Factors Associated With a Patient's Decision to Select a Cost-effective vs the Most Effective Therapy for Their Own Eye Disease.

Importance: Ten percent of the Medicare Part B budget is spent on aflibercept, used to treat a myriad of ocular neovascular diseases. A substantial portion of these costs can be attributed to a few hundred ophthalmologists, raising concerns regarding the influence of pharmaceutical companies on the choice of medication by a relatively small group of clinicians. One approach to protect patients' health care interests is to include them in deliberations on the choice of therapy for their eye disease. Objective: To examine factors associated with patients' choice between an effective and less expensive off-label drug or a more effective, but also more expensive, US Food and Drug Administration (FDA)-approved drug. Design, Setting, and Participants: This retrospective cohort analysis used data from the satellite office of a tertiary referral center from August 2, 2013, to April 9, 2018. Insured patients initiating treatment with anti-vascular endothelial growth factor were included in the analysis. Data were analyzed from March 26, 2018, to June 10, 2020. Interventions: Patients were asked to choose between bevacizumab (approximately $100 per dose), a chemotherapy that is effective, but not FDA approved, for the treatment of ocular vascular disease, or aflibercept (approximately $2000 per dose), an FDA-approved drug for ocular vascular disease that may be more effective than bevacizumab in some patients. Independent of this choice, patients were separately asked by a study coordinator to participate in an invasive clinical study for which they would not be compensated, there was a small risk for an adverse event, and they would not personally benefit from participating (a surrogate marker for altruism). Main Outcomes and Measures: Factors associated with patients' choice of medication, including age, sex, ocular disease, race, and participation in an invasive clinical study. Results: A total of 189 patients were included in the analysis (106 women [56%]; mean [SEM] age, 74.6 [0.8] years). Despite being told that it may not be as effective as aflibercept, 100 patients (53%) selected bevacizumab for their own eye care. An act of altruism (ie, participation in an invasive clinical study) when the patient was making a choice between the 2 drugs was associated with a patient's choice of bevacizumab (odds ratio [OR], 7.03; 95% CI, 2.27-21.80; P < .001); the OR for selecting bevacizumab for patients who never agreed to participate in the clinical study was 0.45 (95% CI, 0.25-0.83; P = .001). Age (OR, 1.00; 95% CI, 0.97-1.03; P = .86), race (OR, 0.70; 95% CI, 0.41-1.22; P = .21), sex (OR, 0.72; 95% CI, 0.39-1.35; P = .31), presence of diabetes (OR, 1.52; 95% CI, 0.59-3.93; P = .39), and type of eye disease (OR, 0.56; 95% CI, 0.30-1.04; P = .07) were not associated with choice of therapy. Conclusions and Relevance: These findings suggest that clinicians must consider the ethical implications of the influence of altruism when patients participate in the decision between cost-effective vs the most effective medicines for their own health care.

Dose-response assessment by quantitative MRI in a phase 1 clinical study of the anti-cancer vascular disrupting agent crolibulin.

The vascular disrupting agent crolibulin binds to the colchicine binding site and produces anti-vascular and apoptotic effects. In a multisite phase 1 clinical study of crolibulin (NCT00423410), we measured treatment-induced changes in tumor perfusion and water diffusivity (ADC) using dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI), and computed correlates of crolibulin pharmacokinetics. 11 subjects with advanced solid tumors were imaged by MRI at baseline and 2-3 days post-crolibulin (13-24 mg/m2). ADC maps were computed from DW-MRI. Pre-contrast T1 maps were computed, co-registered with the DCE-MRI series, and maps of area-under-the-gadolinium-concentration-curve-at-90 s (AUC90s) and the Extended Tofts Model parameters ktrans, ve, and vp were calculated. There was a strong correlation between higher plasma drug [Formula: see text] and a linear combination of (1) reduction in tumor fraction with [Formula: see text] mM s, and, (2) increase in tumor fraction with [Formula: see text]. A higher plasma drug AUC was correlated with a linear combination of (1) increase in tumor fraction with [Formula: see text], and, (2) increase in tumor fraction with [Formula: see text]. These findings are suggestive of cell swelling and decreased tumor perfusion 2-3 days post-treatment with crolibulin. The multivariable linear regression models reported here can inform crolibulin dosing in future clinical studies of crolibulin combined with cytotoxic or immune-oncology agents.

