From nuclear track characterization to machine learning based image classification in neutron autoradiography for boron neutron capture therapy.

Knowledge of the 10B microdistribution is of great relevance in BNCT studies. Since 10B concentration assesment through neutron autoradiography depends on the correct quantification of tracks in a nuclear track detector, image acquisition and processing conditions should be controlled and verified, in order to obtain accurate results to be applied in the frame of BNCT. With this aim, an image verification process was proposed, based on parameters extracted from the quantified nuclear tracks. Track characterization was performed by selecting a set of morphological and pixel-intensity uniformity parameters from the quantified objects (area, diameter, roundness, aspect ratio, heterogeneity and clumpiness). Their distributions were studied, leading to the observation of varying behaviours in images generated by different samples and acquisition conditions. The distributions corresponding to samples coming from the BNC reaction showed similar attributes in each analyzed parameter, proving to be robust to the experimental process, but sensitive to light and focus conditions. Considering those observations, a manual feature extraction was performed as a pre-processing step. A Support Vector Machine (SVM) and a fully dense Neural Network (NN) were optimized, trained, and tested. The final performance metrics were similar for both models: 93%-93% for the SVM, vs 94%-95% for the NN in accuracy and precision respectively. Based on the distribution of the predicted class probabilities, the latter had a better capacity to reject inadequate images, so the NN was selected to perform the image verification step prior to quantification. The trained NN was able to correctly classify the images regardless of their track density. The exhaustive characterization of the nuclear tracks provided new knowledge related to the autoradiographic images generation. The inclusion of machine learning in the analysis workflow proves to optimize the boron determination process and paves the way for further applications in the field of boron imaging.

Measurement of an evaporation coefficient in tissue sections as a correction factor for 10B determination.

Boron neutron capture therapy (BNCT) is a cancer treatment option that combines preferential uptake of a boron compound in tumors and irradiation with thermal neutrons. For treatment planning, the boron concentration in different tissues must be considered. Neutron autoradiography using nuclear track detectors (NTD) can be applied to study both the concentration and microdistribution of boron in tissue samples. Histological sections are obtained from frozen tissue by cryosectioning. When the samples reach room temperature, they undergo an evaporation process, which leads to an increase in the boron concentration. To take this effect into account, certain correction factors (evaporation coefficients, CEv) must be applied. With this aim, a protocol was established to register and analyze mass variation of tissue sections, measured with a semimicro scale. Values of ambient temperature, pressure, and humidity were simultaneously recorded. Reproducible results of evaporation curves and CEv values were obtained for different tissue samples, which allowed the systematization of the procedure. This study could contribute to a more precise determination of boron concentration in tissue samples through the neutron autoradiography technique, which is of great relevance to make dosimetric calculations in BNCT.

Enhancement in the Therapeutic Efficacy of In Vivo BNCT Mediated by GB-10 with Electroporation in a Model of Oral Cancer.

Boron neutron capture therapy (BNCT) combines preferential tumor uptake of 10B compounds and neutron irradiation. Electroporation induces an increase in the permeability of the cell membrane. We previously demonstrated the optimization of boron biodistribution and microdistribution employing electroporation (EP) and decahydrodecaborate (GB-10) as the boron carrier in a hamster cheek pouch oral cancer model. The aim of the present study was to evaluate if EP could improve tumor control without enhancing the radiotoxicity of BNCT in vivo mediated by GB-10 with EP 10 min after GB-10 administration. Following cancerization, tumor-bearing hamster cheek pouches were treated with GB-10/BNCT or GB-10/BNCT + EP. Irradiations were carried out at the RA-3 Reactor. The tumor response and degree of mucositis in precancerous tissue surrounding tumors were evaluated for one month post-BNCT. The overall tumor response (partial remission (PR) + complete remission (CR)) increased significantly for protocol GB-10/BNCT + EP (92%) vs. GB-10/BNCT (48%). A statistically significant increase in the CR was observed for protocol GB-10/BNCT + EP (46%) vs. GB-10/BNCT (6%). For both protocols, the radiotoxicity (mucositis) was reversible and slight/moderate. Based on these results, we concluded that electroporation improved the therapeutic efficacy of GB-10/BNCT in vivo in the hamster cheek pouch oral cancer model without increasing the radiotoxicity.

