Steffen Sammet

Phase II Clinical Trial of Sorafenib in Metastatic Medullary Thyroid Cancer

PURPOSE Mutations in the RET proto-oncogene and vascular endothelial growth factor receptor (VEGFR) activity are critical in the pathogenesis of medullary thyroid cancer (MTC). Sorafenib, a multikinase inhibitor targeting Ret and VEGFR, showed antitumor activity in preclinical studies of MTC. PATIENTS AND METHODS In this phase II trial of sorafenib in patients with advanced MTC, the primary end point was objective response. Secondary end points included toxicity assessment and response correlation with tumor markers, functional imaging, and RET mutations. Using a two-stage design, 16 or 25 patients were to be enrolled onto arms A (hereditary) and B (sporadic). Patients received sorafenib 400 mg orally twice daily. RESULTS Of 16 patients treated in arm B, one achieved partial response (PR; 6.3%; 95% CI, 0.2% to 30.2%), 14 had stable disease (SD; 87.5%; 95% CI, 61.7% to 99.5%), and one was nonevaluable. In a post hoc analysis of 10 arm B patients with progressive disease (PD) before study, one patient had PR of 21+ months, four patients had SD >or= 15 months, four patients had SD <or= 6 months, and one patient had clinical PD. Median progression-free survival was 17.9 months. Arm A was prematurely terminated because of slow accrual. Common adverse events (AEs) included diarrhea, hand-foot-skin reaction, rash, and hypertension. Although serious AEs were rare, one death was seen. Tumor markers decreased in the majority of patients, and RET mutations were detected in 10 of 12 sporadic MTCs analyzed. CONCLUSION Sorafenib is reasonably well tolerated, with suggestion of clinical benefit for patients with sporadic MTC. Caution should be taken because of the rare but fatal toxicity potentially associated with sorafenib.

Amide proton transfer MR imaging of prostate cancer: A preliminary study

To evaluate the capability of amide proton transfer (APT) MR imaging for detection of prostate cancer that typically shows a higher tumor cell proliferation rate and cellular density leading to an MRI‐detectable overall elevated mobile protein level in higher grade tumors.

Predicting Control of Primary Tumor and Survival by DCE MRI During Early Therapy in Cervical Cancer

Purpose:To assess the early predictive power of MRI perfusion and volume parameters, during early treatment of cervical cancer, for primary tumor control and disease-free-survival. Materials and Methods:Three MRI examinations were obtained in 101 patients before and during therapy (at 2–2.5 and 4–5 weeks) for serial dynamic contrast enhanced (DCE) perfusion MRI and 3-dimensional tumor volume measurement. Plateau Signal Intensity (SI) of the DCE curves for each tumor pixel of all 3 MRI examinations was generated, and pixel-SI distribution histograms were established to characterize the heterogeneous tumor. The degree and quantity of the poorly-perfused tumor subregions, which were represented by low-DCE pixels, was analyzed by using various lower percentiles of SI (SI%) from the pixel histogram. SI% ranged from SI2.5% to SI20% with increments of 2.5%. SI%, mean SI, and 3-dimensional volume of the tumor were correlated with primary tumor control and disease-free-survival, using Student t test, Kaplan-Meier analysis, and log-rank test. The mean post-therapy follow-up time for outcome assessment was 6.8 years (range: 0.2–9.4 years). Results:Tumor volume, mean SI, and SI% showed significant prediction of the long-term clinical outcome, and this prediction was provided as early as 2 to 2.5 weeks into treatment. An SI5% of <2.05 and residual tumor volume of ≥30 cm3 in the MRI obtained at 2 to 2.5 weeks of therapy provided the best prediction of unfavorable 8-year primary tumor control (73% vs. 100%, P = 0.006) and disease-free-survival rate (47% vs. 79%, P = 0.001), respectively. Conclusions:Our results show that MRI parameters quantifying perfusion status and residual tumor volume provide very early prediction of primary tumor control and disease-free-survival. This functional imaging based outcome predictor can be obtained in the very early phase of cytotoxic therapy within 2 to 2.5 weeks of therapy start. The predictive capacity of these MRI parameters, indirectly reflecting the heterogeneous delivery pattern of cytotoxic agents, tumor oxygenation, and the bulk of residual presumably therapy-resistant tumor, requires future study.

