Hybrid PET/MR imaging in two sarcoma patients - clinical benefits and implications for future trials.

PET/MRI is an evolving hybrid imaging modality which combines the inherent strengths of MRIs soft-tissue and contrast resolution and PETs functional metabolic capabilities. Bone and soft-tissue sarcoma are a relatively rare tumor entity, relying on MRI for local staging and often on PET/CT for lymph node involvement and metastatic spread evaluation. The purpose of this article is to demonstrate the successful use of PET/MRI in two sarcoma patients. We also use these patients as a starting point to discuss how PET/MRI might be of value in sarcoma. Among its potential benefits are: superior TNM staging than either modality alone, decreased radiation dose, more sensitive and specific follow-up and better assessment of treatment response. These potentials need to be investigated in future PET/MRI soft-tissue sarcoma trials.

Clinical oncologic applications of PET/MRI: a new horizon.

Positron emission tomography/magnetic resonance imaging (PET/MRI) leverages the high soft-tissue contrast and the functional sequences of MR with the molecular information of PET in one single, hybrid imaging technology. This technology, which was recently introduced into the clinical arena in a few medical centers worldwide, provides information about tumor biology and microenvironment. Studies on indirect PET/MRI (use of positron emission tomography/computed tomography (PET/CT) images software fused with MRI images) have already generated interesting preliminary data to pave the ground for potential applications of PET/MRI. These initial data convey that PET/MRI is promising in neuro-oncology and head & neck cancer applications as well as neoplasms in the abdomen and pelvis. The pediatric and young adult oncology population requiring frequent follow-up studies as well as pregnant woman might benefit from PET/MRI due to its lower ionizing radiation dose. The indication and planning of therapeutic interventions and specifically radiation therapy in individual patients could be and to a certain extent are already facilitated by performing PET/MRI. The objective of this article is to discuss potential clinical oncology indications of PET/MRI.

Correlation of skeletal muscle blood oxygenation level-dependent MRI and skin laser Doppler flowmetry in patients with systemic sclerosis.

PURPOSE: To investigate the origin of skeletal muscle BOLD MRI alterations in patients with systemic sclerosis (SSc) by correlating BOLD MRI T2* signal of calf muscles with microcirculatory blood flow of calf skin measured by laser Doppler flowmetry (LDF). MATERIALS AND METHODS: BOLD MRI (3T) and LDF measurements were performed in 12 consecutive SSc patients (6 women, 6 men; mean age 54.0 ± 10.0 years) and 12 healthy volunteers (4 men, 8 women; mean age 44.7 ± 13.1 years). For both modalities, the same cuff compression paradigm at mid-thigh level was used. LDF datasets were acquired using a PeriScan PIM II Imager (Perimed AB, Stockholm, Sweden) at the upper calf corresponding to the level of MR imaging. Cross-correlations of BOLD and LDF signal intensity changes depending on time lags between both time series were calculated. RESULTS: Maximal cross-correlations of BOLD T2* and LDF measurements were calculated as 0.93 (healthy volunteers) and 0.94 (SSc patients) for a BOLD time lag of approximately 10 s. Key parameter analysis suggested that in contrast to hyperemic BOLD signal loss at maximum value in SSc patients, ischemic T2* decrease cannot be explained by differences of tissue perfusion. CONCLUSION: Skeletal muscle BOLD T2* signal in SSc patients is closely correlated with changes of microperfusion as detected by LDF.

Correlation of muscle BOLD MRI with transcutaneous oxygen pressure for assessing microcirculation in patients with systemic sclerosis.

PURPOSE: To prospectively compare calf muscle BOLD MRI with transcutaneous oxygen pressure (TcPO2 ) measurement in patients with systemic sclerosis (SSc) and healthy volunteers and thereby get insight into the pathogenesis of vasculopathy in this connective tissue disorder. MATERIALS AND METHODS: Twelve patients with SSc (6 women and 6 men, mean age 53.5 ± 10.0 years) and 12 healthy volunteers (4 men and 8 women, mean age 47 ± 12.1 years) were examined using muscle BOLD MRI and TcPO2. A cuff compression at mid-thigh level was performed to provoke ischemia and reactive hyperemia. BOLD measurements were acquired on a 3 Tesla whole body-scanner in the upper calf region using a multi-echo EPI-sequence with four echo-times (TE: 9/20/31/42 ms) and a repetition time of 2 s. Empirical cross-correlation analysis depending on time lags between BOLD- and TcPO2-measurements was performed. RESULTS: Maximal cross-correlation of BOLD T2*- and TcPO2-measurements was calculated as 0.93 (healthy volunteers) and 0.90 (SSc patients) for a time lag of approximately 40 s. Both modalities showed substantial differences regarding time course parameters between the SSc patients and healthy volunteers. CONCLUSION: Skeletal muscle BOLD MRI correlated very well with TcPO2 . T2* changes seem to reflect reoxygenation deficits in deeper muscle tissue of SSc patients.

