A comparison of arterial spin labeling perfusion MRI and DCE‐MRI in human prostate cancer

Perfusion MRI has the potential to provide pathophysiological biomarkers for the evaluating, staging and therapy monitoring of prostate cancer. The objective of this study was to explore the feasibility of noninvasive arterial spin labeling (ASL) to detect prostate cancer in the peripheral zone and to investigate the correlation between the blood flow (BF) measured by ASL and the pharmacokinetic parameters K^trans (forward volume transfer constant), k_ep (reverse reflux rate constant between extracellular space and plasma) and v_e (the fractional volume of extracellular space per unit volume of tissue) measured by dynamic contrast‐enhanced (DCE) MRI in patients with prostate cancer. Forty‐three consecutive patients (ages ranging from 49 to 86 years, with a median age of 74 years) with pathologically confirmed prostate cancer were recruited. An ASL scan with four different inversion times (TI = 1000, 1200, 1400 and 1600 ms) and a DCE‐MRI scan were performed on a clinical 3.0 T GE scanner. BF, K^trans, k_ep and v_e maps were calculated. In order to determine whether the BF values in the cancerous area were statistically different from those in the noncancerous area, an independent t‐test was performed. Spearman's bivariate correlation was used to assess the relationship between BF and the pharmacokinetic parameters K^trans, k_ep and v_e. The mean BF values in the cancerous areas (97.1 ± 30.7, 114.7 ± 28.7, 102.3 ± 22.5, 91.2 ± 24.2 ml/100 g/min, respectively, for TI = 1000, 1200, 1400, 1600 ms) were significantly higher (p < 0.01 for all cases) than those in the noncancerous regions (35.8 ± 12.5, 42.2 ± 13.7, 53.5 ± 19.1, 48.5 ± 13.5 ml/100 g/min, respectively). Significant positive correlations (p < 0.01 for all cases) between BF and the pharmacokinetic parameters K^trans, k_ep and v_e were also observed for all four TI values (r = 0.671, 0.407, 0.666 for TI = 1000 ms; 0.713, 0.424, 0.698 for TI = 1200 ms; 0.604, 0.402, 0.595 for TI = 1400 ms; 0.605, 0.422, 0.548 for TI = 1600 ms). It can be seen that the quantitative ASL measurements show significant differences between cancerous and benign tissues, and exhibit strong to moderate correlations with the parameters obtained using DCE‐MRI. These results show the promise of ASL as a noninvasive alternative to DCE‐MRI. Copyright © 2014 John Wiley & Sons, Ltd.     

Impact of contrast agent injection duration on dynamic contrast‐enhanced MRI quantification in prostate cancer

The volume transfer constant K^trans, which describes the leakage of contrast agent (CA) from vasculature into tissue, is the most commonly reported quantitative parameter for dynamic contrast‐enhanced (DCE‐) MRI. However, the variation in reported K^trans values between studies from different institutes is large. One of the primary sources of uncertainty is quantification of the arterial input function (AIF). The aim of this study is to determine the influence of the CA injection duration on the AIF and tracer kinetic analysis (TKA) parameters (i.e. K^trans, k_ep and v_e). Thirty‐one patients with prostate cancer received two DCE‐MRI examinations with an injection duration of 5 s in the first examination and a prolonged injection duration in the second examination, varying between 7.5 s and 30 s. The DCE examination was carried out on a 3.0 T MRI scanner using a transversal T₁‐weighted 3D spoiled gradient echo sequence (300 s duration, dynamic scan time of 2.5 s). Data of 29 of the 31 were further analysed. AIFs were determined from the phase signal in the left and right femoral arteries. K^trans, k_ep and v_e were estimated with the standard Tofts model for regions of healthy peripheral zone and tumour tissue. We observed a significantly smaller peak height and increased width in the AIF for injection durations of 15 s and longer. However, we did not find significant differences in K^trans, k_ep or v_e for the studied injection durations. The study demonstrates that the TKA parameters K^trans, k_ep and v_e, measured in the prostate, do not show a significant change as a function of injection duration.     

