New radiopharmaceutical agents for the treatment of castration-resistant prostate cancer.

Prostate cancer (PCa) is the fourth most common cancer worldwide in terms of incidence and third among male, but is becoming the most common cancer in developed countries. In many patients the disease will progress despite of castration levels of testosterone, to become castration-resistant PCa (CRPC). Nearly all patients with CRPC show bone metastases. The treatment of patients with bony metastases has dramatically changed during the past three years because of new therapeutic approaches addressed to obtain pain control, reduced skeletal morbidity, and most importantly, increased survival rate. A possible therapy can be based also on the use of radiopharmaceuticals systemically administered to slow or reverse the bone metastatic progression. In facts bone-homing radiopharmaceuticals are taken up in areas of high bone turnover, including areas with high osteoblastic activity. Recently, a bone targeting radiopharmaceutical, Radium-223 dichloride was added to this group of drugs clearly representing a new generation of radiopharmaceutical in bone therapy. Clinical trials had shown that the treatment with Ra-223 allowed the reduction of the risk of death respect to placebo. No other radiometabolic treatment achieved such result, evidentiating the disease-modifying properties of this bone-homing radiopharmaceutical. In an effort to treat patients with disseminated PCa, who became resistant to hormonal therapy, molecular targets have been recently identified. Prostate specific membrane antigen (PSMA) is one attractive target for diagnosis and therapy of metastasized PCa since its expression levels are directly correlated to androgen independence, metastasis, and progression. Gastrin-releasing peptide receptors (GRPr) are also highly overexpressed in PCa. Numerous studies suggest the possibility of a high PCa-specific signal with radiolabeled bombesin analogs targeting GRPr. Low molecular weight peptides directed against these molecular targets have been radiolabeled with positron emitting radionuclides such as 68Ga in order to improve sensitivity and specificity for detecting primary, metastatic, and recurrent PCa by PET/CT over conventional imaging techniques. Although peptide radionuclide ligand therapy studies have just initiated, the diagnostic relevance of 68Ga labeled specific tracers has already been established its clinical utility and represents a valid tool against this common and deadly cancer.

The widened use of exogenous stimulation with recombinant human TSH to treat metastatic thyroid carcinoma in Italy.

Recently, in Italy, the reimbursement for the use of rhTSH in preparing patients for radiometabolic treatment of iodine-avid metastases from differentiated thyroid cancer has been made possible. Intramuscular administration of rhTSH increases the radioiodine uptake and thyroglobulin production by thyroid cells. In addition to the previous indications on the use of rhTSH (mainly: serum thyreoglobulin assay with or without 131I scintigraphy and ablation with 131I of remnants in low risk patients), the reimbursement is now allowed for the treatment with radioiodine of iodine-avid loco-regional and distant metastases, in subjects with inability to reach adequate TSH levels and/or severe clinical conditions which could be potentially worsened by other concurrent diseases (history of stroke or transient ischemic attack, severe cardiac disease, renal failure or major psychiatric disorders). The Italian Medicines Agency (AIFA) approved this use (and added this hormone in the special list of drugs regulated by the D.Lgs 648/96) on the basis of a series of scientific evidences, proposed by a "team of experts". In the present paper we illustrate the scientific background of the use of rhTSH (clinical usefulness, economic considerations, aspects related to a better quality of life) that allowed the modification of the reimbursement and how it was made possible in the Italian legislative context.

Sestamibi SPECT in the detection of myocardial viability in patients with chronic ischemic left ventricular dysfunction: comparison between visual and quantitative analysis.

BACKGROUND: Technetium 99m sestamibi cardiac scintigraphy is widely used as a means of predicting myocardial viability in patients with chronic ischemic left ventricular (LV) dysfunction. No data are available comparing the results of visual and quantitative analysis of tomographic imaging in the assessment of myocardial viability. The aim of this study was to directly compare visual and quantitative analysis of resting sestamibi single photon emission computed tomography in the identification of viable myocardium in patients with chronic LV dysfunction. METHODS AND RESULTS: Sixty-five patients with an earlier myocardial infarction and LV dysfunction that had occurred within 1 week underwent echocardiography and resting sestamibi SPECT. In each patient, regional tracer distribution was visually assessed and quantitatively measured in 13 segments. Regional LV function was evaluated in corresponding segments by means of echocardiography. All patients underwent revascularization, and echocardiography was repeated 12 months later as a means of assessing the recovery of regional LV function. Among all akinetic or dyskinetic revascularized segments, 66 of 112 viable segments (59%) and 85 of 100 nonviable segments (81%) were identified by means of visual analysis. Eighty-two of 112 viable segments (73%; P<.05 vs. visual analysis) and 74 of 100 nonviable segments (74%; P = .3 vs. visual analysis) were identified by means of quantitative analysis, with a threshold of 55%. Receiver operating characteristic curve areas constructed by using visual and quantitative analyses for the detection of myocardial viability in all 212 akinetic or dyskinetic segments were 0.79+/-0.04 and 0.81+/-0.03, respectively (P = not significant). Overall concordance in the detection of myocardial viability between visual and quantitative analysis was observed in 165 of akinetic or dyskinetic dysfunctional segments (78%), with a kappa value of 0.6. CONCLUSIONS: The results of this study demonstrate that, in patients with chronic myocardial infarction and LV dysfunction, visual and quantitative analysis of sestamibi tomographic images at rest have similar overall accuracy in predicting the recovery of LV function after coronary revascularization procedures.

