Classifying neovascular age-related macular degeneration with a deep convolutional neural network based on optical coherence tomography images.

Neovascular age-related macular degeneration (nAMD) is among the main causes of visual impairment worldwide. We built a deep learning model to distinguish the subtypes of nAMD using spectral domain optical coherence tomography (SD-OCT) images. Data from SD-OCT images of nAMD (polypoidal choroidal vasculopathy, retinal angiomatous proliferation, and typical nAMD) and normal healthy patients were analyzed using a convolutional neural network (CNN). The model was trained and validated based on 4749 SD-OCT images from 347 patients and 50 healthy controls. To adopt an accurate and robust image classification architecture, we evaluated three well-known CNN structures (VGG-16, VGG-19, and ResNet) and two customized classification layers (fully connected layer with dropout vs. global average pooling). Following the test set performance, the model with the highest classification accuracy was used. Transfer learning and data augmentation were applied to improve the robustness and accuracy of the model. Our proposed model showed an accuracy of 87.4% on the test data (920 images), scoring higher than ten ophthalmologists, for the same data. Additionally, the part that our model judged to be important in classification was confirmed through Grad-CAM images, and consequently, it has a similar judgment criteria to that of ophthalmologists. Thus, we believe that our model can be used as an auxiliary tool in clinical practice.

The landscape of angiogenesis subtypes for breast cancer: a comprehensive analysis based on the Cancer Genome Atlas.

PURPOSE: Breast cancer is a common malignant tumor in women with a poor prognosis. This study aimed to investigate angiogenesis subtypes of breast cancer and unveil the etiology and molecular features of breast cancer. METHODS: Based on the angiogenesis gene set derived from AmiGO2, and breast cancer data in the Cancer Genome Atlas (TCGA), we define a novel cluster of angiogenesis subtypes for patients by consensus clustering. The gene regulation, immune landscape, molecular characteristics, and clinical features as well as enrichment pathways were explored in the angiogenesis subtypes of breast cancer. RESULTS: Two angiogenesis subtypes were established through consensus clustering, among which subtype1 included 275 patients and subtype2 included 813 patients. A total of 643 differential expressed genes and 109 miRNAs were found between the two subtypes. The gene set enrichment analysis showed that the enriched hallmark pathways in subtype2 were related to the cancer tumorigenesis and breast cancer progression, including estrogen response early estrogen response late, epithelial-mesenchymal transition (EMT), especially angiogenesis. The mutant-allele tumor heterogeneity and tumor mutation burden of non-angiogenesis subtype were significantly higher than that in the angiogenesis subtype. The stroma score, immune score and ESTIMATE score were significantly higher in angiogenesis subtype, while the tumor purity in angiogenesis subtype was considerably lower. Finally, most immune checkpoints were expressed higher in the angiogenesis subtype. CONCLUSIONS: The omics analysis has established a novel angiogenesis subtype of breast cancer and identified the characteristics of the immune microenvironment and genomic alteration of breast cancer. Thus, this angiogenesis subtype might provide new evidence for inhibiting the progression and immunotherapy response in breast cancer.

The vascular landscape of human cancer.

Tumors depend on a blood supply to deliver oxygen and nutrients, making tumor vasculature an attractive anticancer target. However, only a fraction of patients with cancer benefit from angiogenesis inhibitors. Whether antiangiogenic therapy would be more effective if targeted to individuals with specific tumor characteristics is unknown. To better characterize the tumor vascular environment both within and between cancer types, we developed a standardized metric - the endothelial index (EI) - to estimate vascular density in over 10,000 human tumors, corresponding to 31 solid tumor types, from transcriptome data. We then used this index to compare hyper- and hypovascular tumors, enabling the classification of human tumors into 6 vascular microenvironment signatures (VMSs) based on the expression of a panel of 24 vascular "hub" genes. The EI and VMS correlated with known tumor vascular features and were independently associated with prognosis in certain cancer types. Retrospective testing of clinical trial data identified VMS2 classification as a powerful biomarker for response to bevacizumab. Thus, we believe our studies provide an unbiased picture of human tumor vasculature that may enable more precise deployment of antiangiogenesis therapy.

