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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&ndash, 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.

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).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.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 (p0.05). 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.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.

Thermal neutron attenuation capacity of Li4SiO4 was evaluated to assess its potential capabilities as a beam shaping material for boron neutron capture therapy (BNCT) facilities. Samples of Li4SiO4 were prepared by two different synthesis methods, using different raw materials and were characterized using x-ray, electron diffraction and transmission electron microscopy. Neutron measurements were performed at the BNCT and the neutron radiography facilities of Centro Atomico Bariloche. Considering its natural isotopic abundance, Li4SiO4 proved to be remarkably effective in comparison with other neutron-absorbing materials. Given the availability of natural Lithium in local salt mines and the scalable feasibility, Li4SiO4 qualifies as a potential material for BNCT beam shaping applications.

Boron neutron capture therapy (BNCT) is based on selective accumulation of B-10 carriers in tumor followed by neutron irradiation. We demonstrated, in 2001, the therapeutic effect of BNCT mediated by BPA (boronophenylalanine) in the hamster cheek pouch model of oral cancer, at the RA-6 nuclear reactor. Between 2007 and 2011, the RA-6 was upgraded, leading to an improvement in the performance of the BNCT beam (B2 configuration). Our aim was to evaluate BPA-BNCT radiotoxicity and tumor control in the hamster cheek pouch model of oral cancer at the new “B2” configuration. We also evaluated, for the first time in the oral cancer model, the radioprotective effect of histamine against mucositis in precancerous tissue as the dose-limiting tissue. Cancerized pouches were exposed to: BPA-BNCT; BPA-BNCT + histamine; BO: Beam only; BO + histamine; CONTROL: cancerized, no-treatment. BNCT induced severe mucositis, with an incidence that was slightly higher than in “B1” experiments (86 vs 67%, respectively). BO induced low/moderate mucositis. Histamine slightly reduced the incidence of severe mucositis induced by BPA-BNCT (75 vs 86%) and prevented mucositis altogether in BO animals. Tumor overall response was significantly higher in BNCT (94–96%) than in control (16%) and BO groups (9–38%), and did not differ significantly from the “B1” results (91%). Histamine did not compromise BNCT therapeutic efficacy. BNCT radiotoxicity and therapeutic effect at the B1 and B2 configurations of RA-6 were consistent. Histamine slightly reduced mucositis in precancerous tissue even in this overly aggressive oral cancer model, without compromising tumor control. Fil: Monti Hughes, Andrea. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Longhino, Juan. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; Argentina Fil: Boggio, Esteban. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; Argentina Fil: Medina, Vanina Araceli. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina Fil: Martinel Lamas, Diego José. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina Fil: Garabalino, Marcela Alejandra. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina Fil: Heber, Elisa Mercedes. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina Fil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina Fil: Itoiz, María Elina. Universidad de Buenos Aires. Facultad de Odontología; Argentina. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Aromando, Romina Flavia. Universidad de Buenos Aires. Facultad de Odontología; Argentina Fil: Nigg, David W.. Idaho National Laboratory; Estados Unidos Fil: Trivillin, Verónica Andrea. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina Fil: Schwint, Amanda Elena. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina

