Interstitial Volume Fraction Research Articles

The relationship between parameters measured using intravoxel incoherent motion and dynamic contrast-enhanced MRI in patients with breast cancer undergoing neoadjuvant chemotherapy: a longitudinal cohort study.

The primary aim of this study was to explore whether intravoxel incoherent motion (IVIM) can offer a contrast-agent-free alternative to dynamic contrast-enhanced (DCE)-MRI for measuring breast tumor perfusion. The secondary aim was to investigate the relationship between tissue diffusion measures from DWI and DCE-MRI measures of the tissue interstitial and extracellular volume fractions. A total of 108 paired DWI and DCE-MRI scans were acquired at 1.5 T from 40 patients with primary breast cancer (median age: 44.5 years) before and during neoadjuvant chemotherapy (NACT). DWI parameters included apparent diffusion coefficient (ADC), tissue diffusion (Dt), pseudo-diffusion coefficient (Dp), perfused fraction (f), and the product f×Dp (microvascular blood flow). DCE-MRI parameters included blood flow (Fb), blood volume fraction (vb), interstitial volume fraction (ve) and extracellular volume fraction (vd). All were extracted from three tumor regions of interest (whole-tumor, ADC cold-spot, and DCE-MRI hot-spot) at three MRI visits: pre-treatment, after one, and three cycles of NACT. Spearman's rank correlation was used for assessing between-subject correlations (r), while repeated measures correlation was employed to assess within-subject correlations (rrm) across visits between DWI and DCE-MRI parameters in each region. No statistically significant between-subject or within-subject correlation was found between the perfusion parameters estimated by IVIM and DCE-MRI (f versus vb and f×Dp versus Fb; P=0.07-0.81). Significant moderate positive between-subject and within-subject correlations were observed between ADC and ve (r=0.461, rrm=0.597) and between Dt and ve (r=0.405, rrm=0.514) as well as moderate positive within-subject correlations between ADC and vd and between Dt and vd (rrm=0.619 and 0.564, respectively) in the whole-tumor region. No correlations were observed between the perfusion parameters estimated by IVIM and DCE-MRI. This may be attributed to imprecise estimates of fxDp and vb, or an underlying difference in what IVIM and DCE-MRI measure. Care should be taken when interpreting the IVIM parameters (f and f×Dp) as surrogates for those measured using DCE-MRI. However, the moderate positive correlations found between ADC and Dt and the DCE-MRI parameters ve and vd confirms the expectation that as the interstitial and extracellular volume fractions increase, water diffusion increases.

Associations of Biomarkers of Tubular Injury and Inflammation with Biopsy Features in Type 1 Diabetes.

Whether biomarkers of tubular injury and inflammation indicate subclinical structural kidney pathology early in type 1 diabetes remains unknown. We investigated associations of biomarkers of tubular injury and inflammation with kidney structural features in 244 adults with type 1 diabetes from the Renin-Angiotensin System Study, a randomized, placebo-controlled trial testing effects of enalapril or losartan on changes in glomerular, tubulointerstitial, and vascular parameters from baseline to 5-year kidney biopsies. Biosamples at biopsy were assessed for kidney injury molecule 1 (KIM-1), soluble TNF receptor 1 (sTNFR1), arginine-to-citrulline ratio in plasma, and uromodulin and epidermal growth factor (EGF) in urine. We examined cross-sectional correlations between biomarkers and biopsy features and baseline biomarker associations with 5-year changes in biopsy features. Participants' mean age was 30 years (SD 10) and diabetes duration 11 years (SD 5); 53% were women. The mean GFR measured by iohexol disappearance was 128 ml/min per 1.73 m 2 (SD 19) and median urinary albumin excretion was 5 μ g/min (interquartile range, 3-8). KIM-1 was associated with most biopsy features: higher mesangial fractional volume (0.5% [95% confidence interval (CI), 0.1 to 0.9] greater per SD KIM-1), glomerular basement membrane (GBM) width (14.2 nm [95% CI, 6.5 to 22.0] thicker), cortical interstitial fractional volume (1.1% [95% CI, 0.6 to 1.6] greater), fractional volume of cortical atrophic tubules (0.6% [95% CI, 0.2 to 0.9] greater), and arteriolar hyalinosis index (0.03 [95% CI, 0.1 to 0.05] higher). sTNFR1 was associated with higher mesangial fractional volume (0.9% [95% CI, 0.5 to 1.3] greater) and GBM width (12.5 nm [95% CI, 4.5 to 20.5] thicker) and lower GBM surface density (0.003 μ m 2 / μ m 3 [95% CI, 0.005 to 0.001] lesser). EGF and arginine-to-citrulline ratio correlated with severity of glomerular and tubulointerstitial features. Baseline sTNFR1, uromodulin, and EGF concentrations were associated with 5-year glomerular and tubulointerstitial feature progression. Biomarkers of tubular injury and inflammation were associated with kidney structural parameters in early type 1 diabetes and may be indicators of kidney disease risk. Renin Angiotensin System Study (RASS/B-RASS), NCT00143949. This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_11_17_CJN0000000000000333.mp3.

