Experimental Studies of Boronophenylalanine ((10)BPA) Biodistribution for the Individual Application of Boron Neutron Capture Therapy (BNCT) for Malignant Melanoma Treatment.

PURPOSE: Patients with the same histopathologic diagnosis of cutaneous melanoma treated with identical protocols of boron neutron capture therapy (BNCT) have shown different clinical outcomes. The objective of the present studies was to evaluate the biodistribution of boronophenilalanina ((10)BPA) for the potential application of BNCT for the treatment of melanoma on an individual basis. METHODS AND MATERIALS: The boronophenilalanine (BPA) uptake was evaluated in 3 human melanoma cell lines: MEL-J, A375, and M8. NIH nude mice were implanted with 4 10(6) MEL-J cells, and biodistribution studies of BPA (350 mg/kg intraperitoneally) were performed. Static infrared imaging using a specially modified infrared camera adapted to measure the body infrared radiance of small animals was used. Proliferation marker, Ki-67, and endothelial marker, CD31, were analyzed in tumor samples. RESULTS: The in vitro studies demonstrated different patterns of BPA uptake for each analyzed cell line (P<.001 for MEL-J and A375 vs M8 cells). The in vivo studies showed a maximum average boron concentration of 25.9 ± 2.6 µg/g in tumor, with individual values ranging between 11.7 and 52.0 µg/g of (10)B 2 hours after the injection of BPA. Tumor temperature always decreased as the tumors increased in size, with values ranging between 37 °C and 23 °C. A significant correlation between tumor temperature and tumor-to-blood boron concentration ratio was found (R(2) = 0.7, rational function fit). The immunohistochemical studies revealed, in tumors with extensive areas of viability, a high number of positive cells for Ki-67, blood vessels of large diameter evidenced by the marker CD31, and a direct logistic correlation between proliferative status and boron concentration difference between tumor and blood (R(2) = 0.81, logistic function fit). CONCLUSION: We propose that these methods could be suitable for designing new screening protocols applied before melanoma BNCT treatment for each individual patient and lesion.

Incidencia de cáncer de tiroides en la provincia de Neuquén, período 2001-2012 / Incidence rate of thyroid cancer in Neuquén (2001-2012)

En los últimos años se ha demostrado un aumento en la incidencia de cáncer de tiroides (CT). En nuestro país no existe un registro nacional de cáncer por lo que la incidencia del mismo no ha sido establecida. Con el objetivo de conocer su incidencia en la provincia del Neuquén y compararla con la reportada en la literatura revisamos los informes histopatológicos con diagnóstico de CT en el periodo 2001-2012.Se evaluó tamaño tumoral, edad, sexo y tipo histológico. Se dividió el periodo en 4 trienios y se analizó la diferencia de estas características en cada uno de los mismos. Encontramos una incidencia de 4,72/100.000 hab/año, a expensas casi exclusivamente de carcinoma papilar, y 5 veces mayor en mujeres que en hombres (7,78 y 1,55 respectivamente). Al analizar trienios, se observó un aumento en el número de casos en el último de ellos (47, 49, 49 y 84 respectivamente). La media de tamaño tumoral fue de 22,2 ± 1,1 mm. El tamaño tumoral en hombres (31,8 ± 3,7 mm) fue significativamente mayor que en mujeres (20,4 ± 1,0 mm). En cuanto a la distribución de los tumores por tamaño, hay una disminución significativa en la media del tamaño tumoral en el 4.° trienio y un aumento en la proporción de tumores < 10 mm. La incidencia de CT en la provincia argentina de Neuquén es similar a la reportada en la literatura observando un aumento de casos incidentes

During the past decades, an increasing incidence of thyroid cancer (TC) has been reported worldwide. In Argentina there is no national cancer registry, and its incidence has therefore not been established. The aim of our study was to determine the incidence of TC in the province of Neuquén and to compare it to that reported in the literature. The medical records of 229 patients admitted over a period of 12 years (2001 to 2012) were used for data analysis. Tumor size, age, sex, and histological type were evaluated. The study period was divided into four three-year periods, and differences in each of these features were analyzed. We found an incidence of 4.72/100,000 inhabitants/year, and almost all patients had papillary TC. TC was five times more common in females as compared to males (7.78 and 1.55 respectively). Mean tumor size was 22.2 ± 1.1 mm. Tumor size was significantly greater in men (31.8 ± 3.7 mm) than in women (20.4 ± 1.0 mm). When grouped by three-year periods, a higher number of cases was found in the last one (47, 49, 49 and 84 respectively). As regards tumor distribution by size, there was a significant decrease in mean tumor size in the fourth period and an increase in the proportion of tumors <10 mm. We report an increase in TC incidence in the Argentinean province of Neuquén which is similar to the overall increase reported in the international literature. During the past decades, an increasing incidence of thyroid cancer (TC) has been reported worldwide. In Argentina there is no national cancer registry, and its incidence has therefore not been established. The aim of our study was to determine the incidence of TC in the province of Neuquén and to compare it to that reported in the literature. The medical records of 229 patients admitted over a period of 12 years (2001 to 2012) were used for data analysis. Tumor size, age, sex, and histological type were evaluated. The study period was divided into four three-year periods, and differences in each of these features were analyzed. We found an incidence of 4.72/100,000 inhabitants/year, and almost all patients had papillary TC. TC was five times more common in females as compared to males (7.78 and 1.55 respectively). Mean tumor size was 22.2 ± 1.1mm. Tumor size was significantly greater in men (31.8 ± 3.7 mm) than in women (20.4 ± 1.0 mm). When grouped by three-year periods, a higher number of cases was found in the last one (47, 49, 49 and 84 respectively). As regards tumor distribution by size, there was a significant decrease in mean tumor size in the fourth period and an increase in the proportion of tumors < 10 mm. We report an increase in TC incidence in the Argentinean province of Neuquén which is similar to the overall increase reported in the international literatura

Incidence rate of thyroid cancer in Neuquén (2001-2012).

