The Role of Preoperative CT Perfusion Imaging in Assessing Colorectal Cancer Angiogenesis and its Clinical Value.

Purpose: Angiogenesis, the formation of new blood vessels, plays a crucial role in tumor growth and metastasis. Understanding the vascular characteristics of colorectal cancer through preoperative computed tomography (CT) perfusion parameters can provide valuable insights into the tumor's aggressiveness and potential for spread. Additionally, exploring the correlation between these parameters and serum tumor marker levels may offer a comprehensive perspective on the disease's biological behavior. Methods: In this retrospective study, we investigated 42 colorectal cancer patients. Based on microvascular density (MVD) measured by immunohistochemistry (IHC), participants were categorized into either a high-density group (n = 24) with MVD ≥ 35/field of view or a low-density group (n = 18) with MVD < 35/field of view. Additionally, a control group comprised 25 patients with pathologically confirmed benign colorectal lesions. This study design allowed us to assess the correlation between MVD and colorectal cancer, differentiating between high and low microvascular density groups, while also comparing results to a control group for comprehensive analysis. Results: Colorectal cancer was associated with significantly higher levels of blood volume (BV; high-density group: 7.65±1.36 mL/100g; low-density group: 6.73±1.29 mL/100g), blood flow (BF; high-density group: 67.33±12.16 ml/(100g·min); low-density group: 52.84±11.43 ml/(100g·min)), permeability surface (PS; high-density group: 35.19±6.32 ml/(100g·min); low-density group: 22.27±4.85 ml/(100g·min)), serum glycoprotein antigen 19-9 (CA19-9; high-density group: 45.38±5.41 g/ml); low-density group: 23.43±3.59 g/ml), glycoprotein antigen 125 (CA125; high-density group: 27.56±3.73 g/ml); low-density group: 12.63±2.59 g/ml), and carcinoembryonic antigen (CEA; high-density group: 17.87±3.12 g/ml); low-density group: 8.51±2.87 g/ml) versus benign colorectal lesions, with more significant changes observed in the high-density group versus the low-density group (P ≤ .001). The three groups showed similar mean transit time (MTT). The AUCs under the ROC curves for BV, BF, PS, and TTP were 0.901, 0.898, 0.963, and 0.983, respectively. Pearson correlation analysis showed a positive correlation of patients' serum CA19-9 with BV, BF, and PS., Serum CA125 and CEA were positively correlated with BF and PS, and the above indicators were negatively correlated with TTP. Conclusions: In conclusion, our study highlights the potential of preoperative CT perfusion imaging as a valuable tool for evaluating angiogenesis in colorectal cancer and its correlation with serum tumor markers. The identified associations open avenues for further research to delve into specific aspects of angiogenesis and tumor markers. Future investigations could focus on elucidating the molecular mechanisms underlying the observed correlations, potentially identifying novel therapeutic targets. Additionally, exploring the dynamic changes in angiogenesis and tumor markers during different stages of colorectal cancer progression may provide a more comprehensive understanding. Moreover, assessing the prognostic value of these imaging and biomarker correlations in larger, diverse patient cohorts could enhance their clinical utility. Our findings lay the groundwork for these future research directions, emphasizing the need for continued exploration to advance our knowledge and improve clinical strategies for colorectal cancer management.

Dual-Energy CT Perfusion of Invasive Tumor Front in Non-Small Cell Lung Cancers.