Non-invasive imaging of interstitial fluid transport parameters in solid tumors in vivo

In this paper, new and non-invasive imaging methods to assess interstitial fluid transport parameters in tumors in vivo are developed, analyzed and experimentally validated. These parameters include extracellular volume fraction (EVF), interstitial fluid volume fraction (IFVF) and interstitial hydraulic conductivity (IHC), and they are known to have a critical role in cancer progression and drug delivery effectiveness. EVF is defined as the volume of extracellular matrix per unit volume of the tumor, while IFVF refers to the volume of interstitial fluid per unit bulk volume of the tumor. There are currently no established imaging methods to assess interstitial fluid transport parameters in cancers in vivo. We develop and test new theoretical models and imaging techniques to assess fluid transport parameters in cancers using non-invasive ultrasound methods. EVF is estimated via the composite/mixture theory with the tumor being modeled as a biphasic (cellular phase and extracellular phase) composite material. IFVF is estimated by modeling the tumor as a biphasic poroelastic material with fully saturated solid phase. Finally, IHC is estimated from IFVF using the well-known Kozeny–Carman method inspired by soil mechanics theory. The proposed methods are tested using both controlled experiments and in vivo experiments on cancers. The controlled experiments were performed on tissue mimic polyacrylamide samples and validated using scanning electron microscopy (SEM). In vivo applicability of the proposed methods was demonstrated using a breast cancer model implanted in mice. Based on the controlled experimental validation, the proposed methods can estimate interstitial fluid transport parameters with an error below 10% with respect to benchmark SEM data. In vivo results demonstrate that EVF, IFVF and IHC increase in untreated tumors whereas these parameters are observed to decrease over time in treated tumors. The proposed non-invasive imaging methods may provide new and cost-effective diagnostic and prognostic tools to assess clinically relevant fluid transport parameters in cancers in vivo.

Morphological changes in the myocardium of rats with chronic alcohol intoxication after treatment with new GABAand glutamic acid derivatives

Aim. To study pathohistological changes in the myocardium of rats with chronic alcohol intoxication (CAI) after treatment with a new glutamic acid derivative glufimet (compound RSPU-238) and a new gamma-aminobutyric acid (GABA) derivative (compound RSPU-260).Materials and methods. Experiments were performed on female Wistar rats aged 10 months. The rats were divided into the following groups: group 1 – intact females; group 2 – a control group which included animals after CAI simulated by replacing drinking water with 10% ethanol solution for 24 weeks; groups 3 and 4 – experimental groups, in which females were intraperitoneally administered with glufimet at a dose of 28.7 mg / kg and RSPU260 at a dose of 25 mg / kg once a day for 14 days after cessation of alcohol solution consumption; group 5 – a group of animals receiving a reference listed drug mildronate at a dose of 50 mg / kg according to a regimen similar to that of the studied compounds. Changes in microstructural and morphometric parameters of the left ventricular myocardium were assessed using light microscopy.Results. In animals after CAI, the cardiomyocyte volume fraction decreased, while the interstitial and vascular volume fractions increased. Degeneration of cardiomyocytes, such as their wave-like deformation, loss of transverse striation, foci of plasmolysis, and fragmentation of muscle fibers were revealed. In rats treated with glufimet, the structural changes in cardiomyocytes were minimal. Lower vascular plethora was observed; blood vessels were characterized by single stasis and sludge. The cardiomyocyte volume fraction was 9.7% greater than in control animals, while the interstitial and vascular volume fractions were 66.0 and 70.0% smaller, respectively. The animals treated with the RSPU-260 compound had no significant degenerative changes in cardiomyocytes and small vessels similar to the experimental animals injected with glufimet. Mildronate had a less pronounced cardioprotective effect.Conclusion. Administration of new GABA and glutamic acid derivatives to animals with simulated chronic alcohol intoxication leads to improvement of the microstructure in cardiomyocytes compared with control rats. This indicates pronounced cardioprotective effects of the studied neuroactive amino acid derivatives.

An Unsupervised Autoencoder Developed from Dynamic Contrast-Enhanced (DCE)-MRI Datasets for Classification of Acute Tumor Response in an Animal Model

