Impact of rs12917 MGMT Polymorphism on [18F]FDG-PET Response in Pediatric Hodgkin Lymphoma (PHL).

PURPOSE: The enzyme O6-methylguanine-DNA methyltransferase (MGMT) is an important component of the DNA repair machinery. MGMT removes O6-methylguanine from the DNA by transferring the methyl group to a cysteine residue in its active site. Recently, we detected the single nucleotide polymorphism (SNP) rs12917 (C/T) in the MGMT sequence adjacent to the active site in Hodgkin lymphoma (HL) cell line KM-H2. We now investigated whether this SNP is also present in other HL cell lines and patient samples. Furthermore, we asked whether this SNP might have an impact on metabolic response in 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ([18F]FDG-PET), and on overall treatment outcome based on follow-up intervals of at least 34 months. PROCEDURES: We determined the frequency of this MGMT polymorphism in 5 HL cell lines and in 29 pediatric HL (PHL) patients. The patient cohort included 17 female and 12 male patients aged between 4 and 18 years. After characterization of the sequence, we tested a possible association between rs12917 and age, gender, Ann Arbor stage, treatment group, metabolic response following two courses of OEPA (vincristine, etoposide, prednisone, and doxorubicin) chemotherapy, radiotherapy indication, and relapse status. RESULTS: We detected the minor T allele in four of five HL cell lines. 11/29 patients carried the minor T allele whereas 18/29 patients showed homozygosity for the major C allele. Interestingly, we observed significantly better metabolic response in PHL patients carrying the rs12917 C allele resulting in a lower frequency of radiotherapy indication. CONCLUSION: MGMT polymorphism rs12917 seems to affect chemotherapy response in PHL. The prognostic value of this polymorphism should be investigated in a larger patient cohort.

Six versus eight doses of rituximab in patients with aggressive B cell lymphoma receiving six cycles of CHOP: results from the "Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas" (PETAL) trial.

Standard first-line treatment of aggressive B cell lymphoma comprises six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus eight doses of rituximab (R). Whether adding two doses of rituximab to six cycles of R-CHOP is of therapeutic benefit has not been systematically investigated. The Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial investigated the ability of [18F]-fluorodesoxyglucose PET scanning to guide treatment in aggressive non-Hodgkin lymphomas. Patients with B cell lymphomas and a negative interim scan received six cycles of R-CHOP with or without two extra doses of rituximab. For reasons related to trial design, only about a third underwent randomization between the two options. Combining randomized and non-randomized patients enabled subgroup analyses for diffuse large B cell lymphoma (DLBCL; n = 544), primary mediastinal B cell lymphoma (PMBCL; n = 37), and follicular lymphoma (FL) grade 3 (n = 35). With a median follow-up of 52 months, increasing the number of rituximab administrations failed to improve outcome. A non-significant trend for improved event-free survival was seen in DLBCL high-risk patients, as defined by the International Prognostic Index, while inferior survival was observed in female patients below the age of 60 years. Long-term outcome in PMBCL was excellent. Differences between FL grade 3a and FL grade 3b were not apparent. The results were confirmed in a Cox proportional hazard regression model and a propensity score matching analysis. In conclusion, adding two doses of rituximab to six cycles of R-CHOP did not improve outcome in patients with aggressive B cell lymphomas and a fast metabolic treatment response.

Effectiveness and side-effects of peptide receptor radionuclide therapy for neuroendocrine neoplasms in Germany: A multi-institutional registry study with prospective follow-up.

BACKGROUND: Monocentric and retrospective studies indicate effectiveness of peptide receptor radionuclide therapy targeting somatostatin receptors of neuroendocrine neoplasms. We assessed overall and progression-free survival and adverse events of peptide receptor radionuclide therapy by a multi-institutional, board certified registry with prospective follow-up in five centres in Germany. METHODS: A total of 450 patients were included and followed for a mean of 24.4 months. Most patients had progressive low- or intermediate grade neuroendocrine neoplasms and 73% were pretreated with at least one therapy. Primary neuroendocrine neoplasms were mainly derived of pancreas (38%), small bowel (30%), unknown primary (19%) or bronchial system (4%). Patients were treated with Lutetium-177 in 54%, with Yttrium-90 in 17% and with both radionuclides in 29%. Overall and progression-free survival was determined with Kaplan-Meier curves and uni-variate log rank test Cox models. FINDINGS: Median overall survival of all patients was 59 (95% confidence interval [CI] 49-68.9) months. Overall survival was significantly inferior in the patients treated with Yttrium-90 solely (hazard ratio, 3.22; 95% CI, 1.83-5.64) compared to any peptide receptor radionuclide therapy with Lutetium-177. Grade II (hazard ratio, 2.06; 95% CI, 0.79-5.32) and grade III (hazard ratio, 4.22; 95% CI, 1.41-12.06) neuroendocrine neoplasms had significantly worse overall survival than grade I neuroendocrine neoplasms. Patients with small neuroendocrine neoplasms of small bowel had significantly increased survival (hazard ratio, 0.39; 95% CI, 0.18-0.87) compared to neuroendocrine neoplasms of other locations. Median progression-free survival was 41 (35.9-46.1) months and significantly inferior in patients treated with Yttrium solely (hazard ratio, 2.7; 95% CI, 1.71-4.55). Complete remission was observed in 5.6% of patients, 22.4% had a partial remission, 47.3% were stable and 4% were progressive as best response. Adverse events of bone marrow and kidney function higher than grade III occurred in 0.2-1.5% of patients. INTERPRETATION: These results indicate that peptide receptor radionuclide therapy is a highly effective therapy for patients with low to intermediate grade neuroendocrine neoplasms with minor adverse events.

