Clinical indications to the use of (99m)Tc-EDDA/HYNIC-TOC to detect somatostatin receptor-positive neuroendocrine tumors.

The aim of this study was to define, retrospectively, the utility to perform (99m)Tc-EDDA/HYNIC-Tyr3-octreotide ((99m)Tc-EDDA/HYNIC-TOC) scan in patients with NET. We studied 50 consecutive patients affected by different types of NET and divided in two groups. Group 1: 34 patients with known lesions in which (99m)Tc-EDDA/HYNIC-TOC was performed for staging, characterisation or to choose the appropriate treatment. Group 2: 16 patients suspected of having NET or in follow up after surgery. Patients were injected with 370 MBq of (99m)Tc-EDDA/HYNIC-Tyr3-octreotide and whole-body and SPET images acquired 2-3 hours after injection. Overall, 29 patients (58%) had a positive scan, with a sensitivity, specificity and accuracy of 70.3%, 76.9% and 72%, respectively (78.1%, 50% and 76.5%, in group 1 and 20%, 81.2%, 62.5% in group 2). In patients from group 1 (99m)Tc-HYNIC-TOC scintigraphy showed a concordance of 68% with another imaging procedure and in 9 patients revealed a greater number of lesions. In the second group, false negative results were especially found in patients with medullary thyroid cancer with negative radiological findings and elevated calcitonin. In conclusion, (99m)Tc-EDDA/HYNIC-TOC is highly indicated for in vivo histological characterization of known NET lesions, previously identified by other imaging modalities or biopsy, to plan appropriate therapy especially for patients with inoperable disease. In patients with only biochemical suspicion of NET and in those with negative markers, this scintigraphy does not significantly modify the clinical management.

Endoscopic banding for esophageal variceal bleeding: technique and patient outcome.

AIM: Endoscopic variceal ligation (EVL) is recommended for the treatment of esophageal variceal bleeding. The aim of this study was to assess the most cost-effective timing of endoscopic follow-up after variceal eradication. METHODS: Cirrhotics with esophageal varices treated between January 2008 and January 2009 until reached variceal obliteration were retrospectively analyzed for technical aspects and for outcomes. RESULTS: Out of 127 patients treated with EVL, 103 were included. Number of sessions to achieve variceal obliteration and number of bands for each session were 2.8±1.3 (range 1-7) and 4.6±1 (range 2-7), respectively. The placement of >5 bands per session was not associated with higher incidence of complications (19.6% vs. 17.8%, P=ns). Esophageal ulcers were observed in 42% of patients when the interbanding interval was <20 days (versus 15% for interval >20 days, P<0.05). Once obliteration was achieved, varices reappeared in 28% of patients; the early appearance of small varices was not associated with bleeding. CONCLUSION: A longer interbanding interval reduces the incidence of procedural-related complications. After variceal obliteration an early endoscopic control is not useful because it does not influence the approach and does not change the patient outcome.

Midodrine in the prevention of hepatorenal syndrome type 2 recurrence: a case-control study.

BACKGROUND: Hepatorenal syndrome is a severe complication of cirrhosis. Treatment with terlipressin has currently the best efficacy pedigree, inducing hepatorenal syndrome reversal in a high proportion of patients. However, hepatorenal syndrome recurrence after terlipressin withdrawal is very common, especially in type 2 hepatorenal syndrome. Midodrine, an oral adrenergic vasoconstrictor, has been suggested to be an effective therapy in hepatorenal syndrome. AIMS: To analyse the impact of treatment with midodrine after hepatorenal syndrome type 2 reversal induced by terlipressin on the prevention of hepatorenal syndrome recurrence. PATIENTS AND METHODS: A case-control design was used. The outcome of 10 patients with hepatorenal syndrome type 2 treated successfully with terlipressin and then with midodrine (7.5-12.5mg/tid) was compared with that of an historical control group of hepatorenal syndrome type 2 patients responders to treatment with terlipressin. Patients and controls were matched by age, plasma renin activity (PRA) levels and severity of renal and liver failure. RESULTS: Cases and controls were similar with respect to pre-treatment with terlipressin. The hepatorenal syndrome recurrence probability was the same in the two groups (cases and control: 9/10, 90%, p=ns). No significant differences were found between cases and controls with respect to serum creatinine (1.9+/-0.1mg/dl vs. 2+/-0.2mg/dl), blood creatinine clearance (28+/-5ml/min vs. 24+/-5ml/min), urinary sodium excretion (12+/-6mequiv./d vs. 19+/-4mequiv./d) and PRA levels (17+/-3ng/ml/h) vs. 20+/-3ng/ml/h) after terlipressin withdrawal (p=ns). CONCLUSIONS: These results show that in patients responders to terlipressin hepatorenal syndrome recurrence is not different between patients treated with midodrine and subjects who did not receive vasoconstrictor treatment after terlipressin withdrawal. These data suggest that midodrine is not effective in preventing hepatorenal syndrome type 2 recurrence.