<h3>Purpose/Objective(s)</h3> Recent studies have shown that vascular parameters of brain tumors derived from DCE-MRI may act as potential biomarkers for radiation-induced acute effects. However, accurate characterization of the spatial regions affected by radiation therapy (RT) remains challenging. Here, we introduce an unsupervised adaptive model for classification and ranking of the RT-affected regions in an animal model of cerebral U-251n tumors. <h3>Materials/Methods</h3> Twenty-three immune-compromised-RNU rats were implanted with human U251n cancer cells to form an orthotopic glioma (IACUC #1509). For each rat, 28 days after implantation, two DCE-MRI studies (Dual Gradient Echo, DGE, FOV: 32 × 32 mm², T_R/(T_E1-T_E2) = 24 ms/(2 ms-4 ms), flip angle = 18°, 400 acquisitions, 1.55 sec interval with Magnevist contrast agent, CA injection at ∼ 24 sec) were performed 24h apart using a 7T MRI scanner. A single 20 Gy stereotactic radiation exposure was performed before the second MRI, which was acquired 1-6.5 hrs after RT. DCE-MRI analysis was done using a model selection technique to distinguish three different brain regions as follows: Normal vasculature (Model 1: No leakage, only plasma volume, v_p, is estimated), leaky tumor tissues with no back-flux to the vasculature (Model 2: v_p and forward volumetric transfer constant, K^trans, are estimated), and leaky tumor tissues with back-flux (Model 3: v_p, K^trans, and interstitial volume fraction, v_e, are estimated). Normalized time traces of DCE-MRI information (24 pre, and 24 post-RT for each rat, total of 64108 training datasets) of tumors and their soft surrounding normal tissues were extracted from the 3 different model regions. To eliminate high-dimensional data similarity, an unsupervised autoencoder (AE) was trained to map out the model-derived data into a feature space (latent variables, N=10). For each model, the pre and post RT latent variables were compared (by appropriate tests of significance: ANOVA/Welch, CI=95%) to reveal RT-discriminant features. Pearson correlation coefficients were used to compare the decoded data to rank the effect of RT on different models. <h3>Results</h3> The time trace of DCE-MRI information of rat brain in normal (Model 1, non-leaky) and highly permeable (Model 3) regions are less impacted by RT (Higher correlation between pre and post RT: r=0.8518, p<0.0001 and r=0.9040, p<0.0001 for Model 1 and Model 3, respectively) compared to the peritumoral regions pertaining to Model 2 (r= 0.8077, p<0.0001). <h3>Conclusion</h3> This pilot study suggests that among different brain regions, peritumoral zones (infiltrative tumor borders with enhanced rim) are highly affected by RT. Spatial assessment of RT-affected brain regions can play a key role in optimization of treatment planning in cancer patients, but presents a challenging task in conventional DCE-MRI. This study represents an important step toward classification and ranking the RT-affected brain spatial regions according to their vascular response following hypofractionated RT.

Urinary Proteomics Identifies Cathepsin D as a Biomarker of Rapid eGFR Decline in Type 1 Diabetes.

Understanding mechanisms underlying rapid estimated glomerular filtration rate (eGFR) decline is important to predict and treat kidney disease in type 1 diabetes (T1D). We performed a case-control study nested within four T1D cohorts to identify urinary proteins associated with rapid eGFR decline. Case and control subjects were categorized based on eGFR decline ≥3 and <1 mL/min/1.73 m2/year, respectively. We used targeted liquid chromatography-tandem mass spectrometry to measure 38 peptides from 20 proteins implicated in diabetic kidney disease. Significant proteins were investigated in complementary human cohorts and in mouse proximal tubular epithelial cell cultures. The cohort study included 1,270 participants followed a median 8 years. In the discovery set, only cathepsin D peptide and protein were significant on full adjustment for clinical and laboratory variables. In the validation set, associations of cathepsin D with eGFR decline were replicated in minimally adjusted models but lost significance with adjustment for albuminuria. In a meta-analysis with combination of discovery and validation sets, the odds ratio for the association of cathepsin D with rapid eGFR decline was 1.29 per SD (95% CI 1.07-1.55). In complementary human cohorts, urine cathepsin D was associated with tubulointerstitial injury and tubulointerstitial cathepsin D expression was associated with increased cortical interstitial fractional volume. In mouse proximal tubular epithelial cell cultures, advanced glycation end product-BSA increased cathepsin D activity and inflammatory and tubular injury markers, which were further increased with cathepsin D siRNA. Urine cathepsin D is associated with rapid eGFR decline in T1D and reflects kidney tubulointerstitial injury.

Dynamic contrast-enhanced magnetic resonance imaging for risk stratification in patients with prostate cancer.

To investigate the usefulness of perfusion parameters derived from dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) of patients diagnosed as prostate cancer (PCa) in differentiating clinically significant cancer [CSC, Gleason score (GS) ≥7] from non-CSC (GS 6). A total of 94 patients diagnosed between August 2018 and September 2020 as PCa by radical prostatectomy were included in this retrospective study (mean age: 68.7 years, range, 47-83 years). All of the patients had undergone DCE-MRI on a single 3T-MR scanner. Whole-tumor volume was measured by reviewing a pathologic topographic map as a reference standard. The quantitative DCE perfusion parameters, including volume transfer constant (Ktrans), rate constant (kep), extracellular extravascular space (EES) volume fraction (ve), plasma volume fraction (vp) and area of region of interest (ROI) were calculated under an extended Tofts model. A receiver operating characteristic (ROC) curve analysis by pair-wise comparison was performed to compare the diagnostic performances of the perfusion parameters. The study population comprised GS 6 (n=17), GS 7 (n=57), GS 8 (n=9) and GS 9 (n=11) cases. Among the perfusion parameters, ve differed significantly between CSC (0.238±0.095) and non-CSC (0.300±0.126) (P=0.0308). Area under the curve (AUC) was 0.643 (95% CI, 0.538-0.739), and a maximum accuracy of 64%, a sensitivity of 66%, and a specificity of 53% were estimated. Area of ROI also differed significantly between CSC (201.89±163.87 mm2) and non-CSC (84.99±85.82 mm2) (P=0.0054). AUC was 0.807 (95% CI, 0.713-0.881), and maximum accuracy, sensitivity, and specificity were 81%, 82%, and 76%, respectively. Size of the tumor and interstitial space volume fraction are significant parameters in differentiating aggressiveness in PCa.

