High-dose mitoxantrone + melphalan (MITO/L-PAM) as conditioning regimen supported by peripheral blood progenitor cell (PBPC) autograft in 113 lymphoma patients: high tolerability with reversible cardiotoxicity.

Hematological and extrahematological toxicity of high-dose (hd) mitoxantrone (MITO) and melphalan (L-PAM) as conditioning regimen prior to peripheral blood progenitor cell (PBPC) autograft was evaluated in 113 lymphoma patients (87 at disease onset). Autograft was the final part of a hd-sequential (HDS) chemotherapy program, including a debulkying phase (1-2 APO +/- 2 DHAP courses) and then sequential administration of hd-cyclophosphamide, methotrexate (or Ara-C) and etoposide, at 10 to 30 day intervals. Autograft phase included: (1) hd-MITO, given at 60 mg/m2 on day -5; (2) hd-L-PAM, given at 180 mg/m2 on day -2; (3) PBPC autograft, with a median of 11 x 10(6) CD34+/kg, or 70 x 10(4) CFU-GM/kg, on day 0. A rapid hematological recovery was observed in most patients, with ANC >500/microL and Plt >20,000/microl values reached at a median of 11 and 10 days since autograft, respectively. The good hemopoietic reconstitution allowed the delivery of consolidation radiotherapy (RT) to bulky sites in 53 out of 57 candidate patients, within 1 to 3 months following autograft; five of these patients required back-up PBPC re-infusion due to severe post-RT pancytopenia. Few severe infectious complications were recorded. There was one single fatal event due to severe pancytopenia following whole abdomen RT. Cardiac toxicity was evaluated as left ventricular ejection fraction (LVEF), monitored by cardiac radionuclide scan. LVEF prior to and after autograft was significantly reduced (median values: 55% vs 46%) in 58 evaluated patients; however, a significant increase to a median value of 50% was observed in 45 patients evaluated at 1 to 3 years since autograft. At a median follow-up of 3.6 years, 92 patients are alive, with a 7-year overall survival projection and 6.7-year failure-free survival projection of 77% and 69%, respectively. We conclude that a conditioning regimen with hd-MITOIL-PAM fits well within the HDS program. It implies good tolerability and reversible cardiotoxicity and it may have contributed to the good long-term outcome observed in this series of patients.

Radionuclide angiocardiographic evaluation of the cardiovascular effects of recombinant human IGF-I in normal adults.

OBJECTIVE: IGF-I possesses specific myocardial receptors and is able to promote cardiac remodelling and even inotropic effects in both humans and other animals. In fact, reduced cardiac mass and performance are present in GH deficiency and these alterations are counteracted by recombinant human (rh) GH replacement, restoring IGF-I levels. Recently, the acute administration of 60 microg/kg rhIGF-I has also been reported to be able to improve cardiac performance evaluated by echocardiography or impedance cardiography in normal subjects. The aim of our study was to verify the effects of a subcutaneous low dose of rhIGF-I (20 microg/kg) on cardiac performance in humans. METHODS: In six healthy male adults (mean+/-S. e.m.: 35.7+/-4.3 years of age), the effects of rhIGF-I on left ventricular function evaluated by radionuclide angiocardiography and on circulating IGF-I, GH, insulin, glucose and catecholamines levels were studied. RESULTS: Administration of rhIGF-I increased circulating IGF-I (peak at +150 min vs baseline: 330.2+/- 9.6 vs 199. 7+/-8.7 microg/l, P<0.03) to levels which persisted similarly up to +180min. Neither GH nor catecholamine levels were modified by rhIGF-I administration, while insulin and glucose levels showed a slight but significant decrease. Basal left ventricular ejection fraction (61.8+/-2.0%) significantly increased at +180 min after rhIGF-I (65.3+/-2.7%, P<0.03). No change was recorded in mean blood pressure while a non-significant trend towards a reduction of heart rate was present by +120 min. CONCLUSIONS: These findings indicate that even subcutaneous administration of a low dose of rhIGF-I has acute inotropic effects as evaluated by radionuclide angiocardiography in healthy adults.

GH-independent cardiotropic activities of hexarelin in patients with severe left ventricular dysfunction due to dilated and ischemic cardiomyopathy.