[Cardiac tomography with 99mTc-tetrofosmin after nitrate administration in patients with ischemic cardiopathy and left ventricular dysfunction]. / Tomografia cardiaca con 99mTc tetrofosmina dopo somministrazione di nitrati in pazienti con cardiopatia ischemica e disfunzione ventricolare sinistra.

PURPOSE: To investigate the role of technetium-99m (99mTc) tetrofosmin single-photon emission Computed Tomography (SPECT) associated with nitrate administration in the detection of hypoperfused but still viable myocardium in patients with chronic coronary artery disease and left ventricular (LV) dysfunction. MATERIAL AND METHODS: Twenty-two patients (mean age 54 +/- 11 years) with coronary artery disease, previous myocardial infarction and LV dysfunction (LV ejection fraction 38 +/- 13%) were examined. On different days all patients underwent 99mTc tetrofosmin (740 MBq) SPECT under control conditions at rest and after sublingual nitroglycerin administration (10 mg). Regional tetrofosmin activity was quantitatively measured in 22 myocardial segments per patient. In each segment, tracer uptake was expressed as a percentage of the region with the peak activity. RESULTS: Under control conditions, 267 myocardial segments (55%) showed normal tetrofosmin uptake (> 70% of peak activity), 107 segments (22%) showed a moderate reduction (51-70%) and 110 segments (23%) a severe reduction (< or = 50%) in tracer uptake. Among the 110 segments with a severe reduction in tetrofosmin uptake, 20 (18%) showed increased tracer uptake > or = 10% of after nitrate administration (from 44 +/- 5% to 58 +/- 3%, p < 0.0001). The remaining 90 (82%) segments with a severe reduction in tetrofosmin uptake did not show any change after nitroglycerin administration (from 38 +/- 9% to 39 +/- 8%, p = ns). CONCLUSIONS: In patients with chronic coronary artery disease and LV dysfunction, tetrofosmin cardiac SPECT associated with sublingual nitrate administration allows the detection of severely hypoperfused but still viable myocardium.

Technetium 99m furifosmin regional myocardial uptake in patients with previous myocardial infarction: relation to thallium-201 activity and left ventricular function.

BACKGROUND: This study was designed to compare the results of rest-redistribution thallium-201 imaging with those of rest technetium 99m furifosmin single photon emission computed tomography in the same patients with chronic ischemic left ventricular (LV) dysfunction. METHODS: Twenty-one patients (mean age 62 +/- 9 years) with chronic myocardial infarction and LV dysfunction (mean LV ejection fraction 34% +/- 8%) underwent rest-redistribution thallium imaging and resting furifosmin single photon emission computed tomography on the same day. In each patient, regional thallium and furifosmin activity was quantitatively measured in 13 myocardial segments. Regional LV function was assessed in corresponding segments by echocardiography. RESULTS: At thallium imaging, 91 (33%) segments had normal uptake, 16 (6%) showed reversible defects, and the remaining 166 (61%) irreversible defects. Of these 166 irreversible defects, 74 (45%) had moderate (> or =58% of peak activity) and 92 (55%) severe (<58% of peak activity) reduction of thallium uptake. Regional furifosmin uptake was significantly related to both rest (r = 0.87, P < .0001) and redistribution (r = 0.90, P < .0001) thallium activity. Agreement in the evaluation of regional perfusion status between thallium and furifosmin imaging was observed in 70% of the 84 hypokinetic segments (kappa = 0.54) and in 76% of the 78 akinetic or dyskinetic segments (kappa = 0.60). Concordance in the detection of myocardial viability between thallium and furifosmin imaging was observed in 69 (82%) of hypokinetic regions (kappa = 0.60) and in 65 (83%) of akinetic or dyskinetic regions (kappa = 0.67). CONCLUSIONS: These results suggest that in patients with chronic coronary artery disease and LV dysfunction, quantitative rest-redistribution thallium scintigraphy and furifosmin tomography at rest provide similar results in the evaluation of perfusion status and in the detection of myocardial viability.

