Juan F. Batista

Phase I single-dose study of intracavitary-administered Nimotuzumab labeled with 188 Re in adult recurrent high-grade glioma

Radioimmunotherapy (RIT) may improve the management of malignant gliomas. A Phase I clinical trial was performed to evaluate, for the first time, the toxicity and clinical effect of an intracavitary administration of a single dose of Nimotuzumab (h-R3) labeled wit 188-Re. Nimotuzumab is a humanized monoclonal antibody directed against epidermal growth factor receptors. Three patients with anaplastic astrocytoma (AA) and 8 with glioblastoma multiforme (GBM) were intended to be treated with 3 mg of mAb labelled with 10 or 15 mCi of 188-Re. In patients treated with 10 mCi (n=6) transitory worsening of pre-existing neurological symptoms were observed. Two patients treated with 15 mCi (n=4) developed early severe neurological symptoms and one also developed late severe toxicity (radionecrosis). In the group treated with 10 mCi, 1 GBM patient died in progression 6 months after the treatment, 2 patients (1 GBM and 1 AA) developed stable disease during 3 months. One GBM patient had partial response for more than 1 year and 2 patients (1 GBM and 1 AA) were asymptomatic and in complete response after 3 years of treatment. Maximal tolerated dose of the radioimmunoconjugate 188-Re-Nimotuzumab was 3 mg of the h-R3 labelled with 10 mCi of 188-Re. The radioimmunoconjugate showed a high retention in the surgical created resection cavity and the brain adjacent tissues with a mean value of 85.5 % of the injected dose one hour post-administration. This radioimmunoconjugate may be relatively safe and a promising therapeutic approach for treating high grade gliomas.

Phase I/II clinical trial of the humanized anti-EGF-r monoclonal antibody h-R3 labelled with 99mTc in patients with tumour of epithelial origin.

AimTo evaluate the biodistribution, internal radiation dosimetry and toxicity of the humanized MAb h-R3 labelled with 99mTc in humans. MethodsTwenty-five patients with suspected epithelial-derived tumours were included in this study and divided into two groups: group I consisted of 10 patients who received 3 mg/1110 MBq (3 mg/30 mCi); and group II consisted of 15 patients who received 6 mg/2220 MBq (6 mg/60 mCi). Single photon emission computed tomography (SPECT) and planar images, and multiple blood and urine samples were collected up to 24 h after injection. Haematological parameters and adverse effects were classified according to the WHO criteria. Biodistribution, human anti-mouse antibody (HAMA) response and absorbed doses were estimated and reported. ResultsLiver, spleen, kidneys and heart were identified as source organs. Their higher uptakes were 53.3±6.4%ID, 2.0±1.4%ID, 9.8±4.3%ID and 2.8±0.9%ID, respectively. The urinary bladder and large intestine also had a significant uptake. The mean urinary excretion was around 22%ID. The liver received the highest absorbed doses followed by the kidneys and the urinary bladder wall. There were no haematological or biochemical abnormalities with clinical significance related to the product. No patient developed HAMA response. Preliminary analysis of clinical results showed a sensitivity of 76.5% and a specificity of 100%. ConclusionsThe results of this study suggest that 99mTc-h-R3 could be used in patients in a safe and effective way, for the diagnosis of epithelial-derived tumours at the two evaluated dose levels.

Biodistribution and internal dosimetry of the 188Re-labelled humanized monoclonal antibody anti-epidemal growth factor receptor, nimotuzumab, in the locoregional treatment of malignant gliomas.

