Optimized time‐resolved imaging of contrast kinetics (TRICKS) in dynamic contrast‐enhanced MRI after peptide receptor radionuclide therapy in small animal tumor models

Anti‐tumor efficacy of targeted peptide‐receptor radionuclide therapy (PRRT) relies on several factors, including functional tumor vasculature. Little is known about the effect of PRRT on tumor vasculature. With dynamic contrast‐enhanced (DCE‐) MRI, functional vasculature is imaged and quantified using contrast agents. In small animals DCE‐MRI is a challenging application. We optimized a clinical sequence for fast hemodynamic acquisitions, time‐resolved imaging of contrast kinetics (TRICKS), to obtain DCE‐MRI images at both high spatial and high temporal resolution in mice and rats. Using TRICKS, functional vasculature was measured prior to PRRT and longitudinally to investigate the effect of treatment on tumor vascular characteristics. Nude mice bearing H69 tumor xenografts and rats bearing syngeneic CA20948 tumors were used to study perfusion following PRRT administration with ¹⁷⁷lutetium octreotate. Both semi‐quantitative and quantitative parameters were calculated. Treatment efficacy was measured by tumor‐size reduction. Optimized TRICKS enabled MRI at 0.032 mm³ voxel size with a temporal resolution of less than 5 s and large volume coverage, a substantial improvement over routine pre‐clinical DCE‐MRI studies. Tumor response to therapy was reflected in changes in tumor perfusion/permeability parameters. The H69 tumor model showed pronounced changes in DCE‐derived parameters following PRRT. The rat CA20948 tumor model showed more heterogeneity in both treatment outcome and perfusion parameters. TRICKS enabled the acquisition of DCE‐MRI at both high temporal resolution (T_res) and spatial resolutions relevant for small animal tumor models. With the high T_res enabled by TRICKS, accurate pharmacokinetic data modeling was feasible. DCE‐MRI parameters revealed changes over time and showed a clear relationship between tumor size and K_trans. Copyright © 2015 John Wiley & Sons, Ltd.     

Multimodal approach to assess tumour vasculature and potential treatment effect with DCE‐US and DCE‐MRI quantification in CWR22 prostate tumour xenografts

The aim of this study was to compare intratumoural heterogeneity and longitudinal changes assessed by dynamic contrast‐enhanced ultrasound (DCE‐US) and dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) in prostate tumour xenografts. In vivo DCE‐US and DCE‐MRI were obtained 24 h pre‐ (day 0) and post‐ (day 2) radiation treatment with a single dose of 7.5 Gy. Characterization of the tumour vasculature was determined by Brix pharmacokinetic analysis of the time–intensity curves. Histogram analysis of voxels showed significant changes (p < 0.001) from day 0 to day 2 in both modalities for k_ep, the exchange rate constant from the extracellular extravascular space to the plasma, and k_el, the elimination rate constant of the contrast. In addition, k_ep and k_el values from DCE‐US were significantly higher than those derived from DCE‐MRI at day 0 (p < 0.0001) for both groups. At day 2, k_el followed the same tendency for both groups, whereas k_ep showed this tendency only for the treated group in intermediate‐enhancement regions. Regarding k_ep median values, longitudinal changes were not found for any modality. However, at day 2, k_ep linked to DCE‐US was correlated to MVD in high‐enhancement areas for the treated group (p = 0.05). In contrast, correlation to necrosis was detected for the control group in intermediate‐enhancement areas (p < 0.1). Intratumoural heterogeneity and longitudinal changes in tumour vasculature were assessed for both modalities. Microvascular parameters derived from DCE‐US seem to provide reliable biomarkers during radiotherapy as validated by histology. Furthermore, DCE‐US could be a stand‐alone or a complementary technique. Copyright © 2015 John Wiley & Sons, Ltd.     

