Fibrinogen aptamer functionalized gold-coated iron-oxide nanoparticles for targeted imaging of thrombi.

Targeting of molecular constituents of thrombi with aptamer functionalized core-shell nanoparticles (CSN) allowed for high resolution clot delineation in T2-weighted magnetic resonance imaging. Meanwhile, the gold-coating demonstrated sufficient contrast capabilities in computed tomography (1697 HU µM-1). This targeted CSN formulation could allow for precise imaging of blood clots at low nanomolar concentrations.

Methylenetetrahydrofolate reductase deficiency alters cellular response after ischemic stroke in male mice.

Objective: Elevated homocysteine concentrations are a risk factor for stroke. A common genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR 677 C→T) results in elevated levels of homocysteine. MTHFR plays a critical role in the synthesis of S-adenosylmethionine (SAM), a global methyl donor. Our previous work has demonstrated that Mthfr+/- mice, which model the MTHFR polymorphism in humans, are more vulnerable to ischemic damage. The aim of this study was to investigate the cellular mechanisms by which the MTHFR-deficiency changes the brain in the context of ischemic stroke injury.Methods: In the present study, three-month-old male Mthfr+/- and wild-type littermate mice were subjected to photothrombosis (PT) damage. Four weeks after PT damage, animals were tested on behavioral tasks, in vivo imaging was performed using T2-weighted MRI, and brain tissue was collected for histological analysis.Results: Mthfr+/- animals used their non-impaired forepaw more to explore the cylinder and had a larger damage volume compared to wild-type littermates. In brain tissue of Mthfr+/- mice methionine adenosyltransferase II alpha (MAT2A) protein levels were decreased within the damage hemisphere and increased levels in hypoxia-induced factor 1 alpha (HIF-1α) in non-damage hemisphere. There was an increased antioxidant response in the damage site as indicated by higher levels of nuclear factor erythroid 2-related factor 2 (Nrf2) in neurons and astrocytes and neuronal superoxide dismutase 2 (SOD2) levels.Conclusions: Our results suggest that Mthfr+/- mice are more vulnerable to PT-induced stroke damage through the regulation of the cellular response. The increased antioxidant response we observed may be compensatory to the damage amount.

Quantitative analysis of repaired rabbit supraspinatus tendons (± channeling) using magnetic resonance imaging at 7 Tesla.

BACKGROUND: The quantitative assessment of supraspinatus tendons by conventional magnetic resonance is limited by low contrast-to-noise ratio (CNR). Magnetic resonance imaging (MRI) scanners operating at 7 Tesla offer high signal-to noise ratio (SNR), low CNR and high spatial resolution that are well-suited for rapidly relaxing tissues like tendons. Few studies have applied T2 and T2* mapping to musculoskeletal imaging and to the rotator cuff tendons. Our objective was to analyze the T2 and T2* relaxation times from surgically repaired supraspinatus tendons and the effect of bone channeling. METHODS: One supraspinatus tendon of 112 adult female New Zealand white rabbits was surgically detached and repaired one week later. Rabbits were randomly assigned to channeling (n=64) or control (n=48) groups and harvested at 0, 1, 2, and 4 weeks. A 7T magnet was used for signal acquisition. For T2 mapping, a sagittal multi slice 2D multi-echo spin-echo (MESE) CPMG sequence with fat saturation was applied and T2* mapping was performed using a 3D UTE sequence. Magnetic resonance images from supraspinatus tendons were analyzed by two raters. Three regions of interest were manually drawn on the first T2-weighted dataset. For T2 and T2*, different ROI masks were generated to obtain relaxation times. RESULTS: T2-weighted maps but not T2*-weighted maps generated reliable signals for relaxation time measurement. Torn supraspinatus tendons had lower T2 than controls at the time of repair (20.0±3.4 vs. 25.6±3.9 ms; P<0.05). T2 increased at 1, 2 and 4 postoperative weeks: 22.7±3.1, 23.3±3.9 and 24.0±5.1 ms, respectively, and values were significantly different from contralateral supraspinatus tendons (24.8±3.1; 26.8±4.3 and 26.5±3.6 ms; all P<0.05). Bone channeling did not affect T2 (P>0.05). CONCLUSIONS: Supraspinatus tendons detached for 1 week had shorter T2 relaxation time compared to contralateral as measured with 7T MRI.

