Tumor Perfusion Research Articles

NIMG-23. A NOVEL APPROACH TO PERFUSION MRI STUDIES IN BRAIN TUMOR PATIENTS USING ENDOGENOUS DEOXYHEMOGLOBIN AS A CONTRAST AGENT: A PROOF-OF-CONCEPT STUDY

Abstract BACKGROUND Assessment of resting perfusion in brain tumors is clinically relevant and relies on dynamic susceptibility contrast magnetic resonance imaging using gadolinium contrast. Preliminary studies have introduced the use of controlled hemoglobin desaturation by means of a transient hypoxic stimulus during echo-planar imaging(EPI) as a surrogate for gadolinium for resting perfusion assessment in healthy subjects. In this proof of concept study, we investigated whether this approach is feasible in brain tumors and warrant further validation. METHODS A computer controlled gas blender was used to induce transient and standardized hypoxic stimulus in isocapnic conditions during EPI acquisition in a heterogenous cohort of tumor patients. The induced blood-oxygen-level-dependent(BOLD) signal changes determined by transit of a bolus of deoxygenated blood in the brain vasculature were used as a surrogate of gadolinium to calculate cerebral blood volume(CBV), cerebral blood flow(CBF) and mean transit time(MTT) using a global arterial input functions obtained through the BOLD signal measured over the middle cerebral artery as previously described by Poublanc et al. Perfusion parameters were calculated in the whole-brain voxel-by-voxel and in automatically segmented region of interest(ROI) using SPM, AFNI, Verbena softwares and MATLAB in-house written scripts. RESULTS Nine patients were included. MTT, rCBV, rCBF were calculated voxel-per-voxel. Obtained maps were overlayed on the co-registered T1 MRI scans and compared to T1CE and FLAIR to identify perfusion patterns in tumor ROIs (contrast enhancement, edema, necrosis). The deoxy-hemoglobin BOLD MRI perfusion were compared to clinical DSC-MRI when available and showed high qualitative agreement. CONCLUSION Transient and precise hemoglobin desaturation by controlled hypoxic gas modulation is safe and repeatable in brain tumor patients. The induced BOLD signal change allows measurement of resting perfusion, which qualitatively closely mimic gadolinium perfusion in different brain tumors. Deoxyhemoglobin-based perfusion warrant further quantitative validation against gadolinium in a larger cohort of heterogenous tumor patients.

Anisotropic Hollow Structure with Chemotaxis Enabling Intratumoral Autonomic Therapy.

Effective intratumoral drug penetration is pivotal for successful cancer treatment. However, due to the disrupted capillary networks and poor perfusion in solid tumors, there exist challenges to realize autonomous directional drug penetration and controlled drug release within the tumor. Considering the specificity of glucose within tumor tissue, we draw inspiration from nature and engineer asymmetrical hollow structures exhibiting chemotaxis towards high glucose levels. By incorporating multiple shells into these structures, we enhance the local chemical concentration gradients, thereby improving cellular uptake and precise targeting. The advantages of anisotropic hollow multishell structure (a-HoMS) can be reflected from the diffusion coefficient and directivity, which increase by 73.4% and 265% respectively compared to conventional isotropic hollow spheres, achieving the most linear movement while ensuring the speed of movement. Furthermore, the multi-level porosity and temporal-spatial order of a-HoMS enable sequential drug delivery that inhibits angiogenesis with inducing cell apoptosis. After the eradication of localized tumor cells, the a-HoMS can automatically migrate to the alive tumor cells under the glucose gradient, inducing another cycle of drug delivery and chemotaxis, resulting in excellent antitumor efficacy. These anisotropic HoMS demonstrate intelligence, adaptability, and precision in tumor therapy, providing valuable insights for programmable treatment within tissues.

