Combined estimation of B1and T1for dynamic contrast-enhanced MRI by accounting for incomplete spoiling of transverse magnetization.

Objective.The variable flip angle (VFA) method for longitudinal relaxation time (T1) measurement is inherently sensitive to inaccuracies in the radiofRequency transmit field (B1) and incomplete spoiling of transverse magnetization. The objective of this study is to devise a computational method that addresses the problems of incomplete spoiling andB1inhomogeneity in the estimation ofT1using VFA method.Approach. Using an analytical expression of the gradient echo signal with account of incomplete spoiling, we first showed that ill-posedness in the simultaneous estimation ofB1andT1can be lifted with the use of flip angles larger than the Ernst angle. We then devised a nonlinear optimization method based on this signal model of incomplete spoiling for simultaneous estimation ofB1andT1.Main results. We evaluated the proposed method on a graded-concentration phantom to show that the derivedT1estimates offers an improvement over the regular VFA method and compares well with reference values measured by inversion recovery. Reduction of the number of flip angles from 17 to 5 yielded consistent results indicating that the proposed method is numerically stable.T1estimates derived from in-vivo brain imaging were consistent with literature values for gray and white matter tissues.Significance. Contrary to the common notion thatB1correction in the VFA method forT1mapping should be performed separately, we show that combined estimation ofB1andT1is feasible by the proposed method simply with the acquisition of 5 flip angles, as demonstrated on both phantom and in-vivo imaging data.

A simple B 1 correction method for dynamic contrast-enhanced MRI.

The double-angle method (DAM) is commonly used as a reference standard in radiofrequency field (B 1) mapping studies. This study explored two aspects of DAM: (i) use of small flip angle pairs to reduce the repetition time (TR) needed for adequate longitudinal relaxation (T 1); and (ii) the effect of using different flip angle ratios for B 1 mapping. Results of phantom studies show that B 1 correction using small flip angle pairs ≤ 60° with TR = 5000 ms can allow for accurate estimation of T 1 up to about 1500 ms; and that increasing the ratio of the two flip angles used for B 1 correction resulted in more accurate estimation of T 1. These modifications allow 3-dimensional (3D) B 1 mapping to be consistently performed with the same 3D spoiled gradient echo sequence used for T 1 mapping in dynamic contrast-enhanced MRI.

Understanding K trans: a simulation study based on a multiple-pathway model.

The transfer constant K trans is commonly employed in dynamic contrast-enhanced MRI studies, but the utility and interpretation of K trans as a potential biomarker of tumor vasculature remains unclear. In this study, computer simulations based on a comprehensive tracer kinetic model with multiple pathways was used to provide clarification on the interpretation and application of K trans. Tissue concentration-time curves pertaining to a wide range of transport conditions were simulated using the multiple-pathway (MP) model and fitted using the generalized kinetic (GK) and extended GK models. Relationships between K trans and plasma flow F p, vessel permeability PS and extraction rate EF p under various transport conditions were assessed by correlation and regression analysis. Results show that the MP model provides an alternative two-tier interpretation of K trans based on the vascular transit time. K trans is primarily associated with F p and EF p respectively, in the slow and rapid vascular transit states, independent of the magnitude of PS. The relative magnitudes of PS and F p only serve as secondary constraints for which K trans can be further associated with EF p and PS in the slow and rapid transit states, respectively.

Intravoxel incoherent motion and diffusion tensor imaging of early renal fibrosis induced in a murine model of streptozotocin induced diabetes.