Bevacizumab for the treatment of non-small cell lung cancer patients with synchronous brain metastases.

Bevacizumab is FDA-approved in the treatment of primary brain tumors, but its efficacy in patients with brain metastases could be better-studied. This study examines a population of non-small cell lung cancer (NSCLC) patients with synchronous brain metastases to identify predictors of the decision to use bevacizumab and survival following bevacizumab treatment. Primary cancer registry data were used to determine which NSCLC patients diagnosed in the years 2010 through 2012 had synchronous brain metastases at the time of diagnosis, and Medicare claims used to identify a population of patients treated with bevacizumab. Record of bevacizumab treatment was found for 81 and 666 patients with and without brain metastases, respectively. After adjusting for clinical and demographic characteristics, bevacizumab was associated with 0.88 times the hazard of mortality in the elderly NSCLC population (95% CI: 0.81-0.96, p: 0.003) and a corresponding hazard ratio of 0.75 in the population of elderly NSCLC patients with synchronous brain metastases (95% CI: 0.59-0.96, p: 0.020). Bevacizumab may benefit NSCLC patients with synchronous brain metastases more than it does patients without intracranial disease, possibly as a result of its multiple potential mechanisms of action simultaneously inhibiting angiogenesis and minimizing vasogenic edema.

Assessment of the Antitumor Potentiality of Newly Designed Steroid Derivatives: Pre-Clinical Study.

Cancer is recognized as one of the most prevalent contributors to mortality in several nations and it remains one of the common health issues globally. In particular, hepatocellular carcinoma (HCC) has become a public health problem along with the increase of hepatitis B (HBV) and hepatitis C (HCV) virus infections. Based on this fact, our study goaled to synthesize newly hybrid drugs containing heterocyclic rings incorporated to steroid moiety and to examine the potential antitumor activity of the newly designed heterosteroid derivatives against HCC induced in animal model. Several heterocyclic steroids were synthesized 2-7 and confirmed via the analytical and spectral data (IR, 1H NMR13C NMR and Mass spectroscopy). Compounds 3, 4, and 5 were chosen to be investigated as anticancer agents in HCC rat model by means of validated biomarkers (alfa -fetoprotein, endoglin, lipocali-2 and heat shock protein-70). Following administration of compounds 3, 4 or 5, availability of the active tumor marker molecules was significantly dropped and a substantial decrease of the angiogenic and inflammatory mediators was also evident. These findings were supported by the histological examination of liver tissue. Taken together, this study indicates the potential anticancer activity of the newly synthesized heterosteroid derivatives against HCC in vivo. The antitumor activity of these compounds was likely attributable to modulating some signal transduction pathways involved in tumorigenesis, angiogenesis and inflammation.

Reinforcement learning-based control of tumor growth under anti-angiogenic therapy.

BACKGROUND AND OBJECTIVES: In recent decades, cancer has become one of the most fatal and destructive diseases which is threatening humans life. Accordingly, different types of cancer treatment are studied with the main aim to have the best treatment with minimum side effects. Anti-angiogenic is a molecular targeted therapy which can be coupled with chemotherapy and radiotherapy. Although this method does not eliminate the whole tumor, but it can keep the tumor size in a given state by preventing the formation of new blood vessels. In this paper, a novel model-free method based on reinforcement learning (RL) framework is used to design a closed-loop control of anti-angiogenic drug dosing administration. METHODS: A Q-learning algorithm is developed for the drug dosing closed-loop control. This controller is designed using two different values of the maximum drug dosage to reduce the tumor volume up to a desired value. The mathematical model of tumor growth under anti-angiogenic inhibitor is used to simulate a real patient. RESULTS: The effectiveness of the proposed method is shown through in silico simulation and its robustness to patient parameters variation is demonstrated. It is demonstrated that the tumor reaches its minimal volume in 84 days with maximum drug inlet of 30 mg/kg/day. Also, it is shown that the designed controller is robust with respect to  ±â€¯20% of tumor growth parameters changes. CONCLUSION: The proposed closed-loop reinforcement learning-based controller for cancer treatment using anti-angiogenic inhibitor provides an effective and novel result such that with a clinically valid and safe dosage of drug, the volume reduces up to 1mm3 in a reasonable short period compared to the literature.

