The combination of vitamins and omega-3 fatty acids has an enhanced anti-inflammatory effect on microglia.

Neuroinflammation is a common phenomenon in the pathology of many brain diseases. In this paper we explore whether selected vitamins and fatty acids known to modulate inflammation exert an effect on microglia, the key cell type involved in neuroinflammation. Previously these nutrients have been shown to exert anti-inflammatory properties acting on specific inflammatory pathways. We hypothesized that combining nutrients acting on converging anti-inflammatory pathways may lead to enhanced anti-inflammatory properties as compared to the action of a single nutrient. In this study, we investigated the anti-inflammatory effect of combinations of nutrients based on the ability to inhibit the LPS-induced release of nitric oxide and interleukin-6 from BV-2 cells. Results show that omega-3 fatty acids, vitamins A and D can individually reduce the LPS-induced secretion of the pro-inflammatory cytokines by BV-2 cells. Moreover, we show that vitamins A, D and omega-3 fatty acids (docosahexaenoic and eicosapentaenoic) at concentrations where they individually had little effect, significantly reduced the secretion of the inflammatory mediator, nitric oxide, when they were combined. The conclusion of this study is that combining different nutrients acting on convergent anti-inflammatory pathways may result in an increased anti-inflammatory efficacy.

Nuclear imaging of prostate cancer with gastrin-releasing-peptide-receptor targeted radiopharmaceuticals.

Prostate cancer is one of the most common causes of cancer in men. Evaluating the different stages of prostate cancer with conventional imaging techniques still proves difficult. Nuclear imaging might provide a technique that is able to evaluate prostate cancer, but clinical application has been limited due to lack of accuracy of current radiopharmaceuticals. The development of radiopharmaceuticals that can be targeted to specific antigens, overexpressed in prostate cancer, but sparse in normal tissue, is crucial. Peptides are of particular interest because of their favourable characteristics, leading to increased attention for nuclear imaging of the gastrin-releasing-peptide-receptor (GRPR) with radiolabelled bombesin-like peptides. Several derivatives of bombesin and its truncated form have been prepared for imaging with single photon emission computed tomography (SPECT) or positron emission tomography (PET), thereby delivering potent candidates for further clinical evaluation. This article provides an overview of the development and preclinical evaluation of radiolabelled bombesin analogues for in vivo targeting of GRPR in prostate cancer. The effect of the radionuclide, chelator, spacer and unnatural amino acids on affinity, metabolic stability and image quality are discussed, as well as agonistic or antagonistic properties. Potent candidates are proposed based on these selection criteria: (I) high affinity for GRPR, with rapid and specific tumour uptake (II) high hydrophilicity resulting in the preferred renal-urinary mode of excretion and low hepatobiliary excretion, (III) high stability, but relatively rapid clearance from blood. Also, a summary is made of clinical studies that report on the detection of prostate cancer with GRPR targeted radiopharmaceuticals.

PET visualization of microglia in multiple sclerosis patients using [11C]PK11195.

Activated microglia are involved in the immune response of multiple sclerosis (MS). The peripheral benzodiazepine receptor (PBR) is expressed on microglia and up-regulated after neuronal injury. [11C]PK11195 is a positron emission tomography (PET) radioligand for the PBR. The objective of the present study was to investigate [11C]PK11195 imaging in MS patients and its additional value over magnetic resonance imaging (MRI) concerning the immuno-pathophysiological process. Seven healthy and 22 MS subjects were included. Semiquantitative [11C]PK11195 uptake values were assessed with normalization on cortical grey matter. Uptake in Gadolinium-lesions was significantly increased compared with normal white matter. Uptake in T2-lesions was generally decreased, suggesting a PBR down-regulation. However, uptake values increased whenever a clinical or MR-relapse was present, suggestive for a dynamic process with a transient PBR up-regulation. During disease progression, an increase of normal-appearing white matter (NAWM) uptake was found, propagating NAWM as the possible real burden of disease. In conclusion, [11C]PK11195 and PET are able to demonstrate inflammatory processes with microglial involvement in MS.

Intra-arterial radionuclide therapy for liver tumours: effect of selectivity of catheterization and 131I-Lipiodol delivery on tumour uptake and response.

