Tumor Blood Volume Research Articles

Grading of skull base meningiomas by combined perfusion: arterial spin labeling and T2* dynamic susceptibility perfusion

BackgroundConventional MRI has no distinction between high- and low-grade meningiomas, which has a crucial for choice of therapeutic plan, especially skull base meningiomas which need more meticulous endoscopy-approached surgery. The aim of our study was to evaluate role of perfusion by arterial spin labeling and dynamic susceptibility perfusion in grading of skull base meningiomas.ResultsThe relative arterial spin labeling (ASL), tumor blood flow (TBF), and tumor blood volume (TBV) ratios showed significant differences between low- and high-grade meningiomas.ConclusionsMRI perfusion is a useful in differentiation between low- and high-grade meningiomas. There is significant correlation between ASL and DSC perfusion supporting possibility of using ASL in clinical practice as an alternative technique to DSC perfusion, particularly for patients with renal impairment where no contrast injection needed.

Local Magnetic Hyperthermia and Systemic Gemcitabine/Paclitaxel Chemotherapy Triggers Neo-Angiogenesis in Orthotopic Pancreatic Tumors without Involvement of Auto/Paracrine Tumor Cell VEGF Signaling and Hypoxia.

There is a growing interest in exploring the therapeutically mediated modulation of tumor vascularization of pancreatic cancer, which is known for its poorly perfused tumor microenvironment limiting the delivery of therapeutic agents to the tumor site. Here, we assessed how magnetic hyperthermia in combination with chemotherapy selectively affects growth, the vascular compartment of tumors, and the presence of tumor cells expressing key regulators of angiogenesis. To that purpose, a orthotopic PANC-1 (fluorescent human pancreatic adenocarcinoma) mouse tumor model (Rj:Athym-Foxn1nu/nu) was used. Magnetic hyperthermia was applied alone or in combination with systemic chemotherapy (gemcitabine 50 mg per kg body weight, nab-pacitaxel 30 mg/kg body weight) on days 1 and 7 following magnetic nanoparticle application (dose: 1 mg per 100 mm3 of tumor). We used ultrasound imaging, immunohistochemistry, multi-spectral optoacoustic tomography (MSOT), and hematology to assess the biological parameters mentioned above. We found that magnetic hyperthermia in combination with gemcitabine/paclitaxel chemotherapy was able to impact tumor growth (decreased volumes and Ki67 expression) and to trigger neo-angiogenesis (increased small vessel diameter) as a result of the therapeutically mediated cell damages/stress in tumors. The applied stressors activated specific pro-angiogenic mechanisms, which differed from those seen in hypoxic conditions involving HIF-1α, since (a) treated tumors showed a significant decrease of cells expressing VEGF, CD31, HIF-1α, and neuropilin-1; and (b) the relative tumor blood volume and oxygen level remained unchanged. Neo-angiogenesis seems to be the result of the activation of cell stress pathways, like MAPK pathways (high number of pERK-expressing tumor cells). In the long term, the combination of magnetic hyperthermia and chemotherapy could potentially be applied to transiently modulate tumor angiogenesis and to improve drug accessibility during oncologic therapies of pancreatic cancer.

Tumor treating fields increases blood-brain barrier permeability and relative cerebral blood volume in patients with glioblastoma.

200kHz tumor treating fields (TTFields) is clinically approved for newly-diagnosed glioblastoma (nGBM). Because its effects on conventional surveillance MRI brain scans are equivocal, we investigated its effects on perfusion MRI (pMRI) brain scans. Each patient underwent institutional standard pMRI: dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast (DSC) pMRI at three time points: baseline, 2-, and 6-months on-adjuvant therapy. At each timepoint, the difference between T1 pre- versus post-contrast tumor volume (ΔT1) and these pMRI metrics were evaluated: normalized and standardized relative cerebral blood volume (nRCBV, sRCBV); fractional plasma volume (Vp), volume of extravascular extracellular space (EES) per volume of tissue (Ve), blood-brain barrier (BBB) permeability (Ktrans), and time constant for gadolinium reflux from EES back into the vascular system (Kep). Between-group comparisons were performed using rank-sum analysis, and bootstrapping evaluated likely reproducibility of the results. Among 13 pMRI datasets (11 nGBM, 2 recurrent GBM), therapies included temozolomide-only (n = 9) and temozolomide + TTFields (n = 4). No significant differences were found in patient or tumor characteristics. Compared to temozolomide-only, temozolomide + TTFields did not significantly affect the percent-change in pMRI metrics from baseline to 2 months. But during the 2- to 6-month period, temozolomide + TTFields significantly increased the percent-change in nRCBV (+26.9% [interquartile range 55.1%] vs -39.1% [37.0%], p = 0.049), sRCBV (+9.5% [39.7%] vs -30.5% [39.4%], p = 0.049), Ktrans (+54.6% [1768.4%] vs -26.9% [61.2%], p = 0.024), Ve (+111.0% [518.1%] vs -13.0% [22.5%], p = 0.048), and Vp (+98.8% [2172.4%] vs -24.6% [53.3%], p = 0.024) compared to temozolomide-only. Using pMRI, we provide initial in-human validation of pre-clinical studies regarding the effects of TTFields on tumor blood volume and BBB permeability in GBM.