Comparison of Photon Isoeffective Dose Models Based on In Vitro and In Vivo Radiobiological Experiments for Head and Neck Cancer Treated with BNCT.

Boron neutron capture therapy (BNCT) is a treatment modality for cancer that involves radiations of different qualities. A formalism that proved suitable to compute doses in photon-equivalent units is the photon isoeffective dose model. This study addresses the question whether considering in vitro or in vivo radiobiological studies to determine the parameters involved in photon isoeffective dose calculations affects the consistency of the model predictions. The analysis is focused on head and neck squamous cell carcinomas (HNSCC), a main target that proved to respond to BNCT. The photon isoeffective dose model for HNSCC with parameters from in vitro studies using the primary human cell line UT-SCC-16A was introduced and compared to the one previously reported with parameters from an in vivo oral cancer model in rodents. Both models were first compared in a simple scenario by means of tumor dose and control probability calculations. Then, the clinical impact of the different dose models was assessed from the analysis of a group of squamous cell carcinomas (SCC) patients treated with BNCT. Traditional dose calculations using the relative biological effectiveness factors derived from the SCC cell line were also analyzed. Predictions of tumor control from the evaluated models were compared to the patients' outcome. The quantification of the biological effectiveness of the different radiations revealed that relative biological effectiveness/compound biological effectiveness (RBE/CBE) factors for the SCC cell line are up to 20% higher than those assumed in clinical BNCT, highlighting the importance of using experimental data intimately linked to the tumor type to derive the model's parameters. The comparison of the different models showed that photon isoeffective doses based on in vitro data are generally greater than those from in vivo data (∼8-16% for total tumor absorbed doses of 10-15 Gy). However, the predictive power of the two models was not affected by these differences: both models fulfilled conditions to guarantee a good predictive performance and gave predictions statistically compatible with the clinical outcome. On the other hand, doses computed with the traditional model were substantially larger than those obtained with both photon isoeffective models. Moreover, the traditional model is statistically rejected, which reinforces the assertion that its inconsistencies are intrinsic and not due to the use of RBE/CBE factors obtained for a tumor type different from HN cancer. The results suggest that the nature of the radiobiological data would not affect the consistency of the photon isoeffective dose model in the studied cases of SCC head and neck cancer treated with BPA-based BNCT.

Importance of radiobiological studies for the advancement of boron neutron capture therapy (BNCT).

Boron neutron capture therapy (BNCT) is a tumour selective particle radiotherapy, based on the administration of boron carriers incorporated preferentially by tumour cells, followed by irradiation with a thermal or epithermal neutron beam. BNCT clinical results to date show therapeutic efficacy, associated with an improvement in patient quality of life and prolonged survival. Translational research in adequate experimental models is necessary to optimise BNCT for different pathologies. This review recapitulates some examples of BNCT radiobiological studies for different pathologies and clinical scenarios, strategies to optimise boron targeting, enhance BNCT therapeutic effect and minimise radiotoxicity. It also describes the radiobiological mechanisms induced by BNCT, and the importance of the detection of biomarkers to monitor and predict the therapeutic efficacy and toxicity of BNCT alone or combined with other strategies. Besides, there is a brief comment on the introduction of accelerator-based neutron sources in BNCT. These sources would expand the clinical BNCT services to more patients, and would help to make BNCT a standard treatment modality for various types of cancer. Radiobiological BNCT studies have been of utmost importance to make progress in BNCT, being essential to design novel, safe and effective clinical BNCT protocols.

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.

Neutron autoradiography to study the microdistribution of boron in the lung.