Time-of-Flight Magnetic Resonance Angiography at 7 Tesla

Objectives:Magnetic resonance angiography (MRA) is noninvasive and does not require the application of high doses of contrast agents, and thus is used in the clinical routine for evaluation of cerebrovascular diseases, eg, aneurysm and arteriovenous malformations. However, more subtle microvascular disease usually cannot be seen with the resolution capabilities of standard field strength MRA. The purpose of this study was to evaluate the ability of 7-T time-of-flight (ToF) MRA to depict the arterial brain vasculature and to compare the results to data from 1.5 T and 3 T. Materials and Methods:The study was IRB approved and complied with The Health Insurance Portability and Accountability Act. All subjects gave written informed consent. Eight healthy volunteers (age: 36 ± 10 years; 3 female, 5 male) were investigated using ToF MRA at 7 T, 3 T, and 1.5 T. Signal intensities of the large, primary vessels of the Circle of Willis were measured and signal-to-noise ratios were calculated. Visibility of smaller arteries was evaluated. Results:The results show that ultrahigh field allows depiction of the large vessels of the Circle of Willis. Although it provides only small increases in signal-to-noise ratios for these vessels, compared with 1.5 T and 3 T, it additionally demonstrates considerably more first- and second-order branches. Conclusions:Because of its considerably enhanced potential to depict vessels of the Circle of Willis and its first- and second-order branches, ToF MRA at 7 T may become an important tool in future neuroradiology research and clinical care.

Direct delayed human adenoviral BMP-2 or BMP-6 gene therapy for bone and cartilage regeneration in a pony osteochondral model

OBJECTIVE To evaluate healing of surgically created large osteochondral defects in a weight-bearing femoral condyle in response to delayed percutaneous direct injection of adenoviral (Ad) vectors containing coding regions for either human bone morphogenetic proteins 2 (BMP-2) or -6. METHODS Four 13mm diameter and 7mm depth circular osteochondral defects were drilled, 1/femoral condyle (n=20 defects in five ponies). At 2 weeks, Ad-BMP-2, Ad-BMP-6, Ad-green fluorescent protein (GFP), or saline was percutaneously injected into the central drill hole of the defect. Quantitative magnetic resonance imaging (qMRI) and computed tomography (CT) were serially performed at 12, 24, and 52 weeks. At 12 (one pony) or 52 weeks, histomorphometry and microtomographic analyses were performed to assess subchondral bone and cartilage repair tissue quality. RESULTS Direct delivery of Ad-BMP-6 demonstrated delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) and histologic evidence of greater Glycosaminoglycan (GAG) content in repair tissue at 12 weeks, while Ad-BMP-2 had greater non-mineral cartilage at the surface at 52 weeks (p<0.04). Ad-BMP-2 demonstrated greater CT subchondral bone mineral density (BMD) by 12 weeks and both Ad-BMP-2 and -6 had greater subchondral BMD at 52 weeks (p<0.05). Despite earlier (Ad-BMP-6) and more persistent (Ad-BMP-2) chondral tissue and greater subchondral bone density (Ad-BMP-2 and -6), the tissue within the large weight-bearing defects at 52 weeks was suboptimal in all groups due to poor quality repair cartilage, central fibrocartilage retention, and central bone cavitation. Delivery of either BMP by this method had greater frequency of subchondral bone cystic formation (p<0.05). CONCLUSIONS Delivery of Ad-BMP-2 or Ad-BMP-6 via direct injection supported cartilage and subchondral bone regeneration but was insufficient to provide long-term quality osteochondral repair.