Assessment of Brain Tumour Perfusion Using Early-Phase 18F-FET PET: Comparison with Perfusion-Weighted MRI

PurposeMorphological imaging using MRI is essential for brain tumour diagnostics. Dynamic susceptibility contrast (DSC) perfusion-weighted MRI (PWI), as well as amino acid PET, may provide additional information in ambiguous cases. Since PWI is often unavailable in patients referred for amino acid PET, we explored whether maps of relative cerebral blood volume (rCBV) in brain tumours can be extracted from the early phase of PET using O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET).ProcedureUsing a hybrid brain PET/MRI scanner, PWI and dynamic 18F-FET PET were performed in 33 patients with cerebral glioma and four patients with highly vascularized meningioma. The time interval from 0 to 2 min p.i. was selected to best reflect the blood pool phase in 18F-FET PET. For each patient, maps of MR-rCBV, early 18F-FET PET (0–2 min p.i.) and late 18F-FET PET (20–40 min p.i.) were generated and coregistered. Volumes of interest were placed on the tumour (VOI-TU) and normal-appearing brain (VOI-REF). The correlation between tumour-to-brain ratios (TBR) of the different parameters was analysed. In addition, three independent observers evaluated MR-rCBV and early 18F-FET maps (18F-FET-rCBV) for concordance in signal intensity, tumour extent and intratumoural distribution.ResultsTBRs calculated from MR-rCBV and 18F-FET-rCBV showed a significant correlation (r = 0.89, p < 0.001), while there was no correlation between late 18F-FET PET and MR-rCBV (r = 0.24, p = 0.16) and 18F-FET-rCBV (r = 0.27, p = 0.11). Visual rating yielded widely agreeing findings or only minor differences between MR-rCBV maps and 18F-FET-rCBV maps in 93 % of the tumours (range of three independent raters 91–94%, kappa among raters 0.78–1.0).ConclusionEarly 18F-FET maps (0–2 min p.i.) in gliomas provide similar information to MR-rCBV maps and may be helpful when PWI is not possible or available. Further studies in gliomas are needed to evaluate whether 18F-FET-rCBV provides the same clinical information as MR-rCBV.

Tumoral and peritumoral vascularization of brain tumours: a study comparing an intraoperative ultrasensitive Doppler and a preoperative first-pass perfusion MRI

IntroductionSurgery for gliomas can be guided by neuronavigation using magnetic resonance imaging (MRI) and intraoperative B-mode ultrasound. An ultrasensitive Doppler (USD) using plane waves is a new method of microvascularization imaging which can be used intraoperatively and could identify tumoral and peritumoral areas with neoangiogenesis but its value requires evaluation. The aim of this pilot study then was to evaluate the correlations between ultrasound measurements of glioma vascularization (tumoral and peritumoral region) obtained by a USD intraoperatively and first-pass perfusion measurements obtained on preoperative MRI. Methods18 patients with proven glial tumors were selected for the analysis. They underwent preoperative MRI and intraoperative USD acquisition. The MRI scans were re-aligned to the reference ultrasound slice plane, and for each patient a segmentation of the tumoral and peritumoral zone was performed. Two perfusion parameters were studied: relative cerebral tumor blood volume (rCCBV) in MRI and fractional moving blood volume (FMBV) in a USD. We studied the correlations between mean rCCBV and mean FMBV measured in the tumoral and peritumoral zones in the reference ultrasound slice plane. ResultsThe mean rCCBV and mean FMBV measured in the tumoral zone were significantly and strongly correlated (r = 0.80; p < 0.001). The mean rCCBV and mean FMBV measured in the peritumoral zone were not statistically correlated, although a tendency towards a correlation was noted (r = 0.45; p = 0.067). ConclusionThere was a good correlation between a tumor FMBV obtained by a USD intraoperatively and rCCBV on a preoperative MRI validating the reliability of USD for intraoperative analyses of tumor microvascularization in gliomas.

A physiologically based pharmacokinetic model for [68Ga]Ga-(HA-)DOTATATE to predict whole-body distribution and tumor sink effects in GEP-NET patients

