Disseminated tuberculosis after pregnancy progressed to paradoxical response to the treatment: report of two cases.

BACKGROUND: Early postpartum women are more likely to develop tuberculosis than nonpregnant women mainly due to immune reconstitution after delivery. Paradoxical response (PR) during antituberculosis treatment also arises via recovery from immunosuppression. However, no study focused on PR during antituberculosis treatment in a postpartum patient has been reported. CASE PRESENTATION: We present two sequential cases (Patient 1: 26-year-old; Patient 2: 29-year-old) of postpartum tuberculosis with pulmonary and extrapulmonary lesions (Patient 1: peritonitis; Patient 2: psoas abscess secondary to spondylitis). Both cases progressed to PR (worsening of pre-existing lung infiltrations (Patients 1, 2) and new contralateral effusion (Patient 2)) in a relatively short time after initiation of treatment (Patient 1: 1 week; Patient 2: 3 weeks), suggesting that immune modulations during pregnancy and delivery may contribute to the pathogenesis of both disseminated tuberculosis and its PR. The pulmonary lesions and effusion of both cases gradually improved without change of chemotherapy regimen. CONCLUSION: Physicians should recognize PR in tuberculosis patients with postpartum and then evaluate treatment efficacy.

Near-threshold (7)Li(p,n)(7)Be neutrons on the practical conditions using thick Li-target and Gaussian proton energies for BNCT.

The near threshold (7)Li(p,n)(7)Be neutrons generated by incident proton energy having Gaussian distribution with mean energies from 1.85 to 1.95MeV, were studied as a practical neutron source for BNCT wherein an RFQ accelerator and a thick Li-target are used. Gaussian energy distributions with the standard deviation of 0, 10, 20 and 40keV for mean proton energies from 1.85 to 1.95MeV were surveyed in 0.01MeV increments. A thick liquid Li-target whose dimensions were established in our previous experiments (i.e., 1mm-thick with 50mm width and 50mm length) was considered in this study. The suitable incident proton energy and physical dimensions of Pb layer which serves as a gamma absorber and a Polyethylene layer which is used as a BDE were surveyed by means of the concepts of TPD. Dose distribution were calculated by using MCNP5. A proton beam with mean energy of 1.92MeV and a Gaussian energy distribution with a standard deviation of 20keV at a current of 10mA was selected from the viewpoint of irradiation time and practically achievable proton current. The suitable thicknesses of Pb gamma absorber was estimated to be about 3cm. The estimated thickness of the polyethylene BDE was about 24mm for an ideal proton current of 13mA, and was 18mm for a practical proton current of 10mA.

Development of liquid-lithium film jet-flow for the target of (7)Li(p,n)(7)Be reactions for BNCT.

A feasibility study on liquid lithium target in the form of a flowing film was performed to evaluate its potential use as a neutron generation target of (7)Li(p,n)(7)Be reaction in BNCT. The target is a windowless-type flowing film on a concave wall. Its configuration was adapted for a proton beam which is 30mm in diameter and with energy and current of up to 3MeV and 20mA, respectively. The flowing film of liquid lithium was 0.6mm in thickness, 50mm in width and 50mm in length. The shapes of the nozzle and concave back wall, which create a stable flowing film jet, were decided based on water experiments. A lithium hydrodynamic experiment was performed to observe the stability of liquid lithium flow behavior. The flowing film of liquid lithium was found to be feasible at temperatures below the liquid lithium boiling saturation of 342°C at the surface pressure of 1×10(-3)Pa. Using a proto-type liquid lithium-circulating loop for BNCT, the stability of the film flow was confirmed for velocities up to 30m/s at 220°C and 250°C in vacuum at a pressure lower than 10(-3) Pa. It is expected that for practical use, a flowing liquid lithium target of a windowless type can solve the problem of radiation damage and target cooling.

Feasibility study on pinhole camera system for online dosimetry in boron neutron capture therapy.

