Uma média de 80 % dos radiofármacos usados nas clínicas são marcados com 99mTc por suas propriedades físicas adequadas e fácil obtenção através de geradores de 99Mo/99mTc. A Diretoria de Radiofarmácia (DIRF) do IPEN-CNEN/SP desenvolveu um gerador cromatográfico tipo gel de MoZr com 99Mo produzido pela da reação 98Mo(n,)99Mo que ocorre no reator Nuclear IEA-R1 do IPEN-CNEN/SP. O gel é composto de molibdato de zircônio com volume de eluição de 12 mL com uma atividade de 11100 MBq (300 mCi) produzindo uma concentração radioativa de 925 MBq (25 mCi)/mL. O gerador de fissão produz uma concentração radioativa maior, de 1850 MBq (50 mCi)/mL. Pretende-se com esse trabalho desenvolver um gerador 99 Mo/99mTc tipo gel com a qual se possa eluir 99mTc obtendo-se uma concentração radioativa adequada para atender a demanda de mercado sem perder a qualidade. Foram desenvolvidos dois tipos de sistemas de concentração o único e o em série. O sistema mais adequado para o gerador de 99Mo/99mTc do tipo gel de MoZr estéril e automatizado à vácuo foi o sistema de concentração em série utilizando o cartucho Dionex 2,5 cc/QMA. O gerador de gel é eluído com 10 mL de solução de NaCl 0,1 % sendo o pertecnetato retido no cartucho aniônico QMA e eluído com 4 mL de solução de NaCl de 0,9 %. O processo dura no máximo 30 minutos. A eficiência de eluição do sistema de concentração foi de 90 %. No início de 2009 aconteceu uma crise mundial do abastecimento de 99Mo fazendo com que surgisse a necessidade do desenvolvimento de tecnologias alternativas para a produção de geradores de 99Mo/99mTc utilizando 99Mo produzido por fissão ou o desenvolvimento de um método adequado para estender a vida útil deste gerador. Os resultados deste trabalho mostraram que é possível utilizar o mesmo sistema de concentração desenvolvido para o gerador de gel, o que levará a um fator de concentração de 3 para o 99mTc eluído. / On average 80% of the radiopharmaceuticals used in Nuclear Medicine are labeled with 99mTc due to its physical properties and easy attainment through of 99Mo/99mTc generators. The Directory of Radiopharmacy (DIRF) of IPEN-CNEN/SP developed a gel type chromatographic generator of MoZr with 99Mo produced by 98Mo(n,)99Mo reaction that occurs at the IEA-R1 Nuclear Reactor. The gel is composed of zirconium molibdate with elution volume of 12 mL with an activity of 11100 MBq (300 mCi) producing a radioactive concentration of 925 MBq (25 mCi)/mL. The fission generator gives a higher radioactive concentration around 1850 MBq (50 mCi)/mL. The aim of this work is to study a system of post-elution concentration of 99mTc for the attainment of a high enough radioactive concentration to meet the demands of the market, with a proved quality. Two types of systems of post-elution concentration were developed: the single and the tandem. The most appropriate system for the gel generator of 99Mo/99mTc, being at the same time sterile and vacuum automated, was the tandem system using Dionex 2.5 cc/QMA cartridges. The gel generator is eluted with 10 mL of solution of 0.1% NaCl and the pertechnetate anion is retained in the QMA cartridge and further eluted with 4 mL of saline. The process takes no more than 30 minutes. The elution efficiency of the system of concentration was 90 %. At the beginning of 2009 a global crisis in the supply of 99Mo took place making it necessary the development of alternative technologies for the production of 99Mo/99mTc generators using fission produced 99Mo and the development of an appropriate method to extend the useful life of this generator. The results of this study showed that the same system developed for the post- concentration of the gel generator can be employed for the fission generator, using the tandem system, giving a concentration factor of 3 for the elution of 99mTc.