BackgroundLittle is known about parameters that have a relevant impact on (dis)similarities in biodistribution between various 68Ga-labeled somatostatin analogues. Additionally, the effect of tumor burden on organ uptake remains unclear. Therefore, the aim of this study was to describe and compare organ and tumor distribution of [68Ga]Ga-DOTATATE and [68Ga]Ga-HA-DOTATATE using a physiologically based pharmacokinetic (PBPK) model and to identify factors that might cause biodistribution and tumor uptake differences between both peptides. In addition, the effect of tumor burden on peptide biodistribution in gastroenteropancreatic (GEP) neuroendocrine tumor (NET) patients was assessed.MethodsA PBPK model was developed for [68Ga]Ga-(HA-)DOTATATE in GEP-NET patients. Three tumor compartments were added, representing primary tumor, liver metastases and other metastases. Furthermore, reactions describing receptor binding, internalization and recycling, renal clearance and intracellular degradation were added to the model. Scan data from GEP-NET patients were used for evaluation of model predictions. Simulations with increasing tumor volumes were performed to assess the tumor sink effect.ResultsData of 39 and 59 patients receiving [68Ga]Ga-DOTATATE and [68Ga]Ga-HA-DOTATATE, respectively, were included. Evaluations showed that the model adequately described image-based patient data and that different receptor affinities caused organ uptake dissimilarities between both peptides. Sensitivity analysis indicated that tumor blood flow and blood volume impacted tumor distribution most. Tumor sink predictions showed a decrease in spleen uptake with increasing tumor volume, which seemed clinically relevant for patients with total tumor volumes higher than ~ 550 mL.ConclusionThe developed PBPK model adequately predicted tumor and organ uptake for this GEP-NET population. Relevant organ uptake differences between [68Ga]Ga-DOTATATE and [68Ga]Ga-HA-DOTATATE were caused by different affinity profiles, while tumor uptake was mainly affected by tumor blood flow and blood volume. Furthermore, tumor sink predictions showed that for the majority of patients a tumor sink effect is not expected to be clinically relevant.

Prognostic Evaluation of CT Imaging Big Data-Assisted Arterial Chemoembolization Combined with 125I Seed Implantation for Non-Small-Cell Lung Cancer.

Objective To investigate the prognostic impact of computed tomography (CT) imaging big data-assisted arterial chemoembolization combined with iodine 125 (125I) seed implantation on patients with non-small-cell lung cancer (NSCLC). Methods A total of 116 patients with intermediate and advanced NSCLC hospitalized in our hospital from August 2019 to August 2020 were selected and divided into a control group and an experiment group (58 cases in each group) by random number table method for the study. The patients in the experiment group were treated with CT imaging big data-assisted arterial chemoembolization combined with 125I seed implantation, while the patients in the control group were treated with arterial chemoembolization alone, with the use of gemcitabine combined with cisplatin (GP) in chemotherapy. The prognostic impact was determined by analyzing recent efficacy; the incidence of adverse effects; tumor size and CT perfusion parameters including blood volume (BV), blood flow (BF), and permeability surface (PS); frailty state and quality of life; and the levels of serum tumor markers including carcinoembryonic antigen (CEA), glycoconjugate antigen 125 (CA125), cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), microRNA- (miRNA-) 137, and miR-379-5p. In addition, frailty status was evaluated using the Fried frailty phenotype (FP) scale, and quality of life was determined according to Karnofsky Performance Status (KPS) score. Kaplan-Meyer (KM) method was used to analyze the survival rate of NSCLC patients after a 12-month follow-up. Results The remission rate in the experiment group (77.59%) was higher than that in the control group (56.90%) (P < 0.05). Tumor size, BV, BF, PS, serum CEA and CA125 levels, and FP value in both groups were dramatically reduced after treatment compared with before treatment, especially in the experiment group after 1 and 3 months of treatment (P < 0.05). Meanwhile, the serum miR-137 and miR-379-5p levels and KPS scores in both groups were higher after treatment than before treatment, especially in the experiment group after 1 and 3 months of treatment (P < 0.05). However, there was no significant difference in the incidence of nausea and vomiting, alopecia, diarrhea, myelosuppression, and hemoptysis of NSCLC patients in both groups after treatment (P > 0.05). Further, the 12-month survival rate of NSCLC patients was higher in the experiment group (84.21%) than in the control group (64.29%) (P < 0.05). Conclusion CT imaging big data-assisted arterial chemoembolization combined with 125I seed implantation for NSCLC can improve recent efficacy and the prognosis of NSCLC patients by inhibiting tumor progression with a certain degree of safety.

Abstract 376: Sonoporated size selected microbubblesand liposomal doxorubicinadditively induce apoptosis in neuroblastoma xenografts