The feasibility of a pinhole camera system for online dosimetry in boron neutron capture therapy (BNCT) was studied. A prototype system was designed and built. Prompt γ-rays from the (10)B(n,α)(7)Li reaction from a phantom irradiated with neutrons were detected with the prototype system. An image was reconstructed from the experimental data. The reconstructed image showed a good separation of the two borated regions in the phantom. The counting rates and signal-to-noise ratio when using the system in actual BNCT applications are also discussed.

Bioconversion of L-arabinose and other carbohydrates from plant cell walls to alpha-glucan by a soil bacterium, Sporosarcina sp. N52.

A Gram-positive bacterium, N52, that produces intracellular glucan from l-arabinose, was isolated from soil and identified as Sporosarcina sp. according to rRNA gene sequence analysis and physiological/biochemical characterizations. Glucan production by N52 increased significantly in the exponential phase of aerobic liquid culture and was maintained at the highest level during the stationary phase, reaching 37.0% of the cell dry weight. The glucan was also produced from other tested sugars originating from plant cell walls and was composed exclusively of alpha-1,4- and alpha-1,6-glucosidic linkages. When distillery waste was treated with N52 for 72 h, the total organic carbon (TOC), chemical oxygen demand and biochemical oxygen demand were reduced by 42.6%, 45.9% and 82.5%, respectively. Bacterial cells accumulated 31.9% of glucan per cell dry weight, fixing 16.0% of the TOC in the soluble fraction. Thus, this strain could provide us with a new process for waste management, including the bioconversion of organic materials to the valuable byproduct, alpha-glucan.

Characteristics of proton beam scanning dependent on Li target thickness from the viewpoint of heat removal and material strength for accelerator-based BNCT.

This study demonstrates the characterization of proton spot scanning on a Li target assembly for accelerator-based BNCT from the viewpoint of heat removal and material strength. These characteristics are investigated as to their dependence on the Li target thickness, considering that the Cu backing plate has more suitable heat removal properties than Li. Two situations are considered in this paper, i.e. the cyclic operation of the spot scanning, and a stalled spot scanning cycle where the proton beam stays focused on a single position on the Li target. It was found that the maximum of the Li temperature and the strain of the Cu backing increase as the cycle period increases. A cycle period less than 120 ms (over 8.3 Hz of frequency) enables the Li temperature to be kept below 150 degrees C and a cycle of less than 115 ms (8.7 Hz) keeps the Cu strain below the critical value for a 230 microm thick Li target, though the values are evaluated conservatively. Against expectation, the Li temperature and Cu strain are larger for a 100 microm thick target than for a 230 microm target. The required cycle period in this case is 23 ms (43 Hz) for maintaining a reasonable Li temperature and 9 ms (110 Hz) to prevent Cu fatigue fracture. For a stall in the spot scanning cycle, the Cu temperature increases as the beam shutdown time increases. The time for Cu to reach its melting point is estimated to be 4.2 ms at the surface, 20 ms at 1mm depth, for both of 100 and 230 microm thick targets. At least 34 ms is estimated to be enough to make a hole on Cu backing plate. A beam shutdown mechanism with a response time of about 20 ms is therefore required.

Evaluation of neutron dosimetry on pancreatic cancer phantom model for application of intraoperative boron neutron-capture therapy.

Pancreatic cancer is one of the most difficult neoplasms to cure and there is a need for new combinated therapy. If sufficient boron compound can be targeted accurate to the tumour, Boron Neutron-Capture Therapy (BNCT) can be applied to pancreatic cancer. We administrated BNCT to a cancer with pancreatic cancer patient using intraoperative irradiation. In this study, we performed preliminary dosimetry of a phantom model of the abdominal cavity. The flux of 8>x10(7)n/cm(2)/s (0.1 ratio) was 4.5 cm in depth from the surface in the case of simple irradiation, and the field of thermal neutrons was spread as 13 cm and 11.5 cm were usage of Void and Void with LiF collimation, respectively in thermal (OO-0011) mode. In the case of epithermal (CO-0000) mode, epithermal and fast components are four times higher at the surface level. In the case of mixed beam (OO-0000) mode, thermal neutron flux was the same as thermal neutron mode at a depth of 10 cm, but the gamma-ray component was two times higher than that of thermal neutron mode. With the use of Void and LiF collimation, thermal neutrons were selectively applied to the tumour combined with the CT-imaging of the cancer patient. This means that we could irradiate the tumour selectively and safely as possible, reducing the effects on neighboring healthy tissues. High resolution whole body dosimetry will be necessary to extend the application of BNCT to pancreatic cancer.