Background Active endothelial cell proliferation occurs at the tumor edge, known as the invading-tumor front. This study focused on perfusion analysis of non-small cell lung cancers. Purpose To analyze dual-phase, dual-energy CT perfusion according to the degree of tumor hypoxia. Materials and Methods This prospective study was performed 2016-2017. A two-phase dual-energy CT protocol was obtained for consecutive participants with operable non-small cell lung cancer. The first pass and delayed iodine concentration within the tumor and normalized iodine uptake, corresponding to the iodine concentration within the tumor normalized to iodine concentration within the aorta, were calculated for the entire tumor and within three peripheral layers automatically segmented (ie, 2-mm-thick concentric subvolumes). The expression of the membranous carbonic anhydrase (mCA) IX, a marker of tumor hypoxia, was assessed in tumor specimens. Comparative analyses according to the histologic subtypes, type of resected tumors, and mCA IX expression were performed. Results There were 33 mCA IX-positive tumors and 16 mCA IX-negative tumors. In the entire tumor, the mean normalized iodine uptake was higher on delayed than on first-pass acquisitions (0.35 ± 0.17 vs 0.13 ± 0.15, respectively; P < .001). A single layer, located at the edge of the tumor, showed higher values of the iodine concentration (median, 0.53 mg/mL vs 0.21 mg/mL, respectively; P = .03) and normalized iodine uptake (0.04 vs 0.02, respectively; P = .03) at first pass in mCA IX-positive versus mCA IX-negative tumors. Within this layer, a functional profile of neovascularization was found in 23 of 33 (70%) of mCA IX-positive tumors, and the median mCA IX score of these tumors was higher than in tumors with a nonfunctional profile of neovascularization (median mCA IX score, 20 vs 2, respectively; P = .03). Conclusion A two-phase dual-energy CT examination depicted higher perfusion between the tumor edge and lung parenchyma in hypoxic tumors. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Murphy and Ryan in this issue.

Ferrite-encapsulated nanoparticles with stable photothermal performance for multimodal imaging-guided atherosclerotic plaque neovascularization therapy.

Pathological angiogenesis is a critical contributor to atherosclerotic plaque rupture. However, there are few effective theranostic strategies to stabilize plaques by suppressing neovascularization. In this study, we fabricated a polymeric nanosystem using 3 nm manganese ferrite (MnFe2O4) and perfluorohexane (PFH) stabilized by polylactic acid-glycolic acid (PLGA) shells and conjugated to the surface of an anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody [ramucirumab (Ram)]. The PFH@PLGA/MnFe2O4-Ram nanoparticles (NPs) were used as atherosclerotic plaque angiogenesis theranostics for multimodal imaging-guided photothermal therapy (PTT). Three-nanometer MnFe2O4 is an excellent magnetic resonance imaging T1 and photoacoustic imaging contrast agent. Upon exposure to near-infrared (NIR) light, MnFe2O4 in the NPs could transform NIR light into thermal energy for the photothermal elimination of plaque angiogenesis. Additionally, optical droplet vaporization of PFH in the NPs triggered by the thermal effect to form gas bubbles enhanced ultrasound imaging. Our in vitro experiments revealed that PFH@PLGA/MnFe2O4-Ram NPs actively accumulated in rabbit aortic endothelial cells, and NP-mediated PTT promoted endothelial cell apoptosis while inhibiting their proliferation, migration, and tubulogenesis. Notably, the PFH@PLGA/MnFe2O4-Ram NPs possessed excellent photostability and biocompatibility. In the rabbit advanced atherosclerotic plaque model, PFH@PLGA/MnFe2O4-Ram NP-guided PTT significantly induced apoptosis of neovascular endothelial cells and improved the hypoxia status in the plaque 3 days after treatment. On day 28, PTT significantly reduced the density of neovessels and subsequently stabilized rabbit plaques by inhibiting plaque hemorrhage and macrophage infiltration. Collectively, these results suggest that PFH@PLGA/MnFe2O4-Ram NP-guided PTT is a safe and effective theranostic strategy for inhibiting atherosclerotic plaque angiogenesis.

The CXCR2/CXCL2 signalling pathway - An alternative therapeutic approach in high-grade glioma.

OBJECTIVE: Besides VEGF, alternative signalling via CXCR2 and its ligands CXCL2/CXCL8 is a crucial part of angiogenesis in glioblastoma. Our aim was to understand the role of CXCR2 for glioma biology and elucidate the therapeutic potential of its specific inhibition. METHODS: GL261 glioma cells were implanted intracranially in syngeneic mice. The 14 or 7 days of local or systemic treatment with CXCR2-antagonist (SB225002) was initiated early on the day of tumour cell implantation or delayed after 14 days of tumour growth. Glioma volume was verified using MRI before and after treatment. Immunofluorescence staining was used to investigate tumour progression, angiogenesis and microglial behaviour. Furthermore, in vitro assays and gene expression analyses of glioma and endothelial cells were performed to validate inhibitor activity. RESULTS: CXCR2-blocking led to significantly reduced glioma volumes of around 50% after early and delayed local treatments. The treated tumours were comparable with controls regarding invasiveness, proliferation and apoptotic cell activity. Furthermore, no differences in CXCR2/CXCL2 expression were observed. However, immunostaining revealed reduction in vessel density and accumulation of microglia/macrophages, whereas interaction of these myeloid cells with tumour vessels was enhanced. In vitro analyses of the CXCR2-antagonist showed its direct impact on proliferation of glioma and endothelial cells if used at higher concentrations. In addition, expression of CXCR2/CXCL2 signalling genes was increased in both cell types by SB225002, but VEGF-relevant genes were unaffected. CONCLUSION: The CXCR2-antagonist inhibited glioma growth during tumour initiation and progression, whereas treatment was well-tolerated by the recipients. Thus, the CXCR2/CXCL2 signalling represents a promising therapeutic target in glioma.