Influence of metabolic syndrome on cerebral perfusion and cognition.

Vascular cognitive impairment (VCI) is associated with chronic cerebral hypoperfusion (CCH) and memory deficits, and often occurs concurrently with metabolic syndrome (MetS). Despite their common occurrence, it is unknown whether CCH and MetS act synergistically to exacerbate VCI-associated pathology. Here, using male Sprague-Dawley rats, we examined the effects of a clinically relevant model of adolescent-onset MetS and adult-onset CCH on neuro-vascular outcomes, combining a cafeteria diet with a 2-vessel occlusion (2VO) model. Using longitudinal imaging, histology, and behavioural assessments, we identified several features of MetS and CCH including reduced cerebral blood volume, white matter atrophy, alterations in hippocampal cell density, and memory impairment. Furthermore, we identified a number of significant associations, potentially predictive of MetS and pathophysiological outcomes. White matter volume was positively correlated to HDL cholesterol; hippocampal cell density was negatively correlated to fasted blood glucose; cerebral blood flow and volume was negatively predicted by the combination of 2VO surgery and increased fasted blood glucose. These results emphasize the importance of including comorbid conditions when modeling VCI, and they outline a highly translational preclinical model that could be used to investigate potential interventions to mitigate VCI-associated pathology and cognitive decline.

Lateral Trochlear Ridge: A Non-Articulating Zone for Anterior-to-Posterior Screw Placement in Fractures Involving the Capitellum and Trochlea.

BACKGROUND: Coronal shear fractures of the distal aspect of the humerus that involve the capitellum and the trochlea are rare; nevertheless, they are difficult to treat because of the complex fracture patterns and osteochondral nature of the fragments, limiting optimal screw placement. The use of anterior-to-posterior screw fixation by a lag technique (without countersinking) could potentially improve the strength of the construct. Our primary research question was to anatomically determine if there is a non-articulating zone for screw placement along the anterior aspect of the lateral trochlear ridge (aLTR) throughout normal elbow range of motion. METHODS: Eight fresh-frozen cadaveric elbows were used. The region of interest was defined with 3 polymeric pins inserted in the inferior, middle, and superior-most aspects of the aLTR of each elbow, with use of an extensor digitorum communis (EDC) split approach. The elbows were then mounted on a magnetic resonance imaging (MRI)-compatible compression frame and subjected to high-resolution 7-T MRI at 90°, 120°, and 145° of flexion (positions of potential impingement), and at neutral and maximal pronation and maximal supination for each position of flexion. Portions of the aLTR that had free adjacent space were identified using the sagittal and coronal scans. This non-articulating region was identified as the "non-articulating zone" (NAZ). RESULTS: The NAZ was found to encompass the proximal 38.2% (range, 30.2% to 48.9%) of the aLTR, measuring, on average, 5.2 mm in width. It was consistently located either directly adjacent to the apex of the ridge or just medial to it. The distal 61.8% of the aLTR articulated with either the ulna or the radial head in some of the elbows. CONCLUSIONS: Our results suggest that there is a portion of the aLTR that, despite being covered with articular cartilage, is non-articulating throughout normal elbow range of motion. CLINICAL RELEVANCE: In situations in which headless anterior-to-posterior and posterior-to-anterior screw insertion results in inadequate fixation of capitellar-trochlear fractures, anterior-to-posterior lag screw instrumentation along the non-articulating portion of the aLTR may provide a location for additional fixation in some patients. However, because of variation between patients, each case must be individualized.

Co-targeting Bulk Tumor and CSCs in Clinically Translatable TNBC Patient-Derived Xenografts via Combination Nanotherapy.

