Peptide receptor radionuclide therapy in patients with metastatic progressive pheochromocytoma and paraganglioma: long-term toxicity, efficacy and prognostic biomarker data of phase II clinical trials.

BACKGROUND: Pheochromocytoma and paraganglioma (PPGL) have currently only limited treatment options available for patients in the metastatic phase (mPPGL) in either post-surgery or inoperable settings. However, these rare tumors overexpress somatostatin receptors and can thus be treated with peptide receptor radionuclide therapy (PRRT). We present data about our 10-year experience treating 46 consecutive mPPGL patients with 90Y-DOTATOC or 177Lu-DOTATATE. PATIENTS AND METHODS: All patients (20 men and 26 women, median age 52 years) showed positive scintigraphic imaging at 111In-octreotide or 68Ga-DOTATOC positron emission tomography/computed tomography (PET/CT). 90Y-DOTATOC was administered in 12 patients, with cumulative dosages ranging from 7.4 to 11 GBq, while 34 patients received 18.5 or 27.5GBq of 177Lu-DOTATATE. We used Southwest Oncology Group Response Evaluation Criteria in Solid Tumors criteria to evaluate treatment efficacy and Common Terminology Criteria for Adverse Events criteria to assess toxicity. The prognostic role of primary tumor site, hormone secretion, succinate dehydrogenase (SDHx) mutation, and metastatic involvement was also evaluated. RESULTS: Both 90Y-DOTATOC and 177Lu-DOTATATE PRRT were well tolerated by patients without significant renal or bone marrow toxicity. The median follow-up was 73 months (range 5-146 months). The overall disease control rate (DCR) was 80% [95% confidence interval (CI) 68.9% to 91.9%] with a mean five cycles of therapy. However, 177Lu-DOTATATE patients showed a longer median overall survival (mOS) than those receiving 90Y-Dotatoc and a better DCR when higher dosages were administered, even if a direct comparison was not carried out. Syndromic patients had a poorer mOS. SDHx mutations did not interfere with treatment efficacy. CONCLUSIONS: PRRT is safe and effective for the treatment of patients with progressive mPPGL, especially at higher dosages. The longer mOS of 177Lu-DOTATATE-treated patients in our protocols indicates the former radiopharmaceutical as the better candidate for further clinical application.

Impact of imaging protocol on left ventricular ejection fraction using gated-SPECT myocardial perfusion imaging.

BACKGROUND: There are limited data on the impact of the imaging protocol (single-day stress-rest, SD, vs. dual-day, DD) on the change in left ventricular (LV) ejection fraction (EF) (post-stress-rest) in relation to ischemia and on outcome. METHODS: Using propensity score matching procedure, 490 of 1121 patients with known CAD, undergoing a SD or a DD in a multicenter study, were evaluated. Stress and rest gated-SPECT myocardial perfusion imaging was used to quantify LV perfusion, EF, and volumes. Outcome was assessed at an average follow-up time of 3.2 years. RESULTS: Post-stress LVEF in SD and DD were comparable across all degrees of ischemia. The change in LVEF in patients with severe ischemia was, however, higher in the DD protocol, independent of the extent of CAD. At follow-up, 240 patients (49.0%) required coronary revascularization (CR) and 52 patients (10.6%) had hard events. The ischemic burden was independently associated with CR and hard-events; the post-stress LVEF was associated with CR but the change in EF was not predictive of either CR or hard events. CONCLUSIONS: In patients with severe ischemia, underestimation of post-stress myocardial stunning could be observed with the SD protocol. Post-stress LVEF and the extent ischemia, but not the change in EF, are predictive of CR and hard events.

A multicentre observational study of radionuclide therapy in patients with painful bone metastases of prostate cancer.