Short-Term Oral Sorafenib for Therapy of Intratumoral Shunts of Hepatocellular Carcinoma to Enable Intraarterial Treatment.

INTRODUCTION: Significant intratumoral shunts between tumor-supplying arteries and portal or liver veins are a contraindication for transarterial therapy of HCC because interventional treatment of these shunts is frequently insufficient. Sorafenib has anti-angiogenic effects and is indicated for palliative treatment of patients with HCC. Here, we report our experience with the use of sorafenib for the closure of intratumoral shunts in patients scheduled for transarterial therapy of HCC. MATERIALS AND METHODS: Three patients with HCC, aged 65, 82 and 79 years, exhibited a significant intratumoral shunting from tumor artery to portal (n = 1) or liver veins (n = 2). In all cases, intratumoral shunting had already been suspected based on pre-interventional CT angiography, and DSA confirmed the shunt. Oral sorafenib (800 mg/day) was administered for at least four weeks, only and specifically to occlude the shunt. Hereafter, patients were re-evaluated by CT and DSA. RESULTS: All patients tolerated the full prescribed dose for at least 4 weeks. In one case, therapy was prolonged with an adapted dose (400 mg/day) due to sorafenib-related hand-foot syndrome. After sorafenib treatment, CT and DSA confirmed a complete closure of intratumoral shunts for all patients. No tumor progression was observed. All three patients hereafter underwent successful transarterial treatment by TACE (n = 2) or TARE (n = 1) without complications. Progression-free survival according to mRECIST was 501, 397 and 599 days, respectively. CONCLUSION: Even short-term oral sorafenib seems to effectively close intratumoral shunts in patients with HCC and thus might enable transarterial treatment of these patients.

Cetuximab-modified CuS nanoparticles integrating near-infrared-II-responsive photothermal therapy and anti-vessel treatment.

BACKGROUND: Photothermal therapy (PTT) has received extensive attention owing to its non-invasive nature and highly therapeutic outcomes. PTT agents and near-infrared (NIR) laser are essential elements in PTT. However, most PTT agents are composed of heavy metals, characterized by serious cytotoxicity and side effects, and NIR irradiation often damages normal tissue owing to the high dose, thus limiting the clinical application of PTT. PURPOSE: In this regard, exploring new perspectives enabling more PTT agents to be enriched into the tumor and NIR laser irradiation decay in PTT is vital. METHODS: In this study, cetuximab (Ab), an anti-angiogenic antibody which targets the EGFR, was modified on CuS NPs (CuS-Ab NPs) to improve the aggregation of CuS NPs in the tumor. RESULTS: The cellular uptake data and the biodistribution results showed comparable accumulation of CuS-Ab NPs in tumor, thus decreasing the cytotoxicity and side effects in normal tissues. More importantly, the modification of Ab in CuS-Ab NPs impressively inhibited the formation and progression of tumor vessels, as demonstrated by immunohistochemistry staining. The introduction of anti-vessel treatment requires CuS-Ab NPs to provide weak PTT, which means that a small amount of laser energy is required, inevitably causing negligible damage to normal tissue. CONCLUSION: Therefore, our tailor-made CuS-Ab NPs have promising potential in clinical applications.

Mechanistic considerations in chemotherapeutic activity of caffeine.