Triple-negative breast cancer (TNBC) accounts disproportionally for the majority of breast cancer-related deaths throughout the world. This is largely attributed to lack of a specific therapy capable of targeting both bulk tumor mass and cancer stem cells (CSC), as well as appropriate animal models to accurately evaluate treatment efficacy for clinical translation. Thus, development of effective and clinically translatable targeted therapies for TNBC is an unmet medical need. We developed a hybrid nanoparticles-based co-delivery platform containing both paclitaxel and verteporfin (PV-NP) to target TNBC patient-derived xenograft (PDX) tumor and CSCs. MRI and IVIS imaging were performed on mice containing PDX tumors to assess tumor vascularity and accumulation of NPs. NF-κB, Wnt, and YAP activities were measured by reporter assays. Mice bearing TNBC PDX tumor were treated with PV-NPs and controls, and tumors progression and CSC subpopulations were analyzed. MRI imaging indicated high vascularization of PDX tumors. IVIS imaging showed accumulation of NPs in PDX tumors. In comparison with control-NPs and free-drug combination, PV-NPs significantly retarded tumor growth of TNBC PDX. PV-NPs simultaneously repressed NF-κB, Wnt, and YAP that have been shown to be crucial for cancer growth, CSC development, and tumorigenesis. In conclusion, NPs containing two clinically used drugs concurrently inhibited NF-κB, Wnt, and YAP pathways and exhibited synergic effects on killing TNBC bulk tumor and CSCs. This combination nanotherapy evaluated with a PDX model may lead to an effective treatment of patients with TNBC.

Prospective comparative diagnostic accuracy evaluation of dynamic contrast-enhanced (DCE) vs. dynamic susceptibility contrast (DSC) MR perfusion in differentiating tumor recurrence from radiation necrosis in treated high-grade gliomas.

BACKGROUND: The appearance of a new enhancing lesion after surgery and chemoradiation for high-grade glioma (HGG) presents a common diagnostic dilemma. Histopathological analysis remains the reference standard in this situation. PURPOSE: To prospectively compare the diagnostic accuracy of dynamic contrast-enhanced (DCE) vs. dynamic susceptibility contrast (DSC) in differentiating tumor recurrence (TR) from radiation necrosis (RN). STUDY TYPE: Prospective diagnostic accuracy study. POPULATION: In all, 98 consecutive treated HGG patients with new enhancing lesion. We excluded 32 patients due to inadequate follow-up or technical limitation. FIELD STRENGTH/SEQUENCE: 3 T DCE and DSC MR. ASSESSMENT: Histogram and hot-spot analysis of cerebral blood volume (CBV), corrected CBV, Ktrans , area under the curve (AUC), and plasma volume (Vp). The reference standard of TR and/or RN was determined by histopathology in 43 surgically resected lesions or by clinical/imaging follow-up in the rest. STATISTICAL TESTS: Mann-Whitney U-tests, receiver operating characteristic (ROC) curve, and logistic regression analysis. RESULTS: A total of 68 lesions were included. There were 37 TR, 28 RN, and three lesions with equal proportions of TR and RN. TR had significantly higher CBV, corrected CBV, CBV ratio, corrected CBV ratio, AUC ratio, and Vp ratio (P < 0.05) than RN on hot-spot analysis. CBV had the highest diagnostic accuracy (AUROC 0.71). On histogram analysis, TR had higher CBV and corrected CBV maximal value compared with RN (P = 0.006, AUROC = 0.70). Only CBV on hot-spot analysis remained significant after correction for multiple comparison, with no significant improvement in diagnostic accuracy when using a combination of parameters (AUROC 0.71 vs. 0.76, P = 0.24). DATA CONCLUSION: DSC-derived CBV is the most accurate perfusion parameter in differentiating TR and RN. DSC and DCE-derived parameters reflecting the blood volume in an enhancing lesion are more accurate than the DCE-derived parameter Ktrans . Clinical practice may be best guided by blood volume measurements, rather than permeability assessment for differentiation of TR from RN. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 4 J. Magn. Reson. Imaging 2019;50:573-582.

NK-Cell Recruitment Is Necessary for Eradication of Peritoneal Carcinomatosis with an IL12-Expressing Maraba Virus Cellular Vaccine.

Despite improvements in chemotherapy and radical surgical debulking, peritoneal carcinomatosis (PC) remains among the most common causes of death from abdominal cancers. Immunotherapies have been effective for selected solid malignancies, but their potential in PC has been little explored. Here, we report that intraperitoneal injection of an infected cell vaccine (ICV), consisting of autologous tumor cells infected ex vivo with an oncolytic Maraba MG1 virus expressing IL12, promotes the migration of activated natural killer (NK) cells to the peritoneal cavity in response to the secretion of IFNγ-induced protein-10 (IP-10) from dendritic cells. The recruitment of cytotoxic, IFNγ-secreting NK cells was associated with reduced tumor burden and improved survival in a colon cancer model of PC. Even in mice with bulky PC (tumors > 8 mm), a complete radiologic response was demonstrated within 8 to14 weeks, associated with 100% long-term survival. The impact of MG1-IL12-ICV upon NK-cell recruitment and function observed in the murine system was recapitulated in human lymphocytes exposed to human tumor cell lines infected with MG1-IL12. These findings suggest that an MG1-IL12-ICV is a promising therapy that could provide benefit to the thousands of patients diagnosed with PC each year. Cancer Immunol Res; 5(3); 211-21. ©2017 AACR.

