Oliver Geier

Diffusion-weighted magnetic resonance imaging for pretreatment prediction and monitoring of treatment response of patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy

Abstract Background. For patients with locally advanced breast cancer (LABC) undergoing neoadjuvant chemotherapy (NACT), the European Guidelines for Breast Imaging recommends magnetic resonance imaging (MRI) to be performed before start of NACT, when half of the NACT has been administered and prior to surgery. This is the first study addressing the value of flow-insensitive apparent diffusion coefficients (ADCs) obtained from diffusion-weighted (DW) MRI at the recommended time points for pretreatment prediction and monitoring of treatment response. Materials and methods. Twenty-five LABC patients were included in this prospective study. DW MRI was performed using single-shot spin-echo echo-planar imaging with b-values of 100, 250 and 800 s/mm2 prior to NACT, after four cycles of NACT and at the conclusion of therapy using a 1.5 T MR scanner. ADC in the breast tumor was calculated from each assessment. The strength of correlation between pretreatment ADC, ADC changes and tumor volume changes were examined using Spearman’s rho correlation test. Results. Mean pretreatment ADC was 1.11 ± 0.21 × 10–3 mm2/s. After 4 cycles of NACT, ADC was significantly increased (1.39 ± 0.36 × 10–3 mm2/s; p=0.018). There was no correlation between individual pretreatment breast tumor ADC and MR response measured after four cycles of NACT (p=0.816) or prior to surgery (p=0.620). Conclusion. Pretreatment tumor ADC does not predict treatment response for patients with LABC undergoing NACT. Furthermore, ADC increase observed mid-way in the course of NACT does not correlate with tumor volume changes.

A simulation of MRI based dose calculations on the basis of radiotherapy planning CT images

Background. The advantage of MRI-based radiotherapy planning is the superior soft tissue differentiation. However, for accurate patient dose calculations, a conversion of the MR images into Hounsfield CT maps is necessary. The aim of the present study was to investigate the dose accuracy that can be achieved with segmented MR-images derived from the planning CT images by assigning fixed densities to different classes of tissues. Methods. Treatment plans for ten prostate cancer patients were selected. A collapsed cone algorithm was used to calculate patient dose distributions. The dose calculations were based on four different image sets: (1) the original CT-series (DDDP), (2) a simulated MR series with all tissue set to a homogenous water equivalent material of density 1.02 g/cm3 (DDW), (3) a simulated MR series with soft tissue set to a water equivalent material with density 1.02 g/cm3 and the bone set to a density of 1.3 g/cm3 (DDW+B1.3), and (4) a simulated MR series identical to (3) but with a bone density equal to 2.1 g/cm3 (DDW+B2.1). The dose distributions were compared by analysing dose difference histograms as well as through a visual display of spatial dose deviations. Results. The population based minimum, mean and maximum dose difference between the DDDP and DDW in the target volume was −2.8, −1.0 and 0.6%, respectively. Corresponding differences between DDDP and DDW+B1.3 were −1.6, 0.2 and 1.5%, respectively, and between DDDP and DDW+B2.1 −4.3, 4.2 and 9.7%, respectively. For the rectum, the differences between CTDP and the other image sets were in the range of −19.5 to 8.8%. For the bladder, the differences were in the range of −9.6 to 7.0%. Conclusions. A systematic study using segmented MR images was undertaken. To achieve an acceptable accuracy in the CTV dose, the MR images should be segmented into bone and water equivalent tissue. Still, significant dose deviation for the organs at risk may be present. As tissue segmentation in real MR images is introduced, segmentation errors and errors that stem from geometrical non-linearities may further reduce the accuracy.

Multi-vendor reliability of arterial spin labeling perfusion MRI using a near-identical sequence: Implications for multi-center studies

INTRODUCTION A main obstacle that impedes standardized clinical and research applications of arterial spin labeling (ASL), is the substantial differences between the commercial implementations of ASL from major MRI vendors. In this study, we compare a single identical 2D gradient-echo EPI pseudo-continuous ASL (PCASL) sequence implemented on 3T scanners from three vendors (General Electric Healthcare, Philips Healthcare and Siemens Healthcare) within the same center and with the same subjects. MATERIAL AND METHODS Fourteen healthy volunteers (50% male, age 26.4±4.7years) were scanned twice on each scanner in an interleaved manner within 3h. Because of differences in gradient and coil specifications, two separate studies were performed with slightly different sequence parameters, with one scanner used across both studies for comparison. Reproducibility was evaluated by means of quantitative cerebral blood flow (CBF) agreement and inter-session variation, both on a region-of-interest (ROI) and voxel level. In addition, a qualitative similarity comparison of the CBF maps was performed by three experienced neuro-radiologists. RESULTS There were no CBF differences between vendors in study 1 (p>0.1), but there were CBF differences of 2-19% between vendors in study 2 (p<0.001 in most gray matter ROIs) and 10-22% difference in CBF values obtained with the same vendor between studies (p<0.001 in most gray matter ROIs). The inter-vendor inter-session variation was not significantly larger than the intra-vendor variation in all (p>0.1) but one of the ROIs (p<0.001). CONCLUSION This study demonstrates the possibility to acquire comparable cerebral CBF maps on scanners of different vendors. Small differences in sequence parameters can have a larger effect on the reproducibility of ASL than hardware or software differences between vendors. These results suggest that researchers should strive to employ identical labeling and readout strategies in multi-center ASL studies.

