Tumor Perfusion Research Articles

Ultrasound-Induced Tumor Perfusion Changes and Doxorubicin Delivery: A Study on Pulse Length and Pulse Repetition Frequency.

To investigate the appropriate combination of pulse length (PL) and pulse repetition frequency (PRF) when performing ultrasound stimulated microbubble (USMB) to enhance doxorubicin (DOX) delivery to tumors. A total of 48 tumor-bearing mice were divided into four groups, namely groups A-D. The mice in groups B-D were treated with chemotherapy and USMB treatment with different combinations of PL and PRF, and group A was control. Contrast-enhanced ultrasound imaging was conducted to analyze tumor blood perfusion. Fluorescence microscopy and high-performance liquid chromatography were used to qualitatively and quantitatively analyse DOX release. The structural changes of tumors were observed under light microscope and transmission electron microscope. Furthermore, another 24 tumor-bearing mice were treated with sonochemotherapy and some related inflammatory factors were measured to explore the underlying mechanism. With PL of three cycles and PRF of 2 kHz, the tumor perfusion area ratio increased by 26.67%, and the DOX concentration was 4.69 times higher than the control (P < .001). With PL of 34.5 cycles and PRF of 200 Hz, the tumor perfusion area ratio decreased by 12.7% and DOX did not exhibit increased extravasation compared with the control. Microvascular rupture and hemorrhage were observed after long PL and low PRF treatment. While vasodilation and higher levels of some vasodilator inflammatory factors were found after treatment with short PL and high PRF. USMB treatment using short PL and high PRF could enhance tumor blood perfusion and increase DOX delivery, whereas long PL and low PRF could not serve the same purpose.

Integrated PK/PD Modeling Relates Smoothened Inhibitor Biomarkers to The Heterogeneous Intratumor Disposition of Cetuximab in Pancreatic Cancer Tumor Models

Therapeutic antibodies have shown little efficacy in the treatment of pancreatic ductal adenocarcinomas (PDAC). Tumor desmoplasia, hypovascularity, and poor perfusion result in insufficient tumor cell exposure, contributing to treatment failure. Smoothened inhibitors of hedgehog signaling (sHHi) increase PDAC tumor permeability, perfusion, and drug delivery, and provide a tool to develop a quantitative, mechanistic understanding as to how the temporal dynamics of tumor priming can impact intratumor distribution of monoclonal antibodies (mAb). A linked pharmacokinetic (PK)/pharmacodynamic (PD) model was developed to integrate the plasma and tumor PK of a sHHi priming agent with its effects upon downstream stromal biomarkers Gli1, hyaluronic acid, and interstitial fluid pressure in PDAC patient-derived xenograft (PDX) tumors. In parallel, in situ tumor concentrations of cetuximab (CTX: anti-epidermal growth factor receptor; EGFR) were quantified as a marker for tumor delivery of mAb or antibody-drug conjugates. A minimal, physiologically-based pharmacokinetic (mPBPK) model was constructed to link sHHi effects upon mechanistic effectors of tumor barrier compromise with the intratumor distribution of CTX, and CTX occupancy of EGFR in tumors. Integration of the mPBPK model of mAb deposition and intratumor distribution with the PK/PD model of tumor responses to priming not only identified physiological parameters that are critical for tumor antibody distribution, but also provides insight into dosing regimens that could achieve maximal tumor disposition of therapeutic antibodies under conditions of transient PDAC tumor permeability barrier compromise that mechanistically-diverse tumor priming strategies may achieve.

NEED OF THE HOUR TO USE MR PERFUSION TO DIFFERENTIATE BETWEEN RADIATION NECROSIS AND TUMOUR RECURRENCE IN KNOWN GLIOMA PATIENTS

