Technetium-99m-anti-tumour necrosis factor alpha scintigraphy as promising predictor of response to corticotherapy in chronic active Graves' ophthalmopathy.

It has been suggested that technetium-99m (99mTc)-anti-tumour necrosis factor alpha (TNF-α) scintigraphy (SCI) may be a useful diagnostic tool in Graves' ophthalmopathy (GO). This study evaluated whether orbit total radioactivity uptake on SCI could be used to predict corticosteroid therapy (CorT) responses in active-GO patients. A longitudinal study of patients with active GO defined by Clinical Active Score (CAS) >3/7 was done. Clinical, laboratory and SCI evaluations were performed at baseline and 3 months after concluding intravenous CorT. SCI (planar and tomographic) was assessed after intravenous injection of 10 mCi of 99mTc-anti-TNF-α. Orbits and cerebral hemispheres were defined as regions of interest (ROIs) to enable orbit/hemisphere ROI-ratios of total radioactive uptake. ROI-ratios were considered positive at >2·5. Average total radiation uptake (TRU) was also determined for each orbit (AVGROI ). Clinical, laboratory and SCI data were compared between responders (CAS became inactive) and non-responders to CorT (18 patients). At baseline, AVGROI were higher in active OG orbits (67·3 cps) than in inactive ones (33·6 cps; P<0·05). AVGROI (absolute values) reduced (-29·9 cps) in CorT responders and tended (P = 0·067) to differ from variations occurred in non-responders (+6·9 cps in patients with maintained CAS positivity post-treatment). Higher baseline ROI-ratios (4·9 versus 3·3; P = 0·056) and its pronounced reductions following CorT (-37% versus +56% in non-responders; P = 0·036) tended to be associated with good CorT responses in the subgroup of GO history ≥1 year. SCI showed a good association with active eye disease and may be an additional tool to identify CorT responders.

Efficient Synthesis of Glutamate Peptide-Estradiol Conjugate for Imaging Estrogen Receptor-Positive Diseases.

Molecular imaging of estrogen receptor-positive (ER+) pathway-activated system serves the basis of ER+ disease management such as cancers and endometriosis. ER+ patients have better response to endocrine therapy and survive twice as long as negative ER patients. However, tumor resistance resulting from clinical used aromatase inhibitors and antiestrogens is unpredictable. Radiolabeled ER+ ligand could quantify ER+ tissue uptake which helps to stage and restage of the cancer as well as endometriosis. The differential diagnosis of ER+ lesions by using a labeled ligand helps to select the patients for optimal response to endocrine therapy and to discontinue the treatment when resistance occurs. In addition, radiolabeled ER+ ligand serves as basis for image-guided response follow-up. Glutamate receptors are cell surface receptors which are overexpressed in inflammation and infection. Using glutamate peptide as a drug carrier helps to target intracellular genes via glutamate receptor-mediated process. Reports have shown that polyglutamate is a drug carrier that could alter drug solubility and enhance estrogen receptor-ligand binding pocket. However, polyglutamate was a blend of mixed polymer with a wide range of molecular weight. Thus, the structural confirmation and purity of the conjugates were not optimized. To overcome this problem, the efficient synthesis of glutamate peptide-estradiol (GAP-EDL) conjugate was achieved with high purity. EDL was conjugated site-specific at the first glutamate of GAP. The average cell uptake of 68Ga-GAP-EDL was 5-fold higher than the previous reported synthesis. The efficient synthesis of GAP-EDL has greatly enhanced sensitivity and specificity in cell uptake studies. In vivo PET imaging studies indicated that 68Ga-GAP-EDL could image ER (+) tumors in MCF-7 tumor-bearing mice. Therefore, GAP-EDL makes it possible to image ER-enriched endometriosis and cancer.

Ten-Year Experience with Management of Aortoiliac Aneurysms Using Retrograde Endovascular Internal Iliac Artery Preservation.

BACKGROUND: To evaluate the use of retrograde endovascular internal iliac artery preservation (REIIAP) technique for treating aortoiliac aneurysms. METHODS: We reviewed our database for all patients with aortoiliac aneurysms who underwent REIIAP technique between April 2004 and April 2014. Patients underwent implantation of an Apollo aortomonoiliac (Nano Endoluminal, Florianópolis, Brazil), contralateral implantation of a Viabahn stent graft (Gore Medical, Flagstaff, AZ) positioned from the external iliac artery into the internal iliac arteries as a bridging stent and femorofemoral bypass. The outcomes that we evaluated included technical success, operative mortality and morbidity, endoleak, aneurysm diameter, bridging stent occlusion, and reintervention during follow-up. RESULTS: A total of 21 patients (19 men, mean age 73 ± 2.3 years) were identified. Technical success was achieved in all cases, and none of the patients died during the follow-up (mean follow-up 52 ± 38.5 months). Type IB endoleak was diagnosed in 2 patients, bridging stent occlusion was diagnosed in 1 patient, and reintervention was required for 2 patients. Diameter regression was observed in the aorta (P = 0.15), left common iliac artery (P = 0.37), and right common iliac artery (P = 1.22). CONCLUSIONS: This study demonstrates the feasibility of the REIIAP technique presenting high success rate and similar complication rates compared with other therapeutic options during follow-up. These results demonstrated that it is a useful option for selected patients with aortoiliac aneurysms unfit for other techniques.

