Molecular engineering of AIE-active boron clustoluminogens for enhanced boron neutron capture therapy.

The development of boron delivery agents bearing an imaging capability is crucial for boron neutron capture therapy (BNCT), yet it has been rarely explored. Here we present a new type of boron delivery agent that integrates aggregation-induced emission (AIE)-active imaging and a carborane cluster for the first time. In doing so, the new boron delivery agents have been rationally designed by incorporating a high boron content unit of a carborane cluster, an erlotinib targeting unit towards lung cancer cells, and a donor-acceptor type AIE unit bearing naphthalimide. The new boron delivery agents demonstrate both excellent AIE properties for imaging purposes and highly selective accumulation in tumors. For example, at a boron delivery agent dose of 15 mg kg-1, the boron amount reaches over 20 µg g-1, and both tumor/blood (T/B) and tumor/normal cell (T/N) ratios reach 20-30 times higher than those required by BNCT. The neutron irradiation experiments demonstrate highly efficient tumor growth suppression without any observable physical tissue damage and abnormal behavior in vivo. This study not only expands the application scopes of both AIE-active molecules and boron clusters, but also provides a new molecular engineering strategy for a deep-penetrating cancer therapeutic protocol based on BNCT.

Using the photon isoeffective dose formalism to compare and combine BNCT and CIRT in a head and neck tumour.

Boron Neutron Capture Therapy (BNCT) is a radiotherapy technique based on the enrichment of tumour cells with suitable 10-boron concentration and on subsequent neutron irradiation. Low-energy neutron irradiation produces a localized deposition of radiation dose caused by boron neutron capture reactions. Boron is vehiculated into tumour cells via proper borated formulations, able to accumulate in the malignancy more than in normal tissues. The neutron capture releases two high-LET charged particles (i.e., an alpha particle and a lithium ion), losing their energy in a distance comparable to the average dimension of one cell. Thus BNCT is selective at the cell level and characterized by high biological effectiveness. As the radiation field is due to the interaction of neutrons with the components of biological tissues and with boron, the dosimetry requires a formalism to express the absorbed dose into photon-equivalent units. This work analyzes a clinical case of an adenoid cystic carcinoma treated with carbon-ion radiotherapy (CIRT), located close to optic nerve and deep-seated as a practical example of how to apply the formalism of BNCT photon isoeffective dose and how to evaluate the BNCT dose distribution against CIRT. The example allows presenting different dosimetrical and radiobiological quantities and drawing conclusions on the potential of BNCT stemming on the clinical result of the CIRT. The patient received CIRT with a dose constraint on the optic nerve, affecting the peripheral part of the Planning Target Volume (PTV). After the treatment, the tumour recurred in this low-dose region. BNCT was simulated for the primary tumour, with the goal to calculate the dose distribution in isoeffective units and a Tumour Control Probability (TCP) to be compared with the one of the original treatment. BNCT was then evaluated for the recurrence in the underdosed region which was not optimally covered by charged particles due to the proximity of the optic nerve. Finally, a combined treatment consisting in BNCT and carbon ion therapy was considered to show the consistency and the potential of the model. For the primary tumour, the photon isoeffective dose distribution due to BNCT was evaluated and the resulted TCP was higher than that obtained for the CIRT. The formalism produced values that are consistent with those of carbon-ion. For the recurrence, BNCT dosimetry produces a similar TCP than that of primary tumour. A combined treatment was finally simulated, showing a TCP comparable to the BNCT-alone with overall dosimetric advantage in the most peripheral parts of the treatment volume. Isoeffective dose formalism is a robust tool to analyze BNCT dosimetry and to compare it with the photon-equivalent dose calculated for carbon-ion treatment. This study introduces for the first time the possibility to combine the dosimetry obtained by two different treatment modalities, showing the potential of exploiting the cellular targeting of BNCT combined with the precision of charged particles in delivering an homogeneous dose distribution in deep-seated tumours.

HU-based material conversion for BNCT accurate dose estimation.