Purpose: A rhodium self-powered neutron detector (Rh SPND) has been specifically developed by the Comision Nacional de Energia Atomica (CNEA) of Argentina to measure locally and in real time thermal neutron fluxes in patients treated with boron neutron capture therapy (BNCT). In this work, the thermal and epithermal neutron response of the Rh SPND was evaluated by studying the detector response to two different reactor spectra. In addition, during clinical trials of the BNCT Project of the CNEA, on-line neutron flux measurements using the specially designed detector were assessed. Methods: The first calibration of the detector was done with the well-thermalized neutron spectrum of the CNEA RA-3 reactor thermal column. For this purpose, the reactor spectrum was approximated by a Maxwell-Boltzmann distribution in the thermal energy range. The second calibration was done at different positions along the central axis of a water-filled cylindrical phantom, placed in the mixed thermal-epithermal neutron beam of CNEA RA-6 reactor. In this latter case, the RA-6 neutron spectrum had been well characterized by both calculation and measurement, and it presented some marked differences with the ideal spectrum considered for SPND calibrations at RA-3. In addition, the RA-6 neutron spectrum varied with depth in the watermore » phantom and thus the percentage of the epithermal contribution to the total neutron flux changed at each measurement location. Local (one point-position) and global (several points-positions) and thermal and mixed-field thermal neutron sensitivities were determined from these measurements. Thermal neutron flux was also measured during BNCT clinical trials within the irradiation fields incident on the patients. In order to achieve this, the detector was placed on patient's skin at dosimetric reference points for each one of the fields. System stability was adequate for this kind of measurement. Results: Local mixed-field thermal neutron sensitivities and global thermal and mixed-field thermal neutron sensitivities derived from measurements performed at the RA-6 were compared and no significant differences were found. Global RA-6-based thermal neutron sensitivity showed agreement with pure thermal neutron sensitivity measurements performed in the RA-3 spectrum. Additionally, the detector response proved nearly unchanged by differences in neutron spectra from real (RA-6 BNCT beam) and ideal (considered for calibration calculations at RA-3) neutron source descriptions. The results confirm that the special design of the Rh SPND can be considered as having a pure thermal response for neutron spectra with epithermal-to-thermal flux ratios up to 12%. In addition, the linear response of the detector to thermal flux allows the use of a mixed-field thermal neutron sensitivity of 1.95 {+-} 0.05 x 10{sup -21} A n{sup -1}{center_dot}cm{sup 2}{center_dot}s. This sensitivity can be used in spectra with up to 21% epithermal-to-thermal flux ratio without significant error due to epithermal neutron and gamma induced effects. The values of the measured fluxes in clinical applications had discrepancies with calculated results that were in the range of -25% to +30%, which shows the importance of a local on-line independent measurement as part of a treatment planning quality control system. Conclusions: The usefulness of the CNEA Rh SPND for the on-line local measurement of thermal neutron flux on BNCT patients has been demonstrated based on an appropriate neutron spectra calibration and clinical applications.« less

We previously demonstrated the efficacy of boron neutron capture therapy (BNCT) mediated by boronophenylalanine (BPA), GB-10 (Na(2)(10)B(10)H(10)) and (GB-10+BPA) to control tumors, with no normal tissue radiotoxicity, in the hamster cheek pouch oral cancer model. Herein we developed a novel experimental model of field-cancerization and precancerous lesions (globally termed herein precancerous tissue) in the hamster cheek pouch to explore the long-term potential inhibitory effect of the same BNCT protocols on the development of second primary tumors from precancerous tissue. Clinically, second primary tumor recurrences occur in field-cancerized tissue, causing therapeutic failure. We performed boron biodistribution studies followed by in vivo BNCT studies, with 8 months follow-up. All 3 BNCT protocols induced a statistically significant reduction in tumor development from precancerous tissue, reaching a maximum inhibition of 77-100%. The inhibitory effect of BPA-BNCT and (GB-10+BPA)-BNCT persisted at 51% at the end of follow-up (8 months), whereas for GB-10-BNCT it faded after 2 months. Likewise, beam-only elicited a significant but transient reduction in tumor development. No normal tissue radiotoxicity was observed. At 8 months post-treatment with BPA-BNCT or (GB-10+BPA)-BNCT, the precancerous pouches that did not develop tumors had regained the macroscopic and histological appearance of normal (non-cancerized) pouches. A potential new clinical application of BNCT would lie in its capacity to inhibit local regional recurrences.