1H HR‐MAS and genomic analysis of human tumor biopsies discriminate between high and low grade astrocytomas

We investigate the profile of choline metabolites and the expression of the genes of the Kennedy pathway in biopsies of human gliomas (n = 23) using ¹H High Resolution Magic Angle Spinning (HR‐MAS, 11.7 Tesla, 277 K, 4000 Hz) and individual genetic assays. ¹H HR‐MAS spectra allowed the resolution and relative quantification by the LCModel of the resonances from choline (Cho), phosphocholine (PC) and glycerophosphorylcholine (GPC), the three main components of the combined tCho peak observed in gliomas by in vivo ¹H NMR spectroscopy. All glioma biopsies depicted a prominent tCho peak. However, the relative contributions of Cho, PC, and GPC to tCho were different for low and high grade gliomas. Whereas GPC is the main component in low grade gliomas, the high grade gliomas show a dominant contribution of PC. This circumstance allowed the discrimination of high and low grade gliomas by ¹H HR‐MAS, a result that could not be obtained using the tCho/Cr ratio commonly used by in vivo ¹H NMR spectroscopy. The expression of the genes involved in choline metabolism has been investigated in the same biopsies. High grade gliomas depict an upregulation of the β gene of choline kinase and phospholipase C, as well as a downregulation of the cytidyltransferase B gene, the balance of these being consistent with the accumulation of PC. In the low grade gliomas, phospholipase A₁ and lysophospholypase are upregulated and phospholipase D is downregulated, supporting the accumulation of GPC. The present findings offer a promising procedure that will potentially help to accurately grade glioma tumors using ¹H HR‐MAS, providing in addition the genetic background for the alterations of choline metabolism observed in high and low grade gliomas. Copyright © 2009 John Wiley & Sons, Ltd.     

DCE‐MRI prediction of survival time for patients with glioblastoma multiforme: using an adaptive neuro‐fuzzy‐based model and nested model selection technique

This pilot study investigates the construction of an Adaptive Neuro‐Fuzzy Inference System (ANFIS) for the prediction of the survival time of patients with glioblastoma multiforme (GBM). ANFIS is trained by the pharmacokinetic (PK) parameters estimated by the model selection (MS) technique in dynamic contrast enhanced‐magnetic resonance imaging (DCE‐MRI) data analysis, and patient age. DCE‐MRI investigations of 33 treatment‐naïve patients with GBM were studied. Using the modified Tofts model and MS technique, the following physiologically nested models were constructed: Model 1, no vascular leakage (normal tissue); Model 2, leakage without efflux; Model 3, leakage with bidirectional exchange (influx and efflux). For each patient, the PK parameters of the three models were estimated as follows: blood plasma volume (v_p) for Model 1; v_p and volume transfer constant (K^trans) for Model 2; v_p, K^trans and rate constant (k_ep) for Model 3. Using Cox regression analysis, the best combination of the estimated PK parameters, together with patient age, was identified for the design and training of ANFIS. A K‐fold cross‐validation (K = 33) technique was employed for training, testing and optimization of ANFIS. Given the survival time distribution, three classes of survival were determined and a confusion matrix for the correct classification fraction (CCF) of the trained ANFIS was estimated as an accuracy index of ANFIS's performance. Patient age, k_ep and v_e (K^trans/k_ep) of Model 3, and K^trans of Model 2, were found to be the most effective parameters for training ANFIS. The CCF of the trained ANFIS was 84.8%. High diagonal elements of the confusion matrix (81.8%, 90.1% and 81.8% for Class 1, Class 2 and Class 3, respectively), with low off‐diagonal elements, strongly confirmed the robustness and high performance of the trained ANFIS for predicting the three survival classes. This study confirms that DCE‐MRI PK analysis, combined with the MS technique and ANFIS, allows the construction of a DCE‐MRI‐based fuzzy integrated predictor for the prediction of the survival of patients with GBM.     