Assessment of tumor angiogenesis: dynamic contrast‐enhanced MRI with paramagnetic nanoparticles compared with Gd‐DTPA in a rabbit Vx‐2 tumor model

The purpose of this study was to evaluate the suitability of a macromolecular MRI contrast agent (paramagnetic nanoparticles, PNs) for the characterization of tumor angiogenesis. Our aim was to estimate the permeability of PNs in developing tumor vasculature and compare it with that of a low molecular weight contrast agent (Gd‐DTPA) using dynamic contrast‐enhanced MRI (DCE). Male New Zealand white rabbits (n = 5) underwent DCE MRI 12–14 days after Vx‐2 tumor fragments were implanted into the left hind limb. Each contrast agent (PNs followed by Gd‐DTPA) was evaluated using a DCE protocol and transendothelial transfer coefficient (K_i) maps were calculated using a two‐compartment model. Two regions of interest (ROIs) were located within the tumor core and hindlimb muscle and five ROIs were placed within the tumor rim. Comparisons were performed using repeated measures analysis of variance (ANOVA). The K_i values estimated using PNs were significantly lower than those obtained for Gd‐DTPA (p = 0.018). When PNs and Gd‐DTPA data were analyzed separately, significant differences were identified among tumor rim ROIs for PNs (p < 0.0001), but not for Gd‐DTPA data (p = 0.34). The mean K_i for the tumor rim was significantly greater than that of either the core or the hindlimb muscle for both contrast agents (p < 0.05 for each comparison). In summary, the extravasation of Gd‐DTPA was far greater than that of PNs, suggesting that PNs can reveal regional differences in tumor vascular permeability that are not otherwise apparent with clinical contrast agents such as Gd‐DTPA. These results suggest that PNs show potential for the noninvasive delineation of tumor angiogenesis. Copyright © 2010 John Wiley & Sons, Ltd.     

Tumor necrosis factor-alpha augments tumor effects in isolated hepatic perfusion with melphalan in a rat sarcoma model

Isolated hepatic perfusion (IHP) is an attractive approach to treating nonresectable liver tumors, because the effects of systemic chemotherapy are poor and its application is hampered by severe general toxicity. In clinical and experimental settings, the efficacy of isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF alpha) in combination with melphalan to treat melanoma in transit and soft-tissue sarcoma has been well established. In an ILP model in rats, the authors previously observed synergistic anti-tumor effects of TNF and melphalan on BN 175 soft-tissue sarcoma extremity tumors. The aim of the current study was to determine whether similar synergy in anti-tumor effects could be achieved by treating experimental BN 175 soft-tissue sarcoma liver tumors by IHP using these agents. The authors found that IHP with TNF and melphalan resulted in a dramatic increase in regional concentrations of perfused agents with virtually no concomitant systemic leakage. Isolated hepatic perfusion with only carrier solution resulted in a significantly diminished growth rate of BN 175 liver tumors compared with the growth rate of tumors in nonperfused rats. Perfusion with melphalan alone resulted in minimal anti-tumor effects. Perfusion with only TNF had a slight growth-stimulatory effect on the BN 175 liver tumors, but no negative effects on tumor growth were observed. When TNF was added to melphalan, a dramatic anti-tumor effect was observed. Thus, as in the rat ILP setting, the anti-tumor effect is augmented when TNF is added to IHP with melphalan to treat BN 175 soft-tissue sarcoma tumor-bearing rats. Strikingly, the tumor response was potentiated at relatively low concentrations of TNF compared with concentrations that elicited synergy with melphalan in ILP.     

Surrogate MR markers of response to chemo‐ or radiotherapy in association with co‐treatments: a retrospective analysis of multi‐modal studies