Radiopharmaceutical stem cell tracking for neurological diseases.

Although neurological ailments continue to be some of the main causes of disease burden in the world, current therapies such as pharmacological agents have limited potential in the restoration of neural functions. Cell therapies, firstly applied to treat different hematological diseases, are now being investigated in preclinical and clinical studies for neurological illnesses. However, the potential applications and mechanisms for such treatments are still poorly comprehended and are the focus of permanent research. In this setting, noninvasive in vivo imaging allows better understanding of several aspects of stem cell therapies. Amongst the various methods available, radioisotope cell labeling has become one of the most promising since it permits tracking of cells after injection by different routes to investigate their biodistribution. A significant increase in the number of studies utilizing this method has occurred in the last years. Here, we review the different radiopharmaceuticals, imaging techniques, and findings of the preclinical and clinical reports published up to now. Moreover, we discuss the limitations and future applications of radioisotope cell labeling in the field of cell transplantation for neurological diseases.

Rheumatoid arthritis: Nuclear Medicine state-of-the-art imaging.

Rheumatoid arthritis (RA) is an autoimmune disease, which is associated with systemic and chronic inflammation of the joints, resulting in synovitis and pannus formation. For several decades, the assessment of RA has been limited to conventional radiography, assisting in the diagnosis and monitoring of disease. Nevertheless, conventional radiography has poor sensitivity in the detection of the inflammatory process that happens in the initial stages of RA. In the past years, new drugs that significantly decrease the progression of RA have allowed a more efficient treatment. Nuclear Medicine provides functional assessment of physiological processes and therefore has significant potential for timely diagnosis and adequate follow-up of RA. Several single photon emission computed tomography (SPECT) and positron emission tomography (PET) radiopharmaceuticals have been developed and applied in this field. The use of hybrid imaging, which permits computed tomography (CT) and nuclear medicine data to be acquired and fused, has increased even more the diagnostic accuracy of Nuclear Medicine by providing anatomical localization in SPECT/CT and PET/CT studies. More recently, fusion of PET with magnetic resonance imaging (PET/MRI) was introduced in some centers and demonstrated great potential. In this article, we will review studies that have been published using Nuclear Medicine for RA and examine key topics in the area.

Magnetic resonance imaging-radioguided occult lesion localization (ROLL) in breast cancer using Tc-99m macro-aggregated albumin and distilled water control.

BACKGROUND: Magnetic resonance imaging (MRI) guided wire localization presents several challenges apart from the technical difficulties. An alternative to this conventional localization method using a wire is the radio-guided occult lesion localization (ROLL), more related to safe surgical margins and reductions in excision volume. The purpose of this study was to establish a safe and reliable magnetic resonance imaging-radioguided occult lesion localization (MRI-ROLL) technique and to report our initial experience with the localization of nonpalpable breast lesions only observed on MRI. METHODS: Sixteen women (mean age 53.2 years) with 17 occult breast lesions underwent radio-guided localization in a 1.5-T MR system using a grid-localizing system. All patients had a diagnostic MRI performed prior to the procedure. An intralesional injection of Technetium-99m macro-aggregated albumin followed by distilled water was performed. After the procedure, scintigraphy was obtained. Surgical resection was performed with the help of a gamma detector probe. The lesion histopathology and imaging concordance; the procedure's positive predictive value (PPV), duration time, complications, and accuracy; and the rate of exactly excised lesions evaluated with MRI six months after the surgery were assessed. RESULTS: One lesion in one patient had to be excluded because the radioactive substance came back after the injection, requiring a wire placement. Of the remaining cases, there were four malignant lesions, nine benign lesions, and three high-risk lesions. Surgical histopathology and imaging findings were considered concordant in all benign and high-risk cases. The PPV of MRI-ROLL was greater if the indication for the initial MR examination was active breast cancer. The median procedure duration time was 26 minutes, and all included procedures were defined as accurate. The exact and complete lesion removal was confirmed in all (100%) patients who underwent six-month postoperative MRI (50%). CONCLUSIONS: MRI-ROLL offers a precise, technically feasible, safe, and rapid means for performing preoperative MRI localizations in the breast.

