Histamine reduces boron neutron capture therapy-induced mucositis in an oral precancer model.

OBJECTIVES: Searching for more effective and selective therapies for head and neck cancer, we demonstrated the therapeutic effect of boron neutron capture therapy (BNCT) to treat oral cancer and inhibit long-term tumor development from field-cancerized tissue in the hamster cheek pouch model. However, BNCT-induced mucositis in field-cancerized tissue was dose limiting. In a clinical scenario, oral mucositis affects patients' treatment and quality of life. Our aim was to evaluate different radioprotectors, seeking to reduce the incidence of BNCT-induced severe mucositis in field-cancerized tissue. MATERIALS AND METHODS: Cancerized pouches treated with BNCT mediated by boronophenylalanine at 5 Gy were treated as follows: control: saline solution; Hishigh : histamine 5 mg kg(-1) ; Hislow : histamine 1 mg kg(-1) ; and JNJ7777120: 10 mg kg(-1). RESULTS: Hislow reduced the incidence of severe mucositis in field-cancerized tissue to 17% vs CONTROL: 55%; Hishigh : 67%; JNJ7777120: 57%. Hislow was non-toxic and did not compromise the long-term therapeutic effect of BNCT or alter gross boron concentration. CONCLUSION: Histamine reduces BNCT-induced mucositis in experimental oral precancer without jeopardizing therapeutic efficacy. The fact that both histamine and boronophenylalanine are approved for use in humans bridges the gap between experimental work and potential clinical application to reduce BNCT-induced radiotoxicity in patients with head and neck cancer.

Boron neutron capture therapy for oral precancer: proof of principle in an experimental animal model.

OBJECTIVES: Field-cancerized tissue can give rise to second primary tumours, causing therapeutic failure. Boron neutron capture therapy (BNCT) is based on biological targeting and would serve to treat undetectable foci of malignant transformation. The aim of this study was to optimize BNCT for the integral treatment for oral cancer, with particular emphasis on the inhibitory effect on tumour development originating in precancerous conditions, and radiotoxicity of different BNCT protocols in a hamster cheek pouch oral precancer model. MATERIALS AND METHODS: Groups of cancerized hamsters were locally exposed to single or double (2 or 4 weeks apart) applications of BNCT at different dose levels, mediated by the boron compounds boronophenylalanine (BPA) or BPA and decahydrodecaborate (GB-10) administered jointly. Cancerized, sham-irradiated hamsters served as controls. Clinical status, tumour development from field-cancerized tissue and mucositis were followed for 8 months. RESULTS: A double application (4 weeks apart) of BNCT mediated by GB-10+ BPA at a total dose of 10 Gy in two 5-Gy doses rendered the best therapeutic advantage (63-100% inhibition of tumour development from field-cancerized tissue), minimizing dose-limiting mucositis. CONCLUSION: BNCT can be optimized for the integral treatment for head and neck cancer, considering the implications for field-cancerized tissue.

First application of dynamic infrared imaging in boron neutron capture therapy for cutaneous malignant melanoma.

PURPOSE: The purpose of this study is to assess the potential of dynamic infrared imaging (DIRI) as a functional, noninvasive technique for evaluating the skin acute toxicity and tumor control within the framework of the Argentine boron neutron capture therapy (BNCT) program for cutaneous malignant melanoma. METHODS: Two patients enrolled in the Argentine phase I/II BNCT clinical trial for cutaneous malignant melanoma were studied with DIRI. An uncooled infrared camera, providing a video output signal, was employed to register the temperature evolution of the normal skin and tumor regions in patients subjected to a mild local cooling (cold stimulus). In order to study the spatial correlation between dose and acute skin reactions, three-dimensional representations of the superficial dose delivered to skin were constructed and cameralike projections of the dose distribution were coregistered with visible and infrared images. RESULTS: The main erythematous reaction was observed clinically between the second and fifth week post-BNCT. Concurrently, with its clinical onset, a reactive increase above the basal skin temperature was observed with DIRI in the third week post-BNCT within regions that received therapeutic doses. Melanoma nodules appeared as highly localized hyperthermic regions. 2 min after stimulus, these regions reached a temperature plateau and increased in size. Temperature differences with respect to normal skin up to 10 degrees C were observed in the larger nodules. CONCLUSIONS: Preliminary results suggest that DIRI, enhanced by the application of cold stimuli, may provide useful functional information associated with the metabolism and vasculature of tumors and inflammatory processes related to radiation-induced changes in the skin as well. These capabilities are aimed at complementing the clinical observations and standard imaging techniques, such as CT and Doppler ultrasound.

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.

Anatomical description of anaesthetic spread after deep erector spinae block at L-4. / Estudio anatómico de la distribución del volumen administrado tras bloqueo en el plano profundo del erector espinal a nivel lumbar.

