Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Deep inspiration breath-hold (DIBH) is an excellent technique to reduce the incidental radiation received by the heart during radiotherapy in patients with breast cancer. However, DIBH is costly and time-consuming for patients and radiotherapy staff. In Asian countries, the use of DIBH is restricted due to the limited number of patients with a high mean heart dose (MHD) and the shortage of radiotherapy personnel and equipment compared to that in the USA. This study aimed to develop, evaluate, and compare the performance of ten machine learning algorithms for predicting MHD using a patient’s body mass index and single-slice CT parameters to identify patients who may not require DIBH. Machine learning models were built and tested using a dataset containing 207 patients with left-sided breast cancer who were treated with field-in-field radiotherapy with free breathing. The average MHD was 251 cGy. Stratified repeated four-fold cross-validation was used to build models using 165 training data. The models were compared internally using their average performance metrics: F2 score, AUC, recall, accuracy, Cohen’s kappa, and Matthews correlation coefficient. The final performance evaluation for each model was further externally analyzed using 42 unseen test data. The performance of each model was evaluated as a binary classifier by setting the cut-off value of MHD ≥ 300 cGy. The deep neural network (DNN) achieved the highest F2 score (78.9%). Most models successfully classified all patients with high MHD as true positive. This study indicates that the ten models, especially the DNN, might have the potential to identify patients who may not require DIBH.

DOI： 10.3390/curroncol30080537

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Magnetic resonance (MR) images require a process known as windowing for optimizing the display conditions. However, the conventional windowing process often fails to achieve the preferred display conditions for observers due to various factors. This study proposes a novel framework for predicting the preferred windowing parameters for each observer using Bayesian statistical modeling. MR images obtained from 1000 patients were divided into training and test sets at a 7:3 ratio. The image intensity and windowing parameters were standardized using previously reported methods. Bayesian statistical modeling was utilized to predict the windowing parameters preferred by three MR imaging (MRI) operators. The performance of the proposed framework was evaluated by assessing the mean relative error (MRE), mean absolute error (MAE), and Pearson's correlation coefficient (ρ) of the test set. In addition, the naive method, which presumes that the average value of the windowing parameters for each acquisition sequence and body region in the training set is optimal, was also used for comparison. Three MRI operators and three radiologists conducted visual assessments. The mean MRE, MAE, and ρ values for the window level and width (WL/WW) in the proposed framework were 12.6 and 13.9, 42.9 and 85.4, and 0.98 and 0.98, respectively. These results outperformed those obtained using the naive method. The visual assessments revealed no significant differences between the original and predicted display conditions, indicating that the proposed framework accurately predicts individualized windowing parameters with the additional advantages of robustness and ease of use. Thus, the proposed framework can effectively predict the windowing parameters preferred by each observer.

DOI： 10.1016/j.heliyon.2023.e19038

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BACKGROUND: Computed tomography (CT) angiography (CTA) is a non-invasive imaging method used to detect arteries and examine various brain diseases. When CTA is performed for follow-up or postoperative evaluation, reproducibility of vessel delineation is required. A reproducible and stable contrast enhancement can be achieved by manipulating the factors affecting it. Previous studies have investigated several factors that alter the contrast enhancement of arteries. However, no reports establishing the effect of different operators on contrast enhancement exist. PURPOSE: To assess the differences between inter-operator arterial contrast enhancement in cerebral CTA using Bayesian statistical modeling. METHODS: Image data were obtained using a multistage sampling method from the cerebral CTA scans of patients who underwent the process between January 2015 and December 2018. Several Bayesian statistical models were developed, and the objective variable was the mean CT number of the bilateral internal carotid arteries after contrast enhancement. The explanatory variables were sex, age, fractional dose (FD), and the operator's information. The posterior distributions of the parameters were computed via Bayesian inference using the Markov chain Monte Carlo (MCMC) method, with the Hamiltonian Monte Carlo method employed as the algorithm. The posterior predictive distributions were computed using the posterior distributions of the parameters. Finally, the differences between inter-operator arterial contrast enhancement on the CT number in cerebral CTA were estimated. RESULTS: The posterior distributions showed that all parameters representing the difference between operators included zero at the 95% credible intervals (CIs). The maximum mean difference between inter-operator CT number in the posterior predictive distribution was only 12.59 Hounsfield units (HUs). CONCLUSIONS: The Bayesian statistical modeling results suggest that contrast enhancement of cerebral CTA examination between operator-to-operator differences in postcontrast CT number was small compared to those within-operator differences resulting from factors not considered in the model.