In Argentina, a multi-institutional project has been established to assess the feasibility of applying BNCT ex-situ to the treatment of patients with multiple metastases in both lungs. Within this context, this work aims at applying the neutron autoradiography technique to study boron microdistribution in the lung. A comprehensive analysis of the different aspects for the generation of autoradiographic images of both normal and metastatic BDIX rat lungs was achieved. Histology, boron uniformity, optimal tissue thickness and water content in tissue were explored for the two types of samples. A qualitative and a quantitative analysis were performed. No heterogeneities in uptake were observed in normal lung. Conversely, samples with metastasis showed preferential boron uptake in the tumour areas with respect to surrounding tissue. Surrounding tissue would present a slightly higher uptake of boron than the normal lung. Quantitative results of boron concentration values and ratios determined by neutron autoradiography were obtained. In order to contribute to BNCT dosimetry, further analysis increasing the number of samples is warranted.

Experimental studies of boron neutron capture therapy (BNCT) using histone deacetylase inhibitor (HDACI) sodium butyrate, as a complementary drug for the treatment of poorly differentiated thyroid cancer (PDTC).

PURPOSE: The present study analyzed different protocols of administration of boronophenylalanine (BPA) and sodium butyrate (NaB) to increase the BNCT efficacy for poorly differentiated thyroid cancer (PDTC). MATERIALS AND METHODS: Nude mice implanted with human PDTC cells (WRO) were distributed into four protocols: 1) BPA; 2) BPA + ip NaB; 3) BPA + oral NaB; 4) Control. Biodistribution and histologic studies were performed. LAT (BPA transporter) isoforms gene expression was assessed by RT-PCR. RESULTS: Tumor growth delay was observed in animals of the Protocol #3 (p < 0.05). NaB (Protocol #2) increased tumor boron uptake 2-h post BPA injection (p < 0.05). On the other hand, NaB upregulated the expression of all the isoforms of the LAT transporter in vitro. Histologic studies showed a significant decrease of mitotic activity and an increase of vacuoles in tumors of Protocol #3. Neutrons alone or combined with NaB caused some tumor growth delay (p < 0.05), while in the BNCT and BNCT + NaB groups, there was a halt in tumor growth in 70 and 80% of the animals, respectively. CONCLUSIONS: Intraperitoneally administration of NaB increased boron uptake while oral administration for a longer period of time induced tumor growth delay previous to BPA administration. The use of NaB via ip would optimize the irradiation results.

BNCT research activities at the Granada group and the project NeMeSis: Neutrons for medicine and sciences, towards an accelerator-based facility for new BNCT therapies, medical isotope production and other scientific neutron applications.

The Granada group in BNCT research is currently performing studies on: nuclear and radiobiological data for BNCT, new boron compounds and a new design for a neutron source for BNCT and other applications, including the production of medical radioisotopes. All these activities are described in this report.

The essential role of radiobiological figures of merit for the assessment and comparison of beam performances in boron neutron capture therapy.

PURPOSE: Boron Neutron Capture Therapy (BNCT) is a treatment modality that uses an external neutron beam to selectively inactive boron10-loaded tumor cells. This work presents the development and innovative use of radiobiological probability models to adequately evaluate and compare the therapeutic potential and versatility of beams presenting different neutron energy spectra. M&M: Aforementioned characteristics, collectively refer to as the performance of a beam, were defined on the basis of radiobiological probability models for the first time in BNCT. A model of uncomplicated tumor control probability (UTCP) for HN cancer was introduced. This model considers a NTCP able to predict severe mucositis and a TCP for non-uniform doses derived herein. A systematic study comprising a simplified HN cancer model is presented as a practical application of the introduced radiobiological figures of merit (FOM) for assessing and comparing the performance of different clinical beams. Applications involving treated HN cancer patients were also analyzed. RESULTS: The maximum UTCP proved suitable and sensitive to assess the performance of a beam, revealing particularities of the studied sources that the physical FOMs do not highlight. The radiobiological FOMs evaluated in patients showed to be useful tools both for retrospective analysis of the BNCT treatments, and for prospective studies of beam optimization and feasibility. CONCLUSIONS: The presented developments and applications demonstrated that it is possible to assess and compare performances of completely different beams fairly and adequately by assessing the radiobiological FOM UTCP. Thus, this figure would be a practical and essential aid to guide treatment decisions.

Carboranylanilinoquinazoline EGFR-inhibitors: toward 'lead-to-candidate' stage in the drug-development pipeline.