Cdk5: An Emerging Kinase in Pain Signaling.

Pain is an important survival mechanism for an organism. It can turn into severe mental and physical disorder however, if the molecular and/or cellular pathways involved in pain signaling are altered. Chronic pain is characterized by an altered pain perception that includes allodynia (a response to a normally non-noxious stimulus) and hyperalgesia (an exaggerated response to a normally noxious stimulus). Past few years of pain research has been mainly focused on precise understanding of the molecular and cellular nociceptive signatures altered during chronic pain, so that more effective pain relievers can be developed. The importance of protein kinases in normal cellular homeostasis and disease pathogenesis has evolved rapidly in the past few decades. The recent advancement defining the role of multiple protein kinases in regulating neuronal plasticity and pain sensitization has gained enough attention of pharmaceutical industry to develop specific and selective kinase inhibitors as analgesics. Cyclin-dependent kinase 5 (Cdk5) is one such emerging kinase in pain biology. We will discuss here the recent advancement and therapeutic potential of Cdk5 in pain signaling.

Clinical implications of skeletal muscle blood-oxygenation-level-dependent (BOLD) MRI.

Blood-oxygenation-level-dependent (BOLD) contrast in magnetic resonance (MR) imaging of skeletal muscle mainly depends on changes of oxygen saturation in the microcirculation. In recent years, an increasing number of studies have evaluated the clinical relevance of skeletal muscle BOLD MR imaging in vascular diseases, such as peripheral arterial occlusive disease, diabetes mellitus, and chronic compartment syndrome. BOLD imaging combines the advantages of MR imaging, i.e., high spatial resolution, no exposure to ionizing radiation, with functional information of local microvascular perfusion. Due to intrinsic contrast provoked via changes in hemoglobin oxygen saturation, it is a safe and easy applicable procedure on standard whole-body MR devices. Therefore, BOLD MR imaging of skeletal muscle is a potential new diagnostic tool in the clinical evaluation of vascular, inflammatory, and muscular pathologies. Our review focuses on the current evidence concerning the use of BOLD MR imaging of skeletal muscle under pathological conditions and highlights ways for future clinical and scientific applications.

In vitro evaluation of photon and carbon ion radiotherapy in combination with chemotherapy in glioblastoma cells.

BACKGROUND: To evaluate the cytotoxic effect of carbon ion radiotherapy and chemotherapy in glioblastoma cells in vitro. METHODS AND MATERIALS: The human glioblastoma (GBM) cell line U87 was irradiated with photon radiotherapy (RT) doses of 2 Gy, 4 Gy and 6 Gy. Likewise, irradiation with carbon ions was performed with single carbon doses of 0.125, 0.5, 2 and 3 Gy. Four chemotherapeutic substances, camptothecin, gemcitabine, paclitaxel and cisplatinum, were used for single and combination experiments. The assessment of the effect of single and double treatment on cell viability was performed using the clonogenic growth assay representing the radiobiological gold standard. RESULTS: The RBE of carbon ions ranges between 3.3 and 3.9 depending on survival level and dose. All chemotherapeutic substances showed a clear does-response relationhips. in their characteristic concentrations. For subsequent combination experiments, two dose levels leading to low and medium reduction of cell survival were chosen. Combination experiments showed additive effects independently of the drugs' mechanisms of action. Paclitaxel and campthothecin demonstrated the most prominent cytotoxic effect in combination with carbon ion radiotherapy. CONCLUSION: In conclusion, combination of carbon ion radiotherapy with chemotherapies of different mechanisms of action demonstrates additive effects. The most dominant effect was produced by paclitaxel, followed by camptothecin, as espected from previously published work. The present data serve as an important radiobiological basis for further combination experiments, as well as clinical studies on combination treatments.

Effects of covert and overt paradigms in clinical language fMRI.