Review of radiological classifications of pancreatic cancer with peripancreatic vessel invasion: are new grading criteria required?

Pancreatic cancer is mainly diagnosed at an advanced stage when adjacent vessel invasion is present; however, radical resection is potentially curative for selected patients with adjacent vessel invasion. Therefore, accurately judging the resectability of patients with adjacent vessel invasion represents a crucially important step in diagnosis and treatment. Currently, decisions regarding resectability are based on imaging studies, commonly contrast computed tomography (CT). Several radiological classifications have been published for vascular infiltration in pancreatic cancer. However, radiologists always formulate these CT grading systems according to their own experience, resulting in different judgment methods and parameters. And it is controversial in evaluating performance and clinical application. Besides, the conventional CT grading systems mainly focus on the evaluation of vessel invasion so as to less on the outcome of patient evaluation. In this review, we summarize the mainstream CT grading systems for vascular invasion in pancreatic cancer, with the aim of improving the clinical value of CT grading systems for predicting resectability and survival.

Vascular architecture as a diagnostic marker for differentiation of World Health Organization thymoma subtypes and thymic carcinoma.

AIMS: Thymomas and thymic squamous cell carcinomas (TSQCCs) are rare thymic epithelial tumours. Data on angiogenesis and vascular phenotype in these tumours are limited, and no study has taken histological World Health Organization (WHO) subtypes into account. The aim of this study was to compare vascularization, pericytes coverage and expression of angiogenic growth factors in different WHO-defined subtypes of thymoma METHODS AND RESULTS: Vascular density, diameter and architecture and expression of α-smooth muscle actin (SMA), platelet-derived growth factor (PDGF) receptor-ß (PDGFRß), vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1) and VEGF receptor 2 (VEGFR2) were investigated in WHO type A, AB, B1, B2 and B3 thymomas and TSQCCs, by the use of immunostaining, quantitative morphometry, and tumour vessel isolation by trypsin digestion. Expression levels of angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2), VEGF-A, PDGF-B and Hif-1α were examined by quantitative reverse transcription polymerase chain reaction. A and AB thymomas were characterized by a dense network of capillary-like vessels with tight pericyte coverage, whereas B thymomas showed a loose vascular network with increasing vascular diameters and increasing expression of SMA and PDGFRß from B1 to B3 thymomas and TSQCCs. VEGFR1 and VEGFR2 were expressed in vessels of all analysed tumour entities, and at higher levels in epithelial cells of A and B3 thymomas and TSQCCs. mRNA of Ang-2, but not of Ang-1, was significantly up-regulated in all thymoma subtypes, with the highest levels being found in A thymomas. In TSQCCs, Ang-1 and VEGF were the predominantly up-regulated growth factors. Hif-1α was only up-regulated in B3 thymomas and TSQCCs. CONCLUSION: Thymomas and TSQCCs differ significantly in their vascular architecture and expression of key angiogenic growth factors. The findings could help to improve the differential diagnosis of difficult-to-classify thymic epithelial tumours, and indicate different mechanisms of tumour angiogenesis and functional differences of tumour vessels of major thymoma subtypes and TSQCCs.

Vascular patterns of nonpigmented tumoral skin lesions: confocal perspectives.

BACKGROUND: The characteristic vascular patterns of nonpigmented skin tumors have been established by dermoscopy. Recently, in vivo reflectance confocal microscopy (RCM) has become an established method for the noninvasive examination of skin tumors. OBJECTIVES: Determination of the value of RCM on the vascularity of nonpigmented skin tumors. METHODS: One hundred and twenty two tumoral lesions have been evaluated by RCM in terms of their vascular structures. They were classified in five groups as basal cell carcinoma (BCC), seborrheic keratosis (SK), squamous cell carcinoma (SCC)/keratoacanthoma, actinic keratosis (AK)/Bowen disease and others. Vascular morphologies were investigated as curved linear, straight linear, branching, tubular/canalicular, round and polymorphic vessels in six types. LIMITATIONS: Relatively, small number of patients with some tumor subgroups is limitation. Larger prospective studies are required before firm conclusions can be drawn. RESULTS: Excellent compliance was obtained in interobserver analysis. Branching vessels had a high predictive value for basal cell carcinoma (BCC) with RCM (P < 0.001). Also vascular polymorphism was more frequently (69.4%) seen in malignant nonpigmented tumors (P < 0.05) than benign nonpigmented tumors (30.6%). Furthermore, vessels with opposite flows had high predictive value for malignant tumors (P < 0.05) compared with benign tumors. CONCLUSION: Vascular properties can be evaluated in the diagnosis of nonpigmented tumoral skin lesions via RCM.