Background: Carboranylanilinoquinazoline-hybrids, developed for boron neutron capture therapy, have demonstrated cytotoxicity against murine-glioma cells with EGFR-inhibition ability. In addition, their adequate aqueous/metabolic stabilities and ability to cross blood-brain barrier make them good leads as to become antiglioma drugs. Aim: Analyze drug-like properties of representative carboranylanilinoquinazolines. Materials & methods: To expand carboranylanilinoquinazolines therapeutic spectrum, we studied their ability to act against glioma-mammal cells, U-87 MG and other tyrosine kinase-overexpress cells, HT-29. Additionally, we predicted theoretically and studied experimentally drug-like properties, in other words, organization for economic cooperation and development-recommended toxicity-studies and, due to some aqueous-solubility problems, and vehicularization for oral and intravenous administrations. Conclusion: We have identified a promising drug-candidate with broad activity spectrum, appropriate drug-like properties, adequate toxicological behavior and able ability to be loaded in suitable vehicles.

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.

Electroporation optimizes the uptake of boron-10 by tumor for boron neutron capture therapy (BNCT) mediated by GB-10: a boron biodistribution study in the hamster cheek pouch oral cancer model.

Boron neutron capture therapy (BNCT) is a promising cancer binary therapy modality that utilizes the nuclear capture reaction of thermal neutrons by boron-10 resulting in a localized release of high- and low-linear energy transfer (LET) radiation. Electrochemotherapy (ECT) is based on electroporation (EP) that induces opening of pores in cell membranes, allowing the entry of compounds. Because EP is applied locally to a tumor, the compound is incorporated preferentially by tumor cells. Based on the knowledge that the therapeutic success of BNCT depends centrally on the boron content in tumor and normal tissues and that EP has proven to be an excellent facilitator of tumor biodistribution of an anti-tumor agent, the aim of this study was to evaluate if EP can optimize the delivery of boronated compounds. We performed biodistribution studies and qualitative microdistribution analyses of boron employing the boron compound sodium decahydrodecaborate (GB-10) + EP in the hamster cheek pouch oral cancer model. Syrian hamsters with chemically induced exophytic squamous cell carcinomas were used. A typical EP treatment was applied to each tumor, varying the moment of application with respect to the administration of GB-10 (early or late). The results of this study showed a significant increase in the absolute and relative tumor boron concentration and optimization of the qualitative microdistribution of boron by the use of early EP + GB-10 versus GB-10 without EP. This strategy could be a tool to improve the therapeutic efficacy of BNCT/GB-10 in vivo.

Toward a clinical application of ex situ boron neutron capture therapy for lung tumors at the RA-3 reactor in Argentina.

PURPOSE: Many types of lung tumors have a very poor prognosis due to their spread in the whole organ volume. The fact that boron neutron capture therapy (BNCT) would allow for selective targeting of all the nodules regardless of their position, prompted a preclinical feasibility study of ex situ BNCT at the thermal neutron facility of RA-3 reactor in the province of Buenos Aires, Argentina. (l)-4p-dihydroxy-borylphenylalanine fructose complex (BPA-F) biodistribution studies in an adult sheep model and computational dosimetry for a human explanted lung were performed to evaluate the feasibility and the therapeutic potential of ex situ BNCT. METHODS: Two kinds of boron biodistribution studies were carried out in the healthy sheep: a set of pharmacokinetic studies without lung excision, and a set that consisted of evaluation of boron concentration in the explanted and perfused lung. In order to assess the feasibility of the clinical application of ex situ BNCT at RA-3, a case of multiple lung metastases was analyzed. A detailed computational representation of the geometry of the lung was built based on a real collapsed human lung. Dosimetric calculations and dose limiting considerations were based on the experimental results from the adult sheep, and on the most suitable information published in the literature. In addition, a workable treatment plan was considered to assess the clinical application in a realistic scenario. RESULTS: Concentration-time profiles for the normal sheep showed that the boron kinetics in blood, lung, and skin would adequately represent the boron behavior and absolute uptake expected in human tissues. Results strongly suggest that the distribution of the boron compound is spatially homogeneous in the lung. A constant lung-to-blood ratio of 1.3 ± 0.1 was observed from 80 min after the end of BPA-F infusion. The fact that this ratio remains constant during time would allow the blood boron concentration to be used as a surrogate and indirect quantification of the estimated value in the explanted healthy lung. The proposed preclinical animal model allowed for the study of the explanted lung. As expected, the boron concentration values fell as a result of the application of the preservation protocol required to preserve the lung function. The distribution of the boron concentration retention factor was obtained for healthy lung, with a mean value of 0.46 ± 0.14 consistent with that reported for metastatic colon carcinoma model in rat perfused lung. Considering the human lung model and suitable tumor control probability for lung cancer, a promising average fraction of controlled lesions higher than 85% was obtained even for a low tumor-to-normal boron concentration ratio of 2. CONCLUSIONS: This work reports for the first time data supporting the validity of the ovine model as an adequate human surrogate in terms of boron kinetics and uptake in clinically relevant tissues. Collectively, the results and analysis presented would strongly suggest that ex situ whole lung BNCT irradiation is a feasible and highly promising technique that could greatly contribute to the treatment of metastatic lung disease in those patients without extrapulmonary spread, increasing not only the expected overall survival but also the resulting quality of life.