AIM: To investigate acute cardiotropic activities of hexarelin in patients with severe left ventricular dysfunction due to ischemic (iCMP) and dilated cardiomyopathy (dCMP). METHODS AND RESULTS: We studied the effect of intravenous hexarelin administration on growth hormone (GH) levels and left ventricular ejection fraction (LVEF) evaluated by radionuclide angiography in eight patients with dCMP (age 53.0+/-2.8, LVEF 16.7+/-2.1%) and five patients with iCMP (age 52.0+/-2.8 years, LVEF 22.6+/-2.1). Results were compared with a group of seven normal subjects (age 37.4+/-3.4 years, LVEF 64.0+/-1.5%) and seven patients with severe growth-hormone deficiency (GHD; age 42.0+/-4.4 years, LVEF 50.0+/-1.9%) previously studied with the same methodology. In dCMP and iCMP patients hexarelin induced a similar significant (P<0.05) increase in GH levels. In iCMP patients hexarelin induced a LVEF increase (peak LVEF 26.2+/-2.5%, P<0.05) as observed in normals and GHD, while in dCMP LVEF was unchanged (peak LVEF 17.7+/-1.7, P=NS). In all groups other hemodynamic parameters were unchanged. CONCLUSIONS: Acute hexarelin administration increases LVEF in iCMP patients (as in normals and GHD) but not in dCMP patients in spite of a similar GH releasing effect and basal LVEF. A possible explanation of the positive inotropic effect of hexarelin in iCMP could be a direct stimulation on viable myocardium or myocardial contractile reserve.

Cardiac effects of hexarelin in hypopituitary adults.

Growth hormone (GH)-releasing peptides possess specific pituitary, hypothalamic, and myocardial receptors. Seven adult male patients with GH deficiency (GHD) (age, mean+/-S.E.M.: 42.0+/-4.0 year) were studied by equilibrium radionuclide angiocardiography after i.v. administration of hexarelin, a peptide GH secretagogue. Data for these patients were compared with those for nine adult male controls (37.0+/-2.7 year). The GH response to hexarelin was negligible in patients with GHD compared to control subjects (CS) (peak: 1.9+/-0.9 vs. 45.7+/-3.6 microg/l, P<0.001). Basal left ventricular ejection fraction (LVEF) in patients with GHD was lower than that in CS (50+/-1% vs. 63+/-2%, P<0.001). Hexarelin administration increased LVEF both in patients with GHD and in CS (peak: 57+/-2 vs. 70+/-2, respectively, P<0.05 vs. baseline) without changing catecholamine levels, mean blood pressure (MBP), or cardiac output in either group. In conclusion, the acute administration of hexarelin exerts a short-lasting positive inotropic effect in humans, probably GH-independent and mediated by specific myocardial receptors for GH secretagogues.

The role of cortex in central pain syndromes: preliminary results of a long-term technetium-99 hexamethylpropyleneamineoxime single photon emission computed tomography study.

The role of the somatosensory cortex in central pain syndromes is widely questioned. Two recent position emission tomography studies detected a strong activation of the parietal and cingular cortices after brief nociceptive stimuli. On the other hand, a recent single photon emission computed tomography study found no cortical activation in five patients affected by central poststroke pain and algodystrophia. In this study, we present the single photon emission computed tomography findings in five patients suffering from central pain syndromes. Two of these, one with facial postrhizotomy anesthesia dolorosa and the other with central poststroke pain, showed a decrease of blood flow in the parietal lobe, further decreasing after stimulation by nonpainful maneuvers. Our results suggest that somatosensory cortical areas might be involved in the generation of anomalous pain states in some cases of central pain syndromes.

Cerebral blood flow and volume in symptom-free migraineurs: a SPECT study.

Both CBF and CBV were evaluated by gamma-camera SPECT in 14 patients with classic migraine, all studied while symptom-free. Nuclear data were correlated with CT and MRI. A decreased regional CBF was observed in 13 of the 14 patients. The decreased perfusion was localized in the frontal lobe in 6 patients, the temporal lobe in one, the parietal lobe in 11 and the occipital lobe in 5 patients. The parieto-occipital cortex was involved more often than the frontal cortex; the association of hypoperfusion with parieto-occipital cortex was quite high. The right parieto-occipital regions were affected more often than the left ones. Regional CBV was increased in 8 patients. There was good topographical concordance between decreased CBF and increased CBV, but the increase of CBV was in general more evident at the periphery of the hypoperfusion. It is of interest that the only patient with a normal CBF study had a pathological CBV study. Apparently, CBF derangements are very common in symptom-free patients with classic migraine, a CBF decrease being often accompanied by a CBV increase. In these patients both CT and MRI have a lower diagnostic yield than SPECT.