Biological tumor volume in 18FET-PET before radiochemotherapy correlates with survival in GBM.

OBJECTIVE: The aim of this prospective longitudinal study was to identify static and dynamic O-(2-[(18)F]fluoroethyl)-L-tyrosine PET ((18)FET-PET)-derived imaging biomarkers in patients with glioblastoma (GBM). METHODS: Seventy-nine patients with newly diagnosed GBM were included; 42 patients underwent stereotactic biopsy (unresectable tumors) and 37 patients microsurgical tumor resection. All patients were scheduled to receive radiotherapy plus concomitant and adjuvant temozolomide (RCx/TMZ). (18)FET-PET evaluation using static and dynamic analysis was done before biopsy/resection, after resection, 4 to 6 weeks following RCx, and after 3 cycles of TMZ. Endpoints were survival and progression-free-survival. Prognostic factors were obtained from proportional hazards models. RESULTS: Biological tumor volume before RCx (BTV(preRCx)) was the most important (18)FET-PET-derived imaging biomarker and was independent of MGMT promoter methylation and clinical prognostic factors: patients with smaller BTV(preRCx) had significantly longer progression-free and overall survival (OS). (18)FET time-activity curves (TACs) before treatment and their changes after RCx were also related to outcome; patients with initially increasing TACs experienced longer OS. CONCLUSION: BTV(preRCx) and TAC represent important (18)FET-PET-derived imaging biomarkers in GBM. Increasing TACs are associated with prolonged OS. The BTV(preRCx) is a strong prognostic factor for progression-free survival and OS independent of the mode of surgery. Our data furthermore suggest that patients harboring resectable GBM might benefit from maximal PET-guided tumor resection.

Prediction of oligodendroglial histology and LOH 1p/19q using dynamic [(18)F]FET-PET imaging in intracranial WHO grade II and III gliomas.

Oligodendroglial components (OC) and loss of heterozygosity on chromosomes 1p and 19q (LOH 1p/19q) are associated with better outcome in patients with glioma. We aimed to assess the fitness of [(18)F]fluoroethyltyrosine positron-emission-tomography (FET-PET) for noninvasively identifying these important prognostic/predictive factors. One hundred forty-four patients with MRI-suspected WHO grade II and III glioma underwent FET-PET scans prior to histological diagnosis. FET-PET analyses included maximal tumoral uptake (SUV(max)/BG), biological tumor volume (BTV), mean tumoral uptake (SUV(mean)/BG), total tumoral uptake (SUV(total)/BG), and kinetic analysis. Suspicion of OC was based on static and dynamic FET-uptake parameters. PET results were correlated with histology and 1p/19q status. OC tumors exhibited significantly higher uptake values, compared with astrocytomas (AC) (SUV(max)/BG 3.1 vs 2.3, BTV 15.5 mL vs 7.2 mL, SUV(total)/BG 38.5 vs 17.4, P < .01 each; SUV(mean)/BG 2.2 vs 2.1, P < .05). These differences were more pronounced in WHO grade II gliomas. Comparable results were found with respect to 1p/19q status. Kinetic analysis misclassified 18 of 34 low-grade OC tumors as high-grade glioma but misclassified only 5 of 45 of the low-grade ACs. FET-based suspicion of OC resulted in concordance rates of both 76% for the prediction of OC and LOH 1p/19q. FET-uptake was significantly higher in gliomas with OC, compared with AC, and likewise in 1p/19q codeleted, compared with noncodeleted tumors. However, FET-PET analysis did not reliably predict the presence of OC/LOH 1p/19q in the individual patient, mostly because of an overlap in PET characteristics of OC tumors and high-grade AC. Histological examination is still required for an accurate diagnosis.