Thesis(MSc(Med)Pharmacy)) -- University of Limpopo, 2011. / ABSTRACT Introduction: Non-invasive detection of tumour hypoxia theoretically adds value to the. outcome of treatment; however the practical aspect of using 99mTc-EC-MN in cervical cancer remains un-attempted. 99mTc-EC-MN has been used to indirectly detect hypoxia in many tumours (head and neck) and other hypoxic states such as strokes and MI. This study aims to determine the value of using this tracer in early stage cervical cancer. Objectives: This study aimed to investigate the use of 99mTc-EC-MN to determine the degree of hypoxia in cervical cancer. The original study design was to determine whether SPECT with 99mTc-EC-MN would detect ~l'poxi~cervicalc;ancer 'lesions and compare the results with the histological report. The practice of safe handling of radiopharmaceuticals and gaining knowledge in conducting research formed part of the secondary objective of the study. Due to circumstances beyond the control of the researcher, the focus of the study changed from a clinical to a chemistry-based project. Method development: Safety of EC-MN was tested through determination of the labelling efficiency with pertechnetate initially by ITLC-SG. Ethyl acetate, ethanol, saline and ac;etone were selected to develop 99mTc-EC-MN chromatograms to identify the system which best displays separation. Radio-ITLC displayed multiple peaks due to high residual activity in ethyl acetate- and acetone-developed scans. Saline- and ethanol-developed scans showed better separation of 99mTc-EC-MN but separation from free pertechnetate was difficult. Radio HPLC coupled with a diode array detector was used to successfully separate the labelled product, 99mTc-EC-MN from free pertechnetate, thereby achieving good radiolabelling. Clinical application: After the relative safety of the product was established, it was injected IV in the selected patient who had early stage cervical carcinoma. Clinical examinations which included pre-operative WBC, ultrasonography of the kidneys and bladder, and chest x-rays were performed. Histological analysis was performed after surgery and gave results that were insufficient to conclude the absence or the presence of tumour hypoxia. Detection of 99mTc-EC-MN was analysed from blood-flow and -pool images, thyroid and pelvic static, SPECT, and WBS images obtained from a gamma scintillation camera. Faint hot spots consistent with low levels of free pertechnetate were detected in the salivary glands. Hot areas which paralleled the bio-distribution of the 99mTc-EC-MN were also detected in the thyroid, liver, intestines, kidneys, and bladder. There was no tracer detection in the pelvic area. Conclusions: Experience was gained in QC procedures and aseptic preparation of radiopharmaceuticals, and in conducting and co-managing a chemical and clinical based research. Radiochemically related findings demonstrated that tin (II) chloride can be solubilised in water; 99mTc-EC-MN migrates with the solvent front in saline and ethanol developed ITLSG scans; and ITLC cannot sufficiently separate 99mTc-EC-MN from free pertechnetate. Successful labelling of EC-MN was confirmed by scintigraphy and showed tracer distribution that parallels those previously described. Successful labelling of EC-MN with 99mTc can be achieved up to two years after kit manufacture given appropriate storage conditions for the EC-MN. The hypoxic status of the tumour remained inconclusive; therefore the prognostic impact of 99mTc-EC-MN in cervical cancer remains unknown. Recommendations: Product stability and potential expiry should be available for all products, even in the developmental stages and particularly for clinical trials. A simple QC method to separate 99mTc-EC-MN from free pertechnetate should be developed. Further studies are required in order to confirm the efficacy of 99mTc-EC-NM in determining tumour hypoxia in cervical cancer. If a suitable animal model is not available, patients with known cancer tissue hypoxia should be evaluated and compared with those who are non-hypoxic

Uma média de 80 % dos radiofármacos usados nas clínicas são marcados com 99mTc por suas propriedades físicas adequadas e fácil obtenção através de geradores de 99Mo/99mTc. A Diretoria de Radiofarmácia (DIRF) do IPEN-CNEN/SP desenvolveu um gerador cromatográfico tipo gel de MoZr com 99Mo produzido pela da reação 98Mo(n,)99Mo que ocorre no reator Nuclear IEA-R1 do IPEN-CNEN/SP. O gel é composto de molibdato de zircônio com volume de eluição de 12 mL com uma atividade de 11100 MBq (300 mCi) produzindo uma concentração radioativa de 925 MBq (25 mCi)/mL. O gerador de fissão produz uma concentração radioativa maior, de 1850 MBq (50 mCi)/mL. Pretende-se com esse trabalho desenvolver um gerador 99 Mo/99mTc tipo gel com a qual se possa eluir 99mTc obtendo-se uma concentração radioativa adequada para atender a demanda de mercado sem perder a qualidade. Foram desenvolvidos dois tipos de sistemas de concentração o único e o em série. O sistema mais adequado para o gerador de 99Mo/99mTc do tipo gel de MoZr estéril e automatizado à vácuo foi o sistema de concentração em série utilizando o cartucho Dionex 2,5 cc/QMA. O gerador de gel é eluído com 10 mL de solução de NaCl 0,1 % sendo o pertecnetato retido no cartucho aniônico QMA e eluído com 4 mL de solução de NaCl de 0,9 %. O processo dura no máximo 30 minutos. A eficiência de eluição do sistema de concentração foi de 90 %. No início de 2009 aconteceu uma crise mundial do abastecimento de 99Mo fazendo com que surgisse a necessidade do desenvolvimento de tecnologias alternativas para a produção de geradores de 99Mo/99mTc utilizando 99Mo produzido por fissão ou o desenvolvimento de um método adequado para estender a vida útil deste gerador. Os resultados deste trabalho mostraram que é possível utilizar o mesmo sistema de concentração desenvolvido para o gerador de gel, o que levará a um fator de concentração de 3 para o 99mTc eluído. / On average 80% of the radiopharmaceuticals used in Nuclear Medicine are labeled with 99mTc due to its physical properties and easy attainment through of 99Mo/99mTc generators. The Directory of Radiopharmacy (DIRF) of IPEN-CNEN/SP developed a gel type chromatographic generator of MoZr with 99Mo produced by 98Mo(n,)99Mo reaction that occurs at the IEA-R1 Nuclear Reactor. The gel is composed of zirconium molibdate with elution volume of 12 mL with an activity of 11100 MBq (300 mCi) producing a radioactive concentration of 925 MBq (25 mCi)/mL. The fission generator gives a higher radioactive concentration around 1850 MBq (50 mCi)/mL. The aim of this work is to study a system of post-elution concentration of 99mTc for the attainment of a high enough radioactive concentration to meet the demands of the market, with a proved quality. Two types of systems of post-elution concentration were developed: the single and the tandem. The most appropriate system for the gel generator of 99Mo/99mTc, being at the same time sterile and vacuum automated, was the tandem system using Dionex 2.5 cc/QMA cartridges. The gel generator is eluted with 10 mL of solution of 0.1% NaCl and the pertechnetate anion is retained in the QMA cartridge and further eluted with 4 mL of saline. The process takes no more than 30 minutes. The elution efficiency of the system of concentration was 90 %. At the beginning of 2009 a global crisis in the supply of 99Mo took place making it necessary the development of alternative technologies for the production of 99Mo/99mTc generators using fission produced 99Mo and the development of an appropriate method to extend the useful life of this generator. The results of this study showed that the same system developed for the post- concentration of the gel generator can be employed for the fission generator, using the tandem system, giving a concentration factor of 3 for the elution of 99mTc.