NeuMANTA is a new generation boron neutron capture therapy (BNCT)-specific treatment planning system developed by the Neuboron Medical Group and upgraded to an important feature, a Hounsfield unit (HU)-based material conversion algorithm. The range of HU values was refined to 96 specific groups and established corresponding to tissue information. The elemental compositions and mass densities have an important effect on the calculated dose distribution. The region of interest defined in the treatment plan can be converted into multiple material compositions based on HU values or assigned specified single material composition in NeuMANTA. Different material compositions may cause normal tissue maximum dose rates to differ by more than 10% in biologically equivalent doses and to differ by up to 6% in physically absorbed doses. Although the tumor has a lower proportion of BNCT background dose, the material composition difference may affect the minimum dose of biologically equivalent dose and physically absorbed dose by more than 3%. In addition, the difference in material composition could lead to a change in neutron moderation as well as scattering. Therefore, the material composition has a significant impact on the assessment of normal tissue side effects and tumor control probability. It is essential for accurate dose estimation in BNCT.

Correcting for the heterogeneous boron distribution in a tumor for BNCT dose calculation.

Most treatment planning systems of boron neutron capture therapy perform dose calculations based on the assumption of a homogeneous boron distribution in tumors, which leads to dose distortion due to the difference between the tumor-to-normal tissue ratio (TNR) range measured in positron emission tomography images (PET) and the target delineation in computed tomography images of the treatment plan. The heterogeneous boron distribution in the target of the treatment plan can be obtained by image fusion. This study provides a way to quantify a heterogeneous boron distribution based on PET images. Theoretically, the same mean TNR for dose calculation by homogeneous or heterogeneous boron distribution should get almost the same mean dose. However, slightly different mean doses are found due to the partial volume effect for a small target volume. The wider the boron distribution is, the higher the impact on the dose-volume histogram distribution is. Dose distribution with homogeneous boron distribution may be overestimated in low boron uptake regions by wrong boron concentration and neutron flux depression. To accurately give the tumor prescription dose and achieve better tumor control, for low dose regions of the tumor should be considered more boron neutron capture therapy treatments or combined with other treatment modalities. The heterogeneous boron distribution must be taken into consideration to have an accurate dose estimation. Therefore, the way how medical physicists and clinicians process the TNR in gross tumor volume should be refined, and the method demonstrated in the work provides a good reference.

Introduction to the Monte Carlo dose engine COMPASS for BNCT.

The Monte Carlo method is the most commonly used dose calculation method in the field of boron neutron capture therapy (BNCT). General-purpose Monte Carlo (MC) code (e.g., MCNP) has been used in most treatment planning systems (TPS) to calculate dose distribution, which takes overmuch time in radiotherapy planning. Based on this, we developed COMPASS (COMpact PArticle Simulation System), an MC engine specifically for BNCT dose calculation. Several optimization algorithms are used in COMPASS to make it faster than general-purpose MC code. The parallel computation of COMPASS is performed by the message passing interface (MPI) library and OpenMP commands, which allows the user to increase computational speed by increasing the computer configurations. The physical dose of each voxel is calculated for developing a treatment plan. Comparison results show that the computed dose distribution of COMPASS is in good agreement with MCNP, and the computational efficiency is better than MCNP. These results validate that COMPASS has better performance than MCNP in BNCT dose calculation.

Nucleophilic radiosynthesis of boron neutron capture therapy-oriented PET probe [18F]FBPA using aryldiboron precursors.

A reliable copper-mediated nucleophilic radiosynthesis of the PET imaging probe [18F]FBPA was developed using novel aryldiboron precursors. The carrier-free [18F]FBPA with radiochemical purity >99% was prepared routinely via the two-step synthesis with an automatic module and can be used for clinical PET imaging of tumours.

Boron Neutron Capture Therapy: From Nuclear Physics to Biomedicine.

Boron Neutron Capture Therapy (BNCT) is a binary radiation treatment exploiting a nuclear reaction occurring in tumor cells [...].