Concordance of hypervascular liver nodule characterization between the organ procurement and transplant network and liver imaging reporting and data system classifications.

PURPOSE: To determine the rate of agreement between the Organ Procurement and Transplant Network (OPTN) and Liver Imaging Reporting and Data System (LI-RADS) classifications for hypervascular liver nodules at least 1 cm in diameter, and for patient eligibility for hepatocellular/MELD (Model for Endstage Liver Disease) exception points. MATERIALS AND METHODS: This retrospective study was approved by our Institutional Review Board and was compliant with the Health Insurance Portability and Accountability Act. The requirement for informed consent was waived. This study included 200 hypervascular hepatocellular nodules at least 1 cm in diameter on computed tomography (CT) or magnetic resonance imaging (MRI) examinations in 105 patients with chronic liver disease. Three radiologists blinded to clinical data independently evaluated nodule characteristics, including washout, capsule, size, and size on prior examination. Based on those characteristics, nodules were automatically classified as definite hepatocellular carcinoma (HCC) or not definite HCC using both the OPTN and LI-RADS classifications. Using these classifications and the Milan criteria, each examination was determined to be "below transplant criteria," "within transplant criteria," or "beyond transplant criteria." Agreement was assessed between readers and classification systems, using Fleiss' kappa, intraclass correlation coefficients (ICCs), and simple proportions. RESULTS: Interreader agreement was moderate for nodule features (κ = 0.59-0.69) and nodule classification (0.66-0.69). The two systems were in nearly complete agreement on nodule category assignment (98.7% [592/600]) and patient eligibility for transplant exemption priority (99.4% [313/315]). A few discrepancies occurred for the nodule feature of growth (1.3% [8/600]) and for nodule category assignment (1.3% [8/600]). CONCLUSION: Agreement between the OPTN and LI-RADS classifications is very strong for categorization of hypervascular liver nodules at least 1 cm in diameter, and for patient eligibility for hepatocellular/MELD exception points. Interreader variability is much higher than intersystem variability.

[PI-RADS classification: structured reporting for MRI of the prostate]. / PI-RADS-Klassifikation: Strukturiertes Befundungsschema für die MRT der Prostata.

PURPOSE: To flesh out the ESUR guidelines for the standardized interpretation of multiparametric magnetic resonance imaging (mMRI) for the detection of prostate cancer and to present a graphic reporting scheme for improved communication of findings to urologists. MATERIALS AND METHODS: The ESUR has recently published a structured reporting system for mMRI of the prostate (PI-RADS). This system involves the use of 5-point Likert scales for grading the findings obtained with different MRI techniques. The mMRI includes T2-weighted MRI, diffusion-weighted imaging, dynamic contrast-enhanced MRI, and MR spectroscopy. In a first step, the fundamentals of technical implementation were determined by consensus, taking into account in particular the German-speaking community. Then, representative images were selected by consensus on the basis of examinations of the three institutions. In addition, scoring intervals for an aggregated PI-RADS score were determined in consensus. RESULTS: The multiparametric methods were discussed critically with regard to implementation and the current status. Criteria used for grading mMRI findings with the PI-RADS classification were concretized by succinct examples. Using the consensus table for aggregated scoring in a clinical setting, a diagnosis of suspected prostate cancer should be made if the PI-RADS score is 4 or higher (≥ 10 points if 3 techniques are used or ≥ 13 points if 4 techniques are used). Finally, a graphic scheme was developed for communicating mMRI prostate findings. CONCLUSION: Structured reporting according to the ESUR guidelines contributes to quality assurance by standardizing prostate mMRI, and it facilities the communication of findings to urologists.