Imaging of the rabbit supraspinatus enthesis at 7 Tesla: a 4-week time course after repair surgery and effect of channeling.

PURPOSE: To image the supraspinatus enthesis reformation of rabbit shoulders by magnetic resonance at 7 Tesla (T) using T2 mapping after surgical repair and to assess the effects of channeling aimed at enhancing enthesis reformation. MATERIALS AND METHODS: In 112 rabbits, the distal supraspinatus (SSP) tendon was unilaterally detached and reattached after 1 week. At the first surgery, channeling was performed at the footprint in 64 rabbits. At the second surgery, the SSP tendon of all rabbits was re-attached to the greater tuberosity. The shoulders were harvested at 0, 1, 2, or 4 weeks after the repair surgery and were imaged at 7T. Quantitative T2 mapping was performed using multi slice two-dimensional multi-echo spin-echo sequence with fat saturation. Enthesis regions of interests were drawn on three slices at the footprint to measure T2 relaxation times. RESULTS: Tendon repair (F(2, 218) = 44; P < 2.2e-16) and postoperative duration (F(3, 218) = 4.8; P = 0.006) both affected significantly the T2 values while channeling had no significant effect. For the time effect, the only pair with a statistical difference was the 0-week and 4-week for the channeling groups (P = 0.023). CONCLUSION: Enthesis reformation early after surgical repair of the SSP distal tendon was characterized by increasing T2 values. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:461-467.

Differentiation of lipoma from liposarcoma on MRI using texture and shape analysis.

RATIONALE AND OBJECTIVES: To determine if differentiation of lipoma from liposarcoma on magnetic resonance imaging can be improved using computer-assisted diagnosis (CAD). MATERIALS AND METHODS: Forty-four histologically proven lipomatous tumors (24 lipomas and 20 liposarcomas) were studied retrospectively. Studies were performed at 1.5T and included T1-weighted, T2-weighted, T2-fat-suppressed, short inversion time inversion recovery, and contrast-enhanced sequences. Two experienced musculoskeletal radiologists blindly and independently noted their degree of confidence in malignancy using all available images/sequences for each patient. For CAD, tumors were segmented in three dimensions using T1-weighted images. Gray-level co-occurrence and run-length matrix textural features, as well as morphological features, were extracted from each tumor volume. Combinations of shape and textural features were used to train multiple, linear discriminant analysis classifiers. We assessed sensitivity, specificity, and accuracy of each classifier for delineating lipoma from liposarcoma using 10-fold cross-validation. Diagnostic accuracy of the two radiologists was determined using contingency tables. Interreader agreement was evaluated by Cohen kappa. RESULTS: Using optimum-threshold criteria, CAD produced superior values (sensitivity, specificity, and accuracy are 85%, 96%, and 91%, respectively) compared to radiologist A (75%, 83%, and 80%) and radiologist B (80%, 75%, and 77%). Interreader agreement between radiologists was substantial (kappa [95% confidence interval]=0.69 [0.48-0.90]). CONCLUSIONS: CAD may help radiologists distinguish lipoma from liposarcoma.

Arterial input functions determined from MR signal magnitude and phase for quantitative dynamic contrast-enhanced MRI in the human pelvis.

Dynamic contrast-enhanced (DCE) MRI is often used to measure the transfer constant (Ktrans) and distribution volume (ve) in pelvic tumors. For optimal accuracy and reproducibility, one must quantify the arterial input function (AIF). Unfortunately, this is challenging due to inflow and signal saturation. A potential solution is to use MR signal phase (ϕ), which is relatively unaffected by these factors. We hypothesized that phase-derived AIFs (AIFϕ) would provide more reproducible Ktrans and ve values than magnitude-derived AIFs (AIF|S|). We tested this in 27 prostate dynamic contrast-enhanced MRI studies (echo time=2.56 ms, temporal resolution=13.5 s), using muscle as a standard. AIFϕ peak amplitude varied much less as a function of measurement location (inferior-superior) than AIF|S| (5.6±0.6 mM vs. 2.6±1.5 mM), likely as a result of ϕ inflow insensitivity. However, our main hypothesis was not confirmed. The best AIF|S| provided similar reproducibility versus AIFϕ (interpatient muscle Ktrans=0.039±0.021 min(-1) vs. 0.037±0.025 min(-1), ve=0.090±0.041 vs. 0.062±0.022, respectively).