Diffusion-weighted MRI compared to FDG PET/CT for assessment of early treatment response in lymphoma.

Background 18F fluoro-deoxyglucose (FDG) positron emission tomography / computed tomography (PET/CT) is a well-recognized diagnostic tool used for staging and monitoring of therapy response for lymphomas. During the past decade diffusion-weighted (DW) magnetic resonance imaging (MRI) is increasingly being included in the assessment of tumor response for various cancers. Purpose To compare the change in maximum standardized uptake value (ΔSUVmax) from FDG PET/CT with the change in apparent diffusion coefficient (ΔADC) from DW MRI after initiation of the first cycle of chemotherapy in patients with Hodgkins lymphoma (HL) and in patients with diffuse large B-cell lymphoma (DLBCL). Material and Methods Twenty-seven consecutive patients with histologically proven lymphoma and lymphomatous lymph nodes (LLN) of the neck (19 with HL, 8 with DLBCL) underwent FDG PET/CT and MRI of the neck before and after initiation of the first cycle of chemotherapy. The mean time interval from initiation of chemotherapy to imaging was 19 days and 2 days for FDG PET/CT and MRI, respectively. For each patient ΔSUVmax, ΔADC, and change in volume of the same LLN were compared. Results There was a significant mean decrease of SUVmax by 70%, but no significant change in ADC. There was no significant reduction in LLN volume. Conclusion There was no significant correlation between ΔSUVmax and ΔADC. Thus, our data do not support that FDG PET/CT can be replaced by early DW MRI for response evaluation in lymphoma patients.

Associations between tumor vascularization assessed by in vivo DCE-MRI and the presence of disseminated tumor cells in bone marrow in breast cancer patients at the time of diagnosis

To explore possible associations between in vivo pharmacokinetic dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) parameters and the presence of disseminated tumor cells (DTCs) in bone marrow in breast cancer patients at the time of diagnosis.

Study on liver blood vessel movement during breathing cycle

Liver blood vessel movement information is important for improving the accuracy of minimally invasive therapies such as high intensity focused ultrasound and radio frequency ablation. In this paper, we present a rigid registration of centerlines obtained from multiscale vessel enhanced liver images to understand the movement of liver during breathing cycle. The method uses modified vesselness filter for finding vessel-enhanced images. The vesselness images are used for finding the centerlines of the vessels and then used for registering rigidly using the iterative closest point algorithm. Our study has shown on volunteer magnetic resonance images, the liver blood vessels move an average of approximately 3cms during the breathing cycle. Our method can potentially be used to correct for respiratory motion during image-guided liver procedures.

Towards personalized computer simulation of breast cancer treatment: a multi-scale pharmacokinetic and pharmacodynamic model informed by multi-type patient data

Mathematical modeling and simulation have emerged as a potentially powerful, time and cost effective approach to personalized cancer treatment. The usefulness of mechanistic models to disentangle complex multi-scale cancer processes such as treatment response has been widely acknowledged. However, a major barrier for multi-scale models to predict the outcomes of therapeutic regimens in a particular patient lies in their initialization and parameterization which need to reflect individual cancer characteristics accurately. In this study we use multi-type routinely acquired measurements on a single breast tumor, including histopathology, magnetic resonance imaging, and molecular profiling to personalize parts of a complex multi-scale model of breast cancer treated with chemotherapeutic and anti-angiogenic agents. We model the dynamics of drugs in tissue (pharmacokinetics) and the corresponding effects on their targets (pharmacodynamics). We developed a open-source computer program that simulates cross-sections of tumors under 12-week therapy regimes and use it to individually reproduce and elucidate treatment outcomes of four patients. For two of the tumors that did not respond to therapy, we used model simulations to suggest alternative regimes, depending on their individual characteristics, with improved outcomes. We found that more frequent doses of chemothereapy reduce tumor burden in a low proliferative tumor while lower doses of anti-angiogenic agents improve drug penetration in a poorly perfused tumor. In addition to bridge multi-type clinical data to shed light on individual treatment outcomes, our approach identified a few tumor-related aspects that need to be clinically portraited better to allow for future model-driven personalized cancer therapy.