The study of magnetic resonance (MR) markers over the past decade has provided evidence that the tumor microenvironnement and hemodynamics play a major role in determining tumor response to therapy. The aim of the present work is to predict and monitor the efficacy of co‐treatments to radio‐ and chemotherapy by noninvasive MR imaging. Ten different co‐treatments were involved in this retrospective analysis of our previously published data, including NO‐mediated co‐treatments (insulin and isosorbide dinitrate), anti‐inflammatory drugs (hydrocortisone, NS‐398), anti‐angiogenic agents (thalidomide, SU5416 and ZD6474), a vasoactive agent (xanthinol nicotinate), botulinum toxin and carbogen breathing. Dynamic contrast enhanced (DCE) MRI, intrinsic susceptibility‐weighted (BOLD) MRI and electronic paramagnetic resonance (EPR) oximetry all reflect tumor microenvironment hemodynamic variables that are known to influence tumor response. Eight MR‐derived parameters (markers) were tested for their ability to predict therapeutic outcome (factor of increase in regrowth delay) in experimental tumor models (TLT and FSaII) after radiation therapy and/or chemotherapy with cyclophosphamide, namely tumor pO₂ and O₂ consumption rate (using EPR oximetry); tumor blood flow and permeability, i.e. V _p, K _trans, K _ep and percentage of perfused vessels (using DCE‐MRI); and BOLD signal intensity and R ₂* (using functional MRI). This multi‐modal comparison of co‐treatment efficacy points out the limitations of each MR marker and identifies in vivo pO₂ as a relevant endpoint for radiation therapy. DCE parameters (V _p and K _ep) were identified as a relevant endpoints for cyclophosphamide chemotherapy in our tumor models. This study helps qualify relevant imaging endpoints in the preclinical setting of cancer therapy. Copyright © 2010 John Wiley & Sons, Ltd.     

Multi‐modal magnetic resonance imaging and histology of vascular function in xenografts using macromolecular contrast agent hyperbranched polyglycerol (HPG‐GdF)

Macromolecular gadolinium (Gd)‐based contrast agents are in development as blood pool markers for MRI. HPG‐GdF is a 583 kDa hyperbranched polyglycerol doubly tagged with Gd and Alexa 647 nm dye, making it both MR and histologically visible. In this study we examined the location of HPG‐GdF in whole‐tumor xenograft sections matched to in vivo DCE‐MR images of both HPG‐GdF and Gadovist. Despite its large size, we have shown that HPG‐GdF extravasates from some tumor vessels and accumulates over time, but does not distribute beyond a few cell diameters from vessels. Fractional plasma volume (fPV) and apparent permeability–surface area product (aPS) parameters were derived from the MR concentration–time curves of HPG‐GdF. Non‐viable necrotic tumor tissue was excluded from the analysis by applying a novel bolus arrival time (BAT) algorithm to all voxels. aPS derived from HPG‐GdF was the only MR parameter to identify a difference in vascular function between HCT116 and HT29 colorectal tumors. This study is the first to relate low and high molecular weight contrast agents with matched whole‐tumor histological sections. These detailed comparisons identified tumor regions that appear distinct from each other using the HPG‐GdF biomarkers related to perfusion and vessel leakiness, while Gadovist‐imaged parameter measures in the same regions were unable to detect variation in vascular function. We have established HPG‐GdF as a biocompatible multi‐modal high molecular weight contrast agent with application for examining vascular function in both MR and histological modalities. Copyright © 2015 John Wiley & Sons, Ltd.     

Induction of systemic serum procalcitonin and cardiocirculatory reactions after isolated limb perfusion with recombinant human tumor necrosis factor-alpha and melphalan

OBJECTIVES: Isolated, hyperthermic limb perfusion (ILP) with recombinant human tumor necrosis factor-alpha (rhTNF-alpha) and melphalan is a highly effective treatment for locoregional metastases of malignant melanoma and for advanced soft tissue sarcoma of the limb. The major systemic side effects are characterized by the induction of a systemic inflammatory response syndrome (SIRS). Procalcitonin (PCT), a serum marker of bacterial sepsis, was investigated with respect to its role in SIRS after ILP. SETTING: University surgical oncology division with an integrated eight-bed intensive care unit. PATIENTS: Thirty-seven patients were treated by ILP with rhTNF-alpha and melphalan (n = 26) or with cytostatics alone (n = 11) for soft tissue sarcoma or malignant melanoma. INTERVENTIONS: The course of serum PCT, interleukin (IL)-6, and IL-8 was analyzed intra- and postoperatively. Hemodynamic variables including heart rate, mean arterial pressure, cardiac index, pulmonary arterial pressure, pulmonary capillary occlusion pressure, and pulmonary and systemic vascular resistance were recorded in parallel. MEASUREMENTS AND MAIN RESULTS: PCT was significantly elevated over baseline after ILP with a maximum between 8 hrs (peak level 16.0+/-18.8 (SD) ng/mL) and 36 hrs (13.8+/-15.7 ng/mL) (p < .001). The increase in serum PCT was significantly more pronounced after ILP with rhTNF-alpha/melphalan than after ILP with cytostatics alone (p < .001). IL-6 and IL-8 were also significantly increased after ILP (p = .001), reaching peak concentrations at 1 hr and 4 hrs postoperatively. Significant changes in heart rate, mean arterial pressure, cardiac index, and systemic vascular resistance were observed during and after ILP; however, PCT levels could not be correlated to these variables. Pulmonary arterial pressure, pulmonary capillary occlusion pressure, and pulmonary vascular resistance showed no significant changes. CONCLUSIONS: Serum procalcitonin is induced as part of the SIRS after ILP with rhTNF-alpha/melphalan. It may be induced directly by rhTNF-alpha or other cytokines, because serum peaks of IL-6 and IL-8 precede the peak of PCT. Because there is no correlation between serum levels of PCT and hemodynamic variables, this marker cannot be applied to assess the severity of SIRS reaction after ILP.     