ObjectiveTo evaluate the biodistribution, internal radiation dosimetry and safety of the 188Re-labelled humanized monoclonal antibody nimotuzumab in the locoregional treatment of malignant gliomas. MethodsSingle doses of 370 or 555 MBq of 188Re-labelled nimotuzumab were locoregionally administered to nine patients with recurrent high-grade gliomas, according to an approved dose-escalation study. SPECT, planar scintigraphy and magnetic resonance images were combined for dosimetric and pharmacokinetic studies. Blood and urine samples were collected to evaluate clinical laboratory parameters and for absorbed doses calculations. Biodistribution, internal dosimetry, human anti-mouse antibody response and toxicity were evaluated and reported. ResultsThe 188Re-nimotuzumab showed a high retention in the surgically created resection cavity with a mean value of 85.5±10.3%ID 1 h post-injection. It produced mean absorbed doses in the tumour region of approximately 24.1±2.9 Gy in group I (patients receiving 370 MBq) and 31.1±6.4 Gy in group II (patients receiving 555 MBq); the normal organs receiving the highest absorbed doses were the kidneys, liver and urinary bladder. About 6.2±0.8%ID was excreted by the urinary pathway. The maximum tolerated dose was 370 MBq because two patients showed severe adverse effects after they received 555 MBq of 188Re-nimotuzumab. No patient developed human anti-mouse antibody response. ConclusionsA locoregional single dose of 188Re-labelled nimotuzumab of approximately 370 MBq could be used safely in the routine treatment of patients suffering with high-grade gliomas. The efficacy of this therapy needs to be evaluated in a phase II clinical trial.

Improved detection of myocardial perfusion reversibility by rest-nitroglycerin Tc-99m-MIBI: comparison with Tl-201 reinjection

BackgroundThe role of nitroglycerin (NTG) in Tc-99m-methoxyisobutil isonitrile (MIBI) studies to improve the assessment of myocardial viability in patients with coronary artery disease and its comparison with Tl-201 reinjection has not yet been clarified. This study aimed to test whether sublingual administration of NTG could improve the capability of Tc-99m-MIBI to detect reversibility in exercise-induced perfusion defects and to compare it with the Tl-201 stress-redistribution-reinjection protocol.Methods and ResultsThirty-eight patients (33 men, 5 women; mean age 49.3±8.2 years with previous myocardial infarction [mean evolution 7.1±3.9 months]) underwent exercise, redistribution, and reinjection Tl-201 imaging, as well as exercise, rest, and NTG MIBI myocardial scintigraphy (3-day protocol). A total of 494 myocardial segments were assessed by quantitative analysis. Of the 136 myocardial segments with fixed defects on exercise-rest sestamibi imaging, 109 (80%) did not change after NTG MIBI study, and 27 (20%) demonstrated enhanced uptake. In the 140 myocardial segments with fixed defects on exercise-redistribution thallium imaging, 112 (80%) did not improve after Tl-201 reinjection study, and 28 (20%) showed increased activity. The observed agreement on reversibility detection between NTG MIBI and Tl-201 reinjection, with the 210 segments with perfusion defects used for this analysis on both studies, was 78%, with a significant kappa=.56±.07 SE.ConclusionOur data suggest that the use of an NTG MIBI protocol results in an incremental improvement for detecting exercise-induced perfusion defect reversibility and achieves results similar to those from a Tl-201 reinjection protocol.

Doppler-ultrasound pilot study of the effects of long-term policosanol therapy on carotid-vertebral atherosclerosis

Abstract This pilot study was conducted to document the beneficial lipid-lowering effect of policosanol on hemodynamic carotid-vertebral atherosclerosis (CVA) abnormalities. Twenty-two patients with mild CVA, including 12 patients with type II hyperlipidemia, were enrolled in this randomized, double-blind, Phase II, placebo-controlled trial. Eleven patients received 5 mg of oral policosanol twice daily, and 11 patients received placebo twice daily; all patients were treated for 1 year. Five functional Doppler-ultrasound flow parameters were measured on six arteries per patient and classified by using an objective response system. In the policosanol group, progression and stabilization of disease were absent, mixed response was lower, and regression was six times more frequent (6 of 11 patients); these findings were not statistically significant compared with the placebo group ( P = 0.06). The progression/regression (P:R) ratio in the policosanol group had a mean (0.5) two times lower than that in the control group (1.2) ( P = 0.03). The decrease in the P:R ratio was associated independently with a moderate percent reduction of the low-density lipoprotein cholesterol:high-density lipoprotein cholesterol ratio. Although the sample size and 1-year follow-up do not allow conclusions to be drawn, these results suggest that policosanol, in combination with a low-fat diet, improves hemodynamic abnormalities in patients with mild CVA and normal lipid levels or type II hyperlipidemia.