Background: The molecular and cellular mechanisms corresponding to the compensatory and maladaptive hypertrophy and remodeling of the left ventricle with chronic doxorubicin (DOX) treatment are currently unclear. Non-invasive methods of determining these changes are still deficient. To investigate these changes, 8 groups of rats in 4 different studies including a control saline group of the same age, gender and strain were evaluated for cardiac morphology and function including: (1) DOX dose response using a cumulative dose of 7.5mg/kg, and 15mg/kg in 8-10 week old female Sprague-Dawley (SD) rats, (2) strain differences were investigated in response to a cumulative dose of 15mg/kg in 8-10 week old female Fisher (F344) rats compared to the SD rats treated with same dose, (3) the role of gender and aging were studied in response to DOX at a cumulative dose of 3mg/kg in male and female neonates, and (4) combined losartan and a cumulative dose of 15mg/kg of DOX in 8-10 week old female SD rats compared to controls of saline and 15mg/kg treated SD rats. Method: Onset of cardiac toxicity was assessed by echocardiography and the rat model of heart failure was developed when the fractional shortening declined ≤ 40%. The mean arterial pressure and single-photon-emission computer tomography scanning and Tc-99m-HYNIC-Annexin V were performed at week 10 to analyze blood pressure and quantify apoptosis, respectively. All rats were euthanized at week 10 except for the neonates and two of the 7.5mg/kg-treated SD rats that were left alive for study of long -term cardiac side effects. The heart and kidney tissues were harvested for protein isolation and histopathological studies. Blood samples were collected for hematological and lipid profile analysis in all the rats. Results: A dose- and time-dependent increase in LVmass coincided with a parallel increase in MAP, kidney damage, expression of myocardial erbB2, heat shock protein 90 Akt, mTOR, GSK-3β, TGF-β, pSMAD2, and cardiomyocyte apoptosis in SD rats treated with 7.5mg/kg and 15mg/kg of DOX at week 10. The 7.5 kg/kg treatment showed adaptive hypertrophy whereas the 15mg/kg treatment group showed maladaptive hypertrophy. However decompensation was apparent by week 14 in other rats treated with 7.5mg/kg. LVmass, FS, MAP, kidney damage, red blood cells and blood lipid levels were not significantly altered in the F344 rats compared to the 15 mg/kg-treated SD rats. Losartan supplementation reduced the left ventricular hypertrophy, improved myocardial contractility, and reduced TGF-β expression compared to the DOX-treated SD rats. The 3mg/kg of DOX in neonates induced cardiac toxicity and deaths in about 60% of males 50 weeks after treatment; the females instead developed mammary tumors. Conclusion: The results of this study suggest that age, gender, and strain differences are risks factors for doxorubicin-induced harmful reno-cardiovascular toxicity. The inhibition of TGF-β expression by losartan can be used in prevention of chronic doxorubicin-induced cardiac toxicity without interfering with its anti-tumor activities.