DOI： 10.1002/mp.16549

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Introduction: In the standardization of panoramic radiography quality, the education and training of beginners on panoramic radiographic imaging are important. We evaluated the relationship between positioning error factors and multiple image analysis results for reproducible panoramic radiography. Material and methods: Using a panoramic radiography system and a dental phantom, reference images were acquired on the Frankfurt plane along the horizontal direction, midsagittal plane along the left–right direction, and for the canine on the forward–backward plane. Images with positioning errors were acquired with 1–5 mm shifts along the forward–backward direction and 2–10° rotations along the horizontal (chin tipped high/low) and vertical (left–right side tilt) directions on the Frankfurt plane. The cross-correlation coefficient and angle difference of the occlusion congruent plane profile between the reference and positioning error images, peak signal-to-noise ratio (PSNR), and deformation vector value by deformable image registration were compared and evaluated. Results: The cross-correlation coefficients of the occlusal plane profiles showed the greatest change in the chin tipped high images and became negatively correlated from 6° image rotation (r = −0.29). The angle difference tended to shift substantially with increasing positioning error, with an angle difference of 8.9° for the 10° chin tipped low image. The PSNR was above 30 dB only for images with a 1-mm backward shift. The positioning error owing to the vertical rotation was the largest for the deformation vector value. Conclusions: Multiple image analyses allow to determine factors contributing to positioning errors in panoramic radiography and may enable error correction. This study based on phantom imaging can support the education of beginners regarding panoramic radiography.

DOI： 10.2478/pjmpe-2023-0010

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Diffusion kurtosis (DK) imaging (DKI), a type of restricted diffusion-weighted imaging, has been reported to be useful for tumor diagnoses in clinical studies. We developed a software program to simultaneously create DK images with apparent diffusion coefficient (ADC) maps and conducted an initial clinical study. Multi-shot echo-planar diffusion-weighted images were obtained at b-values of 0, 400, and 800 sec/mm2 for simple DKI, and DK images were created simultaneously with the ADC map. The usefulness of the DK image and ADC map was evaluated using a pixel analysis of all pixels and a median analysis of the pixels of each case. Tumor and normal tissues differed significantly in both pixel and median analyses. In the pixel analysis, the area under the curve was 0.64 for the mean kurtosis (MK) value and 0.77 for the ADC value. In the median analysis, the MK value was 0.74, and the ADC value was 0.75. The MK and ADC values correlated moderately in the pixel analysis and strongly in the median analysis. Our simple DKI system created DK images simultaneously with ADC maps, and the obtained MK and ADC values were useful for differentiating head and neck tumors from normal tissue.