Pharmacokinetic Modeling of Targeted Ultrasound Contrast Agents for Quantitative Assessment of Anti-Angiogenic Therapy: a Longitudinal Case-Control Study in Colon Cancer.

PURPOSE: To evaluate quantitative and semi-quantitative ultrasound molecular imaging (USMI) for antiangiogenic therapy monitoring in human colon cancer xenografts in mice. PROCEDURES: Colon cancer was established in 17 mice by injection of LS174T (Nr = 9) or CT26 (Nn = 8) cancer cells to simulate clinical responders and non-responders, respectively. Antiangiogenic treatment (bevacizumab; Nrt = Nnt = 5) or control treatment (saline; Nrc = 4, Nnc = 3) was administered at days 0, 3, and 7. Three-dimensional USMI was performed by injection at days 0, 1, 3, 7, and 10 of microbubbles targeted to the vascular endothelial growth factor receptor 2 (VEGFR2). Microbubble binding rate (kb), estimated by first-pass binding model fitting, and semi-quantitative parameters late enhancement (LE) and differential targeted enhancement (dTE) were compared at each day to evaluate their ability to assess and predict the response to therapy. Correlation analysis with the ex-vivo immunohistological quantification of VEGFR2 expression and the percentage blood vessel area was also performed. RESULTS: Significant changes in the USMI parameters during treatment were observed only in the responders treated with bevacizumab (p-value < 0.05). Prediction of the response to therapy as early as 1 day after treatment was achieved by the quantitative parameter kb (p-value < 0.01), earlier than possible by tumor volume quantification. USMI parameters could significantly distinguish between clinical responders and non-responders (p-value << 0.01) and correlated well with the ex-vivo quantification of VEGFR2 expression and the percentage blood vessels area (p-value << 0.01). CONCLUSION: USMI (semi)quantitative parameters provide earlier assessment of the response to therapy compared to tumor volume, permit early prediction of non-responders, and correlate well with ex-vivo angiogenesis biomarkers.

Spatiotemporal heterogeneity of tumor vasculature during tumor growth and antiangiogenic treatment: MRI assessment using permeability and blood volume parameters.

Tumor heterogeneity is an important concept when assessing intratumoral variety in vascular phenotypes and responses to antiangiogenic treatment. This study explored spatiotemporal heterogeneity of vascular alterations in C6 glioma mice during tumor growth and antiangiogenic treatment on serial MR examinations (days 0, 4, and 7 from initiation of vehicle or multireceptor tyrosine kinase inhibitor administration). Transvascular permeability (TP) was quantified on dynamic-contrast-enhanced MRI (DCE-MRI) using extravascular extracellular agent (Gd-DOTA); blood volume (BV) was estimated using intravascular T2 agent (SPION). With regard to region-dependent variability in vascular phenotypes, the control group demonstrated higher TP in the tumor center than in the periphery, and greater BV in the tumor periphery than in the center. This distribution pattern became more apparent with tumor growth. Antiangiogenic treatment effect was regionally heterogeneous: in the tumor center, treatment significantly suppressed the increase in TP and decrease in BV (ie, typical temporal change in the control group); in the tumor periphery, treatment-induced vascular alterations were insignificant and BV remained high. On histopathological examination, the control group showed greater CD31, VEGFR2, Ki67, and NG2 expression in the tumor periphery than in the center. After treatment, CD31 and Ki67 expression was significantly suppressed only in the tumor center, whereas VEGFR2 and α-caspase 3 expression was decreased and NG2 expression was increased in the entire tumor. These results demonstrate that MRI can reliably depict spatial heterogeneity in tumor vascular phenotypes and antiangiogenic treatment effects. Preserved angiogenic activity (high BV on MRI and high CD31) and proliferation (high Ki67) in the tumor periphery after treatment may provide insights into the mechanism of tumor resistance to antiangiogenic treatment.

