tumour there was a significant risk of death peri-operatively when compared with non-invasive cases. CLINICAL RELEVANCE: Due to the significantly higher mortality risk associated with invasion of the CVC, a more sensitive method than CT should be investigated to determine vascular invasion of mediastinal masses pre-operatively.

Prognostic value of bone marrow angiogenesis in multiple myeloma: use of light microscopy as well as computerized image analyzer in the assessment of microvessel density and total vascular area in multiple myeloma and its correlation with various clinical, histological, and laboratory parameters.

We studied the prognostic value of parameters of angiogenesis on bone marrow biopsies in newly diagnosed multiple myeloma (MM) patients. Angiogenesis parameters studied were the microvessel count done manually on light microscopy (MVD-A), microvessel count done by using computerized image analyzer (MVD-B), and total vascular area (TVA) measured by computerized image analyzer. One hundred ten newly diagnosed cases of MM treated at Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, were analyzed with respect to clinical features, laboratory findings, histological features, angiogenesis parameters, and responses to the treatment on follow-up. Twenty age- and sex-matched controls were studied for comparing with angiogenesis of the test cases. Bone marrow microvessels were examined using immunohistochemical staining for CD34. MVD-A (range 4.9-85.2; mean 28.2; SD 19.4), MVD-B (range 2.0-26.9; mean 11.7; SD 5.9), and TVA measured in percentage (range 0.1-17.1; mean 2.4; SD 2.5) were measured for test cases (n = 110). Grading of angiogenesis parameters of the test cases were done; such that angiogenesis parameters of controls (taken as baseline) were grade I. There was a statistically highly significant correlation between (MVD-A vs MVD-B, pcc = 0.92; MVD-A vs TVA, pcc = 0.78; MVD-B vs TVA, pcc = 0.76). The myeloma cases had significantly higher angiogenesis parameters when compared with controls (Kruskall-Wallis test, P < 0.001). "Complete responders" (n = 38/110) had significant lower angiogenesis (Mann-Whitney U test, P < 0.001) than "nonresponders" (n = 72/110). On treatment follow-up "rapid disease progressors" had the highest levels of angiogenesis (mean rank for MVD-A = 84.7, MVD-B = 82.1, and TVA = 81.1). On multivariate (logistic regression) analysis, factors found to have independent prognostic significance in complete responders (adjusted odd ratio (95% CI, P value)] were: (a) MVD-B grade I [0.134 (0.10-0.16, P < 0.001)], (b) clinical substage A [0.163 (0.12-0.19, P = 0.008)], (c) Bartl's histological stage II & I [0.262 (0.2-0.32, P = 0.021)], (d) MVD-A grade I [0.28 (0.22-0.36, P = 0.03)], (e) beta2 microglobulin levels less than 3,400 ng/dl [0.31 (0.23-0.42, P = 0.04)]. Kaplan-Meier survival analysis for myeloma-related death (n = 16) shows a mean survival time (in months) of 24.75; SE = 3; 95% CI = 21-28. We conclude that MVD (particularly MVD-B) is a very good predictor for the complete response in patients of MM and should be done routinely on bone marrow biopsies.

Assessment of breast cancer vascularisation by Doppler ultrasound as a prognostic factor of survival.

Tumor growth and metastasis in breast cancer are correlated to neoangiogenesis, which became a potential candidate as a prognostic factor in this tumor type. Several studies have used immunohistochemical staining to count microvessel density as a marker of neoangiogenesis. This hospital-based retrospective pilot study measured vascularisation of early breast cancer by Doppler ultrasound and determined its value as a prognostic factor of overall survival in 147 women. The number of tumor related arteries were detected by color-coded Doppler ultrasound. We identified < or =10 tumor arteries and >10 tumor arteries in 117 and 30 women, respectively. Only weak correlation was found between the number of tumor arteries and established clinicopathological parameters such as tumor size (r=0.25) and lymph node involvement (r=0.13). In an univariate analysis, the strongest predictors of overall survival were number of tumor arteries [relative risk (RR) 4.60 (1.96-10.78)], positive axillary lymph nodes [RR 4.48 (1.59-12.60)] and angioinvasion [RR 4.26 (1.93-9.37)]. These three parameters were also found to be independent predictors of overall survival in a multivariate analysis [RR 3.21 (1.13-9.10) for positive lymph nodes; RR 2.69 (1.33-5.41) for number of tumor arteries; RR 2.84 (1.27-6.34) for angioinvasion]. Tumor vascularisation detected by Doppler ultrasound appears to be an independent predictor of overall survival in women with early breast cancer.