Abstract Background: Neuroblastoma (NB) is the second most common malignancy diagnosed in infants, accounting for 15% of pediatric tumor deaths. Half of children with NB receive an intensive regimen including high-dose chemotherapy with 50% survival, resulting in acute and long term toxicities. One of the challenges of chemotherapy is irregular tumor vasculature. Thus, increasing targeted drug delivery without increasing drug dosage can result in enhanced drug efficacy and improved patient outcomes. We have shown that sonoporation (focused ultrasound-guided gas-filled microbubbles) increases high dose liposomal doxorubicin (L-DOX) uptake in NB xenografts by increasing tumor perfusion. However, these studies used polydisperse microbubbles (PMB), which were developed for imaging purposes. We hypothesized that MB size restriction would control their response to ultrasound pressure, yielding a higher L-DOX payload despite using using lower L-DOX dosages. Methods: Nude mice received 1x10^6 NGP cells (NB cells) intrarenally. When tumors reached 1 gram, NB xenografts received an intravenous polydisperse (PMB) or 4-5uM (SIMB) microbubble infusion with or without 1mg/kg liposomal doxorubicin (L-DOX) under focused ultrasound. Tumors were measured over 7 days with calipers, others sacrificed 24 hours after treatment for histology and immunohistochemistry. We assessed endomucin and isolectin-B4 (endothelium), Zona occludens-1 (ZO-1) (tight junction), and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL, apoptosis). Results: Tumors receiving low dose L-DOX alone or PMB sonoporation with L-DOX were not different from untreated controls after 7 days. SIMB alone resulted in a slower tumor growth than control tumors (20 vs 100% p&amp;lt;0.05); L-DOX coupled with SIMB resulted in further tumor growth restriction 7 days after treatment (0 vs 100% p&amp;lt;0.05). SIMB increased tumor apoptosis (TUNEL staining) in the absence of L-DOX compared to controls (7 vs 58% of area p=0.003) as well as in the presence of L-DOX (7 vs 78% of area p&amp;lt;0.001). PMBs did not change TUNEL levels regardless of L-DOX. Tumor vascular lumens (widest axis within the endothelial marker endomucin) confirmed PMB duplicates lumen diameter compared to controls (p&amp;lt;0.05), and revealed SIMB triplicates lumen diameter (p&amp;lt;0.01) regardless of L-DOX. SIMB resulted in loss of tight junction protein ZO-1 both in vasculature and tumor cells and widespread L-DOX uptake. Together, our data shows SIMB sonoporation increases tumor blood volume and vascular permeability leading to higher chemotherapy uptake and apoptosis. Conclusions: Together, our data shows SIMB sonoporation enables chemotherapy uptake in poorly perfused NB xenografts by increasing perfusion and permeability, potentiating apoptotic effects. SIMB sonoporation could reduce acute and long term toxicities. Citation Format: Sonia L. Hernandez, Rachael Sundland, Donia Ballan, Aditi Bellary, Jessica J. Kandel, Jameel Feshitan, Shashank Sirsi. Sonoporated size selected microbubblesand liposomal doxorubicinadditively induce apoptosis in neuroblastoma xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 376.

Changes in Magnetic Resonance Imaging Radiomic Features in Response to Androgen Deprivation Therapy in Patients with Intermediate- and High-risk Prostate Cancer

AimsThe benefits of neoadjuvant androgen deprivation therapy (nADT) in the management of intermediate- and high-risk prostate cancer patients have been well-established. The aim of this study was to identify radiomic prognostic features derived from routine anatomic magnetic resonance imaging (MRI) sequences that can predict the response of the prostate cancer to nADT. Materials and methodsPatients with intermediate- and high-risk prostate cancer (with one of clinical stage ≥ T2c, Gleason score ≥7 or presenting prostate-specific antigen ≥10) who received 3 months of ADT prior to radical external beam radiotherapy were enrolled into this study. The relative blood volume and the relative blood flow were used as dynamic MRI kinetic parameters to quantify vascular changes as responses to nADT. For all pre- and post-nADT data sets, a combination of T2-weighted and contrast-enhanced T1-weighted anatomic images were used to define regions of interest (ROI) as the dominant malignant nodules (DMNs) and the benign prostate (the entire prostate with the summed DMNs being subtracted). MRI textural radiomic features associated with prostate cancer response in the literature of energy and homogeneity were selected. Pyradiomics was used to extract textural features of the ROIs. A Wilcoxon signed-rank test was carried out to investigate if there were statistically significant differences in values of radiomic features between: (i) benign prostate ROI and DMN pre-nADT; (ii) pre- and post-nADT of benign prostate ROI; (iii) pre- and post-nADT of DMN. Changes in radiomic features and dynamic MRI kinetic parameters were correlated using the Spearman correlation test. ResultsTwenty prostate cancer patients were recruited into the study. The median time between the first baseline scan and the first on-treatment scan was 91.5 days (range 82–105). One patient had no discernible tumour visible, leaving 19 patients with evaluable data for the analysis. Baseline homogeneity and energy values differed significantly between benign and malignant tissue (P < 0.01). In response to nADT, homogeneity and energy showed reciprocal changes, significantly increased in benign prostate while decreasing in the DMN. The reduction in tumour homogeneity and energy feature values showed a positive association with the decline in tumour blood flow and tumour blood volume induced by androgen deprivation as derived from dynamic MRI parameters. ConclusionEnergy and homogeneity radiomic features derived from MRI of benign and malignant prostate showed significant reciprocal changes in response to nADT. This study confirms the potential of these radiomic features to act as surrogate markers of tumour androgen sensitivity due to their strong association with ADT-induced physiological effects in prostate tumours.