Molecular imaging of potential bone metastasis from differentiated thyroid cancer: a case report.

INTRODUCTION: Molecular imaging of the spine is a rarely used diagnostic method for which only a few case reports exist in the literature. Here, to the best of our knowledge we present the first case of a combination of molecular imaging by single photon emission computer tomography and positron emission tomography used in post-operative spinal diagnostic assessment. CASE PRESENTATION: We present the case of a 50-year-old Caucasian woman experiencing progressive spinal cord compression caused by a vertebral metastasis of a less well differentiated thyroid cancer. Following tumor resection and vertebral stabilization, total thyroidectomy was performed revealing follicular thyroid carcinoma pT2 pNxM1 (lung, bone). During follow-up our patient underwent five radioiodine therapy procedures (5.3 to 5.7 GBq each) over a two-year period. Post-therapeutic I-131 scans showed decreasing uptake in multiple Pulmonary metastases. However, following an initial decrease, stimulated thyroglobulin remained at pathologically increased levels, indicating further neoplastic activity. F18 Fludeoxyglucose positron emission tomography, which was performed in parallel, showed remaining hypermetabolism in the lungs but no hypermetabolism of the spinal lesions correlating with the stable neurological examinations. While on single photon emission computer tomography images Pulmonary hyperfixation of I-131 disappeared (most likely indicating dedifferentiation), there was persistent spinal hyperfixation at the operated level and even higher fixation at the spinal process of L3. Based on the negative results of the spinal F18 fludeoxyglucose positron emission tomography, a decision was made not to operate again on the spine since our patient was completely asymptomatic and the neurological risk seemed to be too high. During further follow-up our patient remained neurologically stable. CONCLUSIONS: Molecular imaging by F18 fludeoxyglucose positron emission tomography helps to exclude metabolically active spinal metastases and to spare further risky surgery.

Iterative reconstruction or filtered backprojection for semi-quantitative assessment of dopamine D2 receptor SPECT studies?

PURPOSE: In routine clinical practice striatal dopamine D(2) receptor binding is generally assessed using data reconstructed by filtered backprojection (FBP). The aim of this study was to investigate the use of an iterative reconstruction algorithm (ordered subset expectation maximization, OSEM) and to assess whether it may provide comparable or even better results than those obtained by standard FBP. METHODS: In 56 patients with parkinsonian syndromes, single photon emission computed tomography (SPECT) scans were acquired 2 h after i.v. application of 185 MBq [(123)I]iodobenzamide (IBZM) using a triple-head gamma camera (Siemens MS 3). The scans were reconstructed both by FBP and OSEM (3 iterations, 8 subsets) and filtered using a Butterworth filter. After attenuation correction the studies were automatically fitted to a mean template with a corresponding 3-D volume of interest (VOI) map covering striatum (S), caudate (C), putamen (P) and several reference VOIs using BRASS software. RESULTS: Visual assessment of the fitted studies suggests a better separation between C and P in studies reconstructed by OSEM than FBP. Unspecific background activity appears more homogeneous after iterative reconstruction. The correlation shows a good accordance of dopamine receptor binding using FBP and OSEM (intra-class correlation coefficients S: 0.87; C: 0.88; P: 0.84). Receiver-operating characteristic (ROC) analyses show comparable diagnostic power of OSEM and FBP in the differentiation between idiopathic parkinsonian syndrome (IPS) and non-IPS. CONCLUSION: Iterative reconstruction of IBZM SPECT studies for assessment of the D(2) receptors is feasible in routine clinical practice. Close correlations between FBP and OSEM data suggest that iteratively reconstructed IBZM studies allow reliable quantification of dopamine receptor binding even though a gain in diagnostic power could not be demonstrated.

Current molecular imaging of spinal tumors in clinical practice.