DOI： 10.18926/AMO/65492

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This study aimed to examine the dosimetric effect of intensity-modulated proton therapy (IMPT) with a multi-leaf collimator (MLC) in treating malignant glioma. We compared the dose distribution of IMPT with or without MLC (IMPTMLC+ or IMPTMLC-, respectively) using pencil beam scanning and volumetric-modulated arc therapy (VMAT) in simultaneous integrated boost (SIB) plans for 16 patients with malignant gliomas. High- and low-risk target volumes were assessed using D2%, V90%, V95%, homogeneity index (HI), and conformity index (CI). Organs at risk (OARs) were evaluated using the average dose (Dmean) and D2%. Furthermore, the dose to the normal brain was evaluated using from V5Gy to V40Gy at 5 Gy intervals. There were no significant differences among all techniques regarding V90%, V95%, and CI for the targets. HI and D2% for IMPTMLC+ and IMPTMLC- were significantly superior to those for VMAT (p < 0.01). The Dmean and D2% of all OARs for IMPTMLC+ were equivalent or superior to those of other techniques. Regarding the normal brain, there was no significant difference in V40Gy among all techniques whereas V5Gy to V35Gy in IMPTMLC+ were significantly smaller than those in IMPTMLC- (with differences ranging from 0.45% to 4.80%, p < 0.05) and VMAT (with differences ranging from 6.85% to 57.94%, p < 0.01). IMPTMLC+ could reduce the dose to OARs, while maintaining target coverage compared to IMPTMLC- and VMAT in treating malignant glioma.

DOI： 10.1016/j.meddos.2023.01.008

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A number of restricted diffusion (RD) imaging techniques, such as diffusion kurtosis (DK) imaging and Q space imaging, have been developed and proven to be useful for the diagnosis of diseases, including cerebral gliomas and cerebrovascular infarction. In particular, apparent diffusion coefficient (ADC) subtraction method (ASM) imaging has become available recently as a novel RD imaging technique. ASM is based on the difference between the ADC values in an image pair of two ADC maps, ADC basic (ADCb) and ADC modify (ADCm), which are created from diffusion-weighted images taken using short and long effective diffusion times, respectively. The present study aimed to assess the potential of different types of ASM imaging by comparing them with DK imaging which is the gold-standard RD imaging technique. In the present basic study using both polyethylene glycol phantom and cell-containing bio-phantom, three different types of ASM images were created using different calculation processes. ASM/A is an image calculated by dividing the absolute difference between ADCb and ADCm by ADCb several times. By contrast, ASM/S is an image created by dividing the absolute difference between ADCb and ADCm by the standard deviation of ADCb several times. As for positive ASM/A image (PASM/A), the positive image, which was resultant after subtracting ADCb from ADCm, was divided by ADCb several times. A comparison was made between the types of ASM and DK images. The results showed the same tendency between ASM/A in addition to both ASM/S and PASM/A. By increasing the number of divisions by ADCb from three to five times, ASM/A images transformed from DK-mimicking to more RD-sensitive images compared with DK images. These observations suggest that ASM/A images may prove useful for future clinical applications in RD imaging protocols for the diagnosis of diseases.

DOI： 10.1371/journal.pone.0282462

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Authorship：Last author   Language：English   Publisher：Hirosaki University Press.  

We validated the calculation accuracies and times between the pencil beam algorithm (PBA) and the Monte Carlo (MC) algorithm in the new proton pencil beam scanning system. Thirty-three (homogeneous phantom) and three (heterogeneous phantom) uniform-dose plans were verified for cubic targets. These plans were calculated using the PBA and five MC statistical uncertainties of 0.3%, 0.5%, 1.0%, 1.5%, and 2.0%. We also evaluated the required dose calculation times per beam with the statistical analysis. Then, eight clinically realistic beams were validated as the end-toend test. The dose differences of 0.3% and 0.5% uncertainty MC plans were satisfied our tolerance (< ±3.0%). All five uncertainty MC plans improved at least the average/minimum gamma score from 93.8%/33.5% to 98.5%/88.9% for homogeneous (2%/2 mm) and 96.7%/83.9% to 98.8%/94.1% for heterogeneous (3%/3 mm) than PBA plans. However, the average calculation times of 0.3% and 0.5% uncertainties in MC plans were 15.5 and 5.8 times longer than in PBA plans (p < 0.001). The endto-end tests satisfied the acceptable with a statistical uncertainty of MC below 0.5%. Although the dose calculation times would be significantly increased, we suggest that the statistical uncertainty of MC below 0.5% is appropriate for clinical use with PBS plans.