INTRODUCTION: To assess if parameters in intravoxel incoherent motion (IVIM) and diffusion tensor imaging (DTI) can be used to evaluate early renal fibrosis in a mouse model of diabetic nephropathy. MATERIALS & METHODS: In a population of 38 male CD1 mice (8weeks old, 20-30g), streptozotocin induced diabetes was created in 20 mice via a single intraperitoneal injection of streptozotocin at 150mg/kg, while 18 mice served as control group. IVIM parameters were acquired at 0, 12 and 24weeks after injection of streptozotocin using a range of b values from 0 to 1200s/mm2. DTI parameters were obtained using 12 diffusion directions and lower b values of 0, 100 and 400s/mm2. DTI and IVIM parameters were obtained using region of interests drawn over the renal parenchyma. Histopathological analysis of the right kidney was performed in all mice. Results were analyzed using an unpaired t-test with P<0.05 considered statistically significant. RESULTS: Renal cortex fractional anisotropy (FA) was significantly lower in the diabetes group at week 12 as compared with the control group. Renal cortex apparent diffusion coefficient and tissue diffusivity were significantly higher in the diabetes group at week 12 compared with the control group at 12weeks. Blood flow was significantly decreased at the renal medulla at 24weeks. Histopathological analysis confirmed fibrosis in the diabetes group at 24weeks. CONCLUSION: FA is significantly reduced in diabetic nephropathy. FA might serve a potential role in the detection and therapy monitoring of early diabetic nephropathy.

A phase Ib study of selumetinib (AZD6244, ARRY-142886) in combination with sorafenib in advanced hepatocellular carcinoma (HCC).

BACKGROUND: Treatment with sorafenib, although associated with inhibition of tumour growth and angiogenesis in in vivo studies, leads to up-regulation of pERK. The addition of MEK inhibition could potentially abrogate this effect and potentiate anti-tumour activity. This phase I study investigated the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK) and biomarker correlates of selumetinib combined with sorafenib in patients with advanced hepatocellular carcinoma (HCC). METHODS: Patients with Child-Pugh (CP) score ≤7 were treated with 400 mg twice daily of sorafenib with escalating doses of selumetinib in a 3 + 3 study design. The dose-limiting toxicity (DLT) evaluation period was 28 days. PK of selumetinib was determined. Angiogenic effect was evaluated with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS: Twenty-seven patients of Asian ethnicity were enrolled. The MTD was selumetinib 75 mg daily with sorafenib 400 mg twice daily. DLT included grade 3 transaminitis, diarrhoea and fatigue. Most common treatment-related adverse events at MTD (all grades) were diarrhoea (85%), rash (59%), hypertension (44%), fatigue (30%), anorexia (22%) and hand-foot syndrome (22%). Four patients (15%) had PR and 13 (48%) had SD. PR or SD was observed for ≥6 months in seven patients. The median overall survival was 14.4 months. Selumetinib exposures in combination with sorafenib were comparable to other monotherapy studies. A reduction in permeability-surface area product noted in DCE-MRI with treatment correlated with worse survival outcomes. CONCLUSION: The MTD of selumetinib was 75 mg daily when combined with sorafenib 400 mg twice a day in CP ≤7 HCC. Acceptable adverse events and encouraging anti-tumour activity warrant further evaluation. DCE-MRI findings deserve prospective evaluation. CLINICALTRIALSGOV IDENTIFIER: NCT01029418.

Dynamic contrast-enhanced magnetic resonance imaging: applications in oncology.

Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) allows functional characterisation of tissue perfusion characteristics and acts as a biomarker for tumour angiogenesis. It involves serial acquisition of MRI images before and after injection of contrast, as such, tissue perfusion and permeability can be assessed based on the signal enhancement kinetics. The ability to evaluate whole tumour volumes in a non-invasive manner makes DCE MRI especially attractive for potential oncological applications. Here we provide an overview of the current research involving DCE MRI as a biomarker for the diagnosis and characterisation of malignancies, prediction of the therapeutic response and survival outcomes, as well as radiation therapy planning.

Assessment of tumor blood flow distribution by dynamic contrast-enhanced CT.