Background: The molecular and cellular mechanisms corresponding to the compensatory and maladaptive hypertrophy and remodeling of the left ventricle with chronic doxorubicin (DOX) treatment are currently unclear. Non-invasive methods of determining these changes are still deficient. To investigate these changes, 8 groups of rats in 4 different studies including a control saline group of the same age, gender and strain were evaluated for cardiac morphology and function including: (1) DOX dose response using a cumulative dose of 7.5mg/kg, and 15mg/kg in 8-10 week old female Sprague-Dawley (SD) rats, (2) strain differences were investigated in response to a cumulative dose of 15mg/kg in 8-10 week old female Fisher (F344) rats compared to the SD rats treated with same dose, (3) the role of gender and aging were studied in response to DOX at a cumulative dose of 3mg/kg in male and female neonates, and (4) combined losartan and a cumulative dose of 15mg/kg of DOX in 8-10 week old female SD rats compared to controls of saline and 15mg/kg treated SD rats. Method: Onset of cardiac toxicity was assessed by echocardiography and the rat model of heart failure was developed when the fractional shortening declined ≤ 40%. The mean arterial pressure and single-photon-emission computer tomography scanning and Tc-99m-HYNIC-Annexin V were performed at week 10 to analyze blood pressure and quantify apoptosis, respectively. All rats were euthanized at week 10 except for the neonates and two of the 7.5mg/kg-treated SD rats that were left alive for study of long -term cardiac side effects. The heart and kidney tissues were harvested for protein isolation and histopathological studies. Blood samples were collected for hematological and lipid profile analysis in all the rats. Results: A dose- and time-dependent increase in LVmass coincided with a parallel increase in MAP, kidney damage, expression of myocardial erbB2, heat shock protein 90 Akt, mTOR, GSK-3β, TGF-β, pSMAD2, and cardiomyocyte apoptosis in SD rats treated with 7.5mg/kg and 15mg/kg of DOX at week 10. The 7.5 kg/kg treatment showed adaptive hypertrophy whereas the 15mg/kg treatment group showed maladaptive hypertrophy. However decompensation was apparent by week 14 in other rats treated with 7.5mg/kg. LVmass, FS, MAP, kidney damage, red blood cells and blood lipid levels were not significantly altered in the F344 rats compared to the 15 mg/kg-treated SD rats. Losartan supplementation reduced the left ventricular hypertrophy, improved myocardial contractility, and reduced TGF-β expression compared to the DOX-treated SD rats. The 3mg/kg of DOX in neonates induced cardiac toxicity and deaths in about 60% of males 50 weeks after treatment; the females instead developed mammary tumors. Conclusion: The results of this study suggest that age, gender, and strain differences are risks factors for doxorubicin-induced harmful reno-cardiovascular toxicity. The inhibition of TGF-β expression by losartan can be used in prevention of chronic doxorubicin-induced cardiac toxicity without interfering with its anti-tumor activities.

Los objetivos básicos de este trabajo son: 1. Valorar la sensibilidad, especificidad, valor global, valor predictivo positivo y valor predictivo negativo de la tomogammagrafía de perfusión gatillada con 99mTc MIBI para el diagnóstico de la enfermedad coronaria en los pacientes sin infarto previo. 2. Aplicar el teorema de Bayes con la finalidad de determinar para qué valores de prevalencia de la enfermedad coronaria resulta más apropiada la indicación de la tomogammagrafía de perfusión con 99mTc MIBI. 3. Comprobar cuáles son los niveles mínimos de consumo miocárdico de oxigeno (frecuencia cardíaca, presión arterial sistólica y producto frecuencia cardiaca por presión arterial sistólica) y de consumo máximo de oxigeno (Mets) para conseguir un rendimiento óptimo de la tomogammagrafía de perfusión con 99mTc MIBI. 4. Estudiar el incremento que representa para la precisión diagnóstica de la tomogammagrafía de perfusión con 99mTc MIBI el asociar la administración de dipiridamol endovenoso durante la realización de la prueba de esfuerzo convencional en aquellos pacientes en los que la ergometría es insuficiente. 5. Valorar el rendimiento diagnóstico de la adicion de atropina a dipiridamol en pacientes con imposibilidad para realizar esfuerzos físicos. 6. Determinar el papel de la tomogammagrafía de perfusión con 99mTc MIBI en el diagnóstico de la enfermedad coronaria multivaso. 7. Comprobar el grado de coincidencia entre la tomogammagrafía de perfusión 99mTc MIBI y la coronariografía en el diagnóstico de la lesión culpable. 8. Cuantificar el miocardio en riesgo mediante la tomogammagrafía de perfusión con 99mTc MIBI y correlacionarlo con la cuantificación coronariográfica. 9. Valorar la fracción de eyección, volúmenes ventriculares de fin de sístole y de diástole y el engrosamiento sistólico con mapa polar inmediatamente posterior al apremio físico o farmacológico y en reposo para cuantificar la progresión fisiologica de la función ventricular o el deterioro de la contractilidad secundaria a la presencia de isquemia y/o atontamiento miocárdico.