A dosimetry intercomparison between the boron neutron capture therapy groups of the Massachusetts Institute of Technology (MIT) and the Comisión Nacional de Energía Atómica (CNEA), Argentina was performed to enable combined analyses of NCT patient data between the different centers. In-air and dose versus depth measurements in a rectangular water phantom were performed at the hyperthermal neutron beam facility of the RA-6 reactor, Bariloche. Calculated dose profiles from the CNEA treatment planning system NCTPlan that were calibrated against in-house measurements required normalizations of 1.0 (thermal neutrons), 1.13 (photons), and 0.74 (fast neutrons) to match the dosimetry of MIT.

Recently, Boron neutron capture therapy (BNCT) was successfully applied to treat experimental squamous cell carcinomas (SCC) of the hamster cheek pouch mucosa, with no damage to normal tissue. It was also shown that treating spontaneous nasal planum SCC in terminal feline patients with low dose BNCT is safe and feasible. In an extension of this work, the present study aimed at evaluation of the response of tumor and dose-limiting normal tissues to potentially therapeutic BNCT doses. Biodistribution studies with (10)B-boronophenylalanine (BPA enriched in (10)B) as a (10)B carrier were performed on three felines that showed advanced nasal planum SCC without any standard therapeutic option. Following the biodistribution studies, BNCT mediated by (10)BPA was done using the thermalized epithermal neutron beam at the RA-6 Nuclear Reactor. Follow-up included clinical evaluation, assessment of macroscopic tumor and normal tissue response and biopsies for histopathological analysis. The treated animals did not show any apparent radiation-induced toxicity. All three animals exhibited partial tumor control and an improvement in clinical condition. Enhanced therapeutic efficacy was associated with a high (10)B content of the tumor and a small tumor size. BNCT is therefore believed to be potentially effective in the treatment of spontaneous SCC. However, improvement in targeting (10)B into all tumor cells and delivering a sufficient dose at a greater depth are still required for the treatment of deep-seated, large tumors. Future studies are needed to evaluate the potential efficacy of the dual mode cellular (e.g. BPA-BNCT) and vascular (e.g. GB-10-BNCT) targeting protocol in a preclinical scenario, employing combinations of (10)B compounds with different properties and complementary uptake mechanisms.

A Phase I/II protocol for treating cutaneuos melanomas with BNCT was designed in Argentina by the Comisión Nacional de Energía Atómica and the medical center Instituto Roffo. The first of a cohort of thirty planned patients was treated on October 9, 2003. This article depicts the protocol-based procedure and describes the first clinical case, treatment regime and planning, patient irradiation, retrospective dosimetric analysis and clinical outcome. Considering the low acute skin toxicity and the complete response in 21 of the 25 subcutaneous melanoma nodules treated, a second irradiation was performed in a different location of the extremity of the same patient. The corresponding clinical outcome is still under evaluation.

Irregular fields for boron neutron capture therapy (BNCT) have been already proposed to spare normal tissue in the treatment of superficial tumors. This added dependence would require custom measurements and/or to have a secondary calculation system. As a first step, we implemented the sector-integration method for irregular field calculation in a homogeneous medium and on the central beam axis . The dosimetric responses (fast neutron and photon dose and thermal neutron flux), are calculated by sector integrating the measured responses of circular fields over the field boundary. The measurements were carried out at our BNCT facility, the RA-6 reactor (Argentina). The input data were dosimetric responses for circular fields measured at different depths in a water phantom using ionisation and activation techniques. Circular fields were formed by shielding the beam with two plates: borated polyethilene plus lead. As a test, the dosimetric responses of a 7×4 cm2 rectangular field, were measured and compared to calculations, yielding differences less than 3% in equivalent dose at any depth indicating that the tool is suitable for redundant calculations.