A distinct feature of the tumor vasculature is its tortuosity and irregular branching of vessels, which can translate to a wider dispersion and higher variability of blood flow in the tumor. To enable tumor blood flow variability to be assessed in vivo by imaging, a tracer kinetic model that accounts for flow dispersion is developed for use with dynamic contrast-enhanced (DCE) CT. The proposed model adopts a multiple-pathway approach and allows for the quantification of relative dispersion in the blood flow distribution, which reflects flow variability in the tumor vasculature. Monte Carlo simulation experiments were performed to study the possibility of reducing the number of model parameters based on the Akaike information criterion approach and to explore possible noise and tissue conditions in which the model might be applicable. The model was used for region-of-interest analysis and to generate perfusion parameter maps for three patient DCE CT cases with cerebral tumors, to illustrate clinical applicability.

In vivo measurement of gadolinium diffusivity by dynamic contrast-enhanced MRI: a preclinical study of human xenografts.

Compartmental tracer kinetic models currently used for analysis of dynamic contrast-enhanced MRI data yield poor fittings or parameter values that are unphysiological in necrotic regions of the tumor, as these models only describe microcirculation in perfused tissue. In this study, we explore the use of Fick's law of diffusion as an alternative method for analysis of dynamic contrast-enhanced MRI data in the necrotic regions. Xenografts of various human cancer cell lines were implanted in 14 mice that were subjected to dynamic contrast-enhanced MRI performed using a spoiled gradient recalled sequence. Tracer concentration was estimated using the variable flip angle technique. Poorly perfused and necrotic tumor regions exhibiting delayed and slow enhancement were identified using a k-means clustering algorithm. Tracer behavior in necrotic regions was shown to be consistent with Fick's diffusion equation and the in vivo gadolinium diffusivity was estimated to be 2.08 (±0.88) × 10(-4) mm(2)/s. This study proposes the use of gadolinium diffusivity as an alternative parameter for quantifying tracer transport within necrotic tumor regions.

A Phase 1 dose-finding and pharmacodynamic study of rapamycin in combination with bevacizumab in patients with unresectable hepatocellular carcinoma.

BACKGROUND & AIMS: Preclinical studies have demonstrated the additive effect of rapamycin with bevacizumab for hepatocellular carcinoma treatment. We conducted a Phase 1 study to evaluate the safety and pharmacokinetics of the combination in patients with hepatocellular carcinoma. METHODS: Adult participants with advanced hepatocellular carcinoma received intravenous bevacizumab (5mg/kg every 14 days) and oral rapamycin (1-6 mg/day; 3+3 dose escalation design). Computed tomography assessed tumour response and treatment safety. Pharmacokinetics assessment established rapamycin blood concentrations pre- and post-dose. Dynamic contrast-enhanced computed tomography analysed the tumour region for blood flow, permeability surface area product, fractional intravascular blood volume and extracellular-extravascular volume. RESULTS: Twenty-four participants were treated. There were two dose limiting toxicities with rapamycin 5mg: grade 3 thrombocytopenia and grade 3 mucositis. The maximally tolerated dose of rapamycin was 4 mg. Adverse events (grade 1-2) included hyperglycaemia (83%), thrombocytopenia (75%), fatigue (46%), mucositis (46%), anorexia (42%), diarrhoea (33%) and proteinuria (12.5%). Of 20 evaluable participants, one reached complete response that lasted 4.5 months, two reached partial response, 14 reached stable disease and three had progressive disease. Median overall survival was 9.4 months; progression-free survival was 5.5 months. Dose level and steady state area under the concentration time curve for hour zero to infinity of rapamycin correlated inversely with blood flow rate and change in permeability-surface area. After 22 days of treatment, there were significant reductions from baseline in blood flow rate, permeability-surface area and fractional intracellular blood volume. CONCLUSIONS: The recommended Phase 2 dose of rapamycin is 4 mg in combination with bevacizumab. Evidence of anti-vascular activity was observed together with promising clinical activity.

Interpretation and applicability of empirical tissue enhancement metrics in dynamic contrast-enhanced MRI based on a multiple pathway model.