DCE and DW-MRI monitoring of vascular disruption following VEGF-Trap treatment of a rat glioma model

Vascular‐targeted therapies have shown promise as adjuvant cancer treatment. As these agents undergo clinical evaluation, sensitive imaging biomarkers are needed to assess drug target interaction and treatment response. In this study, dynamic contrast enhanced MRI (DCE‐MRI) and diffusion‐weighted MRI (DW‐MRI) were evaluated for detecting response of intracerebral 9 L gliosarcomas to the antivascular agent VEGF‐Trap, a fusion protein designed to bind all forms of Vascular Endothelial Growth Factor‐A (VEGF‐A) and Placental Growth Factor (PGF). Rats with 9 L tumors were treated twice weekly for two weeks with vehicle or VEGF‐Trap. DCE‐ and DW‐MRI were performed one day prior to treatment initiation and one day following each administered dose. Kinetic parameters (K^trans, volume transfer constant; k_ep, efflux rate constant from extravascular/extracellular space to plasma; and v_p, blood plasma volume fraction) and the apparent diffusion coefficient (ADC) over the tumor volumes were compared between groups. A significant decrease in kinetic parameters was observed 24 hours following the first dose of VEGF‐Trap in treated versus control animals (p < 0.05) and was accompanied by a decline in ADC values. In addition to the significant hemodynamic effect, VEGF‐Trap treated animals exhibited significantly longer tumor doubling times (p < 0.05) compared to the controls. Histological findings were found to support imaging response metrics. In conclusion, kinetic MRI parameters and change in ADC have been found to serve as sensitive and early biomarkers of VEGF‐Trap anti‐vascular targeted therapy. Copyright © 2011 John Wiley & Sons, Ltd.     

Prediction of pathologic response to neoadjuvant chemotherapy in patients with breast cancer using diffusion‐weighted imaging and MRS

The aim of this study was to determine whether tumor size, MRS parameters and apparent diffusion coefficient (ADC) measurements could be applied to predict pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC). Ninety patients with breast cancer (median size, 4.5 cm; range, 1.6–9.5 cm) were evaluated with single‐voxel ¹H MRS and dynamic contrast‐enhanced MRI. Diffusion‐weighted imaging was performed in 41 of these patients using a 1.5‐T scanner before and after completion of NAC. Pre‐ and post‐treatment measurements and changes in tumor size, MRS parameters [absolute and normalized total choline‐containing compound (tCho) integral and tCho signal‐to‐noise ratio (SNR)] and ADCs in pCR versus non‐pCR were compared using the nonparametric Mann–Whitney test. Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic performance of each parameter. After NAC, 30 patients (33%) showed pCR and 60 (67%) showed non‐pCR. At pretreatment, ADC was the only significant parameter in differentiating between pCR and non‐pCR [(0.83 ± 0.05) × 10^–3 versus (0.97 ± 0.14) × 10^–3 mm²/s] (p = 0.014). Post‐treatment measurements after completion of NAC and changes in tumor size (both p < 0.001), MRS parameters (p = 0.027 and p = 0.020 for absolute tCho integral, p = 0.036 and p = 0.023 for normalized tCho integral, and p = 0.032 and p = 0.061 for tCho SNR) and ADC (p = 0.003 and p < 0.001) were significantly different between the pCR and non‐pCR groups, except for changes in tCho SNR. In ROC analysis, the areas under the ROC curve (AUCs) of 0.63–0.73 were obtained for tumor size and MRS parameters. AUCs for pre‐ and post‐treatment ADC and changes in ADC were 0.75, 0.80 and 0.96, respectively. The optimal cut‐off of the percentage change in ADC for predicting pCR was 40.7%, yielding 100% sensitivity and 91% specificity. Patients with pCR showed significantly lower pretreatment ADCs than those with non‐pCR. The change in ADC after NAC was the most accurate predictor of pCR. Copyright © 2012 John Wiley & Sons, Ltd.     

DCE‐ and DW‐MRI as early imaging biomarkers of treatment response in a preclinical model of triple negative breast cancer