DOI： 10.51083/radiatenvironmed.12.1_53

CiNii Books

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Spandidos Publications  

DOI： 10.3892/etm.2023.11808

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Clinical research using restricted diffusion-weighted imaging, especially diffusion kurtosis (DK) imaging, has been progressing, with reports on its effectiveness in the diagnostic imaging of cerebral infarctions, neurodegenerative diseases, and tumors, among others. However, the application of DK imaging in daily clinical practice has not spread because of the long imaging time required and the use of specific software for image creation. Herein, with the aim of promoting clinical research using DK imaging at any medical facility, we evaluated fast DK imaging using a new software program. We developed a new macro program that produces DK images using general-purpose, inexpensive software (Microsoft Excel and ImageJ), and we evaluated fast DK imaging using bio-phantoms and a healthy volunteer in clinical trials. The DK images created by the new software with diffusion-weighted images captured with short-time imaging sequences were similar to the original DK images captured with long-time imaging sequences. The DK images using three b-values, which can reduce the imaging time by 43%, were equivalent to the DK images using five b-values. The DK imaging technique developed herein might allow any medical facility to increase its daily clinical use of DK imaging and easily conduct clinical research.

DOI： 10.18926/AMO/63739

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

The apparent diffusion coefficient subtraction method (ASM) was developed as a new restricted diffusionweighted imaging technique for magnetic resonance imaging (MRI). The usefulness of the ASM has been established by in vitro basic research using a bio-phantom, and clinical research on the application of the ASM for the human body is needed. Herein, we developed a short-time sequence for ASM imaging of the heads of healthy volunteers (n=2), and we investigated the similarity between the obtained ASM images and diffusion kurtosis (DK) images to determine the utility of the ASM for clinical uses. This study appears to be the first to report ASM images of the human head. We observed that the short-time sequence for the ASM imaging of the head can be scanned in approx. 3 min at 1.5T MRI. The noise reduction effect of median filter processing was confirmed on the ASM images scanned by this sequence. The obtained ASM images showed a weak correlation with the DK images, indicating that the ASM images are restricted diffusion-weighted images. The new shorttime imaging sequence could thus be used in clinical studies applying the ASM.

DOI： 10.18926/AMO/63205

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The usefulness of the field-in-field with two reference points (FIF w/ 2RP) method, in which the dose reference points are set simultaneously at two positions in the irradiation field and the high-dose range is completely eliminated, was examined in the present study with the aim of decreasing acute skin toxicity in adjuvant breast radiotherapy (RT). A total of 573 patients with breast cancer who underwent postoperative whole breast RT were classified into 178 cases with wedge (W) method, 142 cases with field-in-field without 2 reference points (FIF w/o 2RP) method and 253 cases with FIF w/ 2RP method. Using the FIF w/ 2RP method, the high-dose range was the lowest among the three irradiation methods. The planning target volume (PTV) V105% and the breast PTV for evaluation (BPe) V105% decreased to 0.09 and 0.10%, respectively. The FIF w/ 2RP method vs. the FIF w/o 2RP method had a strong association (η) with PTV V105% (η=0.79; P<0.001) and BPe V105% (η=0.76; P<0.001). The FIF w/ 2RP method had a significant impact on lowering the skin toxicity grade in weeks 3 and 4, and increasing the occurrence of skin toxicity grade 0. The FIF w/ 2RP method vs. the W method had a moderate association with skin toxicity grade at week 3 (η=0.49; P<0.001). Using the FIF w/ 2RP method, the high-dose range V105% of the target decreased to 0%, and skin adverse events were decreased in conjunction. For patients with early-stage breast cancer, particularly patients with relatively small-sized breasts, the FIF w/ 2RP method may be an optimal irradiation method.