Computer simulations based on a physiologically realistic tracer kinetic model with multiple pathways was used to provide insights on the applicability and interpretation of tissue enhancement metrics such as the maximum slope, peak enhancement and area under curve, commonly used in dynamic contrast-enhanced (DCE) MRI. Results show that physiological conditions of the tissue that could affect the accuracy of the maximal slope method include a high blood flow, increased variability of flow within the vasculature or a low vascular volume. Interestingly, changes in permeability and interstitial volume might not affect the accuracy of the maximal slope method. Time-to-peak and peak value of the tissue enhancement curve are not strictly properties of the tissue alone, and they cannot be linearly related to intrinsic tissue parameters such as blood flow, blood volume, capillary permeability, interstitial volume and mean transit time. Similar to the normalized initial area under tissue concentration curve, an alternative estimate of the total tracer distribution volume can be simply given by the ratio of tracer concentration in the tissue and artery sampled at the final DCE scan.

Issues of discontinuity in the impulse residue function for deconvolution analysis of dynamic contrast-enhanced MRI data.

Recent dynamic contrast-enhanced MRI studies using the adiabatic tissue homogeneity model have highlighted potential issues of difficulty in convergence during data-fitting and reduced parameter precision, due to discontinuities in the adiabatic tissue homogeneity model. This study presents two solutions (an analytic approach and a discrete correction method) to such convergence problems and show that these problems can be attributed to an inaccurate approximation of the convolution integral based on the standard trapezoidal quadrature. It is further explained that such issues of discontinuity in the impulse residue function do not pertain only to the adiabatic tissue homogeneity model, but are generic to all tracer kinetic models, if the difference in bolus arrival time between the arterial input and tissue voxels were to be accounted for simultaneously during model-fitting.

Dynamic contrast-enhanced MRI of neuroendocrine hepatic metastases: A feasibility study using a dual-input two-compartment model.

Neuroendocrine hepatic metastases exhibit various contrast uptake enhancement patterns in dynamic contrast-enhanced MRI. Using a dual-input two-compartment distributed parameter model, we analyzed the dynamic contrast-enhanced MRI datasets of seven patient study cases with the aim to relate the tumor contrast uptake patterns to parameters of tumor microvasculature. Simulation studies were also performed to provide further insights into the effects of individual microcirculatory parameter on the tumor concentration-time curves. Although the tumor contrast uptake patterns can be influenced by many parameters, initial results indicate that hepatic blood flow and the ratio of fractional vascular volume to fractional interstitial volume may potentially distinguish between the patterns of neuroendocrine hepatic metastases.

High temporal resolution dynamic contrast-enhanced MRI at 7 Tesla: a feasibility study with mouse liver model.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been widely applied to evaluate microcirculatory parameters in clinical settings. However, pre-clinical studies involving DCE-MRI of small animals remain challenging with the requirement for high spatial and temporal resolution for quantitative tracer kinetic analysis. This study illustrates the feasibility of applying a high temporal resolution (2 s) protocol for liver imaging in mice by analyzing the DCE-MRI datasets of mice liver with a dual-input two-compartment tracer kinetic model. Phantom studies were performed to validate the T(1) estimates derived by the proposed protocol before applying it in mice studies. The DCE-MRI datasets of mice liver were amendable to tracer kinetic analysis using a dual-input two-compartment model. Estimated micro-circulatory parameters were consistent with liver physiology, indicating viability of applying the technique for pre-clinical drug developments.

Perfusion CT in squamous cell carcinoma of the upper aerodigestive tract: long-term predictive value of baseline perfusion CT measurements.

BACKGROUND AND PURPOSE: PCT studies hold short-term predictive value in patients treated with chemoradiotherapy. Our aim was to examine the long-term predictive value of baseline PCT studies for local tumor control and overall survival in SCCA of the upper aerodigestive tract treated with chemoradiotherapy. MATERIALS AND METHODS: Eighty-four patients with advanced SCCA underwent PCT followed by concomitant chemoradiation. The acquired perfusion maps represented BF, BV, MTT, and PS. Visual analysis of the parametric maps for identification of tumor perfusion patterns was conducted. ROC curves, t tests, and Kaplan-Meier survival curves were plotted for local disease control and overall survival. RESULTS: The median time of local tumor control was 24 months. The BF and PS values were significantly higher in patients who had no recurrence than in those with local failure (P < or = .02). The BF and PS were predictive (P < or = .0006) but BV and MTT held no significant predictive values for local tumor control. The patients with high BF and PS had a longer local tumor control than the patients with hypoperfused tumors (P = .0007). A visually detected BF-BV mismatch had a sensitivity/specificity of 63%/66% (P = .03) and 59%/69% (P = .03) for local tumor control and OS, respectively. Patients without mismatch lived significantly longer than patients with mismatch (P = .01). CONCLUSIONS: BF, PS, and mismatch of BF-BV are significant predictors of local tumor control after chemoradiation in SCCA of the upper aerodigestive tract.