Conventional MR imaging may be non-specific in diagnosing low-grade gliomas. Better modalities are used nowadays including MRS (spectroscopy), perfusion, and diffusion-weighted imaging (1).&#x0D; MR perfusion is better than CT perfusion in various aspects. MR perfusion does not expose the patient to ionizing radiation. CT perfusion, on the other hand, can be harmful if the patient receives repeated doses. However, CT perfusion may be more readily available in emergency settings and can be quicker to perform than MR perfusion, which requires a longer acquisition time. CT perfusion can also provide more precise measurements of blood flow in small vessels than MR perfusion. Ultimately, the choice between MR perfusion and CT perfusion depends on the specific clinical situation and the preferences of the medical team.&#x0D; Perfusion MRI studies have become an increasingly important tool in the management of high-grade gliomas as well. Perfusion MRI allows clinicians to assess the vascularity of these tumors, providing information on tumor grade, response to treatment, and prognosis. Perfusion imaging can be performed using various techniques, including dynamic susceptibility contrast (DSC) MRI and arterial spin labeling (ASL) MRI. DSC-MRI is the most commonly used technique, and it provides information on cerebral blood volume (CBV) and cerebral blood flow (CBF) in the tumor and surrounding tissue. ASL-MRI, on the other hand, measures blood flow by magnetically labeling arterial blood water protons and can provide information on tumor perfusion without the use of contrast agents. Overall, perfusion MRI studies have demonstrated significant potential for improving the diagnosis, management, and prognosis of high-grade gliomas. MR brain perfusion is a type of imaging technique that can be used to differentiate between radiation-related changes and tumor recurrence in patients who have undergone radiation therapy for brain tumors. (2).&#x0D; &#x0D; Tumor resection followed by chemoradiation remains the current criterion standard treatment for high-grade gliomas. Radiation therapy can cause changes in the brain that may appear similar to tumor recurrence on conventional MRI scans. However, MR brain perfusion can detect differences in blood flow patterns between tumor tissue and normal brain tissue, which can help to differentiate between radiation-related changes/necrosis and tumor recurrence (3).&#x0D; Every institute should start using MR perfusion studies to differentiate these. This will eventually help in patient correct diagnosis and reduction in morbidity and mortality.&#x0D; Key-words:&#x0D; Gliomas, MR Perfusion, CT Perfusion, Tumour Recurrence, Radiation Necrosis.&#x0D; &#x0D; Conflict of Interest: All authors declare no conflict of interest.&#x0D; &#x0D; Funding Role: None to declare.&#x0D; &#x0D; Author Contributions: All authors contributed equally to the drafting of study.&#x0D; &#x0D; Ethical Statement: Written as per the ethical guidelines of hospital board.&#x0D; &#x0D;

EFSUMB Technical Review - Update 2023: Dynamic Contrast-Enhanced Ultrasound (DCE-CEUS) for the Quantification of Tumor Perfusion.

Dynamic contrast-enhanced ultrasound (DCE-US) is a technique to quantify tissue perfusion based on phase-specific enhancement after the injection of microbubble contrast agents for diagnostic ultrasound. The guidelines of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) published in 2004 and updated in 2008, 2011, and 2020 focused on the use of contrast-enhanced ultrasound (CEUS), including essential technical requirements, training, investigational procedures and steps, guidance regarding image interpretation, established and recommended clinical indications, and safety considerations. However, the quantification of phase-specific enhancement patterns acquired with ultrasound contrast agents (UCAs) is not discussed here. The purpose of this EFSUMB Technical Review is to further establish a basis for the standardization of DCE-US focusing on treatment monitoring in oncology. It provides some recommendations and descriptions as to how to quantify dynamic ultrasound contrast enhancement, and technical explanations for the analysis of time-intensity curves (TICs). This update of the 2012 EFSUMB introduction to DCE-US includes clinical aspects for data collection, analysis, and interpretation that have emerged from recent studies. The current study not only aims to support future work in this research field but also to facilitate a transition to clinical routine use of DCE-US.

Sononeoperfusion effect by ultrasound and microbubble promotes nitric oxide release to alleviate hypoxia in a mouse MC38 tumor model