Energy metabolism measurements in spinal cord tumors, as well as in osseous spinal tumors/metastasis in vivo, are rarely performed only with molecular imaging (MI) by positron emission tomography (PET). This imaging modality developed from a small number of basic clinical science investigations followed by subsequent work that influenced and enhanced the research of others. Apart from precise anatomical localization by coregistration of morphological imaging and quantification, the most intriguing advantage of this imaging is the opportunity to investigate the time course (dynamics) of disease-specific molecular events in the intact organism. Most importantly, MI represents one of the key technologies in translational molecular neuroscience research, helping to develop experimental protocols that may later be applied to human patients. PET may help monitor a patient at the vertebral level after surgery and during adjuvant treatment for recurrent or progressive disease. Common clinical indications for MI of primary or secondary CNS spinal tumors are: (i) tumor diagnosis, (ii) identification of the metabolically active tumor compartments (differentiation of viable tumor tissue from necrosis) and (iii) prediction of treatment response by measurement of tumor perfusion or ischemia. While spinal PET has been used under specific circumstances, a question remains as to whether the magnitude of biochemical alterations observed by MI in CNS tumors in general (specifically spinal tumors) can reveal any prognostic value with respect to survival. MI may be able to better identify early disease and to differentiate benign from malignant lesions than more traditional methods. Moreover, an adequate identification of treatment effectiveness may influence patient management. MI probes could be developed to image the function of targets without disturbing them or as treatment to modify the target's function. MI therefore closes the gap between in vitro and in vivo integrative biology of disease. At the spinal level, MI may help to detect progression or recurrence of metastatic disease after surgical treatment. In cases of nonsurgical treatments such as chemo-, hormone- or radiotherapy, it may better assess biological efficiency than conventional imaging modalities coupled with blood tumor markers. In fact, PET provides a unique possibility to correlate topography and specific metabolic activity, but it requires additional clinical and experimental experience and research to find new indications for primary or secondary spinal tumors.

Predominant influence of MGMT methylation in non-resectable glioblastoma after radiotherapy plus temozolomide.

BACKGROUND: Patients with non-resectable glioblastoma generally exhibit a poor prognosis, even after radiotherapy plus concomitant and adjuvant temozolomide (XRT/TMZ→TMZ). Unfortunately, no data are available concerning the predictive value of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation for this important subpopulation. For clarification, a prospective study was conducted. METHODS: Adult patients with a non-resectable glioblastoma were included. A molecular stereotactic biopsy technique was used for tumour characterisation combining histopathological diagnosis with small sample size adjusted methylation-specific PCR (MSP) and sodium bisulfite sequencing. Treatment included XRT (60 Gy in 30 fractions)/TMZ (daily dose of 75 mg/m(2))→TMZ (150-200 mg/m(2) per day for 5 days of every 28-day cycle). The primary end point was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and treatment response (TR). Patients were categorised in the Radiation Therapy Oncology Group (RTOG)-recursive partitioning analysis (RPA) Classes III (N=4), IV (N=12), V (N=28) and VI (N=12). RESULTS AND DISCUSSION: The success rates of MSP and sequence analyses were 100%. The MGMT promoter was methylated in 30/56 tumours, which was associated with an increased PFS (median 56 versus 20 weeks; hazard ratio 0.15; range 0.07 to 0.33; p<0.0001), higher frequency of TR (93.3% vs 46.2%; p=0.0008) and increased OS (median 104 vs 28 weeks; hazard ratio 0.18; range 0.08 to 0.38; p<0.0001). The transient perioperative morbidity was 1.8%. CONCLUSION: MGMT promoter methylation has a predominant favourable influence even for the important subpopulation with non-resectable glioblastoma. The molecular stereotactic biopsy technique is safe and effective for predictive evaluation and helps to avoid both over- and undertreatment.

The value of the dopamine D2/3 receptor ligand 18F-desmethoxyfallypride for the differentiation of idiopathic and nonidiopathic parkinsonian syndromes.

UNLABELLED: We evaluated the utility of the selective dopamine D(2/3) receptor ligand (18)F-desmethoxyfallypride ((18)F-DMFP) for the differential diagnosis of patients with idiopathic parkinsonian syndrome (IPS) and nonidiopathic parkinsonian syndrome (non-IPS). On the basis of the superior sensitivity of PET, we hypothesized that (18)F-DMFP should have properties for the differential diagnosis of these syndromes superior to what has been reported for the more conventional SPECT procedures. METHODS: A series of 81 patients with parkinsonism (26 women, 55 men; mean age +/- SD, 68 +/- 11 y) were included in this retrospective analysis. A 30-min (18)F-DMFP PET recording was acquired starting 1 h after injection of the tracer (180-200 MBq, intravenously). The specific binding (SB) in divisions of the striatum was calculated relative to the occipital cortex using an observer-independent semiautomatic volume-of-interest-based technique. The optimal SB threshold was defined by means of receiver-operating-characteristic analysis, which was also used for the evaluation of the diagnostic performance of SB, ratios between striatal subregions, and absolute asymmetries in SB. RESULTS: Significant differences (P < 0.001) were found in striatal SB between IPS and non-IPS, most notably in the posterior putamen, for which the diagnostic power for discrimination of IPS and non-IPS was the highest (sensitivity, 87%; specificity, 96%; and accuracy, 91%). A further gain of diagnostic power (sensitivity, 92%; specificity, 96%; and accuracy, 94%) was obtained through discriminant analysis combining 3 parameters: SB of the posterior putamen, the posterior-to-anterior putamen ratio, and the posterior putamen-to-caudate ratio. CONCLUSION: (18)F-DMFP PET is useful for the differential diagnosis of IPS and non-IPS in patients with parkinsonism. The findings are consistent with relative sparing of D(2/3) receptors in the dopamine-denervated putamen of IPS patients, in contrast to a more substantial loss of striatal dopamine receptors in non-IPS patients. The PET procedure for this differential diagnosis was superior to the reported experience with (123)I-iodobenzamide SPECT.