ХАРАКТЕРИСТИКА СОСТОЯНИЯ МИОКАРДА И ПРОФИБРОТИЧЕСКИХ ФАКТОРОВ ПРИ РАЗВИТИИ ГИПЕРТОНИЧЕСКОГО СЕРДЦА

Introduction. Myocardial damage caused by arterial hypertension is manifested by changes in myocardial geometry and mass, as well as increased content of collagen and fibrous tissue in the myocardium. Excessive accumulation of collagen in myocardium is the result of imbalance between proteolytic enzymes such as matrix metalloproteinases 1 (MMP-1) and tissue inhibitors of matrix metalloproteinase 1 (TIMMP-1), high content of transforming growth factor β1 (TFG-β1), which was found in fibroblasts and macrophages. Aim. The aim of the study was to investigate the role of MMP-1 activation, its tissue inhibitor TIMMP-1 and TGF-β1 in blood in the development of myocardial fibrosis in locomotive train workers with arterial hypertension. Material and methods. 82 patients with arterial hypertension and 20 virtually healthy control subjects were examined. The patients of the analyzed groups underwent evaluation of the data of daily blood pressure monitoring, echocardiographic examination, based on which the types of left ventricular remodeling, the content of matrix metalloproteinase 1 and its tissue inhibitor activity, the level of transforming growth factor β1 in blood serum were identified. Calculation of the volume fraction of interstitial collagen was performed. Results and discussion. The study established statistically significant signs of structural changes in the left ventricular myocardium, which primarily indicated its marked left ventricular hypertrophy against the background of arterial hypertension due to chronic pressure overload. Statistically significant increase of all levels of serum markers of collagen metabolism was revealed in patients with arterial hypertension in comparison with the control group. Patients with arterial hypertension have a restructuring of the intercellular matrix components and imbalance in the MMP-1/TIMMP-1 system characterized by a shift of the collagen balance towards fibrosis (increase of THF-β1, TIMMP-1 level, decrease of MMP-1/TIMMP-1 52 ВЕСТНИК СОВРЕМЕННОЙ КЛИНИЧЕСКОЙ МЕДИЦИНЫ 2021 Том 14, вып. 6ОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯ ratio and increase of interstitial collagen volume fraction). Significant increase of interstitial collagen volume fraction index in the group of patients with arterial hypertension comparing to the control group also indirectly indicates high intensity of interstitial collagen genesis in myocardium of these patients. Conclusion. In arterial hypertension, serum levels of THF-β1, MMP-1, and TIMMP-1 increase, which indirectly indicates an increase in myocardial collagen content.

Imaging acute effects of bevacizumab on tumor vascular kinetics in a preclinical orthotopic model of U251 glioma.

The effect of a human vascular endothelial growth factor antibody on the vasculature of human tumor grown in rat brain was studied. Using dynamic contrast-enhanced magnetic resonance imaging, the effects of intravenous bevacizumab (Avastin; 10 mg/kg) were examined before and at postadministration times of 1, 2, 4, 8, 12 and 24 h (N = 26; 4-5 per time point) in a rat model of orthotopic, U251 glioblastoma (GBM). The commonly estimated vascular parameters for an MR contrast agent were: (i) plasma distribution volume (vp ), (ii) forward volumetric transfer constant (Ktrans ) and (iii) reverse transfer constant (kep ). In addition, extracellular distribution volume (VD ) was estimated in the tumor (VD-tumor ), tumor edge (VD-edge ) and the mostly normal tumor periphery (VD-peri ), along with tumor blood flow (TBF), peri-tumoral hydraulic conductivity (K) and interstitial flow (Flux) and tumor interstitial fluid pressure (TIFP). Studied as % changes from baseline, the 2-h post-treatment time point began showing significant decreases in vp , VD-tumor, VD-edge and VD-peri , as well as K, with these changes persisting at 4 and 8 h in vp , K, VD-tumor, -edge and -peri (t-tests; p < 0.05-0.01). Decreases in Ktrans were observed at the 2- and 4-h time points (p < 0.05), while interstitial volume fraction (ve ; = Ktrans /kep ) showed a significant decrease only at the 2-h time point (p < 0.05). Sustained decreases in Flux were observed from 2 to 24 h (p < 0.01) while TBF and TIFP showed delayed responses, increases in the former at 12 and 24 h and a decrease in the latter only at 12 h. These imaging biomarkers of tumor vascular kinetics describe the short-term temporal changes in physical spaces and fluid flows in a model of GBM after Avastin administration.