Effect of trimetazidine on 99Tcm-tetrofosmin uptake in patients with coronary artery disease.

Myocardial uptake of 99Tcm-tetrofosmin in vivo is determined by a combination of flow and metabolic status of myocytes. The accumulation of tetrofosmin in the mitochondria is related to their ability to transduce metabolic energy into electronegative membrane potential. Trimetazidine (TMZ), an anti-ischaemic drug, appears to have a metabolic cytoprotective effect related to mitochondrial function, since it does not induce systemic or coronary haemodynamic changes. In this study, we evaluated the effects of TMZ on tetrofosmin uptake in hypoperfused myocardial regions in patients with coronary artery disease (CAD). Twenty-two patients, 14 with previous myocardial infarction (group A) and eight with a history of angina (group B), with angiographically documented CAD were studied. All patients underwent two tetrofosmin SPET studies at rest, before (baseline) and 1 week after TMZ administration (post-TMZ). On quantitative analysis, 131 segments showed less tetrofosmin uptake at baseline. In these segments, tetrofosmin uptake was 51 +/- 13% at baseline and 55 +/- 15% post-TMZ (P < 0.001 vs control). In the 86 hypoperfused segments of group A, tetrofosmin uptake was 48 +/- 14% at baseline and 52 +/- 17% post-TMZ (P < 0.001 vs control). In the 45 hypoperfused segments of group B, tetrofosmin uptake was 56 +/- 9% at baseline and 60 +/- 10% post-TMZ (P < 0.001 vs control). In the remaining 309 segments, no significant difference in tetrofosmin uptake before and after TMZ was observed. In conclusion, our results suggest that TMZ administration may increase myocardial uptake of tetrofosmin in hypoperfused regions at rest in patients with CAD, based on its metabolic effect.

[Heart tomography with 99mTc sestamibi and echocardiography with dobutamine in the identification of reversible left ventricular dysfunction in patients with acute myocardial infarction]. / Tomografia cardiaca con 99mTc sestamibi ed ecocardiografia con dobutamina nell'identificazione della disfunzione ventricolare sinistra reversibile nei pazienti con infarto acuto del miocardio.

INTRODUCTION: We investigated the role of technetium-99m (99mTc) sestamibi cardiac imaging and dobutamine echocardiography in detecting myocardial viability early after acute myocardial infarction. MATERIAL AND METHODS: Nineteen patients (mean age 52 +/- 10 years) underwent coronary angiography, low-dose dobutamine echocardiography and rest 99mTc sestamibi imaging within 10 days of myocardial infarction. All patients were revascularized. Resting echocardiogram was repeated 8 months later to evaluate segmental functional recovery. RESULTS: Sixty-one of 108 akinetic or dyskinetic segments at baseline showed functional recovery after revascularization. Sensitivity in predicting segmental functional recovery was 87% for sestamibi imaging and 66% for dobutamine echocardiography (p < 0.001), while specificity and accuracy were comparable. Sestamibi activity was the strongest predictor of segmental functional recovery (p < 0.001). CONCLUSIONS: Dobutamine echocardiography predicts functional recovery after myocardial infarction. However, sestamibi imaging is useful to identify patients with dysfunctional segments without contractile reserve which may benefit by revascularization.

Gastrointestinal manifestations in children with cerebral palsy.

We describe the prevalence and nature of gastrointestinal (GI) symptoms in 58 children affected by cerebral palsy (range: from 6 months to 12 years of age) referred to a pediatric neurology outpatient clinic. In each patient we assessed (GI) symptoms and defined the associated GI functional or structural abnormalities. Furthermore, we tried to correlate the type of GI dysfunction with findings on computed tomography (CT) or magnetic resonance imaging (MRI) of the brain. Our results showed that 92% of children with cerebral palsy had clinically significant gastrointestinal symptoms. Swallowing disorders were present in 60% of patients, regurgitation and/or vomiting in 32%, abdominal pain in 32%, episodes of chronic pulmonary aspiration in 41% and chronic constipation in 74%. Dysfunction of the oral and/or pharyngeal phase of swallowing was found in 28 of 30 (93%) patients with swallowing disorders. Of the 45 patients with symptoms suggesting gastroesophageal reflux, 41 (91%) had an abnormal pH-monitoring and/or esophagitis. Furthermore, a significant delay in the scintigraphic gastric emptying of liquids was found in 12 of 18 patients (67%) and an abnormal esophageal motility in 11 of the 18 (61%) investigated patients. In 25 patients with chronic constipation evaluation of colonic transit showed a delay at level of the proximal segments of the colon in 13 (52%), at level of the left colon and rectum in 9 (36%) and in 3 (12%) at level of the rectum only. Computed tomography and/or magnetic resonance imaging were normal in 5 (9%) and abnormal in 53 (91%) of the 58 children with cerebral palsy. No GI symptom was significantly associated with any kind of abnormal neuroimaging. In conclusion, children with cerebral palsy exhibited diffuse GI clinical manifestations, mostly due to disorders of GI motility. The GI symptoms seemed not to be related to any specific finding on CT or MRI of the brain.

