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  • Introduction Personalized medicine is the major goal of tran

    2019-04-24

    Introduction Personalized medicine is the major goal of translational research in the post-genomic era. Numerous biomarkers have been identified by genomic or proteomic approach that can reclassify the disease fatty acid amide hydrolase and predict clinical outcome. However, to define a specific disease phenotype, it is not necessarily depend on molecular or genomic technologies. Angiogenesis is one of the factors that correlate with the tumor aggressiveness and clinical outcome of patients with malignant solid tumors such as melanoma, prostate cancer, breast cancer, and also in so called “liquid tumors” such as leukemia or lymphomas and multiple myeloma. Microvessel density (MVD) is traditional “gold standard” for quantification of angiogenesis in tumor tissue. MVD increased in patients with acute leukemia with active disease in comparison to healthy controls or patients in remission. It is also known that various parameters such as age, karyotype, and performance status are prognostic factors in acute myeloid leukemia (AML) patients before they receive chemotherapy. However, MVD can be measured only in the limited area of the bone marrow (BM) biopsy specimen; thus, it cannot be used to assess the global or in vivo tumor angiogenesis. None of the functional status of the tumor blood vessel (such as permeability, elimination rate) could be determined by the above-mentioned immunohistochemical methods of MVD. On the other hand, once patients achieve complete remission (CR) after standardized treatment, an ideal prognostic predictor that should be rapidly and easily measurable and reproducible to be adopted into routine clinical practice is still absent. Although the likelihood of relapse declines sharply to less than 10% once CR persists for 3 years, the challenge remains of maintaining remission. The ability to detect patients at high risk of relapse may help in the design of therapeutic strategies to improve the duration of remission. Therefore, an accurate assessment of bone marrow microenvironment in these patients in whom CR is achieved is essential to detect early relapse and evaluate treatment effectiveness. Because the BM microenvironment should change considerably after the initial induction chemotherapy, it is reasonable that the data collected at CR status would be more useful than pretreatment data to predict the survival outcome of these patients. For example, findings in a recent study suggested that neutrophil count and platelet count at the time of CR can serve as independent factors for prediction of relapse-free survival (RFS). Another study described that the cytogenetic analysis performed at the time of CR is a predictor of overall survival (OS), RFS, and relapse rate in AML patients. The aggressiveness of angiogenesis is not only well known in acute leukemia, but also noted in multiple myeloma. Multiple myeloma (MM) is a malignant plasma cell proliferation typically found in BM. Although MM cells (MCs) depend on the BM microenvironment to provide the signals essential for their growth and survival, in a fraction of patients MCs acquire the ability to proliferate in sites outside the BM. Such occurrences appear as extramedullary disease (EMD), indicating that MCs have become independent of the BM microenvironment. The exact mechanism underlying the development of EMD in MM patients is not clear. One hypothesis suggests an alteration in the interaction between MCs and the BM microenvironment. Therefore, the BM “angiogenesis” might also play a major role in not only promoting the growth and survival of MCs but also the disease progression itself. The interaction between MCs and BM endothelial cells upregulates a number of angiogenic cytokines, such as vascular endothelial growth factor or matrix metalloproteinases. Such cytokines further stimulate BM angiogenesis and myeloma progression, as well as possible extramedullary dissemination. New technologies for cancer image with functional assessment are now possible in vivo by Doppler sonography, dynamic contrast-enhanced (DCE)-MRI, DCE computed tomography (CT), and fluorodeoxyglucose-18 positron emission tomography (PET). DCE-MRI is a noninvasive and quantitative method of investigating microvascular structure and function by tracking the pharmacokinetics of injected low-molecular-weight contrast agents as they pass through the tumor vasculature. This technique provides a direct quantification of blood vessel density, vascular flow, and permeability. Up to date, DCE-MRI is one of the most widely used noninvasive methods of measuring the perfusion and permeability of a biological tissue in the body, such as vertebral BM. In addition, functional imaging biomarkers may be used to assess treatment response earlier. This modality is being increasingly used in many oncological studies, including those of patients with hematologic cancers, to characterize tumor angiogenesis and invasiveness and to monitor the treatment response. There have been increasing attempts to use this approach to assess spatial and temporal heterogeneity in tumor angiogenesis and to predict tumor biologic aggressiveness and treatment response in not only solid tumors, but also in leukemia/lymphoma, multiple myeloma, and myelodysplastic syndrome.