The utility of multiparametric MRI to characterize hypoxic tumor subvolumes in comparison to FMISO PET/CT. Consequences for diagnosis and chemoradiation treatment planning in head and neck cancer

Background and PurposeHypoxia is an essential metabolic marker that determines chemo- and radiation resistance in head-and-neck squamous cell carcinoma (HNSCC) patients. Our exploratory analysis aimed to identify multiparametric MRI (mpMRI) parameters linked to hypoxia that might be used as surrogate for [18F]FMISO-PET in diagnosis and chemoradiation treatment (CRT) of HNSCC. Materials and Methods21 patients undergoing definitive CRT for HNSCC were prospectively imaged with serial [18F]FMISO-PET and 3 Tesla mpMRI for T1- and T2-weighted and dynamic contrast-enhanced perfusion and diffusion-weighted measurements (ktrans, ve, kep, ADC) in weeks 0, 2 and 5 and FDG-PET in week 0. [18F]FMISO-PET-derived hypoxic subvolumes (HSV) and complementary non-hypoxic subvolumes (nonHSV) were created for tumor and lymph nodes and projected on the mpMRI scans after PET/MRI co-registration. MpMRI and [18F]FMISO-PET parameters within HSVs and nonHSVs were statistically compared. ResultsFMISO-PET-based HSVs of the primary tumors on MRI were characterized by lower ADC at all time points (p = 0.012 at baseline; p = 0.015 in week 2) and reduced interstitial space volume fraction ve and perfusion ktrans at baseline (p = 0.006, p = 0.047) compared to nonHSVs. Hypoxic lymph nodes were characterized by significantly lower ADC values at baseline (p = 0.039), but not at later time points and a reduction in ktrans-based perfusion at week 2 (p = 0.018). ConclusionMpMRI parameters differ significantly between hypoxic and non-hypoxic tumor regions, defined on FMISO-PET/CT as gold standard and might represent surrogate markers for tumor hypoxia. These findings suggest that mpMRI may be useful in the future as a surrogate modality for hypoxia imaging in order to personalize CRT.

P931Assosiation of the levels of galectin-3 and MMP-1 with the type of myocardial dyssynchrony in patients with heart failure and concomitant type 2 diabetes mellitus

Abstract Background Myocardial dyssynchrony leads to heart remodeling and the progression of heart failure (HF) in patients with type 2 diabetes mellitus. Studying the mechanisms of the development of myocardial dyssynchrony can help in timely diagnosis and treatment. Aims To study the association of the level of galectin-3 and matrix metalloproteinase 1 (MMP-1) and the type of myocardial dyssynchrony in patients with heart failure and concomitant type 2 diabetes mellitus. Methods 98 patients with heart failure and concomitant type 2 diabetes mellitus were examined, average age (67.45 + 10.32) years. Patients were divided into two groups due to the presence or absence of myocardial dyssynchrony: the first group: with myocardial dyssynchrony (n = 56), the second group: patients without myocardial dyssynchrony ( n = 42). All patients were examined for electrical (enhanced QRS ≥ 120 ms) and mechanical myocardial dyssynchrony using echocardiographic and electrocardiographic methods for assessing intraventricular, interventricular, atrioventricular and combined myocardial dyssynchrony, as well as serum concentration of fibrosis markers - galectin-3 and MMP-1. The determination of percentage of interstitial collagen volume fraction (CVF) was performed in both groups. Results To determine the levels of fibrosis markers depending on the presence of diabetes, the results of patients with myocardial dyssynchrony (n = 56) were compared with the results of the control group without myocardial dyssynchrony (n = 42). In patients with myocardial dyssynchrony, there was an increase in the levels of galectin-3 (7.49 + 0.6 ng / ml) and CVF (7.6 ± 4.03%), a decrease in MMP-1 (0.46 + 0.2 ng / ml ) compared with the group without myocardial dyssynchrony (p &amp;lt;0.05). An increase in galectin-3 levels was observed in the presence of combined forms of myocardial dyssynchrony. In patients with a combination of intraventricular, interventricular, or atrioventricular myocardial dyssynchrony (n = 28), the levels of galectin-3 (9.03 + 0.3 ng / ml) and CVF (8.04 + 1.6%) were the highest; in patients with isolated forms of myocardial dyssynchrony, the levels of galectin-3 (6.67 + 0.2 ng / ml) and CVF (6,93 + 1,4%) were significantly lower. MMP-1 was greater in patients with isolated forms of myocardial dyssynchrony (0.78 + 0.2 ng / ml), compared with patients with combined forms of myocardial dyssynchrony (0.2 + 0.01 ng / ml) (p &amp;lt;0.05 ). Conclusions An association is observed between myocardial dyssynchrony and the levels of galectin-3 and MMP-1 in the blood. These findings are important for prognostic implications and require further research.

Dual-input tracer kinetic modeling of dynamic contrast-enhanced MRI in thoracic malignancies.