Anisotropic Hollow Structure with Chemotaxis Enabling Intratumoral Autonomic Therapy

Effective intratumoral drug penetration is pivotal for successful cancer treatment. However, due to the disrupted capillary networks and poor perfusion in solid tumors, there exist challenges to realize autonomous directional drug penetration and controlled drug release within the tumor. Considering the specificity of glucose within tumor tissue, we draw inspiration from nature and engineer asymmetrical hollow structures exhibiting chemotaxis towards high glucose levels. By incorporating multiple shells into these structures, we enhance the local chemical concentration gradients, thereby improving cellular uptake and precise targeting. The advantages of anisotropic hollow multishell structure (a‐HoMS) can be reflected from the diffusion coefficient and directivity, which increase by 73.4% and 265% respectively compared to conventional isotropic hollow spheres, achieving the most linear movement while ensuring the speed of movement. Furthermore, the multi‐level porosity and temporal‐spatial order of a‐HoMS enable sequential drug delivery that inhibits angiogenesis with inducing cell apoptosis. After the eradication of localized tumor cells, the a‐HoMS can automatically migrate to the alive tumor cells under the glucose gradient, inducing another cycle of drug delivery and chemotaxis, resulting in excellent antitumor efficacy. These anisotropic HoMS demonstrate intelligence, adaptability, and precision in tumor therapy, providing valuable insights for programmable treatment within tissues.

Role of Contrast Perfusion Weighted Magnetic Resonance Imaging in Grading of Brain Tumors with Histopathological Correlation

Background: Traditional MRI sequences provide precise anatomical information about brain tumors. But these sequences can’t quantitatively evaluate vascular physiology, or capture tumor biology at the molecular level; which is important for tumor grading, therapeutic assessment, and prognostication. Furthermore, non-enhancing parts of the tumor affected brain, which generally indicates peri-tumoral brain edema with infiltrative tumor cells, is not visible on conventional MRI sequences. Perfusion weighted Magnetic Resonance Imaging (PW-MRI) techniques such as Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) and Dynamic Susceptibility Contrast Magnetic Resonance Imaging (DSC-MRI) have shown promise as imaging biomarkers for glioma therapy, since these new sequences can also provide information about vascular hemodynamics. Our study was first prospective study from Himalayan belt of India, wherein we tried to assess the role of PW-MRI in the grading of brain tumors, with histopathological correlation. Aim and Objective: To compare tumor perfusion and histopathological tumor grading, in evaluation of brain tumor especially gliomas. Material and Method: 40 patients who were referred to Department of Radiodiagnosis for evaluation of brain tumor, and who gave informed consent, were included in this prospective study, done over a period of 18 months. All patients underwent MRI, followed by surgical resection. Observation and Result: In our study, diagnostic accuracy was 90% for mean rCBV (lesion) (cut off: 7 by ROC), mean rCBF (lesion) (cut off: 13.9 by ROC), and rCBF ratio (cut off: 2.9 by ROC); for differentiating benign versus malignant brain tumor. rCBF ratio was found to be best diagnostic parameter with sensitivity of 96%, specificity of 80%, positive predictive value of 89%, negative predictive value of 92%, diagnostic accuracy of 90%, area under ROC curve=0.909, and p value<0.001. Conclusion: We come to conclusion that high grade brain tumor display higher CBF, than do low grade brain tumor. Three parameters showed good diagnostic accuracy, which includes rCBF ratio, mean rCBF (lesion), and mean rCBV (lesion). These parameters can be used to predict the grade of the brain tumor, with good diagnostic accuracy.

Advanced imaging reveals enhanced malignancy in glioblastomas involving the subventricular zone: evidence of increased infiltrative growth and perfusion.

Glioblastoma's infiltrative growth and heterogeneity are influenced by neural, molecular, genetic, and immunological factors, with the precise origin of these tumors remaining elusive. Neurogenic zones might serve as the tumor stem cells' nest, with tumors in contact with these zones exhibiting worse outcomes and more aggressive growth patterns. This study aimed to determine if these characteristics are reflected in advanced imaging, specifically diffusion and perfusion data. In this monocentric retrospective study, 137 glioblastoma therapy-naive patients (IDH-wildtype, grade 4) with advanced preoperative MRI, including perfusion and diffusion imaging, were analyzed. Tumors and neurogenic zones were automatically segmented. Advanced imaging metrics, including cerebral blood volume (CBV) from perfusion imaging, tissue volume mask (TVM), and free water corrected fractional anisotropy (FA-FWE) from diffusion imaging, were extracted. SVZ infiltration positively correlated with CBV, indicating higher perfusion in tumors. Significant CBV differences were noted between high and low SVZ infiltration cases at specific percentiles. Negative correlation was observed with TVM and positive correlation with FA-FWE, suggesting more infiltrative tumor growth. Significant differences in TVM and FA-FWE values were found between high and low SVZ infiltration cases. Glioblastomas with SVZ infiltration exhibit distinct imaging characteristics, including higher perfusion and lower cell density per voxel, indicating a more infiltrative growth and higher vascularization. Stem cell-like characteristics in SVZ-infiltrating cells could explain the increased infiltration and aggressive behavior. Understanding these imaging and biological correlations could enhance the understanding of glioblastoma evolution.