Three-region MRI-based whole-body attenuation correction for automated PET reconstruction

INTRODUCTION In this study we proposed and developed a simple attenuation mapping approach based on magnetic resonance imaging (MRI) for the purpose of reconstructing positron emission tomography (PET) images in PET/MRI imaging devices. METHODS After experimental development, an in vivo calibration was performed by whole-body scanning of five beagles on both a PET/CT and an MRI. The attenuation was determined by using an automated segmentation algorithm to segment regions of background, lung, soft tissue and bone, and assigning them values of 0.002, 0.030, 0.098 and 0.130 cm(-1), respectively. RESULTS The CT-attenuated and MRI-attenuated PET images had average standardized uptake values (SUVs) that differed by 1-6% for most regions of interest (ROIs). Also, mean relative differences (MRDs) between the images were between 5% and 9% for most regions. The only exception is bone, where the three-region MRI-attenuated PET images had an SUV 10% less on average than the CT-attenuation images, and the MRD averaged 14%. Also, additional segmentation of the bone in the four-region MRI-attenuated PET images reduced the SUV difference to 3% and the MRD to 6%. CONCLUSION Therefore, despite the improvements in the four-region segmentation, the three-region segmentation, without delineation of osseous tissues, produces high-quality images that are sufficient for most expected clinical and research purposes.

APPLICATION ACCURACY OF COMPUTED TOMOGRAPHY-BASED, IMAGE-GUIDED NAVIGATION OF TEMPORAL BONE

OBJECTIVE Although frameless stereotactic techniques have become indispensable in neurosurgery, their technical complexity requires careful definition and evaluation. Navigation is of particular concern when it is applied to approach a complex, tight surgical area like the temporal bone, where every millimeter is important. Theoretically, the temporal bone is an ideal location in which to use image-guided navigation because its bony construct precludes pre- and intraoperative shift. In this context, the feasibility of using a navigational system is determined by the systems accuracy and by the spatial characteristics of the targets. Literature addressing the accuracy of image guidance techniques in temporal bone surgery is relatively sparse. Accuracy of these systems within the temporal bone is still under investigation. We investigated the application accuracy of computed tomography-based, frameless, image-guided navigation to identify various bony structures in the temporal bone via a retrosigmoid approach. METHODS In a total of 10 operations, we performed a retrosigmoid approach simulating operative conditions on either side of 5 whole, fresh cadaveric heads. Six titanium microscrews were implanted around the planned craniotomy site as permanent bone reference markers before the surgical procedure. High-resolution computed tomographic scans were obtained (slice thickness, 0.6-mm, contiguous non-overlapping slices; gantry setting, 0 degrees; scan window diameter, 225 mm; pixel size, >0.44 × 0.44). We used a Stryker navigation system (Stryker Instruments, Kalamazoo, MI) for intraoperative navigation. External and internal targets were selected for calculation of navigation accuracy. RESULTS The system calculated target registration error to be 0.48 ± 0.21 mm, and the global accuracies (navigation accuracies) were calculated using external over-the-skull and internal targets within the temporal bone. Overall navigation accuracy was 0.91 ± 0.28 mm; for reaching internal targets within temporal bone, accuracy was 0.94 ± 0.22 mm; and for external targets, accuracy was 0.83 ± 0.11 mm. Ninety-five percent of targets could be reached within 1.4 mm of their actual position. CONCLUSION Using high-resolution computed tomography and bone-implanted reference markers, frameless navigation can be as accurate as frame-based stereotaxy in providing a guide to maximize safe surgical approaches to the temporal bone. Although error-free navigation is not possible with the submillimetric accuracy required by direct anatomic contouring of tiny structures within temporal bone, it still provides a road map to maximize safe surgical exposure.

Lateral supraorbital approach vs pterional approach: an anatomic qualitative and quantitative evaluation.