DOI： 10.3892/mco.2021.2355

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Reports on irradiation dose distribution in breast cancer radiotherapy with sufficient sample size are limited in Asian patients. Elucidating dose distribution in Asian patients is particularly important as their breast volume differs compared to patients in Europe and North America. Here, we examined dose distribution in the irradiation field relative to breast volume for three irradiation methods historically used in our facility. We investigated the influence of breast volume on each irradiation method for Asian women. A total of 573 women with early-stage breast cancer were treated with breast-conserving surgery and adjuvant radiotherapy. Three methods were compared: wedge (W), field-in-field (FIF), and wedge-field-in-field (W-FIF). In patients with small breast volume, FIF decreased low- and high-dose areas within the planning target volume, and increased optimal dose area more than W. In patients with medium and large breast volumes, FIF decreased high-dose area more than W. The absolute values of correlation coefficients of breast volume to low-, optimal-, and high-dose areas and mean dose were significantly lower in FIF than in W. The correlation coefficients of V107% were 0.00 and 0.28 for FIF and W, respectively. FIF is an excellent irradiation method that is less affected by breast volume than W in Asian breast cancer patients.

DOI： 10.18926/AMO/62225

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Diffusion-weighted imaging may be used to obtain the apparent diffusion coefficient (ADC), which aids the diagnosis of cerebral infarction and tumors. An ADC reflects elements of free diffusion. Diffusion kurtosis imaging (DKI) has attracted attention as a restricted diffusion imaging technique. The ADC subtraction method (ASM) was developed to visualize restricted diffusion with high resolution by using two ADC maps taken with different diffusion times. We conducted the present study to provide a bridge between the reported basic ASM research and clinical research. We developed new imaging software for clinical use and evaluated its performance herein. This software performs the imaging process automatically and continuously at the pixel level, using ImageJ software. The new software uses a macro or a plugin which is compatible with various operating systems via a Java Virtual Machine. We tested the new imaging software's performance by using a Jurkat cell bio-phantom, and the statistical evaluation of the performance clarified that the ASM values of 99.98% of the pixels in the bio-phantom and physiological saline were calculated accurately (p<0.001). The new software may serve as a useful tool for future clinical applications and restricted diffusion imaging research.

DOI： 10.18926/AMO/61880

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3892/br.2020.1359

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3892/mmr.2019.10523

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

We used image-processing software to analyze the setup errors at the skin surface position of breast cancer patients (n=66) who underwent post-operative whole breast irradiation at our hospital in 2014-2015. The sixty-six digital reconstructed radiographs (DRR) were created at the treatment planning for each patient. The lineacgraphies (n=377) were taken after the patients' setup during radiotherapy. The lineacgraphies and DRR were superimposed at the skin surface position for each patient with the image-processing software. We measured the deviations of the isocenters for the nipple-lung (X) direction and craniocaudal (Y) direction and the deviation of the rotation angle of the XY axes between the lineacgraphy and DRR on the superimposed images. The systematic error (μ, Σ) and random error (σ) were calculated from the X and Y deviations and rotation angle deviation. The μ of X, Y, and rotation angle were 0.01 mm, -1.2 mm, and 0.05°, respectively. The Σ of X, Y, and rotation angle were 1.8 mm, 1.5 mm, and 0.9°, respectively. The σ of X, Y, and rotation angle were 2.0 mm, 1.5 mm, and 1.0°, respectively. Our analyses thus revealed that evaluations using image-processing software at the skin surface position in routine breast radiotherapy result in sufficiently small setup errors.