Computer-assisted and fractal-based morphometric assessment of microvascularity in histological specimens of gliomas.

Fractal analysis is widely applied to investigate the vascular system in physiological as well as pathological states. We propose and examine a computer-aided and fractal-based image analysis technique to quantify the microvascularity in histological specimens of WHO grade II and III gliomas. A computer-aided and fractal-based analysis was used to describe the microvessels and to quantify their geometrical complexity in histological specimens collected from 17 patients. The statistical analysis showed that the fractal-based indexes are the most discriminant parameters to describe the microvessels. The computer-aided quantitative analysis also showed that grade III gliomas are generally more vascularized than grade II gliomas. The fractal parameters are reliable quantitative indicators of the neoplastic microvasculature, making them potential surrogate biomarkers. The qualitative evaluation currently performed by the neuropathologist can be combined with the computer-assisted quantitative analysis of the microvascularity to improve the diagnosis and optimize the treatment of patients with brain cancer.

[The Thyroid Imaging Reporting and Data System (TIRADS) for ultrasound of the thyroid]. / Le système TIRADS en échographie thyroïdienne.

PURPOSE: To develop a standardized system for analyzing and reporting thyroid ultrasound, or Thyroid Imaging Reporting and Data System (TIRADS), in order to improve the management of patients with thyroid nodules. MATERIALS AND METHODS: An atlas of imaging features, a standardized vocabulary, a report template and TIRADS categories 0 to 6 were defined, based on the BI-RADS system used for mammography. The diagnostic efficacy of the system was tested by a retrospective review of 500 nodules (159 cancers and 341 benign nodules) and comparing US imaging features to histological findings. RESULTS: Five signs allow accurate detection of 90% of thyroid cancers. The score of a nodule can be easily defined by using an organigram. Sensitivity, specificity and odds-ratio of the score were respectively 95%, 68% and 40. CONCLUSION: TIRADS is a quality assurance tool for thyroid ultrasound. It contains an image atlas, a standardized report and categories to evaluate thyroid nodules to easily assess the risk of individual nodules being cancers and facilitate patient management.

Angiogenesis and clinicopathologic characteristics in different hepatocellular carcinoma subtypes defined by EpCAM and α-fetoprotein expression status.

Recently, two hepatic lineage markers epithelial cell adhesion molecule (EpCAM) and α-fetoprotein (AFP) were used to classify hepatocellular carcinoma (HCC) into four subtypes with prognostic implication. In the present study, we further evaluated the clinicopathologic and angiogenic characteristics among these HCC subtypes. EpCAM expression was investigated by immunohistochemistry in 115 HCC primary tumors. Based on EpCAM immunostaining and serum AFP levels, 115 HCC cases were classified into four subtypes: EpCAM+AFP+ (26.1%), EpCAM-AFP+ (20.0%), EpCAM+AFP- (20.8%), and EpCAM-AFP- (33.1%). EpCAM+AFP+ and EpCAM-AFP+ HCC were associated with late TNM stages and high frequencies of venous invasion, whereas EpCAM+AFP- and EpCAM-AFP- subtypes were associated with early TNM stages and low frequencies of venous invasion. Furthermore, EpCAM+AFP+ HCC had a significantly higher microvessel density (MVD) and higher level of VEGF (Vascular epithelial growth factor) expression than the other three subtypes. In conclusion, our study indicated that subtype classification of HCC based on EpCAM and AFP status had clinicopathologic and biologic implications in aggressive phenotype and angiogenesis. We also suggest that the EpCAM+AFP+ HCC patients might be potential therapeutic candidates for anti-angiogenesis therapy.

Association of interferon-gamma, interleukin-10, and tumor necrosis factor-alpha gene polymorphisms with occurrence and severity of Eales' disease.