Cerebral perfusion mapping using a robust and efficient method for deconvolution analysis of dynamic contrast-enhanced images

Dynamic contrast-enhanced (DCE) imaging using MRI or CT is emerging as a promising tool for diagnostic imaging of cerebral disorders and the monitoring of tumor response to treatment. In this study, we present a robust and efficient deconvolution method based on a linearized model of the impulse residue function, which allows for the mapping of functional cerebral parameters such as cerebral blood flow, volume, mean transit time, and permeability. Monte Carlo simulation studies were performed to study the accuracy and stability of the proposed method, before applying it to clinical study cases of patients with cerebral tumors imaged using DCE CT. Functional parameter maps generated using the proposed method revealed the locations of the cerebral tumors and were found to be of sufficiently good clarity for marked regional differences in tissue vascularity and permeability to be assessed. In particular, tumor visualization and delineation were found to be better on the parameter maps that were indicative of the breakdown of the blood-brain barrier.     

Dynamic contrast‐enhanced computed tomography for the quantification of tumor response to vasoactive agents in a rat tumor model: preliminary results

Rationale and Objectives

The purpose of this pilot study was to establish the ability of dynamic contrast enhanced computed tomography (DCE‐CT) to detect changes in tumor blood flow (BF) and oxygenation induced by vasoactive substances in rats.

Materials and Methods

Under ultrasound guidance, a fiber‐optic probe was guided into thigh tumors in eight rats and attached to an oxygenation/blood flow‐sensing device. A DCE‐CT sequence was acquired at the oxygen‐sensing probe tip during injection of iodinated contrast media. Group 1 rats (n = 6) were administered a vasodilator (hydralazine, 5 mg/kg i.v.) and group 2 rats (n = 2) were given physiologic saline in a similar volume. DCE‐CT was repeated at the probe tip after 30 min. BF in the whole tumor and at the probe tip were estimated pre‐ and post‐drug administration and the percentage change was calculated.

Results

DCE‐CT defined significant differences between pre‐ and post‐drug BF in the whole tumor (p = 0.007) and at the probe tip (p = 0.03). Estimates of percentage change in BF in the whole tumor agreed with fiber‐optic measure of percentage change perfusion (r² = 0.60; p = 0.02) and pO₂ (r² = 0.65; p = 0.02). Estimates of percentage change in BF at the probe tip agreed with fiber‐optic measures of percentage change in perfusion (r² = 0.83; p = 0.001) and pO₂ (r² = 0.62; p = 0.02).

Conclusions

Preliminary results indicate that DCE‐CT is capable of identifying alterations in tumor BF in rats. The percentage change in BF agrees with a validated estimate of tumor perfusion and oxygenation. This research technique may prove useful for assessment of tumor BF during combined chemotherapeutic and radiation therapy to improve outcome. Copyright © 2010 John Wiley & Sons, Ltd.     

