Experimental verification of a non-invasive method to monitor the lateral pencil beam position in an anthropomorphic phantom for carbon-ion radiotherapy.

The dose conformation and the sparing of neighboring critical healthy structures are improved in carbon-ion beam radiotherapy in comparison to conventional photon radiotherapy. Inter and intrafractional plan adaptation strategies may preclude the quality assurance (QA) of the actually applied treatment plan before the treatment starts. Therefore, independent measurements of the positions of scanned pencil 12C ion beams are of interest in order to monitor the beam application during the treatment and the beam in the isocenter. In this work, secondary ions outgoing from a patient-like phantom are exploited for the assessment of the lateral pencil beam position in a clinic-like 12C treatment fraction. The experiment was performed at the Heidelberg Ion-Beam Therapy Center (HIT) in Germany. A carbon-ion treatment plan was used to treat a 100 cm3 tumor volume in the center of an Alderson head phantom. Two silicon pixel detectors based on the Timepix3 technology developed at CERN were operated in synchronization to detect and to track outgoing secondary ions. We established an analysis of the measured secondary ion track distribution which enabled us to follow the beam scanning movement of the carbon-ion pencil beam by assessing the lateral position of the single beam spots. The precision of the developed method was found to range from 0.84 mm to 2.59 mm. For beam energies greater than 197.58 MeV/n, the mean of absolute distances of the measured lateral pencil beam positions with respect to the pencil beam positions measured by the beam application system (averaged over each energy layer) were smaller than 2 mm. We conclude that the presented method has shown capabilities of monitoring the lateral pencil beam positions by means of secondary ions with precision and sensitivity of clinical interest.

[Molecular imaging in neurological diseases]. / Molekulare Bildgebung bei neurologischen Erkrankungen.

In neurodegeneration and in neuro-oncology, the standard imaging procedure, magnetic resonance imaging (MRI), shows limited sensitivity and specificity. Molecular imaging with specific positron-emission tomography (PET) and single-photon emission computed tomography (SPECT) tracers allows various molecular targets and metabolic processes to be assessed and is thus a valuable adjunct to MRI. Two important examples are referred to here: amino acid transport for neuro-oncological issues, and the recently approved PET tracers for detecting amyloid depositions during the preclinical stage of Alzheimer's disease. This review discusses the clinical relevance and indications for the following nuclear medicine imaging procedures: amyloid PET, (18)F-fluorodeoxyglucose (FDG)-PET, and dopamine transporter (DaT)-SPECT for the diagnosis of dementia and the differential diagnosis of Parkinson's disease, in addition to amino acid PET for the diagnosis of brain tumors and somatostatin receptor imaging in meningioma.

Hypothyroidism during second-line treatment of multidrug-resistant tuberculosis: a prospective study.

SETTING: Hypothyroidism is an adverse effect of certain anti-tuberculosis drugs. DESIGN: This is a prospective study of the frequency and possible pathomechanisms associated with hypothyroidism due to second-line treatment of multidrug-resistant tuberculosis. Fifty human immunodeficiency virus negative patients and 20 controls were included. All participants underwent ultrasonography of the thyroid and measurement of thyroid stimulating hormone (TSH). TSH levels were checked every 3 months. If hypothyroidism was present, T3, T4 and thyroid peroxidase autoantibodies were measured, and imaging extended to scintigraphy and repeated ultrasonography. RESULTS: Before treatment, 7 patients (14%) and 1 control (5%) were hypothyreotic. During the first 6 months of treatment, TSH levels increased in 41 patients (82%), 39 (78%) had values above the normal range and 19 (38%) had overt hypothyroidism. As none of the patients had signs of autoimmune thyroiditis, interaction with anti-tuberculosis drugs was assumed to be the cause of hypothyroidism. Nine patients died during treatment, all of whom had developed hypothyroidism. In seven, the metabolic situation at their death was known, and they had become euthyreotic following levothyroxine substitution. CONCLUSION: TSH levels should be checked before initiating anti-tuberculosis treatment and after 3 and 6 months to start timely replacement of levothyroxine. Further studies are needed to elucidate the exact pathomechanism involved in hypothyroidism and whether hypothyroidism can be used as predictor of treatment failure.

