Rafal Panek

Model free approach to kinetic analysis of real-time hyperpolarized 13C magnetic resonance spectroscopy data.

Real-time detection of the rates of metabolic flux, or exchange rates of endogenous enzymatic reactions, is now feasible in biological systems using Dynamic Nuclear Polarization Magnetic Resonance. Derivation of reaction rate kinetics from this technique typically requires multi-compartmental modeling of dynamic data, and results are therefore model-dependent and prone to misinterpretation. We present a model-free formulism based on the ratio of total areas under the curve (AUC) of the injected and product metabolite, for example pyruvate and lactate. A theoretical framework to support this novel analysis approach is described, and demonstrates that the AUC ratio is proportional to the forward rate constant k. We show that the model-free approach strongly correlates with k for whole cell in vitro experiments across a range of cancer cell lines, and detects response in cells treated with the pan-class I PI3K inhibitor GDC-0941 with comparable or greater sensitivity. The same result is seen in vivo with tumor xenograft-bearing mice, in control tumors and following drug treatment with dichloroacetate. An important finding is that the area under the curve is independent of both the input function and of any other metabolic pathways arising from the injected metabolite. This model-free approach provides a robust and clinically relevant alternative to kinetic model-based rate measurements in the clinical translation of hyperpolarized 13C metabolic imaging in humans, where measurement of the input function can be problematic.

The predictive value of early assessment after one cycle of induction chemotherapy with 18F-FDG-PET/CT and DW-MRI for response to radical chemoradiotherapy in head and neck squamous cell carcinoma

The objective of this study was to assess the predictive value of early assessment (after 1 cycle of induction chemotherapy [IC]) with 18F-FDG PET/CT and diffusion-weighted (DW) MRI for subsequent response to radical chemoradiotherapy in locally advanced head and neck squamous cell carcinoma (HNSCC). Methods: Twenty patients with stage III–IVa HNSCC prospectively underwent 18F-FDG PET/CT and DW MRI before and 2 wk after each cycle of IC (first cycle, IC1; second cycle, IC2). Response was assessed 3 mo after completion of chemoradiotherapy with clinical examination, MRI, and 18F-FDG PET/CT. Patients with persistent disease were classed as nonresponders. Changes in functional and molecular imaging parameters after IC1 were compared between responders and nonresponders with the Mann–Whitney U test. The significance threshold was set at a P value of less than 0.05. Results: Responders showed a significantly greater reduction in metabolic tumor volume (P = 0.03) and total lesion glycolysis (P = 0.04) after IC1 than nonresponders. Responders also showed a tendency toward a larger but statistically nonsignificant increase in apparent diffusion coefficient after IC1. There was no significant difference in the changes from baseline between the IC1 and IC2 for all functional and molecular imaging parameters, indicating that most biologic response to IC measured by 18F-FDG PET/CT and DW MRI was observed early after the first cycle of IC. Conclusion: Our preliminary data indicate that the 18F-FDG PET/CT–derived metabolic tumor volume or total lesion glycolysis, acquired after IC1, are early predictive biomarkers for ultimate response to subsequent chemoradiotherapy. These early biomarkers enable identification of patients at risk of treatment failure at an early time point, permitting treatment individualization and consideration of alternative strategies such as radiotherapy dose escalation or surgery.

Repeatability and sensitivity of T2* measurements in patients with head and neck squamous cell carcinoma at 3T

To determine whether quantitation of T2* is sufficiently repeatable and sensitive to detect clinically relevant oxygenation levels in head and neck squamous cell carcinoma (HNSCC) at 3T.