Pharmacokinetics of contrast agents targeted to the tumor vasculature in molecular magnetic resonance imaging

Molecular magnetic resonance imaging (MRI) is increasingly used to investigate tumor angiogenic activity non‐invasively. However, the pharmacokinetic behavior and tumor penetration of the often large contrast agent particles is thus far unknown. Here, pharmacokinetic analysis of cyclic asparagine–glycine–arginine (cNGR) labeled paramagnetic quantum dots (pQDs) was developed to quantify the contrast agent's homing efficacy to activated endothelial cells of angiogenic tumor vessels using dynamic contrast‐enhanced (DCE) MRI. cNGR homes to CD13, an overexpressed aminopeptidase on angiogenic tumor endothelial cells. First, a two‐compartment pharmacokinetic model, comprising the blood space and endothelial cell surface, was compared with a three‐compartment model additionally including the extravascular–extracellular component. The resulting extravasation parameter was irrelevantly small and was therefore neglected. Next, the association constant K_a, the dissociation constant k_d and the fractional plasma volume v_P were determined from the time‐series data using the two‐compartment model. Magnitude and spatial distribution of the parameters were compared for cNGR‐labeled and unlabeled pQDs. The tumor area with significant K_a values was approximately twice as large for cNGR‐pQDs compared with unlabeled pQDs (p < 0.05), indicating more contrast agent binding for cNGR‐pQDs. Using cNGR‐pQDs, a two‐fold larger area with significant K_a was also found for the angiogenic tumor rim compared with tumor core (p < 0.05). It was furthermore found that both contrast agents perfused the tumor at all depths, thereby providing unequivocal evidence that rim/core differences can indeed be ascribed to stronger angiogenic activity in the rim. Summarizing, molecular DCE‐MRI with pharmacokinetic modeling provides unique information on contrast agent delivery and angiogenic activity in tumors. Copyright © 2010 John Wiley & Sons, Ltd.     

Comparison of dynamic contrast‐enhanced MRI and quantitative SPECT in a rat glioma model

Pharmacokinetic modeling of dynamic contrast‐enhanced (DCE) MRI data provides measures of the extracellular‐extravascular volume fraction (v_e) and the volume transfer constant (K^trans) in a given tissue. These parameter estimates may be biased, however, by confounding issues such as contrast agent and tissue water dynamics, or assumptions of vascularization and perfusion made by the commonly used model. In contrast to MRI, radiotracer imaging with SPECT is insensitive to water dynamics. A quantitative dual‐isotope SPECT technique was developed to obtain an estimate of v_e in a rat glioma model for comparison with the corresponding estimates obtained using DCE‐MRI with a vascular input function and reference region model. Both DCE‐MRI methods produced consistently larger estimates of v_e in comparison to the SPECT estimates, and several experimental sources were postulated to contribute to these differences. Copyright © 2012 John Wiley & Sons, Ltd.     

MRI tumor characterization using Gd‐GlyMe‐DOTA‐perfluorooctyl‐mannose‐conjugate (Gadofluorine M™), a protein‐avid contrast agent

The rationale and objectives were to define the MRI tumor‐characterizing potential of a new protein‐avid contrast agent, Gd‐GlyMe‐DOTA‐perfluorooctyl‐mannose‐conjugate (Gadofluorine M?; Schering AG, Berlin, Germany) in a chemically induced tumor model of varying malignancy. Because of the tendency for this agent to form large micelles in water and to bind strongly to hydrophobic sites on proteins, it was hypothesized that patterns of dynamic tumor enhancement could be used to differentiate benign from malignant lesions, to grade the severity of malignancies and to define areas of tumor necrosis. Gadofluorine M, 0.05 mmol Gd kg^?1, was administered intravenously to 28 anesthetized rats that had developed over 10 months mammary tumors of varying degrees of malignancy as a consequence of intraperitoneal administration of N‐ethyl‐N‐nitrosourea (ENU), 45–250 mg kg^?1. These tumors ranged histologically from benign fibroadenomas to highly undifferentiated adenocarcinomas. Dynamic enhancement data were analyzed kinetically using a two‐compartment tumor model to generate estimates of fractional plasma volume (fPV), apparent fractional extracellular volume (fEV*) and an endothelial transfer coefficient (K^PS) for this contrast agent. Tumors were examined microscopically for tumor type, degree of malignancy (Scarff–Bloom–Richardson score) and location of necrosis. Eighteen tumor‐bearing rats were successfully imaged. MRI data showed an immediate strong and gradually increasing tumor enhancement. K^PS and fEV*, but not fPV obtained from tumors correlated significantly (p < 0.05) with the SBR tumor grade, r = 0.65 and 0.56, respectively. Estimates for K^PS and fEV* but not fPV were significantly lower in a group consisting of benign and low‐grade malignant tumors compared with the group of less‐differentiated high‐grade tumors (1.61 ± 0.64 vs 3.37 ± 1.49, p < 0.01; 0.45 ± 0.17 vs 0.78 ± 0.24, p < 0.01; and 0.076 ± 0.048 vs 0.121 ± 0.088, p = 0.24, respectively). It is concluded that the protein‐avid MRI contrast agent Gadofluorine M enhances tumors of varying malignancy depending on the tumor grade, higher contrast agent accumulation for more malignant lesions. The results show potential utility for differentiating benign and low‐grade malignant lesions from high‐grade cancers. Copyright © 2006 John Wiley & Sons, Ltd.     