A Novel Approach to Design and Evaluate BNCT Neutron Beams Combining Physical, Radiobiological, and Dosimetric Figures of Merit.

(1) Background:The quality of neutron beams for Boron Neutron Capture Therapy (BNCT) is currently defined by its physical characteristics in air. Recommendations exist to define whether a designed beam is useful for clinical treatment. This work presents a new way to evaluate neutron beams based on their clinical performance and on their safety, employing radiobiological quantities. (2) Methods: The case study is a neutron beam for deep-seated tumors from a 5 MeV proton beam coupled to a beryllium target. Physical Figures of Merit were used to design five beams; however, they did not allow a clear ranking of their quality in terms of therapeutic potential. The latter was then evaluated based on in-phantom dose distributions and on the calculation of the Uncomplicated Tumor Control Probability (UTCP). The safety of the beams was also evaluated calculating the in-patient out-of-beam dosimetry. (3) Results: All the beams ensured a UTCP comparable to the one of a clinical beam in phantom; the safety criterion allowed to choose the best candidate. When this was tested in the treatment planning of a real patient treated in Finland, the UTCP was still comparable to the one of the clinical beam. (4) Conclusions: Even when standard physical recommendations are not met, radiobiological and dosimetric criteria demonstrate to be a valid tool to select an effective and safe beam for patient treatment.

The Effect of Low-Dose Gamma Irradiation on the Uptake of Boronophenylalanine to Enhance the Efficacy of Boron Neutron Capture Therapy in an Orthotopic Oral Cancer Model.

The success of boron neutron capture therapy (BNCT) mainly depends on the boron concentration in the tumor and a high tumor/normal tissue (T/N) boron ratio or a high tumor/blood (T/B) boron ratio. Therefore, the effective enhancement of boron ratios is the first priority. Our study investigated whether a low-dose of γ-radiation (LDR) could improve boron ratios and enhance the therapeutic effects of BNCT in an orthotopic human oral squamous cell carcinoma-bearing animal model. SAS/luc cells were used to establish the orthotopic tumor-bearing model. The pharmacokinetics of boronophenylalanine (BPA) administration with 400 mg/kg of body weight both alone and in combination with LDR (0.1 Gy) was evaluated, and BNCT was performed at the Tsing Hua Open-pool Reactor (THOR). The radiation doses were evaluated using a treatment planning system. Moreover, tumor growth and metastasis were monitored via bioluminescence imaging (BLI). The therapeutic effects after BNCT were evaluated using BLI, histopathological findings and the overall survival rate. LDR increased the BPA accumulation in tumors by 52.2%. T/N and T/B ratios were enhanced from 3.77 to 5.31 and from 3.47 to 4.46, respectively. Radiation dose was increased by 44.3%. Notably, tumor recurrence and cervical lymph node metastasis were observed in the BNCT group, which had a survival rate of 50%. Complete responses were found in the combined-treatment group, which had a survival rate of 100%. No toxicity was found according to the histopathological findings. Conclusively, LDR increased BPA accumulation in the tumor and the T/N and T/B ratios, resulting in BNCT efficacy improvement and the overall survival rate extension.

A bi-tapered and air-gapped beam shaping assembly used for AB-BNCT.

The 7Li(p,n)7Be reaction, which leads to a soft neutron field, is often chosen as the neutron producing reaction used for accelerator-based boron neutron capture therapy (AB-BNCT). This study aims to design a compact beam shaping assembly (BSA) and auxiliary system for a 7Li(p,n)7Be reaction-based neutron source and to evaluate the relationship between the BSA design and the consequent neutron beam quality for further optimization. In this study, five types of moderator shapes for the BSA model were designed. Both the in-air and in-phantom figures of merit were considered to evaluate the performance of the BSA designs. It was found that the BSA with a bi-tapered and air-gapped design could generate a high-intensity epithermal neutron beam, which could be used to treat deep-seated brain tumors within a reasonable time.

The overview and prospects of BNCT facility at Tsing Hua Open-pool reactor.