Variations in lithium target thickness and proton energy stability for the near-threshold 7Li(p,n)7Be accelerator-based BNCT.

The usable range of thickness for the solid lithium target in the accelerator-based neutron production for BNCT via the near-threshold (7)Li(p,n)(7)Be reaction was investigated. While the feasibility of using a (7)Li-target with thickness equal to that which is required to slow down a mono-energetic 1.900 MeV incident proton to the 1.881 MeV threshold of the (7)Li(p,n)(7)Be reaction (i.e., t(min) = 2.33 microm) has already been demonstrated, dosimetric properties of neutron fields from targets greater than t(min) were assessed as thicker targets would last longer and offer more stable neutron production. Additionally, the characteristics of neutron fields generated by (7)Li(p,n)(7)Be for Gaussian incident protons with mean energy of 1.900 MeV were evaluated at a (7)Li-target thickness t(min). The main evaluation index applied in this study was the treatable protocol depth (TPD) which corresponds to the depth in an irradiated medium that satisfies the requirements of the adapted dose protocol. A maximum TPD (TPD(max)) was obtained for each irradiation condition from the relationship between the TPD and the thickness of boron dose enhancer (BDE) used. For a mono-energetic 1.900 MeV proton beam, the deepest TPD(max) of 3.88 cm was attained at the (7)Li-target thickness of t(min) and a polyethylene BDE of 1.10 cm. When the intended TPD for a BNCT clinical treatment is shallower than the deepest TPD(max), the usable (7)Li-target thickness would be between t(min) and an upper limit t(upper) whose value depends on the BDE thickness used. In terms of the effect of stability of the incident proton energy, Gaussian incident proton energies stable to within +/-10 keV of 1.900 MeV were found to be feasible for the neutron production via the near-threshold (7)Li(p,n)(7)Be reaction for BNCT provided that a suitable BDE is used.

TPD-based evaluation of near threshold mono-energetic proton energies for the (7)Li(p,n)(7)Be production of neutrons for BNCT.

An evaluation of mono-energetic proton energies ranging from 1.885 MeV to 1.920 MeV was carried out to determine the viability of these near threshold energies in producing neutrons for BNCT via the (7)Li(p,n)(7)Be reaction. Neutron fields generated at these proton energies were assessed using the treatable protocol depth (TPD) and the maximum TPD (TPD(max)) as evaluation indices. The heavy charged particle (HCP) dose rate to tumour was likewise applied as a figure of merit in order to account for irradiation time and required proton current. Incident proton energies closer to the reaction threshold generated deeper TPDs compared to higher energy protons when no boron dose enhancers (BDE) were placed in the irradiation field. Introducing a BDE resulted in improved TPDs for high proton energies but their achievable TPD(max) were comparatively lower than that obtained for lower proton energies. In terms of the HCP dose rate to tumour, higher proton energies generated neutron fields that yielded higher dose rates both at TPD(max) and at fixed depths of comparison. This infers that higher currents are required to deliver the prescribed treatment dose to tumours for proton beams with energies closer to the (7)Li(p,n)(7)Be reaction threshold and more achievable proton currents of around 10 mA or less for proton energies from 1.900 MeV and above. The dependence on incident proton energy of the TPD, TPD(max) and the HCP dose rate to tumour with respect to the (10)B concentration in tumour and healthy tissues were also clarified in this study. Increasing the (10)B concentration in tumour while maintaining a constant T/N ratio resulted in deeper TPD(max) where a greater change in TPD(max) was obtained for proton energies closer to the (7)Li(p,n)(7)Be reaction threshold. The HCP dose rates to tumour for all proton energies also went up, with the higher proton energies benefiting more from the increased (10)B concentration.