This work evaluates quantitative dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) and diffusion‐weighted MRI (DW‐MRI) parameters as early biomarkers of response in a preclinical model of triple negative breast cancer (TNBC). The standard Tofts' model of DCE‐MRI returns estimates of the volume transfer constant (K^trans) and the extravascular extracellular volume fraction (v_e). DW‐MRI returns estimates of the apparent diffusion coefficient (ADC). Mice (n = 38) were injected subcutaneously with MDA‐MB‐231. Tumors were grown to approximately 275 mm³ and sorted into the following groups: saline controls, low‐dose Abraxane (15 mg/kg) and high‐dose Abraxane (25 mg/kg). Animals were imaged at days zero, one and three. On day three, tumors were extracted for immunohistochemistry. The positive percentage change in ADC on day one was significantly higher in both treatment groups relative to the control group (p < 0.05). In addition, the positive percentage change in K^trans was significantly higher than controls (p < 0.05) on day one for the high‐dose group and on days one and three for the low‐dose group. The percentage change in tumor volume was significantly different between the high‐dose and control groups on day three (p = 0.006). Histology confirmed differences at day three through reduced numbers of proliferating cells (Ki67 staining) in the high‐dose group (p = 0.03) and low‐dose group (p = 0.052) compared with the control group. Co‐immunofluorescent staining of vascular maturity [using von Willebrand Factor (vWF) and α‐smooth muscle actin (α‐SMA)] indicated significantly higher vascular maturation in the low‐dose group compared with the controls on day three (p = 0.03), and trending towards significance in the high‐dose group compared with controls on day three (p = 0.052). These results from quantitative imaging with histological validation indicate that ADC and K^trans have the potential to serve as early biomarkers of treatment response in murine studies of TNBC.     

Choline kinase overexpression increases invasiveness and drug resistance of human breast cancer cells

A direct correlation exists between increased choline kinase (Chk) expression, and the resulting increase of phosphocholine levels, and histological tumor grade. To better understand the function of Chk and choline phospholipid metabolism in breast cancer we have stably overexpressed one of the two isoforms of Chk‐α known to be upregulated in malignant cells, in non‐invasive MCF‐7 human breast cancer cells. Dynamic tracking of cell invasion and cell metabolism were studied with a magnetic resonance (MR) compatible cell perfusion assay. The MR based invasion assay demonstrated that MCF‐7 cells overexpressing Chk‐α (MCF‐7‐Chk) exhibited an increase of invasion relative to control MCF‐7 cells (0.84 vs 0.3). Proton MR spectroscopy studies showed significantly higher phosphocholine and elevated triglyceride signals in Chk overexpressing clones compared to control cells. A test of drug resistance in MCF‐7‐Chk cells revealed that these cells had an increased resistance to 5‐fluorouracil and higher expression of thymidylate synthase compared to control MCF‐7 cells. To further characterize increased drug resistance in these cells, we performed rhodamine‐123 efflux studies to evaluate drug efflux pumps. MCF‐7‐Chk cells effluxed twice as much rhodamine‐123 compared to MCF‐7 cells. Chk‐α overexpression resulted in MCF‐7 human breast cancer cells acquiring an increasingly aggressive phenotype, supporting the role of Chk‐α in mediating invasion and drug resistance, and the use of phosphocholine as a biomarker of aggressive breast cancers. Copyright © 2010 John Wiley & Sons, Ltd.     

Intratumor mapping of intracellular water lifetime: metabolic images of breast cancer?

Shutter‐speed pharmacokinetic analysis of dynamic‐contrast‐enhanced (DCE)‐MRI data allows evaluation of equilibrium inter‐compartmental water interchange kinetics. The process measured here – transcytolemmal water exchange – is characterized by the mean intracellular water molecule lifetime (τ_i). The τ_i biomarker is a true intensive property not accessible by any formulation of the tracer pharmacokinetic paradigm, which inherently assumes it is effectively zero when applied to DCE‐MRI. We present population‐averaged in vivo human breast whole tumor τ_i changes induced by therapy, along with those of other pharmacokinetic parameters. In responding patients, the DCE parameters change significantly after only one neoadjuvant chemotherapy cycle: while K^trans (measuring mostly contrast agent (CA) extravasation) and k_ep (CA intravasation rate constant) decrease, τ_i increases. However, high‐resolution, (1 mm)², parametric maps exhibit significant intratumor heterogeneity, which is lost by averaging. A typical 400 ms τ_i value means a trans‐membrane water cycling flux of 10¹³ H₂O molecules s^?1/cell for a 12 µm diameter cell. Analyses of intratumor variations (and therapy‐induced changes) of τ_i in combination with concomitant changes of v_e (extracellular volume fraction) indicate that the former are dominated by alterations of the equilibrium cell membrane water permeability coefficient, P_W, not of cell size. These can be interpreted in light of literature results showing that τ_i changes are dominated by a P_W(active) component that reciprocally reflects the membrane driving P‐type ATPase ion pump turnover. For mammalian cells, this is the Na⁺,K⁺‐ATPase pump. These results promise the potential to discriminate metabolic and microenvironmental states of regions within tumors in vivo, and their changes with therapy. © 2014 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.     