Pancreatic scintigraphy with 99mTc-interleukin-2 at diagnosis of type 1 diabetes and after 1 year of nicotinamide therapy.

BACKGROUND: To evaluate the clinical utility of pancreatic scintigraphy with 99mTc-interleukin-2 to identify Type 1 diabetic patients with pancreatic inflammation at diagnosis. METHODS: 99mTc-interleukin-2 scintigraphy was performed on 42 newly diagnosed Type 1 diabetic patients, before and after 1 year of treatment with nicotinamide (25 or 50 mg/kg/day) in addition to intensive insulin therapy. Metabolic status was monitored every 3 months for 1 year. Sixteen normal subjects were studied as control. RESULTS: Significant pancreatic accumulation of 99mTc-interleukin-2 was found in 31% of the patients at the time of diagnosis. Patients positive or negative for pancreatic accumulation of interleukin-2 scintigraphy did not show any difference in metabolic or immunologic parameters at diagnosis. Positive patients, however, showed higher C-peptide values at 3 months and lower insulin requirement at 1 year, compared to negative patients (insulin requirement (IR): 0.33+/-0.11 vs 0.67+/-0.24 IU/kg/day, positive vs negative patients; p=0.0001); patients positive to IL2 scintigraphy treated with nicotinamide at 25 mg/kg were the only group showing a significant reduction in IR 1 year after diagnosis (IRt0: 0.53+/-0.30 vs IRt12: 0.28+/-0.07 IU/kg/day; p=0.013). After 1 year, all the positive patients showed a significant decrease in pancreatic uptake of 99mTc-interleukin-2 (P/B: 7.87+/-2.28 at diagnosis vs 5.00+/-1.23 after 1 year; p<0.0001 paired t-test). CONCLUSION: 99mTc-interleukin-2 scintigraphy at diagnosis of Type 1 diabetes may identify patients with pancreatic inflammation. In such patients, treated with nicotinamide at 25 mg/kg, insulin requirement and pancreatic inflammation after 1 year were significantly reduced suggesting that IL2 scintigraphy may be of potential use for assessing the autoimmune phenomena in endocrine pancreas.

Noradrenalin vs terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded, pilot study.

BACKGROUND/AIMS: Treatment of hepatorenal syndrome (HRS) is based on vasoconstrictors. Terlipressin is the one with the soundest evidence. Noradrenalin has been suggested as an effective alternative. The current study was aimed at assessing the efficacy and safety of noradrenalin vs terlipressin in patients with HRS. METHODS: Twenty-two consecutive cirrhotic patients with HRS (9 with HRS type 1; 13 with HRS type 2) were included. Patients were randomly assigned to be treated with noradrenalin (0.1-0.7 microg/kg/min) and albumin (10 patients) or with terlipressin (1-2 mg/4h) and albumin (12 patients). Treatment was administered until HRS reversal or for a maximum of two weeks. Patients were followed-up until liver transplantation or death. RESULTS: Reversal of HRS was observed in 7 of the 10 patients (70%) treated with noradrenalin and in 10 of the 12 patients (83%) treated with terlipressin, p=ns. Treatment led in both groups to a significant improvement in renal and circulatory function. No patient developed signs of myocardial ischemia. CONCLUSIONS: Data from this unblinded, pilot study suggest that noradrenalin is as effective and safe as terlipressin in patients with HRS. These results would support the use of noradrenalin, a cheap and widely available drug, in the management of these patients.

High resolution small animal single photon emission computed tomography: uptake of [99mTc]bombesin and [123I]ioflupane by rat brain.