Introdução: A incidência do melanoma cutâneo (MC) está crescendo mais rapidamente que a de qualquer outro câncer. Devido ao seu potencial para metástases e à falta de terapias efetivas para a maioria dos pacientes em estágio avançado, o diagnóstico precoce do MC é crucial. Alguns dos fatores prognósticos mais importantes no MC são a espessura de Breslow e a presença de metástase linfonodal. O Tecnécio-99m-sestamibi (MIBI) é um radiofármaco usado rotineiramente em cintilografias miocárdicas e tem conhecidas propriedades para detecção de tumores malignos, incluindo câncer de mama, tumores cerebrais e melanomas primários e metastáticos. Objetivo: Avaliar a correlação entre a espessura de Breslow e a intensidade da captação de MIBI (IC-MIBI) em lesões primárias de MC. Métodos: Foram selecionados pacientes com lesões clinica e dermatoscopicamente suspeitas de MC. Os pacientes receberam uma injeção intravenosa de 740 – 1110 MBq (20 mCi) de MIBI. Após 10 minutos, o equipamento gamma-probe foi usado para detectar a IC-MIBI na lesão cutânea e em 2 pontos equidistantes na pele normal. A razão entre as contagens radioativas na lesão e a média da pele normal foi considerada a IC-MIBI. A seguir, pacientes realizaram SPECT (Single Photon Emission Computed Tomography) do local da lesão e da região linfonodal correspondente. Exérese da lesão cutânea e exame anatomopatológico foram então realizados. Pacientes portadores de lesões com Breslow > 1 mm ou < 1mm com ulceração/regressão espontânea realizaram biópsia do linfonodo sentinela. Resultados: Dezesseis pacientes com 20 lesões foram estudados (8 homens, 8 mulheres, de 34 – 81 anos, média 61 anos). Quatorze lesões eram melanomas e 6 eram nevos melanocíticos (NM). Cinco lesões eram melanomas in situ. A média da espessura de Breslow foi de 0,45 mm (variação: 0,30 – 14,90 mm). A média da IC-MIBI foi 1,54 (±0.58) contagens radioativas nos MC e 1,04 (±0.10) nos NM (P = 0.007). Houve forte correlação positiva entre a IC-MIBI e a espessura de Breslow (rs = 0.74, P= 0.003). Analisando as lesões em categorias de Breslow, houve diferença estatisticamente significativa (P < 0.001) entre as lesões com Breslow < 1mm (IC-MIBI = 1.23 ± 0.28 contagens radioativas) e Breslow > 1 mm (IC-MIBI = 2.32 ± 0.32 contagens radioativas). Nenhum dos NM apareceu nas imagens de SPECT. Dos MC, 4 lesões, que apresentavam Breslow > 1mm, apareceram nas imagens de SPECT. Conclusão: Neste estudo, embora tenha demonstrado uma diferença significativa entre melanomas finos (< 1mm) e espessos (> 1mm), a IC-MIBI no local da lesão não foi diferente entre NM e melanomas finos ou in situ. Por isso, MIBI parece ser útil principalmente em melanomas espessos, o que também foi confirmado pela positividade do SPECT apenas nestes casos. Entretanto, a possibilidade de correlacionar a IC-MIBI com categorias de Breslow pode facilitar os procedimentos cirúrgicos, permitindo a remoção de melanomas com margens cirúrgicas adequadas e a realização ou não de biópsia de linfonodo sentinela em um mesmo momento cirúrgico, reduzindo morbidade e custos. / Introduction: Given its propensity to metastasize, and lack of effective therapies for most patients with advanced disease, early detection of melanoma is a clinical imperative. The most important prognostic factors are Breslow thickness and nodal metastases. Technetium-99m-sestamibi (MIBI) is a radiopharmaceutical used routinely for cardiologic scintigraphy and has also well-known tumor-seeking properties. It has been used successfully to detect various tumors, including breast cancer, brain tumors, and primary and metastatic melanoma. Objetive: This study has been designed in order to evaluate the correlation between Breslow thickness and MIBI uptake by primary CM lesions. Methods: Patients were recruited by a dermatologist on the grounds of a clinically and dermoscopically suspicious melanocytic lesion. Patients received intravenous injection of 740 – 1110 MBq (20 mCi) of MIBI. After 10 minutes, gamma-probe was used to detect the intensity of MIBI uptake by the cutaneous lesion and at two equidistant points on normal skin. The ratio number of radioactive counts at cutaneous lesion / mean of radioactive counts at normal skin was considered to determinate the MIBI uptake intensity (MIBI-UI). Then, SPECT imaging of the lesion site and respective lymph node region was obtained. After scintigraphy, exeresis of the cutaneous lesion and histological analysis were performed. Lesions with Breslow thickness > 1 mm or < 1 mm with ulceration/spontaneous regression underwent sentinel lymph node biopsy. Results: Sixteen patients with 20 lesions were investigated (8 males, 8 females, age range 34 – 81 years, mean 61 years). Fourteen lesions were CM and 6 were melanocytic nevi (MN). Five lesions were melanoma in situ. Breslow thickness median was 0.45 mm (range 0.30 - 14,9 mm). The mean MIBI-UI was 1.54 (±0.58) radioactive counts in CM and 1.04 (±0.10) radioactive counts in MN (P = 0.007). There was strong positive correlation between MIBI-UI and Breslow thickness (rs = 0.74, P= 0.003). Grouping the lesions on Breslow categories, there was a statistically significant difference (P < 0.001) between lesions with Breslow thickness < 1 mm (MIBI-UI = 1.23 ± 0.28 radioactive counts) and Breslow thickness > 1 mm (MIBI-UI = 2.32 ± 0.32 radioactive counts). None of the MN appeared at SPECT images. Of melanomas, 4 (28,6%) were SPECT positive at cutaneous site. All those were Breslow thickness > 1 mm. Conclusion: On this study, although there is a significant difference between thin (< 1 mm) and thick (> 1 mm) melanomas, MIBI intensity at the lesion site is not different between benign nevus and in situ or thin melanomas. Then, MIBI seems to be useful mainly in thick melanomas, as also confirmed by the positivity of the SPECT image only in these cases. However, the possibility of correlating MIBI uptake intensity with Breslow categories may facilitate surgical procedures, allowing to remove melanomas with appropriated surgical margins and to perform or not sentinel lymph node biopsy in the same surgical time, reducing morbidity and cost.