Characterization of moderator assembly dimension for accelerator boron neutron capture therapy of brain tumors using 7Li(p, n) neutrons at proton energy of 2.5 MeV.

The characteristics of moderator assembly dimension are investigated for the usage of 7Li(p,n) neutrons by 2.5 MeV protons in boron newtron capture therapy (BNCT) of brain tumors in the present study. The indexes checked are treatable protocol depth (TPD), which is the greatest depth of the region satisfying the dose requirements in BNCT protocol, proton current necessary to complete BNCT by 1 h irradiation, and the heat flux deposited in the Li target which should be removed. Assumed materials are D2O for moderator, and mixture of polyethylene and LiF with 50 wt % for collimator. Dose distributions have been computed with MCNP 4B and 4C codes. Consequently, realized TPD does not show a monotonical tendency for the Li target diameter. However, the necessary proton current and heat flux in the Li target decreases as the Li target diameter increases, while this trend reverses at around 10 cm of the Li target diameter for the necessary proton current in the condition of this study. As to the moderator diameter, TPD does not exhibit an apparent dependence. On the other hand, necessary proton current and heat flux decrease as the moderator diameter increases, and this tendency saturates at around 60 cm of the moderator diameter in this study. As to the collimator, increase in inner diameter is suitable from the viewpoint of increasing TPD and decreasing necessary proton current and heat flux, while these indexes do not show apparent difference for collimator inner diameters over 14 cm for the parameters treated here. The practical viewpoint in selecting the parameters of moderator assembly dimension is to increase TPD, within the technically possible condition of accelerated proton current and heat removal from the Li target. In this process, the values for which the resultant characteristics mentioned above saturate or reverse would be important factors.

Characteristics of boron-dose enhancer dependent on dose protocol and 10B concentration for BNCT using near-threshold 7Li(p,n)7Be direct neutrons.

The dependence of boron-dose enhancer (BDE) characteristics on dose protocol and 10B concentration was evaluated for BNCT using near-threshold 7Li(p,n)7Be direct neutrons. The treatable protocol depth (TPD) was utilized as an evaluation index. MCNP calculations were performed for near-threshold 7Li(p,n)7Be at a proton energy of 1.900 MeV and for a polyethylene BDE. The effect of dose protocol on BDE characteristics was reflected in terms of the optimum BDE thickness needed for maximum TPD which was found to be independent of the treatable dose but was observed to vary for different combinations of the tolerance doses for heavy charged particles and gamma rays. For the 10B concentration dependence, the TPD was increased by increasing the T/N ratio, i.e., the ratio of the 10B concentration in the tumour (10B(Tumour)) to that in the normal tissue (10B(Normal)), and by increasing 10B(Tumour) and 10B(Normal) at constant T/N ratio. It was found that the use of BDE becomes unnecessary from the viewpoint of increasing the TPD, when 10B(Tumour) is over a certain level which is decided by the conditions of the dose protocol.

Optimization parameters for BDE in BNCT using near threshold 7Li(p,n)7Be direct neutrons.

The dose contribution of (10)B(n,alpha)(7)Li reaction in BNCT using near threshold (7)Li(p,n)(7)Be direct neutrons can be increased through the use of materials referred to as boron-dose enhancers (BDE). In this paper, possible BDE optimization criteria were determined from the characteristics of candidate BDE materials namely (C(2)H(4))(n), (C(2)H(3)F)(n), (C(2)H(2)F(2))(n), (C(2)HF(3))(n), (C(2)D(4))(n), (C(2)F(4))(n), beryllium metal, graphite, D(2)O and (7)LiF. The treatable protocol depth (TPD) was used as the assessment index for evaluating the effect of these materials on the dose distribution in a medium undergoing BNCT using near threshold (7)Li(p,n)(7)Be direct neutrons. The maximum TPD (TPD(max)) did not exhibit an explicit dependence on material type as evidenced by its small range and arbitrary variations. The dependence of TPD on BDE thickness was influenced by the BDE material used as indicated by the sharply peaked TPD versus BDE thickness curves for materials with hydrogen compared to the broader curves obtained for those without hydrogen. The BDE thickness required to achieve TPD(max) (BDE(TPD(max))) were also found to be thinner for materials with hydrogen. The TPD(max), the dependence of TPD on BDE thickness, and the BDE(TPD(max)) were established as appropriate BDE optimization parameters. Based on these criteria and other practical considerations, the suitable choice as BDE among the candidate materials considered in this study for treatments involving tumors located at shallow depths would be (C(2)H(4))(n) while beryllium metal was judged as more appropriate for treatment of deep-seated tumors.