DCE‐MRI in experimental chronic pancreatitis

To assess pancreatic perfusion in experimental chronic pancreatitis (CP) by dynamic contrast‐enhanced (DCE) magnetic resonance imaging (MRI). DCE MRI on a 1.5 T MR scanner was performed on 21 piglets with the ligation of pancreatic duct. They were divided into four groups based on pathology, including seven normal pigs and seven, three and four piglets with grade I, II and III CP, respectively. The signal intensity measured in the pancreatic body on DCE MRI was plotted against time to create a signal intensity–time (SI–T) curve for each piglet. The steepest slope (SS), time‐to‐peak (TTP) and peak enhancement ratio (PER) of the SI–T curve were noted. In the four groups, on the SI–T curve derived from DCE MRI, the SS was, respectively, 10.88 ± 1.20, 10.59 ± 1.02, 6.67 ± 1.31 and 5.48 ± 1.97%/s (F = 20.509, p = 0.000) from normal piglets to piglets with grade III CP. The TTP was 13.82 ± 3.09, 12.31 ± 5.52, 20.55 ± 3.79 and 37.26 ± 14.56 s (F = 10.681, p = 0.000) and the PER was 62.95 ± 20.20, 60.44 ± 20.00, 46.33 ± 22.70 and 67.65 ± 32.66% (F = 0.529, p = 0.668), respectively. The SS (r = –0.719, p = 0.000) and TTP (r = 0.538, p = 0.012) of the SI–T curve was correlated to the severity of CP, respectively. DCE MRI has a potential to diagnose moderate to advanced CP. The SS and TTP of the SI–T curve were correlated to the severity of CP. Copyright © 2009 John Wiley & Sons, Ltd.     

18F‐FDG PET/CT and MRI in the follow‐up of head and neck squamous cell carcinoma

We evaluated the diagnostic performance of ¹⁸F‐FDG PET/CT and MRI for the assessment of head and neck squamous cell carcinoma (HNSCC) relapse. Since early treatment might prevent inoperable relapse, we also evaluated THE performance of early unenhanced ¹⁸F‐FDG PET/CT in residual tumor detection. The study was prospectively performed on 32 patients who underwent ¹⁸F‐FDG PET/CT and MRI before treatment and at 4 and 12 months after treatment. ¹⁸F‐FDG PET/CT was also performed 2 weeks after the end of radiotherapy. Histopathology or a minimum of 18 months follow‐up were used as gold standard. Before treatment ¹⁸F‐FDG PET/CT and MRI detected all primary tumors except for two limited vocal fold lesions (sensitivity 94%). MRI was more sensitive than ¹⁸F‐FDG PET/CT for the detection of local extension sites (sensitivity 75 vs 58%), but at the cost of a higher rate of false positive results (positive predictive value 74 vs 86%). For relapse detection at 4 months, sensitivity was significantly higher for ¹⁸F‐FDG PET/CT (92%) than for MRI (70%), but the diagnostic performances were not significantly different at 12 months. For the detection of residual malignant tissue 2 weeks post‐radiotherapy, sensitivity and specificity of ¹⁸F‐FDG PET/CT were respectively 86 and 85% (SUV cut‐off value 5.8). ¹⁸F‐FDG PET/CT is effective in the differentiation between residual tumor and radiation‐induced changes, as early as 2 weeks after treatment of a primary HNSCC. For follow‐up, performance of ¹⁸F‐FDG PET/CT and MRI are similar except for a higher sensitivity of ¹⁸F‐FDG PET/CT at 4 months. Copyright © 2011 John Wiley & Sons, Ltd.     