During the past decades, an increasing incidence of thyroid cancer (TC) has been reported worldwide. In Argentina there is no national cancer registry, and its incidence has therefore not been established. The aim of our study was to determine the incidence of TC in the province of Neuquén and to compare it to that reported in the literature. The medical records of 229 patients admitted over a period of 12 years (2001 to 2012) were used for data analysis. Tumor size, age, sex, and histological type were evaluated. The study period was divided into four three-year periods, and differences in each of these features were analyzed. We found an incidence of 4.72/100,000 inhabitants/year, and almost all patients had papillary TC. TC was five times more common in females as compared to males (7.78 and 1.55 respectively). Mean tumor size was 22.2 ± 1.1 mm. Tumor size was significantly greater in men (31.8 ± 3.7 mm) than in women (20.4 ± 1.0 mm). When grouped by three-year periods, a higher number of cases was found in the last one (47, 49, 49 and 84 respectively). As regards tumor distribution by size, there was a significant decrease in mean tumor size in the fourth period and an increase in the proportion of tumors <10mm. We report an increase in TC incidence in the Argentinean province of Neuquén which is similar to the overall increase reported in the international literature.

First evaluation of the biologic effectiveness factors of boron neutron capture therapy (BNCT) in a human colon carcinoma cell line.

PURPOSE: DNA lesions produced by boron neutron capture therapy (BNCT) and those produced by gamma radiation in a colon carcinoma cell line were analyzed. We have also derived the relative biologic effectiveness factor (RBE) of the neutron beam of the RA-3- Argentine nuclear reactor, and the compound biologic effectiveness (CBE) values for p-boronophenylalanine ((10)BPA) and for 2,4-bis (α,ß-dihydroxyethyl)-deutero-porphyrin IX ((10)BOPP). METHODS AND MATERIALS: Exponentially growing human colon carcinoma cells (ARO81-1) were distributed into the following groups: (1) BPA (10 ppm (10)B) + neutrons, (2) BOPP (10 ppm (10)B) + neutrons, (3) neutrons alone, and (4) gamma rays ((60)Co source at 1 Gy/min dose-rate). Different irradiation times were used to obtain total absorbed doses between 0.3 and 5 Gy (±10%) (thermal neutrons flux = 7.5 10(9) n/cm(2) sec). RESULTS: The frequency of micronucleated binucleated cells and the number of micronuclei per micronucleated binucleated cells showed a dose-dependent increase until approximately 2 Gy. The response to gamma rays was significantly lower than the response to the other treatments (p < 0.05). The irradiations with neutrons alone and neutrons + BOPP showed curves that did not differ significantly from, and showed less DNA damage than, irradiation with neutrons + BPA. A decrease in the surviving fraction measured by 3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazolium bromide (MTT) assay as a function of the absorbed dose was observed for all the treatments. The RBE and CBE factors calculated from cytokinesis block micronucleus (CBMN) and MTT assays were, respectively, the following: beam RBE: 4.4 ± 1.1 and 2.4 ± 0.6; CBE for BOPP: 8.0 ± 2.2 and 2.0 ± 1; CBE for BPA: 19.6 ± 3.7 and 3.5 ± 1.3. CONCLUSIONS: BNCT and gamma irradiations showed different genotoxic patterns. To our knowledge, these values represent the first experimental ones obtained for the RA-3 in a biologic model and could be useful for future experimental studies for the application of BNCT to colon carcinoma.

Optimization of boron neutron capture therapy for the treatment of undifferentiated thyroid cancer.

PURPOSE: To analyze the possible increase in efficacy of boron neutron capture therapy (BNCT) for undifferentiated thyroid carcinoma (UTC) by using p-boronophenylalanine (BPA) plus 2,4-bis (alpha,beta-dihydroxyethyl)-deutero-porphyrin IX (BOPP) and BPA plus nicotinamide (NA) as a radiosensitizer of the BNCT reaction. METHODS AND MATERIALS: Nude mice were transplanted with a human UTC cell line (ARO), and after 15 days they were treated as follows: (1) control, (2) NCT (neutrons alone), (3) NCT plus NA (100 mg/kg body weight [bw]/day for 3 days), (4) BPA (350 mg/kg bw) + neutrons, (5) BPA + NA + neutrons, and (6) BPA + BOPP (60 mg/kg bw) + neutrons. The flux of the mixed (thermal + epithermal) neutron beam was 2.8 x 10(8) n/cm(2)/sec for 83.4 min. RESULTS: Neutrons alone or with NA caused some tumor growth delay, whereas in the BPA, BPA + NA, and BPA + BOPP groups a 100% halt of tumor growth was observed in all mice at 26 days after irradiation. When the initial tumor volume was 50 mm(3) or less, complete remission was found with BPA + NA (2 of 2 mice), BPA (1 of 4), and BPA + BOPP (7 of 7). After 90 days of complete regression, recurrence of the tumor was observed in BPA + NA (2 of 2) and BPA + BOPP (1 of 7). The determination of apoptosis in tumor samples by measurements of caspase-3 activity showed an increase in the BNCT (BPA + NA) group at 24 h (p < 0.05 vs. controls) and after the first week after irradiation in the three BNCT groups. Terminal transferase dUTP nick end labeling analysis confirmed these results. CONCLUSIONS: Although NA combined with BPA showed an increase of apoptosis at early times, only the group irradiated after the combined administration of BPA and BOPP showed a significantly improved therapeutic response.