Prognosis of hibernating myocardium is independent of recovery of function: evidence from a routine based follow-up study.

Revascularization of hibernating segments improves both ventricular function (VF) and survival. In this study, we determined whether this relation is true in a routine based patients population with mildly reduced VF. Two to 6 years after undergoing 201Tl scintigraphy to detect hibernation, 153 patients were interviewed in order to collect medical information. This population was divided into four groups, according to the presence or absence of myocardial hibernation and of revascularization. Age, gender and left ventricular ejection fraction (LVEF) were similar in the four groups. Hard cardiac events (HEs) were noted in 14/33 (41%) patients with uncorrected hibernation, while in the other three groups HEs were recorded in fewer than 3% of patients. Univariate analysis indicated that the presence of hibernation, regardless of its extension, was the highest significant predictor of HEs. Multivariate analysis indicated that hibernation, stress ischaemia, age and absence of revascularization were significant predictors of HEs. These findings were not related to changes in LVEF or to New York Heart Association (NYHA) class during follow-up. In this routine based patient population, with mildly reduced VF, the rate of HEs seems to be related to uncorrected hibernation regardless of its extension. In these patients revascularization of hibernating segments is effective in reducing the risk of HEs while its role in improving VF or NYHA class is negligible.

Biodistribution of stealth and non-stealth solid lipid nanospheres after intravenous administration to rats.

Drug-free stealth and non-stealth solid lipid nanospheres (SLNs) were administered intravenously to rats to evaluate their tissue distribution and their transport across the blood-brain barrier. Two types of experiments were performed using unlabelled and labelled SLNs. Rats were administered labelled non-stealth or stealth nanospheres (NSSLNs and SSLNs) and their tissue distribution was monitored for 60 min. In another experiment, rats were injected with unlabelled NSSLNs or SSLNs and the cerebrospinal fluid (CSF) was analysed using transmission electron microscopy (TEM) to confirm the presence of the SLNs. Some differences were found in the biodistribution between labelled NSSLNs and SSLNs. In particular, the radioactivity in the liver and the lung was much lower for SSLNs than for NSSLNs, confirming a difference in their uptake. Both types of SLNs were detected in the brain. TEM analysis showed both types of SLNs in rat CSF.

Pertechnetate release from a water/oil microemulsion and an aqueous solution after subcutaneous injection in rabbits.

A water-oil microemulsion and an aqueous solution, both carrying pertechnetate, were injected subcutaneously in rabbits; release was observed by imaging the administration sites with a gamma-camera. Disappearance from the injection site of pertechnetate in aqueous solution was about ten times faster than that of pertechnetate in a microemulsion.

Choosing new adsorbents for endogenous ultrapure infusion fluid: performances, safety and flow distribution.

Adsorption may notably contribute to the removal of uremic toxins and to the efficiency of hemodialysis. We examined different uncoated stationary matrixes, charcoals and synthetic resins to establish their adsorptive capacities in relation to low (urea, creatinine) and high molecular weight (beta2-microglobulin, myoglobin) compounds in in vitro conditions (steady state and flow-through) using isotonic solutions or uremic ultrafiltrate. Trace metal, particle release analyses and scanning electron microscopy of different adsorbents were performed. Dynamic flow-distribution studies were made using 99Technetium and analysing the different regions of interest by single head gamma-camera. We show that adsorbents may differ greatly as to their adsorptive capacity depending on flow rate, nature, and total mass of the compounds to be removed from the ultrafiltrate. These studies suggest a methodological approach for screening stationary matrixes for possible application in hemodialysis.

Assessing the accuracy and reproducibility of computer-assisted analysis of (123) I-FP-CIT SPECT using BasGan (V2).

