VueBox® for quantitative analysis of contrast-enhanced ultrasound in liver tumors

Dynamic contrast-enhanced ultrasound (DCE-US) enables quantification of tumor perfusion. VueBox is a platform independent external software using DICOM cine loops which objectively provides various DCE-US parameters of tumor vascularity. This review summaries its use for diagnosis and treatment monitoring of liver tumors. The existing literature provides evidence on the successful application of Vuebox based DCE-US for characterization and differential diagnosis of focal liver lesions, as well as on its use for monitoring of local ablative therapies and of modern systemic treatment in oncology.

Multiparametric Magnetic Resonance Imaging for Immediate Target Hit Assessment of CD13—Targeted Tissue Factor tTF-NGR in Advanced Malignant Disease

Early assessment of target hit in anti-cancer therapies is a major task in oncologic imaging. In this study, immediate target hit and effectiveness of CD13-targeted tissue factor tTF-NGR in patients with advanced malignant disease enrolled in a phase I trial was assessed using a multiparametric MRI protocol. Seventeen patients with advanced solid malignancies were enrolled in the trial and received tTF-NGR for at least one cycle of five daily infusions. Tumor target lesions were imaged with multiparametric MRI before therapy initiation, five hours after the first infusion and after five days. The imaging protocol comprised ADC, calculated from DWI, and DCE imaging and vascular volume fraction (VVF) assessment. DCE and VVF values decreased within 5 h after therapy initiation, indicating early target hit with a subsequent decrease in tumor perfusion due to selective tumor vessel occlusion and thrombosis induced by tTF-NGR. Simultaneously, ADC values increased at five hours after tTF-NGR administration. In four patients, treatment had to be stopped due to an increase in troponin T hs, with subsequent anticoagulation. In these patients, a reversed effect, with DCE and VVF values increasing and ADC values decreasing, was observed after anticoagulation. Changes in imaging parameters were independent of the mean vessel density determined by immunohistochemistry. By using a multiparametric imaging approach, changes in tumor perfusion after initiation of a tumor vessel occluding therapy can be evaluated as early as five hours after therapy initiation, enabling early assessment of target hit.

Early Detection of Response to Radiotherapy Treatment with 11C-Acetate PET Imaging

11C-Acetate radiotracer with Positron Emission Tomography (PET) imaging is currently used in cardiovascular imaging for perfusion and oxygen consumption measurement. It is also used, among other diseases, for prostate cancer as this radiotracer does not accumulate in the bladder. The present study reports the assessment of the radiotherapy treatment by measuring the tumor perfusion and oxygenation before and at mid-treatment by imaging with dynamic 11C-Acetate in patients with head and neck cancer. A pre-treatment dynamic 11C-Acetate and a clinical static 18F-FDG PET were conducted before initiation of the treatment, and the second 11C-Acetate dynamic scan was performed after four weeks of radiotherapy (i.e., after a dose of 35 Gy for a total of 70 Gy). The two-tissue compartment model was applied to 11C-Acetate images to extract the perfusion and oxygen consumption. The results showed a reduction in tumor volume by more than 50% compared to the initial volume in patient-1. Besides, patient-2 has displayed a more reduced tumor volume after 4 weeks of treatment. The 11C-Acetate rate constant k2 representing oxygen consumption increased after radiotherapy dose in both patients. This increase of k2 could reflect the reoxygenation process inside the tumor, and it can reflect the early treatment response. In conclusion, 11C-Acetate could predict the early changes in the tumor perfusion and the oxidative metabolism to optimally adjust the treatment.

The Effects of Physical Exercise on Tumor Vasculature: Systematic Review and Meta-analysis

A wealth of evidence supports an association between physical exercise, decreased tumor growth rate, and reduced risk of cancer mortality. In this context, the tumor vascular microenvironment may play a key role in modulating tumor biologic behavior. The present systematic review and meta-analysis aimed to summarize the evidence regarding the effects of physical exercise on tumor vasculature in pre-clinical studies. We performed a computerized research on the PubMed, Scopus, and EBSCO databases to identify pre-clinical studies that evaluated the effect of physical exercise on tumor vascular outcomes. Mean differences were calculated through a random effects model. The present systematic review included 13 studies involving 373 animals. From these, 11 studies evaluated chronic intratumoral vascular adaptations and 2 studies assessed the acute intratumoral vascular adaptations to physical exercise. The chronic intratumoral vascular adaptations resulted in higher tumor microvessel density in 4 studies, increased tumor perfusion in 2 studies, and reduced intratumoral hypoxia in 3 studies. Quantitatively, regular physical exercise induced an increased tumor vascularization of 2.13 [1.07, 3.20] (p<0.0001). The acute intratumoral vascular adaptations included increased vascular conductance and reduced vascular resistance, which improved tumor perfusion and attenuated intratumoral hypoxia. In pre-clinical studies, physical exercise seems to improve tumor vascularization.