Utility of perfusion CT in characterizing the pancreatic tumors

Purpose: The aim of this study was to apply perfusion CT (Computed Tomography) technique to various pancreatic masses and to prospectively evaluate the perfusion parameters of pancreatic lesions and to compare these parameters with the parameters of normal pancreatic parenchyma. Materials and Methods: A total of 33 subjects with pancreatic tumors underwent perfusion CT. The perfusion parameters like tBF & pBF (Tumor Blood-Flow and Pancreatic Blood-Flow), tPEI & pBF (Tumor Peak Enhancement Index and Pancreatic Peak Enhancement Index), tTTP & pTTP (Tumor Time to Peak and Pancreatic Time to peak) and tBV & pBV (Tumor Blood-Volume and Pancreatic Blood-Volume) were obtained by placing an ROI (Region of Interest) on the tumor and the normal pancreas respectively. Descriptive statistics of the perfusion values of the tumor and the normal pancreas was tabulated and statistical significance was calculated using Mann Whitney U test. Results: 26 patients had adenocarcinoma, 4 had endocrine tumors, 2 had metastases and 1 had Ewing’s sarcoma. Adenocarcinomas showed significantly lower BF (Blood-Flow), PEI (Peak Enhancement Index) and Blood volume (BV) but significantly higher TTP (Time to Peak) as compared to the normal pancreas (P

Efficacy of endovascular intratumoral embolization for meningioma: assessment using dynamic susceptibility contrast-enhanced perfusion-weighted imaging

BackgroundIn preoperative embolization for intracranial meningioma, endovascular intratumoral embolization is considered to be more effective for the reduction of tumorous vascularity than proximal feeder occlusion. In this study, we aimed...

Quantitative analysis of vascular changes during photoimmunotherapy using speckle variance optical coherence tomography (SV-OCT).

Near-infrared (NIR) photoimmunotherapy (NIR-PIT) is an emerging cancer therapy based on a monoclonal antibody and phthalocyanine dye conjugate. Direct tumor necrosis and immunogenic cell death occur during NIR irradiation. However, the alteration of tumor blood vessels and blood volume inside the blood vessels induced by the NIR-PIT process is still unknown. In our study, a speckle variance (SV) algorithm combined with optical coherence tomography (OCT) technology was applied to monitor the change of blood vessels and the alterations of the blood volume inside the blood vessels during and after NIR-PIT treatment. Vascular density and the measurable diameter of the lumen in the blood vessel (the diameter of the region filled with blood) were extracted for quantitively uncovering the alterations of blood vessels and blood volume induced by NIR-PIT treatment. The results indicate that both the density and the diameter of the lumen in the blood vessels decrease during the NIR-PIT process, while histological results indicated the blood vessels were dilated. The increase of permeability of blood vessels could lead to the increase of the blood pool volume within the tumor (shown in histology) and results in the decrease of free-moving red blood cells inside the blood vessels (shown in SV-OCT).

Differences Between CT-Perfusion and Biphasic Contrast-enhanced CT for Detection and Characterization of Hepatocellular Carcinoma: Potential Explanations for Discrepant Cases.

To compare the diagnostic value of liver perfusion computed tomography (PCT) and biphasic contrast-enhanced CT (bpCECT) for detection and characterization of hepatocellular carcinoma (HCC), and to identify potential causes for inter-modal discrepancies. In this retrospective study, 162 cases with a total of 325 HCC-typical lesions were evaluated using both PCT and bpCECT (mean time between examinations=15 days, range=0-13 days). HCC diagnosis was performed by multi-modality imaging including lesion growth at follow-up. For PCT, a total acquisition time of 40 s (26 measurements) each 1.5 s using 80 kV and 100 mAs, as well as 50 ml iodine contrast agent (at 5 ml/s) covering the entire liver was used. Mean arterial liver perfusion (ALP), portal venous perfusion (PVP) and hepatic arterial index (HPI) for both tumor and non-involved liver parenchyma; mean blood flow, blood volume and k-trans for tumor were quantified. Tumor localization, and size were registered. bpCECT consisted of unenhanced, arterial (30-33 s delay), and portal-venous (70-75 s) phases performed using 120 kV, 200-250 mAs, thin-slice reformates (<1 mm), 100 ml contrast agent (at 3 ml/s) followed by 50 ml saline flush. Finally, we divided the results according to detection by PCT only (i.e. missed by pbCECT), and by both PCT and pbCECT. PCT detected 272 lesions compared to 217 with bpCECT only. HCCs in liver segments 4 and 5 were significantly better detected by PCT (p<0.005). Furthermore, PCT detected significantly smaller HCCs than did bpCECT (p<0.001). Lesions detected by both methods had significantly higher mean ALP (p=0.03) and HPI (p=0.02), and lower mean PVP (p=0.01). Tumor blood flow, blood volume and k-trans proved not to be significant for lesion detection. The mean ALP, HPI, and PVP in inconspicuous cirrhotic liver were also not significant for lesion detection. The PVP(tumor)/HPI(liver) ratio of detected lesions was significantly higher for PCT alone (p=0.04). Pretreated, still vital lesions were better detected by bpCECT. Detection of smaller HCC lesions, lesions located in liver segments 4 and 5, as well as lesions presenting lower ALP and HPI, and higher PVP(tumor)/HPI(liver) ratio was better using both methods, emphasizing the important role of PCT.