Tumor hypoperfusion not only impedes therapeutic drug delivery and accumulation, but also leads to a hypoxic and acidic tumor microenvironment, resulting in tumor proliferation, invasion, and therapeutic resistance. Sononeoperfusion effect refers to tumor perfusion enhancement using ultrasound and microbubbles. This study aimed to further investigate hypoxia alleviation by sononeoperfusion effect and explore the characteristics and mechanism of sononeoperfusion effect. To stimulate the sononeoperfusion effect, mice bearing MC38 colon cancers were included in this study and diagnostic ultrasound for therapy was set at a mechanical index (MI) of 0.1, 0.3, and 0.5, frequency of 3 MHz, pulse length of 5 cycles, and pulse repetition frequency of 2000 Hz. The results demonstrated that a single ultrasound and microbubble (USMB) treatment resulted in tumor perfusion enhancement at MI = 0.3, and nitric oxide (NO) concentration increased at MI = 0.3/0.5 (P < 0.05). However, there were no significant difference in the hypoxia-inducible factor-1α (HIF-1α) or D-lactate (D-LA) (P > 0.05) levels. Multiple sononeoperfusion effects were observed at MI = 0.3/0.5 (P < 0.05). For each treatment, USMB slightly but steadily improved the tumor tissue oxygen partial pressure (pO2) during and post treatment. It alleviated tumor hypoxia by decreasing HIF-1α, D-LA level and the hypoxic immunofluorescence intensity at MI = 0.3/0.5 (P < 0.05). The sononeoperfusion effect was not stimulated after eNOS inhibition. In conclusion, USMB with appropriate MI could lead to a sononeoperfusion effect via NO release, resulting in hypoxia amelioration. The tumors were not resistant to multiple sononeoperfusion effects. Repeated sononeoperfusion is a promising approach for relieving tumor hypoxia and resistance to therapy.

Diffusion heterogeneity and vascular perfusion in tumor and peritumoral areas for prediction of overall survival in patients with high-grade glioma

ObjectiveTo evaluation of diffusion heterogeneity and vascular perfusion in tumor and peritumoral areas for prognostic prediction in high-grade glioma (HGG, WHO III/IV grade). MethodsForty patients with HGG underwent diffusion kurtosis imaging (DKI), intravoxel incoherent motion (IVIM), and arterial spin labeling (ASL) MRI before operation. After normalization, the parameters were divided into diffusion heterogeneity parameters (rD, rMD, rMK, rKr, rKa) and vascular perfusion parameters (rD*, rF, rCBF). Univariate and multivariate Cox regression analyses were used to evaluate associations between overall survival (OS) and the above parameters, clinical factors, and IDH1 status. The Mann-Whitney test was used to evaluate differences in the parameters between different IDH1 states. ResultsIn the univariate Cox regression analysis, OS was significantly associated with tumor resection range, IDH1 status, tumor heterogeneity parameters (rD, rMD, rMK, rKr, rKa), and rCBF in tumor area(all p < 0.05). In addition, rD and rCBF measured in the peritumoral region were also predictors of poor OS (both p < 0.01). Multivariate Cox regression analysis indicated that rMK in the tumor area and rCBF in the peritumoral area (hazard ratio = 7.900 and 5.466, respectively, for each 0.1 increase in the normalized value) were independent predictors of OS. ConclusionThe rMK of tumor area and rCBF of peritumoral area had independent predictive value for OS in patients with HGG. Advances in knowledgeThis study explored useful imaging biomarkers from the diffusion heterogeneity and vascular perfusion of tumor and peritumoral areas in HGG, which is useful to help clinician to make precise therapeutic plans, and predict the prognostic for glioma patients.

P15.08.A MRI PHENOTYPES OF GLIOBLASTOMAS EARLY AFTER TREATMENT ARE SUGGESTIVE OF OVERALL PATIENT SURVIVAL

Abstract BACKGROUND Distinguishing between true tumor progression (TP) and treatment induced abnormalities (e.g. pseudo-progression (PP) after radiotherapy) early after treatment on conventional MRI scans remains challenging for glioblastomas (GBM). Despite MRI perfusion techniques being promising in differentiating between TP and PP, individual imaging markers have only showed a modest association with tumor progression and overall survival. Therefore, we aimed to establish brain MRI phenotypes of glioblastomas early after treatment by combined analysis of radiological scoring of structural and perfusion tumor characteristics and assessed the relation with recurrence rate and overall-survival time. MATERIAL AND METHODS MR images and clinical data were retrospectively collected from 67 histologically confirmed GBM patients. Non-invasive (arterial spin labeling, ASL) and contrast-based (dynamic susceptibility contrast DSC) perfusion MRI, T2-FLAIR and post-contrast 3D-T1w scans were acquired on a 3T-MR scanner at around 3 months post-radiotherapy. Structural (presence and type of (enhancing) lesion patterns) and perfusion (increase, decrease or iso) MRI markers (MRIm) were visually scored by a neuroradiologist. Additionally, volume and eccentricity of the enhancing and T2-hyperintense areas were calculated.Subsequently, patients were grouped based on their similarity on tumor perfusion and structural brain MRIm by means of hierarchical clustering. These subgroups were then compared using a chi-square test and one way ANOVA. Survival outcome was assessed using a multivariate cox proportional hazard model, both unadjusted and adjusted for age, KPS and extension of resection. Progression at 9 months (when unavailable at 3/6 months) post-radiotherapy and clinical parameters were compared between subgroups using a chi-square test. RESULTS Four subgroups of patients were established with significantly different tumor perfusion and structural radiological markers (p≤0.05) and therefore showed distinct MRI phenotypes of GBM. Subgroup 1 had less aggressive MRIm with mostly nodular enhancing lesions; subgroup 2 had the least aggressive MRIm with mostly patchy enhancing lesions; subgroup 3 showed the most aggressive MRIm and subgroup 4 showed moderately aggressive MRIm. TP and PP did not differ significantly between subgroups (p = 0.775). However, after performing an adjusted and unadjusted cox regression analysis we found that subgroup 1 and 3 were at increased risk of mortality, respectively (subgroup 1 - HR: 2.649 (95% CI: 1.119 - 6.270; subgroup 3 - HR: 2.363 (95% CI: 1.110 - 5.030); p=0.03). CONCLUSION Our study suggests that differences in MRI phenotypes of GBM at 3 months post-radiotherapy can be indicative of overall patient survival. The early prognostic information our method provides might in the future be beneficial for treatment decisions in GBM patients.