Tumoral Pharmacokinetic-Pharmacodynamic Simulation of Doxorubicin-Encapsulated Polymeric Micelles Using a Tissue-Isolated Tumor Perfusion System.

Pharmacokinetic (PK) elucidation of polymeric micelles delivering anticancer drugs is crucial for accurate antitumor PK-pharmacodynamic (PK-PD) simulations. Particularly, establishing a methodology to quantify the tumor inflow and outflow of anticancer drugs encapsulated in polymeric micelles is an essential challenge. General tumor biodistribution experiments are disadvantageous in that inflow quantification is easy, but outflow quantification is challenging. We addressed this issue by proposing a quantification method that combines a tissue-isolated tumor perfusion system with microdialysis. This method aims to determine tumoral drug inflow and outflow by quantifying the drugs released from the polymeric micelles via a tumor-embedded microdialysis probe and perfusate, respectively. Furthermore, we evaluated the feasibility of this method by perfusing pH-sensitive polyethylene glycol-poly(aspartate-hydrazone-doxorubicin/phenylalanine)n (PPDF-Hyd-DOX) in a tissue-isolated tumor perfusion system, and we quantified tumor inflow and outflow released DOX. Based on the quantitative results, we performed compartmental analyses by incorporating the gamma-distributed delay function and calculated the PK rate constants. These parameters were input into a tumor-bearing rat compartment model for ex vivo-in vivo extrapolation (EVIVE) of the rat plasma PPDF-Hyd-DOX concentrations and simulated intratumorally released DOX concentrations. The simulation profiles demonstrated a good fit with the Walker 256 intratumoral released DOX concentration profiles previously reported. This EVIVE-PK model was coupled with the threshold natural-growth tumor PD model, and PK-PD analysis was performed. This model exhibited a better fit to the tumor weight profile of Walker 256-bearing rats treated with PPDF-Hyd-DOX than that of our previously reported PK-PD model. Thus, EVIVE, based on a tissue-isolated tumor perfusion system with microdialysis, is a promising approach for the PK-PD simulation of polymeric micelle anticancer therapy.

A size-switchable nanocluster remodels the immunosuppressive microenvironment of tumor and tumor-draining lymph nodes for improved cancer immunotherapy

Remodeling the immunosuppressive tumor microenvironment (TME) by immunomodulators has been well studied in the past years. However, strategies that enable concurrent modulation of both the immunosuppressive TME and tumor-draining lymph nodes (TDLNs) are still in the infancy. Here, we report a pH-sensitive size-switchable nanocluster, SPN-R848, to achieve simultaneous accumulation in tumor and TDLNs for immune activation. SPN-R848 with original size around 150 nm was formed by self-assembly of resiquimod (R848)-conjugated polyamidoamine (PAMAM) derivative, which could disintegrate into its small constituents (～ 8 nm) upon exposure to tumor acidity. The size reduction not only enhanced their accumulation and perfusion in the primary tumor, but promoted their transport and distribution in TDLNs. Accordingly, SPN-R848 remarkably remodeled the immunosuppressive TME by polarizing M2 to M1 macrophages and activated dendritic cells (DCs) in TDLNs, which synergistically facilitated the production and stimulation of cytotoxic T cells, and inhibited tumor growth in breast cancer and melanoma mouse models. Our study suggests that co-activation of immune microenvironments in both tumor and TDLNs may represent a promising direction to elicit strong antitumor immunity.