INTRODUCTION: Thoracic erector spinae plane (ESP) block is now used for postoperative analgesia. However, although reports of lumbar ESP have been published, the anesthetic spread and mechanism of action of this technique remains unclear. We describe the lumbar ESP block technique and evaluate the spread of 20ml of solution administered at the level of the transverse process of L4 in a cadaver model. METHODS: Observational study after 12 lumbar ESP blocks at L4 on a fresh cadaver model (6 bilaterally). The spread of 20ml of injected contrast solution was assessed by computed tomography in all 6 samples. Four of the samples were evaluated by anatomical study, 2 by plane dissection, and 2 others were frozen and cut into 2-2.5cm axial slices. RESULTS: The injected solution spread from L2 to L5 in a cranio-caudal direction in the erector spinae muscle, reaching the facet joints medially and the thoracolumbar fascia laterally. In 33% of cases the solution did not spread anterior to the transverse process; in 51%, spread was minimal and did not affect the corresponding spinal nerves, and in 2 samples (16%), spread was extensive and reached the corresponding spinal nerves. CONCLUSIONS: Lumbar ESP at L4 always acts on the posterior branches of the spinal nerves, but seldom spreads to the paravertebral space to block the spinal nerve.

Unifying dose specification between clinical BNCT centers in the Americas.

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.

Examining the sustainability potential of a multisite pilot to integrate alcohol screening and brief intervention within three primary care systems.

The U.S. Preventive Services Task Force recommends that clinicians adopt universal alcohol screening and brief intervention as a routine preventive service for adults, and efforts are underway to support its widespread dissemination. The likelihood that healthcare systems will sustain this change, once implemented, is under-reported in the literature. This article identifies factors that were important to postimplementation sustainability of an evidence-based practice change to address alcohol misuse that was piloted within three diverse primary care organizations. The Centers for Disease Control and Prevention funded three academic teams to pilot and evaluate implementation of alcohol screening and brief intervention within multiclinic healthcare systems in their respective regions. Following the completion of the pilots, teams used the Program Sustainability Assessment Tool to retrospectively describe and compare differences across eight sustainability domains, identify strengths and potential threats to sustainability, and make recommendations for improvement. Health systems varied across all domains, with greatest differences noted for Program Evaluation, Strategic Planning, and Funding Stability. Lack of funding to sustain practice change, or data monitoring to promote fit and fidelity, was an indication of diminished Organizational Capacity in systems that discontinued the service after the pilot. Early assessment of sustainability factors may identify potential threats that could be addressed prior to, or during implementation to enhance Organizational Capacity. Although this study provides a retrospective assessment conducted by external academic teams, it identifies factors that may be relevant for translating evidence-based behavioral interventions in a way that assures that they are sustained within healthcare systems.

Photon iso-effective dose for cancer treatment with mixed field radiation based on dose-response assessment from human and an animal model: clinical application to boron neutron capture therapy for head and neck cancer.

Boron neutron capture therapy (BNCT) is a treatment modality that combines different radiation qualities. Since the severity of biological damage following irradiation depends on the radiation type, a quantity different from absorbed dose is required to explain the effects observed in the clinical BNCT in terms of outcome compared with conventional photon radiation therapy. A new approach for calculating photon iso-effective doses in BNCT was introduced previously. The present work extends this model to include information from dose-response assessments in animal models and humans. Parameters of the model were determined for tumour and precancerous tissue using dose-response curves obtained from BNCT and photon studies performed in the hamster cheek pouch in vivo models of oral cancer and/or pre-cancer, and from head and neck cancer radiotherapy data with photons. To this end, suitable expressions of the dose-limiting Normal Tissue Complication and Tumour Control Probabilities for the reference radiation and for the mixed field BNCT radiation were developed. Pearson's correlation coefficients and p-values showed that TCP and NTCP models agreed with experimental data (with r > 0.87 and p-values >0.57). The photon iso-effective dose model was applied retrospectively to evaluate the dosimetry in tumours and mucosa for head and neck cancer patients treated with BNCT in Finland. Photon iso-effective doses in tumour were lower than those obtained with the standard RBE-weighted model (between 10% to 45%). The results also suggested that the probabilities of tumour control derived from photon iso-effective doses are more adequate to explain the clinical responses than those obtained with the RBE-weighted values. The dosimetry in the mucosa revealed that the photon iso-effective doses were about 30% to 50% higher than the corresponding RBE-weighted values. While the RBE-weighted doses are unable to predict mucosa toxicity, predictions based on the proposed model are compatible with the observed clinical outcome. The extension of the photon iso-effective dose model has allowed, for the first time, the determination of the photon iso-effective dose for unacceptable complications in the dose-limiting normal tissue. Finally, the formalism developed in this work to compute photon-equivalent doses can be applied to other therapies that combine mixed radiation fields, such as hadron therapy.

Reprint of Application of BNCT to the treatment of HER2+ breast cancer recurrences: Research and developments in Argentina.

In the frame of the Argentine BNCT Project a new research line has been started to study the application of BNCT to the treatment of locoregional recurrences of HER2+ breast cancer subtype. Based on former studies, the strategy considers the use of immunoliposomes as boron carriers nanovehicles to target HER2 overexpressing cells. The essential concerns of the current stage of this proposal are the development of carriers that can improve the efficiency of delivery of boron compounds and the dosimetric assessment of treatment feasibility. For this purpose, an specific pool of clinical cases that can benefit from this application was determined. In this work, we present the proposal and the advances related to the different stages of current research.