The whole picture of the BNCT facility at Tsing Hua Open-pool Reactor will be presented which consists of the following aspects: the construction project, the beam quality, routine operations including the QA program for the beam delivery, determination of boron-10 concentration in blood, T/N ratio, and the clinical affairs including the patient recruit procedure and the patient irradiation procedure. The facility is positioned to serve for conducting clinical trials, emergent (compassionate) treatments, and R&D works.

A Rare Experience of Infective Residual Sheath in the Wall of the Innominate Vein after Extraction of Implantable-Defibrillators.

BACKGROUND: Cardiac device-related infective endocarditis is an uncommon but potentially fatal complication. Therefore, cardiac devices should be removed as soon as a device-related infection is suspected. CASE REPORT: A 56-year-old male with a history of arrhythmogenic right ventricular dysplasia with implantable cardioverter-defibrillators (ICDs) 7 years earlier and re-implantation of ICDs due to dysfunction 18 months ago presented with erosion of the ICD pocket with Pseudomonas bacteremia. For the past year, only multiple wound debridements were performed. Accordingly, we performed debridement and removal of the generator during this admission; however, bacteremia still persisted. Using transesophageal echocardiography, we detected vegetation on the pacing leads and tricuspid valve in the right atrium. We performed thoracotomy with tricuspid valve repair and pacing wire removal. However, anterior chest pain and refractory bacteremia occurred 3 months later after discharge, and an infectious foreign body in the wall of the innominate vein was detected using chest computer tomography. Thoracotomy was again performed for resection of the innominate vein with the infection source. Postoperative recovery was good, with no systemic infection or bacteremia. CONCLUSIONS: Pacing lead extraction is a common procedure following cardiac rhythm management device-related infection. However, residual foreign body-related bacteremia should be suspected in cases with fever of unknown origin after primary surgery. Preserving the innominate vein with patch repair is a feasible option. However, a postoperative 4-week course of antibiotics is recommended.

A penetrating atherosclerotic ulcer rupture in the ascending aorta with hemopericardium: a case report.

BACKGROUND: Acute aortic syndrome, including classic aortic dissection, intramural aortic hematoma, and penetrating atherosclerotic ulcer (PAU), is a term used to describe a group of conditions with similar clinical symptoms, but with different pathophysiological mechanisms. PAU is a lesion that penetrates the internal elastic lamina through the media. It is usually located in the descending aorta and rarely observed in the ascending aorta. CASE PRESENTATION: A 76-year-old man with a history of essential hypertension was brought to the emergency department (ED) because of a sudden-onset chest pain at rest. He had not been taking his medication as ordered. His vital signs in the ED were a blood pressure of 82/60 mmHg, heart rate of 158 beats per min, respiratory rate of 22 breaths per min, and a body temperature of 37.2 °C. An electrocardiogram did not show an ST segment elevation, and cardiac enzymes were within normal limits. No widening mediastinum was found on chest radiography, but a large pericardial effusion with an impending cardiac tamponade was revealed on echocardiography. The diagnosis of PAU rupture in the ascending aorta with hemopericardium was made with chest computed tomography. An emergent sternotomy and ascending aorta reconstruction were performed. A ruptured ulcerative plaque through the intima to the adventitia without flap dissection in the ascending aorta was confirmed. The patient was discharged 18 days after the operation. CONCLUSIONS: Although PAU in the ascending aorta is uncommon, it is commonly lethal when it ruptures. With the current advances in endovascular techniques and devices, endovascular repair of PAU in the ascending aorta is currently recommended only for high-risk patients unsuitable for open repair. However, we anticipate that endovascular repair may become feasible in patients with PAU in the ascending aorta in the future.

Fractionated Boron Neutron Capture Therapy in Locally Recurrent Head and Neck Cancer: A Prospective Phase I/II Trial.