Intracavitary moderator balloon combined with (252)Cf brachytherapy and boron neutron capture therapy, improving dosimetry in brain tumour and infiltrations.

OBJECTIVE: This article proposes a combination of californium-252 ((252)Cf) brachytherapy, boron neutron capture therapy (BNCT) and an intracavitary moderator balloon catheter applied to brain tumour and infiltrations. METHODS: Dosimetric evaluations were performed on three protocol set-ups: (252)Cf brachytherapy combined with BNCT (Cf-BNCT); Cf-BNCT with a balloon catheter filled with light water (LWB) and the same set-up with heavy water (HWB). RESULTS: Cf-BNCT-HWB has presented dosimetric advantages to Cf-BNCT-LWB and Cf-BNCT in infiltrations at 2.0-5.0 cm from the balloon surface. However, Cf-BNCT-LWB has shown superior dosimetry up to 2.0 cm from the balloon surface. CONCLUSION: Cf-BNCT-HWB and Cf-BNCT-LWB protocols provide a selective dose distribution for brain tumour and infiltrations, mainly further from the (252)Cf source, sparing the normal brain tissue. ADVANCES IN KNOWLEDGE: Malignant brain tumours grow rapidly and often spread to adjacent brain tissues, leading to death. Improvements in brain radiation protocols have been continuously achieved; however, brain tumour recurrence is observed in most cases. Cf-BNCT-LWB and Cf-BNCT-HWB represent new modalities for selectively combating brain tumour infiltrations and metastasis.

Assessing advantages of sequential boron neutron capture therapy (BNCT) in an oral cancer model with normalized blood vessels.

BACKGROUND: We previously demonstrated the therapeutic success of sequential boron neutron capture therapy (Seq-BNCT) in the hamster cheek pouch oral cancer model. It consists of BPA-BNCT followed by GB-10-BNCT 24 or 48 hours later. Additionally, we proved that tumor blood vessel normalization with thalidomide prior to BPA-BNCT improves tumor control. The aim of the present study was to evaluate the therapeutic efficacy and explore potential boron microdistribution changes in Seq-BNCT preceded by tumor blood vessel normalization. MATERIAL AND METHODS: Tumor bearing animals were treated with thalidomide for tumor blood vessel normalization, followed by Seq-BNCT (Th+ Seq-BNCT) or Seq-Beam Only (Th+ Seq-BO) in the window of normalization. Boron microdistribution was assessed by neutron autoradiography. RESULTS: Th+ Seq-BNCT induced overall tumor response of 100%, with 87 (4)% complete tumor response. No cases of severe mucositis in dose-limiting precancerous tissue were observed. Differences in boron homogeneity between tumors pre-treated and not pre-treated with thalidomide were observed. CONCLUSION: Th+ Seq-BNCT achieved, for the first time, response in all treated tumors. Increased homogeneity in tumor boron microdistribution is associated to an improvement in tumor control.