Imaging of integrin alpha(v)beta(3) expression in patients with malignant glioma by [18F] Galacto-RGD positron emission tomography.

Inhibitors targeting the integrin alpha(v)beta(3) are promising new agents currently tested in clinical trials for supplemental therapy of glioblastoma multiforme (GBM). The aim of our study was to evaluate (18)F-labeled glycosylated Arg-Gly-Asp peptide ([(18)F]Galacto-RGD) PET for noninvasive imaging of alpha(v)beta(3) expression in patients with GBM, suggesting eligibility for this kind of additional treatment. Patients with suspected or recurrent GBM were examined with [(18)F]Galacto-RGD PET. Standardized uptake values (SUVs) of tumor hotspots, galea, and blood pool were derived by region-of-interest analysis. [(18)F]Galacto-RGD PET images were fused with cranial MR images for image-guided surgery. Tumor samples taken from areas with intense tracer accumulation in the [(18)F]Galacto-RGD PET images and were analyzed histologically and immunohistochemically for alpha(v)beta(3) integrin expression. While normal brain tissue did not show significant tracer accumulation (mean SUV, 0.09 +/- 0.04), GBMs demonstrated significant but heterogeneous tracer uptake, with a maximum in the highly proliferating and infiltrating areas of tumors (mean SUV, 1.6 +/- 0.5). Immunohistochemical staining was prominent in tumor microvessels as well as glial tumor cells. In areas of highly proliferating glial tumor cells, tracer uptake (SUVs) in the [(18)F]Galacto-RGD PET images correlated with immunohistochemical alpha(v)beta(3) integrin expression of corresponding tumor samples. These data suggest that [(18)F] Galacto-RGD PET successfully identifies alpha(v)beta(3) expression in patients with GBM and might be a promising tool for planning and monitoring individualized cancer therapies targeting this integrin.

Intraindividual comparison of 68Ga-DOTA-TATE and 18F-DOPA PET in patients with well-differentiated metastatic neuroendocrine tumours.

AIM: To compare the diagnostic impact of (68)Ga-DOTA-TATE and (18)F-DOPA PET in the diagnosis of well-differentiated metastatic neuroendocrine tumours (NET). METHODS: PET/CT using both (68)Ga-DOTA-TATE and (18)F-DOPA was performed in 25 patients with histologically proven metastatic NET (nine gut, five pancreas, six lung, one paranasal sinus, four with unknown primary). Analyses of PET examinations were patient-based (pathological uptake: yes/no), and based on tumour regions (primary tumour if present and metastases of liver, lung, bones and lymph nodes). The results were compared with the results of contrast enhanced CT, and with plasma serotonin levels, which were available in 24 of the 25 patients. RESULTS: Patient-based sensitivities were 96% for (68)Ga-DOTA-TATE PET and 56% for (18)F-DOPA PET. (68)Ga-DOTA-TATE PET delineated metastases in 54 of 55 positive metastatic tumour regions in contrast to 29 of 55 delineated by (18)F-DOPA PET. Overall, (68)Ga-DOTA-TATE was superior to (18)F-DOPA in 13 patients (two patients showed fewer positive tumour regions with (18)F-DOPA PET). The results were comparable in 12 patients. In 13 of 24 patients, plasma serotonin levels were elevated, and 11 of these 13 patients showed pathological uptake of (18)F-DOPA. Of the 11 patients with normal levels of serotonin, 3 also showed positive (18)F-DOPA uptake. In patients positive for (18)F-DOPA uptake the maximum tumour SUVs were correlated with the levels of serotonin (r=0.66, p=0.01). CONCLUSION: In this study (68)Ga-DOTA-TATE PET proved clearly superior to (18)F-DOPA PET for detection and staging of NET. (18)F-DOPA uptake tended to be increased in those patients with elevated plasma serotonin. We conclude that (18)F-DOPA PET should be employed in patients with NET with negative (68)Ga-DOTA-TATE PET and elevated plasma serotonin.

[123I] ADAM brainstem binding correlates with the loudness dependence of auditory evoked potentials.