PURPOSE: Eales' disease (ED) is an idiopathic retinal vasculitis characterized by capillary nonperfusion and neovascularization. Previous reports on ED demonstrated that T-cell-mediated immunoresponse and differential cytokine production in inflammatory and angiogenic stage seem to influence the extent and severity of this disease. Therefore, the purpose of this study is to investigate the influence of cytokine gene polymorphisms on occurrence and severity of ED. METHODS: One hundred twenty-one patients with ED were recruited from an Eastern Indian population and compared with 223 matched healthy control subjects. Genotyping of IFN-γ, IL-10, and TNF-α were performed by amplification refractory mutation system polymerase chain reaction (ARMS-PCR). RESULTS: A statistically significant association was found between the IL-10 -1082AA (P = 0.002), TNF-α -308AA (P = 0.0017) genotypes and the IL-10 ATA haplotype (P = 0.0123) and the occurrence of ED. In addition IL-10 -1082GG (P = 0.0005), TNF-α -308GG (P < 0.0001) genotype were found to be protective against disease occurrence. A synergistically low IL-10/high TNF-α genotype increased the risk of development (P < 0.0001) and the severity (P = 0.019) of ED. CONCLUSIONS: These data suggest that a low IL-10-expressing and high TNF-α-expressing genotype of the host can influence the occurrence and severity of outcome of ED.

Canine classical seminoma: a specific malignant type with human classifications is highly correlated with tumor angiogenesis.

BACKGROUND: Human seminoma is classified as classical seminoma (SE) and spermatocytic seminoma (SS). Human SE is known to be more malignant and metastasizing more frequently than SS. Tumor angiogenesis is highly related with tumor progression and metastasis, with microvessel density (MVD) being an important parameter of metastatic potential. Canine seminoma is not yet well-established as SE or SS type including correlation with angiogenesis. We classified canine SE and SS, and then compared them to tumor associated vessels. METHODS: Twenty-three cases of canine seminomas (2 intratubular, 9 diffuse, and 12 intratubular/diffuse seminomas showing both intratubular and diffuse patterns) were classified as SE or SS by immunohistochemistry (IHC) using monoclonal antibody against PLAP and by PAS stain. The histopathological data were then compared to see if there was a correlation with SE or SS. Angiogenesis of seminomas were evaluated by immunohistochemical assay using polyclonal antibody against Von Willebrand factor (vWF) and by calculating the means of MVD, vessels area and perimeters using computerized image analysis. Statistical Package for Social Sciences (SPSS) program was used for various statistical analyses. RESULTS: The numbers of PLAP+/PAS+ canine SEs were 8/23 (34.8%) and PLAP-/PAS- SSs were 15/23 (61.2%). All SE cases (8/8, 100%) were intratubular/diffuse types. SS types included 2 intratubular (2/15, 13.3%), 9 diffuse (9/15, 60%), and 4 intratubular/diffuse (4/15, 26.7%) types. MVD and vascular parameters in SEs were significantly higher than in SSs, showing the highest value in the intratubular/diffuse type. Seminomas observed with neoplastic cells invasion of vessels presented higher perimeter and area values than seminomas without conformed neoplastic cells invasion. CONCLUSION: In this study, we demonstrated a positive relationship between canine SE and tumor angiogenesis. Furthermore, we also showed that a tumor cells invasion of vessels were a correlated vascular parameter. Although metastasis of canine seminomas has rarely been reported, our results support that canine SE could have high metastatic potential similar to the human counterpart. Further studies are required to clarify the relationship between canine SE and clinical data with metastatic factors.

[Classification of solid soft tissue tumours by ultrasonography]. / Sonografische Klassifikation solider Weichteiltumoren.

PURPOSE: Malignant soft tissue tumours appear infrequently in comparison to benign lesions. Clinical misdiagnosis leads to inadequate or delayed therapy in many cases of soft tissue sarcoma. The present study explores the question if ultrasonography as a widely-used diagnostic tool allows for a discrimination of benign and malignant soft tissue tumours. MATERIALS AND METHODS: In a prospective study over a period of 8 years 224 histologically ascertained solid soft tissue tumours, thereof 120 sarcomas and 27 aggressive benign lesions were investigated by B-mode and colour Doppler sonography. The echotexture was analysed computer-based using the parameters echogenicity, homogeneity and vascularisation in all lesions. RESULTS: Different tumour groups showed typical patterns of echotexture, which enabled a classification using 6 categories, distinguishing homogenous hyperechoic, heavily inhomogeneous and homogenous hypoechoic lesions, each group linked to an elevated or low vascularisation. Implementation of the proposed classification revealed a sensitivity in the detection of soft tissue sarcomas and aggressive benign lesions of 94.4 % with a specificity of 79.7 % and an accuracy of 89.7 %. CONCLUSION: Ultrasonography allows for a determination of the diagnostic and therapeutic procedure in soft tissue tumours. Due to the fact that soft tissue sarcomas present hypervascularised almost exclusively, predominantly homogenous hypoechoic, rarely homogenous hyperechoic, and aggressive benign tumours present homogenous hypoechoic predominantly, such patterns require a biopsy prior to further surgical therapy. However, in homogenous hyperechoic lesions displaying a low blood flow either a primary resection or a conservative treatment with follow-up examinations can be discussed depending on clinical findings and history of the patient. Although the group of heavily inhomogeneous tumours within our collective consisted of benign lesions exclusively, biopsy should be recommended in theses cases in order to exclude a soft tissue sarcoma.