Exploring Boron Neutron Capture Therapy for non-small cell lung cancer.

Boron Neutron Capture Therapy (BNCT) is a radiotherapy that combines biological targeting and high LET radiation. It consists in the enrichment of tumour with (10)B and in the successive irradiation of the target with low energy neutrons producing charged particles that mainly cause non-repairable damages to the cells. The feasibility to treat Non Small Cells Lung Cancer (NSCLC) with BNCT was explored. This paper proposes a new approach to determine treatment plans, introducing the possibility to choose the irradiation start and duration to maximize the tumour dose. A Tumour Control Probability (TCP) suited for lung BNCT as well as other high dose radiotherapy schemes was also introduced. Treatment plans were evaluated in localized and disseminated lung tumours. Semi-ideal and real energy spectra beams were employed to assess the best energy range and the performance of non-tailored neutron sources for lung tumour treatments. The optimal neutron energy is within [500 eV-3 keV], lower than the 10 keV suggested for the treatment of deep-seated tumours in the brain. TCPs higher than 0.6 and up to 0.95 are obtained for all cases. Conclusions drawn from [Suzuki et al., Int Canc Conf J 1 (4) (2012) 235-238] supporting the feasibility of BNCT for shallow lung tumours are confirmed, however discussions favouring the treatment of deeper lesions and disseminated disease are also opened. Since BNCT gives the possibility to deliver a safe and potentially effective treatment for NSCLC, it can be considered a suitable alternative for patients with few or no treatment options.

Boron biodistribution for BNCT in the hamster cheek pouch oral cancer model: combined administration of BSH and BPA.

Sodium mercaptoundecahydro-closo-dodecaborate (BSH) is being investigated clinically for BNCT. We examined the biodistribution of BSH and BPA administered jointly in different proportions in the hamster cheek pouch oral cancer model. The 3 assayed protocols were non-toxic, and showed preferential tumor boron uptake versus precancerous and normal tissue and therapeutic tumor boron concentration values (70-85ppm). All 3 protocols warrant assessment in BNCT studies to contribute to the knowledge of (BSH+BPA)-BNCT radiobiology for head and neck cancer and optimize therapeutic efficacy.

Biodistribution of the boron carriers boronophenylalanine (BPA) and/or decahydrodecaborate (GB-10) for Boron Neutron Capture Therapy (BNCT) in an experimental model of lung metastases.

BNCT was proposed for the treatment of diffuse, non-resectable tumors in the lung. We performed boron biodistribution studies with 5 administration protocols employing the boron carriers BPA and/or GB-10 in an experimental model of disseminated lung metastases in rats. All 5 protocols were non-toxic and showed preferential tumor boron uptake versus lung. Absolute tumor boron concentration values were therapeutically useful (25-76ppm) for 3 protocols. Dosimetric calculations indicate that BNCT at RA-3 would be potentially therapeutic without exceeding radiotolerance in the lung.

Apoptosis through Bcl-2/Bax and cleaved caspase up-regulation in melanoma treated by boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is a binary treatment involving selective accumulation of boron carriers in a tumor followed by irradiation with a thermal or epithermal neutron beam. The neutron capture reaction with a boron-10 nucleus yields high linear energy transfer (LET) particles, alpha and (7)Li, with a range of 5 to 9 µm. These particles can only travel very short distances and release their damaging energy directly into the cells containing the boron compound. We aimed to evaluate proliferation, apoptosis and extracellular matrix (ECM) modifications of B16F10 melanoma and normal human melanocytes after BNCT. The amounts of soluble collagen and Hsp47, indicating collagen synthesis in the ECM, as well as the cellular markers of apoptosis, were investigated. BNCT decreased proliferation, altered the ECM by decreasing collagen synthesis and induced apoptosis by regulating Bcl-2/Bax in melanoma. Additionally, BNCT also increased the levels of TNF receptor and the cleaved caspases 3, 7, 8 and 9 in melanoma. These results suggest that multiple pathways related to cell death and cell cycle arrest are involved in the treatment of melanoma by BNCT.