AIM: The aims of this study were: 1) to perform brain single photon emission computed tomography (SPECT) in anesthetized rats with high resolution cameras (HRC) equipped with parallel hole collimation resolution of about 1 mm (HRC1) and 2 mm (HRC2); 2) to assess when and with which radio-tracer HRC1 SPECT shows advantages over HRC2. METHODS: We used two multicrystal HRCs with parallel square hole collimators, whose pure tungsten septa closely fit the crystals, in turn matched with a 4 inch2 position sensitive photomultiplier. HRC1 showed 1.1 mm and HCR2 2.1 mm resolution at collimator contact. HRCs performed 180 degrees semi-circular orbits around the head of rats: image reconstruction occurred with ordered subsets expectation maximization algorithms. Resolution of SPECT was measured with a Derenzo Phantom, resulting 1.4 mm for HRC1 and 2.3 mm for HRC2. Three rats were studied with [(99m)Tc]HMPAO, 3 rats with [(99m)Tc]bombesin (BN) and 48 h later with [(123)I]ioflupane (DaTSCAN). SPECT studies were reviewed by two experienced operators. RESULTS: Technetium-99m-HMPAO SPECT showed similar images with HRC1 and HRC2. The uptake of BN by amygdale, hippocampus and olfactory tract was detected by both cameras. DaTSCAN SPECT with HRC1 showed detailed image of the tail of the caudatus: this image was not obtained with HRC2. DaTSCAN and BN SPECT showed amygdale with both HRCs. However, only the central nucleus of amygdale takes up DaTSCAN, whereas central, lateral and basolateral amygdaloid nuclei express BN receptors. Only HRC1 SPECT showed amygdale larger with BN than with DaTSCAN. CONCLUSION: Spatial resolution of 1.4 mm is appropriate to detect selected subcerebral structures.

Use of a 99mTc labeled anti-TNFalpha monoclonal antibody in Crohn's disease: in vitro and in vivo studies.

AIM: Crohn's disease (CD) is a chronic inflammatory bowel disease characterized by a cellular-mediated immune response driven by cytokines secreted mainly by T helper 1 cells (Th1). In active phases of the disease, an increased production and release of tumor necrosis factor a (TNFalpha) by macrophages and monocytes of the lamina propria has been described. The aim of this study was to detect the presence of TNFalpha within the gut mucosa in patients with active CD by using (99m)Tc-labelled chimeric human/mouse monoclonal antibody anti-TNFalpha (Infliximab, Remicade). METHODS: Infliximab has been labeled with (99m)Tc after reduction of disulfide bound by 2-ME method. In vitro binding assay and biodistribution in animal of [(99m)Tc]Infliximab has been performed to evaluate the retention of its biological activity. Ten patients with active CD refractory to conventional medical therapies were studied. Images of the abdomen were acquired at 6 to 20 h after i.v. injection of about 10 mCi of [(99m)Tc]Infliximab and a week later, all patients were also studied with [(99m)Tc]HMPAO-labeled autologous white blood cells (WBC). RESULTS: A product with high labeling efficiency (>95%) and stability has been obtained. In vitro tests with stimulated T-cells expressing TNFalphalpha indicated that [(99m)Tc] Infliximab retains its binding activity to cell bound TNFalpha as compared to unlabelled Infliximab. The degree of [(99m)Tc]Infliximab uptake by the inflamed bowel evaluated at 20 h postinjection was much less than that seen with labeled WBC and with a different distribution. Three of these patients received anti-TNFalpha (Infliximab) for therapeutic purposes with good clinical results despite the scintigraphy with (99m)Tc-Infliximab was negative in 2 of them. CONCLUSION: Scintigraphy with [(99m)Tc]Infliximab shows the presence of little TNFalpha in the affected bowel of patients with active CD. Therefore, the clinical benefit that patients have from Infliximab therapy is unlikely the consequence of a local a reduction of TNFalpha and the mechanism of action of Infliximab, in therapeutic doses, deserves further investigations.

New radiopharmaceuticals for imaging rheumatoid arthritis.

Rheumatoid arthritis (RA) is an incapacitating chronic inflammatory disease of the joints that, because of frequent relapses, requires life-long treatment. In patients affected with RA an important treatment objective is to achieve specific immune suppression in order to extinguish the immune process and arrest the disease, thus preventing or delaying complications and avoiding disease recurrence. The side effects of anti-inflammatory drugs given to improve the quality of life of these patients can be reduced with the use of specific immune therapies that block, as selectively as possible, the pathologic mechanism responsible for the disease. New therapeutic options for specific, targeted therapies for treating RA are being developed, and trials to assess the efficacy and safety of these approaches are underway. However, these therapies rely primarily on clinical assessment to evaluate treatment efficacy. It would be useful, therefore, to have an objective and reliable method that directly highlights the immune processes underlying the disease. Currently available radiopharmaceuticals for imaging RA, with a special emphasis on recently developed agents and their use in therapy decision-making and follow-up are the focus of this article.