Caffeine (1,3,7-trimethylxanthine) is one of the most commonly consumed food ingredient throughout the world for thousands of years. It is naturally present in beans, leaves, seeds, and fruits of more than 60 plants and the most common sources are cocoa beans, coffee beans, tea leaves, kola nuts, and guarana berries. Several epidemiological studies suggested that consumption of coffee reduces the risk of different types of cancers. Understanding the chemotherapeutic molecular mechanisms of caffeine would facilitate in designing efficacious combination strategies with other anticancer drugs. Therefore, the aim of this review is to identify and highlight all the mechanisms involved in chemotherapeutic activity of caffeine. Mechanistically, caffeine has been shown to affect cell cycle progression at checkpoints, induce apoptosis, and inhibit drug efflux from cells. Caffeine at lower (micromolar) and relatively non-toxic concentrations has been shown to promote anti-tumor immune response (A2 A) and to inhibit tumor angiogenesis (A3) and migration (A2B) by antagonizing adenosine receptors. Considering the fact that a lower (micromolar) and relatively non-toxic concentrations of caffeine are required for its anti-tumor immune response and antiangiogenic activity, developing a combination strategy with immune checkpoint (PD-1 or CTLA-4) inhibitors would represent a novel approach to treat cancer.

HIV antiretroviral exposure in pregnancy induces detrimental placenta vascular changes that are rescued by progesterone supplementation.

Adverse birth outcomes are common in HIV-positive pregnant women receiving combination antiretroviral therapy (cART), especially when cART is initiated in early pregnancy. The mechanisms remain poorly understood. Using a mouse model we demonstrate that protease inhibitor based-cART exposure beginning on day 1 of pregnancy was associated with a pro-angiogenic/pro-branching shift in the placenta driven by lower Flt-1 levels and higher Gcm-1 expression. Micro-CT imaging revealed an increase in the number of arterioles in cART-treated placentas, which correlated with fetal growth restriction. Delaying initiation of cART, or supplementing cART-treated mice with progesterone, prevented the pro-angiogenic/pro-branching shift and the associated placenta vascular changes. In agreement with our mouse findings, we observed an increase in the number of terminal-villi capillaries in placentas from HIV-positive cART-exposed women compared to HIV-negative controls. Capillary number was inversely correlated to maternal progesterone levels. Our study provides evidence that cART exposure during pregnancy influences placenta vascular formation that may in turn contribute to fetal growth restriction. Our findings highlight the need for closer investigation of the placenta in HIV-positive pregnancies, particularly for pregnancies exposed to cART from conception, and suggest that progesterone supplementation could be investigated as a possible intervention to improve placenta function in HIV-positive pregnant women.

Integration of different criteria for borderline resectable pancreatic cancer using classification tree analysis: the use of radiological tumour-vascular interface in correlation with surgical and pathological outcomes.

AIM: To integrate various criteria for borderline resectable pancreatic cancer (BRPC) based on radiological parameters using classification tree analysis. MATERIALS AND METHODS: The institutional review board approved this retrospective study and waived the requirement for informed consent. Two hundred and thirty-five tumour-vein interfaces and 67 tumour-artery interfaces in 245 patients with surgically confirmed pancreatic ductal adenocarcinoma who underwent both preoperative computed tomography (CT) and magnetic resonance imaging (MRI) were assessed by two independent readers. Radiological parameters for evaluation of the tumour-vascular interface were boundary, length of interface, degree of circumferential interface, and contour deformity of affected vessels. Classification tree analysis was performed to determine parameters associated with vascular invasion using pathological and surgical results as the reference standard. RESULTS: In the classification tree analysis for the tumour-vein interface, contour deformity and degree of circumferential interface were the first and second determining factors, respectively, for both surgical and pathological vascular invasion. For the tumour-artery interface, boundary and degree of circumferential interface were the first and second determining factors for surgical invasion, while contour deformity and length of interface were the first and second determining factors for pathological invasion. The BRPC group of modified criteria arbitrarily formed based on the results had similar surgical (74.1-81.6%) and pathological (54.3-63.3%) venous invasion compared to that of the National Comprehensive Cancer Network (NCCN) criteria, and the lowest surgical (33.3%) and pathological (6.7%) arterial invasion compared with those in previously established criteria for BRPC (43.3-55.6% and 22.2-26.1%, respectively). CONCLUSION: Various criteria for BRPCs were integrated using classification tree analysis, and a modified criterion for BRPC, which provides satisfactory results, was established.

Anti-RhoJ antibody functionalized Au@I nanoparticles as CT-guided tumor vessel-targeting radiosensitizers in patient-derived tumor xenograft model.