Pulmonary perfusion with dynamic contrast‐enhanced (DCE‐) MRI is typically assessed using a single‐input tracer kinetic model. Preliminary studies based on perfusion CT are indicating that dual‐input perfusion modeling of lung tumors may be clinically valuable as lung tumors have a dual blood supply from the pulmonary and aortic system. This study aimed to investigate the feasibility of fitting dual‐input tracer kinetic models to DCE‐MRI datasets of thoracic malignancies, including malignant pleural mesothelioma (MPM) and nonsmall cell lung cancer (NSCLC), by comparing them to single‐input (pulmonary or systemic arterial input) tracer kinetic models for the voxel‐level analysis within the tumor with respect to goodness‐of‐fit statistics. Fifteen patients (five MPM, ten NSCLC) underwent DCE‐MRI prior to radiotherapy. DCE‐MRI data were analyzed using five different single‐ or dual‐input tracer kinetic models: Tofts‐Kety (TK), extended TK (ETK), two compartment exchange (2CX), adiabatic approximation to the tissue homogeneity (AATH) and distributed parameter (DP) models. The pulmonary blood flow (BF), blood volume (BV), mean transit time (MTT), permeability‐surface area product (PS), fractional interstitial volume (v I), and volume transfer constant (K Trans) were calculated for both single‐ and dual‐input models. The pulmonary arterial flow fraction (γ), pulmonary arterial blood flow (BFPA) and systemic arterial blood flow (BFA) were additionally calculated for only dual‐input models. The competing models were ranked and their Akaike weights were calculated for each voxel according to corrected Akaike information criterion (cAIC). The optimal model was chosen based on the lowest cAIC value. In both types of tumors, all five dual‐input models yielded lower cAIC values than their corresponding single‐input models. The 2CX model was the best‐fitted model and most optimal in describing tracer kinetic behavior to assess microvascular properties in both MPM and NSCLC. The dual‐input 2CX‐model‐derived BFA was the most significant parameter in differentiating adenocarcinoma from squamous cell carcinoma histology for NSCLC patients.

Imaging Biomarkers Multiparametric 3 Tesla MRI and FMISO Hypoxia PET during Chemoradiotherapy in HNSCC and Their Relation to Outcome

To prospectively assess in HNSCC patients the effect of chemoradiotherapy (CRT) on tumor hypoxia and tissue properties with [18F]FMISO PET/CT (FMISO PET) and multiparametric (mp) MRI at baseline and at an early (week 2) and late (week 5) time point during treatment and to analyze whether mpMRI and PET parameters are related with outcome. Patients with stage III to IVb HNSCC undergoing definitive CRT (total dose 70 Gy, 3 cycles of cisplatin over 7 weeks) were included. Patients were prospectively imaged with [18F]FDG PET/CT at baseline and with serial FMISO PET and serial 3 Tesla mpMRI for T1w-, T2w- as well as contrast-enhanced perfusion and diffusion-weighted measurements (ktrans, ve and apparent diffusion coefficient (ADC) maps) in weeks 0, 2 and 5. Patients were identified as responders or non-responders during follow-up regarding loco-regional control (LRC) and overall survival (OS). Tumor volumes were contoured and SUVmax FMISO PET and mean values for mpMRI parameters were compared between responders and non-responders with the t-test and Log Rank test at a significance level of p≤0.05. A complete set of serial FMISO PET data and 3 T MRI was available in 21 patients. Of those, 12 patients were diagnosed with local recurrence. Baseline tumor volume and FMISO-PET-derived tumor hypoxia (SUVmax FMISO) were higher among patients with local recurrence as compared to locally controlled patients (p=n.s.). On Kaplan-Meier analysis stratified at median change in SUVmax FMISO between weeks 0 to 5 (ΔFMISOwk0-5), LRC was higher for ΔFMISOwk0-5 > median (p=n.s.). For ADC, an increase was found from week 0 to 5 (responders > non-responders). LRC was significantly higher for patients with ΔADCwk0-5 and %ΔADCwk0-5 > median (Log Rank, p=0.04 and p=0.005). In perfusion MRI, ktrans increased from week 0 to 5 for both non-responders and responders (p=n.s.). For non-responders, ktrans reached a maximum at week 2, while for responders, ktrans showed a steady increase until week 5. Interstitial space volume fraction ve did not differ significantly between responders and non-responders and increased between week 0 and 5 (p=n.s.). Baseline ADC below median was significantly (p=0.013) correlated with improved OS. ADCweek2 below median was associated with improved OS (p=n.s.). Baseline ve below median was significantly correlated with improved OS (p=0.043) and associated with increased LRC (p=n.s.). Multiparametric MRI parameters ADC and interstitial space volume fraction ve obtained at baseline were significantly correlated with improved OS and an increase of ADC between week 0 to 5 was significantly correlated with improved LRC. FMISO-PET-derived tumor hypoxia and mean values of MRI parameters ktrans and ve differed between relapsing and non-relapsing patients, however without reaching statistical significance in this cohort. The correlations found for ve and ADC may suggest predictive power for OS and LRC depending on baseline imaging and the dynamics of ADC.