Introdução: A incidência do melanoma cutâneo (MC) está crescendo mais rapidamente que a de qualquer outro câncer. Devido ao seu potencial para metástases e à falta de terapias efetivas para a maioria dos pacientes em estágio avançado, o diagnóstico precoce do MC é crucial. Alguns dos fatores prognósticos mais importantes no MC são a espessura de Breslow e a presença de metástase linfonodal. O Tecnécio-99m-sestamibi (MIBI) é um radiofármaco usado rotineiramente em cintilografias miocárdicas e tem conhecidas propriedades para detecção de tumores malignos, incluindo câncer de mama, tumores cerebrais e melanomas primários e metastáticos. Objetivo: Avaliar a correlação entre a espessura de Breslow e a intensidade da captação de MIBI (IC-MIBI) em lesões primárias de MC. Métodos: Foram selecionados pacientes com lesões clinica e dermatoscopicamente suspeitas de MC. Os pacientes receberam uma injeção intravenosa de 740 – 1110 MBq (20 mCi) de MIBI. Após 10 minutos, o equipamento gamma-probe foi usado para detectar a IC-MIBI na lesão cutânea e em 2 pontos equidistantes na pele normal. A razão entre as contagens radioativas na lesão e a média da pele normal foi considerada a IC-MIBI. A seguir, pacientes realizaram SPECT (Single Photon Emission Computed Tomography) do local da lesão e da região linfonodal correspondente. Exérese da lesão cutânea e exame anatomopatológico foram então realizados. Pacientes portadores de lesões com Breslow > 1 mm ou < 1mm com ulceração/regressão espontânea realizaram biópsia do linfonodo sentinela. Resultados: Dezesseis pacientes com 20 lesões foram estudados (8 homens, 8 mulheres, de 34 – 81 anos, média 61 anos). Quatorze lesões eram melanomas e 6 eram nevos melanocíticos (NM). Cinco lesões eram melanomas in situ. A média da espessura de Breslow foi de 0,45 mm (variação: 0,30 – 14,90 mm). A média da IC-MIBI foi 1,54 (±0.58) contagens radioativas nos MC e 1,04 (±0.10) nos NM (P = 0.007). Houve forte correlação positiva entre a IC-MIBI e a espessura de Breslow (rs = 0.74, P= 0.003). Analisando as lesões em categorias de Breslow, houve diferença estatisticamente significativa (P < 0.001) entre as lesões com Breslow < 1mm (IC-MIBI = 1.23 ± 0.28 contagens radioativas) e Breslow > 1 mm (IC-MIBI = 2.32 ± 0.32 contagens radioativas). Nenhum dos NM apareceu nas imagens de SPECT. Dos MC, 4 lesões, que apresentavam Breslow > 1mm, apareceram nas imagens de SPECT. Conclusão: Neste estudo, embora tenha demonstrado uma diferença significativa entre melanomas finos (< 1mm) e espessos (> 1mm), a IC-MIBI no local da lesão não foi diferente entre NM e melanomas finos ou in situ. Por isso, MIBI parece ser útil principalmente em melanomas espessos, o que também foi confirmado pela positividade do SPECT apenas nestes casos. Entretanto, a possibilidade de correlacionar a IC-MIBI com categorias de Breslow pode facilitar os procedimentos cirúrgicos, permitindo a remoção de melanomas com margens cirúrgicas adequadas e a realização ou não de biópsia de linfonodo sentinela em um mesmo momento cirúrgico, reduzindo morbidade e custos. / Introduction: Given its propensity to metastasize, and lack of effective therapies for most patients with advanced disease, early detection of melanoma is a clinical imperative. The most important prognostic factors are Breslow thickness and nodal metastases. Technetium-99m-sestamibi (MIBI) is a radiopharmaceutical used routinely for cardiologic scintigraphy and has also well-known tumor-seeking properties. It has been used successfully to detect various tumors, including breast cancer, brain tumors, and primary and metastatic melanoma. Objetive: This study has been designed in order to evaluate the correlation between Breslow thickness and MIBI uptake by primary CM lesions. Methods: Patients were recruited by a dermatologist on the grounds of a clinically and dermoscopically suspicious melanocytic lesion. Patients received intravenous injection of 740 – 1110 MBq (20 mCi) of MIBI. After 10 minutes, gamma-probe was used to detect the intensity of MIBI uptake by the cutaneous lesion and at two equidistant points on normal skin. The ratio number of radioactive counts at cutaneous lesion / mean of radioactive counts at normal skin was considered to determinate the MIBI uptake intensity (MIBI-UI). Then, SPECT imaging of the lesion site and respective lymph node region was obtained. After scintigraphy, exeresis of the cutaneous lesion and histological analysis were performed. Lesions with Breslow thickness > 1 mm or < 1 mm with ulceration/spontaneous regression underwent sentinel lymph node biopsy. Results: Sixteen patients with 20 lesions were investigated (8 males, 8 females, age range 34 – 81 years, mean 61 years). Fourteen lesions were CM and 6 were melanocytic nevi (MN). Five lesions were melanoma in situ. Breslow thickness median was 0.45 mm (range 0.30 - 14,9 mm). The mean MIBI-UI was 1.54 (±0.58) radioactive counts in CM and 1.04 (±0.10) radioactive