A multicentre observational study was conducted by the Italian Association of Nuclear Medicine between 1996 and 1998. Twenty-nine Nuclear Medicine Departments participated. The aims of the study were to systematically evaluate the efficacy, toxicity and repeatability of radionuclide therapy of painful bone metastases (RTBM) in a large number of patients and to assess its incidence in patients with prostate cancer. Out of 818 treatments performed with a single i.v. dose of 148 MBq of strontium-89 chloride or 1,295 MBq of rhenium-186 hydroxyethylidene diphosphonate (HEDP), 610 could be evaluated (527 with 89Sr and 83 with 186Re-HEDP). Eighty-one patients received multiple (up to five) RTBM. The total number of retreatments was 100. Patients were followed up for a period of 3-24 months. Results, assessed according to pain relief and consumption of analgesic drugs, were expressed at four levels: 1, no response; 2, mild response; 3, good response; 4, excellent response. Responses were: level 1 in 19%, level 2 in 21.3%, level 3 in 33.3% and level 4 in 26.4% of cases. Retreatments showed significantly (P<0.01) worse responses (48% levels 3+4), in comparison to first RTBM. Duration of palliation was 5.0+/-3.5 months, and was longer in cases of excellent response, in first RTBM, in patients with limited metastases and when 89Sr was used. Better responses were found in cases of limited skeletal disease, under good clinical conditions, when life expectancy exceeded 3 months, and in radiologically osteoblastic or mixed bone lesions. The only statistically significant predictive factor was life expectancy (P<0.001). Flare phenomenon (14.1% of cases) did not correlate with the response. Haematological toxicity (mild to moderate in most cases) mainly affected platelets, and was observed in 25.5% of cases overall and in 38.9% of retreatments. RTBM did not seem to prolong life, though in some cases scintigraphic regression of bone metastases was observed. The two radiopharmaceuticals did not show any statistically significant differences in palliative efficacy and toxicity, either in first RTBM or in retreatments.

Underestimation of regional myocardial perfusion with Tc-99m sestamibi single-day rest-stress SPECT: a "drug washout" pitfall?

Myocardial perfusion scintigraphy with a Tc-99m sestamibi single-day SPECT protocol is a widely used technique to examine patients with possible or known coronary artery disease. A 76-year-old man with a clinical history suggestive of ischemic heart disease underwent Tc-99m sestamibi myocardial SPECT imaging with a same-day rest and stress protocol after temporary discontinuation of his current therapy, which included calcium channel and beta blockers and nitrates. The scintigraphic pattern was consistent with an asymptomatic infarction of the posterolateral myocardial wall and periinfarct ischemia. One week later, the patient had a Tc-99m sestamibi myocardial SPECT study at rest without discontinuing therapy, and scintigraphic images showed normalization of the posterolateral wall perfusion defect. The angiographic study showed a 90% stenosis of the circumflex artery. This case suggests that, during a 1-day cardiac SPECT protocol, washout of therapeutic pharmaceuticals may be responsible for underestimation of myocardial rest perfusion in territory supplied by a coronary artery with a critical stenosis.

New insights on flow-independent mechanisms of 99mTc-HMPAO retention in nervous tissue: in vitro study.