Reproducibility of manual and semi-automated late enhancement quantification in patients with Fabry disease.

Background Late enhancement (LE) imaging is increasingly used for diagnosis of non-ischemic cardiomyopathy. However, the mostly patchy appearance of LE in this context may reduce the reproducibility of LE measurement. Purpose To report intra- and inter-observer variabilities of LE measurements in Fabry disease using manual and semi-automated quantification. Material and Methods Twenty MRI data-sets of male patients aged 44 ± 7 years were analyzed twice (interval 12 months) by one observer and additionally once by a second observer. Left ventricular (LV) parameters were determined using cine MRI. Gradient-echo LE images were analyzed by manual planimetry and by a semi-automatic prototype software. Variabilities were determined by Bland-Altman analyses and additionally intra-class correlation coefficient (ICC) values were calculated to survey intra- and inter-observer reproducibility. Results The amount of LE was 5.2 ± 5.1 mL or 2.8 ± 2.6 % of LV mass (observer 2). LE was detected predominantly intramurally in a patchy pattern. All patients had LE restricted to the basal infero-lateral parts of the LV. The extent of LE correlated to LV mass (207 ± 70 g, P < 0.05, r = 0.6). The intra- and inter-observer variabilities were −0.6 to 1.0 mL and −0.7 to 1.6 mL, respectively (95% confidence intervals). ICC values were 0.981–0.999. The semi-automatic software allowed quantification of LE areas in all patients. The comparison of LE amount determined by semi-automatic software versus manual planimetry yielded an intra-observer variability ranging from −1.9 to 2.3 mL. Conclusion Semi-automatic planimetry of patchy LE in patients with Fabry disease is feasible. The determined intra- and inter-observer variabilities for manual and semi-automatic planimetry were in the range of 20–40% of LE amount with high ICC values.

Abstract 1471: Immunotherapy revised: Ipilimumab potentiates the vascular response to stereotactic radiosurgery in patients with brain metastases

Introduction: While immunotherapy is a promising treatment option for advanced metastatic disease, the survival benefit of adding ipilimumab to stereotactic radiosurgery (SRS) in unselected patients with metastases to the brain seems limited [1, 2]. Moreover, because conventional diagnostic methods for assessing treatment response were not designed for these therapies, the mechanisms of action in vivo are poorly understood. To reveal potential synergistic effects of adding ipilimumab to SRS, we here present preliminary data on the vascular response to SRS and ipilimumab in patients with brain metastases from malignant melanomas and non-small cell lung cancer. Methods: Voxel-wise estimations of blood volume and vessel calibers were acquired by perfusion MRI and Vessel Architectural Imaging [3], respectively, in 13 patients with brain metastases from lung cancer receiving SRS only (N = 6; 7 lesions) and malignant melanomas receiving SRS only (N = 4; 5 lesions) or SRS and ipilimumab (N = 3; 5 lesions). Regions of enhancing tumor were identified on contrast-enhanced MRIs, whereas peri-tumoral tissue regions included a region containing a 2mm wide dilation of the enhancing tumor and outside the SRS target area. MRIs were performed at baseline (pre SRS) and repeated every three months. Ipilimumab (3mg/kg) were administered intravenously over 90 min every third week for four cycles. SRS was delivered to the tumor (visual metastasis + 2 mm margin) with a peripheral dose of 18 Gy or 25 Gy, depending on tumor size. Results: For patients treated with SRS only, the vessel calibers decreased with a median value of 15% in the peri-tumoral area at 3 months following SRS (P Conclusion: The enlarged average vessel calibers and the subsequent lack of an increase in blood volume suggest ipilimumab helps clean up the vascular bed by removing small caliber vessels and effectively reducing the capillary vessel density. Our advanced MRI data provide valuable and novel insights into the biological mechanisms of response to ipilimumab and at study end may help identify patients with metastatic disease that benefit from this therapy by prolonged survival. References: 1. Mathew et al, Melanoma Res 2013. 23(3):191-5 2. Patel et al, Am J Clin Oncol 2015. May 16:[Epub] 3. Emblem et al, Nat Med 2013. 19(9):1178-83 Citation Format: Ingrid Digernes, Cathrine Saxhaug, Oliver Geier, Edmund Reitan, Einar Waldeland, Kunt Hakon Hole, Kari Dolven Jacobsen, Aslaug Helland, Kyrre Eeg Emblem. Immunotherapy revised: Ipilimumab potentiates the vascular response to stereotactic radiosurgery in patients with brain metastases. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1471.