DOI： 10.18926/AMO/56167

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

The aim of this study was to create a new phantom for a 3 Tesla (3T) magnetic resonance imaging (MRI) device for the calculation of the apparent diffusion coefficient (ADC) using diffusion-weighted imaging (DWI), and to mimic the ADC values of normal and tumor tissues at various temperatures, including the physiological body temperature of 37 C. The phantom was produced using several concentrations of sucrose from 0 to 1.2 M, and the DWI was performed using various phantom temperatures. The accurate ADC values were calculated using the DWIs of the phantoms, and an empirical formula was developed to calculate the ADC values of the phantoms from an arbitrary sucrose concentration and arbitrary phantom temperature. The empirical formula was able to produce ADC values ranging between 0.33 and 3.02x10(-3) mm(2)/sec, which covered the range of ADC values of the human body that have been measured clinically by 3T MRI in previous studies. The phantom and empirical formula developed in this study may be available to mimic the ADC values of the clinical human lesion by 3T MRI.

DOI： 10.3892/ol.2014.2187

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It is well known that many tumor tissues show lower apparent diffusion coefficient (ADC) values, and that several factors are involved in the reduction of ADC values. The aim of this study was to clarify how much each factor contributes to decreases in ADC values. We investigate the roles of cell density, extracellular space, intracellular factors, apoptosis and necrosis in ADC values using bio-phantoms. The ADC values of bio-phantoms, in which Jurkat cells were encapsulated by gellan gum, were measured by a 1.5-Tesla magnetic resonance imaging device with constant diffusion time of 30 sec. Heating at 42° C was used to induce apoptosis while heating at 48°C was used to induce necrosis. Cell death after heating was evaluated by flow cytometric analysis and electron microscopy. The ADC values of bio-phantoms including non-heated cells decreased linearly with increases in cell density, and showed a steep decline when the distance between cells became less than 3/um. The analysis of ADC values of cells after destruction of cellular structures by sonication suggested that approximately two-thirds of the ADC values of cells originate from their cellular structures. The ADC values of bio-phantoms including necrotic cells increased while those including apoptotic cells decreased. This study quantitatively clarified the role of the cellular factors and the extracellular space in determining the ADC values produced by tumor cells. The intermediate diffusion time of 30 msec might be optimal to distinguish between apoptosis and necrosis.

DOI： 10.18926/AMO/52009

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

The roles of cell density, extracellular space, intracellular factors, and apoptosis induced by the molecularly targeted drug rituximab on the apparent diffusion coefficient (ADC) values were investigated using bio-phantoms. In these bio-phantoms, Ramos cells (a human Burkitt's lymphoma cell line) were encapsulated in gellan gum. The ADC values decreased linearly with the increase in cell density, and declined steeply when the extracellular space became less than 4 gm. The analysis of ADC values after destruction of the cellular membrane by sonication indicated that approximately 65% of the ADC values of normal cells originate from the cell structures made of membranes and that the remaining 35% originate from intracellular components. Microparticles, defined as particles smaller than the normal cells, increased in number after rituximab treatments, migrated to the extracellular space and significantly decreased the ADC values of bio-phantoms during apoptosis. An in vitro study using bio-phantoms was conducted to quantitatively clarify the roles of cellular factors and of extracellular space in determining the ADC values yielded by tumor cells and the mechanism by which apoptosis changes those values.