In vivo 1H MRS of WSU‐DLCL2 human non‐Hodgkin's lymphoma xenografts: response to rituximab and rituximab plus CHOP

In order to identify early ¹H MRS metabolic markers of response to rituximab immunotherapy and to rituximab plus CHOP (cyclophosphamide, hydroxydoxorubicin, vincristine, and prednisone) combination therapy, we performed an in vivo MRS investigation of a non‐Hodgkin's lymphoma (NHL) xenograft model. Human WSU‐DLCL2 NHL cells were subcutaneously implanted into flanks of female severe combined immunodeficient mice. When tumor volumes reached ～600 mm³, rituximab was administered for three weekly cycles at a dose of 25 mg/kg per cycle with or without CHOP. Before and after treatment, tumor lactate (Lac) and total choline (tCho) were detected using the selective multiple quantum coherence sequence and the stimulated echo acquisition mode sequence, respectively. Rituximab produced a small tumor growth delay (～5 days), whereas treatment with rituximab plus CHOP (RCHOP) led to ～20% tumor regression after three cycles of therapy. After one cycle of rituximab, the tCho/H₂O ratio had decreased significantly (5%, P = 0.003), whereas the Lac/H₂O ratio had not changed (P = 0.58). Both Lac/H₂O and tCho/H₂O had decreased after one cycle of RCHOP treatment (26%, P = 0.001; 10%, P = 0.016, respectively). After two cycles of RCHOP, Ki67 assay of histological tumor specimens indicated ～40% decrease in proliferation (P < 0.001) in the RCHOP‐treated tumors; no change was detected after treatment with rituximab alone. This study suggests that decreases in tCho/H₂O are more sensitive indices of response to rituximab, whereas decreases in Lac/H₂O are more sensitive to response to CHOP combination therapy. Copyright © 2008 John Wiley & Sons, Ltd.     

Assessment of early docetaxel response in an experimental model of human breast cancer using DCE‐MRI,ex vivo HR MAS,and in vivo 1H MRS

The purpose of this study was to evaluate the use of dynamic contrast‐enhanced (DCE) MRI, in vivo ¹H MRS and ex vivo high resolution magic angle spinning (HR MAS) MRS of tissue samples as methods to detect early treatment effects of docetaxel in a breast cancer xenograft model (MCF‐7) in mice. MCF‐7 cells were implanted subcutaneously in athymic mice and treated with docetaxel (20, 30, and 40 mg/kg) or saline six weeks later. DCE‐MRI and in vivo ¹H MRS were performed on a 7 T MR system three days after treatment. The dynamic images were used as input for a two‐compartment model, yielding the vascular parameters K^trans and v_e. HR MAS MRS, histology, and immunohistochemical staining for proliferation (Ki‐67), apoptosis (M30 cytodeath), and vascular/endothelial cells (CD31) were performed on excised tumor tissue. Both in vivo spectra and HR MAS spectra were used as input for multivariate analysis (principal component analysis (PCA) and partial least squares regression analysis (PLS)) to compare controls to treated tumors. Tumor growth was suppressed in docetaxel‐treated mice compared to the controls. The anti‐tumor effect led to an increase in K^trans and v_e values in all the treated groups. Furthermore, in vivo MRS and HR MAS MRS revealed a significant decrease in choline metabolite levels for the treated groups, in accordance with reduced proliferative index as seen on Ki‐67 stained sections. In this study DCE‐MRI, in vivo MRS and ex vivo HR MAS MRS have been used to demonstrate that docetaxel treatment of a human breast cancer xenograft model results in changes in the vascular dynamics and metabolic profile of the tumors. This indicates that these MR methods could be used to monitor intra‐tumoral treatment effects. Copyright © 2009 John Wiley & Sons, Ltd.     