The in vivo assessment of brain serotonergic function might be of clinical relevance in neuropsychiatry. The loudness dependence of auditory evoked potentials (LD) has been proposed as an indirect indicator of cortical serotonergic activity, whereas single photon emission computed tomography (SPECT) and [123I]ADAM allow the selective assessment of brain serotonin transporters (SERT). The aim of this study was to investigate LD and SERT availability as independent variables of the brain serotonergic system in healthy volunteers. Fifteen (six male, nine female) subjects received both neurophysiological and imaging investigations. Evoked potentials were recorded following the application of acoustic stimuli with increasing intensities; the LD was analyzed using dipole source analysis. SPECT was performed four hours after injection of 137 +/- 11.4 MBq [123I]ADAM. As a measure of SERT availability specific ADAM brainstem binding was used. LD correlated significantly with SERT availability (Pearson's correlations: rho = -0.57, p < 0.05). The correlations remained significant after controlling for the effects of age or gender (partial correlations: rho = -0.60, p < 0.05) but were pronounced in the female group (rho = -0.83, p < 0.01). Associations between LD and SERT availability contribute to the understanding of the central serotonergic system and further validate the use of neurophysiological approaches as indirect measures of neurochemical brain activity.

Acute prefrontal rTMS increases striatal dopamine to a similar degree as D-amphetamine.

Prefrontal repetitive transcranial magnetic stimulation (rTMS) has been shown to increase striatal dopaminergic activity. Here we investigated dopaminergic neurotransmission using single photon emission computed tomography (SPECT) and [(123)I]IBZM to indirectly assess the change in endogenous striatal dopamine concentration upon rTMS as compared with d-amphetamine challenge. SPECT imaging was performed twice each in five patients during rTMS, and in two patients who received 0.3 mg/kg D-amphetamine. Administration of rTMS led to a mean relative decrease in striatal IBZM binding by 9.6+/-6.2%, and d-amphetamine challenge (n=4) induced a mean relative reduction by 8+/-2.95% (difference not statistically significant). Acute rTMS challenge showed similar striatal dopaminergic effects to those associated with the administration of d-amphetamine, a substance known to increase synaptic dopamine.

FET PET for the evaluation of untreated gliomas: correlation of FET uptake and uptake kinetics with tumour grading.

PURPOSE: Treatment and prognosis of gliomas depend on their histological tumour grade. The aim of the study was to evaluate the potential of [(18)F]fluoroethyltyrosine (FET) PET for non-invasive tumour grading in untreated patients. METHODS: Dynamic FET PET studies were performed in 54 patients who, based on MRI, were estimated to have low grade (LG; n = 20), intermediate (WHO II-III; n = 4) or high grade (HG; n = 30) tumours. For standard evaluation, tumour SUV(max) and the ratio to background (SUV(max)/BG) were calculated (sum image: 20-40 min). For dynamic evaluation, mean SUV values within a 90% isocontour ROI (SUV90) and the SUV90/BG ratios were determined for each time frame to evaluate the course of FET uptake. Results were correlated with histopathological findings from PET-guided stereotactic biopsies. RESULTS: Histology revealed gliomas in all patients. Using the standard method a statistically significant difference (p = 0.001) was found between LG (n = 20; SUV(max)/BG: 2.16 +/- 0.98) and HG (n = 34; SUV(max)/BG: 3.29 +/- 1.06) gliomas (opt. threshold 2.58: SN71%/SP85%/area under ROC curve [AUC]:0.798), however, with a marked overlap between WHO II to IV tumours. Time activity curves showed slight increase in LG, whereas HG tumours presented with an early peak (10-20 min) followed by a decrease. Dynamic evaluation successfully separated LG from HG gliomas with higher diagnostic accuracy (SN94%/SP100%/AUC:0.967). CONCLUSIONS: Based on the ratio-based method, a statistically significant difference was found between LG and HG gliomas. Due to the interindividual variability, however, no reliable individual grading was possible. In contrast, dynamic evaluation allowed LG and HG gliomas to be differentiated with high diagnostic power and, thus, should supplement the conventional method.

[I-123] ADAM and SPECT in patients with borderline personality disorder and healthy control subjects.

