Zoonotic tuberculosis in human beings caused by Mycobacterium bovis-a call for action.

Mycobacterium tuberculosis is recognised as the primary cause of human tuberculosis worldwide. However, substantial evidence suggests that the burden of Mycobacterium bovis, the cause of bovine tuberculosis, might be underestimated in human beings as the cause of zoonotic tuberculosis. In 2013, results from a systematic review and meta-analysis of global zoonotic tuberculosis showed that the same challenges and concerns expressed 15 years ago remain valid. These challenges faced by people with zoonotic tuberculosis might not be proportional to the scientific attention and resources allocated in recent years to other diseases. The burden of zoonotic tuberculosis in people needs important reassessment, especially in areas where bovine tuberculosis is endemic and where people live in conditions that favour direct contact with infected animals or animal products. As countries move towards detecting the 3 million tuberculosis cases estimated to be missed annually, and in view of WHO's end TB strategy endorsed by the health authorities of WHO Member States in 2014 to achieve a world free of tuberculosis by 2035, we call on all tuberculosis stakeholders to act to accurately diagnose and treat tuberculosis caused by M bovis in human beings.

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.

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.

Aspectos clínico-epidemiológicos en pacientes tratadas quirúrgicamente por enfermedad mamaria / Clinical-epidemiological aspects in patients surgically treatment due to breast disease

Introducción: el cáncer de mama constituye un gran problema de salud, ocupando la tercera causa más frecuente de cáncer en el mundo; mucho se ha investigado y escrito acerca de esa patología, cuyo alcance como problema de salud es muy significativo.Objetivo: describir la frecuencia con que se presentan ciertos aspectos clínicos y epidemiológicos en un grupo de pacientes diagnosticados y tratados quirúrgicamente por enfermedad mamariaMétodo: se realizó un estudio descriptivo, retrospectivo y transversal en pacientes con cáncer de mama, los cuales recibieron tratamiento quirúrgico en el Hospital General Docente Aleida Fernández Chardiet, durante el periodo de enero de 2001 a junio de 2005, en el municipio Güines, provincia Mayabeque. El universo estuvo conformado por todas los pacientes que fueron intervenidas quirúrgicamente, por alguna afección mamaria La muestra la constituyó los pacientes que fueron operados en este periodo, pero que presentaron alguna enfermedad maligna de la mama. Algunas de las variables analizadas fueron: la edad, el color de la piel, el autoexamen de mama.Resultados: el mayor porcentaje de pacientes estuvieron comprendidos entre 46-65 años, predominando el sexo femenino 98,1 por ciento, color blanco de la piel 88,5 por ciento. Elevado porciento de nódulos y dolor mamario como motivo de consulta; el 53,8 por ciento se realizaba autoexamen de mama. El 66,4 por ciento tuvo una sobrevida mayor de 5 años y actualmente más de la mitad 54,8 por ciento se encuentran vivas.Conclusiones: los pacientes diagnosticados con cáncer de mama y tratados quirúrgicamente en el área de salud, se asocian a un tiempo de sobrevida muy favorable, siendo el mayor motivo de consulta la presencia de nódulos y el dolor mamario

Introduction: breast cancer is a major health problem, ranking the third most common cause of cancer in the world, much has been researched and written about that pathology, of which scope as a health problem is very significant.Objective: To describe the frequency with which certain clinical and epidemiological aspects are presented in a group of patients diagnosed and surgically treated for breast disease.Method: a descriptive, retrospective and cross-sectional study was performed in patients with breast cancer who received surgical treatment at Aleida Fernández Chardiet General Teaching Hospital during the period from January 2001 to June 2005, in Güines municipality, Mayabeque province. The universe consisted of all patients who underwent surgery for some breast condition. The sample was constituted by all the patients who were operated in this period, but showed some malignant breast disease. Some of the variables analyzed were: age, skin color, breast self-examination.Results: the highest percentage of patients were between 46-65 years, predominantly female 98,1 per cent, white skin color 88,5 per cent. High percentage of nodules and breast pain as a reason for consultation, 53,8 per cent performed breast self-examination. 66,4 per cent had a higher survival rate of 5 years and currently more than half 54,8 per cent are alive.Conclusions: patients diagnosed with breast cancer and surgically treated in the health area, are associated with a favorable survival time, being the main reason for consultation the presence of nodules and breast pain

Radiofármacos en inmunocentelleografía y radioinmunoterapia / Radiopharmaceuticals in immunoscintigraphy and radioimmunotherapy

La alta morbilidad y letalidad del cáncer, hacen que esta enfermedad se considere, tanto en Cuba como en el mundo, un serio problema de salud. La radioimmunodiagnosis y la radioinmunoterapia, basadas en los crecientes avances en biotecnología y el conocimiento que hoy aportan la biología molecular y celular, devienen herramientas muy prometedoras en la lucha contra el cáncer. En este trabajo se hace una breve revisión de los radiofármacos desarrollados en Cuba, a partir de biomoléculas producidas y una panorámica de una serie de anticuerpos monoclonales y radionúclidos utilizados en aplicaciones clínicas. Las aplicaciones en radioimmunodiagnosis, se han basado en radiofármacos de 99mTc obtenidos a partir de kits liofilizados de anticuerpos monoclonales murinos. Se examinan también las perspectivas de la aplicación de radioinmunoterapia a partir de las experiencias internacionales, particularmente en el tratamiento del linfoma no Hodgkin, teniendo en cuenta la disponibilidad de diferentes anticuerpos monoclonales ya humanizados y de ? a partir de tecnologías existentes en centros cubanos de investigación-producción.