ASO Author Reflections: Liver Resections with Vascular Reconstruction Using Veno-Venous Bypass and Cold Perfusion for Tumors with Venous Obstruction.

ASO Author Reflections: Liver Resections with Vascular Reconstruction Using Veno-Venous Bypass and Cold Perfusion for Tumors with Venous Obstruction.

Vascular phenotyping of the invasive front in breast cancer using a 3D angiogenesis atlas.

Vascular remodeling at the invasive tumor front (ITF) plays a critical role in progression and metastasis of triple negative breast cancer (TNBC). Therefore, there is a crucial need to characterize the vascular phenotype (i.e. changes in the structure and function of vasculature) of the ITF and tumor core (TC) in TNBC. This requires high-resolution, 3D structural and functional microvascular data that spans the ITF and TC (i.e. ∼4-5mm from the tumor's edge). Since such data are often challenging to obtain with most conventional imaging approaches, we employed a unique "3D whole-tumor angiogenesis atlas" derived from orthotopic xenografts to characterize the vascular phenotype of the ITF and TC in TNBC. First, high-resolution (8μm) computed tomography (CT) images of "whole-tumor" microvasculature were acquired from eight orthotopic TNBC xenografts, of which three tumors were excised at post-inoculation day 21 (i.e. early-stage) and five tumors were excised at post-inoculation day 35 (i.e. advanced-stage). These 3D morphological CT data were combined with soft tissue contrast from MRI as well as functional data generated in silico using image-based hemodynamic modeling to generate a multi-layered "angiogenesis atlas". Employing this atlas, blood vessels were first spatially stratified within the ITF (i.e. ≤1mm from the tumor's edge) and TC (i.e. >1mm from the tumor's edge) of each tumor xenograft. Then, a novel method was developed to visualize and characterize microvascular remodeling and perfusion changes in terms of distance from the tumor's edge. The angiogenesis atlas enabled the 3D visualization of changes in tumor vessel growth patterns, morphology and perfusion within the ITF and TC. Early and advanced stage tumors demonstrated significant differences in terms of their edge-to-center distributions for vascular surface area density, vascular length density, intervessel distance and simulated perfusion density (p≪0.01). Elevated vascular length density, vascular surface area density and perfusion density along the circumference of the ITF was suggestive of a preferential spatial pattern of angiogenic growth in this tumor cohort. Finally, we demonstrated the feasibility of differentiating the vascular phenotypes of ITF and TC in these TNBC xenografts. The combination of a 3D angiogenesis atlas and image-based hemodynamic modeling heralds a new approach for characterizing the role of vascular remodeling in cancer and other diseases.