Rapid monitoring of oxygenation by 19F magnetic resonance imaging: Simultaneous comparison with fluorescence quenching.

The aim of this study was to develop an MRI fluorocarbon oximetry technique using snapshot inversion recovery and compare it with fluorescence quenching fiber-optic probe oximetry (OxyLite) performed simultaneously in experimental mouse tumors. The oxygen reporter probe hexafluorobenzene (HFB) was injected directly into the tumors, along with the insertion of the OxyLite probe. Tumor oxygenation (pO(2)) was modified using carbogen or lethal doses of the anesthetic gas. MRI pO(2) maps were generated in 1.5 min with an in-plane spatial resolution of 1.88 mm. MRI and OxyLite showed consistent baseline and postmortem pO(2) values. Increases in tumor pO(2) during carbogen breathing showed similar kinetics for the two methods. The pO(2) values observed using the OxyLite corresponded with relatively hypoxic values observed by MRI. The apparent discrepancy between mean values might be due to the difference in sampling volumes of the techniques and the observation of multiple locations using (19)F MRI versus a single location using the large optical fiber. Overall, the present method provides a rapid way to map the tumor oxygenation and is particularly suitable to monitor acute changes of pO(2) in tumors.

19F NMR in vivo spectroscopy reflects the effectiveness of perfusion-enhancing vascular modifiers for improving gemcitabine chemotherapy.

Nuclear magnetic resonance spectroscopy of fluorine-19 ((19)F NMR) has proven useful for evaluating kinetics of fluorinated chemotherapy drugs in tumors in vivo. This work investigated how three perfusion-enhancing vascular modifiers (BQ123, thalidomide, and Botulinum neurotoxin type A [BoNT-A]) would affect the chemotherapeutic efficacy of gemcitabine, a fluorinated drug widely used in human cancer treatment. Murine tumor growth experiments demonstrated that only BoNT-A showed a strong trend to enhance tumor growth inhibition by gemcitabine (1.7 days growth delay, P = 0.052, Student t-test). In accord with these results, (19)F NMR experiments showed that only BoNT-A increased significantly the uptake of gemcitabine in tumors (50% increase, P = 0.0008, Student t-test). Further experiments on gemcitabine kinetics (NMR vs time) and distribution ((19)F MRI) confirmed the uptake-enhancing properties of BoNT-A. The results of this study demonstrate that (19)F NMR can monitor modulation of the pharmacokinetics of fluorinated chemotherapy drugs in tumors. The results also show that (19)F NMR data can give a strong indication of the effectiveness of perfusion-enhancing vascular modifiers for improving gemcitabine chemotherapy in murine tumors. (19)F NMR is a promising tool for preclinical evaluation of such vascular modifiers and may ultimately be used in the clinic to monitor how these modifiers affect chemotherapy.

Comparison of a reference region model with direct measurement of an AIF in the analysis of DCE-MRI data.

Models have been developed for analyzing dynamic contrast-enhanced (DCE)-MRI data that do not require measurements of the arterial input function (AIF). In this study, experimental results obtained from a reference region (RR) analysis are compared with results of an AIF analysis in the same set of five animals (four imaged twice, yielding nine data sets), returning estimates of the volume transfer constant (Ktrans) and the extravascular extracellular volume fraction (ve). Student's t-test values for comparisons of Ktrans and ve between the two models were 0.14 (P=0.88) and 0.85 (P>0.4), respectively (where the high P-values indicate no significant difference between values derived from the two models). Linear regression analysis indicated there was a correlation between Ktrans extracted by the two methods: r2=0.80, P=0.001 (where the low P-value indicates a significant linear correlation). For ve there was no such correlation (r2=0.02). The mean (absolute) percent difference between the models was 22.0% for Ktrans and 28.1% for ve. However, the RR parameter values were much less precise than the AIF method. The mean SDs for Ktrans and ve for the RR analysis were 0.024 min-1 and 0.06, respectively, vs. 0.002 min-1 and 0.03 for AIF analysis.