Several authors have demonstrated the good tolerance of hepatic intra-arterial 131I-Lipiodol therapy and report survival rates of 21-25% after 1 year in inoperable patients. This study explored the possibility that more selective hepatic arterial instillation could be a strategy for increasing tumoural uptake and response of 131I-Lipiodol. Between June 1999 and September 2001 we selected 24 patients: 14 received a selective instillation of 131I-Lipiodol to the proper hepatic artery (SEL group); and 10 received a hyperselective instillation in the right or left hepatic artery (HYP-SEL group). The individual 131I-Lipiodol activity as a per cent of the injected activity per millilitre of tumour (%IA/ml tumour) was correlated with the selectivity of instillation in 28 tumours and with tumour response in 24 tumours. Differences in tumour response or tumour uptake between the SEL and HYP-SEL groups were not significant. In general, we observed a %IA/ml tumour of 0.05-2.6% for the uptake of 131I-Lipiodol. The uptake was significantly higher in responsive disease than in stable or progressive disease (P=0.002). A large tumour volume was invariably related to low uptake of 131I-Lipiodol and progressive disease (P=0.008). In conclusion, our study does not support the general use of hyper-selective or super-selective intra-arterial administration of 131I-Lipiodol. This result may be extrapolated to similar types of intra-arterial, loco-regional hepatic radionuclide therapy.

Thyroid uptake and radiation dose after (131)I-lipiodol treatment: is thyroid blocking by potassium iodide necessary?

In radionuclide therapy with iodine-131 labelled pharmaceuticals, free (131)I may be released and trapped by the thyroid, causing an undesirable radiation burden. To prevent this, stable iodide such as potassium iodide (KI) can be given to saturate the thyroid before (131)I is administered. The guidelines of the European Association of Nuclear Medicine do not, however, recommend special precautions when administering (131)I-lipiodol therapy for hepatocellular carcinoma. Nevertheless, some authors have reported (131)I uptake in the thyroid as a consequence of such therapy. In this study, the influence of prophylactic KI on the thyroid uptake and dose (MIRD dosimetry) was prospectively investigated. (131)I-lipiodol was given as a slow bolus selectively in the proper hepatic artery or hyperselectively in the right and/or left hepatic artery. Patients were prospectively randomised into two groups. One group received KI in a dose of 100 mg per day starting 2 days before (131)I-lipiodol administration and continuing until 2 weeks after therapy (KI group; n=31), while the other group received no KI (non-KI group; n=37). Thyroid uptake was measured scintigraphically as a percentage of administered activity 7 days after (131)I-lipiodol ( n=68 treatments). The absorbed radiation dose to the thyroid was assessed by scintigraphy after 7 and 14 days using a mono-exponential fitting model and MIRD dosimetry ( n=40 treatments). The mean activity of (131)I-lipiodol administered was 1,835 MBq in a volume of 2 ( n=17) or 4 ( n=51) ml. Thyroid uptake was lower in the KI group, being 0.23%+/-0.06% of injected activity ( n=31) compared with 0.42%+/-0.20% in the non-KI group ( n=37); the mean thyroid dose was 5.5+/-1.6 Gy in the KI group ( n=19) versus 11.9+/-5.9 Gy in the non-KI group ( n=21). These differences were statistically significant ( P<0.001). No effect of the amount of added cold lipiodol (4 vs 2 ml total volume) or selectivity of (131)I-lipiodol administration was evident ( P>0.1). (131)I-lipiodol is associated with a generally low thyroid uptake and dose that may be significantly decreased by KI premedication. Given the low cost and the very good tolerance of the KI treatment, we believe the use of KI should be recommended in the majority of the patients.

Quality of life assessment in radionuclide therapy: a feasibility study of the EORTC QLQ-C30 questionnaire in palliative (131)I-lipiodol therapy.

The good tolerance of radionuclide therapy has frequently been proposed as a major advantage. This study explored the feasibility of using the EORTC QLQ-C30 questionnaire in palliative iodine-131 lipiodol therapy for hepatocellular carcinoma. Questionnaires were completed during interviews in which all symptoms, co-morbidity and medication were assessed at baseline within 1 week before (131)I-lipiodol therapy, and subsequently after 1 and 3 months, in 20 patients treated with locoregional, intra-arterial (131)I-lipiodol therapy with or without cisplatin. Principal observations were that (1) a number of important scales, i.e. overall quality of life, physical functioning and pain, worsened between 0 and 3 months after (131)I-lipiodol therapy, irrespective of tumour response, and (2) the occurrence of clinical side-effects was associated with a negative impact on quality of life and physical functioning 1 and 3 months after (131)I-lipiodol. The QLQ-C30 can be regarded as a feasible method for quality of life assessment in (131)I-lipiodol therapy for hepatocellular carcinoma and possibly in other radionuclide therapies. These observations should be related to the impact of other treatment modalities on quality of life.