Bone-marrow mononuclear cells reduce neurodegeneration in hippocampal CA1 layer after transient global ischemia in rats.

Global cerebral ischemia (GCI) results in death of the pyramidal neurons in the CA1 layer of the hippocampus. In this study we used the four-vessel occlusion (4VO) model of GCI to investigate a potential neuroprotective role of bone-marrow mononuclear cells (BMMCs) transplantation. BMMCs (3×10(7)) were injected through the carotid artery, 1 or 3 days after ischemia (DAI), and the number of cells undergoing degeneration was investigated in brains at 7 DAI. A significant decrease in the number of dying cells was observed in the treated group, compared to animals treated with saline. Biodistribution of the injected cells (1 or 3 DAI) was investigated by (99m)Technetium labeling of the BMMCs and subsequent image analysis 2h after transplantation. In addition, the presence of CellTrace(™)-labeled BMMCs was investigated in tissue sections of the hippocampal area of these transplanted animals. BMMCs treatment significantly reduced the number of FJ-C positive cells in the hippocampal CA1 layer at 7 DAI. We also observed a decrease in the number of activated microglia/macrophage (ED1-positive cells) in the BMMCs-treated group compared with the untreated group. Our data show that BMMCs are able to modulate the microglial response and reduce neurodegeneration in the CA1 layer.

Biodistribution of bone marrow mononuclear cells after intra-arterial or intravenous transplantation in subacute stroke patients.

AIMS: To assess the biodistribution of bone marrow mononuclear cells (BMMNC) delivered by different routes in patients with subacute middle cerebral artery ischemic stroke. PATIENTS & METHODS: This was a nonrandomized, open-label Phase I clinical trial. After bone marrow harvesting, BMMNCs were labeled with technetium-99m and intra-arterially or intravenously delivered together with the unlabeled cells. Scintigraphies were carried out at 2 and 24 h after cell transplantation. Clinical follow-up was continued for 6 months. RESULTS: Twelve patients were included, between 19 and 89 days after stroke, and received 1-5 × 10(8) BMMNCs. The intra-arterial group had greater radioactive counts in the liver and spleen and lower counts in the lungs at 2 and 24 h, while in the brain they were low and similar for both routes. CONCLUSION: BMMNC labeling with technetium-99m allowed imaging for up to 24 h after intra-arterial or intravenous injection in stroke patients.

Bone-marrow cell therapy induces differentiation of radial glia-like cells and rescues the number of oligodendrocyte progenitors in the subventricular zone after global cerebral ischemia.

The subventricular zone (SVZ) is recognized as one of the neurogenic regions in the adult mammalian central nervous system and the presence of cells that share similar characteristics with developmental radial glia, the radial glia-like cells (RGLCs) has been demonstrated in this region. In this study, we investigated whether and how SVZ cells respond to global ischemia and/or to the intravenous transplant of bone-marrow mononuclear cells (BMMCs). Adult rats were subjected to bilateral common carotid ligation (BCCL) and after 1 day 2×10(7) BMMCs or saline injection. The BMMC transplant stimulated a transitory increase in the proliferation of SVZ cells in the BCCL group. We observed a significant increase in the number of RGLCs 3days after ischemia, in both BCCL and BCCL+BMMC groups. However, this increase persisted in the subsequent days only in BCCL animals that received the transplant. BMMC transplantation also inhibits the reduction of NG2-positive oligodendrocyte progenitors in the SVZ observed in the BCCL group. Interestingly, brain-derived neurotrophic factor (BDNF) expression was up-regulated in the SVZ in the treated animals, but not in the other groups. These data thus suggest that BMMC transplantation modulates the phenotype of RGLCs/progenitors in the SVZ and could have a protective role after ischemia.

Intravenous and intra-arterial administration of bone marrow mononuclear cells after focal cerebral ischemia: Is there a difference in biodistribution and efficacy?

Intravascular delivery of cells has been increasingly used in stroke models and clinical trials. We compared the biodistribution and therapeutic effects of bone marrow mononuclear cells (BMMCs) delivered by intra-arterial (IA) or intravenous (IV) injection after cortical ischemia. For the biodistribution analyses, BMMCs were labeled with (99m)Technetium ((99m)Tc). At 2 h, gamma-well counting of the brain and of the other organs evaluated did not show differences between the non-ischemic and ischemic groups or between injection routes, and the organs with the highest uptake were the liver and lungs, with low uptake in the brain. At 24 h, the liver maintained the highest activity, and a marked decrease was seen in pulmonary uptake in all groups. At this time point, although the activity in the brain remained low, the lesioned hemisphere showed greater homing than the contralateral hemisphere, for both the IV and IA ischemic groups. Histological analysis by CellTrace labeling indicated similar homing between both routes in the peri-infarct region 24 h after transplantation and functional recovery was observed in both groups up to 11 weeks after the lesion. In conclusion, transplantation of BMMCs by IA or IV routes may lead to similar brain homing and therapeutic efficacy after experimental stroke.