Quantitative Assessment of Tumor Responses after Radiation Therapy in a DLD-1 Colon Cancer Mouse Model Using Serial Dynamic Contrast-Enhanced Magnetic Resonance Imaging

Purpose

The purpose of this study was to investigate the predictability of pretreatment values including Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) derived parameters (K^trans, K_ep and V_e), early changes in parameters (K^trans, tumor volume), and heterogeneity (standard deviation of K^trans) for radiation therapy responses via a human colorectal cancer xenograft model.

Materials and Methods

A human colorectal cancer xenograft model with DLD-1 cancer cells was produced in the right hind limbs of five mice. Tumors were irradiated with 3 fractions of 3 Gy each for 3 weeks. Baseline and follow up DCE-MRI were performed. Quantitative parameters (K^trans, K_ep and V_e) were calculated based on the Tofts model. Early changes in K^trans, standard deviation (SD) of K^trans, and tumor volume were also calculated. Tumor responses were evaluated based on histology. With a cut-off value of 0.4 for necrotic factor, a comparison between good and poor responses was conducted.

Results

The good response group (mice #1 and 2) exhibited higher pretreatment K^trans than the poor response group (mice #3, 4, and 5). The good response group tended to show lower pretreatment K_ep, higher pretreatment V_e, and larger baseline tumor volume than the poor response group. All the mice in the good response group demonstrated marked reductions in K^trans and SD value after the first radiation. All tumors showed increased volume after the first radiation therapy.

Conclusion

The good response after radiation therapy group in the DLD-1 colon cancer xenograft nude mouse model exhibited a higher pretreatment K^trans and showed an early reduction in K^trans, demonstrating a more homogenous distribution.     

Early detection of radiation therapy response in non‐Hodgkin's lymphoma xenografts by in vivo 1H magnetic resonance spectroscopy and imaging

The purpose of the study was to investigate the capability of ¹H MRS and MRI methods for detecting early response to radiation therapy in non‐Hodgkin's lymphoma (NHL). Studies were performed on the WSU‐DLCL2 xenograft model in nude mice of human diffuse large B‐cell lymphoma, the most common form of NHL. Radiation treatment was applied as a single 15 Gy dose to the tumor. Tumor lactate, lipids, total choline, T₂ and apparent diffusion coefficients (ADC) were measured before treatment and at 24 h and 72 h after radiation. A Hadamard‐encoded slice‐selective multiple quantum coherence spectroscopy sequence was used for detecting lactate (Lac) while a stimulated echo acquisition mode sequence was used for detection of total choline (tCho) and lipids. T₂‐ and diffusion‐weighted imaging sequences were used for measuring T₂ and ADC. Within 24 h after radiation, significant changes were observed in the normalized integrated resonance intensities of Lac and the methylenes of lipids. Lac/H₂O decreased by 38 ± 15% (p = 0.03), and lipid (1.3 ppm, CH₂)/H₂O increased by 57 ± 14% (p = 0.01). At 72 h after radiation, tCho/H₂O decreased by 45 ± 14% (p = 0.01), and lipid (2.8 ppm, polyunsaturated fatty acid)/H₂O increased by 970 ± 36% (p = 0.001). ADC increased by 14 ± 2% (p = 0.003), and T₂ did not change significantly. Tumor growth delay and regression were observed thereafter. This study enabled comparison of the relative sensitivities of various ¹H MRS and MRI indices to radiation and suggests that ¹H MRS/MRI measurements detect early responses to radiation that precede tumor volume changes. Copyright © 2010 John Wiley & Sons, Ltd.     

Termination kinetics of styrene free‐radical polymerization studied by time‐resolved pulsed laser experiments