Combining iodine-131 Lipiodol therapy with low-dose cisplatin as a radiosensitiser: preliminary results in hepatocellular carcinoma.

A prospective pilot trial was performed in 20 patients randomised to receive either (131)I-Lipiodol therapy alone (n=10) or (131)I-Lipiodol combined with a short low-dose cisplatin infusion (n=10), the aim being to evaluate the possible positive influence of a radiosensitiser on toxicity and tumour response. An activity of 1,354-2,128 MBq (mean 1,824 MBq) [36.6-57.5 mCi (mean 49.3 mCi)] (131)I-labelled Lipiodol was administered by selective instillation in the hepatic artery. Cisplatin was given in a dose of 30 mg/m(2) at day -1 and day +6 (day 0: (131)I-Lipiodol). The primary endpoint of this trial was toxicity of therapy; points of secondary interest were tumour response and survival at 6 months. With the use of cisplatin we found a higher percentage of stable or diminished tumour size (90%, vs 40% without). A benefit in group survival at 6 months was not evident. Low-grade stomatitis in one patient and minor changes in peripheral blood count were probably directly related to cisplatin, but its administration is unlikely to be associated with an excess of serious side-effects. The use of low-dose cisplatin infusion as a radiosensitising agent in (131)I-Lipiodol therapy for hepatocellular carcinoma seems safe and may be beneficial for tumour control. Larger patient groups are necessary for confirmation and to establish the future role of (131)I-Lipiodol in hepatocellular carcinoma.

The anti-tumoral activity of neoadjuvant intra-arterial 131I-lipiodol treatment for hepatocellular carcinoma: a pilot study.

BACKGROUND: The high recurrence rate after curative resection has stimulated the development of adjuvant treatment modalities, such as local embolization. This study was set up to investigate the anti-tumoral potential of neo-adjuvant 131I-lipiodol administration before liver transplantation. METHODS: In this preliminary, prospective study we treated 10 consecutive HCC patients by intra-arterial injection of 131I-lipiodol into the hepatic artery followed by liver transplantation within 1-9 months (mean 3.4). After hepatic catheterization, 1332-2146 MBq (mean 1887 MBq) or 36-58 mCi (mean 51 mCi) was instilled as selective as possible, depending on the distribution of the tumors: non-selectively in the hepatic artery propria (n = 4), selectively in the right and/or left hepatic artery (n = 3) or super-selectively in segmental arteries (n = 3). RESULTS: Anti-tumoral activity was regarded as obvious with 1) a strong decrease of alfa-fetoprotein (AFP), comparing the highest recorded value before and after 131I-lipiodol and/or 2) a downstaging in TNM classification on the posttherapy MRI as compared to the pre-therapy MRI and/or 3) tumors with > 50% necrosis on histo-pathology of the explanted liver, without previous chemoembolization. Either of these criteria were met by 5/10 (50%) of patients. A 4) downstaging in pTNM classification on histopathology compared to the TNM classification of the MRI and/or a 5) tumor necrosis of only 10-50% were regarded as possibly tumor-related but were not accepted as a single criteria of anti-tumoral activity. This was seen in 3/10 (30%) of patients. Clinical side-effects of the 131I-lipiodol therapy were generally mild with a temperature rise in two cases, nausea without vomiting in another two and upper back pain in one patient. In one patient progressive liver failure developed one week after 131I-lipiodol therapy necessitating premature liver transplantation after 4 weeks. CONCLUSION: With the use of stringent anti-tumoral criteria, this study shows evidence of an anti-tumoral effect in 50% of patients. Our data support the evaluation on larger patient numbers to confirm the promising anti-tumoral activity of 131I-lipiodol in HCC patients candidated for liver transplantation.

Patient dosimetry after 131I-MIBG therapy for neuroblastoma and carcinoid tumours.