Predicting pathological complete response (pCR) after stereotactic ablative radiation therapy (SABR) of lung cancer using quantitative dynamic [18F]FDG PET and CT perfusion: a prospective exploratory clinical study

BackgroundStereotactic ablative radiation therapy (SABR) is effective in treating inoperable stage I non-small cell lung cancer (NSCLC), but imaging assessment of response after SABR is difficult. This prospective study aimed to develop a predictive model for true pathologic complete response (pCR) to SABR using imaging-based biomarkers from dynamic [18F]FDG-PET and CT Perfusion (CTP).MethodsTwenty-six patients with early-stage NSCLC treated with SABR followed by surgical resection were included, as a pre-specified secondary analysis of a larger study. Dynamic [18F]FDG-PET and CTP were performed pre-SABR and 8-week post. Dynamic [18F]FDG-PET provided maximum and mean standardized uptake value (SUV) and kinetic parameters estimated using a previously developed flow-modified two-tissue compartment model while CTP measured blood flow, blood volume and vessel permeability surface product. Recursive partitioning analysis (RPA) was used to establish a predictive model with the measured PET and CTP imaging biomarkers for predicting pCR. The model was compared to current RECIST (Response Evaluation Criteria in Solid Tumours version 1.1) and PERCIST (PET Response Criteria in Solid Tumours version 1.0) criteria.ResultsRPA identified three response groups based on tumour blood volume before SABR (BVpre-SABR) and change in SUVmax (ΔSUVmax), the thresholds being BVpre-SABR = 9.3 mL/100 g and ΔSUVmax = − 48.9%. The highest true pCR rate of 92% was observed in the group with BVpre-SABR < 9.3 mL/100 g and ΔSUVmax < − 48.9% after SABR while the worst was observed in the group with BVpre-SABR ≥ 9.3 mL/100 g (0%). RPA model achieved excellent pCR prediction (Concordance: 0.92; P = 0.03). RECIST and PERCIST showed poor pCR prediction (Concordance: 0.54 and 0.58, respectively).ConclusionsIn this study, we developed a predictive model based on dynamic [18F]FDG-PET and CT Perfusion imaging that was significantly better than RECIST and PERCIST criteria to predict pCR of NSCLC to SABR. The model used BVpre-SABR and ΔSUVmax which correlates to tumour microvessel density and cell proliferation, respectively and warrants validation with larger sample size studies.Trial registrationMISSILE-NSCLC, NCT02136355 (ClinicalTrials.gov). Registered May 8, 2014, https://clinicaltrials.gov/ct2/show/NCT02136355

Chemotherapeutic effects on breast tumor hemodynamics revealed by eigenspectra multispectral optoacoustic tomography (eMSOT).

Non-invasive monitoring of hemodynamic tumor responses to chemotherapy could provide unique insights into the development of therapeutic resistance and inform therapeutic decision-making in the clinic.Methods: Here, we examined the longitudinal and dynamic effects of the common chemotherapeutic drug Taxotere on breast tumor (KPL-4) blood volume and oxygen saturation using eigenspectra multispectral optoacoustic tomography (eMSOT) imaging over a period of 41 days. Tumor vascular function was assessed by dynamic oxygen-enhanced eMSOT (OE-eMSOT). The obtained in vivo optoacoustic data were thoroughly validated by ex vivo cryoimaging and immunohistochemical staining against markers of vascularity and hypoxia.Results: We provide the first preclinical evidence that prolonged treatment with Taxotere causes a significant drop in mean whole tumor oxygenation. Furthermore, application of OE-eMSOT showed a diminished vascular response in Taxotere-treated tumors and revealed the presence of static blood pools, indicating increased vascular permeability.Conclusion: Our work has important translational implications and supports the feasibility of eMSOT imaging for non-invasive assessment of tumor microenvironmental responses to chemotherapy.

Magnetic resonance angiography reveals increased arterial blood supply and tumorigenesis following high fat feeding in a mouse model of triple-negative breast cancer.