MRI and ultrasound guided interstitial Nd:YAG laser phototherapy for palliative treatment of advanced head and neck tumors: clinical experience

Interstitial laser phototherapy (ILP) is a technique whereby laser energy is directly applied into tumors at variable depths. This technique is attractive, since it is minimally invasive and carries a low morbidity. It may allow treatment of deep and difficult to reach tumors in the head and neck and other areas when improved noninvasive monitoring techniques of laser-tissue interactions are developed. Recent studies demonstrate, respectively, the efficiency of ultrasound (UTZ) and magnetic resonance imaging (MRI) for real time interstitial needle placement in tumors, identification of vessels, monitoring and quantifying laser-induced tissue damages. We present a case in which a patient with recurrent, metastatic base of skull carcinoma has managed successfully with repeat ILP using MRI and UTZ guidance. Under heavy sedation, needles were placed in the tumor using MRI or UTZ guidance. Tumors were treated with a 600 mum flexible Nd:YAG laser fiberoptic passed through the needles. Laser-induced tissue photoablation was monitored using real time color flow Doppler UTZ or near real time fast spin-echo T2-weighted MRI. Posttreatment fine needle aspiration cytologic study demonstrated the presence of cellular debris and no viable cancer cells. Posttreatment follow-up MRI scans showed significant reduction of tumor size, and positron emission tomography (PET) revealed interval decrease in tumor metabolism. Treatments were accompanied by pain relief and improved functional abilities. ILP has now evolved into minimally invasive outpatient surgical procedure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Low-field paramagnetic resonance imaging of tumor oxygenation and glycolytic activity in mice

A priori knowledge of spatial and temporal changes in partial pressure of oxygen (oxygenation; pO(2)) in solid tumors, a key prognostic factor in cancer treatment outcome, could greatly improve treatment planning in radiotherapy and chemotherapy. Pulsed electron paramagnetic resonance imaging (EPRI) provides quantitative 3D maps of tissue pO(2) in living objects. In this study, we implemented an EPRI set-up that could acquire pO(2) maps in almost real time for 2D and in minutes for 3D. We also designed a combined EPRI and MRI system that enabled generation of pO(2) maps with anatomic guidance. Using EPRI and an air/carbogen (95% O(2) plus 5% CO(2)) breathing cycle, we visualized perfusion-limited hypoxia in murine tumors. The relationship between tumor blood perfusion and pO(2) status was examined, and it was found that significant hypoxia existed even in regions that exhibited blood flow. In addition, high levels of lactate were identified even in normoxic tumor regions, suggesting the predominance of aerobic glycolysis in murine tumors. This report presents a rapid, noninvasive method to obtain quantitative maps of pO(2) in tumors, reported with anatomy, with precision. In addition, this method may also be useful for studying the relationship between pO(2) status and tumor-specific phenotypes such as aerobic glycolysis.     

Therapeutic effect of simvastatin on DMBA‐induced breast cancer in mice

Preclinical studies have shown positive effects of statins against specific cancers. This study aimed to determine the therapeutic effect of simvastatin in 12‐dimethylbenz(a)anthracene (DMBA)‐induced breast cancer. Female albino mice were divided into two groups, with or without DMBA administration. After tumor appearance, DMBA‐treated group was further divided into four groups (D1‐D4) as control (D1), treated with simvastatin at 80 and 40 mg/kg/day, orally (D2 and D3) and tamoxifen (50 mg/kg/day, orally) treated group (D4). After 4 weeks, animals were sacrificed, serum samples were collected and tumors were dissected for histopathological study and determination of selected parameters. The tumor marker carcinoma antigen 15‐3 (CA15‐3), oxidative stress parameters and prostaglandin E2 (PGE2) levels were analyzed in serum and tumors in experimental groups. Tamoxifen and high dose of simvastatin improved parameters of mammary carcinogenesis including mean tumor volume, body weight and percent of mortality as compared to mice with breast tumors without treatment (D1). Additionally, simvastatin usage increased total antioxidant capacity (TAC) level, paraoxonase 1 (PON1) activity in serum and decreased total oxidant status (TOS) and malondialdehyde (MDA) levels in tumors similar to tamoxifen. No significant decrease was found in serum CA 15‐3 and tumor PGE2 levels in simvastatin and tamoxifen treated groups as compared to D1 group. These data suggest that simvastatin has anticancer effects which are relatively similar to that of tamoxifen in an animal model of breast cancer.     