Evaluation of diffusion models in breast cancer

PURPOSE The purpose of this study is to investigate whether the microvascular pseudodiffusion effects resulting with non-monoexponential behavior are present in breast cancer, taking into account tumor spatial heterogeneity. Additionally, methodological factors affecting the signal in low and high diffusion-sensitizing gradient ranges were explored in phantom studies. METHODS The effect of eddy currents and accuracy of b-value determination using a multiple b-value diffusion-weighted MR imaging sequence were investigated in test objects. Diffusion model selection and noise were then investigated in volunteers (n = 5) and breast tumor patients (n = 21) using the Bayesian information criterion. RESULTS 54.3% of lesion voxels were best fitted by a monoexponential, 26.2% by a stretched-exponential, and 19.5% by a biexponential intravoxel incoherent motion (IVIM) model. High correlation (0.92) was observed between diffusion coefficients calculated using mono- and stretched-exponential models and moderate (0.59) between monoexponential and IVIM (medians: 0.96/0.84/0.72 × 10(-3) mm(2)/s, respectively). Distortion due to eddy currents depended on the direction of the diffusion gradient and displacement varied between 1 and 6 mm for high b-value images. Shift in the apparent diffusion coefficient due to intrinsic field gradients was compensated for by averaging diffusion data obtained from opposite directions. CONCLUSIONS Pseudodiffusion and intravoxel heterogeneity effects were not observed in approximately half of breast cancer and normal tissue voxels. This result indicates that stretched and IVIM models should be utilized in regional analysis rather than global tumor assessment. Cross terms between diffusion-sensitization gradients and other imaging or susceptibility-related gradients are relevant in clinical protocols, supporting the use of geometric averaging of diffusion-weighted images acquired with diffusion-sensitization gradients in opposite directions.

The emerging potential of magnetic resonance imaging in personalizing radiotherapy for head and neck cancer: an oncologist's perspective

Head and neck cancer (HNC) is a challenging tumour site for radiotherapy delivery owing to its complex anatomy and proximity to organs at risk (OARs) such as the spinal cord and optic apparatus. Despite significant advances in radiotherapy planning techniques, radiation-induced morbidities remain substantial. Further improvement would require high-quality imaging and tailored radiotherapy based on intratreatment response. For these reasons, the use of MRI in radiotherapy planning for HNC is rapidly gaining popularity. MRI provides superior soft-tissue contrast in comparison with CT, allowing better definition of the tumour and OARs. The lack of additional radiation exposure is another attractive feature for intratreatment monitoring. In addition, advanced MRI techniques such as diffusion-weighted, dynamic contrast-enhanced and intrinsic susceptibility-weighted MRI techniques are capable of characterizing tumour biology further by providing quantitative functional parameters such as tissue cellularity, vascular permeability/perfusion and hypoxia. These functional parameters are known to have radiobiological relevance, which potentially could guide treatment adaptation based on their changes prior to or during radiotherapy. In this article, we first present an overview of the applications of anatomical MRI sequences in head and neck radiotherapy, followed by the potentials and limitations of functional MRI sequences in personalizing therapy.

Lung volume reproducibility under ABC control and self‐sustained breath‐holding

&NA; An Active Breathing Coordinator (ABC) can be employed to induce breath‐holds during CT imaging and radiotherapy of lung, breast and liver cancer, and recently during lung cancer MRI. The apparatus measures and controls respiratory volume, hence subject lung volume reproducibility is its principal measure of effectiveness. To assess ABC control quality, the intra‐session reproducibility of ABC‐induced lung volumes was evaluated and compared with that reached by applying the clinical standard of operator‐guided self‐sustained breath‐holds on healthy volunteers during MRI. Inter‐session reproducibility was investigated by repeating ABC‐controlled breath‐holds on a second visit. Additionally, lung volume agreement with ABC devices used with different imaging modalities in the same institution (MR, CT), or for a breast trial treatment, was assessed. Lung volumes were derived from three‐dimensional (3D) T1‐weighted MRI datasets by three observers employing semiautomatic lung delineation on a radiotherapy treatment planning system. Inter‐observer variability was less than 6% of the delineated lung volumes. Lung volume agreement between the different conditions over all subjects was investigated using descriptive statistics. The ABC equipment dedicated for MR application exhibited good intra‐session and inter‐session lung volume reproducibility (1.8% and 3% lung volume variability on average, respectively). MR‐assessed lung volumes were similar using different ABC equipment dedicated to MR, CT, or breast radiotherapy. Overall, lung volumes controlled by the same or different ABC devices agreed better than with self‐controlled breath‐holds, as suggested by the average ABC variation of 1.8% of the measured lung volumes (99 mL), compared to the 4.1% (226 mL) variability observed on average with self‐sustained breath‐holding.