BACKGROUND: Several minimally invasive modifications of the standard pterional approach have been proposed recently. The lateral supraorbital approach is one of these modifications. OBJECTIVE: To provide a qualitative and quantitative anatomic comparison of the surgical exposure and the operability afforded by the standard pterional approach and the lateral supraorbital approach. METHODS: Eight pterional approaches and 8 lateral supraorbital approaches were used in 8 fresh human cadaver heads. One qualitative and 2 quantitative tools were used to assess the surgical exposure. RESULTS: Qualitatively, the lateral supraorbital approach has the advantages of reduced trauma to the temporalis muscle and exposure that is comparable to that provided by the standard pterional approach to the sellar and suprasellar regions. This approach offers limited exposure of the interpeduncular fossa compared with the pterional one. Quantitatively, the pterional approach provides a greater surgical volume than the lateral supraorbital approach (32.90 mL vs 23.60 mL with P < .05). Also, the pterional approach provides a greater associated surgical operability than the lateral supraorbital approach (exposure score of 66 and 53, respectively). However, the lateral supraorbital approach offers an equivalent access to the anterior communicating artery complex, optic nerve, optic chiasm, and sellar area (the exposure scores were 19 for both approaches). CONCLUSION: From an anatomic point of view, both approaches provide similar exposure to the sellar, suprasellar, and anterior communicating artery areas. The pterional approach provides better exposure of the retrosellar area. The ability to operate in the retrosellar area, as judged by our model, was higher with the pterional than with the lateral supraorbital approach.

Improving the Pharmacokinetic Parameter Measurement in Dynamic Contrast-Enhanced MRI by Use of the Arterial Input Function: Theory and Clinical Application

One of the most powerful features of the dynamic contrast‐enhanced (DCE) MRI technique is its capability to quantitatively measure the physiological or pathophysiological environments assessed by the passage of contrast agent by means of model‐based pharmacokinetic analysis. The widely used two‐compartment pharmacokinetic model developed by Brix and colleges fits tumor data well in most cases, but fails to explain the biexponential arterial input function. In this work, this problem has been attacked from a theoretical point of view, showing that this problem can be solved by adopting a more realistic model assumption when simplifying the general solutions of the two‐compartment pharmacokinetic equations. Pharmacokinetic parameters derived from our model were demonstrated to have comparative tissue specificity to Ktrans from Larssons model, better than those from Brixs model and the empirical area‐under‐the‐curve (AUC). Tissue‐type classifier constructed with the arterial input function–decomposed kep‐kpe pair from our model was also demonstrated to have superior performance than any other classifier based on DCE‐MRI pharmacokinetic parameters or empirical AUC. The feature that this classifier has a near‐zero false‐negative rate makes it a highly desirable tool for clinical diagnostic and response assessment applications. Magn Reson Med 59:1448–1456, 2008.

RF-related heating assessment of extracranial neurosurgical implants at 7T.

PURPOSE The purpose was to evaluate radiofrequency (RF)-related heating of commonly used extracranial neurosurgical implants in 7-T magnetic resonance imaging (MRI). MATERIALS AND METHODS Experiments were performed using a 7-T MR system equipped with a transmit/receive RF head coil. Four commonly used titanium neurosurgical implants were studied using a test procedure adapted from the American Society for Testing and Materials Standard F2182-11a. Implants (n=4) were tested with an MRI turbo spin echo pulse sequence designed to achieve maximum RF exposure [specific absorption rate (SAR) level=9.9W/kg], which was further validated by performing calorimetry. Maximum temperature increases near each implants surface were measured using fiberoptic temperature probes in a gelled-saline-filled phantom that mimicked the conductive properties of soft tissue. Measurement results were compared to literature data for patient safety. RESULTS The highest achievable phantom averaged SAR was determined by calorimetry to be 2.0±0.1W/kg due to the highly conservative SAR estimation model used by this 7-T MR system. The maximum temperature increase at this SAR level was below 1.0°C for all extracranial neurosurgical implants that underwent testing. CONCLUSION The findings indicated that RF-related heating under the conditions used in this investigation is not a significant safety concern for patients with the particular extracranial neurosurgical implants evaluated in this study.