Development of a dose distribution shifter to fit inside the collimator of a Boron Neutron Capture Therapy irradiation system to treat superficial tumours.

The Kansai BNCT Medical Center has a cyclotron based epithermal neutron source for clinical Boron Neutron Capture Therapy. The system accelerates a proton to an energy of 30 MeV which strikes a beryllium target producing fast neutrons which are moderated down to epithermal neutrons for BNCT use. While clinical studies in the past have shown BNCT to be highly effective for malignant melanoma of the skin, to apply BNCT for superficial lesions using this system it is necessary to shift the thermal neutron distribution so that the maximum dose occurs near the surface. A dose distribution shifter was designed to fit inside the collimator to further moderate the neutrons to increase the surface dose and reduce the dose to the underlying normal tissue. Pure polyethylene was selected, and a Monte Carlo simulation was performed to determine the optimum thickness of the polyethylene slab. Compared with the original neutron beam, the shifter increased the thermal neutron flux at the skin by approximately 4 times. The measured and simulated central axis depth distribution and off axis distribution of the thermal neutron flux were found to be in good agreement. Compared with a 2 cm thick water equivalent bolus, a 26% increase in the thermal neutron flux at the surface was obtained, which would reduce the treatment time by approximately 29%. The DDS is a safe, simple and an effective tool for the treatment of superficial tumours for BNCT if an initially fast neutron beam requires moderation to maximise the thermal neutron flux at the tissue surface.

Dielectric-loaded surface plasmon polariton crossing waveguides using multimode interference.

A low-loss low-crosstalk multimode interference (MMI) crossing design for dielectric-loaded surface plasmon polariton waveguides (DLSPPWs), which are SiO2 stripes on Au films, is demonstrated numerically and experimentally. DLSPPWs are compatible with strong surface plasmon polariton (SPP) field confinement and maintain relatively low propagation losses. Unlike simpler crossings without MMI structures, low insertion loss of 0.65 dB and low crosstalk of -20.27 dB is confirmed numerically at a crossing angle of 10° when using tilted mirror-imaged MMI crossings. Similar insertion losses were also confirmed experimentally. The proposed structure will be beneficial for plasmonic device miniaturization and flexible patterning of optical interconnections.

Fatal carotid blowout syndrome after BNCT for head and neck cancers.

Boron neutron capture therapy (BNCT) is high linear energy transfer (LET) radiation and tumor-selective radiation that does not cause serious damage to the surrounding normal tissues. BNCT might be effective and safe in patients with inoperable, locally advanced head and neck cancers, even those that recur at previously irradiated sites. However, carotid blowout syndrome (CBS) is a lethal complication resulting from malignant invasion of the carotid artery (CA); thus, the risk of CBS should be carefully assessed in patients with risk factors for CBS after BNCT. Thirty-three patients in our institution who underwent BNCT were analyzed. Two patients developed CBS and experienced widespread skin invasion and recurrence close to the carotid artery after irradiation. Careful attention should be paid to the occurrence of CBS if the tumor is located adjacent to the carotid artery. The presence of skin invasion from recurrent lesions after irradiation is an ominous sign of CBS onset and lethal consequences.

Frequency-dependent signal processing in apical dendrites of hippocampal CA1 pyramidal cells.

Depending on an animal's behavioral state, hippocampal CA1 pyramidal cells receive distinct patterns of excitatory and inhibitory synaptic inputs. The time-dependent changes in the frequencies of these inputs and the nonuniform distribution of voltage-gated channels lead to dynamic fluctuations in membrane conductance. In this study, using a whole-cell patch-clamp method, we attempted to record and analyze the frequency dependencies of membrane responsiveness in Wistar rat hippocampal CA1 pyramidal cells following noise current injection directly into dendrites and somata under pharmacological blockade of all synaptic inputs. To estimate the frequency-dependent properties of membrane potential, membrane impedance was determined from the voltage response divided by the input current in the frequency domain. The cell membrane of most neurons showed low-pass filtering properties in all regions. In particular, the properties were strongly expressed in the somata or proximal dendrites. Moreover, the data revealed nonuniform distribution of dendritic impedance, which was high in the intermediate segment of the apical dendritic shaft (∼220-260µm from the soma). The low-pass filtering properties in the apical dendrites were more enhanced by membrane depolarization than those in the somata. Coherence spectral analysis revealed high coherence between the input signal and the output voltage response in the theta-gamma frequency range, and large lags emerged in the distal dendrites in the gamma frequency range. Our results suggest that apical dendrites of hippocampal CA1 pyramidal cells integrate synaptic inputs according to the frequency components of the input signal along the dendritic segments receiving the inputs.

