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.

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.

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.

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.

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.

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.

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.

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.

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.

Is iterative reconstruction an alternative to filtered backprojection in routine processing of dopamine transporter SPECT studies?

UNLABELLED: In general, striatal dopamine transporter (DAT) binding is assessed by use of data reconstructed by filtered backprojection (FBP). The aim of this study was to investigate whether the use of an iterative reconstruction algorithm (ordered-subset expectation maximization [OSEM]) may provide results comparable to or even better than those obtained by standard FBP. METHODS: In 50 patients with parkinsonian syndromes, SPECT scans were acquired 4 h after injection of 185 MBq of (123)I-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ((123)I-FP-CIT) by use of a triple-head gamma-camera fitted with low-energy, high-resolution fanbeam collimators. After reconstruction by FBP and OSEM, data were filtered with a Butterworth filter and corrected for attenuation. Patient studies were automatically fitted to a mean template with a corresponding 3-dimensional (3D) volume-of-interest map covering the striatum, caudate, and putamen as well as an occipital reference region to calculate specific DAT binding. In addition, studies with an anthropomorphic 3D striatal phantom were performed to mimic different pathologies. RESULTS: Visual assessment of phantom and patient data suggested a better separation between the caudate and the putamen in studies reconstructed by OSEM than in those reconstructed by FBP. There was an excellent correlation between specific DAT binding assessed by OSEM and that assessed by FBP (R(2) values: striatum, 0.999; caudate, 0.998; putamen, 0.998). Mean specific striatal binding obtained by OSEM was approximately 6% lower than that obtained by FBP. In no case was diagnostic information from OSEM inferior to that from FBP. CONCLUSION: Iterative reconstruction of (123)I-FP-CIT SPECT studies for the assessment of DAT is feasible in routine clinical practice. A close correlation between FBP and OSEM data suggested that the latter also allow reliable quantification of DAT binding. Because of a better separation between the caudate and the putamen in the visual evaluation, as suggested by phantom and patient studies, OSEM may even be considered the preferable approach.

Selective internal radiation therapy with SIR-Spheres in patients with nonresectable liver tumors.

AIM: Transarterial embolization of branches of the hepatic artery with biocompatible 90Y-labeled microspheres (SIR-Spheres) is a local treatment modality for patients with liver tumors, which, most recently, has become available in Europe. The aim of this study was to evaluate the feasibility and efficacy of this selective internal radiation therapy (SIRT). METHODS: Twenty-three patients with nonresectable hepatic metastases or hepatocellular carcinoma nonresponding to polychemotherapy and/or other local treatment were treated with SIRT. SIR-Spheres (mean activity, 2270 MBq) were administered by gentle intra-arterial infusion in the hepatic artery. A follow-up was documented by fluorodeoxyglucose-positron emission tomography (FDG-PET), course of tumor markers, and computed tomography (CT). RESULTS: Common minor side-effects were abdominal pain, nausea, and fever. Mild pancreatitis and peptic ulceration were observed once each. Currently, all patients are still alive, with survival times ranging from 11 to 518 days from SIRT up to the present. Three-month follow-up investigations are available in 13 of 23 patients, which, so far, are showing a marked decrease of FDG uptake, a drop of tumor markers, and unchanged or slightly decreasing lesion size (CT) in 10 of 13 patients. Two patients showed stable findings, while another patient showed progressive disease. Long-term follow-up investigations are available in 2 of 23 patients, showing hepatic and extrahepatic progression 6 and 9 months after SIRT. CONCLUSIONS: Our initial experience confirms that SIRT is a promising local therapeutic approach in patients with nonresectable liver tumors which is feasible and has an acceptable toxicity profile. Prospective data on comparing this treatment alone or in combination with other modalities are needed to answer whether long-term survival in this unfavorable stage of disease can be markedly improved.

Diagnostic performance of a 3-D automated quantification method of dopamine D2 receptor SPECT studies in the differential diagnosis of parkinsonism.