We previously reported biodistribution and pharmacokinetic data for GB-10 (Na210B10H10) and the combined administration of GB-10 and boronophenylalanine (BPA) as boron delivery agents for boron neutron capture therapy (BNCT) in the hamster cheek pouch oral cancer model. The aim of the present study was to assess, for the first time, the response of hamster cheek pouch tumors, precancerous tissue and normal tissue to BNCT mediated by GB-10 and BNCT mediated by GB-10 and BPA administered jointly using the thermalized epithermal beam of the RA-6 Reactor at the Bariloche Atomic Center. GB-10 exerted 75.5% tumor control (partial+complete remission) with no damage to precancerous tissue around tumor or to normal tissue. Thus, GB-10 proved to be a therapeutically efficient boron agent in this model despite the fact that it is not taken up selectively by oral tumor tissue. GB-10 exerted a selective effect on tumor blood vessels leading to significant tumor control with a sparing effect on normal tissue. BNCT mediated by the combined administration of GB-10 and BPA resulted in a reduction in the dose to normal tissue and would thus allow for significant escalation of dose to tumor without exceeding normal tissue tolerance.

This article reports on the progress of the modeling and experimental characterization of the RA-6 reactor neutron beam, designed for the upcoming BNCT clinical trials of skin melanoma, and presents the first theoretical analysis of such beam performance. The aspects relating to surface source modeling and assessment, beam dosimetry,treatment planning system calibration, and treatment planning optimization are presented herein. Several methods and criteria were established in order to provide guidance for future clinical studies conducted in this facility. Following a realistic model, the theoretical analysis was based on a clinical case of malignant melanoma in extremities. Owing to the complex geometry of the tumor, this particular clinical case represents one of the most difficult lesions to be treated. This article discusses the thorough evaluation stage that has led to the optimization of the treatment planning procedure. Two candidate plans were proposed, and dose–volume distributions in the target volume were evaluated on the basis of the application of a series of criteria that define the critical normal structures which limit the dose delivered. In spite of the complexity of the clinical case under review, results showed that only 4% of the tumor volume is underdosed in cases of mean blood 10 B concentration values, even in the most unfavorable analysis. The overall results suggest that this BNCT facility is prepared to rigorously explore the clinical efficacy of the RA-6 beam and the BNCT treatment modality for peripheral melanomas.

From 2008 to 2011, several planned modifications were implemented at the RA-6 reactor in Argentina, leading to significant benefits for future BNCT treatments. New capabilities have been implemented in NCTPlan treatment planning system. To assess the performance of the new BNCT facility, a dosimetric reevaluation of previous clinical cases was performed, taking into account the modifications carried out in the new facility and compared the results of the original treatment plans with optimized plans that are considered as feasible patient setups. Fil: Provenzano, Lucas. Universidad Favaloro; Argentina Fil: Farías, Rubén Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Favaloro; Argentina. Comisión Nacional de Energía Atómica; Argentina Fil: Longhino, Juan Manuel. Comisión Nacional de Energía Atómica; Argentina Fil: Boggio, Esteban F.. Comisión Nacional de Energía Atómica; Argentina Fil: Herrera, Maria Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; Argentina Fil: Moijsecsiuck, Natanael. Universidad Favaloro; Argentina Fil: Fernandez, Carlos. Comisión Nacional de Energía Atómica; Argentina Fil: Santa Cruz, Gustavo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; Argentina Fil: González, Sara Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; Argentina

A feasibility study of performing retrospective dosimetry for the Argentinian reactor Atucha I has been performed. Different samples have been investigated for this pupose, amongst which charpy's prepared from Atucha I base material that have been irradiated in the BR2 reactor at SCK'CEN in an accurately characterised neutron field. The fast neutron fluence was determined using the 54Fe(n,p) reaction, whereas the thermal neutron fluence determination was based on three different reactions. All results agree with the fluences that were determined via routine neutron dosimetry.