Results of RIKEN superconducting electron cyclotron resonance ion source with 28 GHz.

We measured the beam intensity of highly charged heavy ions and x-ray heat load for RIKEN superconducting electron cyclotron resonance ion source with 28 GHz microwaves under the various conditions. The beam intensity of Xe(20+) became maximum at B(min) ∼ 0.65 T, which was ∼65% of the magnetic field strength of electron cyclotron resonance (B(ECR)) for 28 GHz microwaves. We observed that the heat load of x-ray increased with decreasing gas pressure and field gradient at resonance zone. It seems that the beam intensity of highly charged heavy ions with 28 GHz is higher than that with 18 GHz at same RF power.

Production of a highly charged uranium ion beam with RIKEN superconducting electron cyclotron resonance ion source.

A highly charged uranium (U) ion beam is produced from the RIKEN superconducting electron cyclotron resonance ion source using 18 and 28 GHz microwaves. The sputtering method is used to produce this U ion beam. The beam intensity is strongly dependent on the rod position and sputtering voltage. We observe that the emittance of U(35+) for 28 GHz microwaves is almost the same as that for 18 GHz microwaves. It seems that the beam intensity of U ions produced using 28 GHz microwaves is higher than that produced using 18 GHz microwaves at the same Radio Frequency (RF) power.

Activation of inositol 1, 4, 5-trisphosphate receptors during preconditioning low-frequency stimulation leads to reversal of long-term potentiation in hippocampal CA1 neurons.

We investigated the role of inositol 1, 4, 5-trisphosphate receptors (IP3Rs) that were activated during preconditioning low-frequency afferent stimulation (LFS) in the subsequent induction of synaptic plasticity in CA1 neurons in hippocampal slices from mature guinea pigs. In standard perfusate, long-term potentiation (LTP) was induced in the field excitatory postsynaptic potential (EPSP) by the delivery of LFS (80 pulses at 1 Hz), and was reversed by an identical LFS applied 20 min later. However, when CA1 synapses were preconditioned in the presence of an IP3R antagonist and stimulated by the second LFS in the absence of the antagonist, LTP was not reversed, but was increased, by the second LFS. In addition, when CA1 synapses were preconditioned in standard solution, but stimulated by the second LFS in the presence of an N-methyl-d-aspartate receptor (NMDAR) antagonist, LTP was again not reversed, but increased. The excitatory postsynaptic current (EPSC) through NMDARs recorded from CA1 pyramidal neurons increased significantly 20 min after a single LFS and this increase was inhibited when the LFS was delivered in the presence of an IP3R antagonist or a Ca(2+)/calmodulin-dependent protein kinase II inhibitor. These results suggest that activation of IP3Rs by a preconditioning LFS results in postsynaptic protein phosphorylation and/or enhancement of NMDAR activation during a subsequent LFS, leading to reversal of LTP in the field EPSP in hippocampal CA1 neurons.

Cholinergic modulation on spike timing-dependent plasticity in hippocampal CA1 network.

Cholinergic inputs from the medial septum are projected to pyramidal neurons in the hippocampal CA1 region and release acetylcholine (ACh) from their terminals. The cholinergic inputs are considered to be integrated with sensory inputs and to play a crucial role in learning and memory. Meanwhile, it has been reported that the relative timing between pre- and post-synaptic spiking determines the direction and extent of synaptic changes in a critical temporal window, a process known as spike timing-dependent plasticity (STDP). Positive timing where excitatory postsynaptic potential (EPSP) precedes the postsynaptic action potential induces long-term potentiation (LTP) while negative timing where EPSP follows the action potential induces long-term depression (LTD). To investigate the influence of muscarinic activation by cholinergic inputs on synaptic plasticity, STDP-inducing stimuli were applied during the muscarinic induction of a slow EPSP followed by repetitive stimulation in the stratum oriens. As a result, LTP was facilitated and LTD was abolished by the muscarinic activation. Furthermore, interestingly, LTP was also facilitated and LTD was switched to LTP with an increase in ACh concentration following application of the cholinesterase inhibitor eserine. These results indicate that the orientation of plasticity was shifted for potentiation by muscarinic activation. On the other hand, the application of excess ACh concentration completely suppressed STDP, LTP and LTD. In addition, STDP was suppressed in the presence of atropine, a muscarinic ACh receptor antagonist. Taken together, the findings suggest that synaptic plasticity modulation depends on the amount of cholinergic inputs. The modulation of synaptic plasticity by muscarinic activation might be an important stage in the integration of top-down and bottom-up information in hippocampal CA1 neurons.