AIM: The aim of the study was to determine the equivalent total body dose (ETBD) using the cytokinesis-blocked micronucleus assay in 22 131 I-meta-iodobenzylguanidine (131 I-MIBG) therapies (18 neuroblastoma, mean 5097 MBq, SD 1591; and four carcinoid tumours, mean 7681 MBq, SD 487). The results are correlated with the total body radiation dose according to the Medical Internal Radiation Dosimetry (MIRD) formalism. METHODS: For each patient, blood samples were taken immediately before and 1 week after 131I-MIBG therapy. The first blood sample was irradiated in vitro with 60Co gamma-rays to determine the dose-response curve. Micronuclei were scored in 1000 binucleated cells. By using the dose-response curve the ETBD was derived from the increase in micronuclei after 131I-MIBG therapy (second blood sample). Based on three consecutive biplanar scans taken at 3, 6 and 9 days post-administration respectively, the total body dose following the MIRD formalism was calculated. RESULTS: The micronucleus assay was evaluable in only 14 out of 22 131I-MIBG therapies due to cell division inhibition caused by previous chemotherapy treatments and lymphocyte dilution due to blood transfusions given shortly after 131I-MIBG therapy. For these 14 therapies, the mean micronucleus yield after 131I-MIBG therapy was significantly increased (P < 0.01) with a mean of 92 (SD 77) for neuroblastoma patients and with a mean of 35 (SD 8) for carcinoid patients. The increase observed in the present study is greater than previously observed after 131I therapy and 89Sr therapy but much lower than after external beam radiotherapy. For all patients treated with multiple therapies, the initial increase in micronucleus yield had at least partially recovered by the time of the next therapy. This might be explained by an increased turnover of lymphocytes. A mean ETBD of 0.95 Gy (SD 0.55) for neuroblastoma patients and a mean of 0.46 Gy (SD 0.09) for carcinoid patients was calculated. A reasonable correlation (R = 0.87) between the ETBD and the MIRD dose was obtained. The slope value of 0.75 can be explained by the low dose rate effect. CONCLUSIONS: The observation in the present study of important inter-individual variability in the total body dose, with the possibility of high dose values, suggests the necessity of individual dosimetry when administering 131I-MIBG therapy, especially considering that generally more than one therapy is given to each patient.

Vagus nerve stimulation in refractory epilepsy: SPECT activation study.

UNLABELLED: Left-sided vagus nerve stimulation (VNS) is an efficacious treatment for patients with refractory epilepsy. The exact mechanism of action remains to be elucidated. This study investigated the acute effects of initial VNS in patients with refractory complex partial epilepsy with or without secondary generalization (complex partial seizures [CPS] +/- SG) by means of a perfusion activation study with SPECT. METHODS: Twelve patients (mean age, 32.2 +/- 10.2 y; age range, 12-47 y) with a mean duration of CPS +/- SG of 19.8 +/- 10.0 y (range, 5-33 y) received VNS. All patients were considered unsuitable candidates for resective surgery because of nonlocalizing findings on presurgical evaluation. VNS efficacy was evaluated for patients with at least 4-mo follow-up. VNS-induced regional cerebral blood flow alterations were studied by a (99m)Tc-ethyl cysteinate dimer activation study with a single-day split-dose protocol before and immediately after an initial stimulation. Images were acquired on a triple-head camera with fanbeam collimators. After coregistration to a standardized template, both a semiquantitative analysis using predefined volumes of interest and a voxel-by-voxel analysis of the intrasubject activation (statistical parametric mapping) were performed. RESULTS: Seizure-frequency changes ranged from 100% decrease to 0% after VNS. The semiquantitative analysis revealed a consistent decrease of activity in the left thalamus (ratio stimulator on/off = 0.94 +/- 0.04; P = 0.005). These results were concordant with the voxel-by-voxel analysis in which a significant deactivation in the left thalamus was found with spread to the ipsilateral hippocampus. There was no statistically significant correlation between initial VNS-induced thalamic hypoperfusion and seizure reduction at maximum follow-up. CONCLUSION: Our findings are consistent with the hypothesis that acute VNS reduces seizure onset or propagation through inhibition of the thalamic relay center. Differences with limited H2(15)O PET data may be associated with temporal effects caused by a stimulation-induced local hemodynamic response and need further investigation. SPECT allows study of cerebral physiopathologic effects of vagus nerve electrostimulation in complex partial epilepsy.

Acute single photon emission computed tomographic study of vagus nerve stimulation in refractory epilepsy.

