Isolation and Biological Activity of 9-epiTetrodotoxin and Isolation of Tb-242B, Possible Biosynthetic Shunt Products of Tetrodotoxin from Pufferfish.

Tetrodotoxin (TTX, 1) is a potent voltage-gated sodium channel blocker detected in certain marine and terrestrial organisms. We report here a new TTX analogue, 9-epiTTX (2), and a TTX-related compound, Tb-242B (4), isolated from the pufferfish Takifugu flavipterus and Dichotomyctere ocellatus, respectively. NMR analysis suggested that 2 exists as a mixture of hemilactal and 10,8-lactone forms, whereas other reported TTX analogues are commonly present as an equilibrium mixture of hemilactal and 10,7-lactone forms. Compound 2 and TTX were confirmed not to convert to each other by incubation under neutral and acidic conditions at 37 °C for 24 h. Compound 4 was identified as the 9-epimer of Tb-242A (3), previously reported as a possible biosynthetic precursor of TTX. Compound 4 was partially converted to 3 by incubation in a neutral buffer at 37 °C for 7 days, whereas 3 was not converted to 4 under this condition. Compound 2 was detected in several TTX-containing marine animals and a newt. Mice injected with 600 ng of 2 by intraperitoneal injection did not show any adverse symptoms, suggesting that the C-9 configuration in TTX is critical for its biological activity. Based on the structures, 2 and 4 were predicted to be shunt products for TTX biosynthesis.

High-dose-rate brachytherapy using inverse planning optimization with tandem and ovoid applicators for locally advanced cervical cancer: a simulation study.

The purpose of this study was to evaluate the dosimetric advantage of inverse planning optimization (IPO) in locally advanced cervical cancer using high-dose-rate (HDR) brachytherapy (BT). IPO was compared with point A plan and geometric optimization (GO). The three planning methods were evaluated using doses to the virtual organ-at-risk (OAR) and D90 (the minimum dose covering of 90% of the volume) to the virtual high-risk clinical target volume (HR-CTV) based on quantitative analysis. HR-CTV structures measuring 38.5 cm3 and 59.5 cm3 were created based on the outcomes of a European Group cohort study. The HR-CTVs were located either at the center of the cervix (cervical center model) or shifted toward the left (extensive disease model). The distances from the HR-CTVs to the rectum were set at 0 mm, 3 mm, 5 mm, 8 mm, 10 mm, and 15 mm. We analyzed 336 conditions in this study. All doses were evaluated by conversion to doses in 2-Gy fractions of conventional radiotherapy. The D90 of the HR-CTV using GO and IPO could achieve the desired dose in all conditions, providing better results than that of point A plan. IPO makes it possible to deliver a sufficient dose for the D90 of the HR-CTV while reducing OAR doses with smaller HR-CTV values (< 38.5 cm3) in HDR BT. However, taking into consideration the whole treatment planning time, IPO should be used only when the HR-CTV-to-rectum distance is ≤ 5 mm, and the use of GO cannot spare OARs.

Analysis of Prostate Deformation during a Course of Radiation Therapy for Prostate Cancer.

PURPOSE: Accurate analysis of the correlation between deformation of the prostate and displacement of its center of gravity (CoG) is important for efficient radiation therapy for prostate cancer. In this study, we addressed this problem by introducing a new analysis approach. METHOD: A planning computed tomography (CT) scan and 7 repeat cone-beam CT scans during the course of treatment were obtained for 19 prostate cancer patients who underwent three-dimensional conformal radiation therapy. A single observer contoured the prostate gland only. To evaluate the local deformation of the prostate, it was divided into 12 manually defined segments. Prostate deformation was calculated using in-house developed software. The correlation between the displacement of the CoG and the local deformation of the prostate was evaluated using multiple regression analysis. RESULTS: The mean value and standard deviation (SD) of the prostate deformation were 0.6 mm and 1.7 mm, respectively. For the majority of the patients, the local SD of the deformation was slightly lager in the superior and inferior segments. Multiple regression analysis revealed that the anterior-posterior displacement of the CoG of the prostate had a highly significant correlation with the deformations in the middle-anterior (p < 0.01) and middle-posterior (p < 0.01) segments of the prostate surface (R2 = 0.84). However, there was no significant correlation between the displacement of the CoG and the deformation of the prostate surface in other segments. CONCLUSION: Anterior-posterior displacement of the CoG of the prostate is highly correlated with deformation in its middle-anterior and posterior segments. In the radiation therapy for prostate cancer, it is necessary to optimize the internal margin for every position of the prostate measured using image-guided radiation therapy.

Uncertainty in patient set-up margin analysis in radiation therapy.