BACKGROUND: Assessment of post-synaptic D2 receptors with 123I-IBZM SPECT is helpful in distinguishing idiopathic (IPS) from other parkinsonian syndromes (non-IPS). AIM: To evaluate the diagnostic performance of a recently introduced three-dimensional automated quantification method in a large group of parkinsonian patients. METHODS: IBZM SPECT was performed in 101 consecutive patients with IPS (n = 49) and non-IPS (n = 52). Striatal/frontal cortex binding ratios were assessed by a standard manual quantification method and by the automated method. For the latter patient studies were registered to a mean template of healthy controls (n = 13). IBZM binding was calculated from a 3-D volume-of-interest map established on the normal template. The diagnostic performance of the automated and manual approaches were assessed by receiver operating characteristic (ROC) analyses. RESULTS: Specific striatal binding ratios of both quantification methods showed a close linear relationship (y = 0.81x + 0.1188; R2 = 0.8062). At optimal decision thresholds sensitivity and specificity were 87% and 90% for the automated, and 85% and 90% for the manual method, respectively. The area under the ROC curve was 0.92 for the automated and 0.93 for the manual method, showing no statistical difference. The area under the ROC curve corresponding to a false positive fraction from 0% to 20% was 0.163 for the automated and 0.166 for the manual evaluation. CONCLUSIONS: The diagnostic performance of an automated 3-D quantification method for IBZM SPECT studies has been shown to be equal to, or even better than, a standard manual technique. Advantages of automated quantifications are observer independence and fast processing times. This method may be also used as a platform for processing large data sets/multicentre studies in order to objectively evaluate basal ganglia disorders.

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.

Elevated brain serotonin transporter availability in patients with obsessive-compulsive disorder.

BACKGROUND: A central serotonergic dysfunction is considered to be involved in the pathophysiology of obsessive-compulsive disorder (OCD). The aim of this study was to investigate the serotonin transporter availability in patients with OCD as an in vivo marker of the central serotonergic system. METHODS: Nine unmedicated (7 drug-naive) patients with OCD and 10 healthy control subjects were included and received single photon emission computed tomography (SPECT) 20.75 +/- 1.51 hours after injection of a mean 147.20 +/- 6.74 MBq [(123)I]-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([(123)I]beta-CIT). As a measure of brain serotonin transporter availability, a ratio of specific-to-nonspecific [(123)I]beta-CIT binding for the midbrain-pons (V(3)" = [midbrain/pons-occipital]/occipital) was used. RESULTS: Mean specific-to-nonspecific ratios showed a 25% higher midbrain-pons [(123)I]beta-CIT binding in the patients as compared with healthy controls (2.26 +/-.37 vs. 1.81 +/-.23, p <.01). The difference remained significant after adjustment for clinical variables and controlling for age and gender. Stratification of the patients according to onset of the disorder revealed significant differences between controls and patients with early (childhood, adolescence) but not late (adult) onset of OCD. CONCLUSIONS: The study provides evidence of a serotonergic dysfunction in patients with OCD and suggests a serotonergic component in the pathophysiology of the disorder.

Serotonin and dopamine transporter availabilities correlate with the loudness dependence of auditory evoked potentials in patients with obsessive-compulsive disorder.

Brain monoaminergic function is involved in the pathophysiology of psychiatric disorders. The loudness dependence (LD) of the N1/P2 component of auditory evoked potentials has been proposed as a noninvasive indicator of central serotonergic function, whereas single photon emission computed tomography (SPECT) and [123I]beta-CIT can be used to visualize both serotonin (SERT) and dopamine transporters (DAT). The aim of the study was to correlate LD and SPECT measures in patients with obsessive-compulsive disorder, a condition with evidence for a serotonergic dysfunction. A total of 10 subjects received both neurophysiological and imaging investigations. Evoked potentials were recorded following the application of acoustic stimuli with increasing intensities. The LD of the relevant subcomponents (tangential dipoles) was investigated using dipole source analysis. SPECT was performed 20-24 h after injection of a mean 140 MBq [123I]beta-CIT. As a measure of brain SERT and DAT availabilities, a ratio of specific to nonspecific [123I]beta-CIT binding for the midbrain . pons region (SERT) and the striatum (DAT) was used. The LD of the right tangential dipole correlated significantly with both SERT and DAT availabilities (Pearson's correlations: rho = 0.69, p < 0.05, and rho = 0.80, p < 0.01, respectively). The correlations remained significant after controlling for the effects of age, gender, and severity of clinical symptoms. Associations between LD and both SERT and DAT availabilities further validate the use of neurophysiological approaches as noninvasive indirect measures of neurochemical brain function and point at a hypothesized interconnection of central monoaminergic systems.

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.

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.