OBJECTIVE: Serotonergic dysfunction is considered to be involved in the pathophysiology of borderline personality disorder (BPD). The aim of this study was to investigate serotonin transporter availability in patients with BPD as a marker of the central serotonergic system. METHODS: Eight unmedicated patients with BPD and 9 healthy control subjects received single photon emission computed tomography (SPECT) 4 hours after injection of 185 MBq [I-123] ADAM (2-([2-([dimethylamino]methyl)phenyl]thio)). As a measure of brain serotonin transporter (SERT) availability, ratios of specific-to-nonspecific [I-123] ADAM binding for the brainstem and hypothalamus were calculated with an occipital reference. Levels of impulsiveness and depressive symptoms were assessed with the Barratt Impulsiveness Scale and the Beck Depression Inventory. RESULTS: Mean specific-to-nonspecific ratios showed a 43% higher brainstem and a 12% higher hypothalamus ADAM binding in patients, compared with control subjects. We found significant correlations of ADAM binding with both age and impulsiveness but not depression. Associations of BIS scores with ADAM binding remained significant after controlling for age and depression (r = 0.69, p < 0.01). CONCLUSION: The study provides evidence of a serotonergic dysfunction in patients with BPD and suggests a serotonergic component in the pathophysiology of the disorder. SERT binding reflected the level of impulsiveness as a common feature in BPD.

Extended studies of the striatal uptake of 99mTc-NC100697 in healthy volunteers.

UNLABELLED: This study evaluates a new formulation of a (99m)Tc-labeled tropane derivate, (99m)Tc-NC100697, in a human volunteer study. METHODS: Eighty healthy subjects (39 females, 41 males) underwent MRI and SPECT (injected dose [mean +/- SD], 10.6 +/- 1.4 MBq/kg). Forty subjects were investigated 30, 90, 180, 240, 360, and 480 min after injection, and another 40 subjects were imaged 240 min after injection. Specific striatal binding was assessed using 3 different approaches: 3-dimensional volumes of interest (VOIs) drawn on the coregistered MRI scans, manually placed predefined 2-dimensional regions of interest (ROIs), and observer-independent fully automated 3-dimensional VOI analyses based on coregistration of scans with a mean template of controls. Specific striatal dopamine transporter (DAT) binding was estimated for cohorts of ages of 21-30, 31-40, 41-50, 51-60, 61-70, and 71-80 y. The relationship between age and DAT binding was analyzed with linear, "broken-stick," exponential, and logarithmic regression. RESULTS: Serial SPECT scans revealed increasing values of specific DAT binding over time. Consideration of all important variables suggests an optimum imaging time at 4 h after injection. Average DAT binding for the total population was 1.1 +/- 0.2 (striatum), 1.3 +/- 0.2 (caudate), and 1.1 +/- 0.2 (putamen), with mean putamen-to-caudate ratios of 0.83 +/- 0.08 (manual 2-dimensional ROI method). A significant age dependency of striatal DAT binding, best described by a broken-stick (break-point age, 48 y) or logarithmic regression (both r = 0.76), with a lower decline observed in older than in younger subjects. Female subjects presented with slightly higher binding ratios than male subjects, more pronounced in pre- than in postmenopausal women. There was a high correlation between the 3 semiquantitative evaluations. CONCLUSION: The current study has demonstrated the effective use of (99m)Tc-NC100697 for estimating presynaptic striatal DAT binding. The comparison of different semiquantification methods showed that in clinical routine work, this tracer can be reliably evaluated without individual MRI data. Age and a slight sex dependency (especially in premenopausal women) of (99m)Tc-NC100697 binding should be taken into consideration. The data generated in this phase 1 study provides a basis for an age- and sex-matched normal database.

Serial O-(2-[(18)F]fluoroethyl)-L: -tyrosine PET for monitoring the effects of intracavitary radioimmunotherapy in patients with malignant glioma.

PURPOSE: Intracavitary radioimmunotherapy (RIT) offers an effective adjuvant therapeutic approach in patients with malignant gliomas. Since differentiation between recurrence and reactive changes following RIT has a critical impact on patient management, the aim of this study was to analyse the value of serial O-(2-[(18)F]fluoroethyl)-L: -tyrosine (FET) PET scans in monitoring the effects of this locoregional treatment. METHODS: Following conventional therapy, 24 glioma patients (5 WHO III, 19 WHO IV) underwent one to five RIT cycles with either (131)I-labelled (n=19) or (188)Re-labelled (n=5) anti-tenascin antibodies. Patients were monitored with serial FET PET scans (2-12 scans). For semiquantitative evaluation, maximal tumoural uptake (TU(max)) was evaluated and the ratio to background (BG) was calculated. Results of PET were correlated with histopathological findings (n=9) and long-term clinical follow-up for up to 87 months. RESULTS: In seven tumour-free patients, PET revealed slightly increasing but homogeneous FET uptake surrounding the resection cavity with a peak up to 18 months following RIT (TU(max)/BG 2.07+/-0.25) but stable or decreasing values during further follow-up (last follow-up: TU(max)/BG 1.63+/-0.22). Seventeen patients developed regrowth of residual tumour/tumour recurrence showing additional nodular FET uptake (TU(max)/BG 2.79+/-0.53). A threshold value of 2.4 (TU(max)/BG) allowed best differentiation between recurrence and reactive changes (sensitivity 82%, specificity 100%). CONCLUSION: FET PET is a sensitive tool for monitoring the effects of locoregional RIT. Homogeneous, slightly increasing FET uptake around the tumour cavity with a peak up to 18 months after RIT, followed by stable or decreasing uptake, points to benign, therapy-related changes. In contrast, nodular uptake is a reliable indicator of recurrence.