11C-methionine PET/CT after inconclusive 99mTc-MIBI-SPECT/CT for localisation of parathyroid adenomas in primary hyperparathyroidism.

AIM: To investigate the efficacy of PET/CT with 11C-methionine for localizing parathyroid adenomas in patients with suspected primary hyperparathyroidism and inconclusive results of cervical ultrasonography and 99mTc-MIBI-SPECT/CT. PATIENTS, METHOD: Retrospective analysis of imaging data of 18 patients and correlation with clinical outcome, in particular intraoperative findings and histopathology of excised tissue. RESULTS: 12 of 18 patients received surgery. In 10 patients single parathyroid adenomas were found (diameter: 5-20 mm), 2 patients presented parathyroid hyperplasia (5 excised hyperplastic glands (diameter: 2-12 mm). PET/CT correctly localized all adenomas and 1 of 5 hyperplastic glands. The sensitivity per patient was 91.7% (11 of 12), the sensitivity per lesion 73.3% (11 of 15). All lesions missed by PET/CT had a size smaller than 9 mm and a volume of less than 0.2 ml. In 6 patients no surgery was performed. Five of them had a negative or atypical PET/CT. Further follow-up indicated familial hypocalciuric hypercalcemia in 3 of them (thus, PET/CT true negative), in the remaining 2 patients no validation is available. One patient with 2 highly suggestive lesions rejected surgery so far. CONCLUSION: PET/CT with 11C-methionine is a very sensitive method for the detection of parathyroid adenomas, even if they are too small to be visualized by 99mTc-MIBI-SPECT/CT.

Simultaneous PET/MR imaging in a human brain PET/MR system in 50 patients--current state of image quality.

OBJECTIVES: The present work illustrates the current state of image quality and diagnostic accuracy in a new hybrid BrainPET/MR. MATERIALS AND METHODS: 50 patients with intracranial masses, head and upper neck tumors or neurodegenerative diseases were examined with a hybrid BrainPET/MR consisting of a conventional 3T MR system and an MR-compatible PET insert. Directly before PET/MR, all patients underwent a PET/CT examination with either [18F]-FDG, [11C]-methionine or [68Ga]-DOTATOC. In addition to anatomical MR scans, functional sequences were performed including diffusion tensor imaging (DTI), arterial spin labeling (ASL) and proton-spectroscopy. Image quality score of MR imaging was evaluated using a 4-point-scale. PET data quality was assessed by evaluating FDG-uptake and tumor delineation with [11C]-methionine and [68Ga]-DOTATOC. FDG uptake quantification accuracy was evaluated by means of ROI analysis (right and left frontal and temporo-occipital lobes). The asymmetry indices and ratios between frontal and occipital ROIs were compared. RESULTS: In 45/50 patients, PET/MR examination was successful. Visual analysis revealed a diagnostic image quality of anatomical MR imaging (mean quality score T2 FSE: 1.27±0.54; FLAIR: 1.38±0.61). ASL and proton-spectroscopy was possible in all cases. In DTI, dental artifacts lead to one non-diagnostic dataset (mean quality score DTI: 1.32±0.69; ASL: 1.10±0.31). PET datasets of PET/MR and PET/CT offered comparable tumor delineation with [11C]-methionine; additional lesions were found in 2/8 [(68)Ga]-DOTATOC-PET in the PET/MR. Mean asymmetry index revealed a high accordance between PET/MR and PET/CT (1.5±2.2% vs. 0.9±3.6%; mean ratio (frontal/parieto-occipital) 0.93±0.08 vs. 0.96±0.05), respectively. CONCLUSIONS: The hybrid BrainPET/MR allows for molecular, anatomical and functional imaging with uncompromised MR image quality and a high accordance of PET results between PET/MR and PET/CT. These results justify the application of this technique in further clinical studies and may contribute to the transfer into whole-body PET/MR systems.

FDG-PET/CT-guided biopsy of bone metastases sets a new course in patient management after extensive imaging and multiple futile biopsies.