Comparison of transport of chemotherapeutic drugs in voxelized heterogeneous model of human brain tumor

Systemic administration of chemotherapeutic drugs is widely used in the treatment of cancer. However, a good understanding of drug transport barriers that influence the treatment efficacy is still lacking. In this study, a voxelized numerical model based on dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) and computational fluid dynamics (CFD) is employed to study the transport and efficacy of three different chemotherapeutic drugs, namely methotrexate, doxorubicin and cisplatin in human brain tumors. DCE-MRI data provides realistic heterogeneous vasculature of the tumor, the permeability of tissue to contrast agent, interstitial volume fraction (porosity) of the tissue and patient-specific arterial input function (AIF). The permeability of tissue to aforementioned drugs is determined by correlating it with the permeability of tissue to the contrast agent. The model is employed to simulate drug concentration in the tissue and compare the effect of heterogeneous vasculature on the distribution of the drugs in the tumor. The drug accumulation is observed to be higher in high permeability areas initially, and in higher porosity areas at later times. Furthermore, it is observed that methotrexate remains in the interstitial space of the tumor in higher concentration for a longer duration as compared to other two drugs, facilitating more tumor cell killing.

High-frequency temperature pulse-response behavior through a porous nanocomposite scaffold for measuring the uptake of biological fluids.

The measurement of biological fluid uptake into a scaffold sensor has been modeled by measuring the response of induced high-frequency temperature pulses. For this, a heat transport equation is used, developed from Extended Thermodynamics, also equivalent to Cattaneo's equation, as well as an effective thermal conductivity. The effective thermal conductivity is experimentally validated against data measurements of a carbon nanotube porous nanocomposite, embedded with silica nanoparticles. This nanocomposite serves also as the case study for the scaffold sensor. The uptake of the biological fluid in this scaffold sensor is equivalent to a change in the effective thermal conductivity, monitored by an increase of the interstitial volume fraction. By imposing a high-frequency temperature oscillation, the temperature response at the other end of the porous medium is calculated. Depending on the ratio of the relaxation time and the thermal diffusion time, the temperature response can be of oscillatory nature or of an exponential growth to an asymptotic limit. It is observed that an observed phase lag in the temperature response indicates a change in the effective thermal conductivity and thus is a criterion denoting the amount of uptake.

The role of porosity and solid matrix compressibility on the mechanical behavior of poroelastic tissues

We investigate the dependence of the mechanical and hydraulic properties of poroelastic materials on the interstitial volume fraction (porosity) of the fluid flowing through their pores and compressibility of their elastic (matrix) phase. The mechanical behavior of the matrix is assumed of linear elastic type and we conduct a three-dimensional microstructural analysis by means of the asymptotic homogenization technique exploiting the length scale separation between the pores (pore-scale or microscale) and the average tissue size (the macroscale). The coefficients of the model are therefore obtained by suitable averages which involve the solutions of periodic cell problems at the pore-scale. The latter are solved numerically by finite elements in a cubic cell by assuming a cross-shaped interconnected cylindrical structure which results in a cubic symmetric stiffness tensor on the macroscale. Therefore, the macroscale response of the material is fully characterized by six parameters, namely the elastic Young’s and shear moduli, Poisson’s ratio, the hydraulic conductivity, and the poroelastic parameters, i.e. Biot’s modulus and Biot’s coefficient. We present our findings in terms of a parametric analysis conducted by varying the porosity as well as the Poisson’s ratio of the matrix. Our novel three-dimensional results, which are presented in the context of tumor modeling, serve as a robust first step to (a) quantify the macroscale response of poroelastic materials on the basis of their underlying microstructure, (b) relate the compressibility of the tissue, which can be used to distinguish between benign tumor and cancer, to its microstructural properties (such as porosity), and (c) reveal a nontrivial dependency of Biot’s modulus on porosity and compressibility of the matrix, which can pave the way to the optimal design of artificial constructs in terms of fluid volume available for transport of mass and solutes.

DCE-MRI based voxelized computational model for chemotherapeutic drug transport in human brain tumor

Understanding the distribution of chemotherapeutic drugs in tumor when administered systemically is important for assessing the efficiency of anticancer treatment. Despite numerous researches in this field, prediction of drug distribution within the tumors still remains a challenge due to wide heterogeneity of tumor vasculature. In this work, a voxelized computational fluid dynamics (CFD) model based on dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has been employed to simulate the transport of chemotherapeutic drug (doxorubicin) in human brain tumors. The DCE-MRI data provide realistic heterogeneous vasculature of a tumor and help in determining the permeability of the tissue vascular wall to contrast agent and interstitial volume fraction (porosity) of the tissue. The permeability of the tissue to doxorubicin is calculated by correlating it with the permeability of the tissue to contrast agent. Patient-specific arterial input function (AIF) estimation has also been done to make the model patient-specific. The computational model provides steady-state interstitial fluid pressure and velocity values, which are further used to predict transient drug concentration in tumor tissue. Simulation results show that doxorubicin accumulates more in high permeability areas initially. However, drug accumulation increases in areas of higher interstitial volume fraction as time progresses. This observation implies that higher accumulation of chemotherapeutic drugs occurs in higher porosity areas, facilitating larger tumor cell killing in those areas.