A previous work concerning tumor control and skin damage in cutaneous melanoma treatments with BNCT has been extended to include doses, volumes and responses of 104 subcutaneous lesions from all patients treated in Argentina. Acute skin reactions were also scored for these patients, and cumulative dose-area histograms and dose-based figures of merit for skin were calculated. Broadening the tumor response analysis with the latest data showed that the (minimum or mean) tumor dose is not a good predictor of the observed clinical outcome by itself. However, when the tumor volume was included in the model as second explicative variable, the dose increases its significance and becomes a critical variable jointly with the volume (p-values0.05). A preliminary analysis to estimate control doses for two groups of tumor sizes revealed that for small tumor volumes (0.1cm(3)) doses greater than 20 Gy-Eq produce a high tumor control (80%). However, when tumor volumes are larger than 0.1cm(3), control is moderate (40%) even for minimum doses up to 40 Gy-Eq. Some quantities based on skin doses, areas and complication probabilities were proposed as candidates for predicting the severity of the early skin reactions. With the current data, all the evaluated figures of merit derived similar results: ulceration is present among the cases for which these quantities take the highest values.

As part of phase I/II melanoma BNCT clinical trial conducted in Argentina in a cooperative effort of the Argentine Atomic Energy Commission (CNEA) and the Oncology Institute Angel H. Roffo (IOAHR), 7 patients (6 female-1 male) received eight treatment sessions covering ten anatomical areas located in extremities. Mean age of the patients was 64 years (51-74). The treatments were performed between October 2003 and June 2007. All patients presented multiple subcutaneous skin metastases of melanoma and received an infusion containing approximately 14 gr/m(2) of (10)borophenyl-alanine (BPA) followed by the exposition of the area to a mixed thermal-epithermal neutron beam at the RA-6 reactor. The maximum prescribed dose to normal skin ranged from 16.5 to 24 Gy-Eq and normal tissue administered dose varied from 15.8 to 27.5 Gy-Eq. Considering evaluable nodules, 69.3% of overall response and 30.7% of no changes were seen. The toxicity was acceptable, with 3 out of 10 evaluable areas showing ulceration (30% toxicity grade 3).

The effect of Boron Neutron Capture Therapy (BNCT) on normal liver regeneration was examined in the Wistar rat. The model used is clinically relevant to a novel technique proposed for the treatment of multifocal non-resectable liver metastases in man. The success of the technique also requires that BNCT should not significantly impair regeneration of normal hepatocytes.The effect of therapeutic doses of boronophenylalanine (BPA), GB-10 (Na(2)(10)B(10)H(10)) and (GB-10 + BPA) and of BNCT mediated by these boron delivery agents on normal liver regeneration and liver function in the Wistar rat was examined using partial hepatectomy as the regenerative stimulus. The end-points evaluated were body weight, liver weight/body weight ratio, DNA synthesis in terms of 5-bromo-2'-deoxyuridine incorporation, hemogram, kidney function in terms of blood urea nitrogen and creatinine levels, liver function in terms of serum albumin, total and direct bilirubin and liver enzymes (alanine transaminase and aspartate transaminase) and liver histology/architecture.BNCT mediated by BPA, GB-10 or (GB-10 + BPA) did not cause alterations in the outcome of normal liver regeneration, regenerated liver function/proliferation or histology/architecture.The BNCT protocols, at the physical doses selected, did not impair the capacity of normal liver hepatocytes to regenerate.

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.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.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 (p0.05 vs. controls) and after the first week after irradiation in the three BNCT groups. Terminal transferase dUTP nick end labeling analysis confirmed these results.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.

The hypothesis of boron neutron capture therapy (BNCT) research has been that the short-range, high-linear energy transfer radiation produced by the capture of thermal neutrons by (10)B will potentially control tumor and spare normal tissue only if the boron compound selectively targets tumor tissue within the treatment volume. In a previous in vivo study of low-dose BNCT mediated by GB-10 (Na(2)(10)B(10)H(10)) alone or combined with boronophenylalanine (BPA) in the hamster cheek pouch oral cancer model that was primarily designed to evaluate safety and feasibility, we showed therapeutic effects but no associated normal tissue radiotoxicity. In the present study, we evaluated the response of tumor, precancerous and normal tissue to high-dose BNCT mediated by GB-10 alone or combined with BPA. Despite the fact that GB-10 does not target hamster cheek pouch tumors selectively, GB-10-BNCT induced a 70% overall tumor response with no damage to normal tissue. (GB-10+BPA)-BNCT induced a 93% overall tumor response with no normal tissue radiotoxicity. Light microscope analysis showed that GB-10-BNCT selectively damages tumor blood vessels, sparing precancerous and normal tissue vessels. In this case, selective tumor lethality would thus result from selective blood vessel damage rather than from selective uptake of the boron compound.