UNLABELLED: SPECT using 99mTc-hexamethyl propyleneamine oxime (HMPAO) mainly reflects regional cerebral blood flow, however metabolic abnormalities also affect the retention of 99mTc-HMPAO. METHODS: To rule out any flow factor, a test-tube model was used to evaluate the effects of metabolic alterations both on intracellular trapping of 99mTc-HMPAO and on extracellular glutamate and lactate dehydrogenase (LDH) outflow from rat brain slices. RESULTS: Under control conditions, slices took up 7.0%+/-1.4% of 99mTc-HMPAO contained in the medium, whereas prelabeled slices released 10.8%+/-2.6% of their radioactive content; glutamate and LDH outflow were 49.1+/-21.6 pmol/mg protein/ min and 4.8+/-0.9 U/L/mg protein/min, respectively. The control medium was altered by adding a metabolic poison (5 mmol/L azide), removing glucose and replacing O2 with N2 to mimic ischemia (in vitro ischemia) and replacing Krebs solution with hypotonic medium to evoke cell lysis. Both azide and in vitro ischemia induced a significant increase in 99mTc-HMPAO release (15.8%+/-3.3% and 18.3%+/-6.2%, respectively), without any modification in LDH efflux. However, only azide reduced the uptake of the tracer. Conversely, glutamate outflow was massive during in vitro ischemia and was far lower during azide treatment. Under hypotonic medium conditions, the release of 99mTc-HMPAO, glutamate and LDH were dramatically increased. Surprisingly, a two-fold increase of 99mTc-HMPAO uptake was also found. When 1 mmol/L glutathione was added to the medium, to convert native lipophilic 99mTc-HMPAO into hydrophilic derivatives, tracer uptake was inhibited both under control and hypotonic medium conditions. CONCLUSION: This study provides evidence that not only poisoning of the tissue but also in vitro ischemia induced a reduction of 99mTc-HMPAO retention. Moreover, we demonstrated that injuries causing cell membrane disruption led to hyperfixation of 99mTc-HMPAO.

A simplified, practical echocardiographic approach for 3-dimensional surfacing and quantitation of the left ventricle: clinical application in patients with abnormally shaped hearts.

The goal of this study was to validate the quantitative accuracy of a system for 3-dimensional (3D) echocardiographic reconstruction of the left ventricle to assess its volume and function in human beings by using 3 apical views as a simplified technique to promote practical clinical application. End-diastolic and end-systolic volumes (EDV, ESV) and ejection fraction (EF) were obtained by 3D echocardiography in 50 patients with dilated or geometrically distorted left ventricles and compared with values from magnetic resonance imaging (20 consecutive patients), angiography (22 consecutive patients), and radionuclide imaging (8 consecutive patients). Three-dimensional results were also compared with 2-dimensional (2D) echocardiographic estimates. Three-dimensional left ventricular reconstruction provided values that correlated and agreed well with pooled data from the other techniques for EDV (y = 0.93x + 9.1, r = 0.95, standard error of the estimate [SEE] = 15.2 mL, mean difference = -0.5 +/- 15.4 mL), ESV (y = 0.94x + 4.3, r = 0. 96, SEE = 11.4 mL, mean difference = 0.4 +/- 11.5 mL), and EF (y = 0. 90x + 4.1, r = 0.92, SEE = 6.2%, mean difference = -0.9 +/- 6.4%) (all mean differences not significant versus 0), with greater errors by 2D echocardiography. Intraobserver and interobserver variabilities of 3D echocardiography were less than 6% for EDV, ESV, and EF. The overall time for image acquisition and 3D reconstruction was 5 to 8 minutes. Although this 3D method uses only a small number of apical views, it accurately calculates EDV, ESV, and EF in patients with dilated and asymmetric left ventricles and is more accurate than 2D echocardiography. The flexible surface fit used to combine the 3 views provides a convenient visual output as well as quantitation. This simple and rapid 3D method has the potential to facilitate routine clinical applications that assess left ventricular function and changes that occur with remodeling.

Cerebral hypoperfusion detected by SPET in early neuro-Behçet syndrome.

We used brain single-photon emission tomography (SPET) to detect hypoperfused areas in 15 consecutive Behçet syndrome patients. Five were suspected of having neuro-Behçet syndrome, having at least one neurological symptom. For these patients, SPET was performed within 1 month of the onset of nervous system involvement. The 15 patients fulfilled the criteria of the International Study Group for Behçet syndrome. Neurological assessment and SPET were complemented by EEG in all five patients with suspected neuro-Behçet syndrome and by magnetic resonance imaging in three. Brain SPET detected hypoperfused regions in all five neurological patients; EEG showed abnormalities in three. Magnetic resonance imaging was normal in the three patients in whom it was performed. SPET was negative in all patients without neurological involvement and 20 healthy controls. SPET detected a reduction in brain blood flow in early neuro-Behçet syndrome, but there was no definitive correlation between the hypoperfused brain regions and the clinical features. Further studies are required to evaluate the significance of brain hypoperfusion and the value of SPET in the early diagnosis of neuro-Behçet syndrome.