A 73-year-old man with a history of prostate and bladder carcinoma and persistent back pain was diagnosed by MRI with multiple vertebral metastases including a compression fracture of T7. He received radiotherapy for pain relief and for vertebral instability with incipient spinal stenosis, but additional targeted systemic therapy was intended. Therefore, multiple attempts at minimally invasive and open biopsies for histological characterisation of the bone metastases were performed, but failed to provide a conclusive specimen, although CT, MRI and bone scintigraphy were used for biopsy planning. Only histopathological analysis of an (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT-guided additional biopsy at a site with high metabolic activity yielded the final diagnosis of bone metastases of a neuroendocrine small cell cancer of unknown origin; hence, the patient had a third malignancy requiring a different therapy regimen and diagnostic work-up.

How the serotonin transporter 5-HTTLPR polymorphism influences amygdala function: the roles of in vivo serotonin transporter expression and amygdala structure.

The serotonin transporter-linked promoter region (5-HTTLPR) polymorphism of the serotonin transporter gene is associated with amygdala response during negative emotion. The aim of this study was to investigate whether this genotype effect on amygdala function is mediated by current serotonin transporter (5-HTT) levels or rather by genetically induced influences during neurodevelopment, shaping brain structure. A total of 54 healthy subjects underwent functional and structural magnetic resonance imaging, [(11)C]DASB positron emission tomography and 5-HTTLPR genotyping to analyze the interrelationships between amygdala activation during processing of unpleasant stimuli, 5-HTTLPR genotype, amygdala volumes and 5-HTT levels in the midbrain and in other brain regions. In line with previous research, carriers of the short allele (S) showed increased amygdala activation. Path analysis demonstrated that this genotype effect was not procured by current 5-HTT availability but by amygdala structure, with smaller amygdala volumes in the S than in the LL genotype, as well as smaller volumes being associated with increased amygdala activation. Our findings stress the role of genetic effects during neurodevelopment.

[Detection of bone metastasis of prostate cancer - comparison of whole-body MRI and bone scintigraphy]. / Nachweis ossärer Metastasen des Prostatakarzinoms - Vergleich der Leistungsfähigkeit der Ganzkörper-MRT und der Skelettszintigrafie.

PURPOSE: Prostate cancer continues to be the third leading cancer-related mortality of western men. Early diagnosis of bone metastasis is important for the therapy regime and for assessing the prognosis. The standard method is bone scintigraphy. Whole-body MRI proved to be more sensitive for early detection of skeletal metastasis. However, studies of homogenous tumor entities are not available. The aim of the study was to compare bone scintigraphy and whole-body MRI regarding the detection of bone metastasis of prostate cancer. MATERIALS AND METHODS: 14 patients with histologically confirmed prostate cancer and a bone scintigraphy as well as whole-body MRI within one month were included. The mean age was 68 years. Scintigraphy was performed using the planar whole-body technique (ventral and dorsal projections). Suspect areas were enlarged. Whole-body MRI was conducted using native T 1w and STIR sequences in the coronary plane of the whole body, sagittal imaging of spine and breath-hold STIR and T 1w-Flash-2D sequences of ribs and chest. Bone scintigraphy and whole-body MRI were evaluated retrospectively by experienced radiologists in a consensus reading on a lesion-based level. RESULTS: Whole-body MRI detected significantly more bone metastasis (p = 0.024). 96.4 % of the demonstrated skeletal metastases in bone scintigraphy were founded in whole-body MRI while only 58.6 % of the depicted metastases in MRI were able to be located in scintigraphy. There was no significant difference regarding bone metastasis greater than one centimeter (p = 0.082) in contrast to metastasis less than one centimeter (p = 0.035). Small osteoblastic metastases showed a considerably higher contrast in T 1w sequences than in STIR imaging. Further advantages of whole-body MRI were additional information about extra-osseous tumor infiltration and their complications, for example stenosis of spinal canal or vertebral body fractures, found in 42.9 % of patients. CONCLUSION: Whole-body MRI using native STIR and T 1w sequences is superior to bone scintigraphy for the detection of small bone metastasis of prostate cancer. Simultaneous clarification of associated complications demonstrates further advantages.