PURPOSE: To investigate the efficacy and safety of fractionated boron neutron capture therapy (BNCT) for recurrent head and neck (H&N) cancer after photon radiation therapy. METHODS AND MATERIALS: In this prospective phase 1/2 trial, 2-fraction BNCT with intravenous L-boronophenylalanine (L-BPA, 400 mg/kg) was administered at a 28-day interval. Before each fraction, fluorine-18-labeled-BPA-positron emission tomography was conducted to determine the tumor/normal tissue ratio of an individual tumor. The prescription dose (D80) of 20 Gy-Eq per fraction was selected to cover 80% of the gross tumor volume by using a dose volume histogram, while minimizing the volume of oral mucosa receiving >10 Gy-Eq. Tumor responses and adverse effects were assessed using the Response Evaluation Criteria in Solid Tumors v1.1 and the Common Terminology Criteria for Adverse Events v3.0, respectively. RESULTS: Seventeen patients with a previous cumulative radiation dose of 63-165 Gy were enrolled. All but 2 participants received 2 fractions of BNCT. The median tumor/normal tissue ratio was 3.4 for the first fraction and 2.5 for the second, whereas the median D80 for the first and second fraction was 19.8 and 14.6 Gy-Eq, respectively. After a median follow-up period of 19.7 months (range, 5.2-52 mo), 6 participants exhibited a complete response and 6 exhibited a partial response. Regarding acute toxicity, 5 participants showed grade 3 mucositis and 1 participant showed grade 4 laryngeal edema and carotid hemorrhage. Regarding late toxicity, 2 participants exhibited grade 3 cranial neuropathy. Four of six participants (67%) receiving total D80 > 40 Gy-Eq had a complete response. Two-year overall survival was 47%. Two-year locoregional control was 28%. CONCLUSIONS: Our results suggested that 2-fraction BNCT with adaptive dose prescription was effective and safe in locally recurrent H&N cancer. Modifications to our protocol may yield more satisfactory results in the future.

Demonstration of the importance of a dedicated neutron beam monitoring system for BNCT facility.

The neutron beam monitoring system is indispensable to BNCT facility in order to achieve an accurate patient dose delivery. The neutron beam monitoring of a reactor-based BNCT (RB-BNCT) facility can be implemented through the instrumentation and control system of a reactor provided that the reactor power level remains constant during reactor operation. However, since the neutron flux in reactor core is highly correlative to complicated reactor kinetics resulting from such as fuel depletion, poison production, and control blade movement, some extent of variation may occur in the spatial distribution of neutron flux in reactor core. Therefore, a dedicated neutron beam monitoring system is needed to be installed in the vicinity of the beam path close to the beam exit of the RB-BNCT facility, where it can measure the BNCT beam intensity as closely as possible and be free from the influence of the objects present around the beam exit. In this study, in order to demonstrate the importance of a dedicated BNCT neutron beam monitoring system, the signals originating from the two in-core neutron detectors installed at THOR were extracted and compared with the three dedicated neutron beam monitors of the THOR BNCT facility. The correlation of the readings between the in-core neutron detectors and the BNCT neutron beam monitors was established to evaluate the improvable quality of the beam intensity measurement inferred by the in-core neutron detectors. In 29 sampled intervals within 16 days of measurement, the fluctuations in the mean value of the normalized ratios between readings of the three BNCT neutron beam monitors lay within 0.2%. However, the normalized ratios of readings of the two in-core neutron detectors to one of the BNCT neutron beam monitors show great fluctuations of 5.9% and 17.5%, respectively.

Hemostatic resuscitation for massive hemorrhage with warm fresh whole blood in a patient with severe blunt trauma.

A 24-year-old male Navy soldier was struck on the left thigh by a ruptured cable and was subsequently thrown into the sea. Initial evaluation showed an Injury Severity Score of 34. Core body temperature was 34.1°C. Laboratory data included a hemoglobin level of 4.5 g/dL and a hematocrit of 13.3%. Prothrombin time was prolonged (>100 seconds), international normalized ratio was elevated (9.99), and partial thromboplastin time was elevated (>180 seconds). The patient was treated for hypothermia, coagulopathy, and metabolic acidosis during resuscitation. The patient was transfused with 16,320 mL of blood during the first 24 hours following the accident, including 4500 mL (18 units) of warm fresh whole blood (WFWB) donated by the patient's military colleagues. The patient was successfully resuscitated, and the injured leg was salvaged. Component therapy can afford replacement of specific deficiencies or requirements, decrease the risk of transfusion-transmitted infectious diseases, and improve resource utilization. However, a protocol of early transfusion with WFWB should be considered during resuscitation following massive hemorrhage in specific conditions such as battle fields or urgent situations.