Changes in perfusion CT of advanced squamous cell carcinoma of the head and neck treated during the course of concomitant chemoradiotherapy.

BACKGROUND AND PURPOSE: Concomitant chemoradiation is a promising therapy for the treatment of locoregionally advanced head and neck carcinoma. The purpose of this study was to prospectively evaluate early changes in primary tumor perfusion parameters during concomitant cisplatin-based chemoradiotherapy of locoregionally advanced SCCHN and to evaluate their predictive value for response of the primary tumor to therapy. MATERIALS AND METHODS: Twenty patients with locoregionally advanced SCCHN underwent perfusion CT scans before therapy and after completion of 40 Gy and 70 Gy of chemoradiotherapy. BF, BV, MTT, and PS of primary tumors were quantified. Differences in perfusion and tumor volume values during the therapy as well as between responders and nonresponders were analyzed, and ROC curves were used to assess predictive value of the baseline and follow-up functional parameters. RESULTS: The tumor volumes at 40 Gy and at 70 Gy were significantly lower compared with baseline values (P = .014 and P = .007). In the 6 nonresponders, measurements after 40 Gy showed a nonsignificant trend of increased BF, BV, and PS values compared with the baseline values (P = .06). In 14 responders, a significant reduction of BF values was recorded after 40 Gy (P = .04) and after 70 Gy (P = .01). In responders, BV values showed a reduction after 40 Gy followed by a plateau after 70 Gy (P = .04), whereas in nonresponders there was a nonsignificant elevation of the BV. Baseline BV predicted short-term tumor response with a sensitivity of 60% and specificity of 100% (P = .01). After completion of 40 Gy of concomitant chemoradiation BV was a more significant predictor than were BF and MTT. CONCLUSIONS: The results suggest that in advanced SCCHN the perfusion CT monitoring might be of predictive value for identifying tumors that may respond to cisplatin-based chemoradiotherapy.

Response and progression-free survival in oropharynx squamous cell carcinoma assessed by pretreatment perfusion CT: comparison with tumor volume measurements.

BACKGROUND AND PURPOSE: Perfusion CT (PCT) provides a rapid, reliable, and non-invasive technique for assessing tumor vascularity. The purpose of this study was to assess whether pretreatment dynamic perfusion CT (PCT) may predict response to induction chemotherapy and midterm progression-free survival (PFS) in advanced oropharynx squamous cell carcinoma (SCCA) and to compare the results with those derived by tumor volume measurements. MATERIALS AND METHODS: Nineteen patients underwent routine contrast-enhanced CT (CECT), pretreatment PCT, and conventional endoscopy. Tumor response was determined according to radiologic (RECIST) criteria. The PCT parameters, tumor volume, radiologic response, and PFS were analyzed with use of Cox-proportional hazards model, receiver operating characteristic (ROC), and Kaplan-Meier analysis. RESULTS: The baseline blood flow (BF), blood volume (BV), and permeability surface area product (PS) were significantly higher, whereas mean transit time (MTT) was significantly lower in the responders than in the nonresponders (P < or = .002). BV showed 100% sensitivity, MTT and PS had the highest specificity (100%), and BF showed 84.2% sensitivity and 66.7% specificity for prediction of tumor response after induction chemotherapy. The pretreatment tumor volume correlated with PFS in the pooled patients group (r = 0.4; P < .0001), whereas postinduction tumor volume correlated significantly with PFS in the responders and nonresponders (r = 0.22-0.64; P < or = .006). Pretreatment tumor volume (P = .0001) and BF (P = .001) were significant predictors for PFS. CONCLUSIONS: Pretreatment PCT parameters may predict response after induction chemotherapy. Tumor volume and BF values may predict PFS in patients with advanced oropharyngeal SCCA.