Application of BNCT to the treatment of HER2+ breast cancer recurrences: Research and developments in Argentina.

In the frame of the Argentine BNCT Project a new research line has been started to study the application of BNCT to the treatment of locoregional recurrences of HER2+ breast cancer subtype. Based on former studies, the strategy considers the use of immunoliposomes as boron carriers nanovehicles to target HER2 overexpressing cells. The essential concerns of the current stage of this proposal are the development of carriers that can improve the efficiency of delivery of boron compounds and the dosimetric assessment of treatment feasibility. For this purpose, an specific pool of clinical cases that can benefit from this application was determined. In this work, we present the proposal and the advances related to the different stages of current research.

Comparative study of the radiobiological effects induced on adherent vs suspended cells by BNCT, neutrons and gamma rays treatments.

The present work is part of a preclinical in vitro study to assess the efficacy of BNCT applied to liver or lung coloncarcinoma metastases and to limb osteosarcoma. Adherent growing cell lines can be irradiated as adherent to the culture flasks or as cell suspensions, differences in radio-sensitivity of the two modalities of radiation exposure have been investigated. Dose related cell survival and cell cycle perturbation results evidenced that the radiosensitivity of adherent cells is higher than that of the suspended ones.

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.

Boron neutron capture therapy of skin melanomas at the RA-6 reactor: a procedural approach to beam set up and performance evaluation for upcoming clinical trials.

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 10B 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.

A new approach to determine tumor-to-blood 10B concentration ratios from the clinical outcome of a BNCT treatment.

A new approach to determine the tumor-to-blood (10)B concentration ratio in boron neutron capture therapy (BNCT) is introduced. It is a statistical method, which uses maximum likelihood estimation on the clinical outcome of a BNCT treatment. Its performance is shown in a clinical case of cutaneous multiple nodular melanomas. The calculations involve a detailed dosimetry analysis, the determination of tumor control probabilities for the different nodules, the maximum likelihood estimation itself, and a parametric bootstrap to obtain confidence intervals for the tumor-to-blood ratio. The obtained ratio is 3.05 +/- 0.46 with a 95%-confidence interval. These results are consistent with those found in literature. Moreover, a single patient with multiple nodules proves enough to get statistically relevant results. The proposed method does not involve surgery and can be performed after a BNCT treatment without being invasive for the patient.

Comparison of the performance of two NCT treatment planning systems using the therapeutic beam of the RA-6 reactor.

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.

Biodistribution studies of boronophenylalanine-fructose in melanoma and brain tumor patients in Argentina.

A study of the (10)B-enriched p-boronophenylalanine-fructose complex ((10)BPA-F) infusion procedure in potential BNCT patients, including four melanoma of extremities and two high-grade gliomas (glioblastoma and ganglioglioma) was performed. T/B and S/B ratios for (10)B concentrations in tumor (T), blood (B) and skin (S) were determined. The T/B ratio for the glioblastoma was in the 1.8-3.4 range. The ganglioglioma did not show any significant boron uptake. For the nodular metastasic melanoma T/B values were between 1.5 and 2.6 (average 2.1+/-0.4), corresponding to the lower limit of the mean values reported for different melanoma categories. This result might suggest a lower boron uptake for nodular metastasic melanomas. S/B was 1.5+/-0.4. An open two-compartment pharmacokinetic model was applied to predict the boron concentration during the course and at the end of a BNCT irradiation.

First BNCT treatment of a skin melanoma in Argentina: dosimetric analysis and clinical outcome.

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.

(9)Be(d,n)(10)B-based neutron sources for BNCT.

In the frame of accelerator-based BNCT, the (9)Be(d,n)(10)B reaction was investigated as a possible source of epithermal neutrons. In order to determine the configuration in terms of bombarding energy, target thickness and Beam Shaping Assembly (BSA) design that results in the best possible beam quality, a systematic optimization study was carried out. From this study, the optimal configuration resulted in tumor doses ≥40Gy-Eq, with a maximum value of 51Gy-Eq at a depth of about 2.7cm, in a 60min treatment. The optimal configuration was considered for the treatment planning assessment of a real Glioblastoma Multiforme case. From this, the resulted dose performances were comparable to those obtained with an optimized (7)Li(p,n)-based neutron source, under identical conditions and subjected to the same clinical protocol.

Design, construction and application of a neutron shield for the treatment of diffuse lung metastases in rats using BNCT.

A model of multiple lung metastases in BDIX rats is under study at CNEA (Argentina) to evaluate the feasibility of BNCT for multiple, non-surgically resectable lung metastases. A practical shielding device that comfortably houses a rat, allowing delivery of a therapeutic, uniform dose in lungs while protecting the body from the neutron beam is presented. Based on the final design obtained by numerical simulations, the shield was constructed, experimentally characterized and recently used in the first in vivo experiment at RA-3.

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.