The effect of exemestane, anastrozole, and tamoxifen on lipid profiles in Japanese postmenopausal early breast cancer patients: final results of National Surgical Adjuvant Study BC 04, the TEAM Japan sub-study.

BACKGROUND: In this Tamoxifen Exemestane Adjuvant Multinational Japan sub-study, we evaluated the time course of changes in serum lipids in postmenopausal women with hormone-sensitive early breast cancer treated with exemestane, anastrozole, or tamoxifen for postoperative adjuvant therapy. PATIENTS AND METHODS: A total of 154 breast cancer patients were assigned to receive exemestane, anastrozole, or tamoxifen in this randomized open-label study. Serum lipid parameters including triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured during 1 year of treatment. RESULTS: TC and LDL-C rapidly decreased in patients treated with tamoxifen at 3 months. Compared with anastrozole and exemestane patients, TC and LDL-C were significantly lower at all assessment time points in tamoxifen patients (P < 0.05). TG increased in tamoxifen patients; it was significantly higher compared with exemestane patients at all assessment time points (P < 0.05). HDL-C slightly decreased in exemestane patients; it was significantly lower compared with anastrozole patients at 3 months and 1 year (P = 0.0179 and 0.0013, respectively). CONCLUSION: Changes of lipid profiles in Japanese postmenopausal women treated with tamoxifen were relatively favorable, while exemestane and anastrozole had no clinically significant effect on the serum lipids.

First results from the new RIKEN superconducting electron cyclotron resonance ion source (invited).

The next generation heavy ion accelerator facility, such as the RIKEN radio isotope (RI) beam factory, requires an intense beam of high charged heavy ions. In the past decade, performance of the electron cyclotron resonance (ECR) ion sources has been dramatically improved with increasing the magnetic field and rf frequency to enhance the density and confinement time of plasma. Furthermore, the effects of the key parameters (magnetic field configuration, gas pressure, etc.) on the ECR plasma have been revealed. Such basic studies give us how to optimize the ion source structure. Based on these studies and modern superconducting (SC) technology, we successfully constructed the new 28 GHz SC-ECRIS, which has a flexible magnetic field configuration to enlarge the ECR zone and to optimize the field gradient at ECR point. Using it, we investigated the effect of ECR zone size, magnetic field configuration, and biased disk on the beam intensity of the highly charged heavy ions with 18 GHz microwaves. In this article, we present the structure of the ion source and first experimental results with 18 GHz microwave in detail.

Effects of exemestane, anastrozole and tamoxifen on bone mineral density and bone turnover markers in postmenopausal early breast cancer patients: results of N-SAS BC 04, the TEAM Japan substudy.

BACKGROUND: Use of aromatase inhibitors in women with postmenopausal breast cancer accompanies risks of bone loss. We evaluated changes in bone mineral density (BMD) and bone turnover markers in patients treated with exemestane, anastrozole or tamoxifen for hormone-sensitive postmenopausal early breast cancer. PATIENTS AND METHODS: Sixty-eight patients enrolled in the Tamoxifen Exemestane Adjuvant Multinational Japan bone substudy were randomly assigned to receive tamoxifen, exemestane or anastrozole. During a 2-year study period, lumbar spine BMD was measured using dual-energy X-ray absorptiometry, and urinary type I collagen cross-linked N-telopeptide (NTX) and serum bone-specific alkaline phosphatase (BAP) were also measured. RESULTS: BMD at 2 years of treatment was higher in tamoxifen patients compared with exemestane and anastrozole patients; however, the intergroup difference was not significant (p = 0.2521 and p = 0.0753, respectively). BMD was higher in exemestane patients compared with anastrozole patients; however, the intergroup difference was not significant (p = 0.7059 and p = 0.8134, respectively). NTX and BAP were significantly lower in tamoxifen patients compared with exemestane and anastrozole patients at 1 and 2 years of treatment (p < 0.05). CONCLUSION: Tamoxifen may provide better bone protection compared with exemestane or anastrozole. The effect of exemestane and anastrozole on bone loss may be comparable in Japanese postmenopausal women.

Production of U beam from RIKEN 18 GHz electron cyclotron resonance ion source.