Breast cancer is the second most commonly diagnosed malignancy among women globally. Past MRI studies have linked a high animal fat diet (HAFD) to increased mammary cancer risk in the SV40Tag mouse model of triple-negative breast cancer. Here, serial MRI examines tumor progression and measures the arterial blood volume feeding mammary glands in low fat diet (LFD) or HAFD fed mice. Virgin female C3(1)SV40Tag mice (n = 8), weaned at 3 weeks old, were assigned to an LFD (n = 4, 3.7 kcal/g, 17.2% kcal from vegetable oil) or an HAFD (n = 4, 5.3 kcal/g, 60% kcal from lard) group. From ages 8 to 12 weeks, weekly fast spin echo MR images and time-of-flight (TOF) MR angiography of inguinal mammary glands were acquired at 9.4 T. Following in vivo MRI, mice were sacrificed. Inguinal mammary glands were excised and fixed for ex vivo MRI and histology. Tumor, blood, and mammary gland volumes for each time point were measured from manually traced regions of interest; tumors were classified as invasive by histopathology-blinded observers. Our analysis confirmed a strong correlation between total tumor volume and blood volume in the mammary gland. Tumor growth rates from weeks 8-12 were twice as high in HAFD-fed mice (0.42 ± 0.14/week) as in LFD-fed mice (0.21 ± 0.03/week), p < 0.004. Mammary gland blood volume growth rate was 2.2 times higher in HAFD mice (0.29 ± 0.11/week) compared with LFD mice (0.13 ± 0.06/week), p < 0.02. The mammary gland growth rate of HAFD-fed mice (0.071 ± 0.011/week) was 2.7 times larger than that of LFD-fed mice (0.026 ± 0.009/week), p < 0.01. This is the first non-invasive, in vivo MRI study to demonstrate a strong correlation between an HAFD and increased cancer burden and blood volume in mammary cancer without using contrast agents, strengthening the evidence supporting the adverse effects of an HAFD on mammary cancer. These results support the potential future use of TOF angiography to evaluate vasculature of suspicious lesions.

HemoSYS: An Image‐based Toolkit for Quantifying Hemodynamics in the Microcirculation

ObjectiveTo develop an easy‐to‐use image‐based toolkit for quantifying spatiotemporal hemodynamic changes in the healthy and pathologic microcirculation.MethodsWe combined the capabilities of two well‐known image processing platforms: Matlab® (MathWorks, MA) and ImageJ into a single framework, and created an interactive graphical user interface (GUI) to manage all aspects of user interactions. The resulting toolkit for quantifying hemodynamic changes, HemoSYS, can be utilized without any prior programming knowledge, and consists of five analysis modules: propagation, clustering, coupling, perturbation, and Fourier. We demonstrate the utility of HemoSYS by using it to quantify hemodynamic changes within the tumor microenvironment (TME) of a murine breast cancer model. To acquire multi‐variable microcirculatory dynamics of the TME, we used a multi‐contrast optical imaging system and obtained wide field (i.e. 5 × 7 mm2) images of tumor extent via fluorescence (FL) imaging of GFP tagged tumor cells, and concurrent image‐sequences of tumor microvasculature or blood volume (BV) via hemoglobin‐based intrinsic optical signal (IOS) imaging, intravascular oxygen saturation (HbSat) via IOS imaging, and blood flow (BF) via laser speckle contrast (LSC) imaging every 30 seconds, for 1 hour.ResultsFig. 1 shows a schematic of HemoSYS illustrating its input data and capabilities. Using HemoSYS on a cohort of 5 animals, we identified the tumor extent and interrogated: (i) the propagation characteristics of an acute hypoxic episode; (ii) the formation and cessation of clusters with distinct microcirculatory dynamics; (iii) the dysregulation of blood flow; (iv) the multi‐variable hemodynamic response to carbogen gas inhalation;and (v) the heterogeneity of microcirculatory dynamics in the frequency domain.ConclusionHemoSYS (freely available upon request) enables characterization of hemodynamic changes in microvascular beds using a systems biology approach. It can be used by anyone interested in quantifying hemodynamic changes from imaging data because it does not require any programming experience. While we demonstrated its utility using wide‐field optical imaging data, HemoSYS could be readily modified to accept input data from additional imaging modalities such as MR, PET, and Photoacoustic imaging. We believe that HemoSYS will become a tool‐of‐choice for image‐based characterization of the microcirculation in any preclinical disease model or tissue bed.Support or Funding InformationThis work was supported by NCI 1R01CA196701, 5R01CA138264 and a Kavli Neuroscience Distinguished Fellowship (JS).Schematic of HemoSYS illustrating its inputs and capabilities.HemoSYS accepts a broad range of inputs, from static images indicating an area of interest (e.g. the tumor extent) to multiple image‐sequences showing concurrent spatiotemporal changes in multiple hemodynamic variables (e.g. BV, HbSat and BF). One can then interactively use HemoSYS’s five modules (i.e. propagation, clustering, coupling, perturbation and Fourier) to quantify and characterize the underlying microcirculation.Figure 1

The reliability of the computed tomography perfusion parameters as a predictor of colorectal cancer grade: influence of tumor region of interest position