The high morbidity-mortality of cancer makes this condition in Cuba, and at international level, a serious health problem. Radioimmunodiagnosis and radioimmunotherapy based in the growing biotechnological advances, and the actual knowledge of molecular and cellular biology, become a highly promising tools in the fight against cancer. In this work we present a brief review of the radiopharmaceuticals developed in our country starting from biomolecules produced en Cuba, as well as a panoramic of several monoclonal antibodies and radionuclides used in clinical applications. Radioimmunodiagnosis applications are based on murine monoclonal antibodies, produced in form of lyophilized kits for ? labeling. We also examined the perspectives of the application of radioimmunotherapy in Cuba starting from the international experiences, particularly in non-Hodgkin’s lymphoma treatment, keeping in mind the availability of different monoclonal antibodies already humanized, as well as of ? from the existing technologies in Cuban research-production centers.

Biodistribución y farmacocinética de 99mTc-ciprofloxacina obtenida de una formulación modificada / Biokinetics performance of 99mTc-ciprofloxacin obtained from a new formulation

El propósito de la presente investigación fue evaluar el comportamiento biocinético de la 99mTc-ciprofloxacina obtenida de una nueva formulación. Un ensayo in vitro y un modelo de infección experimental demostraron su afinidad por bacterias vivas. La vida media en sangre fue de 5,89 +/- 0,85 horas. La biodistribución mostró alta acumulación en músculos infectados y baja en tejidos sanos.

The aim of the present investigation was to evaluate the biokinetics performance of 99mTc-ciprofloxacin obtained from a new formulation. Both in vitro assays and experimental infection models demonstrated its affinity for viable bacteria.Half life in blood was 5.89 +/- 0.85 hours. The biodistribution showed high accumulation on infected muscles and low on healthy tissues.

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.

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.

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.

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.

Evaluación de un método práctico para estabilizar el d, l-HMPAO / Evaluation of a practical method for stabilization of d, l-HMPAO

El objetivo de este estudio fue evaluar la estabilidad del d,l-HMPAO reconstituido y almacenado a -20º C. El kit se reconstituyó con un mililitro de solución salina. Fracciones de 0.333 mililitros fueron almacenadas a -20°C. El marcaje y el control de calidad se realizaron entre los 0-300 minutos posteriores. Fueron realizados estudios de SPECT cerebral y de cuerpo entero a 5 pacientes, con el kit intacto y con más de 30, 60 y 90 minutos de reconstituidos y almacenados. La calidad de las imágenes fue valorada por un observador experimentado. La integridad química se conservó por un tiempo de 2 horas (>80 por ciento de marcaje). Se acumuló en el cerebro entre 3,5-7 por ciento del 99mTc-d,l-HMPAO utilizando el producto hasta 90 minutos después de reconstituido. Las imágenes obtenidas fueron de adecuada utilidad clínica con un significativo ahorro de un 33,4 por ciento por cada dosis.

Pharmacological evaluation of humanized anti-epidermal growth factor receptor, monoclonal antibody h-R3, in patients with advanced epithelial-derived cancer.

Epidermal growth factor receptor (EGFR) overexpression has been detected in many tumors of epithelial origin, and it is often associated with tumor growth advantages and poor prognosis. h-R3 is a genetically engineered humanized antibody (mAb) that recognizes an epitope located in the extracellular domain of human EGFR. The antibody exhibited potent in vitro and in vivo antitumor effect on EGFR overexpressing cell lines. To study safety, pharmacokinetics, and biodistribution, 12 patients with advanced epithelial-derived tumors received single intravenous infusion of h-R3 at four dose levels. Safety evaluation was made according to World Health Organization toxicity criteria. For biodistribution, 3 mg of the total dose were labeled with Technetium and then pooled with the rest of the dose. Anterior and posterior whole-body images were acquired using a gamma camera. Blood samples were taken for pharmacokinetics, antiidiotypic response, and for soluble EGFR detection. After hR3 administration, no evidence of severe toxicity was observed. Secondary reactions were mild and moderate and mainly consisted of tremors, fever, and vomiting. No anaphylactic or skin reactions were detected. Qualitative analysis of whole-body images showed that the liver had the highest mAb uptake. Pharmacokinetic analysis revealed that elimination half-lives and the AUC increased linearly with dose, while total body clearance decreased when increasing doses of h-R3. No relation between shed EGFR and mAb clearance was found. No antiidiotypic response against h-R3 was detected. Several phase II trials are now underway to evaluate the efficacy of h-R3 in the treatment of advanced cancer patients.