Assessment of the risk of antiangiogenic agents before and after surgery.

Angiogenesis plays a critical role in the growth, progression, and metastasis of numerous solid tumor types, and thus, antiangiogenic agents have been studied for many years as potential therapeutic agents. Many different antiangiogenic agents, including monoclonal antibodies and multi-targeted tyrosine kinase inhibitors (TKIs), have been approved for various oncology indications, and promising clinical activity has been demonstrated. However, some of these agents have also been associated with serious safety concerns. Because angiogenesis is an important step in the wound healing process, agents targeting the angiogenesis pathway may interfere with wound healing, thus increasing the risk of surgical wound complications, such as dehiscence, surgical site bleeding, and wound infection. Nevertheless, antiangiogenic agents can be safely used in the perioperative setting if oncologists and surgeons are educated on the biology and pharmacokinetics of these agents. This review discusses the available published literature regarding surgical complications associated with the use of antiangiogenic agents and provides updated clinical recommendations on the optimal timing between surgery and antiangiogenic therapy. Due to the paucity of data surrounding this topic, current and future clinical trials need to evaluate prospectively the potential risks for surgical complications associated with antiangiogenic therapies to establish specific guidelines for their safe and effective use within the surgical oncology community.

Perfusion Computer Tomography Assessment of the Effect of Angiotensin II On Blood Flow Distribution in Rabbits with Intrarenal VX2 Tumors.

BACKGROUND/AIMS: Unlike other organs, which only have one set of capillary network, the renal microvasculature consists of two sets of capillary network series connected by efferent arterioles. Angiotensin II constricts the efferent glomerular artery. Hence, renal tumor blood flow (BF) distribution may be different from tumors in other organs. This study aims to investigate the effects of angiotensin II on the hemodynamics of intrarenal VX2 tumors using perfusion computed tomography(CT). METHODS: Twenty-four male New Zealand white rabbits were randomly divided into three groups: groups A (blank controls), group B (negative controls), and group C (angiotensin II-treated animals). Group B and C were established to the model of intrarenal VX2 tumors. Furthermore, perfusion CT of the kidney was performed in each group. Prior to perfusion CT scan in group C, the mean arterial blood was elevated to 150-160 mmHg by angiotensin II. The BF, blood volume (BV), mean transit time (MTT), capillary permeability-surface area product (PS), and relative permeability-surface area product (RPS) of tumors and renal tissues were calculated. RESULTS: Compared with normal renal cortex tissues in group A, the BF, BV and PS values of tumors in group B were significantly lower, MTT was prolonged and RPS increased. Compared with group B, only the RPS of these tumors increased from 83.23 ± 29.17% to 120.94 ± 31.84% by angiotensin II infusion. Angiotensin II significantly increased the RPS value of the renal cortex distant from the tumor (CDT) and the right renal cortex (RRC). CONCLUSIONS: Perfusion CT can accurately observe the influence of angiotensin II on normal and tumor BF in kidneys. This clarifies the effect of angiotensin II on intrarenal tumor hemodynamics.

Assessment of Heparanase-Mediated Angiogenesis Using Microvascular Endothelial Cells: Identification of λ-Carrageenan Derivative as a Potent Anti Angiogenic Agent.