Alleviating tumor hypoxia and immunosuppression via sononeoperfusion: A new Ally for potentiating anti-PD-L1 blockade of solid tumor

The hypoxic and immunosuppressive tumor microenvironment (TME) remains a major obstacle to impede cancer immunotherapy. Here, we found that sononeoperfusion—a new effect of tumor perfusion enhancement induced by low mechanical index ultrasound stimulated microbubble cavitation (USMC)—ameliorated tumor tissue oxygenation and induced tumor vascular normalization (TVN). This TVN might be associated with the down-regulation of hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF) within tumors. Moreover, the sononeoperfusion effect reduced the accumulation of immunosuppressive cells, such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and M2-like tumor-associated macrophages (M2-TAMs), and decreased the production of immune inhibitory factors like transforming growth factor-β1 (TGF-β1), interleukin 10 (IL-10), chemoattractant chemokines CC-chemokine ligand 22 (CCL22), CCL28, adenosine and lactate within tumors. Notably, flow cytometry analysis revealed that sononeoperfusion not only increased the percentage of tumor infiltrating-CD8+ T cells, but also promoted the generation of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) by these cells. Furthermore, the improved immune TME by sononeoperfusion effect sensitized anti-PD-L1 treatment both in MC38 colon cancer and Lewis lung carcinoma mice, resulting in tumor regression and prolonged survival. Mechanically, the enhanced efficacy of combination therapy was mainly based on promoting the infiltration and function of CD8+ T cells within tumors. Together, sononeoperfusion could ameliorate hypoxia and immunosuppression in the TME, thereby potentiating anti-PD-L1 therapy for solid tumors. This novel method of USMC generating sononeoperfusion effect may provide a new therapeutic modality for facilitating cancer immunotherapy.

Nutrient Levels and Nutrient Sources in Pancreatic Tumors.

It has been known that poor tumor perfusion and dysregulated cancer cell metabolism give rise to tumor microenvironments with unphysiologic nutrient levels, but the precise alterations in metabolite abundance are not well defined. In a 2015 study in Cancer Research, Kamphorst and colleagues published a detailed comparison of the metabolome from human pancreatic tumors and benign tissues. Tumors were depleted in glucose and various nonessential amino acids but, surprisingly, enriched in essential amino acids. The authors attributed these nutrient imbalances to macropinocytosis of extracellular proteins, a RAS-driven amino acid acquisition pathway that was found to be increased in human tumors and supports pancreatic cancer cell growth during amino acid starvation. These findings substantially contributed to the understanding of altered nutrient levels in tumors and extracellular proteins as noncanonical nutrients. Intratumoral nutrient levels in different cancer contexts and signaling pathways that regulate nutrient acquisition by cancer cells remain a focus of current research. See related article by Kamphorst and colleagues, Cancer Res 2015;75:544-53.

Carrier-Free Nanoagent Interfering with Cancer-Associated Fibroblasts' Metabolism to Promote Tumor Penetration for Boosted Chemotherapy.

Elevated production of extracellular matrix (ECM) in tumor stroma is a critical obstacle for drug penetration. Here we demonstrate that ATP-citrate lyase (ACLY) is significantly upregulated in cancer-associated fibroblasts (CAFs) to produce tumor ECM. Using a self-assembling nanoparticle-design approach, a carrier-free nanoagent (CFNA) is fabricated by simply assembling NDI-091143, a specific ACLY inhibitor, and doxorubicin (DOX) or paclitaxel (PTX), the first-line chemotherapeutic drug, via multiple noncovalent interactions. After arriving at the CAFs-rich tumor site, NDI-091143-mediated ACLY inhibition in CAFs can block the de novo synthesis of fatty acid, thereby dampening the fatty acid-involved energy metabolic process. As the lack of enough energy, the energetic CAFs will be in a dispirited state that is unable to produce abundant ECM, thereby significantly improving drug perfusion in tumors and enhancing the efficacy of chemotherapy. Such a simple drug assembling strategy aimed at CAFs' ACLY-mediated metabolism pathway presents the feasibility of stromal matrix reduction to potentiate chemotherapy.