For the RIKEN radio isotope factory (RIBF) project, we produced the multicharged uranium beam with two methods. To produce lower charge state U ion beams (14+-20+) we used the UF(6) gas as an ionized gas. The typical beam intensity of U(14+-20+) was 2-1 particle microA at the extraction voltage of 14 kV. To produce higher charge state U ion beam (U(35+)), we chose the sputtering method. The beam intensity was 70 particle nA at the extraction voltage of 5.4 kV. Using this method, we successfully produced multicharged U beam continuously for one month without break for RIBF commissioning.

The relation between spike-timing dependent plasticity and Ca2+ dynamics in the hippocampal CA1 network.

In our previous study, spike timing dependent synaptic plasticity (STDP) was investigated in the CA1 area of rat hippocampal slices using optical imaging. It was revealed that the profiles of STDP could be classified into two types depending upon layer specific location along the dendrite. The first was characterized by a symmetric time window observed in the proximal region of the stratum radiatum (SR), and the second by an asymmetric time window in the distal region of the SR. Our methods involved the bath-application of bicuculline (GABA(A) receptor antagonist) to hippocampal slices, which revealed that GABAergic interneuron projections were responsible for the symmetry of a time window. In this study, the intracellular Ca2+ increase of hippocampal CA1 neurons, induced by the protocol of timing between pre- and post-synaptic excitation (i.e. STDP protocol), was measured spatially by using optical imaging to investigate how the triggering of STDP is dependent on intracellular calcium concentration. We found that the magnitude of STDP was closely related to the rate of Ca2+ increase ("velocity") of calcium transient during application of induction stimuli. Location dependency was also analyzed in terms of Ca2+ influx. Furthermore, it was shown that decay time constant of Ca2+ dynamics during the application of STDP-inducing stimuli was also significantly correlated with STDP.

Phase shift of subthreshold theta oscillation in hippocampal CA1 pyramidal cell membrane by excitatory synaptic inputs.

Hippocampal CA1 neurons receive multiple rhythmical inputs with relatively independent phases during theta activity. It, however, remains to be determined how these multiple rhythmical inputs affect oscillation properties in membrane potential of the CA1 pyramidal cell. In order to investigate oscillation properties in the subthreshold membrane potential, we generated oscillations in the membrane potential of the CA1 pyramidal cells in rat hippocampal slices in vitro with a sinusoidal current injection into the pyramidal soma at theta band frequencies (4-7 Hz), and analyzed effect of rhythmically excitatory synaptic inputs. The Schaffer collaterals were stimulated with a cyclic Gaussian stimulation method, whose pulse intervals were distributed at 10 pulses/cycle (5 cycles/s). We found that the cyclic Gaussian stimulations induced membrane potential oscillations and their phase delays from the mean of the pulse distribution were dependent on membrane potential oscillation amplitude. We applied four pairs of cyclic Gaussian stimulations and somatic sinusoidal current stimulations at the same frequency (5 Hz) with varying phase differences (-pi/2, 0, pi/2, pi rad). The paired stimulations induced phase distributions of the oscillation in the membrane potential, which showed a dependency on an increasing membrane potential oscillation amplitude response to cyclic Gaussian stimulation. This membrane potential dynamic was exhibited by the mixture of the membrane potential oscillation-amplitude-dependent phase delay and the linear summation of the two sinusoidal waves. These suggest that phases of the membrane potential oscillation are modulated by excitatory synaptic inputs. This phase-modulation by excitatory synaptic inputs may play a crucial role for memory operation in the hippocampus.

Intervertebral disc degeneration associated with lumbosacral transitional vertebrae: a clinical and anatomical study.

We studied 52 patients, each with a lumbosacral transitional vertebra. Using MRI we found that the lumbar discs immediately above the transitional vertebra were significantly more degenerative and those between the transitional vertebrae and the sacrum were significantly less degenerative compared with discs at other levels. We also performed an anatomical study using 70 cadavers. We found that the iliolumbar ligament at the level immediately above the transitional vertebra was thinner and weaker than it was in cadavers without a lumbosacral transitional vertebra. Instability of the vertebral segment above the transitional vertebra because of a weak iliolumbar ligament could lead to subsequent disc degeneration which may occur earlier than at other disc levels. Some stability between the transitional vertebra and the sacrum could be preserved by the formation of either an articulation or by bony union between the vertebra and the sacrum through its transverse process. This may protect the disc from further degeneration in the long term.

Touch imprint cytology and immunohistochemistry for the assessment of sentinel lymph nodes in patients with breast cancer.