Molecular classification and novel targets in hepatocellular carcinoma: recent advancements.

Hepatocellular carcinoma (HCC) is one of most lethal cancers worldwide. Strategic decisions for the advancement of molecular therapies in this neoplasm require a clear understanding of its molecular classification. Studies indicate aberrant activation of signaling pathways involved in cellular proliferation (e.g., epidermal growth factor and RAS/mitogen-activated protein kinase pathways), survival (e.g., Akt/mechanistic target of rapamycin pathway), differentiation (e.g., Wnt and Hedgehog pathways), and angiogenesis (e.g., vascular endothelial growth factor and platelet-derived growth factor), which is heterogeneously presented in each tumor. Integrative analysis of accumulated genomic datasets has revealed a global scheme of molecular classification of HCC tumors observed across diverse etiologic factors and geographic locations. Such a framework will allow systematic understanding of the frequently co-occurring molecular aberrations to design treatment strategy for each specific subclass of tumors. Accompanied by a growing number of clinical trials of molecular targeted drugs, diagnostic and prognostic biomarker development will be facilitated with special attention on study design and with new assay technologies specialized for archived fixed tissues. A new class of genomic information, microRNA dysregulation and epigenetic alterations, will provide insight for more precise understanding of disease mechanism and expand the opportunity of biomarker/therapeutic target discovery. These efforts will eventually enable personalized management of HCC.

Histological classification of chorionic villous vascularization in early pregnancy.

BACKGROUND: The objective of the study was to assess the reproducibility of a new classification for early pregnancy chorionic villous vascularization (Grade: I, normal; IIA, mild hypoplasia; IIB, severe hypoplasia and III, avascular) for routine microscopic examination in daily clinical practice. METHODS: In this observational study, four observers scored first trimester chorionic villous vascularization. Scoring was performed in microscopic slides of chorionic tissue obtained by D&C in 30 patients with early pregnancy loss due to empty sac (n = 10), fetal death (n = 10) and termination of pregnancy (n = 10) using the new classification. Ultrasonographic measurement of trophoblastic thickness (TT) at the implantation site was available in all patients and in a reference group of 100 ongoing singleton pregnancies. The vascularization score could therefore be related to the TT. RESULTS: The new classification resulted in a good-to-excellent agreement in histological scoring (0.73-0.90) between investigators (kappa 0.64-0.86). TT was not related to either vascularization or pregnancy outcome and only partly to hydropic degeneration. CONCLUSION: The vascularization scoring system is a simple, valid and effective method for assessment of chorionic villous vascularization. It is helpful in understanding the underlying cause of pregnancy loss, as the classification can distinguish between normal and abnormal embryonic development. We did not find either a relation between TT and pregnancy outcome or between TT and vascularization.

Characterization of a first-pass gradient-echo spin-echo method to predict brain tumor grade and angiogenesis.