Comparison of a new MR rapid wash-out map with MR perfusion in brain tumors

BackgroundMR perfusion is a standard marker to distinguish progression and therapy-associated changes after surgery and radiochemotherapy for glioblastoma. TRAMs (Treatment Response Assessment Maps) were introduced, which are intended to facilitate the differentiation of vital tumor cells and radiation necrosis by means of late (20–90 min) contrast clearance and enhancement. The differences of MR perfusion and late-enhancement are not fully understood yet.MethodsWe have implemented and established a fully automated creation of rapid wash-out (15–20 min interval) maps in our clinic. We included patients with glioblastoma, CNS lymphoma or brain metastases who underwent our MR protocol with MR perfusion and rapid wash-out between 01/01/2024 and 30/06/2024. Since both wash-out and hyperperfusion are intended to depict the active tumor area, this study involves a quantitative and qualitative comparison of both methods. For this purpose, we volumetrically measured rCBV (relative cerebral blood volume) maps and rapid wash-out maps separately (two raters). Additionally, we rated the agreement between both maps on a Likert scale (0–10).ResultsThirty-two patients were included in the study: 15 with glioblastoma, 7 with CNS lymphomas and 10 with brain metastasis. We calculated 36 rapid wash-out maps (9 initial diagnosis, 27 follow-up).Visual agreement of MR perfusion with rapid wash-out by rating were found in 44 ± 40% for initial diagnosis, and 75 ± 31% for follow-up. We found a strong correlation (Pearson coefficient 0.92, p < 0.001) between the measured volumes of MR perfusion and rapid wash-out. The measured volumes of MR perfusion and rapid wash-out did not differ significantly. Small lesions were often not detected by MR perfusion. Nevertheless, the measured volumes showed no significant differences in this small cohort.ConclusionsRapid wash-out calculation is a simple tool that provides new information and, when used in conjunction with MR perfusion, may increase diagnostic accuracy. The method shows promising results, particularly in the evaluation of small lesions.

Dual hyperpolarized [1-13C]pyruvate and [13C]urea magnetic resonance imaging of prostate cancer

BackgroundAlthough multiparametric (mp) 1H magnetic resonance imaging (MRI) is increasingly used to detect and localize prostate cancer (PC), its correlation with tumor grade is limited. Hyperpolarized (HP) carbon-13 (13C) MR is an emerging imaging technique, which can be used to interrogate key biologic processes through in vivo detection of various HP probes. A distinct attribute of HP 13C MRI is the ability to detect multiple HP probes within a single acquisition. Here we report on the first simultaneous dual HP [1-13C]pyruvate and [13C]urea MRI with correlations to histopathologic findings in a patient with localized PC scheduled for radical prostatectomy. Material and methodsPaired HP 13C and standard mp 1H MRI were performed in a patient with biopsy-proven Gleason score 4 + 3 = 7 adenocarcinoma of the prostate scheduled for radical prostatectomy through a first-in-human pilot study of dual-agent HP MRI (NCT02526368). HP 13C MRI was performed using a clinical 3T scanner with 13C transmit-and-receive capabilities. Dynamic series of HP 13C pyruvate, lactate and urea imaging were acquired following intravenous (IV) injection of co-hyperpolarized [13C]urea (25 mM) and [1–13C]pyruvate (125 mM). The [1-13C]pyruvate-to-[1-13C]lactate conversion rate (kPL) was calculated using an inputless two-site exchange model; AUCurea was the [13C]urea signal summed over time. Following radical prostatectomy, whole-mount prostate histopathological slides were prepared and reviewed by an experienced genitourinary pathologist. ResultsFollowing informed consent, the patient underwent paired mp 1H MRI and dual-agent HP MRI. mp 1H MRI revealed a 1.2 cm lesion in the left apical posterior zone. Dual-agent HP MRI identified a focus of increased [1-13C]pyruvate-to-[1-13C]lactate conversion rate (kPL) extending from the left apical posterior peripheral zone to the right gland. A corresponding area of abnormal tissue perfusion (AUCurea) was seen in the left gland. Metabolism-perfusion mismatch (with several foci of increased kPL/AUCurea) was observed throughout the tumor. Tumor extension to the right midgland was confirmed at the time of radical prostatectomy and staining for lactate dehydrogenase-A was increased throughout the tumor relative to surrounding benign prostatic tissue. ConclusionThis first-in-human radiopathologic study demonstrates the feasibility of dual-agent HP MRI in PC patients. Simultaneous assessment of tumor metabolism and perfusion was able to detect occult disease as well as to show a significant mismatch between intra-tumoral metabolism and tissue perfusion in high-grade PC. Prospective validation of these findings is warranted.