Heparanase is overexpressed by tumor cells and degrades the extracellular matrix proteoglycans through cleavage of heparan sulfates (HS), allowing pro-angiogenic factor release and thus playing a key role in tumor angiogenesis and metastasis. Here we propose new HS analogs as potent heparanase inhibitors: Heparin as a positive control, Dextran Sulfate, λ-Carrageenan, and modified forms of them obtained by depolymerization associated to glycol splitting (RD-GS). After heparanase activity assessment, 11 kDa RD-GS-λ-Carrageenan emerged as the most effective heparanase inhibitor with an IC50 of 7.32 ng/mL compared to 10.7 ng/mL for the 16 kDa unfractionated heparin. The fractionated polysaccharides were then tested in a heparanase-rich medium-based in vitro model, mimicking tumor microenvironment, to determine their effect on microvascular endothelial cells (HSkMEC) angiogenesis. As a preliminary study, we identified that under hypoxic and nutrient poor conditions, MCF-7 cancer cells released much more mature heparanase in their supernatant than in normal conditions. Then a MatrigelTM assay using HSkMEC cultured under hypoxic conditions in the presence (or not) of this heparanase-rich supernatant was realized. Adding heparanase-rich media strongly enhanced angiogenic network formation with a production of twice more pseudo-vessels than with the control. When sulfated polysaccharides were tested in this angiogenesis assay, RD-GS-λ-Carrageenan was identified as a promising anti-angiogenic agent.

Anti-angiogenic treatment in breast cancer: Facts, successes, failures and future perspectives.

Angiogenesis is one of the hallmarks of cancer and a crucial requisite in the development of tumors. Interrupting this process by blocking the vascular endothelial growth factor (VEGF) with the monoclonal antibody bevacizumab has been considered a possible breakthrough in the treatment of various types of cancer, especially for advanced disease. However in breast cancer, studies have shown ambivalent results causing debate about the value of this drug. In this article, we review the evidence for anti-angiogenic treatment options for breast cancer, as well as discuss the possible factors limiting the effectiveness of anti-angiogenic agents and offer a recommendation regarding the future research on these therapies for the treatment of breast cancer.

Assessment of tumor oxygenation and its impact on treatment response in bevacizumab-treated recurrent glioblastoma.

Antiantiogenic therapy with bevacizumab in recurrent glioblastoma is currently understood to both reduce microvascular density and to prune abnormal tumor microvessels. Microvascular pruning and the resulting vascular normalization are hypothesized to reduce tumor hypoxia and increase supply of systemic therapy to the tumor; however, the underlying pathophysiological changes and their timing after treatment initiation remain controversial. Here, we use a novel dynamic susceptibility contrast MRI-based method, which allows simultaneous assessment of tumor net oxygenation changes reflected by the tumor metabolic rate of oxygen and vascular normalization represented by the capillary transit time heterogeneity. We find that capillary transit time heterogeneity, and hence the oxygen extraction fraction combine with the tumoral blood flow (cerebral blood flow) in such a way that the overall tumor oxygenation appears to be worsened despite vascular normalization. Accordingly, hazards for both progression and death are found elevated in patients with a greater reduction of tumor metabolic rate of oxygen in response to bevacizumab and patients with higher intratumoral tumor metabolic rate of oxygen at baseline. This implies that tumors with a higher degree of angiogenesis prior to bevacizumab-treatment retain a higher level of angiogenesis during therapy despite a greater antiangiogenic effect of bevacizumab, hinting at evasive mechanisms limiting bevacizumab efficacy in that a reversal of their biological behavior and relative prognosis does not occur.

Intra-Animal Comparison between Three-dimensional Molecularly Targeted US and Three-dimensional Dynamic Contrast-enhanced US for Early Antiangiogenic Treatment Assessment in Colon Cancer.