AIMS: Accurate evaluation of sentinel nodes is of clinical importance to avoid further surgery for axillary node dissection. A prospective study was carried out to investigate the feasibility and accuracy of touch imprint cytology (TIC) and touch imprint immunohistochemistry (TIHC). METHODS: Two hundred and five sentinel nodes from consecutive 118 patients with primary breast cancer were studied after successful identification of sentinel nodes. Sentinel nodes were sectioned at 2 mm intervals and imprint specimens prepared from all cut surfaces were subjected to Papanicolaou staining and immunohistochemical staining using anti-cytokeratin antibody. RESULTS: Forty-nine sentinel nodes from 40 patients were positive by permanent section. The sensitivity of TIC was 84% (41/49) per sentinel node and 83% (33/40) on a per patient basis. The sensitivity of TIHC was 86% (42/49) per sentinel node and 83% (33/40) on a per patient basis. When the results of TIC and TIHC were combined, the sensitivity was 88% (43/49) per sentinel node and 85% (34/40) on a per patient basis. Among the 156 negative sentinel nodes, four sentinel nodes from four different patients were consistently positive by TIC and TIHC, but only one patient out of 78 node-negative patients was upstaged. CONCLUSIONS: Touch imprint cytology is sufficiently sensitive for intraoperative evaluation of sentinel nodes. A slight improvement in the sensitivity is expected when immunohistochemistry is used. The combination of these methods provides better sensitivity than either method alone.

Phase II study of weekly docetaxel in patients with metastatic breast cancer.

BACKGROUND: This study was conducted to investigate the efficacy and toxicity of weekly docetaxel administration in patients with metastatic breast cancer. PATIENTS AND METHODS: Thirty-seven women were treated with 1 h infusions of docetaxel at 40 mg/m2/week after pre-medication with 8 mg dexamethazone. Each cycle consisted of three consecutive weekly treatments followed by a 1 week rest. All patients were assessed for toxicity; five patients were not assessable for clinical response, time to progression (TTP) and overall survival (OS) because of early treatment failure, but they were included in intention-to-treat analysis. RESULTS: Patients received a median of four cycles (range, 1-9), with a median dose intensity of 28 mg/m2/week (range 22-30) and a median relative dose intensity of 0.95 (range 0.73-1.0). No patients showed complete response, whereas 14 had partial response, which accounted for 38% of objective response rate [95% confidence interval (CI) 22% to 53%]. In addition, three patients (8%, 95% CI 0% to 17%) had stable disease over 6 months. Clinical responses were achieved at a median of three cycles (range 1-4 cycles). The median TTP and OS were 5 and 12 months, respectively. The weekly docetaxel regimen was generally well tolerated. About half of the patients experienced grade > or = 1 neutropenia; only 19% had grade 3/4 neutropenia, including one case of grade 4. No febrile neutropenia was observed and fluid retention syndrome was uncommon. Non-hematologic toxicity, however, such as asthenia/fatigue, nail damage, tearing or hearing disorders, was seen with successive treatment cycles. CONCLUSIONS: Weekly docetaxel at 40 mg/m2/week is an active and feasible regimen for patients with metastatic breast cancer.

Effects of dexamethasone and FK506 on Helicobacter pylori-induced gastritis and bacterial viability in Mongolian gerbils.

FK506 and dexamethasone were used to investigate whether or not immunosuppression affects H. pylori colonization and gastric mucosal damage induced by Helicobacter pylori in Mongolian gerbils. Two weeks after H. pylori infection, FK506 and dexamethasone or vehicle alone were subcutaneously administered once daily for the following 2 weeks. FK506 or vehicle alone was administered subcutaneously once daily for 5 weeks (1 week before and 4 weeks after infection). In H. pylori-infected animals for 4 weeks, hemorrhagic erosions and inflammatory responses (neutrophil infiltration and lymphoid follicle formation) were induced in gastric mucosa at an incidence of 100%. Both FK506 and dexamethasone administered for 2 weeks markedly reduced such mucosal changes. In these animals, H. pylori viability in the stomach was significantly elevated. FK506 administered for 5 weeks also significantly inhibited the hemorrhagic erosions, edema and neutrophil infiltration in the stomach. H. pylori viability was slightly elevated as compared with the control. It was concluded that the host immune responses might play dual roles both by deteriorating gastritis induced by H. pylori and by protecting against H. pylori infection in its early stage.

Phalangeal microgeodic syndrome.

Phalangeal microgeodic syndrome specifically affects the phalanges in infants. The radiographic findings are characterized by small lacunae measuring less than 1 mm in diameter in the phalanges. The symptoms usually subside spontaneously within 2 to 3 months with no residual deformity. Accurate diagnosis is possible by radiologists with knowledge on this disease entity.