BACKGROUND AND PURPOSE: Over the last two decades (123) I-FP-CIT-SPECT, has been used to discriminate neurodegenerative Parkinsonian syndrome from other diseases. BasGan is a freely available software that assists (123) I-FP-CIT-SPECT evaluation by estimating semiquantitative values for each basal nucleus and compares the results to a database of healthy subjects. The aims of this study were: (1) to assess the accuracy of qualitative analysis and of semiquantitative, BasGan-assisted evaluations of (123) I-FP-CIT-SPECT; (2) to compare the accuracy of both methods when applied to "doubtful" cases; (3) to appreciate the reproducibility of the BasGan-assisted evaluations. MATERIALS AND METHODS: Seventy-eight patients were included in this 4-year follow-up study. The diagnostic cut-off for semiquantitative uptake values of each basal nucleus was determined based on ROC curves analysis. Accuracy scores were calculated for the entire population and for "doubtful" cases. Intra- and interoperator reproducibility was assessed. RESULTS: Accuracy of the software-assisted analyses was high for data from each nucleus. In "doubtful" exams accuracy was higher when using BasGan as opposed to relying solely on visual assessment. Intra- and interoperator reproducibility of the BasGan-assisted evaluations was good to excellent. CONCLUSION: BasGan-assisted evaluations of (123) I-FP-CIT-SPECT were very useful, particularly in "doubtful" cases. Multicenter studies are mandatory before routine use of BasGan.

Detection of myocardial viability with 99mTc-labelled myocardial perfusion agents.

Detection of myocardial viability is an important clinical issue in the time course of acute myocardial infarction and in chronic coronary artery disease. The wide availability of myocardial revascularization procedures requires a refinement of specific indications for revascularization whenever left ventricular failure is the most prominent feature of coronary artery disease. In this instance the risk/benefit ratio has to be attentively evaluated with diagnostic tests able to predict favourable changes in regional and global left ventricular function, symptoms, life quality, risk of adverse events and ultimately prognosis. 201Tl has been shown to provide clinically televant information regarding the presence of myocardial viability in patients with extensive regional or global ventricular dysfunction. However, the increasing use of 99mTc labeled myocardial perfusion agents requires a careful evaluation of diagnostic and predictive accuracy of these agents also for the issue of myocardial viability. The widely accepted opinion of a lower predictive accuracy of these agents compared to 201Tl could be no longer true. The available clinical and experimental data indicate, at least for 99mTc-sestamibi, a comparable accuracy when independent and clinically relevant gold standard of viability like post-revascularization functional recovery is considered. Preliminary data indicate that protocols, like nitrate administration, slow infusion or delayed imaging, and accurate quantitation of 99mTc-sestamibi SPECT studies could enhance the predictive accuracy to a level comparable or even better than that of 201Tl and similar to the more demanding PET technology.

Evaluation of left ventricular diastolic function at rest and during exercise by gated radionuclide angiocardiography in coronary artery disease patients.

The peak filling rate (PFR) is an index of the diastolic function and has been proposed as an excellent parameter for the evaluation and early detection of left ventricular (LV) dysfunction. This study contributes to the assessment of LV diastolic function at rest and during submaximal exercise in 19 normal subjects and in 42 patients with coronary artery disease (CAD). The PFR was compared to the ejection fraction (EF) and the peak ejection rate (PER)--both indexes of systolic LV function--after acquiring a high-resolution time-activity curve (time/frame between 10 and 30 msec) with gated radionuclide angiocardiography. In 23 patients with normal EF at rest (greater than or equal to 50%), PFR and PER were abnormally low in 87% and 43% of the cases respectively. During submaximal exercise in 13 CAD patients, EF, PFR and PER varied very little from baseline values but were significantly reduced compared to the values of normal subjects. The PFR proved to be a very sensitive indicator of LV dysfunction in coronary patients but was not capable of discriminating between one-, two- or three-vessel disease. Our results tend to show the PFR to be a good indicator of LV dysfunction at rest and during exercise and its usefulness for the assessment of LV function is becoming more and more evident in clinical practice.

Dopamine D2 receptor imaging with SPECT using IBZM in 16 patients with Parkinson disease.

The striatal D2 receptor was investigated for variability of behavior in 16 patients with Parkinson disease by means of SPECT using 123I-IBZM, a recently synthesized radioligand with high affinity and specificity for this type of receptor. All the patients underwent routine laboratory tests, EEG and cranial CT scanning as well as SPECT. To ensure accurate clinical assessment we used the Hoehn and Yahr, and Webster scales, NUDS and Mini Mental State examination. Our preliminary data indicate: increased uptake by the striatal dopamine receptor in untreated patients with early PD compared with controls (striatum/cerebellum ratio of 1.77 +/- 0.12 vs 1.59 +/- 0.13); a slight but significant lowering of D2 receptor binding when L-Dopa is started (1.49 +/- 0.09); low D2 uptake values in the more severely affected patients; absence of asymmetries in hemiparkinsonism.