We investigated the uncertainty in patient set-up margin analysis with a small dataset consisting of a limited number of clinical cases over a short time period, and propose a method for determining the optimum set-up margin. Patient set-up errors from 555 registration images of 15 patients with prostate cancer were tested for normality using a quantile-quantile (Q-Q) plot and a Kolmogorov-Smirnov test with the hypothesis that the data were not normally distributed. The ranges of set-up errors include the set-up errors within the 95% interval of the entire patient data histogram, and their equivalent normal distributions were compared. The patient set-up error was not normally distributed. When the patient set-up error distribution was assumed to have a normal distribution, an underestimate of the actual set-up error occurred in some patients but an overestimate occurred in others. When using a limited dataset for patient set-up errors, which consists of only a small number of the cases over a short period of time in a clinical practice, the 2.5% and 97.5% intervals of the actual patient data histogram from the percentile method should be used for estimating the set-up margin. Since set-up error data is usually not normally distributed, these intervals should provide a more accurate estimate of set-up margin. In this way, the uncertainty in patient set-up margin analysis in radiation therapy can be reduced.

Analysis of the optimum internal margin for respiratory-gated radiotherapy using end-expiratory phase assessments using a motion phantom.

We aimed to optimize internal margin (IM) determination for respiratory-gated radiotherapy using end-expiratory phase assessments using a motion phantom. Four-dimensional computed tomography (4D CT) data were acquired using a GE LightSpeed RT CT scanner, a respiratory-gating system, and a motion phantom designed to move sinusoidally. To analyze the accuracy of 4D CT temporal resolution, a 25.4 mm diameter sphere was inserted into the motion phantom, and we measured the differences in sphere diameters between static and end-exhalation phase images. In addition, the IM obtained from the maximum intensity projection within the gating window (MIP(GW)) image was compared to theoretical value. Cranial-caudal motion displacement ranged from 5.0 to 30.0 mm, and the respiratory period ranged from 2.0 to 6.0 sec. Differences in sphere diameters between static and end-exhalation phase images ranged from 0.37 to 4.6 mm, with 5.0-mm and 30 mm target displacements, respectively. Differences between the IM obtained from the MIP(GW) and the theoretical values ranged from 1.12 to 6.23 mm with 5.0mm and 30 mm target displacements, respectively. These differences increased in proportion to the target velocity due to a motion artifact generated during tube rotation. In this study, the IMs obtained using the MIPGW image were overestimated in all cases. We therefore propose that the internal target volume (ITV) for respiratory-gated radiotherapy should be determined by adding the calculated value to the end-exhalation phase image. We also demonstrate a methodology for subtracting motion artifacts from the ITV using a motion phantom.

Analysis of post-exposure density growth in radiochromic film with respect to the radiation dose.

The post-exposure density growth (PEDG) is one of the characteristics of radiochromic film (RCF). In film dosimetry using RCF and a flatbed scanner, pixel values read out from the RCF are converted to dose (hereafter, film dose) by using a calibration curve. The aim of this study is to analyze the relationship between the pixel value read out from the RCF and the PEDG, and that between the film dose converted from the RCF and the PEDG. The film (GAFCHROMIC EBT) was irradiated with 10-MV X-rays in an ascending 11-dose-step arrangement. The pixel values of the irradiated EBT film were measured at arbitrary hours using an Epson flatbed scanner. In this study, the reference time was 24 h after irradiation, and all dose conversions from the pixel values read out from the EBT film were made using a calibration curve for 24 h after irradiation. For delivered doses of 33 and 348 cGy, the measured pixel values at 0.1 and 16 h after irradiation represented ranges of -9.6% to -0.7% and -3.9% to -0.3%, respectively, of the reference value. The relative changes between the pixel values read out from the EBT film at each elapsed time and that at the reference time decreased with increasing delivered dose. However, the difference range for all the film doses had a width of approximately -10% of the reference value at elapsed times from 0.1 to 16 h, and it showed no dependence on the delivered dose.

A web-based remote radiation treatment planning system using the remote desktop function of a computer operating system: a preliminary report.

We developed a web-based, remote radiation treatment planning system which allowed staff at an affiliated hospital to obtain support from a fully staffed central institution. Network security was based on a firewall and a virtual private network (VPN). Client computers were installed at a cancer centre, at a university hospital and at a staff home. We remotely operated the treatment planning computer using the Remote Desktop function built in to the Windows operating system. Except for the initial setup of the VPN router, no special knowledge was needed to operate the remote radiation treatment planning system. There was a time lag that seemed to depend on the volume of data traffic on the Internet, but it did not affect smooth operation. The initial cost and running cost of the system were reasonable.