Characterization of denosumab treatment response in giant cell tumors of bone with dynamic contrast-enhanced MRI

Rationale and objectivesDenosumab is a monoclonal antibody used neo-adjuvantly in giant cell tumor of bone (GCTB) to facilitate surgery, or long term for axial tumors where surgery comes with high morbidity. Time intervals for treatment effects to occur are unclear and monitoring tools are limited, complicating optimal drug dose titration. We assessed changes in time intensity curve (TIC) - derived perfusion features on DCE-MRI in GCTB during denosumab treatment and evaluated the duration of treatment effects on tumor perfusion. Materials and methodsPatients with GCTB who underwent dynamic contrast enhanced (DCE) MRI before (t = 0) and after 3 (t = 3), 6 (t = 6) or 12 (t = 12) months of denosumab treatment were retrospectively included in a single center. Regions of interest were placed on tumor compartments with visually most intense enhancement and TICs were created. Time-to-enhancement (TTE), wash-in rate (WIR), maximal relative enhancement (MRE), and area-under-the-curve (AUC) were calculated. Differences in perfusion features were calculated with the Wilcoxon signed-rank test. ResultsIn all 24 patients decreased perfusion on DCE-MRI after start of denosumab treatment was seen. TTE increased between t = 0 and t = 3 (p < 0.001). WIR, MRE and AUC decreased between t = 0 and t = 3 (p < 0.001, p = 0.01 and p = 0.02, respectively). No significant differences in features were found between t = 3 and t = 6 or t = 6 and t = 12. No significant perfusion differences in primary versus recurrent, or axial versus appendicular tumors, were found. ConclusionMRI perfusion significantly changed in GCTB within 3 months of denosumab treatment compared to baseline. No further significant change occurred between 3 and 6, and 6 and 12 months of treatment. These findings suggest that evaluation of treatment response and subsequent consideration of maintenance with lower doses of denosumab, may already be indicated after 3 months. In cases where long term denosumab is the preferred therapy, monitoring change in tumor characteristics on DCE-MRI may aid optimal drug dose titration, minimizing side effects.

Effects of Hyperthermia and Hyperthermic Intraperitoneal Chemoperfusion on the Peritoneal and Tumor Immune Contexture.

Hyperthermia combined with intraperitoneal (IP) drug delivery is increasingly used in the treatment of peritoneal metastases (PM). Hyperthermia enhances tumor perfusion and increases drug penetration after IP delivery. The peritoneum is increasingly recognized as an immune-privileged organ with its own distinct immune microenvironment. Here, we review the immune landscape of the healthy peritoneal cavity and immune contexture of peritoneal metastases. Next, we review the potential benefits and unwanted tumor-promoting effects of hyperthermia and the associated heat shock response on the tumor immune microenvironment. We highlight the potential modulating effect of hyperthermia on the biomechanical properties of tumor tissue and the consequences for immune cell infiltration. Data from translational and clinical studies are reviewed. We conclude that (mild) hyperthermia and HIPEC have the potential to enhance antitumor immunity, but detailed further studies are required to distinguish beneficial from tumor-promoting effects.

A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer.

The lysyl oxidase family represents a promising target in stromal targeting of solid tumors due to the importance of this family in crosslinking and stabilizing fibrillar collagens and its known role in tumor desmoplasia. Using small-molecule drug-design approaches, we generated and validated PXS-5505, a first-in-class highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumor desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumor perfusion and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, while also demonstrating antifibrotic effects in human patient-derived xenograft models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of a pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma.

Tolerable treatment of glioblastoma with redox-cycling ‘mitocans': a comparative study in vivo

ABSTRACTObjectives: The present study describes a pharmacological strategy for the treatment of glioblastoma by redoxcycling ‘mitocans’ such as quinone/ascorbate combination drugs, based on their tumor-selective redox-modulating effects and tolerance to normal cells and tissues.Methods: Experiments were performed on glioblastoma mice (orthotopic model) treated with coenzyme Q0/ascorbate (Q0/A). The drug was injected intracranially in a single dose. The following parameters were analyzed in vivo using MRI orex vivo using conventional assays: tumor growth, survival, cerebral and tumor perfusion, tumor cell density, tissue redox-state, and expression of tumor-associated NADH oxidase (tNOX).Results: Q0/A markedly suppressed tumor growth and significantly increased survival of glioblastoma mice. This was accompanied by increased oxidative stress in the tumor but not in non-cancerous tissues, increased tumor blood flow, and downregulation of tNOX. The redox-modulating and anticancer effects of Q0/A were more pronounced than those of menadione/ascorbate (M/A) obtained in our previous study. No adverse drug-related side-effects were observed in glioblastoma mice treated with Q0/A.Discussion: Q0/A differentiated cancer cells and tissues, particularly glioblastoma, from normal ones by redox targeting, causing a severe oxidative stress in the tumor but not in non-cancerous tissues. Q0/A had a pronounced anticancer activity and could be considered safe for the organism within certain concentration limits. The results suggest that the rate of tumor resorption and metabolism of toxic residues must be controlled and maintained within tolerable limits to achieve longer survival, especially at intracranial drug administration.