Tracer kinetics analysis of dynamic contrast‐enhanced CT and MR data in patients with squamous cell carcinoma of the upper aerodigestive tract: comparison of the results

Purpose: (i) To evaluate the feasibility of tracer kinetics analysis of dynamic contrast‐enhanced (DCE) CT and T2‐weighted MR data of squamous cell carcinoma (SCCA) of the upper aerodigestive tract. (ii) To compare functional parameters derived by both modalities and examine the interchangeability of them as well as the intra‐ and inter‐rater agreement. Materials and methods: Dynamic contrast‐enhanced‐CT and MR images of 23 patients with SCCA were postprocessed using a distributed‐parameter (DP) tracer kinetic model. The evaluated parameters included blood flow (F), intravascular blood volume (v₁), extravascular extracellular blood volume (v₂), intravascular mean transit time (t₁), lag time (t₀), permeability surface area product (PS) and extraction ratio (E). Mean perfusion values, based on region‐of‐interest analysis, of the tumors and the healthy muscle tissue were compared and correlated. Inter‐rater and intra‐rater variability were assessed. Interchangeability of the tumor functional parameters was tested using Pearson’s correlation coeficients and Bland–Altman plots. Results: The mean values in tumor and healthy muscle tissues were significantly different for each modality (0·0001≤P≤0·03). The mean values of all tumor perfusion parameters apart from v₂ and E were significantly different (0·001≤P≤0·009) between the two modalities. The intra‐rater variability was good to very good for all parameters. The inter‐rater variability was moderate to good. Bland–Altman plots of F, t₁, t₀, and v₂ showed moderate interchangeability. There was a proportionality error in v₁ and PS graphs. Conclusion: The estimation of functional parameters in SCCA is feasible using DCE‐CT and ‐MR with a DP model. The parameters are mostly significantly different and the interchangeability of them is limited.     

DW‐MRI and 18F‐FLT PET for early assessment of response to radiation therapy associated with hypoxia‐driven interventions. Preclinical studies using manipulation of oxygenation and/or dose escalation

Early markers of treatment response may help in the management of patients by predicting the outcome of a specific therapeutic intervention. Here, we studied the potential value of diffusion‐weighted MRI (DW‐MRI) and ¹⁸F‐fluorothymidine (¹⁸F‐FLT), markers of cell death and cell proliferation respectively, to predict the response to irradiation. In addition, dose escalation and/or carbogen breathing were used to modulate the response to irradiation. The studies were performed on two hypoxic rat tumor models: rhabdomyosarcoma and 9L‐glioma. The rats were imaged using MRI and PET before and two days after the treatment. In both tumor models, changes in ADC (apparent diffusion coefficient) and ¹⁸F‐FLT SUV (standardized uptake value) were significantly correlated with the tumor growth delay. For both tumor models, the ADC values increased in all irradiated groups two days after the treatment while they decreased in the untreated groups. At the same time, the uptake of ¹⁸F‐FLT increased in the untreated groups and decreased in all treated groups. Yet, ADC values were not sensitive enough to predict the added value of dose escalation or carbogen breathing in either model. Change in ¹⁸F‐FLT uptake was able to predict the higher tumor response when using increased dose of irradiation, but not when using a carbogen breathing challenge. Our results also emphasize that the magnitude of change in ¹⁸F‐FLT uptake was strongly dependent on the tumor model. Copyright © 2015 John Wiley & Sons, Ltd.