DOI： 10.18926/AMO/48566

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

In recent years, magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) has seen wide clinical use, such as for early detection of cerebrovascular diseases and whole body screening for tumors. The apparent diffusion coefficient (ADC) standard phantom, which mimics the ADC values of several lesions in the body, is indispensable for the development of new pulse sequences for DWI, such as diffusion-weighted whole-body imaging with background body-signal suppression (DWIBS). However, information on the ADC values of the previously reported ADC standard phantoms is limited, because these phantoms were made using only a few different materials at a limited range of concentrations, and the ADC values were measured only at certain temperatures. It has been considered difficult, if not impossible, to create a phantom that provides arbitrary ADC values, because it is difficult to calculate the concentrations of the materials and the temperature at ADC measurement. In this study, we used polyethylene glycol (PEG) as a phantom material, and developed an empirical formula to calculate the PEG concentration at any measurement temperature to obtain arbitrary ADC values of the phantom. DWI images of phantoms made using seven different PEG concentrations were taken under heating from 17 to 46 degrees C at 1 degrees C intervals. Using ADC values calculated from these DWI images, we developed two empirical formulas: i) an empirical formula to calculate the ADC values of phantoms made using any PEG concentration at any measurement temperature; and ii) an empirical formula to calculate PEG concentrations to obtain arbitrary ADC values at any measurement temperature. We inspected the accuracy of these empirical formulas by newly made PEG phantoms. A comparison between the ADC values calculated with the empirical formulas and the measured ADC values confirmed the high accuracy of these formulas. PEG phantoms are safe, inexpensive and easy to make, compared with the previously reported ADC standard phantoms. Our empirical formulas enable us to calculate PEG concentrations that provide arbitrary ADC values at any measurement temperature. The empirical formulas could be used within a range of ADC values from 0.37x10(-3) to 3.67x10(-3) mm(2)/s, PEG concentrations from 0 to 120 mM, and measurement temperatures from IS to 45 degrees C. Using these formulas, it would be possible to make standard phantoms that mimic the ADC values of any clinical lesions. The PEG phantom might thus be an excellent new ADC standard phantom for MRI with DWI.

DOI： 10.3892/ijo_00000404

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

Diffusion-weighted magnetic resonance imaging (MRI) is frequently used clinically, and is available for the whole-body screening for tumors. The exact mechanism by which the apparent diffusion coefficient (ADC) value decreases in tumorous tissue remains unclear, although various theories have been proposed, including intracellular and extracellular factor theories. It is impossible to distinguish each factor in the intracellular and extracellular spaces as the source of MR signal generation by means of conventional comparison between MR images and pathological specimens. Other factors which have been reported to affect ADC include cellularity and cellular edema of human tissues, and temperature of phantoms at the time of measurement. We employed a new technique that enables cellular MR imaging using a newly developed bio-phantom containing a living culture tumor cell line, Jurkat-N1. We investigated possible reasons for observed decreases in ADC values for tumors, and we considered the contribution of both the intracellular and extracellular space to such a decrease. The ADC values of the bio-phantom increased with increasing heat exposure from 27 to 45 degrees C. ADC values also increased after the destruction by sonication of tumor cell membranes. ADC values decreased as cellularity increased in the bio-phantorn. ADC values decreased due to cellular edema caused by a low salt concentration in the bio-phantom. Changes in pressure in the bio-phantom had no effect on the observed ADC values. We calculated both the intracellular ADC and extracellular ADC values using the ADC values, cellularity, and cellular volume of Jurkat-N1 cells in the bio-phantom. The extracellular ADC values in the bio-phantom were estimated to be lower than the ADC value of distilled water. These results indicate that not only intracellular ADC values, but also extracellular ADC values contribute to the determination of the ADC values of bio-phantoms. This is the first report to have examined the contribution of intracellular and extracellular space on the ADC values of bio-phantoms containing cultured tumor cells.

DOI： 10.3892/or_00000484

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

We developed a new hybrid gel phantom using carrageenan and gellan gum for the purpose of visualizing three-dimensional temperature distribution. The phantom, which contains carrageenan, gellan gum, non-ionic surface active agent, potassium chloride, n-butanol, sodium azide, and water, shows good transparency at room temperature, and has the advantage that the heated region becomes white and opaque due to segregation of the surface active agent. Carrageenan and gellan gum were added to improve the transparency and fragility of the hybrid gel. Potassium chloride was used to adjust the electrical conductivity of the gel to a range of 5-130 MHz, so that it would be equivalent to that of muscle tissue for each frequency used by electromagnetic heating devices. N-butanol was used to adjust the clouding temperature to a range between 45 and 55 degrees C. In the present study we clarified the important properties of the new phantom, and developed formulae for easy determination of the amounts of ingredients necessary for the desired clouding temperature and electric conductivity. The characteristics of this phantom are: a) a solid form to avoid convection by heat conduction; b) sufficient strength without fragility to form a torso without the use of a reinforcing agent; c) high transparency at room temperature and visualization of the heating area as a white turbidity; d) time-lapse and accurate visualization of the changing temperature area without thermal hysteresis; e) electrical properties similar to those of human tissues; f) ease of production; and g) low cost and good safety. This phantom might assist oncologists in their routine checking and study of the performance of electromagnetic heating devices for hyperthermia and radiofrequency ablation.