An Unsupervised Approach for Treatment Effectiveness Monitoring Using Curvature Learning

Contrast-enhanced ultrasound could assess whether cancer chemotherapeutic agents work in days, rather than waiting 2–3 months, as is typical using the Response Evaluation Criteria in Solid Tumors (RECIST), therefore avoiding toxic side effects and expensive, ineffective therapy. A total of 40 mice were implanted with human colon cancer cells: treatment-sensitive mice in control (n = 10, receiving saline) and treated (n = 10, receiving bevacizumab) groups and treatment-resistant mice in control (n = 10) and treated (n = 10) groups. Each mouse was imaged using 3D dynamic contrast-enhanced ultrasound with Definity microbubbles. Curvature learning, an unsupervised learning approach, quantized pixels into three classes—blue, yellow, and red—representing normal, intermediate, and high cancer probability, both at baseline and after treatment. Next, a curvature learning score was calculated for each mouse using statistical measures representing variations in these three color classes across each frame from cine ultrasound images obtained during contrast administration on a given day (intra-day variability) and between pre- and post-treatment days (inter-day variability). A Wilcoxon rank-sum test compared score distributions between treated, treatment-sensitive mice and all others. There was a statistically significant difference in tumor score between the treated, treatment-sensitive group (n = 10) and all others (n = 30) (p = 0.0051). Curvature learning successfully identified treatment response, detecting changes in tumor perfusion before changes in tumor size. A similar technique could be developed for humans.

Quantitative Perfusion-Weighted Magnetic Resonance Imaging in Uveal Melanoma.

Perfusion-weighted imaging (PWI; magnetic resonance imaging [MRI]) has been shown to provide valuable biological tumor information in uveal melanoma (UM). Clinically used semiquantitative methods do not account for tumor pigmentation and eye movement. We hypothesize that a quantitative PWI method that incorporates these, provides a more accurate description of tumor perfusion than the current clinical method. The aim of this study was to test this in patients with UM before and after radiotherapy. Perfusion-weighted 3T MRIs were retrospectively analyzed in 47 patients with UM before and after radiotherapy. Tofts pharmacokinetic modeling was performed to determine vascular permeability (Ktrans), extracellular extravascular space (ve), and reflux rate (kep). These were compared with semiquantitative clinical parameters including peak intensity and outflow percentage. The effect of tumor pigmentation on peak intensity and outflow percentage was statistically significant (P < 0.01) and relative peak intensity was significantly different between melanotic and amelanotic tumors (1.5 vs. 1.9, P < 0.01). Before radiotherapy, median tumor Ktrans was 0.63 min-1 (range = 0.06-1.42 min-1), median ve was 0.23 (range = 0.09-0.63), and median kep was 2.3 min-1 (range = 0.6-5.0 min-1). After radiotherapy, 85% showed a decrease in Ktrans and kep (P < 0.01). Changes in tumor pigmentation before and after radiotherapy were small and not significant (median increase in T1 of 33 ms, P = 0.55). Quantitative PWI parameters decreased significantly after radiotherapy and can therefore can serve as an early biomarker for treatment response assessment. However, due to the nonsignificant changes in tumor pigmentation before and after radiotherapy, the current semiquantitative method appears to be sufficiently sensitive for detection of changes in tumor perfusion.

Tumor perfusion enhancement by focus ultrasound-induced blood-brain barrier opening to potentiate anti-PD-1 immunotherapy of glioma