[Multimodal imaging with PET, fMRI and genetic research]. / Multimodale Bildgebung mit PET, fMRI und genetischen Untersuchungen.

Within the last decades, functional magnetic resonance imaging (fMRI) has widely replaced previously used methods such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) in the assessment of functional brain activation. However, PET and SPECT remain important tools for in vivo assessment of neurotransmitter receptors and transporters and for the assessment of baseline regional cerebral blood flow. PET and SPECT also provide a unique opportunity to directly quantify genotype effects on protein expression. We review current nuclear imaging techniques for quantification of genotype effects on neurotransmitter receptors and transporters. Furthermore, we describe first multimodal imaging studies that combined PET, fMRI and genetic data in order to measure effects of genotype or the availability of receptor or transporters on functional brain activation. The clinical relevance of these studies will be illustrated and discussed.

Anxiety is associated with reduced central serotonin transporter availability in unmedicated patients with unipolar major depression: a [11C]DASB PET study.

Serotonergic dysfunction may contribute to negative mood states in affective disorders. Some in vivo imaging studies showed reduced availability of serotonin transporters (5-HTT) in the brainstem and thalamus of patients with major depression. We tested the hypothesis that 5-HTT availability is reduced in unmedicated unipolar patients with major depression compared to healthy control subjects matched for gender, age, genotype and smoking status. Availability of 5-HTT was measured in vivo with positron emission tomography and [(11)C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) in the midbrain, thalamus and amygdala. DASB binding was correlated with the severity of depression (Beck's Depression Inventory), anxiety (Spielberger's State-Trait Anxiety Inventory) and personality traits (Temperament and Character Inventory). Patients with major depression displayed reduced 5-HTT availability in the thalamus (P=0.005). In patients, low serotonin transporter availability correlated with high anxiety (thalamus: r=-0.78, P=0.004; midbrain: r=-0.78, P=0.004; amygdala: r=-0.80, P=0.003). Correlations with severity of depression were weaker and did not survive correction for multiple testing. These results support the hypothesis that central serotonergic dysfunction is associated with negative mood states in affective disorders. In the thalamus, a low serotonin reuptake capacity may interfere with thalamic control of cortical excitability and contribute to anxiety rather than depression per se in major depression.

Estimation of the wear volume after total hip replacement. A simple access to geometrical concepts.

Various formulas have been proposed to calculate the volume of prosthetic wear from the penetration depth of the head as assessed on plain radiographs, based on idealized, three-dimensional geometrical models of a prosthetic hip. However, for most published formulas no (or no simple) derivation is available and not all of them are correct. We describe a simple geometrical model that allows for transparent derivation of equations for various components of prosthetic wear volume and compare the calculated volumes with those obtained from published equations. These components are: (1) a right generalized cylinder resulting from a linear shift of a half spherical part of the prosthetic head into the hemispherical cup, (2) an additional wedge that is "cut" from the cup and (3) the wear from an optional additional cylindrical portion of the cup. We emphasize that calculation of a three-dimensional wear volume from linear penetration depth should be based on a geometrical concept that is transparent and simple enough for clinical research, such as the one presented. The incorrect formula of Kabo et al. should be completely abandoned.

Reduced availability of serotonin transporters in obsessive-compulsive disorder correlates with symptom severity - a [11C]DASB PET study.

Reduced availability of brainstem serotonin transporters (5-HTT) has been observed in vivo in obsessive-compulsive disorder (OCD). However, results vary and may be influenced by competition with endogenous serotonin. Using positron emission tomography (PET) and [11C]DASB, a specific 5-HTT ligand that showed no competition with serotonin for 5-HTT binding in vitro, we tested the hypothesis that 5-HTT availability is reduced in OCD patients and correlated with OCD severity. METHODS. 5-HTT availability in the thalamus and the midbrain was measured in nine drug-free OCD patients and compared with 19 healthy controls, matched for the individual combination of 5-HTT genotype, gender and smoking status. OCD severity was assessed with the Yale-Brown obsessive compulsive scale (Y-BOCS). RESULTS. 5-HTT availability was significantly reduced in the thalamus and midbrain of OCD patients. Age and 5-HTT in the thalamus explained 83% of OCD severity in patients that were drug-free for at least 1 year. CONCLUSION. This PET study confirms a central role of the serotonergic system, particularly the thalamus in the pathogenesis of obsessive compulsive disorder.