The clinical success of radiotherapy is greatly hampered due to its intolerable off-target cytotoxicity induced by the high dose of radiation. Meanwhile, low dose of irradiation greatly potentiates the intratumoral angiogenesis, which promotes the local relapse and metastasis of tumor. Therefore, it is essential to reduce the irradiation dosage while inhibiting the tumor angiogenesis during radiotherapy. In this work, tumor vessel specific ultrafine Au@I nanoparticles (AIRA NPs) are fabricated and used as targeted radiosensitizers. Due to the presence of Au and iodine, these AIRA NPs exhibit superb X-ray attenuation for contrast-enhanced computed tomography (CT). Once injected, these AIRA NPs bind specifically to both newly formed tumor vessels in peri- and intratumoral regions and pre-existing tumor vessels. Upon radiation under CT guidance, AIRA NPs remarkably enhanced the killing efficacy against tumors in vivo with respect to radiation alone or anti-angiogenesis chemotherapy. Meanwhile, down-regulation of the level of circulating VEGF cytokine further indicates that our strategy can eradicate tumor without risking the recurrence of hypoxia and angiogenesis. Our demonstration provides a robust method of cancer therapy integrating good biocompatibility, high specificity and relapse-free manner alternative to traditional metal NPs enhanced radiotherapy.

Evaluation of CT vascularization patterns for survival prognosis in patients with hepatocellular carcinoma treated by conventional TACE.

PURPOSE: Transarterial chemoembolization (TACE) is an established treatment for intermediate stage hepatocellular carcinoma (HCC). The aim of this retrospective study was to evaluate the power of lesion vascularization criteria based on computed tomography for prognosis of overall survival before initiation of treatment. METHODS: A total of 59 patients with intermediate stage HCC treated with TACE as first-line treatment were retrospectively evaluated. TACE procedures were performed using doxorubicin, cisplatin, and lipiodol. Response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) were used to determine the initial tumor response. Four vascularization patterns (VP) of the largest target lesion (homogeneous vascularization [VP1], homogeneous vascularization with additional arterial hypervascularization [VP2], heterogeneous vascularization with [VP3] and without zones of hypervascularization [VP4]) were assessed prior to the first TACE and correlated to survival. RESULTS: Kaplan-Meier analysis yielded a median overall survival of 608 days (standard error [SE], 120.5 days). Survival analysis showed significant differences depending on the vascularization patterns (P = 0.012; hazard ratio, 0.327): patients with homogeneously vascularized lesions (VP1, VP2) had a median overall survival of 1091 days (SE, 235.5 days). Patients with heterogeneous vascularization of the lesion (VP3 and VP4) showed a median overall survival of 508 days (SE, 113.9 days). CONCLUSION: The vascularization pattern of the largest HCC lesion is helpful for survival prognosis under TACE treatment and therefore has the potential to be used as an additional parameter for treatment stratification.

PSMA Expression in Tumor Neovasculature Endothelial Cells of Follicular Thyroid Adenoma as Identified by Molecular Imaging Using 68Ga-PSMA Ligand PET/CT.

The prostate-specific membrane antigen (PSMA) is expressed by both prostate cancer and other neoplasms. We report the case of a 65-year-old man with castration-resistant metastatic prostate cancer who underwent Ga-PSMA ligand PET/CT for restaging of disease. Ga-PSMA ligand accumulation was noted in a thyroid lesion, suspicious for thyroid malignancy on complementary ultrasound. Subsequent resection and histopathological analysis showed follicular thyroid adenoma with PSMA expression in tumor neovasculature endothelial cells, but not in thyroid epithelial cells. It is important to be aware that both malignant and benign thyroid neoplasms may show PSMA expression to avoid misinterpretation.

Multiphoton imaging reveals that nanosecond pulsed electric fields collapse tumor and normal vascular perfusion in human glioblastoma xenografts.

Despite the biomedical advances of the last century, many cancers including glioblastoma are still resistant to existing therapies leaving patients with poor prognoses. Nanosecond pulsed electric fields (nsPEF) are a promising technology for the treatment of cancer that have thus far been evaluated in vitro and in superficial malignancies. In this paper, we develop a tumor organoid model of glioblastoma and apply intravital multiphoton microscopy to assess their response to nsPEFs. We demonstrate for the first time that a single 10 ns, high voltage electric pulse (35-45 kV/cm), collapses the perfusion of neovasculature, and also alters the diameter of capillaries and larger vessels in normal tissue. These results contribute to the fundamental understanding of nsPEF effects in complex tissue environments, and confirm the potential of nsPEFs to disrupt the microenvironment of solid tumors such as glioblastoma.