ROS impairs tumor vasculature normalization through an endocytosis effect of caveolae on extracellular SPARC

BackgroundThe accumulation of reactive oxygen species (ROS) in tumor microenvironment (TME) is an important player for tumorigenesis and progression. We aimed to explore the outcomes of ROS on tumor vessels and the potential regulated mechanisms.MethodsExogenous H2O2 was adopted to simulate the ROS setting. Immunofluorescence staining and ultrasonography were used to assess the vascular endothelial coverage and perfusions in the tumors inoculated with Lewis lung cancer (LLC) and melanoma (B16F10) cells of C57BL/6 mice, respectively. ELISA and western-blot were used to detect the expression of secreted acidic and cysteine-rich protein (SPARC) and Caveale-1 in human umbilical vein endothelial cells (HUVEC) extra- and intracellularly. Intracellular translocation of SPARC was observed using electron microscopy and immunofluorescence approaches.ResultUnder the context of oxidative stress, the pericyte recruitment of neovascularization in mouse lung cancer and melanoma tissues would be aberrated, which subsequently led to the disruption of the tumor vascular architecture and perfusion dysfunction. In vitro, HUVEC extracellularly SPARC was down-regulated, whereas intracellularly it was up-regulated. By electron microscopy and immunofluorescence staining, we observed that SPARC might undergo transmembrane transport via caveale-1-mediated endocytosis. Finally, the binding of SPARC to phosphorylated-caveale-1 was also detected in B16F10 tissues.ConclusionIn the oxidative stress environment, neovascularization within the tumor occurs structural deterioration and decreased perfusion capacity. One of the main regulatory mechanisms is the migration of extracellular SPARC from the endothelium to intracellular compartments via Caveolin-1 carriers.

Mapping estimates of vascular permeability with a clinical indocyanine green fluorescence imaging system in experimental pancreatic adenocarcinoma tumors.

Pancreatic cancer tumors are known to be avascular, but their neovascular capillaries are still chaotic leaky vessels. Capillary permeability could have significant value for therapy assessment, and its quantification might be possible with macroscopic imaging of indocyanine green (ICG) kinetics in tissue. The capacity of using standard fluorescence surgical systems for ICG kinetic imaging as a probe for capillary leakage was evaluated using a clinical surgical fluorescence imaging system, as interpreted through vascular permeability modeling. Xenograft pancreatic adenocarcinoma models were imaged in mice during bolus injection of ICG to capture the kinetics of uptake. Image analysis included ratiometric data, normalization, and match to theoretical modeling. Kinetic data were converted into the extraction fraction of the capillary leakage. Pancreatic tumors were usually less fluorescent than the surrounding healthy tissues, but still the rate of tumor perfusion could be assessed to quantify capillary extraction. Model simulations showed that flow kinetics stabilized after about 1min beyond the initial bolus injection and that the relative extraction fraction model estimates matched the experimental data of normalized uptake within the tissue. The kinetics in the time period of 1 to 2min post-injection provided optimal differential data between AsPC1 and BxPC3 tumors, although high individual variation exists between tumors. ICG kinetic imaging during the initial leakage phase was diagnostic for quantitative vascular permeability within pancreatic tumors. Methods for autogain correction and normalized model-based interpretation allowed for quantification of extraction fraction and difference identification between tumor types in early timepoints.

Liver Cancer Vascularity Driven by Extracellular Matrix Stiffness: Implications for Imaging Research.