Technetium-99m sestamibi leg scintigraphy for non-invasive assessment of propionyl-L-carnitine induced changes in skeletal muscle metabolism.

Carnitine derivatives, such as propionyl-l-carnitine (PLC), have been shown to improve walking distance in patients with obstructive peripheral artery disease (PAOD). The aim of this study was to ascertain whether technetium-99m sestamibi leg scintigraphy may be a useful tool in the evaluation of changes in skeletal muscle metabolism induced by chronic therapy with PLC. Twenty patients with clinical and instrumental evidence of PAOD were randomly assigned to a 3-month period of therapy with either PLC or placebo. Rest 99mTc-sestamibi leg scintigraphy and echo-Doppler sonography were performed on all subjects immediately before and upon completion of the treatment period. At the end of the protocol the following results were observed in patients who underwent PLC administration: (a) a significant increase in both thigh and calf 99mTc-sestamibi uptake, in comparison with baseline values (P<0.001); (b) the absence of statistically significant modifications of Doppler blood flow indices of the lower limbs. In conclusion, after chronic administration of PLC, a significant increment in skeletal muscle uptake of 99mTc-sestamibi was demonstrated without any apparent change in regional blood flow. This fact, if proven in further studies, may suggest a role for this tracer as a non-invasive probe of tissue bioenergetics.

Brain perfusion SPET and proton magnetic resonance spectroscopy in the evaluation of two systemic lupus erythematosus patients with mild neuropsychiatric manifestations.

The diagnosis of central nervous system (CNS) involvement appears to be a major problem in systemic lupus erythematosus (SLE), especially when the clinical signs are non-specific or neuroimaging is unremarkable. Two SLE patients with mild neuropsychiatric manifestations were studied with magnetic resonance imaging (MRI), single photon emission tomography (SPET) and localized proton magnetic resonance spectroscopy (H-1 MRS). MRI was normal in both patients. SPET revealed areas of hypoperfusion in both patients. H-1 MRS demonstrated metabolic abnormalities in the regions corresponding to the hypoperfused areas. A correlation between H-1 MRS and SPET was noted: patients with mild neuropsychiatric SLE may have disturbances evident on SPET and H-1 MRS in the presence of normal anatomy on MRI, suggesting that CNS involvement in SLE has very strong physiological and neurometabolic components in individual patients.

Subcellular distribution of technetium-99m-N-NOEt in rat myocardium.

UNLABELLED: The aim of this study was to determine the subcellular distribution of bis(N-ethoxy N-ethyl)dithiocarbamato nitrido technetium(V) (99mTcN-NOEt) in rat heart by differential centrifugation techniques. Extraction of the activity from homogenized rat heart tissue was also performed to assess whether myocardial retention might induce changes in the chemical identity of the complex. METHODS: Anesthetized rats were intravenously injected with 99mTcN-NOEt, the heart tissue was extracted and homogenized and tissue fractions were obtained by differential centrifugation. The efficiency of organelle separation was determined by assay of each centrifugal fraction using enzyme markers. Lactate dehydrogenase (LDH), acid phosphatase (ACP), alkaline phosphatase (ALP) and 5'-nucleotidase (5'ND) activities were assayed using standard spectrophotometric methods. Succinic dehydrogenase (SDH) activity was determined using a p-iodo-nitrotetrazolium-linked assay. Severe cell membrane and organelle disruption were induced by prolonging the homogenization time and their effect on the subcellular distribution of 99mTcN-NOEt was studied. The activity from homogenized heart tissue was extracted using the Folch technique and analyzed by TLC and HPLC. RESULTS: Most of the 99mTcN-NOEt activity was found to be associated with the hydrophobic components of the cell. No evidence of specific association of activity with the cytosolic and mitochondrial components was observed. Organelle and membrane cleavage did not cause release of activity into the cytosol. Approximately 90% of 99mTcN-NOEt activity was extracted from ventricular tissue and the chemical nature of 99mTcN-NOEt was not altered by uptake by myocardium. CONCLUSION: Cell membranes are the most apparent site of localization of 99mTcN-NOEt in heart tissue.