This work evaluates the performance of two NCT treatment planning systems: NCTPlan, developed by the CNEA and the Harvard-MIT group, and SERA, developed by the INEEL/Montana State University group. The study was performed in some simple geometries with the therapeutical hyperthermal beam of the RA-6 facility at Bariloche, Argentina. The first geometry was a rectangular phantom and calculations and measurements were made along the central beam axis and along a parellel axis, 4 cm apart from the central beam axis. Measurements and calculations were also performed in a cylindrical phantom, to explore the behavior of the treatment planning systems in a geometry simulating an extremity, in accordance with the CNEA clinical protocol. Comments on differences in source definitions and cross sections libraries are also included in the text. It can be seen that both codes give acceptable results on the central beam axis and on a lateral axis, showing good agreement with experimental results.

We have shown the selective uptake of borophenylalanine (BPA) by undifferentiated human thyroid cancer (UTC) ARO cells both in vitro and in vivo. Moreover, a 50% histologic cure of mice bearing the tumor was observed when the complete boron neutron capture therapy was applied. More recently we have analyzed the biodistribution of BOPP (tetrakis-carborane carboxylate ester of 2,4-bis-(alpha,beta-dihydroxyethyl)-deutero-porphyrin IX) and showed that when BOPP was injected 5 days before BPA, and the animals were sacrificed 60 min after the i.p. injection of BPA, a significant increase in boron uptake by the tumor was found (38-45 ppm with both compounds vs. 20 ppm with BPA alone). Five days post the i.p BOPP injection and 1h after BPA the ratios were: tumor/blood 3.75; tumor/distal skin 2. Other important ratios were tumor/thyroid 6.65 and tumor/lung 3.8. The present studies were performed in mice transplanted with ARO cells and injected with BOPP and BPA. Only in mice treated with the neutron beam and injected with the boronated compounds we observed a 100% control of tumor growth. Two groups of mice received different total absorbed doses: 3.00 and 6.01 Gy, but no further improvement in the outcome was found compared to the previous results using BPA alone (4.3 Gy).

Purpose Undifferentiated thyroid carcinoma (UTC) lacks an effective treatment. Boron neutron capture therapy (BNCT) is based on the nuclear reaction 10 B(n,α) 7 Li. These particles destroy the tumor locally due to their high linear energy transfer (LET). Mice transplanted with the human cell line of UTC ARO have a selective uptake of 10 B-borophenylalanine (BPA). The complete BNCT was performed to explore its possible application. Methods and materials Mice were distributed into four groups: ( 1 ) no treatment; ( 2 ) neutron beam alone; ( 3 ) 350 mg/kg body weight (b.w.) BPA plus irradiation; ( 4 ) 600 mg/kg b.w. BPA plus irradiation. Follow-up was performed by measurement of tumor volume, histologic analysis, and assessment of DNA damage using the comet assay. Results The tumor continued to grow in Groups 1 and 2. In Group 3, a slow-down of tumor growth was observed in all mice, and a complete stop was observed in 100% of mice of Group 4. Complete disappearance of the tumor was observed in 50% of the mice that had an initial tumor volume of less than 50 mm 3 (Groups 3 and 4). DNA damage showed a progressive increase from Group 1 through 4. Conclusion These data show, for the first time, that UTC is amenable to treatment by BNCT.

The RA-6 reactor located at Bariloche Atomic Center, is a pool type one with 500kW of nominal power and U 90% enriched fuel owned and operated by CN.E.A.