Purpose To perform an intra-animal comparison between (a) three-dimensional (3D) molecularly targeted ultrasonography (US) by using clinical-grade vascular endothelial growth factor receptor 2 (VEGFR2)-targeted microbubbles and (b) 3D dynamic contrast material-enhanced (DCE) US by using nontargeted microbubbles for assessment of antiangiogenic treatment effects in a murine model of human colon cancer. Materials and Methods Twenty-three mice with human colon cancer xenografts were randomized to receive either single-dose antiangiogenic treatment (bevacizumab, n = 14) or control treatment (saline, n = 9). At baseline and 24 hours after treatment, animals were imaged with a clinical US system equipped with a clinical matrix array transducer by using the following techniques: (a) molecularly targeted US with VEGFR2-targeted microbubbles, (b) bolus DCE US with nontargeted microbubbles, and (c) destruction-replenishment DCE US with nontargeted microbubbles. VEGFR2-targeted US signal, peak enhancement, area under the time-intensity curve, time to peak, relative blood volume (rBV), relative blood flow, and blood flow velocity were quantified. VEGFR2 expression and percentage area of blood vessels were assessed ex vivo with quantitative immunofluorescence and correlated with corresponding in vivo US parameters. Statistical analysis was performed with Wilcoxon signed rank tests and rank sum tests, as well as Pearson correlation analysis. Results Molecularly targeted US signal with VEGFR2-targeted microbubbles, peak enhancement, and rBV significantly decreased (P ≤ .03) after a single antiangiogenic treatment compared with those in the control group; similarly, ex vivo VEGFR2 expression (P = .03) and percentage area of blood vessels (P = .03) significantly decreased after antiangiogenic treatment. Three-dimensional molecularly targeted US signal correlated well with VEGFR2 expression (r = 0.86, P = .001), and rBV (r = 0.71, P = .01) and relative blood flow (r = 0.78, P = .005) correlated well with percentage area of blood vessels, while other US perfusion parameters did not. Conclusion Three-dimensional molecularly targeted US and destruction-replenishment 3D DCE US provide complementary molecular and functional in vivo imaging information on antiangiogenic treatment effects in human colon cancer xenografts compared with ex vivo reference standards. © RSNA, 2016 Online supplemental material is available for this article.

[Tyrosine kinase inhibiting the VEGF pathway and elderly people: Tolerance, pre-treatment assessment and side effects management]. / Inhibiteurs de tyrosine kinase ciblant l'angiogenèse et sujets âgés : tolérance, évaluation pré-thérapeutique et gestion des effets indésirables.

Angiogenesis inhibition is a major antitumor strategy that has emerged during the last decade. Oral tyrosine kinase inhibitors (TKI) targeting the VEGF receptor, including sunitinib, sorafenib, axitinib, regorafenib, pazopanib, and vandetanib reduce tumor growth and metastasis. These agents are approved for the treatment of metastatic diseases in first or second-line. They display a narrow therapeutic index. However, data in the elderly and/or in patients with multiple illnesses remain scarce. This population is classically excluded from clinical trials. The aim of this review is to provide an overview of existing literature regarding antiangiogenic TKI tolerance in the elderly (>70 years old). We also highlight key points of the pre-therapeutic evaluation and summarize the management of common toxicities.

Preclinical Assessment of the Efficacy of Anti-Angiogenic Therapies in Hepatocellular Carcinoma.

Diffuse hepatocellular carcinoma (HCC) is a complex affliction in which comorbidities can bias global outcome of cancer therapy. Better methods are thus warranted to directly assess effects of therapy on tumor angiogenesis and growth. As tumor angiogenesis is invariably associated with changes in local blood flow, we assessed the utility of ultrasound imaging in evaluation of the efficacy of anti-angiogenic therapy in a spontaneous transgenic mouse model of HCC. Blood flow velocities were measured monthly in the celiac trunk before and after administration of sorafenib or bevacizumab at doses corresponding to those currently used in clinical practice. Concordant with clinical experience, sorafenib, but not bevacizumab, reduced microvascular density and suppressed tumor growth relative to controls. Evolution of blood flow velocities correlated with microvascular density and with the evolution of tumor size. Ultrasound imaging thus provides a useful non-invasive tool for preclinical evaluation of new anti-angiogenic therapies for HCC.

Hepatocellular carcinoma: Where there is unmet need.

Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor most commonly associated with underlying chronic liver disease, especially hepatitis. It is a growing problem in the United States and worldwide. There are two potential ways to prevent HCC. Primary prevention which is based on vaccination or secondary prevention involving agents that slow down carcinogenesis. Several pathways have been thought to play a role in the development of HCC; specifically, those involving vascular endothelial growth factor (VEGF)-mediated angiogenesis, WNT, phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and c-MET. Currently, there are only a limited number of drugs which have been proven as effective treatment options for HCC and several clinical trials are testing drugs which target aberrations in the pathways mentioned above. In this review, we discuss currently approved therapies, monotherapies and combination therapy for the treatment of HCC.