[The role of muscle scintigraphy with 201Tl in the morphofunctional assessment of obliterative arterial pathology of the lower limbs]. / Ruolo della scintigrafia muscolare con 201Tl nella valutazione morfo-funzionale della patologia arteriosa obliterante degli arti inferiori.

This study was aimed at assessing the role of stress 201Tl leg scintigraphy, compared with digital angiography, in the diagnosis and prognosis of peripheral arterial obstructive disease (PAOD) before and after surgical treatment. Fifty-four patients with known PAOD in Fontaine stages IIb, III or IV submitted to revascularization (36) or lumbar ganglionectomy (18), were examined with both angiography and scintigraphy. A statistical analysis of 360 segments (thighs and calves) was performed; in particular, correlation values were derived from 216 preoperative and 144 postoperative segments (18 patients who underwent lumbar ganglionectomy were not submitted to postoperative angiography). Scintigraphy vs. angiography sensitivity (84%), specificity (80%) and diagnostic accuracy (90%) values obtained in this study are in agreement with those reported in international literature. Scintigraphy yields information on the locoregional perfusion of an angiography-demonstrated anatomic lesion, under physiologic stress, which is particularly useful in symptomatic patients with angiographically unimportant stenoses. At present, 201Tl leg scintigraphy is the only technique yielding semiquantitative data in the assessment of single muscle groups perfusion increase in Fontaine IV patients submitted to lumbar ganglionectomy. The original contribution of this study consists in the evidence of a high predictive value (p < 0.01) of scintigraphy in the calculation of pain-free intervals in the patients with successful revascularization at clinics and angiography. This finding, if confirmed, shows a possible role for 201Tl leg scintigraphy in the diagnosis of peripheral arterial obstructive disease.

[Significance and usefulness of SPECT with Tc-99m HMPAO in the diagnosis of hemicrania with aura]. / Significato ed utilità della SPET con 99mTc HM-PAO nella diagnostica dell'emicrania con aura.

It is generally agreed upon that the attacks of migraine with aura are indicative of abnormal cerebral perfusion, while the permanence of such perfusion abnormalities during the pain-free intervals of migraine remains debated. This study was aimed at assessing: 1) the presence of cerebral perfusion abnormalities also during the interictal phase and 2) the role of SPET with 99mTc HM-PAO to diagnose migraine. Twenty-eight patients (22 women and 6 men), diagnosed as having migraine with aura according to the International Headache Society (Headache Classification Committee criteria), were submitted to SPET studies, within 10 days of the last attack. 99mTc HM-PAO was used as perfusion tracer and a single head rotating gamma camera equipped with a high-resolution collimator was used for data acquisition. The qualitative analysis of SPET images showed slight hypoperfusion areas in 22 of 28 patients (79%). In 12 of 22 patients (55%) a regional correlation was observed between hypoperfusion areas and the neurologic symptoms of aura. The results of the present study are in agreement with the current physiopathologic interpretation of migraine with aura, confirming the instability of cerebral perfusion control, even with instrumental evidence of perfusion abnormalities in the interictal period. Moreover, SPET with 99mTc Hm-PAO seems to be a useful tool in the diagnostic assessment of migraine.

Brain single-photon emission tomography with 99mTc-HMPAO in neuropsychiatric systemic lupus erythematosus: relations with EEG and MRI findings and clinical manifestations.