Effects of 1-year treatment with octreotide on cardiac performance in patients with acromegaly.

The aim of the study was to investigate the effects of 1-yr treatment with octreotide (OCT) on left ventricular diastolic and systolic function, assessed at rest and during physical exercise by gated blood pool cardiac scintigraphy, in 30 patients with active acromegaly. OCT was initially given at a dose of 0.05-0.1 mg, 3 times daily, and the dose was subsequently increased to achieve GH/insulin-like growth factor I (IGF-I) normalization. Hormone normalization after treatment was considered when basal and/or oral glucose test-suppressed GH values were below 2.5 and 1 microg/L, respectively, and IGF-I values were within the normal range for age. To evaluate the response to OCT treatment in terms of cardiac performance, the 30 patients were divided into 2 groups on the basis of normalized (in 13 patients) or nonnormalized (in 17 patients) circulating GH and IGF-I levels. At study entry, hypertension was found in 6 patients (20%), abnormal left ventricular diastolic filling was found in 12 patients (40%), and impaired left ventricular ejection fraction was found in 2 patients at rest (6.6%) and in 18 patients at peak exercise (60%). Before OCT treatment, exercise duration ranged from 6-10 min, and exercise workload ranged from 50-125 watts. After 1-yr treatment with OCT, a significant decrease in circulating GH and IGF-I levels was achieved in all patients, but normalization was obtained only in 13 of 30 patients. In patients achieving circulating GH and IGF-I normalization after OCT treatment but not in those with persistently elevated hormone levels, a significant decrease in heart rate, both at rest (from 75.7 +/- 3.3 to 66.5 +/- 2.9 beats/min; P < 0.01) and after exercise (from 137.5 +/- 4.9 to 123.7 +/- 4.1 beats/min; P < 0.01), and a significant increase in left ventricular ejection fraction, both at rest (from 56.5 +/- 1.8% to 66.5 +/- 2.2%; P < 0.01) and after exercise (from 52.6 +/- 2.4% to 67.1 +/- 1.7%; P < 0.01), were found. In the 17 patients who had persistently high circulating GH and IGF-I levels after 1 yr of OCT treatment, left ventricular ejection fraction was unchanged at rest but was significantly reduced after exercise compared to the basal value (from 64.9 +/- 2.4% to 57.2 +/- 2.6%, P < 0.01); systolic blood pressure at rest was significantly increased (from 128.5 +/- 4.9 to 141.2 +/- 5.4 mm Hg; P < 0.05). In these 17 patients, the ejection fraction response to exercise was significantly impaired, mostly in those less than 40 yr of age (from 11.6 +/- 3.2% to -0.3 +/- 5.6%; P < 0.05). In particular, among 9 patients who had a normal response to exercise at study entry, 6 developed an abnormal response after 1 yr. Left ventricular diastolic filling was unchanged by OCT treatment in all patients. Exercise duration (only in young patients from 7.5 +/- 0.5 to 9.3 +/- 0.7 min; P < 0.05) and exercise workload (in all 13 patients from 80.8 +/- 6.4 to 92.3 +/- 5.9 watts; P < 0.05) were significantly increased in the group of patients with normalized GH and IGF levels, but not in the remaining 17 (from 7.6 +/- 0.4 to 7.5 +/- 0.4 min and from 89.9 +/- 5.5 to 84.4 +/- 4.5 watts, respectively). In conclusion, the results of the present study indicate that suppression of basal or glucose-suppressed GH levels below 2.5 or 1 microg/L, respectively, together with normalization of plasma IGF-I levels for 1 yr are followed by a significant improvement, but not complete normalization, of left ventricular ejection fraction either at rest or at peak exercise without significant changes in diastolic filling. By contrast, the persistence for 1 yr of elevated hormone levels caused a significant increase in systolic blood pressure and impaired cardiac performance. These data suggest that prolonged suppression of circulating GH and IGF-I levels could normalize cardiac performance and probably reverse the poor prognosis for cardiovascular disease in acromegaly.