Contrast-enhanced ultrasound with perflubutane in the assessment of anti-angiogenic effects: early prediction of the anticancer activity of bevacizumab in a mouse xenografted model.

To investigate the feasibility of contrast-enhanced ultrasound (CEUS) with perflubutane for evaluating anti-angiogenic effects, we assessed the contrast enhancement of mice xenograft treated with bevacizumab. SJSA-1 implanted mice were imaged before and 2, 6, 9 and 13 d after initiation of bevacizumab or saline treatment. Intra-tumoral perfusion areas were quantified by binarizing the ultrasound images and the micro-vessel density was observed by CD31 immunohistochemistry. As a result, the perfusion area and its ratio in the tumor were smaller in the bevacizumab group than the control group at 9 and 13 d, although tumor size was not significantly different. CD31-positive areas were smaller in the bevacizumab group than the control group and correlated well with the ratio of intra-tumoral perfusion areas. CEUS with perflubutane was found to have potential for early prediction of the anti-cancer activity of bevacizumab, and the perfusion area measured by binarized ultrasound images could be used as an indicator.

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.

Development and validation of the functional assessment of cancer therapy-antiangiogenesis subscale.

The Functional Assessment of Cancer Therapy (FACT)-Antiangiogenesis (AntiA) Subscale was developed and validated to enhance treatment decision-making and side effect management for patients receiving anti-angiogenesis therapies. Side effects related to anti-angiogenesis therapies were identified from the literature, clinician input, and patient input. Fifty-nine possible patient expressions of side effects were generated. Patient and clinician ratings of the importance of these expressions led us to develop a 24-item questionnaire with clinical and research potential. To assess the scale's reliability and validity, 167 patients completed the AntiA Subscale, the Functional Assessment of Cancer Therapy-general (FACT-G), the FACT-Kidney Symptom Index (FKSI), the FACIT-Fatigue Subscale, the Global Rating of Change Scale (GRC), and the PROMIS Global Health Scale. Patient responses to the AntiA were analyzed for internal consistency, test-retest reliability, convergent and discriminant validity, and responsiveness to change in clinical status. All tested scales were found to have good internal consistency reliability (Cronbach's alpha 0.70-0.92). Test-retest reliability was also good (0.72-0.88) for total and subscale scores and lower for individual items. The total score, subscale scores, and all single items (except nosebleeds) significantly differentiated between groups defined by level of side effect bother. Evaluation of responsiveness to change in this study was not conclusive, suggesting an area for further research. The AntiA is a reliable and valid measure of side effects from anti-angiogenesis therapy.

Current standards and new concepts in MRI and PET response assessment of antiangiogenic therapies in high-grade glioma patients.

Despite multimodal treatment, the prognosis of high-grade gliomas is grim. As tumor growth is critically dependent on new blood vessel formation, antiangiogenic treatment approaches offer an innovative treatment strategy. Bevacizumab, a humanized monoclonal antibody, has been in the spotlight of antiangiogenic approaches for several years. Currently, MRI including contrast-enhanced T1-weighted and T2/fluid-attenuated inversion recovery (FLAIR) images is routinely used to evaluate antiangiogenic treatment response (Response Assessment in Neuro-Oncology criteria). However, by restoring the blood-brain barrier, bevacizumab may reduce T1 contrast enhancement and T2/FLAIR hyperintensity, thereby obscuring the imaging-based detection of progression. The aim of this review is to highlight the recent role of imaging biomarkers from MR and PET imaging on measurement of disease progression and treatment effectiveness in antiangiogenic therapies. Based on the reviewed studies, multimodal imaging combining standard MRI with new physiological MRI techniques and metabolic PET imaging, in particular amino acid tracers, may have the ability to detect antiangiogenic drug susceptibility or resistance prior to morphological changes. As advances occur in the development of therapies that target specific biochemical or molecular pathways and alter tumor physiology in potentially predictable ways, the validation of physiological and metabolic imaging biomarkers will become increasingly important in the near future.