Microwave coagulation/ablation in combination with sorafenib suppresses the overgrowth of residual tumor in VX2 liver tumor model.

OBJECTIVES: Our study is to evaluate the effect of thermal ablation on residual VX2 tumor tissue and the efficiency of sorafenib as an adjuvant therapy after insufficient microwave coagulation (MWC) on a rabbit VX2 liver tumor model. METHODS: Thirty-seven rabbits with orthotic VX2 liver tumors were randomly divided into MWC group (n=11), combination treatment group (n=14), and control group (n=12). The therapeutic efficacy was evaluated by contrast enhanced ultrasound (CEUS), magnetic resonance imaging (MRI), pathological and immunohistochemical examinations. Analysis of enhancement characteristics included enhancement level, pattern, and location. The necrotic degree of tumor was analyzed by semi-quantitative classification. The apparent diffusion coefficiency (ADC) was calculated using diffused weighted image (DWI). RESULTS: The tumor growth was accelerated in MWC group compared with control group and combination treatment group. A low metastasis rate was shown in combination treatment group compared with other two groups. The degree of necrosis in combination treatment group was greater than that in MWC group. The ADC value on DWI was higher compared with that of the control and MWC group, with statistical significance (P<0.05). With adjuvant therapy of sorafenib after insufficient ablation, the microvessel density (MVD) was lower than that of control group, whereas in MWC group the MVD was higher than that of control group, with statistical significance (P<0.05). CONCLUSION: Insufficient thermal ablation promotes residual tumor progression. While the adjuvant therapy of sorafenib serves as an effective way to suppress the overgrowth and neovascularization of residual tumor after insufficient thermal ablation.

Co-option of Liver Vessels and Not Sprouting Angiogenesis Drives Acquired Sorafenib Resistance in Hepatocellular Carcinoma.

BACKGROUND: The anti-angiogenic Sorafenib is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC). However, acquired resistance limits its efficacy. An emerging theory to explain intrinsic resistance to other anti-angiogenic drugs is 'vessel co-option,' ie, the ability of tumors to hijack the existing vasculature in organs such as the lungs or liver, thus limiting the need for sprouting angiogenesis. Vessel co-option has not been evaluated as a potential mechanism for acquired resistance to anti-angiogenic agents. METHODS: To study sorafenib resistance mechanisms, we used an orthotopic human HCC model (n = 4-11 per group), where tumor cells are tagged with a secreted protein biomarker to monitor disease burden and response to therapy. Histopathology, vessel perfusion assessed by contrast-enhanced ultrasound, and miRNA sequencing and quantitative real-time polymerase chain reaction were used to monitor changes in tumor biology. RESULTS: While sorafenib initially inhibited angiogenesis and stabilized tumor growth, no angiogenic 'rebound' effect was observed during development of resistance unless therapy was stopped. Instead, resistant tumors became more locally infiltrative, which facilitated extensive incorporation of liver parenchyma and the co-option of liver-associated vessels. Up to 75% (±10.9%) of total vessels were provided by vessel co-option in resistant tumors relative to 23.3% (±10.3%) in untreated controls. miRNA sequencing implicated pro-invasive signaling and epithelial-to-mesenchymal-like transition during resistance development while functional imaging further supported a shift from angiogenesis to vessel co-option. CONCLUSIONS: This is the first documentation of vessel co-option as a mechanism of acquired resistance to anti-angiogenic therapy and could have important implications including the potential therapeutic benefits of targeting vessel co-option in conjunction with vascular endothelial growth factor receptor signaling.

