Boron Neutron Capture Therapy (BNCT) Mediated by Maleimide-Functionalized Closo-Dodecaborate Albumin Conjugates (MID:BSA) for Oral Cancer: Biodistribution Studies and In Vivo BNCT in the Hamster Cheek Pouch Oral Cancer Model.

BACKGROUND: BNCT (Boron Neutron Capture Therapy) is a tumor-selective particle radiotherapy that combines preferential boron accumulation in tumors and neutron irradiation. Although p-boronophenylalanine (BPA) has been clinically used, new boron compounds are needed for the advancement of BNCT. Based on previous studies in colon tumor-bearing mice, in this study, we evaluated MID:BSA (maleimide-functionalized closo-dodecaborate conjugated to bovine serum albumin) biodistribution and MID:BSA/BNCT therapeutic effect on tumors and associated radiotoxicity in the hamster cheek pouch oral cancer model. METHODS: Biodistribution studies were performed at 30 mg B/kg and 15 mg B/kg (12 h and 19 h post-administration). MID:BSA/BNCT (15 mg B/kg, 19 h) was performed at three different absorbed doses to precancerous tissue. RESULTS: MID:BSA 30 mg B/kg protocol induced high BSA toxicity. MID:BSA 15 mg B/kg injected at a slow rate was well-tolerated and reached therapeutically useful boron concentration values in the tumor and tumor/normal tissue ratios. The 19 h protocol exhibited significantly lower boron concentration values in blood. MID:BSA/BNCT exhibited a significant tumor response vs. the control group with no significant radiotoxicity. CONCLUSIONS: MID:BSA/BNCT would be therapeutically useful to treat oral cancer. BSA toxicity is a consideration when injecting a compound conjugated to BSA and depends on the animal model studied.

Evaluation of local, regional and abscopal effects of Boron Neutron Capture Therapy (BNCT) combined with immunotherapy in an ectopic colon cancer model.

OBJECTIVE: The aim of the present study was to evaluate the local and regional therapeutic efficacy and abscopal effect of BNCT mediated by boronophenyl-alanine, combined with Bacillus Calmette-Guerin (BCG) as an immunotherapy agent in this model. METHODS: The local effect of treatment was evaluated in terms of tumor response in the irradiated tumor-bearing right hind flank. Metastatic spread to tumor-draining lymph nodes was analyzed as an indicator of regional effect. The abscopal effect of treatment was assessed as tumor growth inhibition in the contralateral (non-irradiated) left hind flank inoculated with tumor cells 2 weeks post-irradiation. The experimental groups BNCT, BNCT + BCG, BCG, Beam only (BO), BO +BCG, SHAM (tumor-bearing, no treatment, same manipulation) were studied. RESULTS: BNCT and BNCT + BCG induced a highly significant local anti-tumor response, whereas BCG alone induced a weak local effect. BCG and BNCT + BCG induced a significant abscopal effect in the contralateral non-irradiated leg. The BNCT + BCG group showed significantly less metastatic spread to tumor-draining lymph nodes vs SHAM and vs BO. CONCLUSION: This study suggests that BNCT + BCG-immunotherapy would induce local, regional and abscopal effects in tumor-bearing animals. BNCT would be the main effector of the local anti-tumor effect whereas BCG would be the main effector of the abscopal effect. ADVANCES IN KNOWLEDGE: Although the local effect of BNCT has been widely evidenced, this is the first study to show the local, regional and abscopal effects of BNCT combined with immunotherapy, contributing to comprehensive cancer treatment with combined therapies.

Clinical Veterinary Boron Neutron Capture Therapy (BNCT) Studies in Dogs with Head and Neck Cancer: Bridging the Gap between Translational and Clinical Studies.

Translational Boron Neutron Capture Therapy (BNCT) studies performed by our group and clinical BNCT studies worldwide have shown the therapeutic efficacy of BNCT for head and neck cancer. The present BNCT studies in veterinary patients with head and neck cancer were performed to optimize the therapeutic efficacy of BNCT, contribute towards exploring the role of BNCT in veterinary medicine, put in place technical aspects for an upcoming clinical trial of BNCT for head and neck cancer at the RA-6 Nuclear Reactor, and assess the feasibility of employing the existing B2 beam to treat large, deep-seated tumors. Five dogs with head and neck cancer with no other therapeutic option were treated with two applications of BNCT mediated by boronophenyl-alanine (BPA) separated by 3-5 weeks. Two to three portals per BNCT application were used to achieve a potentially therapeutic dose over the tumor without exceeding normal tissue tolerance. Clinical and Computed Tomography results evidenced partial tumor control in all cases, with slight-moderate mucositis, excellent life quality, and prolongation in the survival time estimated at recruitment. These exploratory studies show the potential value of BNCT in veterinary medicine and contribute towards initiating a clinical BNCT trial for head and neck cancer at the RA-6 clinical facility.

Optimization of the classical oral cancerization protocol in hamster to study oral cancer therapy.