RATIONALE AND OBJECTIVES: The aim of this study was to assess the intrasubject and intersubject reproducibility of functional magnetic resonance imaging (fMRI) language paradigms on language localization and lateralization. MATERIALS AND METHODS: Fourteen healthy volunteers were enrolled prospectively and underwent language fMRI using visually triggered covert and overt sentence generation (SG) and word generation (WG) paradigms. Semiautomated analysis of all functional data was performed using Brain Voyager on an individual basis. Regions of interest for Broca's area, Wernicke's area, and their contralateral homologues were drawn. The Euclidean coordinates of the center of gravidity (x, y, and z) of the respective blood oxygenation level-dependent (BOLD) activation cluster, and the correlation of the measured hemodynamic response to the applied reference function (r), relative BOLD signal change as BOLD signal characteristics were measured in each region of interest. Regional lateralization indexes were calculated for Broca's area, Wernicke's area, and their contralateral homologues separately. Wilcoxon's signed-rank test was applied for statistical comparisons (P values < .05 were considered significant). Ten of the 14 volunteers had three repeated measurements to test intrasession reproducibility and intersession reproducibility. RESULTS: Overall activation rates for the four paradigms were 89% for covert SG, 82% for overt SG, 89% for covert WG, and 100% for overt WG. When comparing covert and overt paradigms, language localization was significantly different in 17% (Euclidean coordinates) and 19% (BOLD signal characteristics), respectively. Language lateralization was significantly different in 75%. Intrasubject and intersubject reproducibility was excellent, with 3.3% significant differences among all five parameters for language localization and 0% significant differences for language lateralization using covert paradigms. CONCLUSIONS: Covert language paradigms (SG and WG) provided highly robust and reproducible localization and lateralization of essential language centers for scans performed on the same and different days. Their overt counterparts achieved confirmatory localization but lower lateralization capabilities. Reference data for presurgical application are provided.

Blood oxygenation level-dependent (BOLD) MRI of human skeletal muscle at 1.5 and 3 T.

PURPOSE: To evaluate the dependence of skeletal muscle blood oxygenation level-dependent (BOLD) effect and time course characteristics on magnetic field strength in healthy volunteers using an ischemia/reactive hyperemia paradigm. MATERIALS AND METHODS: Two consecutive skeletal muscle BOLD magnetic resonance imaging (MRI) measurements in eight healthy volunteers were performed on 1.5 T and 3.0 T whole-body MRI scanners. For both measurements a fat-saturated multi-shot multiecho gradient-echo EPI sequence was applied. Temporary vascular occlusion was induced by suprasystolic cuff compression of the thigh. T2 time courses were obtained from two different calf muscles and characterized by typical curve parameters. Ischemia- and hyperemia-induced changes in R2 (ΔR2) were calculated for both muscles in each volunteer at the two field strengths. RESULTS: Skeletal muscle BOLD changes are dependent on magnetic field strength as the ratio ΔR2(3.0 T)/ΔR2(1.5 T) was found to range between 1.6 and 2.2. Regarding time course characteristics, significantly higher relative T2 changes were found in both muscles at 3.0 T. CONCLUSION: The present study shows an approximately linear field strength dependence of ΔR2 in the skeletal muscle in response to ischemia and reactive hyperemia. Using higher magnetic fields is advisable for future BOLD imaging studies of peripheral limb pathologies.

Detection of adventitial vasa vasorum and intraplaque neovascularization in carotid atherosclerotic lesions with contrast-enhanced ultrasound and their role in atherosclerosis.

INTRODUCTION: The development of new surrogate markers of atherosclerosis is a crucial goal in the clinical setting, as they may allow physicians to recognize unstable lesions early and identify individuals with vulnerable or unstable lesions who bear an increased risk of future cardio--and cerebrovascular complications. These surrogate markers should be capable of being measured noninvasively using safe and reliable methods. Recently, Nambi et al. demonstrated how the combined measurement of carotid intima media thickness (CIMT) and occurrence of carotid plaques improves the risk prediction of cardiovascular outcomes. These results confirm the value of carotid ultrasound (US) when combined with traditional Framingham risk factors in assessing a patient's risk for atherosclerotic disease. Contrast-enhanced ultrasound (CEUS) is a new imaging approach that is evolving and may become a standard clinical tool for further atherosclerotic risk stratification in the future. The contrast agents used in US imaging are safe, commercially available, and approved for use in echocardiography by the FDA. Thus, CEUS is technically feasible with existing approved commercial equipment and can be performed at the bedside or in an outpatient setting. However, US contrast agents are not yet approved by the FDA for visualization and assessment of the carotid artery and its associated pathologies. The cost effectiveness of CEUS has been shown in the context of gastrointestinal imaging, and CEUS of carotid atherosclerotic lesions is emerging as an approach to complement unenhanced US imaging. By providing the direct visualization of adventitial vasa vasorum (VV) and intraplaque neovascularization, CEUS is capable of depicting two new surrogate markers of atherosclerosis - namely, adventitial VV and intraplaque neovascularization.