The single pulse (SP)‐pulsed‐laser polymerization (PLP) technique has been applied to measure k_t/k_p, the ratio of termination to propagation rate coefficients, for the free‐radical bulk polymerization of styrene at temperatures from 60 to 100°C and pressures from 1800 to 2 650 bar. k_t/k_p is obtained by fitting monomer concentration vs. time traces that are determined via time‐resolved (μs) near infrared monitoring of monomer conversion induced by single excimer laser pulses of about 20 ns width. Styrene is a difficult candidate for this kind of measurements as conversion per pulse is small for this low k_p and high k_t monomer. Thus between 160 to 300 SP signals were co‐added to yield a concentration vs. time trace of sufficient quality for deducing k_t/k_p with an accuracy of better than ± 20 per cent. With k_p being known from PLP–SEC experiments, chain‐length averaged k_t values are immediately obtained from k_t/k_p. At given pressure and temperature, k_t is independent of the degree of overall monomer conversion, which, within the present study, has been as high as 20%percnt;. The k_t value, however, is found to slightly increase with the amount of free radicals produced by a single pulse in laser‐induced decomposition of the photoinitiator DMPA (2,2‐dimethoxy‐2‐phenyl acetophenone). This remarkable observation is explained by DMPA decomposition resulting in the formation of two free radicals which significantly differ in reactivity. Extrapolation of SP–PLP k_t data from experiments at rather different DMPA levels and laser pulse energies toward low primary free‐radical concentration, yields very satisfactory agreement of the extrapolated k_t values with recent literature data from chemically and photochemically induced styrene polymerizations.     

A New Insight into the Mechanism of 1,3‐Dienes Cationic Polymerization III: Polymerization of 1,3‐Pentadiene with CF3COOD/TiCl4 Initiating System: Chain‐Ends Structure and Kinetics

A novel method for the investigation of the chain‐end structure of poly(1,3‐pentadiene)s synthesized using the CF₃COOD/TiCl₄ initiating system is developed. It is shown for the first time that the content of trans‐1,2‐structures in the first monomer unit is considerably higher than the content of trans‐1,4‐structures, whereas the content of trans‐1,4‐units is substantially higher than trans‐1,2‐units for the polymer chain as a whole. Another important observation is that chain transfer to monomer is significant even at the earlier stages of the 1,3‐pentadiene polymerization (after 1 s of reaction). The very low functionality at the ω‐end (F_n (Cl) < 0.15) confirms the intensive chain transfer to monomer. This method is also applied for the estimation of the concentration of active species and the rate constant for propagation (k _p) for the cationic polymerization of 1,3‐pentadiene using the CF₃COOD/TiCl₄ initiating system: rate constants for propagation, k _p, of 1.5 × 10³ and 3.3 × 10³ L mol^?1 min^?1 are determined for 1,3‐pentadiene polymerization at 20 and –78 °C, respectively.

     

31P MRSI and 1H MRS at 7 T: initial results in human breast cancer

This study demonstrates the feasibility of the noninvasive determination of important biomarkers of human (breast) tumor metabolism using high‐field (7‐T) MRI and MRS. ³¹P MRSI at this field strength was used to provide a direct method for the in vivo detection and quantification of endogenous biomarkers. These encompass phospholipid metabolism, phosphate energy metabolism and intracellular pH. A double‐tuned, dual‐element transceiver was designed with focused radiofrequency fields for unilateral breast imaging and spectroscopy tuned for optimized sensitivity at 7 T. T₁‐weighted three‐dimensional MRI and ¹H MRS were applied for the localization and quantification of total choline compounds. ³¹P MRSI was obtained within 20 min per subject and mapped in three dimensions over the breast with pixel volumes of 10 mL. The feasibility of monitoring in vivo metabolism was demonstrated in two patients with breast cancer during neoadjuvant chemotherapy, validated by ex vivo high‐resolution magic angle spinning NMR and compared with data from an age‐matched healthy volunteer. Concentrations of total choline down to 0.4 mM could be detected in the human breast in vivo. Levels of adenosine and other nucleoside triphosphates, inorganic phosphate, phosphocholine, phosphoethanolamine and their glycerol diesters detected in glandular tissue, as well as in tumor, were mapped over the entire breast. Altered levels of these compounds were observed in patients compared with an age‐matched healthy volunteer; modulation of these levels occurred in breast tumors during neoadjuvant chemotherapy. To our knowledge, this is the first comprehensive MRI and MRS study in patients with breast cancer, which reveals detailed information on the morphology and phospholipid metabolism from volumes as small as 10 mL. This endogenous metabolic information may provide a new method for the noninvasive assessment of prognostic and predictive biomarkers in breast cancer treatment. Copyright © 2011 John Wiley & Sons, Ltd.     