counts in MN (P = 0.007). There was strong positive correlation between MIBI-UI and Breslow thickness (rs = 0.74, P= 0.003). Grouping the lesions on Breslow categories, there was a statistically significant difference (P < 0.001) between lesions with Breslow thickness < 1 mm (MIBI-UI = 1.23 ± 0.28 radioactive counts) and Breslow thickness > 1 mm (MIBI-UI = 2.32 ± 0.32 radioactive counts). None of the MN appeared at SPECT images. Of melanomas, 4 (28,6%) were SPECT positive at cutaneous site. All those were Breslow thickness > 1 mm. Conclusion: On this study, although there is a significant difference between thin (< 1 mm) and thick (> 1 mm) melanomas, MIBI intensity at the lesion site is not different between benign nevus and in situ or thin melanomas. Then, MIBI seems to be useful mainly in thick melanomas, as also confirmed by the positivity of the SPECT image only in these cases. However, the possibility of correlating MIBI uptake intensity with Breslow categories may facilitate surgical procedures, allowing to remove melanomas with appropriated surgical margins and to perform or not sentinel lymph node biopsy in the same surgical time, reducing morbidity and cost.

Introdução: A incidência do melanoma cutâneo (MC) está crescendo mais rapidamente que a de qualquer outro câncer. Devido ao seu potencial para metástases e à falta de terapias efetivas para a maioria dos pacientes em estágio avançado, o diagnóstico precoce do MC é crucial. Alguns dos fatores prognósticos mais importantes no MC são a espessura de Breslow e a presença de metástase linfonodal. O Tecnécio-99m-sestamibi (MIBI) é um radiofármaco usado rotineiramente em cintilografias miocárdicas e tem conhecidas propriedades para detecção de tumores malignos, incluindo câncer de mama, tumores cerebrais e melanomas primários e metastáticos. Objetivo: Avaliar a correlação entre a espessura de Breslow e a intensidade da captação de MIBI (IC-MIBI) em lesões primárias de MC. Métodos: Foram selecionados pacientes com lesões clinica e dermatoscopicamente suspeitas de MC. Os pacientes receberam uma injeção intravenosa de 740 – 1110 MBq (20 mCi) de MIBI. Após 10 minutos, o equipamento gamma-probe foi usado para detectar a IC-MIBI na lesão cutânea e em 2 pontos equidistantes na pele normal. A razão entre as contagens radioativas na lesão e a média da pele normal foi considerada a IC-MIBI. A seguir, pacientes realizaram SPECT (Single Photon Emission Computed Tomography) do local da lesão e da região linfonodal correspondente. Exérese da lesão cutânea e exame anatomopatológico foram então realizados. Pacientes portadores de lesões com Breslow > 1 mm ou < 1mm com ulceração/regressão espontânea realizaram biópsia do linfonodo sentinela. Resultados: Dezesseis pacientes com 20 lesões foram estudados (8 homens, 8 mulheres, de 34 – 81 anos, média 61 anos). Quatorze lesões eram melanomas e 6 eram nevos melanocíticos (NM). Cinco lesões eram melanomas in situ. A média da espessura de Breslow foi de 0,45 mm (variação: 0,30 – 14,90 mm). A média da IC-MIBI foi 1,54 (±0.58) contagens radioativas nos MC e 1,04 (±0.10) nos NM (P = 0.007). Houve forte correlação positiva entre a IC-MIBI e a espessura de Breslow (rs = 0.74, P= 0.003). Analisando as lesões em categorias de Breslow, houve diferença estatisticamente significativa (P < 0.001) entre as lesões com Breslow < 1mm (IC-MIBI = 1.23 ± 0.28 contagens radioativas) e Breslow > 1 mm (IC-MIBI = 2.32 ± 0.32 contagens radioativas). Nenhum dos NM apareceu nas imagens de SPECT. Dos MC, 4 lesões, que apresentavam Breslow > 1mm, apareceram nas imagens de SPECT. Conclusão: Neste estudo, embora tenha demonstrado uma diferença significativa entre melanomas finos (< 1mm) e espessos (> 1mm), a IC-MIBI no local da lesão não foi diferente entre NM e melanomas finos ou in situ. Por isso, MIBI parece ser útil principalmente em melanomas espessos, o que também foi confirmado pela positividade do SPECT apenas nestes casos. Entretanto, a possibilidade de correlacionar a IC-MIBI com categorias de Breslow pode facilitar os procedimentos cirúrgicos, permitindo a remoção de melanomas com margens cirúrgicas adequadas e a realização ou não de biópsia de linfonodo sentinela em um mesmo momento cirúrgico, reduzindo morbidade e custos. / Introduction: Given its propensity to metastasize, and lack of effective therapies for most patients with advanced disease, early detection of melanoma is a clinical imperative. The most important prognostic factors are Breslow thickness and nodal metastases. Technetium-99m-sestamibi (MIBI) is a radiopharmaceutical used routinely for cardiologic scintigraphy and has also well-known tumor-seeking properties. It has been used successfully to detect various tumors, including breast cancer, brain tumors, and primary and metastatic melanoma. Objetive: This study has been designed in order to evaluate the correlation between Breslow thickness and MIBI uptake by primary CM