Dynamic contrast-enhanced MRI for oncology drug development.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a promising tool for evaluating tumor vascularity, as it can provide vasculature-derived, functional, and quantitative parameters. To implement DCE-MRI parameters as biomarkers for monitoring the effect of antiangiogenic or vascular-disrupting treatment, two crucial elements of surrogate endpoint, ie, validation and qualification, should be satisfied. Although early studies have shown the accuracy and reliability of DCE-MRI parameters for evaluating treatment-driven vascular alterations, there have been an increasing number of studies demonstrating the limitations of DCE-MRI parameters as surrogate endpoints. Therefore, in order to improve the application of DCE-MRI parameters in drug development, it is necessary to establish a standardized evaluation method and to determine the correct therapeutics-oriented meaning of individual DCE-MRI parameter. In this regard, this article describes the biophysical background and data acquisition/analysis techniques of DCE-MRI while focusing on the validation and qualification issues. Specifically, the causes of disagreement and confusion encountered in the preclinical and clinical trials using DCE-MRI are presented in detail. Finally, considering these limitations, we present potential strategies to optimize implementation of DCE-MRI. J. Magn. Reson. Imaging 2016;44:251-264.

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.

Intermediate and advanced hepatocellular carcinoma treated with the antiangiogenic agent sorafenib. Evaluation with unenhanced and contrast-enhanced ultrasonography.

AIMS: To evaluate the sonographic changes observed in hepatocellular carcinoma (HCC) post antiangiogenic treatment with sorafenib. PATIENTS AND METHODS: Twenty one intermediate or advanced HCC patients (19 men, 2 women; mean age: 66.8 years; 32 target tumors-TTs) received sorafenib as monotherapy and were studied with unenhanced ultrasonography (US) and contrast-enhanced ultrasonography (CEUS) with a second generation echo-enhancer (SonoVue) at bimonthly intervals. Changes in lesional size, echotexture and enhancement were evaluated. Response was classified according to RECIST (Response Evaluation Criteria In Solid Tumors) and modified (m) RECIST. RESULTS: Cystic changes were detected on US in 4 patients (7 lesions); CEUS showed a significant (51-100%) decrease of viable, enhancing TTs in the aforementioned patients. Four additional patients (5 lesions) showed a 73-87% decrease of their viable TTs on CEUS, but no changes on US. 13/21 patients showed less than 30% decrease, no change, or increase of their viable TTs. Based on the last sonographic evaluation, response was as follows: RECIST- Complete Response, CR (n=0), Partial Response, PR (n=1), Stable Disease, SD (n=16), Progressive Disease, PD (n=4); mRECIST- CR (n=2), PR (n=6), SD (n=11), PD (n=2). The 8 responders (CR+PR) according to mRECIST had significantly longer mean overall survival (OS) compared to the 13 non-responders (21.5 vs 12.2 months, p=0.018, Kaplan-Meier method). However, statistical significance was reduced (p=0.065) after adjustment for BCLC and Child's class. CONCLUSION: US may occasionally detect changes indicative of the effect of sorafenib on HCC, but CEUS is required to evaluate and grade post-therapeutic reduction of tumoral enhancement. The latter is likely to correlate with OS.

Augmentation of chemotherapeutic infusion effect by TSU-68, an oral targeted antiangiogenic agent, in a rabbit VX2 liver tumor model.

PURPOSE: This study was designed to investigate the in vivo effects of combination therapy with TSU-68 and chemotherapeutic infusion in a rabbit VX2 liver tumor model. METHODS: This study was approved by the animal care committee at our institute. Three weeks before chemotherapeutic infusion, VX2 carcinoma was implanted into the livers of 32 rabbits. One week after chemotherapeutic infusion, vehicle was administered orally for 3 weeks in the control group (n = 16), and TSU-68 was administered orally at a daily dose of 200 mg/kg for 3 weeks in the treated group (n = 16). Computed tomography (CT) was performed before and 1, 2, 3, and 4 weeks after chemotherapeutic infusion. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) on CT scan. The maximum thickness of viable tumor was measured on microscopic sections. RESULTS: According to the RECIST, stable disease was observed in 9 (56%) rabbits and progressive disease in 7 (44%) in the control group, whereas partial response was observed in 1 (6%) rabbit and stable disease in 15 (94%) in the treated group. On pathologic examination, a viable lesion was present in 12 (75%) rabbits in the control group and in 6 (38%) rabbits in the treated group (P = 0.073). The mean maximum thickness of viable tumor in the treated group was significantly smaller than that in the control group (0.74 mm vs. 3.39 mm; P = 0.02). CONCLUSIONS: Oral administration of TSU-68 augmented the effect of chemotherapeutic infusion in a rabbit VX2 liver tumor model.