Extracellular matrix stiffness represents a barrier to effective local and systemic drug delivery. Increasing stiffness disrupts newly formed vessel architecture and integrity, leading to tumor-like vasculature. The resulting vascular phenotypes are manifested through different cross-sectional imaging features. Contrast-enhanced studies can help elucidate the interplay between liver tumor stiffness and different vascular phenotypes. This study aims to correlate extracellular matrix stiffness, dynamic contrast-enhanced computed tomography, and dynamic contrast-enhancement ultrasound imaging features of 2 rat hepatocellular carcinoma tumor models. Buffalo-McA-RH7777 and Sprague Dawley (SD)-N1S1 tumor models were used to evaluate tumor stiffness by 2-dimensional shear wave elastography, along with tumor perfusion by dynamic contrast-enhanced ultrasonography and contrast-enhanced computed tomography. Atomic force microscopy was used to calculate tumor stiffness at a submicron scale. Computer-aided image analyses were performed to evaluate tumor necrosis, as well as the percentage, distribution, and thickness of CD34+ blood vessels. Distinct tissue signatures between models were observed according to the distribution of the stiffness values by 2-dimensional shear wave elastography and atomic force microscopy ( P < 0.05). Higher stiffness values were attributed to SD-N1S1 tumors, also associated with a scant microvascular network ( P ≤ 0.001). Opposite results were observed in the Buffalo-McA-RH7777 model, exhibiting lower stiffness values and richer tumor vasculature with predominantly peripheral distribution ( P = 0.03). Consistent with these findings, tumor enhancement was significantly greater in the Buffalo-McA-RH7777 tumor model than in the SD-N1S1 on both dynamic contrast-enhanced ultrasonography and contrast-enhanced computed tomography ( P < 0.005). A statistically significant positive correlation was observed between tumor perfusion on dynamic contrast-enhanced ultrasonography and contrast-enhanced computed tomography in terms of the total area under the curve and % microvessel tumor coverage ( P < 0.05). The stiffness signatures translated into different tumor vascular phenotypes. Two-dimensional shear wave elastography and dynamic contrast-enhanced ultrasonography adequately depicted different stromal patterns, which resulted in unique imaging perfusion parameters with significantly greater contrast enhancement observed in softer tumors.

Drug transport modeling in solid tumors: A computational exploration of spatial heterogeneity of biophysical properties

Inadequate uptake of therapeutic agents by tumor cells is still a major barrier in clinical cancer therapy. Mathematical modeling is a powerful tool to describe and investigate the transport phenomena involved. However, current models for interstitial flow and drug delivery in solid tumors have not yet embedded the existing heterogeneity of tumor biomechanical properties. The purpose of this study is to introduce a novel and more realistic methodology for computational models of solid tumor perfusion and drug delivery accounting for these regional heterogeneities as well as lymphatic drainage effects.Several tumor geometries were studied using an advanced computational fluid dynamics (CFD) modeling approach of intratumor interstitial fluid flow and drug transport. Hereby, the following novelties were implemented: (i) the heterogeneity of tumor-specific hydraulic conductivity and capillary permeability; (ii) the effect of lymphatic drainage on interstitial fluid flow and drug penetration.Tumor size and shape both have a crucial role on the interstitial fluid flow regime as well as drug transport illustrating a direct correlation with interstitial fluid pressure (IFP) and an inverse correlation with drug penetration, except for large tumors having a diameter larger than 50 mm. The results also suggest that the interstitial fluid flow and drug penetration in small tumors depend on tumor shape. A parameter study on the necrotic core size illustrated that the core effect (i.e. fluid flow and drug penetration alteration) was only profound in small tumors. Interestingly, the impact of a necrotic core on drug penetration differs depending on the tumor shape from having no effect in ideally spherical tumors to a clear effect in elliptical tumors with a necrotic core. A realistic presence of lymphatic vessels only slightly affected tumor perfusion, having no substantial effect on drug delivery.In conclusion, our findings illustrated that our novel parametric CFD modeling strategy in combination with accurate profiling of heterogeneous tumor biophysical properties can provide a powerful tool for better insights into tumor perfusion and drug transport, enabling effective therapy planning.

New approaches to radio- and chemosensitization using proton pump inhibitors through the lens of tumor cell microenvironment patterns