Assessment of therapeutic response of locally advanced breast cancer (LABC) patients undergoing neoadjuvant chemotherapy (NACT) monitored using sequential magnetic resonance spectroscopic imaging (MRSI)

The potential of total choline (tCho) signal‐to‐noise ratio (SNR) (ChoSNR) and tumor volume in the assessment of tumor response in locally advanced breast cancer (LABC) patients (n = 30) undergoing neoadjuvant chemotherapy (NACT) was investigated using magnetic resonance spectroscopic imaging (MRSI) and conventional MRI at 1.5 T. Experiments were carried out sequentially at four time‐points: prior to therapy and after I, II and III NACT and ChoSNR, and the tumor volume was measured. The MR response was compared with the clinical response. Sequential data of 25 patients were retrospectively analyzed by classifying them as clinical responders and non‐responders. In 14 responders, the pre‐therapy ChoSNR was 7.8 ± 5.1. In 10/14 responders, no choline was observed after III NACT while in the remaining four patients the ChoSNR was reduced to 3.6 ± 1.1 (p < 0.05). Non‐responders showed no statistically significant change in ChoSNR. After III NACT, the tumor volume reduced by 84.0 ± 14.8% in responders. Using receiver operating curve (ROC) analysis, cut‐off values of 53% for ChoSNR and 47.5% for volume were obtained to differentiate responders from non‐responders. The sensitivity to detect responders from non‐responders using ChoSNR was 85.7% with 91% specificity while 100% sensitivity was observed for volume but with reduced specificity of 73%. Our results indicate that ChoSNR may serve as a useful parameter to predict tumor response to NACT with higher specificity compared to volume, suggesting its potential in effective treatment management. Copyright © 2010 John Wiley & Sons, Ltd.     

Correlation of tumor characteristics derived from DCE‐MRI and DW‐MRI with histology in murine models of breast cancer

The purpose of this work was to determine the relationship between the apparent diffusion coefficient (ADC, from diffusion‐weighted (DW) MRI), the extravascular, extracellular volume fraction (v_e, from dynamic contrast‐enhanced (DCE) MRI), and histological measurement of the extracellular space fraction. Athymic nude mice were injected with either human epidermal growth factor receptor 2 positive (HER2+) BT474 (n = 15) or triple negative MDA‐MB‐231 (n = 20) breast cancer cells, treated with either Herceptin (n = 8), Abraxane (low dose n = 7, high dose n = 6), or saline (n = 7 for each cell line), and imaged using DW‐ and DCE‐MRI before, during, and after treatment. After the final imaging acquisition, the tissue was resected and evaluated by histological analysis. H&E‐stained central slices were scanned using a digital brightfield microscope and evaluated with thresholding techniques to calculate the extracellular space. For both BT474 and MDA‐MB‐231, the median ADC of the central slice exhibited a significantly positive correlation with the corresponding central slice extracellular space as measured by H&E (p = 0.03, p < 0.01, respectively). Median v_e calculated from the central slice showed differing results between the two cell lines. For BT474, a significant correlation between v_e and extracellular space was calculated (p = 0.02), while MDA‐MB‐231 tumors did not demonstrate a significant correlation (p = 0.64). Additionally, there was no correlation discovered between ADC and v_e with either whole tumor analysis or central slice analysis (p > 0.05). While ADC correlates well with the histologically determined fraction of extracellular space, these data add to the growing body of literature that suggests that v_e derived from DCE‐MRI is not a reliable biomarker of extracellular space for a range of physiological conditions. Copyright © 2015 John Wiley & Sons, Ltd.     

Chain Transfer to 2‐Mercaptoethanol in Methacrylic Acid Polymerization in Aqueous Solution

The chain‐transfer constant, C_S = k_tr/k_p, of 2‐mercaptoethanol (ME) for methacrylic acid (MAA) polymerization in aqueous solution has been measured at MAA concentrations between 5 and 30 wt% to be 0.12 ± 0.01 at 50 °C. Analysis has been carried out via both the Mayo and the chain‐length distribution (CLD) methods. No change of C_S with monomer concentration is observed. The chain‐transfer rate coefficient, k_tr, thus exhibits the same strong dependence on monomer concentration as the propagation rate coefficient, k_p.