lesions. Methods: Patients were recruited by a dermatologist on the grounds of a clinically and dermoscopically suspicious melanocytic lesion. Patients received intravenous injection of 740 – 1110 MBq (20 mCi) of MIBI. After 10 minutes, gamma-probe was used to detect the intensity of MIBI uptake by the cutaneous lesion and at two equidistant points on normal skin. The ratio number of radioactive counts at cutaneous lesion / mean of radioactive counts at normal skin was considered to determinate the MIBI uptake intensity (MIBI-UI). Then, SPECT imaging of the lesion site and respective lymph node region was obtained. After scintigraphy, exeresis of the cutaneous lesion and histological analysis were performed. Lesions with Breslow thickness > 1 mm or < 1 mm with ulceration/spontaneous regression underwent sentinel lymph node biopsy. Results: Sixteen patients with 20 lesions were investigated (8 males, 8 females, age range 34 – 81 years, mean 61 years). Fourteen lesions were CM and 6 were melanocytic nevi (MN). Five lesions were melanoma in situ. Breslow thickness median was 0.45 mm (range 0.30 - 14,9 mm). The mean MIBI-UI was 1.54 (±0.58) radioactive counts in CM and 1.04 (±0.10) radioactive counts in MN (P = 0.007). There was strong positive correlation between MIBI-UI and Breslow thickness (rs = 0.74, P= 0.003). Grouping the lesions on Breslow categories, there was a statistically significant difference (P < 0.001) between lesions with Breslow thickness < 1 mm (MIBI-UI = 1.23 ± 0.28 radioactive counts) and Breslow thickness > 1 mm (MIBI-UI = 2.32 ± 0.32 radioactive counts). None of the MN appeared at SPECT images. Of melanomas, 4 (28,6%) were SPECT positive at cutaneous site. All those were Breslow thickness > 1 mm. Conclusion: On this study, although there is a significant difference between thin (< 1 mm) and thick (> 1 mm) melanomas, MIBI intensity at the lesion site is not different between benign nevus and in situ or thin melanomas. Then, MIBI seems to be useful mainly in thick melanomas, as also confirmed by the positivity of the SPECT image only in these cases. However, the possibility of correlating MIBI uptake intensity with Breslow categories may facilitate surgical procedures, allowing to remove melanomas with appropriated surgical margins and to perform or not sentinel lymph node biopsy in the same surgical time, reducing morbidity and cost.

Neste trabalho foram avaliadas novas rotas de purificação de Mo-99 e I-131 de fissão, por meio de associações inovadoras de técnicas clássicas de purificação química, presentes nos principais processos produtivos destes radioisótopos. Os processos de purificação estudados totalizaram seis combinações diferentes, divididas em dois grupos de três rotas. Foram utilizadas técnicas de cromatografia em coluna, destilação (seca e úmida), precipitação seletiva e extração por solvente. Todas as rotas utilizaram como ponto de partida uma coluna de resina aniônica, responsável por importante etapa de descontaminação, além da separação do Mo-99 e I-131. Nas etapas seguintes, as demais técnicas foram aplicadas de acordo com as configurações de cada rota. As rotas com coluna quelante e com sistema de extração por solvente apresentaram os melhores resultados de purificação para o Mo-99 (84,4%) e o I-131 (74,9%) respectivamente. Os resultados foram comparados em termos de eficiência de recuperação dos radioisótopos, grau de descontaminação e viabilidade operacional em processos de produção. As rotas de melhor desempenho apresentam potencial em termos de aprimoramentos de eficácia e aspectos operacionais, por meio de estudos em maior escala, além de poderem fornecer parâmetros para a construção de celas-piloto de Mo-99 e I-131. / In this work new purification routes of Mo-99 and I-131 fission were evaluated through innovative associations of classical chemical techniques of purification used by the main productive procedures of these radioisotopes. These purification routes were studied using six different combinations of techniques, divided into two groups of three routes. Column chromatography, distillation (dry and wet), selective precipitation and solvent extraction were the techniques applied in this investigation. In all routes, the first step was performed using a column of anionic resin in an important decontamination step, besides the separation of Mo-99 and I-131. In the following steps, other techniques were applied according to the methodology of each route. Chelating column and solvent extraction system showed the best purification results for Mo-99 (84.4 %) and I-131 (74.9 %), respectively. The final results were compared considering radioisotope recovery, decontamination degree and operational feasibility. The best-performing routes presented possibilities for improvements in efficiency and operational aspects, through larger-scale studies. Moreover, parameters for the construction of Mo-99 and I-131 mock-up cells were provided.