Evaluation of the characteristics of boron-dose enhancer (BDE) materials for BNCT using near threshold 7Li(p,n)7Be direct neutrons.

The characteristics of a number of candidate boron-dose enhancer (BDE) materials for boron neutron capture therapy (BNCT) using near threshold 7Li(p,n)7Be direct neutrons were evaluated based on the treatable protocol depth (TPD), defined in this paper. Simulation calculations were carried out by means of MCNP-4B transport code for candidate BDE materials, namely, (C2H4)n, (C2H3F)n, (C2H2F2)n, (C2HF3)n, (C2D4)n, (C2F4)n, beryllium metal, graphite, D2O and 7LiF. Dose protocols applied were those used for intra-operative BNCT treatment for brain tumour currently used in Japan. The maximum TPD (TPDmax) for each BDE material was found to be between 4 cm and 5 cm in the order of (C2H4)n < (C2H3F)n < (C2H2F2)n < (C2HF3)n < beryllium metal < (C2D4)n < graphite < (C2F4)n < D2O < 7LiF. Based on the small and arbitrary variations in the TPDmax for these materials, an explicit advantage of a candidate BDE material could not be established from the TPDmax alone. The dependence of TPD on BDE thickness was found to be influenced by the type of BDE material. For materials with hydrogen, sharp variations in TPD were observed, while those without hydrogen exhibited more moderate fluctuations in TPD as the BDE thickness was varied. The BDE thickness corresponding to TPDmax (BDE(TPDmax)) was also found to depend on the type of BDE material used. Thicker BDE(TPDmax), obtained mostly for BDE materials without hydrogen, significantly reduced the dose rates within the phantom. The TPDmax, the dependence of TPD on BDE thickness and the BDE (TPDmax) were ascertained as appropriate optimization criteria in choosing suitable BDE materials for BNCT. Among the candidate BDE materials considered in this study. (C2H4)n was judged as the suitable material for near-surface tumours and beryllium metal for deeper tumours based on these optimization criteria and other practical considerations.

Potential of alpha-amino alcohol p-boronophenylalaninol as a boron carrier in boron neutron capture therapy, regarding its enantiomers.

PURPOSE: We evaluated the potential of a newly developed (10)B-containing alpha-amino alcohol of p-boronophenylalanine-(10)B (BPA), p-boronophenylalaninol (BPAol), as a boron carrier in boron neutron capture therapy. METHODS: C57BL mice bearing EL4 tumors received 5-bromo-2'-deoxyuridine (BrdU) continuously via implanted mini-osmotic pumps to label all proliferating (P) cells. After oral administration of L-BPA or D-BPA, or intraperitoneal injection of L-BPAol or D-BPAol, the tumors were irradiated with reactor thermal neutron beams. Some of the tumors were heated at 40 degrees C for 30 min (mild temperature hyperthermia (MTH)) right before neutron exposure, and/or tirapazamine (TPZ) was intraperitoneally injected 30 min before irradiation. The tumors were then excised, minced, and trypsinized. The tumor cell suspensions thus obtained were incubated with cytochalasin-B (a cytokinesis blocker), and the micronucleus (MN) frequency in cells without BrdU labeling [ =quiescent (Q) cells] was determined using immunofluorescence staining for BrdU. Meanwhile, 6 h after irradiation, tumor cell suspensions obtained in the same manner were used for determining the apoptosis frequency in Q cells. The apoptosis and MN frequency in total (P+Q) tumor cells were determined from the tumors that were not pretreated with BrdU. RESULTS: Without TPZ or MTH, L- and D-BPAol increased both frequencies markedly, especially for total cells. Although not significantly larger, L-BPA and D-BPAol increased both frequencies slightly more than D-BPA and L-BPAol, respectively. Combination with both MTH and TPZ markedly reduced the sensitivity difference between total and Q cells. CONCLUSION: Both L- and D-BPAol have potential as a (10)B-carrier in neutron capture therapy, especially when combined with both MTH and TPZ.