Receptor targeting agents for imaging inflammation/infection: where are we now?

Over the past 20 years, radiopharmaceutical research has brought to market a wide variety of drugs that aid in the management of infection and inflammation. Finding the best clinical application for existing radiopharmaceuticals can be a challenging task, as clinicians now have to choose from an array of many different radiopharmaceuticals, each suited to identify a specific type of inflammation. With this review, we describe the features of receptor-targeting agents and present the main advantages and limitations to their application in the diagnosis of inflammation and infection. The receptor-specific agents described here include peptides and antibodies as well as radiolabeled antibodies employed for the specific targeting of neutrophils, bacteria, lymphocytes, and molecules involved in inflammatory processes. Because these agents bind to specific receptors, they allow the mapping of receptor expression in vivo. Such mapping represents the future of nuclear medicine imaging, as it aids in diagnosing the type of inflammation, in therapy decision-making, in selecting suitable candidates for therapy, and in evaluating treatment efficacy.

An in vitro study to compare 99mTc-stannous colloids and 99mTc-HMPAO for labelling human leukocytes.

AIM: Aim of the present study was to compare in vitro the labelling efficiency (LE) and cell viability (TBE) of autologous leukocytes labelled with (99m)Tc-SnF(2) and (99m)Tc-HMPAO, and to evaluate the quantity and quality of spontaneously released (99m)Tc (SR) from labelled cells at several time points after labelling. METHODS: A total of 14 patients with different diseases and 18 normal subjects were included in this study. A blood sample was collected from each patient; purified autologous leukocytes were divided into 2 samples and labelled with (99m)Tc-SnF(2) and (99m)Tc-HMPAO. LE was evaluated at the end of labelling and TBE and SR were evaluated at 10 min and 1 h, 2 h and 4 h after labelling. RESULTS: LE of (99m)Tc-SnF(2)-WBC was higher than (99m)Tc-HMPAO-WBC (61.2+/-18.7% and 43.3+/-11.3; p<0.0001) and we found an inverse correlation between blood glucose and labelling efficiency for both methods (p=0.02). Minimal differences were also observed between 2 methods after 10 min and 1 h, as far as the cell viability is concerned. The percentage of radioactivity spontaneously released from (99m)Tc-SnF(2)-WBC was significantly higher compared to (99m)Tc-HMPAO-WBC at each time point. Radioactivity released from labelled cells was predominantly (99m)Tc-SnF(2) and (99m)Tc-HMPAO with few free (99m)Tc (<20%). CONCLUSION: Both radiopharmaceuticals are not toxic for WBC. Labelling with (99m)Tc-SnF(2) give a higher LE than with (99m)Tc-HMPAO; however, radiolabelled colloids are more released from labelled cells over a period of 4 h. While (99m)Tc-HMPAO is physiological excreted into gastrointestinal tract, (99m)Tc-SnF(2) can be re-uptaken in vivo by reticulo-endothelial cells of liver and spleen. These findings suggest that (99m)Tc-SnF(2)-WBC might be better than (99m)Tc-HMPAO-WBC for studying inflammatory bowel diseases.

The developing role of peptide radiopharmaceuticals in the study of chronic inflammation: new techniques for novel therapeutic options.

Chronic inflammatory diseases usually lead to fibrosis of the target organ and consequent hypo function. They are often relapsing, invalidating and require life-long treatment. In this class of patients it is very important to try and achieve specific immune suppression to extinguish the immune process with the aim of preventing the disease, preventing or delaying complications and avoiding disease relapse, often requiring surgical intervention. It is important that, while attempting to improve the quality of life of these patients by means of anti-inflammatory drugs, side effects are reduced to a minimum via the use of specific immune therapies that block as selectively as possible the pathologic mechanism responsible for the disease. New therapeutic options are being developed for specific targeted therapies. Several trials are being performed to assess the efficacy and safety of this approach. All of them, however, rely on the clinical assessment of the patients to evaluate the effect of treatment. It would be important to use an objective and reliable method to highlight directly the immune process underlying the individual disease. This manuscript reviews the radiopharmaceuticals available or recently developed for imaging chronic inflammatory diseases and their use for therapy decision making and follow-up.