Usefulness of 99Tcm-tetrofosmin scintimammography in palpable breast tumours

The aim of this exploratory study was to assess the potential of discriminating malignant from non-malignant lesions using 99Tcm-tetrofosmin scintimammography in the detection of palpable breast tumours. Nine patients with palpable masses were studied; seven had malignant lesions and two had non-malignant lesions. All diagnoses were established by fine-needle aspiration (FNA) biopsy cytology. Each patient received 925 MBq (25 mCi) 99Tcm-tetrosfosmin intravenously. Planar prone views were acquired in the right lateral, left lateral and anterior positions, and the axillary regions were included in the field of view. Scintimammography showed focally increased tracer uptake in seven patients with a positive FNA result. The two patients with a negative FNA result showed no increased uptake. We suggest that 99Tcm-tetrosfosmin shows promise as a radiopharmaceutical in the detection and discrimination of the nature of palpable breast tumours. Larger studies are required to confirm these findings.

Lipid levels as predictors of silent myocardial ischemia in a type 2 diabetic population in Havana

INTRODUCTION Silent myocardial ischemia is frequent in type 2 diabetics, therefore, symptoms cannot be relied upon for diagnosis and followup in these patients. Various studies relate blood lipid levels to cardiovascular diseases, and several authors describe certain lipoproteins as independent predictors of ischemia. OBJECTIVE Identify blood lipid levels that predict silent myocardial ischemia in a type 2 diabetic population in Havana. METHODS From May 2005 through May 2009, assessment was done of 220 asymptomatic type 2 diabetics in ten polyclinics in Havana using laboratory tests and Single-Photon Emission-Computed Tomography, synchronized with electrocardiogram, known as gated SPECT (gSPECT). Coronary angiography was used for confirmation when gSPECT detected ischemia. Patients were classified into two groups: gSPECT positive and gSPECT negative. Descriptive statistics (mean and standard deviation) were calculated for all variables and mean comparison tests were conducted. Classification trees were developed relating lipid values to gSPECT results, identifying optimal cutoff points for their use as indicators of silent myocardial ischemia in the total study population and for each sex separately. RESULTS GSPECT found silent myocardial ischemia in 29.1% of those examined, and 68.4% of angiograms found multivessel disease. gSPECT-positive diabetics had higher levels of total cholesterol, LDL, and triglycerides (p < 0.05). HDL levels were lower in this group (p < 0.05). Classification trees showed optimal cutoff points, indicators for silent ischemia, for: HDL ≤44 mg/dL, LDL >119.9 mg/dL, and triglycerides >107.2 mg/d; 80.4% of diabetics with these HDL and triglyceride values had ischemia. HDL was the most important normalized variable when the entire population was analyzed. Analysis by sex showed a greater percentage of silent ischemia in men (33.3%) than in women (24.8%). The most important normalized variables were LDL of >100.8 mg/dL for men and HDL of ≤44 mg/dL for women. CONCLUSIONS A considerable percentage of the study population had silent myocardial ischemia. Type 2 diabetics with ischemia had higher levels of total cholesterol, LDL and triglycerides. HDL levels were significantly lower in these patients. The association of low HDL with high triglycerides was a strong indicator of myocardial ischemia in type 2 diabetics without clinical cardiovascular signs. KEYWORDS Lipids, type 2 diabetes, silent myocardial ischemia, decision trees, diagnostic imaging, Single-Photon Emission-Computed Tomography, cardiac-gated SPECT, early detection, Cuba.

Use of Tc-99m glucoheptonate scintimammography as a potential alternative for the diagnosis of breast cancer.

Breast cancer is the most common malignancy in women. Tc-99m MIBI is a radiopharmaceutical commonly used for tumor scintigraphy studies. Tc-99m GH is a radiopharmaceutical originally used for the assessment of renal function. As a result of the rapid clearance and progressive accumulation of GH in tumors, these tumors may be using this glucose analog as a substrate for energy. The authors describe 2 cases. A 74-year-old woman had an infiltrating lobular breast carcinoma and negative mammography. The breast malignancy was visualized with Tc-99m GH. Tc-99m MIBI was negative for tumor. A 38-year-old woman had infiltrating ductal carcinoma. Mammography and scintigraphy with both radiopharmaceuticals were positive.