Complex relationship between changes in oxygenation status and changes in R*2: the case of insulin and NS-398, two inhibitors of oxygen consumption.

Insulin and NS-398 have been reported to inhibit oxygen consumption in experimental tumor models, thereby increasing oxygenation and radiosensitization. The aim of this work was to use MRI to study changes in murine FSaII tumor hemodynamics after administration of those oxygen consumption inhibitors. A multiple-echo gradient-echo (GRE) MRI sequence (4.7 T) was used to map changes in three factors: the GRE signal (at TE=20 ms), the parameter S0 (theoretical signal at TE=0 ms), and the relaxation rate R*2. Perfusion maps were obtained by dynamic contrast-enhanced (DCE) MRI. Insulin caused a significant decrease in the tumor blood oxygen level-dependent (BOLD) signal over time. factor This was likely the result of decreased blood flow, since both S0 and the percentage of perfused tumor decreased as well. Tumor R*2 did not change significantly in response to the treatments, which is surprising considering that other non-MRI techniques (electron paramagnetic resonance (EPR) oximetry and fiber-optic probes) have shown that tumor oxygenation increases after treatment. This suggests that metabolic changes associated with vasoactive challenges may have an unpredictable influence on blood saturation and R*2. In conclusion, this study further emphasizes the fact that changes in BOLD signal and R*2 in tumors do not depend uniquely on changes in oxygenation status.

Botulinum toxin potentiates cancer radiotherapy and chemotherapy.

PURPOSE: Structural and functional abnormalities in the tumor vascular network are considered factors of resistance of solid tumors to cytotoxic treatments. To increase the efficacy of anticancer treatments, efforts must be made to find new strategies for transiently opening the tumor vascular bed to alleviate tumor hypoxia (source of resistance to radiotherapy) and improve the delivery of chemotherapeutic agents. We hypothesized that Botulinum neurotoxin type A (BoNT-A) could interfere with neurotransmitter release at the perivascular sympathetic varicosities, leading to inhibition of the neurogenic contractions of tumor vessels and therefore improving tumor perfusion and oxygenation. EXPERIMENTAL DESIGN: To test this hypothesis, BoNT-A was injected locally into mouse tumors (fibrosarcoma FSaII, hepatocarcinoma transplantable liver tumor), and electron paramagnetic resonance oximetry was used to monitor pO(2) in vivo repeatedly for 4 days. Additionally, contrast-enhanced magnetic resonance imaging was used to measure tumor perfusion in vivo. Finally, isolated arteries were mounted in wire myograph to monitor specifically the neurogenic tone developed by arterioles that were co-opted by the surrounding growing tumor cells. RESULTS: Using these tumor models, we showed that local administration of BoNT-A (two sites; dose, 29 units/kg) substantially increases tumor oxygenation and perfusion, leading to a substantial improvement in the tumor response to radiotherapy (20 Gy of 250-kV radiation) and chemotherapy (cyclophosphamide, 50 mg/kg). This observed therapeutic gain results from an opening of the tumor vascular bed by BoNT-A because we showed that BoNT-A could inhibit neurogenic tone in the tumor vasculature. CONCLUSIONS: The opening of the vascular bed induced by BoNT-A offers a way to significantly increase the response of tumors to radiotherapy and chemotherapy.

The role of vessel maturation and vessel functionality in spontaneous fluctuations of T2*-weighted GRE signal within tumors.