Exercise Hemodynamics After Aortic Valve Replacement for Severe Aortic Stenosis

Severe aortic stenosis (AS) is often accompanied by diastolic dysfunction. After aortic valve replacement (AVR), the left ventricle often undergoes considerable reverse remodeling. Despite this, diastolic dysfunction may persist after AVR. The aims of this study were to determine the incidence of elevated left ventricular (LV) filling pressure at rest and during exercise among patients with severe AS after AVR and to describe factors related to elevated LV filling pressure, especially its association with LV and left atrial remodeling and myocardial fibrosis. Thirty-seven patients undergoing AVR were included. Echocardiography, cardiac computed tomography, and magnetic resonance imaging were performed before AVR. An LV biopsy sample was obtained during AVR and analyzed for collagen fraction. One year after AVR, right heart catheterization with exercise was performed. A mean pulmonary capillary wedge pressure (PCWP)≥28mm Hg during exercise was considered elevated. Twelve patients (32%) had elevated exercise PCWP 1year after AVR. Exercise PCWP was highest among patients undergoing concomitant coronary artery bypass graft surgery (30±7 vs 25±6mm Hg, P=.04) and among patients with preoperative stroke volume index<35mL/m2 (28±8 vs 23±4mm Hg, P<.05). Baseline LV ejection fraction was lower among patients with elevated PCWP (56±8% vs 64±8%, P=.01), and coronary calcium score was significantly higher (median 870 AU [interquartile range, 454-2,491 AU] vs 179 AU [interquartile range, 63-513 AU], P=.02). Conversely, exercise PCWP was not related to the presence of high LV wall mass or to the severity of AS. Among patients undergoing isolated AVR, there was a correlation between LV interstitial volume fraction and PCWP (r=0.57, P=.01) and mean pulmonary artery pressure (r=0.51, P=.03) during exercise. Elevated filling pressure during exercise was seen in one third of patients after AVR in this population and was seen primarily among patients with coexisting ischemic heart disease or diffuse myocardial fibrosis but was unrelated to preoperative severity of AS and LV remodeling.

Role of Kidney Biopsies for Biomarker Discovery in Diabetic Kidney Disease.

Although estimated glomerular filtration rate and albuminuria are well-established biomarkers of diabetic kidney disease (DKD), additional biomarkers are needed, especially for the early stages of the disease when both albuminuria and estimated glomerular filtration rate may still be in the normal range and are less helpful for identifying those at risk of progression. Traditional biomarker studies for early DKD are challenging because of a lack of good early clinical end points, and most rely on changes in existing imprecise biomarkers to assess the value of new biomarkers. There are well-characterized changes in kidney structure, however, that are highly correlated with kidney function, always precede the clinical findings of DKD and, at preclinical stages, predict DKD progression. These structural parameters may thus serve as clinically useful end points for identifying new biomarkers of early DKD. In addition, investigators are analyzing tissue transcriptomic data to identify pathways involved in early DKD which may have associated candidate biomarkers measurable in blood or urine, and differentially expressed microRNAs and epigenetic modifications in kidney tissue are beginning to yield important observations which may be useful in identifying new clinically useful biomarkers. This review examines the emerging literature on the use of kidney tissue in biomarker discovery in DKD.

Changes in multimodality functional imaging parameters early during chemoradiation predict treatment response in patients with locally advanced head and neck cancer

ObjectiveTo assess the optimal timing and predictive value of early intra-treatment changes in multimodality functional and molecular imaging (FMI) parameters as biomarkers for clinical remission in patients receiving chemoradiation for head and neck squamous cell carcinoma (HNSCC).MethodsThirty-five patients with stage III-IVb (AJCC 7th edition) HNSCC prospectively underwent 18F–FDG-PET/CT, and diffusion-weighted (DW), dynamic contrast-enhanced (DCE) and susceptibility-weighted MRI at baseline, week 1 and week 2 of chemoradiation. Patients with evidence of persistent or recurrent disease during follow-up were classed as non-responders. Changes in FMI parameters at week 1 and week 2 were compared between responders and non-responders with the Mann–Whitney U test. The significance threshold was set at a p value of <0.05.ResultsThere were 27 responders and 8 non-responders. Responders showed a greater reduction in PET-derived tumor total lesion glycolysis (TLG40%; p = 0.007) and maximum standardized uptake value (SUVmax; p = 0.034) after week 1 than non-responders but these differences were absent by week 2. In contrast, it was not until week 2 that MRI-derived parameters were able to discriminate between the two groups: larger fractional increases in primary tumor apparent diffusion coefficient (ADC; p < 0.001), volume transfer constant (Ktrans; p = 0.012) and interstitial space volume fraction (Ve; p = 0.047) were observed in responders versus non-responders. ADC was the most powerful predictor (∆ >17%, AUC 0.937).ConclusionEarly intra-treatment changes in FDG-PET, DW and DCE MRI-derived parameters are predictive of ultimate response to chemoradiation in HNSCC. However, the optimal timing for assessment with FDG-PET parameters (week 1) differed from MRI parameters (week 2). This highlighted the importance of scanning time points for the design of FMI risk-stratified interventional studies.