Background. Chaotic and improper angiogenesis in the tumor tissue causes deficit in O2 perfusion in tumors, a decreased capacity to deliver nutrients and remove metabolism products from cells, creating preconditions for the formation of hypoxic and alkaline microenvironment which drives tumor progression, invasion and metastases. Recent studies have shown that the use of proton pump inhibitors (PPIs) increases sensitivity of the tumor cells that are resistant to cytotoxic drugs and radiation therapy.&#x0D; Purpose – to provide insight into the modern data on the possibilities of the use of proton pump inhibitors for overcoming radio- and chemoresistance.&#x0D; Materials and methods. The selection of publications was performed in such databases as Pubmed, eBook Business Collection, Clinical Key Elsevier, Cochrane Library in which the data on the ways of overcoming radio- and chemoresistance of tumor cells using PPIs were described. At the first stage, the search of literature sources was carried out by the following keywords: radioresistance, proton pump inhibitors, tumor cell microenvironment. At the second stage, the abstracts of the articles were studied, and those publications that did not match the criteria of our work were excluded. At the third stage, full texts of the selected articles were studied for relevance and eligibility to be included in the references.&#x0D; Results and discussion. The modulation of the acidic tumor cell microenvironment is a prospective direction of antitumor treatment. The abnormal pH-gradient between the extracellular environment and the cell cytoplasm is mediated by different ion/proton pumps, including vacuolar H+-ATPase, Na+/H– exchangers, monocarboxylate transporters, carbonic anhydrases, etc. Several studies have revealed that PPIs inhibit not only the H+/K+-ATPase in gastric parietal cells, but also the vacuolar H+-ATPase (V-ATPase) overexpressed in tumor cells. The addition of PPIs to treatment regimen has demonstrated effectiveness in tumor processes of different localization, including those in colorectal cancer, ovarian cancer, lung cancer, pancreatic cancer, prostate cancer, and breast cancer.&#x0D; Conclusions. The obtained data from the analysis of literature sources indicate the potential of conducting preclinical and clinical trials of the effectiveness of PPIs as the new radio- and chemosensitizing drugs in Ukraine.

Ultrasound stiffness and perfusion markers correlate with tumor volume responses to immunotherapy

Immunotherapy has revolutionized the treatment of dozens of cancers and became a standard of care for some tumor types. However, the majority of patients do not benefit from current immunotherapeutics and many develop severe toxicities. Therefore, the identification of biomarkers to classify patients as likely responders or non-responders to immunotherapy is a timely task. Here, we test ultrasound imaging markers of tumor stiffness and perfusion. Ultrasound imaging is non-invasive and clinically available and can be used both for stiffness and perfusion evaluation. In this study, we employed syngeneic orthotopic models of two breast cancers, a fibrosarcoma and a melanoma, to demonstrate that ultrasound-derived measures of tumor stiffness and perfusion (i.e., blood volume) correlate with the efficacy of immune checkpoint inhibition (ICI) in terms of changes in primary tumor volume. To modulate tumor stiffness and perfusion and thus, get a range of therapeutic outcomes, we employed the mechanotherapeutic tranilast. Mechanotherapeutics combined with ICI are advancing through clinical trials, but biomarkers of response have not been tested until now. We found the existence of linear correlations between tumor stiffness and perfusion imaging biomarkers as well as strong linear correlations between the stiffness and perfusion markers with ICI efficacy on primary tumor growth rates. Our findings set the basis for ultrasound biomarkers predictive of ICI therapy in combination with mechanotherapeutics. Statement of significanceHypothesis: Monitoring Tumor Microenvironment (TME) mechanical abnormalities can predict the efficacy of immune checkpoint inhibition and provide biomarkers predictive of response. Tumor stiffening and solid stress elevation are hallmarks of tumor patho-physiology in desmoplastic tumors. They induce hypo-perfusion and hypoxia by compressing tumor vessels, posing major barriers to immunotherapy. Mechanotherapeutics is a new class of drugs that target the TME to reduce stiffness and improve perfusion and oxygenation. In this study, we show that measures of stiffness and perfusion derived from ultrasound shear wave elastography and contrast enhanced ultrasound can provide biomarkers of tumor response.

The Efficacy of Nanoparticle Delivery to Hypoxic Solid Tumors by ciRGD Co-Administration Depends on Neuropilin-1 and Neutrophil Levels.

The ability to improve nanoparticle delivery to solid tumors is an actively studied domain, where various mechanisms are looked into. In previous work, the authors have looked into nanoparticle size, tumor vessel normalization, and disintegration, and here it is aimed to continue this work by performing an in-depth mechanistic study on the use of ciRGD peptide co-administration. Using a multiparametric approach, it is observed that ciRGD can improve nanoparticle delivery to the tumor itself, but also to tumor cells specifically better than vessel normalization strategies. The effect depends on the level of tumor perfusion, hypoxia, neutrophil levels, and vessel permeability. This work shows that upon characterizing tumors for these parameters, conditions can be selected that can optimally benefit from ciRGD co-administration as a means to improve NP delivery to solid tumors.