[11C]Vinblastine syntheses and preliminary imaging in cancer patients.

PURPOSE: The primary aim of this work was to establish a radiolabeling procedure of vinblastine, a vinca alkaloid widely used in chemotherapy, with the positron-emitter carbon-11 for application in positron-emission-tomography (PET) studies in cancer patients. The optimized reaction conditions were transferred to an automated radiosynthesizer system for the preparation of [11C]vinblastine under GMP conditions for human use. We report about the whole body activity distribution after injection of [11C]vinblastine as well as the pharmacokinetic behavior in selected organs and the tumor in two patients that were investigated with [11C]vinblastine PET before chemotherapy. METHODS: For carbon-11 labeling of vinblastine the reaction conditions were determined with respect to the two possible labeling precursors (i.e. [11C]methyl iodide and [11C]diazomethane), solvent, reaction temperature and reaction time. Both, [11C]diazomethane and [11C]methyl iodide were tested as labeling precursors with the corresponding demethyl compound of vinblastine, i.e. the vinblastine acid and the potassium salt of vinblastine acid. Two patients with renal carcinoma underwent [11C]vinblastine PET before chemotherapy. One patient underwent a second scan during infusion of unlabeled vinblastine at a therapeutic dose. RESULTS: Best results for the labeling procedure were found when methylation was carried out at 100 degrees C within 20 min using 2 mg/mL of the potassium salt of vinblastine acid in DMSO and [11C]methyl iodide as labeling precursor. Based on [11C]methyl iodide starting activity a radiochemical yield of up 53 % [11C]vinblastine was achieved. In addition, the synthesis was transferred to a remotely controlled module for routine GMP conform production for human use. In large scale production runs up to 1 GBq of [11C]vinblastine was obtained ready for injection within 45 min after EOB. In one patient, whole body PET scans 40 min after injection of 112 MBq [11C]vinblastine showed a focally increased [11C]vinblastine uptake and [11C]vinblastine metabolite uptake, respectively in the known metastases, along with a slow but continuous washout during the measurement interval (0-60 min p.i.). Another patient showed no focally increased [11C]vinblastine uptake and [11C]vinblastine metabolite uptake in the tumor, where radioactivity concentration was comparable to that in the blood. In this patient, a second PET scan during infusion of unlabeled vinblastine revealed similar kinetics with a trend towards delayed hepatic metabolism and higher blood and tumor concentrations. Whereas this patient showed a partial response to chemotherapy, the first patient did not, hypothetically due to the observed vinblastine washout from the tumor. CONCLUSIONS: The carbon-11 labeling of vinblastine using [11C]methyl iodide is superior to the method using [11C]diazomethane. A well working automated radiosynthesis was established for the production of [11C]vinblastine for PET-investigations in cancer patients. The individual pharmacokinetic behavior of the chemo-therapeutic agent to the tumor can be assessed with PET, thus, can be considered to be a realistic approach for individualized chemotherapy.

Midbrain serotonin transporter binding potential measured with [11C]DASB is affected by serotonin transporter genotype.

BACKGROUND: Homozygote carriers of two long (L) alleles of the serotonin transporter (5-HTT) regulatory region displayed in vitro a twofold increase in 5-HTT expression compared with carriers of one or two short (S) alleles. However, in vivo imaging studies yielded contradictory results. Recently, an A > G exchange leading to differential transcriptional activation of 5-HTT mRNA in lymphobalstoid cell lines was discovered in the 5-HTT regulatory region. In vitro and in vivo evidence suggests that [(11)C]DASB, a new 5-HTT ligand offers some advantages over the ligands used in previous studies in measuring 5-HTT density independent of synaptic levels of serotonin. METHOD: We assessed 5-HTT binding potential (BP (2)) in the midbrain of 19 healthy subjects with positron emission tomography and [(11)C]DASB. Accounting for the hypothesized functional similarity of L (G) and S in driving 5-HTT transcription, we assessed whether L (A) L (A) homozygotes display increased midbrain BP (2) compared with carriers of at least one S allele. RESULTS: BP (2) in the midbrain was significantly increased in L (A) L (A) homozygotes compared with carriers of at least one S allele. Interestingly, the genotype effect on the midbrain was significantly different from that on the thalamus and the amygdala where no group differences were detected. CONCLUSIONS: This in vivo study provides further evidence that subjects homozygous for the L (A) allele display increased expression of 5-HTT in the midbrain, the origin of central serotonergic projections.