Biodistribution of bone marrow mononuclear cells in chronic chagasic cardiomyopathy after intracoronary injection.

BACKGROUND: Animal and human clinical studies have indicated that bone marrow (BM) mononuclear cell (MNC) therapy for Chagasic Cardiomyopathy (ChC) is feasible, safe and potentially efficacious. Nevertheless, little is known about the retention of these cells after intracoronary (IC) infusion. METHODS: Our study investigated the homing of technetium-99m ((99m)Tc) labeled BM MNCs and compared it to thallium-201 ((201)Tl) myocardial perfusion images using the standard 17-segment model. Six patients with congestive heart failure of chagasic etiology were included. RESULTS: Scintigraphic images revealed an uptake of 5.4%±1.7, 4.3%±1.5 and 2.3%±0.6 of the total infused radioactivity in the heart after 1, 3 and 24h, respectively. The remaining activity was distributed mainly to the liver and spleen. Of 102 segments analyzed, homing took place in 36%. Segments with perfusion had greater homing (58.6%) than those with decreased or no perfusion (6.8%), p<0.0001. There was no correlation between the number of injected cells and the number of segments with homing for each patient (r=-0.172, p=0.774). CONCLUSIONS: These results indicate that (99m)Tc-BM MNCs delivered by IC injection homed to the chagasic myocardium. However, cell biodistribution was heterogeneous and limited, being strongly associated with the myocardial perfusion pattern at rest. These initial data suggest that the IC route may present limitations in chagasic patients and that alternative routes of cell administration may be necessary.

Migration and homing of bone-marrow mononuclear cells in chronic ischemic stroke after intra-arterial injection.

Cell-based treatments have been considered a promising therapy for neurological diseases. However, currently there are no clinically available methods to monitor whether the transplanted cells reach and remain in the brain. In this study we investigated the feasibility of detecting the distribution and homing of autologous bone-marrow mononuclear cells (BMMCs) labeled with Technetium-99 m ((99m)Tc) in a cell-based therapy clinical study for chronic ischemic stroke. Six male patients (ages 24-65 years) with ischemic cerebral infarcts within the middle cerebral artery (MCA) between 59 and 82 days were included. Cell dose ranged from 1.25x10(8) to 5x10(8). Approximately 2x10(7) cells were labeled with (99m)Tc and intra-arterially delivered together with the unlabeled cells via a catheter navigated to the MCA. None of the patients showed any complications on the 120-day follow-up. Whole body scintigraphies indicated cell homing in the brain of all patients at 2 h, while the remaining uptake was mainly distributed to liver, lungs, spleen, kidneys and bladder. Moreover, quantification of uptake in Single-Photon Emission Computed Tomography (SPECT) at 2 h showed preferential accumulation of radioactivity in the hemisphere affected by the ischemic infarct in all patients. However, at 24 h homing could only distinguished in the brains of 2 patients, while in all patients uptake was still seen in the other organs. Taken together, these results indicate that labeling of BMMCs with (99m)Tc is a safe and feasible technique that allows monitoring the migration and engraftment of intra-arterially transplanted cells for at least 24 h.

Low dosage of 131iodine effects on chromosomes.

The aim of this study was to evaluate the effect on human lymphocyte chromosomes of the (131)I dosage used in scintigraphy on thyroid patients. Until now, there has been as absence of conclusive reports on the effects produced by such dosage. Samples were obtained from 21 patients, and the blood was collected in two occasions: Twenty-four hours prior (control) and after administration of the radionuclide (test). Cells were placed in 1640 RPMI medium with bovine calf serum and incubated with phytohaemagglutinin for 48 and 72 hr at 37 degrees C. Chromosomes were stained with Giemsa Gurr (2 percent, pH = 6.8), and analyzed by two independent investigators by optical microscopy. Of the 6,300 metaphases analyzed from the 48- and 72-hr cultures, 1,146 and 216 gaps and 682 and 52 breaks were found in the test group, respectively. Of the 6,300 metaphases analyzed from the control group, 291 gaps and 119 breaks were observed in the 48-hr cultures whereas in the 72-hr cultures, 10 gaps, and no breaks were found. Our results show that (131)I is responsible for the observed chromosome alterations (paired t-test, p <.05). We suggest re-evaluating the use of (131)I and replacing it with the (123)I, mainly on those patients at fertile age.