On the a priori identifiability of the two-compartment distributed parameter model from residual tracer data acquired by dynamic contrast-enhanced imaging.

Tracer kinetics models are commonly employed to estimate physiological parameters related to blood transport and capillary-tissue exchange. A priori identifiability addresses the question of whether the parameters in a model can be uniquely determined from a given experiment. It has been previously shown that the one- and two-compartment distributed parameter (DP) models are nonidentifiable from tracer outflow data obtained by arterial-venous sampling. In this correspondence, we show that both DP models are a priori identifiable from residual tracer data obtained by dynamic contrast-enhanced (DCE) imaging. We list the various parameters of the DP models that can be uniquely estimated from DCE imaging data, and discuss this seemingly different outcome for DCE imaging experiments, as compared with the arterial-venous sampling experiments.

Delineation and segmentation of cerebral tumors by mapping blood-brain barrier disruption with dynamic contrast-enhanced CT and tracer kinetics modeling-a feasibility study.

Dynamic contrast-enhanced (DCE) imaging is a promising approach for in vivo assessment of tissue microcirculation. Twenty patients with clinical and routine computed tomography (CT) evidence of intracerebral neoplasm were examined with DCE-CT imaging. Using a distributed-parameter model for tracer kinetics modeling of DCE-CT data, voxel-level maps of cerebral blood flow (F), intravascular blood volume (vi) and intravascular mean transit time (t1) were generated. Permeability-surface area product (PS), extravascular extracellular blood volume (ve) and extraction ratio (E) maps were also calculated to reveal pathologic locations of tracer extravasation, which are indicative of disruptions in the blood-brain barrier (BBB). All maps were visually assessed for quality of tumor delineation and measurement of tumor extent by two radiologists. Kappa (kappa) coefficients and their 95% confidence intervals (CI) were calculated to determine the interobserver agreement for each DCE-CT map. There was a substantial agreement for the tumor delineation quality in the F, ve and t1 maps. The agreement for the quality of the tumor delineation was excellent for the vi, PS and E maps. Concerning the measurement of tumor extent, excellent and nearly excellent agreement was achieved only for E and PS maps, respectively. According to these results, we performed a segmentation of the cerebral tumors on the base of the E maps. The interobserver agreement for the tumor extent quantification based on manual segmentation of tumor in the E maps vs. the computer-assisted segmentation was excellent (kappa = 0.96, CI: 0.93-0.99). The interobserver agreement for the tumor extent quantification based on computer segmentation in the mean images and the E maps was substantial (kappa = 0.52, CI: 0.42-0.59). This study illustrates the diagnostic usefulness of parametric maps associated with BBB disruption on a physiology-based approach and highlights the feasibility for automatic segmentation of cerebral tumors.

Bispectral analysis of snore signals for obstructive sleep apnea detection.

Obstructive sleep apnea (OSA) is an insidious condition of recurring upper airway closure during sleep. Apart from polysomnography, many researchers tried to explore alternative methods to detect OSA. However, not much work has been done to address the non-Gaussian and nonlinear behavior of the snore signals, which the power spectrum may not adequately account for. Therefore, this paper presents the use of bispectral analysis of snore signals for OSA detection. The raw snore signals were denoised using a modified level-wavelet-dependent thresholding scheme under an undecimated wavelet environment. Subsequently, nonlinear properties in the noise-suppressed snore signals were extracted to discriminate between apneic and benign snores. Results show that apneic snores exhibit higher degree of phase coupling phenomena than benign snores. This preliminary study suggests that the bispectral analysis of snore signals might be useful to distinguish apneic patients from benign patients.