Moderate therapeutic efficacy of positron emission tomography-navigated repetitive transcranial magnetic stimulation for chronic tinnitus: a randomised, controlled pilot study.

BACKGROUND: Tinnitus has been shown to respond to modulations of cortical activity by high-frequency and low-frequency repetitive transcranial magnetic stimulation (rTMS). OBJECTIVE: To determine the tinnitus-attenuating effects of a 2-week daily regimen of rTMS, navigated to the maximum of tinnitus-related increase in regional cerebral blood flow. METHODS: Six patients with chronic tinnitus were enrolled in this sham-controlled crossover study and treated with 2x2 weeks of suprathreshold 1 Hz rTMS (30 min) applied to the region with maximal tinnitus-related increase in regional cerebral blood flow delineated by functional imaging with [15O]H2O positron emission tomography and a control area. Tinnitus-related distress was assessed before and after each treatment and 2 weeks after the end of the 4-week course of stimulation using a validated tinnitus questionnaire. Additional self-assessment scores of tinnitus change, loudness and annoyance were obtained. RESULTS: In five of six patients, rTMS induced greater reduction of the tinnitus questionnaire score than sham stimulation. In two patients, all parameters measured (tinnitus change score, tinnitus loudness, tinnitus annoyance) showed unequivocal improvement. At the group level, the degree of response in the tinnitus questionnaire score was correlated with tinnitus-associated activation of the anterior cingulate cortex. Two weeks after the final stimulation, tinnitus had returned to baseline in all patients but one. CONCLUSION: Tinnitus can be attenuated by low-frequency rTMS navigated to each person's maximum tinnitus-related cortical hyperactivity. The effects are only moderate; interindividual responsiveness varies and the attenuation seems to wear off within 2 weeks after the last stimulation session. Notably, tinnitus-related anterior cingulate cortex activation seems to predict the response to rTMS treatment.

Impact of staging with 18F-FDG-PET on outcome of patients with stage III non-small cell lung cancer: PET identifies potential survivors.

PURPOSE: The aim of this study was to analyse the impact of FDG-PET staging on treatment results of neo-adjuvant radiochemotherapy in patients with advanced non-small cell lung cancer (NSCLC). We compared prospectively the outcome of two patient groups with stage III NSCLC undergoing the same neo-adjuvant radio-chemotherapy (NARCT). In one group, FDG-PET was part of the pretherapeutic staging, whereas in the other group, no PET scans were performed. METHODS: One hundred and eighty-eight patients with advanced stage III NSCLC were selected for a phase II trial of NARCT. The first 115 patients underwent conventional workup (CWU) and FDG-PET before inclusion (group I); the remaining 73 patients underwent CWU only (group II). All patients were followed up according to a standardised protocol for at least 11 months (up to 64 months). Overall survival and disease-free survival were used as parameters of therapeutic success and analysed statistically. RESULTS: After staging, 157/188 patients were included in the clinical trial. Thirty-one were excluded owing to the results of FDG-PET, in most cases because of the detection of previously unknown distant metastases. Overall survival and metastasis-free survival were significantly longer in patients of group I stratified by FDG-PET than in group II (p=0.006 and 0.02 respectively). Another significant factor for survival was complete tumour resection (p=0.02). Gender, histological tumour type, tumour grade and UICC stage had no significant influence. CONCLUSION: Pretherapeutic staging by FDG-PET significantly influences the results of NARCT and subsequent surgery by identifying patients not eligible for curative treatment.