Analysis of 18F-FET PET for grading of recurrent gliomas: is evaluation of uptake kinetics superior to standard methods?

UNLABELLED: The aim of the present study was to evaluate whether extended analyses of O-(2-18F-fluoroethyl)-L-tyrosine (FET) uptake kinetics provide results superior to those of standard tumor-to-background ratios in predicting tumor grade in patients with pretreated gliomas. METHODS: Dynamic 18F-FET PET studies (0-40 min after injection of 180 MBq of 18F-FET) were performed on 45 glioma patients with suspected tumor recurrence after multimodal treatment. For the standard method, tumoral maximal standardized uptake value (SUVmax) and the ratio to the background were derived from a summed image 20-40 min after injection. Dynamic data evaluation comprised several approaches: first, SUV within a 90% isocontour threshold (SUV90) and the respective ratio to the background calculated for each time frame between 5 and 40 min after injection; second, the time to peak analysis; and third, various parameters accounting for the individual time course of 18F-FET uptake. Results were correlated with the histopathologic findings of MRI/PET-guided stereotactic biopsies and were evaluated with respect to their discriminatory power to separate low- from high-grade tumors using receiver-operating characteristic (ROC) analyses. RESULTS: The parameters taking into account the individual time course of 18F-FET uptake were able to differentiate low-grade from high-grade recurrent astrocytomas with high diagnostic accuracy, reaching the best differentiation with a sensitivity and specificity of 92% and an area under the ROC curve (AUC) of 0.94. For the other parameters, the respective values were considerably lower (time to peak: 85% sensitivity and 88% specificity; SUV90-to-background ratio for single-frame evaluation of the early-uptake phase: 100% sensitivity, 62% specificity, and 0.81 AUC). The lowest performance was provided by the standard method (SUVmax: 73% sensitivity, 54% specificity, and 0.60 AUC; SUVmax-to-background ratio: 62% sensitivity, 62% specificity, and 0.59 AUC). Time-activity curves (5-40 min after injection) slightly and steadily increased in tumor-free patients and in low-grade tumors, whereas high-grade tumors showed an early peak around 10-15 min after injection followed by a decrease. CONCLUSION: This study has shown differences in the dynamics of 18F-FET uptake between recurrent low- and high-grade gliomas. Therefore, parameters addressing the different kinetic behaviors allow discrimination with high diagnostic power between these 2 prognostically different groups. Thus, the techniques introduced here are clearly superior to the yet most widely used standard method.

Striatal dopamine release after prefrontal repetitive transcranial magnetic stimulation in major depression: preliminary results of a dynamic [123I] IBZM SPECT study.

Though there is considerable evidence that prefrontal repetitive transcranial magnetic stimulation (rTMS) exerts antidepressant effects, the neurobiological action of rTMS in patients with depression is poorly understood. Preclinical studies in animals and humans have demonstrated that prefrontal rTMS can induce dopamine release in mesostriatal and mesolimbic regions. We therefore investigated whether rTMS also modulates striatal dopaminergic neurotransmission in depressed patients using a dynamic [123I] iodobenzamide (IBZM) single photon emission computed tomography (SPECT) approach. Five patients with a major depressive episode (DSM-IV) underwent an acute 10 Hz rTMS challenge with 3000 stimuli over the left dorsolateral prefrontal cortex during an [123I] IBZM-SPECT bolus and constant infusion protocol. In four subjects the protocol was repeated after a three week rTMS standard treatment. Striatal IBZM binding to dopamine D2 receptors was assessed with a region-of-interest (ROI) technique. The change in striatal IBZM binding after the rTMS challenge was regarded as measure of change in endogenous striatal dopamine. Data of nine SPECT investigations showed a significant reduction by 9.6+/-6.2% in IBZM binding to striatal dopamine D2 receptors after rTMS challenge compared to baseline (p=0.01, Wilcoxon test). In this preliminary study, the reduction of IBZM binding observed after rTMS challenge is suggestive of a release in endogenous dopamine induced by prefrontal rTMS. In future, this approach can be used to differentiate specific and non-specific reward-related effects of rTMS on dopaminergic neurotransmission.