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

OBJECTIVE: To evaluate the biodistribution, internal radiation dosimetry and safety of the 188Re-labelled humanized monoclonal antibody nimotuzumab in the locoregional treatment of malignant gliomas. METHODS: Single 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. RESULTS: The 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. CONCLUSIONS: A 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.

Immunoscintigraphy With 99mTc-Nimotuzumab for Planning Immunotherapy in Patients With Bone Metastases Due to Prostate Cancer.

Detection of bone metastases indicates poor prognosis for patients with prostate cancer. The immunotherapy with monoclonal antibody has been an important advance in the treatment of the cancer in the last years. Nimotuzumab is a humanized IgG1 monoclonal antibody directed against epidermal growth factor receptor that has been evaluated in solid tumors. The authors show images of 2 patients with bone metastases secondary to prostate cancer, "pre-cold therapy" with nimotuzumab. Immunoscintigraphic images were acquired 4 and 24 hours after the intravenous administration of 1110 MBq (30 mCi) of Tc-labeled nimotuzumab. Bone metastases expressing the receptor are visualized.

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.

AIM: To evaluate the biodistribution, internal radiation dosimetry and toxicity of the humanized MAb h-R3 labelled with Tc in humans. METHODS: Twenty-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. RESULTS: Liver, 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%. CONCLUSIONS: The results of this study suggest that Tc-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.

Immunoscintigraphy and radioimmunotherapy in Cuba: experiences with labeled monoclonal antibodies for cancer diagnosis and treatment (1993-2013).

INTRODUCTION The availability of monoclonal antibodies in Cuba has facilitated development and application of innovative techniques (immunoscintigraphy and radioimmunotherapy) for cancer diagnosis and treatment. Objective Review immunoscintigraphy and radioimmunotherapy techniques and analyze their use in Cuba, based on the published literature. In this context, we describe the experience of Havana's Clinical Research Center with labeled monoclonal antibodies for cancer diagnosis and treatment during the period 1993-2013. EVIDENCE ACQUISITION Basic concepts concerning cancer and monoclonal antibodies were reviewed, as well as relevant international and Cuban data. Forty-nine documents were reviewed, among them 2 textbooks, 34 articles by Cuban authors and 13 by international authors. All works published by the Clinical Research Center from 1993 through 2013 were included. Bibliography was obtained from the library of the Clinical Research Center and Infomed, Cuba's national health telematics network, using the following keywords: monoclonal antibodies, immunoscintigraphy and radioimmunotherapy. RESULTS Labeling the antibodies (ior t3, ior t1, ior cea 1, ior egf/r3, ior c5, h-R3, 14F7 and rituximab) with radioactive isotopes was a basic line of research in Cuba and has fostered their use as diagnostic and therapeutic tools. The studies conducted demonstrated the good sensitivity and diagnostic precision of immunoscintigraphy for detecting various types of tumors (head and neck, ovarian, colon, breast, lymphoma, brain). Obtaining different radioimmune conjugates with radioactive isotopes such as 99mTc and 188Re made it possible to administer radioimmunotherapy to patients with several types of cancer (brain, lymphoma, breast). The objective of 60% of the clinical trials was to determine pharmacokinetics, internal dosimetry and adverse effects of monoclonal antibodies, as well as tumor response; there were few adverse effects, no damage to vital organs, and a positive tumor response in a substantial percentage of patients. CONCLUSIONS Cuba has experience with production and radiolabeling of monoclonal antibodies, which facilitates use of these agents. Studies in Cuba conducted by the Clinical Research Center over the past 20 years have yielded satisfactory results. Evidence obtained suggests promising potential of monoclonal antibodies and nuclear medicine, with immunoscintigraphy and radioimmunotherapy techniques providing alternatives for cancer diagnosis and treatment in Cuba.

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.

Intramyocardial gene transfer of vascular endothelial growth factor 121 improves myocardial perfusion and function in the ischemic porcine heart

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that is angiogenic in vitro and in vivo. Several studies report on gene transfer of VEGF121 to promote angiogenesis in the ischemic myocardium of animals and patients. We hypothesized that intramyocardial administration of naked plasmid DNA encoding VEGF121 could improve myocardial perfusion and function in a porcine model of myocardial ischemia. Yorkshire swine underwent thoracotomy and placement of an ameroid constrictor on the circumflex coronary artery. Four weeks later, pVEGF121 plasmid was administered into the ischemic myocardium. Four weeks after gene transfer, SPECT imaging demonstrated significant reduction in the ischemic area in pVEGF121-treated animals compared with controls. In the pVEGF121 group, most of the animals evolved from light ischemia to a normal perfusion. In contrast, control animals exhibited similar or impaired ischemic conditions. Our results indicate that intramyocardial gene transfer of VEGF121 as naked plasmid DNA results in significant improvement in myocardial perfusion and function.