OBJECTIVE(S): The hamster carcinogenesis model recapitulates oral oncogenesis. Dimethylbenz[a]anthracene (DMBA) cancerization induces early severe mucositis, affecting animal's welfare and causing tissue loss and pouch shortening. "Short" pouches cannot be everted for local irradiation for boron neutron capture therapy (BNCT). Our aim was to optimize the DMBA classical cancerization protocol to avoid severe mucositis, without affecting tumor development. We evaluated BNCT in animals cancerized with this novel protocol. MATERIALS AND METHODS: We studied: Classical cancerization protocol (24 applications) and Classical with two interruptions (completed at the end of the cancerization protocol). BNCT mediated by boronophenylalanine (BPA) was performed in both groups. RESULTS: The twice-interrupted group exhibited a significantly lower percentage of animals with severe mucositis versus the non-interrupted group (17% versus 71%) and a significantly higher incidence of long pouches (100% versus 53%). Tumor development and the histologic characteristics of tumor and precancerous tissue were not affected by the interruptions. For both groups, overall tumor response was more than 80%, with a similar incidence of BNCT-induced severe mucositis. CONCLUSION(S): The twice-interrupted protocol reduced severe mucositis during cancerization without affecting tumor development. This favored the animal's welfare and reduced the number of animals to be cancerized for our studies, without affecting BNCT response.

Different oral cancer scenarios to personalize targeted therapy: Boron Neutron Capture Therapy translational studies.

Boron neutron capture therapy (BNCT) is a targeted therapy, which consists of preferential accumulation of boron carriers in tumor followed by neutron irradiation. Each oral cancer patient has different risks of developing one or more carcinomas and/or oral mucositis induced after treatment. Our group proposed the hamster oral cancer model to study the efficacy of BNCT and associated mucositis. Translational studies are essential to the advancement of novel boron delivery agents and targeted strategies. Herein, we review our work in the hamster model in which we studied BNCT induced mucositis using three different cancerization protocols, mimicking three different clinical scenarios. The BNCT-induced mucositis increases with the aggressiveness of the carcinogenesis protocol employed, suggesting that the study of different oral cancer patient scenarios would help to develop personalized therapies.

Efeitos agudos do treinamento concorrente sobre os níveis séricos de leptina e cortisol em adultos jovens sobrepesados / Acute effects of concurrent training on serum leptin and cortisol in overweight young adults

OBJETIVO: Este estudo teve como objetivo analisar os efeitos imediatos do treinamento concorrente sobre a leptina e os níveis de cortisol em adultos jovens com sobrepeso. MÉTODOS: Este estudo utilizou uma metodologia quase-experimental. Foram 20 indivíduos voluntários de ambos os sexos, divididos em um grupo sobrepesado treinamento (GST n = 10) e um grupo sobrepesado controle (n = 10). A coleta de sangue foi realizada com os indivíduos em repouso após jejum de 12 horas. Os níveis de leptina e cortisol foram analisados por radioimunoensaio e ensaio por quimioluminescência chimiluminescence antes e imediatamente após o treinamento. ANOVA two way foi utilizada para análise estatística com nível de significância de p < 0,05. RESULTADOS: Na análise da leptina sérica, observou-se diferença significativa intergrupos (GST x GSC) nos momentos pré-intervenção (p = 0,02) e pós-intervenção (p = 0,01). Na análise intragrupos, não foram observadas alterações significativas. E na análise do cortisol sérico intergrupos (GST x GSC), foi observada uma diferença significativa nos momentos pré-intervenção (p = 0,01) e pós-intervenção (p = 0,01), porém, na análise intragrupos, não houve alterações significativas. CONCLUSÃO: Uma única sessão de treinamento concorrente não é suficiente para promover alterações agudas nos níveis de leptina e cortisol dos jovens adultos sobrepesados voluntários deste estudo.

OBJECTIVE: This study aimed to analyze the immediate effects of concurrent training on leptin and cortisol levels in overweight young adults. METHODS: This study used a quasi-experimental methodology. We included 20 volunteers of both sexes, randomly divided into a training competitor group (TCG n = 10) and a control group (C n = 10). Blood collection was performed in individuals at rest after fasting for 12 hours. The leptin and cortisol levels were analyzed by radioimmunoassay and chimiluminescence immunoassay before and immediately after training. Two-way ANOVA was used for statistical analysis with a significance level of p <0.05. RESULTS: In the analysis of leptin levels, there was significant difference between groups (TCG x C) in the pre intervention (p = 0.02) and post intervention (p = 0.01). In the intra groups, no significant changes were found, and in the analysis of cortisol levels between groups (TGC x C), a significant difference in the pre intervention (p = 0.01) and post intervention (p = 0.01) was observed; however, in the intra groups there were no significant changes. CONCLUSION: A single concurrent training session is not sufficient to promote acute changes in the leptin and cortisol levels of the volunteer overweight young adults in this study.