ObjectiveTo demonstrate the feasibility of using focused ultrasound to enhance delivery of PD-1 inhibitors in glioma rats and determine if such an approach increases treatment efficacy. MethodsC6 glioma in situ rat model was used in this study. Transcranial irradiation with FUS combined with microbubbles was administered to open the blood-brain barrier (BBB). The efficacy of BBB opening was evaluated in normal rats. The rats with glioma were grouped to evaluate the role of PD-1 inhibitors combined with FUS-induced immune responses in suppressing glioma when the BBB opens. Flow cytometry was used to examine the changes of immune cell populations of lymphocytes in peripheral blood, tumor tissue and spleen tissue of the rats. A section of rat brain tissue was also used for histological and immunohistochemical analysis. The survival of the rats was then monitored; the tumor progression and changes in blood perfusion of tumor were dynamically observed in vivo using multimodal MRI. ResultsFUS combined with microbubbles could enhance the blood perfusion of tumors by increasing the permeability of BBB (p < 0.0001), thus promoting the infiltration of CD4+ T lymphocytes (p < 0.01). Compared with the control group, the combination treatment group had increased in the infiltration number of CD4+(p < 0.05) and CD8+ T (p < 0.05); the tumor volume of the combined treatment group was smaller than that of the control group (p < 0.01) and the survival rate of the rats was prolonged (p < 0.05). ConclusionsIn this study, we demonstrated that the transient opening of the BBB induced by FUS enhanced tumor vascular perfusion and facilitated the delivery of PD-1 inhibitors, ultimately improving the therapeutic efficacy for glioblastoma.

Anticancer transmission effects induced by hybrid plasma bubble-activated medium

As an indirect application of cold atmospheric plasma, the use of plasma-activated solutions has recently attracted significant attention for intracavity tumor perfusion therapy. Here, an underwater plasma-bubble reactor with three discharge modes was applied to activate a cell culture medium, with the aim of inhibiting the growth of bladder cancer T24 cells in vitro. The results showed that although the reactive species in cell culture medium generated by the underwater bubble plasma varied between the dielectric barrier discharge (DBD) mode, spark mode, and hybrid mode, the plasma-activated cell culture medium (PAM) corresponding to all three discharge modes effectively decreased the viability of T24 cells. However, after co-culturing the PAM-pretreated T24 cells with normal T24 cells, it was observed that normal T24 cells were not affected by either the DBD or spark mode; however, the hybrid mode PAM-pretreated T24 cells further induced inactivation and apoptosis of normal T24 cells. Further studies suggested that the aqueous reactive species generated by the underwater bubble plasma in hybrid mode not only induced the apoptosis of T24 cells directly but also triggered PAM-pretreated T24 cell-derived exosome-mediated anticancer activity toward cancer cells. These results may provide a strategy for enhancing the anticancer extent and effect of PAM as well as advancing its clinical application.

3D Single Vessel Fractional Moving Blood Volume (3D-svFMBV): Fully Automated Tissue Perfusion Estimation Using Ultrasound.

Power Doppler ultrasound (PD-US) is the ideal modality to assess tissue perfusion as it is cheap, patient-friendly and does not require ionizing radiation. However, meaningful inter-patient comparison only occurs if differences in tissue-attenuation are corrected for. This can be done by standardizing the PD-US signal to a blood vessel assumed to have 100% vascularity. The original method to do this is called fractional moving blood volume (FMBV). We describe a novel, fully-automated method combining image processing, numerical modelling, and deep learning to estimate three-dimensional single vessel fractional moving blood volume (3D-svFMBV). We map the PD signals to a characteristic intensity profile within a single large vessel to define the standardization value at the high shear vessel margins. This removes the need for mathematical correction for background signal which can introduce error. The 3D-svFMBV was first tested on synthetic images generated using the characteristics of uterine artery and physiological ultrasound noise levels, demonstrating prediction of standardization value close to the theoretical ideal. Clinical utility was explored using 143 first-trimester placental ultrasound volumes. More biologically plausible perfusion estimates were obtained, showing improved prediction of pre-eclampsia compared with those generated with the semi-automated original 3D-FMBV technique. The proposed 3D-svFMBV method overcomes the limitations of the original technique to provide accurate and robust placental perfusion estimation. This not only has the potential to provide an early pregnancy screening tool but may also be used to assess perfusion of different organs and tumors.

Dynamic contrast enhanced ultrasound in differential diagnosis of hepatocellular carcinoma: A systematic review and meta-analysis.