Noninvasive Imaging of Cycling Hypoxia in Head and Neck Cancer Using Intrinsic Susceptibility MRI

Purpose: To evaluate intrinsic susceptibility (IS) MRI for the identification of cycling hypoxia, and the assessment of its extent and spatial distribution, in head and neck squamous cell carcinoma (HNSCC) xenografts and patients. Experimental Design: Quantitation of the transverse relaxation rate, R2*, which is sensitive to paramagnetic deoxyhemoglobin, using serial IS-MRI acquisitions, was used to monitor temporal oscillations in levels of paramagnetic deoxyhemoglobin in human CALR xenografts and patients with HNSCC at 3T. Autocovariance and power spectrum analysis of variations in R2* was performed for each imaged voxel, to assess statistical significance and frequencies of cycling changes in tumor blood oxygenation. Pathologic correlates with tumor perfusion (Hoechst 33342), hypoxia (pimonidazole), and vascular density (CD31) were sought in the xenografts, and dynamic contrast-enhanced (DCE) MRI was used to assess patient tumor vascularization. The prevalence of fluctuations within patient tumors, DCE parameters, and treatment outcome were reported. Results: Spontaneous R2* fluctuations with a median periodicity of 15 minutes were detected in both xenografts and patient tumors. Spatially, these fluctuations were predominantly associated with regions of heterogeneous perfusion and hypoxia in the CALR xenografts. In patients, R2* fluctuations spatially correlated with regions of lymph nodes with low Ktrans values, typically in the vicinity of necrotic cores. Conclusions: IS-MRI can be used to monitor variations in levels of paramagnetic deoxyhemoglobin, associated with cycling hypoxia. The presence of such fluctuations may be linked with impaired tumor vasculature, the presence of which may impact treatment outcome. Clin Cancer Res; 23(15); 4233–41. ©2017 AACR.

Blood transfusion during radical chemo-radiotherapy does not reduce tumour hypoxia in squamous cell cancer of the head and neck

Background:Patients with head and neck squamous cell carcinoma (HNSCC) undergoing radical chemo-radiation (CRT) frequently receive transfusion with packed red cells (PRCT) during radiotherapy on the basis that PRCT increases tumour oxygenation and overcomes hypoxia-induced radio-resistance. This is likely to be a significant oversimplification given the fact that tumour hypoxia is the result of several intrinsic and extrinsic factors, including many that are not directly related to serum haemoglobin (Hb). Therefore, we have studied the effect of PRCT on tumour oxygenation in a prospective cohort of patients who developed low Hb during radical CRT for HNSCC.Methods:This was a prospective study of 20 patients with HNSCC receiving radical CRT undergoing PRCT for Hb<11.5 g dl−1. Patients underwent pretransfusion and posttransfusion intrinsic susceptibility-weighted (SWI) MRI and dynamic contrast-enhanced (DCE) MRI. Blood samples were obtained at the time of MRI scanning and two further time points for measuring Hb and a panel of serum cytokine markers of tumour hypoxia. 3D T2* and Ktrans maps were calculated from the MRI data for primary tumours and cervical lymph node metastases.Results:PRCT produced no change (11 patients) or reduced (1 patient) T2* (tumour oxygenation) in 12 of the 16 (75%) evaluable primary tumours. Three of the four patients with improved tumour oxygenation progressed or had partial response following treatment completion. There were variable changes in Ktrans (tumour perfusion or vessel permeability) following PRCT that were of small magnitude for most tumours. Pre- and Post-PRCT levels of measured cytokines were not significantly different.Conclusions:This study suggests that PRCT during radical CRT for HNSCC does not improve tumour oxygenation. Therefore, oncologists should consider changing practice according to NICE and American Association of Blood Banks guidelines on PRCT for anaemia.

Slice Encoding for Metal Artefact Correction in magnetic resonance imaging examinations for radiotherapy planning

Background and purpose Magnetic resonance (MR) and computed tomography (CT) images are degraded in the presence of metallic implants. We investigate whether SEMAC (Slice Encoding for Metal Artifact Correction) MR is advantageous for radiotherapy (RT) planning. Methods Conventional and SEMAC MR protocols were compared (1.5 T). A spine fixation device suspended in gelatine, two patients with spine fixation devices and six patients with bilateral hip replacements were scanned with both conventional and SEMAC protocols. In spine patients the visibility of the spinal canal and spinal cord was assessed; in prostate patients, the visibility of the prostate, pelvic structures and the pelvic girdle. Results The signal loss volume surrounding the spine fixation device was reduced by approximately 20% when the SEMAC protocol was employed, and registration errors were reduced. For spine patients, the spinal canal was completely visible only using the SEMAC protocol. In hip replacement patients, metal artifacts were local; the signal loss extended to the internal surface of the acetabulum in eight implants with conventional protocols, but only in four using SEMAC. Conclusions SEMAC MR contributes towards correct co-registration of MR and CT images for RT planning, and is particularly relevant when the TV or OARs are close to implants.

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.