BackgroundThe aim of this study is to prospectively determine whether the computed tomography perfusion (CTP) can predict the tumor grade in colorectal cancer (CRC), and investigation of the best position of the tumor region of interest (ROI) could improve the tumor grade differentiation.ResultsThe mean blood flow (mBF) at the tumor edge was significantly different among different tumor grades with the highest value noted in moderately differentiated and the lowest value in poorly differentiated CRC (111.67 ± 38.91 vs. 52.25 ± 21.97 ml/min/100 g, respectively, P = 0.03). At the tumor center, the BF and blood volume (BV) showed highest value in moderately differentiated and the lowest value in poorly differentiated CRC (P < 0.001, 0.02 respectively). The ROC curve revealed that the BF at the tumor edge showed its best results as regard its sensitivity 73.9% and specificity 82.1% in the characterization of moderately differentiated CRC from the other subtypes at > 92.2 ml/100 g/min cut off point and their AUC and P value were (0.82 and < 0.001 respectively), while the AUC of the BF at the tumor center was 0.81 and its P value was 0.03. In the characterization of poorly differentiated CRC from the other subtypes, BF cut off value at < 67.32 ml/100 g/min at the tumor edge showed the best performance of its sensitivity 88% and specificity 88% with 0.92 AUC and P value was < 0.001, while the AUC of the BF at the tumor center was 0.89. BF was higher at the edge than at the center of the tumor (88.53 ± 22.45 vs. 78.79 ± 28.98 ml/min/100 g; P < 0.001 respectively).ConclusionsPCT could help in prediction of the poorly and the moderately differentiated CRC and the mBF was the most reliable parameter in prediction of the grade. The variation in ROI position has no substantial difference in the prediction of the tumor grade; however, this variation has a significant impact on the measurements of the PCT parameters especially the BF.

HemoSYS: A Toolkit for Image-based Systems Biology of Tumor Hemodynamics

Abnormal tumor hemodynamics are a critical determinant of a tumor’s microenvironment (TME), and profoundly affect drug delivery, therapeutic efficacy and the emergence of drug and radio-resistance. Since multiple hemodynamic variables can simultaneously exhibit transient and spatiotemporally heterogeneous behavior, there is an exigent need for analysis tools that employ multiple variables to characterize the anomalous hemodynamics within the TME. To address this, we developed a new toolkit called HemoSYS for quantifying the hemodynamic landscape within angiogenic microenvironments. It employs multivariable time-series data such as in vivo tumor blood flow (BF), blood volume (BV) and intravascular oxygen saturation (Hbsat) acquired concurrently using a wide-field multicontrast optical imaging system. The HemoSYS toolkit consists of propagation, clustering, coupling, perturbation and Fourier analysis modules. We demonstrate the utility of each module for characterizing the in vivo hemodynamic landscape of an orthotropic breast cancer model. With HemoSYS, we successfully described: (i) the propagation dynamics of acute hypoxia; (ii) the initiation and dissolution of distinct hemodynamic niches; (iii) tumor blood flow regulation via local vasomotion; (iv) the hemodynamic response to a systemic perturbation with carbogen gas; and (v) frequency domain analysis of hemodynamic heterogeneity in the TME. HemoSYS (freely downloadable via the internet) enables vascular phenotyping from multicontrast in vivo optical imaging data. Its modular design also enables characterization of non-tumor hemodynamics (e.g. brain), other preclinical disease models (e.g. stroke), vascular-targeted therapeutics, and hemodynamic data from other imaging modalities (e.g. MRI).

Forecasting tumor and vasculature response dynamics to radiation therapy via image based mathematical modeling

BackgroundIntra-and inter-tumoral heterogeneity in growth dynamics and vascularity influence tumor response to radiation therapy. Quantitative imaging techniques capture these dynamics non-invasively, and these data can initialize and constrain predictive models of response on an individual basis.MethodsWe have developed a family of 10 biologically-based mathematical models describing the spatiotemporal dynamics of tumor volume fraction, blood volume fraction, and response to radiation therapy. To evaluate this family of models, rats (n = 13) with C6 gliomas were imaged with magnetic resonance imaging (MRI) three times before, and four times following a single fraction of 20 Gy or 40 Gy whole brain irradiation. The first five 3D time series data of tumor volume fraction, estimated from diffusion-weighted (DW-) MRI, and blood volume fraction, estimated from dynamic contrast-enhanced (DCE-) MRI, were used to calibrate tumor-specific model parameters. The most parsimonious and well calibrated of the 10 models, selected using the Akaike information criterion, was then utilized to predict future growth and response at the final two imaging time points. Model predictions were compared at the global level (percent error in tumor volume, and Dice coefficient) as well as at the local or voxel level (concordance correlation coefficient).ResultThe selected model resulted in < 12% error in tumor volume predictions, strong spatial agreement between predicted and observed tumor volumes (Dice coefficient > 0.74), and high level of agreement at the voxel level between the predicted and observed tumor volume fraction and blood volume fraction (concordance correlation coefficient > 0.77 and > 0.65, respectively).ConclusionsThis study demonstrates that serial quantitative MRI data collected before and following radiation therapy can be used to accurately predict tumor and vasculature response with a biologically-based mathematical model that is calibrated on an individual basis. To the best of our knowledge, this is the first effort to characterize the tumor and vasculature response to radiation therapy temporally and spatially using imaging-driven mathematical models.