Non-invasive differential diagnosis between hepatocellular carcinoma (HCC) and other liver cancer (i.e. cholangiocarcinoma or metastasis) is highly challenging and definitive diagnosis still relies on histological exam. The patterns of enhancement and wash-out of liver nodules can be used to stratify the risk of malignancy only in cirrhotic patients and HCC frequently shows atypical features. Dynamic contrast-enhanced ultrasound (DCEUS) with standardized software could help to overcome these obstacles, providing functional and quantitative parameters and potentially improving accuracy in the evaluation of tumor perfusion. To explore clinical evidence regarding the application of DCEUS in the differential diagnosis of liver nodules. A comprehensive literature search of clinical studies was performed to identify the parameters of DCEUS that could relate to histological diagnosis. In accordance with the study protocol, a qualitative and quantitative analysis of the evidence was planned. Rise time was significantly higher in HCC patients with a standardized mean difference (SMD) of 0.83 (95%CI: 0.48-1.18). Similarly, other statistically significant parameters were mean transit time local with a SMD of 0.73 (95%CI: 0.20-1.27), peak enhancement with a SMD of 0.37 (95%CI: 0.03-0.70), area wash-in area under the curve with a SMD of 0.47 (95%CI: 0.13-0.81), wash-out area under the curve with a SMD of 0.55 (95%CI: 0.21-0.89) and wash-in and wash-out area under the curve with SMD of 0.51 (95%CI: 0.17-0.85). SMD resulted not significant in fall time and wash-in rate, but the latter presented a trend towards greater values in HCC compared to intrahepatic cholangiocarcinoma. DCEUS could improve non-invasive diagnosis of HCC, leading to less liver biopsy and early treatment. This quantitative analysis needs to be applied on larger cohorts to confirm these preliminary results.

Comparison of CT and MRI in the Diagnosis of Liver Tumors: A Retrospective Case-Control Analysis.

To compare the diagnostic value of multi-slice computed tomography (CT) and magnetic resonance imaging (MRI) in liver tumors. Retrospective selection of CT and MRI imaging data from 109 cases of liver tumors treated in our hospital from January 2020 to March 2023. The selection was determined through pathological examination. According to the pathological examination results, 61 cases were benign tumors, and 48 cases were malignant tumors. The hepatic portal flow (HPF), hepatic artery perfusion index (HPI) and hepatic artery perfusion (HAF) of malignant tumors were significantly lower than in benign tumors (P<0.05). The signal enhancement ratio of malignant tumors was significantly higher than in benign tumors, and the peak time was significantly lower than in benign tumors (P<0.05). The sensitivity (97.92%) and accuracy (97.25%) of the combined examination were significantly higher than those of MRI (83.33%, 90.83%) or CT alone (81.25%, 88.99%) (P<0.05). CT and MRI have high application value in the diagnosis and evaluation of liver tumors, and the combination of these two methods can further improve diagnostic sensitivity and accuracy, providing an objective reference for early diagnosis and treatment of liver cancer.</p>.

Power-Doppler-based NH002 microbubble sonoporation with chemotherapy relieves hypoxia and enhances the efficacy of chemotherapy and immunotherapy for pancreatic tumors

Pancreatic ductal adenocarcinoma (PDAC) poses challenges due to late-stage diagnosis and limited treatment response, often attributed to the hypoxic tumor microenvironment (TME). Sonoporation, combining ultrasound and microbubbles, holds promise for enhancing therapy. However, additional preclinical research utilizing commercially available ultrasound equipment for PDAC treatment while delving into the TME's intricacies is necessary. This study investigated the potential of using a clinically available ultrasound system and phase 2-proven microbubbles to relieve tumor hypoxia and enhance the efficacy of chemotherapy and immunotherapy in a murine PDAC model. This approach enables early PDAC detection and blood-flow-sensitive Power-Doppler sonoporation in combination with chemotherapy. It significantly extended treated mice's median survival compared to chemotherapy alone. Mechanistically, this combination therapy enhanced tumor perfusion and substantially reduced tumor hypoxia (77% and 67%, 1- and 3-days post-treatment). Additionally, cluster of differentiation 8 (CD8) T-cell infiltration increased four-fold afterward. The combined treatment demonstrated a strengthening of the anti-programmed death-ligand 1(αPDL1) therapy against PDAC. Our study illustrates the feasibility of using a clinically available ultrasound system with NH-002 microbubbles for early tumor detection, alleviating hypoxic TME, and improving chemotherapy and immunotherapy. It suggests the development of an adjuvant theragnostic protocol incorporating Power-Doppler sonoporation for pancreatic tumor treatment.