The medical-irradiation characteristics for neutron capture therapy at the Heavy Water Neutron Irradiation Facility of Kyoto University Research Reactor.

At the Heavy Water Neutron Irradiation Facility of the Kyoto University Research Reactor, the mix irradiation of thermal and epi-thermal neutrons, and the solo irradiation of epi-thermal neutrons are available additionally to the thermal neutron irradiation, and then the neutron capture therapy (NCT) at this facility became more flexible, after the update in 1996. The estimation of the depth dose distributions in NCT clinical irradiation, were performed for the standard irradiation modes of thermal, mixed and epi-thermal neutrons, from the both sides of experiment and calculation. On the assumption that the 10B concentration in tumor part was 40 ppm and the ratio of tumor to normal tissue was 3.5, the advantage depth were estimated to 5.4, 6.0, and 8.0, for the respective standard irradiation modes. It was confirmed that the various irradiation conditions can be selected according to the target-volume conditions, such as size, depth, etc. Besides, in the viewpoint of the radiation shielding for patient, it was confirmed that the whole-body exposure is effectively reduced by the new clinical collimators, compared with the old one.

Controllability of depth dose distribution for neutron capture therapy at the Heavy Water Neutron Irradiation Facility of Kyoto University Research Reactor.

The updating construction of the Heavy Water Neutron Irradiation Facility of the Kyoto University Research Reactor has been performed from November 1995 to March 1996 mainly for the improvement in neutron capture therapy. On the performance, the neutron irradiation modes with the variable energy spectra from almost pure thermal to epi-thermal neutrons became available by the control of the heavy-water thickness in the spectrum shifter and by the open-and-close of the cadmium and boral thermal neutron filters. The depth distributions of thermal, epi-thermal and fast neutron fluxes were measured by activation method using gold and indium, and the depth distributions of gamma-ray absorbed dose rate were measured using thermo-luminescent dosimeter of beryllium oxide for the several irradiation modes. From these measured data, the controllability of the depth dose distribution using the spectrum shifter and the thermal neutron filters was confirmed.

Irradiation characteristics of BNCT using near-threshold 7Li(p, n)7Be direct neutrons: application to intra-operative BNCT for malignant brain tumours.

A calculation method for the dosage of neutrons by near-threshold 7Li(p, n)7Be and gamma rays by 7Li(p, p'gamma)7Li was validated through experiments with variable distance between the Li target and the phantom, focusing on large angular dependence. The production of neutrons and gamma rays in the Li target was calculated by Lee's method and their transport in the phantom was calculated using the MCNP-4B code. The dosage in intra-operative boron neutron capture therapy (BNCT) using near-threshold 7Li(p, n)7Be direct neutrons was evaluated using the validated calculation method. The effectiveness of the usage of the direct neutrons was confirmed from the existence of the region satisfying the requirements of the protocol utilized in intra-operative BNCT for brain tumours in Japan. The boron-dose enhancer (BDE) introduced in this paper to increase the contribution of the 10B(n, alpha)7Li dose in the living body was effective. The void utilized to increase the dose in deep regions was also effective with BDE. For the investigation of 1.900 MeV proton beams, for example, it was found that intraoperative BNCT using near-threshold 7Li(p, n)7Be direct neutrons is feasible.