Central nervous system (CNS) involvement in patients with systemic lupus erythematosus (SLE) is often difficult to evaluate because of protean neuropsychiatric (NP) manifestations and lack of reliable diagnostic markers. In the reported study the role of single-photon emission tomography (SPET) with technetium-99m hexamethylpropylene amine oxime (HMPAO) in the evaluation of CNS involvement in SLE was assessed and the relations between SPET perfusion defects, EEG examination, magnetic resonance imaging (MRI) findings and clinical presentation were examined. Twenty SLE patients with different NP manifestations were studied. Multiple areas of hypoperfusion, especially in the territory of the middle cerebral artery, were demonstrated by SPET analysis in all 20 patients. The number of hypoperfused areas and the degree of hypoperfusion, expressed by an asymmetry index (AI), were more marked in patients with multiple NP manifestations. MRI and EEG evaluations were positive for 14 of 18 and for 12 of 20 patients, respectively. In the patients with positive SPET and MRI, 87 MRI focal lesions and 63 hypoperfused areas were found, and for 51 of these 63 at least one MRI lesion was found in the same anatomical region. SPET examination of patients with a normal EEG showed fewer hypoperfused areas and a lower degree of asymmetry compared to patients with an abnormal EEG. SPET of patients with focal EEG abnormalities showed more hypoperfused areas (difference not statistically significant) and a higher AI than did SPET of the patients with diffuse EEG abnormalities. Seven of 11 anatomical regions with focal EEG abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

Quality assessment of tumor marker determinations: a proposal for a supraregional scheme.

The use of tumor marker tests has increased progressively in the last decade concomitant with the advent of new monoclonal antibodies and their growing use in clinical oncology for various follow-up programs. External quality assessment (EQA) schemes widely adopted in clinical chemistry, have been extended in the last decade to immunoassays of hormones and tumor markers. EQA results can provide realistic information on the quality of the assays, performed under routine conditions. The goal of this article is to report the main results and discrepancies encountered so far in External Quality Assessment programs on tumor markers.

Sister chromatid exchanges in cultured amniocytes exposed to diagnostic ultrasound in vitro.

An in vitro system has been set up to study the possible genetic effects of diagnostic ultrasound (US) on the developing fetus. Amniotic cells were cultured by the in situ technique. Well established clones were exposed to US for various lengths of time using a linear array transducer within a sound transparent apparatus. Cells were then grown in the presence of 5-bromo-2'-deoxyuridine and processed for scoring the number of sister chromatid exchanges (SCE) as the cytogenetic endpoint. There was no linear relationship between the SCE frequency and the duration of US exposure. Variance analysis showed that only interindividual variability was a significant component of total variation. Neither the main effect of treatment nor the interaction effect were statistically significant. The data suggest that US delivered from a diagnostic unit to actively growing cultured fetal cells in a system closely mimicking the conditions of US exposure during amniocentesis does not induce SCE.

[Nuclear medicine in the integrated diagnosis of fatigue fractures]. / La medicina nucleare nella diagnostica integrata della patologia da affaticamento.

Nuclear medicine applications deal with the functional and dynamic study of organs and apparatuses in each diagnostic protocol. Bone scintigraphy (diagnostic accuracy: 80%) plays an important role in the differential diagnosis of the various musculoskeletal conditions in sports, mainly in the so-called "stress syndrome". The method is rather simple, including three steps: 1) study of radioactivity in the ROI; 2) capillary phase, with early imaging; 3) bone phase, with a static image 5 hours after injection. Slight differences in marker uptake, with fusiform and elongated marker accumulation areas, can be seen in the tibial stress syndrome, which exhibits no increase in the vascular phase, while in stress fractures, mainly in the late stages, increased activity can be seen in the arteriolar and capillary phases. Stress fractures are divided into 5 stages, from stage 1 = < 20% skeletal involvement to stage 5 = complete fracture, with > 80% bone involvement. The advantages of 3-phase bone scintigraphy can be summarized as follows: 1) it yields objective information, where clinics and radiology are often negative; 2) it allows the differential diagnosis between soft tissue lesions and bone fractures even in an early stage; 3) it allows prognosis to be made and the resumption of sport activity to be planned.