Acute hypoxia (transient cycles of hypoxia-reoxygenation) is known to occur in solid tumors and is generally believed to be caused by tumor blood flow instabilities. It was recently demonstrated that T2*-weighted (T2*w) gradient echo (GRE) MRI is a powerful non-invasive method for investigating periodic changes in tumor pO2 and blood flow associated with acute hypoxia. Here, the possible correlation between tumor vessel immaturity, vessel functionality and T2*w GRE signal fluctuations was investigated. Intramuscularly implanted FSa II fibrosarcoma-bearing mice were imaged at 4.7 T. Maps of spontaneous fluctuations of MR signal intensity in tumor tissue during air breathing were obtained using a T2*w GRE sequence. This same sequence was also employed during air-5% CO2 breathing (hypercapnia) and carbogen breathing (hypercapnic hyperoxia) to obtain parametric maps representing vessel maturation and vessel function, respectively. Vascular density, vessel maturation and vessel perfusion were also assessed histologically by using CD31 labeling, alpha-smooth muscle actin immunoreactivity and Hoechst 33242 labeling, respectively. About 50% of the tumor fluctuations occurred in functional tumor regions (responsive to carbogen) and 80% occurred in tumor regions with immature vessels (lack of response to hypercapnia). The proportion of hypercapnia-responsive voxels were found to be twice as great in fluctuating than in non-fluctuating tumor areas (P: 0.22 vs 0.13). Similarly, the proportion of functional voxels was somewhat greater in fluctuating tumor areas (P: 0.54 vs 0.43). The mean values of MR signal changes during hypercapnia (VD) and during carbogen breathing (VF) (significant voxels only) were also larger in fluctuating than in non-fluctuating tumor areas (P < 0.05). This study demonstrated that adequate vessel functionality and advanced vessel maturation could explain at least in part the occurrence of spontaneous T2*w GRE signal fluctuations. Functionality and maturation are not required for signal fluctuations, however, because a large fraction of fluctuations could still occur in non-perfused and/or immature vessels.

Changes in the tumor microenvironment during low-dose-rate permanent seed implantation iodine-125 brachytherapy.

PURPOSE: There is a lack of data regarding how the tumor microenvironment (e.g., perfusion and oxygen partial pressure [pO2]) changes in response to low-dose-rate (LDR) brachytherapy. This may be why some clinical issues remain unresolved, such as the appropriate use of adjuvant external beam radiation therapy (EBRT). The purpose of this work was to obtain some basic preclinical data on how the tumor microenvironment evolves in response to LDR brachytherapy. METHODS AND MATERIALS: In an experimental mouse tumor, pO2 (measured by electron paramagnetic resonance) and perfusion (measured by dynamic contrast-enhanced magnetic resonance imaging) were monitored as a function of time (0-6 days) and distance (0-2 mm and 2-4 mm) from an implanted 0.5 mCi iodine-125 brachytherapy seed. RESULTS: For most of the experiments, including controls, tumors remained hypoxic at all times. At distances of 2-4 mm from radioactive seeds ( approximately 1.5 Gy/day), however, there was an early, significant increase in pO2 within 24 h. The pO2 in that region remained elevated through Day 3. Additionally, the perfusion in that region was significantly higher than for controls starting at Day 3. CONCLUSION: It may be advantageous to give adjuvant EBRT shortly (approximately 1 to 2 days) after commencement of clinical LDR brachytherapy, when the pO2 in the spatial regions between seeds should be elevated. If chemotherapy is given adjuvantly, it may best be administered just a little later (approximately 3 or 4 days) after the start of LDR brachytherapy, when perfusion should be elevated.

Improvement in breast lesion characterization with dynamic contrast-enhanced MRI using pharmacokinetic modeling and bookend T(1) measurements.

Dynamic contrast-enhanced breast MR imaging was performed on 14 patients (five cancerous lesions, nine benign) with slice-selective spoiled gradient-recalled echo (2D SPGR) imaging. Adiabatic saturation recovery T(1) measurements were performed before (T(1pre)) and after (T(1post)) 2D SPGR imaging. These two "bookend" T(1) measurements were used to calibrate the equations which were employed to convert the time course of the 2D SPGR signal strength to T(1)-vs.-time, which in turn was used to compute the gadolinium concentration-vs.-time ([C](t)) in the lesion. The extraction-flow product (EF) was computed for each lesion by pharmacokinetic modeling of [C](t). For this study, EF provided a sensitivity and specificity for cancer of 100% and 78%, respectively. When only T(1pre) was used to estimate [C](t) (which assumes a priori knowledge of the shape and amplitude of the slice profile), the sensitivity and specificity fell to 80% and 56%, respectively. This is presumably due to unexpected variations in the shape and/or amplitude of the slice profile, which could be caused by factors such as patient-to-patient variations in breast geometry or inconsistently set transmit gains. Therefore, both T(1pre) and T(1post) measurements are necessary for optimum sensitivity and specificity using pharmacokinetic analysis.