[Effect of high-dose verapamil on systolic and diastolic cardiac function of non-cardiological patients and review of the literature]. / Effet du vérapamil oral à forte dose sur la fonction cardiaque systolique et diastolique de patients non cardiologiques et revue de la littérature.

We studied the effects of high doses of oral verapamil (480 mg daily) in a group of 28 patients undergoing intravenous drug therapy for terminal digestive tumor. One additional patient was prematurely withdrawn from the study due to the occurrence of second degree atrioventricular block, which regressed after the interruption of verapamil. Gated radionuclide angiocardiography was performed before and after treatment (mean duration 2 days). Verapamil induced a significant reduction of blood pressure and heart rate (132 +/- 19 mm Hg vs 124 +/- 18 mm Hg, p = 0.005 for systolic blood pressure, 80 +/- 13 mm Hg vs 76 +/- 9 mm Hg, p = 0.04 for diastolic blood pressure and 81 +/- 17 bpm vs 77 +/- 13 bpm, p = 0.02 for heart rate). Left ventricular ejection fraction and peak filling rate were not impaired (65 +/- 7% vs 64 +/- 7%, p = NS and 2.52 +/- 0.65 EDV/s vs 2.42 +/- 0.51 EDV/s, p = NS), while peak ejection rate decreased slightly (2.96 +/- 0.72 EDV/s vs 2.72 +/- 0.50 EDV/s, p = 0.01). Conversely, there was significant alteration of right ventricular systolic indexes (50 +/- 7% vs 46 +/- 7%, p = 0.01 for the ejection fraction and 2.06 +/- 0.53 EDV/s vs 1.88 +/- 0.44 EDV/s, p = 0.008 for the peak ejection rate), without change in the peak filling rate (1.54 +/- 0.46 EDV/s vs 1.46 +/- 0.46 EDV/s, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

[Long-term prognosis of patients with silent ischemia]. / Pronostic à long terme des patients avec ischémie silencieuse.

To study the long-term evolution in patients with silent ischemia we investigated 242 coronary patients showing ischemic signs on exercise T1-201 scintigraphy. The findings in a group of 106 patients with angina were compared with those in a group of 136 patients without angina during exercise and followed up for an average of 60 months. Multiple comparisons of clinical features, ECG, hemodynamic and angiographic data showed no significant differences between the two groups. However, the extent of ischemia detected by T1-201 was significantly smaller in patients with silent ischemia although their work-load and double product were higher.--During the follow-up cardiac mortality (11% vs 11%), unstable angina (27% vs 20%) and myocardial infarction (23% vs 20%) were found with the same frequency in patients with angina compared with those with silent ischemia. Bypass surgery was performed more frequently (55% vs 37%) in patients with symptomatic ischemia. Long-term evolution in our coronary patients with episodes of silent ischemia was similar to that in patients with ischemia accompanied by angina, and showed numerous complications. Therefore, we should try to treat not only angina but also, and especially, ischemia.

Left ventricular function at 24 hours, 14 days and 6 months after acute myocardial infarction.

To determine the natural history of left ventricular function at rest and during exercise and to assess the impact of this variable on subsequent mortality, 165 patients were studied with radionuclide angiography within 24 hours of acute myocardial infarction. The ejection fraction of the 19 patients who died during the 6 month follow-up was lower than that of the 146 survivals: 41 +/- 16% vs 50 +/- 13% (P less than 0.001). Before hospital discharge (14 +/- 4 days), 83 patients had a rest and submaximal exercise radionuclide study. The ejection fraction of the 42 patients with anterior infarction was 44 +/- 12% and remained unchanged during exercise, while the 41 patients with posterior infarction had a resting value of 54 +/- 9% which increased to 57 +/- 10% (P less than 0.001) during exercise. The ejection fraction during exercise increased slightly but significantly in 37/61 patients with single vessel disease, while it did not change in the 24/61 patients with multivessel disease. At a mean of 4 +/- 1 months following infarction, 58 patients underwent a symptom-limited exercise radionuclide study. Mean value of resting ejection fraction for the group or anterior-posterior infarction subgroups did not change from initial or predischarge values. The 27 patients with anterior infarction showed no change in ejection fraction during exercise, while the 31 patients with posterior infarction increased their ejection fraction from 53 +/- 11% to 57 +/- 12% (P less than 0.001). Thus, ejection fraction measured by radionuclide angiography 24 hours following acute myocardial infarction provides useful prognostic information.(ABSTRACT TRUNCATED AT 250 WORDS)