BACKGROUND AND PURPOSE: No widespread clinical method provides specific information about the angiogenic characteristics of gliomas. We characterized blood volume and vascular morphologic parameters from combined gradient-echo (GE) and spin-echo (SE) MR imaging and assessed their relationship to tumor grade, a known correlate of glioma angiogenesis. METHODS: Simultaneous GE and SE echo-planar imaging was performed with bolus gadolinium administration (0.20-0.25 mmol/kg) in 73 patients with glioma. To diminish possible T1 changes due to contrast agent extravasation, a preload (0.05-0.10 mmol/kg) was administered before the study, and a postprocessing correction algorithm was applied. Image maps of total (GE) and microvascular (SE) relative cerebral blood volume (rCBV) and the mean vessel diameter (mVD) calculated from the ratio of GE and SE relaxation rate changes (DeltaR2*/DeltaR2) were compared with tumor grade. A nonparametric K nearest-neighbor decision rule was applied to determine if the combined data could be used to distinguish low-grade (I-II) from high-grade (III-IV) tumors on a per-patient basis. RESULTS: For whole tumors, significant correlations were found between GE rCBV and grade (P < .0001) and between mVD and grade (P = .0001) but not between SE rCBV and grade (P = .08). For areas of highest SE rCBV (microvascular hotspots), SE rCBV and tumor grade were significantly correlated (P = .0007). In terms of differentiation, 69% of low-grade tumors and 96% of high-grade tumors were correctly classified. CONCLUSION: Combined GE and SE MR imaging provides information consistent with neoplastic angiogenesis, demonstrating its potential to aid in optimizing treatments, categorizing lesions, and influencing patient care.

Evaluation and clinical correlations of bone marrow angiogenesis in myelofibrosis with myeloid metaplasia.

Recent observations have underscored the biologic relevance of intratumoral angiogenesis and its potential impact on prognosis. Increased bone marrow angiogenesis has been demonstrated in a variety of hematologic disorders, including multiple myeloma. The extent and prognostic significance of bone marrow angiogenesis in 114 patients with myelofibrosis with myeloid metaplasia (MMM) was investigated. A control group of 44 patients without bone marrow disease, 15 patients with polycythemia vera, and 17 patients with essential thrombocythemia was also studied. Bone marrow microvessel density was assessed by a semiquantitative method, visual microvessel grading, and 2 separate quantitative methods, visual count and computerized image analysis. Angiogenesis estimation by all 3 methods was highly comparable. On visual microvessel grading, a grade 3 or 4 increase in bone marrow angiogenesis was demonstrated in 70% of patients with MMM, 33% of patients with polycythemia vera, 12% of patients with essential thrombocythemia, and 0% of normal controls. In a multivariate analysis, increased angiogenesis in MMM correlated significantly with increased spleen size and was found to be a significant and independent risk factor for overall survival. Increases in marrow angiogenesis correlated with hypercellularity and megakaryocyte clumping. In contrast, these 2 features were inversely proportional to reticulin fibrosis, whereas increases in marrow angiogenesis were independent of reticulin fibrosis. These preliminary findings suggest that neo-angiogenesis is an integral component of the bone marrow stromal reaction in MMM and may provide useful prognostic information and a rationale for the therapeutic investigation of anti-angiogenic agents.

Vascular grading of angiogenesis: prognostic significance in breast cancer.

The study aimed to evaluate the prognostic value of angiogenesis by vascular grading of primary breast tumours, and to evaluate the prognostic impact of adding the vascular grade to the Nottingham Prognostic Index (NPI). The investigation included 836 patients. The median follow-up time was 11 years and 4 months. The microvessels were immunohistochemically stained by antibodies against CD34. Angiogenesis was graded semiquantitatively by subjective scoring into three groups according to the expected number of microvessels in the most vascular tumour area. The vascular grading between observers was moderately reproduced (kappa = 0.59). Vascular grade was significantly associated with axillary node involvement, tumour size, malignancy grade, oestrogen receptor status and histological type. In univariate analyses vascular grade significantly predicted recurrence free survival and overall survival for all patients (P < 0.0001), node-negative patients (P < 0.0001) and node-positive patients (P < 0.0001). Cox multivariate regression analysis showed that vascular grading contributed with independent prognostic value in all patients (P < 0.0001). A prognostic index including the vascular grade had clinical impact for 24% of the patients, who had a shift in prognostic group, as compared to NPI, and implied a better prognostic dissemination. We concluded that the angiogenesis determined by vascular grading has independent prognostic value of clinical relevance for patients with breast cancer.