Are high energy proton beams ideal for AB-BNCT? A brief discussion from the viewpoint of fast neutron contamination control.

High energy proton beam (>8MeV) is favorable for producing neutrons with high yield. However, the produced neutrons are of high energies. These high energy neutrons can cause severe fast neutron contamination and degrade the BNCT treatment quality if they are not appropriately moderated. Hence, this study aims to briefly discuss the issue, from the viewpoint of fast neutron contamination control, whether high energy proton beam is ideal for AB-BNCT or not. In this study, D2O, PbF4, CaF2, and Fluental(™) were used standalone as moderator materials to slow down 1-, 6-, and 10-MeV parallelly incident neutrons. From the calculated results, we concluded that neutrons produced by high energy proton beam could not be easily moderated by a single moderator to an acceptable contamination level and still with reasonable epithermal neutron beam intensity. Hence, much more complicated and sophisticated designs of beam shaping assembly have to be developed when using high energy proton beams.

Dose estimation of animal experiments at the THOR BNCT beam by NCTPlan and Xplan.

Dose estimation of animal experiments affects many subsequent derived quantities, such as RBE and CBE values. It is important to ensure the trustiness of calculated dose of the irradiated animals. However, the dose estimation was normally calculated using simplified geometries and tissue compositions, which led to rough results. This paper introduces the use of treatment planning systems NCTplan and Xplan for the dose estimation. A mouse was taken as an example and it was brought to hospital for micro-PET/CT scan. It was found that the critical organ doses of an irradiated mouse calculated by simplified model were unreliable in comparison to Xplan voxel model. The difference could reach the extent of several tenths percent. It is recommended that a treatment planning system should be introduced to future animal experiments to upgrade the data quality.

Dosimetric performance evaluation regarding proton beam incident angles of a lithium-based AB-BNCT design.

The (7)Li(p,xn)(7)Be nuclear reaction, based on the low-energy protons, could produce soft neutrons for accelerator-based boron neutron capture therapy (AB-BNCT). Based on the fact that the induced neutron field is relatively divergent, the relationship between the incident angle of proton beam and the neutron beam quality was evaluated in this study. To provide an intense epithermal neutron beam, a beam-shaping assembly (BSA) was designed. And a modified Snyder head phantom was used in the calculations for evaluating the dosimetric performance. From the calculated results, the intensity of epithermal neutrons increased with the increase in proton incident angle. Hence, either the irradiation time or the required proton current can be reduced. When the incident angle of 2.5-MeV proton beam is 120°, the required proton current is ∼13.3 mA for an irradiation time of half an hour.

Computational study of room scattering influence in the THOR BNCT treatment room.

BNCT dosimetry has often employed heavy Monte Carlo calculations for the beam characterization and the dose determination. However, these calculations commonly ignored the scattering influence between the radiations and the room structure materials in order to facilitate the calculation speed. The aim of this article attempts to explore how the room scattering affects the physical quantities such as the capture reaction rate and the gamma-ray dose rate under in-phantom and free-air conditions in the THOR BNCT treatment room. The geometry and structure materials of the treatment room were simulated in detail. The capture reaction rates per atom, as well as the gamma-ray dose rate were calculated in various sizes of phantoms and in the free-air condition. Results of this study showed that the room scattering has significant influence on the physical quantities, whether in small phantoms or in the free-air condition. This paper may be of importance in explaining the discrepancies between measurements and calculations in the BNCT dosimetry using small phantoms, in addition to provide a useful consideration with a better understanding of how the room scattering influence acts in a BNCT facility.