PURPOSE: Left-sided vagus nerve stimulation (VNS) is an efficacious treatment for patients with refractory epilepsy. The precise mechanism of action remains to be elucidated. Only limited data on VNS-induced changes in regional cerebral blood flow (rCBF) are available. The aim of this study was to investigate rCBF changes during initial VNS with single-photon emission computed tomography (SPECT). METHODS: In 12 patients (8 women, 4 men) with mean age of 32 years and mean duration of epilepsy of 19 years, VNS-induced rCBF changes were studied by means of a 99mTc-ethyl cysteinate dimer activation study with a single-day split-dose protocol before and immediately after initial stimulation. Images were acquired on a triple-head camera with fan-beam collimators and were reconstructed with scatter and attenuation correction. After coregistration to a standardized template, both a semiquantitative analysis using predefined volumes-of-interest (VOIs) as well as voxel-by-voxel analysis of the intrasubject activation were performed. During follow-up, efficacy of VNS in terms of seizure-frequency reduction was studied. RESULTS: The semiquantitative analysis, with reference to the total counts in all VOIs, revealed a significant decrease of activity in the left thalamus immediately after the initial stimulation train. These results agreed with voxel-by-voxel analysis. In our study ipsilateral thalamic hypoperfusion was the most significant finding. Mean frequency of complex partial seizures was reduced from 30 per month before implantation to six per month after implantation. CONCLUSIONS: VNS induces rCBF changes immediately after initial stimulation that can be studied with SPECT. VNS-induced changes in the thalamus may play an important role in suppression of seizures. However, no significant relation between the level of hypoperfusion and subsequent clinical efficacy was found.

99Tc(m)-ECD SPET perfusion changes by internal pallidum stimulation in Parkinson's disease.

High-frequency stimulation of the internal pallidum is an effective surgical approach for patients with advanced Parkinson's disease suffering from motor fluctuations and L-dopa induced dyskinesia. To study the acute effects of internal pallidum stimulation, changes in cerebral blood flow were measured by means of a single-day split-dose protocol using 99Tc(m)-ECD SPET. Nine patients with advanced Parkinson's disease and with a clinical picture predominated by tremor and drug-induced dyskinesia, were imaged before and immediately after electrostimulation. Brain perfusion data were mirrored to the same electrode side (five left and four right implants), co-registered and analysed statistically on a voxel-by-voxel basis (Statistical Parametric Mapping) and by an automated volume-of-interest approach. Acute stimulation of the internal pallidum induced a significantly decreased perfusion in the ipsilateral thalamus and striatum, as well as in the right parietal cortex. For the subgroup of seven patients with effective motor score improvements, a significant correlation between thalamic and striatal perfusion changes and UPDRS III motor score was present (P = 0.04). These results suggest that effective stimulation of the internal globus pallidus may produce symptom relief through decreased activity in pallido-thalamo-cortical circuits.

Recent and future evolutions in NeuroSPECT with particular emphasis on the synergistic use and fusion of imaging modalities.

Recent and future evolutions in neuroSPECT apply to radiopharmaceuticals techniques and the synergistic use of different imaging modalities in the work-up of neurological disorders. The introduction of Technetium labelled perfusion tracers, which could pass the intact blood-brain barrier, together with the implementation of the tomographic principle, by making the conventional gamma camera rotating, enabled estimation of regional cerebral blood flow and indirectly of local brain metabolism. In addition at present Thallium-201 and Tc-99m sestaMIBI allow functional detection of viable tumor tissue, without interference from previous surgery or radiotherapy as seen using CT-scan or MRI. In neurology this has led to the recognition of SPECT by the American Academy of Neurology (Therapeutics and technology subcommittee) as an established or promising tool in major neurological disorders such as dementia, stroke and epilepsy, while other domains such as brain oncology are considered investigational. With regard to radiopharmaceuticals, recent evolutions mainly include the development of mostly Iodine-123 labelled receptor ligands, some of which are already commercially available. For instrumentation advances consist e.g. of multidetector systems equipped with fanbeam collimators, attenuation and scatter correction or coincidence detection. Given the present role for nuclear neurology it may be expected that these additional radiopharmaceutical and technical innovations will continue to stimulate the development of SPECT of the brain. The synergistic use of several imaging techniques such as CT, (functional) MRI, source imaging, SPECT and PET represents a multimodal holistic approach to probe cerebral functions for research and clinical purposes. Clinical indications, in which this synergistic use is illustrated include e.g. support of the clinical diagnosis of dementia of the Alzheimer type, presurgical ictal detection of seizure focus, detection of acute ischemia and differential diagnosis between radiation necrosis and brain tumor recurrence. The synergistic use of imaging modalities, optimally applied using image fusion, allows to overcome the intrinsic limitations and to enhance the specific advantages of the different approaches as it leads to increased precision and accuracy, as well for spatial anatomofunctional correlation as for quantification.