Anticoagulation therapy promotes the tumor immune-microenvironment and potentiates the efficacy of immunotherapy by alleviating hypoxia

PurposeHere, this study verifies that cancer-associated thrombosis (CAT) accelerates hypoxia, which is detrimental to the tumor immune microenvironment by limiting tumor perfusion. Therefore, we designed an oral anticoagulant therapy to improve the immunosuppressive tumor microenvironment and potentiate the efficacy of immunotherapy by alleviating tumor hypoxia.Experimental designA novel oral anticoagulant (STP3725) was developed to consistently prevent CAT formation. Tumor perfusion and hypoxia were analyzed with or without treating STP3725 in wild-type and P selectin knockout mice. Immunosuppressive cytokines and cells were analyzed to evaluate the alteration of the tumor microenvironment. Effector lymphocyte infiltration in tumor tissue was assessed by congenic CD45.1 mouse lymphocyte transfer model with or without anticoagulant therapy. Finally, various tumor models including K-Ras mutant spontaneous cancer model were employed to validate the role of the anticoagulation therapy in enhancing the efficacy of immunotherapy.ResultsCAT was demonstrated to be one of the perfusion barriers, which fosters immunosuppressive microenvironment by accelerating tumor hypoxia. Consistent treatment of oral anticoagulation therapy was proved to promote tumor immunity by alleviating hypoxia. Furthermore, this resulted in decrease of both hypoxia-related immunosuppressive cytokines and myeloid-derived suppressor cells while improving the spatial distribution of effector lymphocytes and their activity. The anticancer efficacy of αPD-1 antibody was potentiated by co-treatment with STP3725, also confirmed in various tumor models including the K-Ras mutant mouse model, which is highly thrombotic.ConclusionsCollectively, these findings establish a rationale for a new and translational combination strategy of oral anticoagulation therapy with immunotherapy, especially for treating highly thrombotic cancers. The combination therapy of anticoagulants with immunotherapies can lead to substantial improvements of current approaches in the clinic.

Tumor perfusion evaluation using dynamic contrast-enhanced ultrasound after electrochemotherapy and IL-12 plasmid electrotransfer in murine melanoma

Electrochemotherapy with bleomycin (ECT BLM) is an effective antitumor treatment already used in clinical oncology. However, ECT alone is still considered a local antitumor therapy because it cannot induce systemic immunity. When combined with adjuvant gene electrotransfer of plasmid DNA encoding IL-12 (GET pIL-12), the combined therapy leads to a systemic effect on untreated tumors and distant metastases. Although the antitumor efficacy of both therapies alone or in combination has been demonstrated at both preclinical and clinical levels, data on the predictors of efficacy of the treatments are still lacking. Herein, we evaluated the results of dynamic contrast-enhanced ultrasound (DCE-US) as a predictive factor for ECT BLM and GET pIL-12 in murine melanoma. Melanoma B16F10 tumors grown in female C57Bl/6NCrl mice were treated with GET pIL-12 and ECT BLM. Immediately after therapy, 6 h and 1, 3, 7 and 10 days later, tumors were examined by DCE-US. Statistical analysis was performed to inspect the correlation between tumor doubling time (DT) and DCE-US measurements using semilinear regression models and Bland–Altman plots. Therapeutic groups in which DCE-US showed reduced tumor perfusion had longer tumor DTs. It was confirmed that the DCE-US parameter peak enhancement (PE), reflecting relative blood volume, had predictive value for the outcome of therapy: larger PE correlated with shorter DT. In addition, perfusion heterogeneity was also associated with outcome: tumors that had more heterogeneous perfusion had faster growth, i.e., shorter DTs. This study demonstrates that DCE-US can be used as a method to predict the efficacy of electroporation-based treatment.

Arterial Spin Labeling MRI for Predicting Microvascular Invasion of T1 Staging Renal Clear Cell Carcinoma Preoperatively

BackgroundMicrovascular invasion (MVI) is a valuable factor for T1 staging renal clear cell carcinoma (ccRCC) operation strategy decision, which is confirmed histopathologically post-operation. This study aimed to prospectively evaluate the performance of arterial spin labeling (ASL) MRI for predicting MVI of T1 staging ccRCC preoperatively.Methods16 volunteers and 39 consecutive patients were enrolled. MRI examinations consisted of ASL (three post label delays separately) of the kidney, followed by T1 and T2-weighted imaging. Two sessions of ASL were used to evaluate the reproducibility on volunteers. Renal blood flow of renal cortex, medulla, the entire and solid part of the tumor were measured on ASL images. Conventional imaging features were extracted. MVI and WHO/ISUP classification were evaluated histopathologically. A paired t‐test was used to compare the renal cortex and medulla between ASL 1 and ASL 2. The reproducibility was assessed using the intraclass correlation. Differences in mean perfusion between the entire and the solid parts of tumors with or without MVI were assessed separately using Student’s t test. The diagnostic performance was assessed. Logistic regression analysis was used to indicate the independent prediction index for MVI.ResultsThe two sessions of ASL showed no significant difference between the mean cortex values of RBF. The cortical RBF measurements demonstrated good agreement. 12 ccRCCs presented with MVI histopathologically. Mean perfusion of the solid part of tumors with MVI were 536.4 ± 154.8 ml/min/100 g (PLD1), 2912.5 ± 939.3 ml/min/100 g (PLD2), 3280.3 ± 901.2 ml/min/100 g (PLD3). Mean perfusion of the solid part of tumors without MVI were 453.5 ± 87.2 ml/min/100 g (PLD1), 1043.6 ± 695.8 ml/min/100 g (PLD2), 1577.6 ± 1085.8 ml/min/100 g (PLD3). These two groups have significant difference at all the PLDs (p &lt; 0.05). The RBF of PLD1 of the solid part of tumor perfusion showed well diagnostic performance for predicting MVI: sensitivity 75%, specificity 100%, positive predictive value 66.7%, and negative predictive value 95.7%. The maximum diameter of the tumor, ill-defined margin, and the solid part of tumor perfusion were the independent prediction index for MVI.ConclusionASL MR imaging has good reproducibility for renal cortex, and good diagnostic performance for predicting MVI for ccRCC.