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

We previously developed a new microscopic observation system that enables time-lapse quantitative analysis of apoptosis and necrosis. With this system we quantitatively analyzed adriamycin (ADR)-induced cell death using manganese superoxide dismutase (MnSOD)- and wild-type p53-gene transfectants on SaOS(2) a p53-deficient human osteosarcoma cell line. A highly MnSOD-over-expressing cell line, SaOS(2)FM(H), acquired ADR-tolerance compared to the parent cell line SaOS(2). The ADR-tolerance of SaOS(2)FM(H) diminished by L-buthionine-[S,R]-sulfoximine (BSO), which did not change ADR-sensitivity of SaOS, to the similar ADR-sensitivity of SaOS(2). A wild-type p53-expressing cell line, SaOS(2)wtp53, significantly increased in ADR-sensitivity compared to SaOS, This ADR-sensitivity of SaOS,wtp53 was enhanced by BSO. When isosorbide 5-mono-nitrate was combined with BSO, isosorbide 5-mononitrate increased ADR sensitivity of a moderately MnSOD-over-expressing cell line. SaOS,FM(L), decreased that of SaOS, FM(H), and did not change those of SaOS, and SaOS2wtp53 compared to BSO alone. Time-lapse microscopic observations during ADR treatment for 24 h indicated that the most cells of each cell line underwent apoptosis, and a few cells (less than 11%) died by necrosis. When cells were treated with isoconcentration of ADR, apoptosis of SaOS,FM(H) was less than that of SaOS(2). BSO, which did not change ADR-sensitivity of SaOS(2), increased appearance rate of ADR-induced apoptosis, but not necrosis of MnSOD-over-expressing cell lines. When iso-survival dose of ADR, which reduced surviving fraction to 0.01, was given for each cell line, no difference was observed in appearance of either apoptosis or necrosis between SaOS(2) and MnSOD-overexpressing cell lines. On the other hands, appearance of both apoptosis and the following secondary necrosis of SaOS(2) wtp53 was significantly accelerated compared to those of SaOS(2). These findings indicate that hydrogen peroxide overload on p53-independent pathway due to MnSOD overexpression plus BSO might increase the apoptosis frequency without acceleration of apoptotic process of each cell, resulting in negating ADR-tolerance of MnSOD-overexpressing cell lines.

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

Manganese superoxide dismutase (MnSOD) is a mitochondrial enzyme that converts cytotoxic superoxide radicals into hydrogen peroxide. MnSOD activity is lower in tumor cells, and MnSOD overexpression reportedly ameliorates malignant phenotypes. We established stable MnSOD overexpressing cell lines from a human osteosarcoma cell line, SaOS(2), and then investigated the effects of MnSOD overexpression on plating efficiency (PE) and the involvement of reactive oxygen species, including nitric oxide (NO) in those effects. The PE of SaOS(2)FM(L), a moderate MnSOD overexpression cell line, increased, while that of SaOS2FM(H), a high MnSOD overexpression cell line, decreased. Although we assessed PE using a colony-formation assay, time-lapse microscopic observation revealed that cells attached to the flasks had undergone neither apoptosis nor necrosis. Moreover, MnSOD overexpression did not affect cell doubling time. Therefore, MnSOD overexpression might correlate directly with cellular adhesion's effect on PE changes. When L-buthionine-[S,R]-sulfoximine (BSO) was administered to increase the intracellular concentration of hydrogen peroxide, the PEs of both cell lines decreased, and when hydrogen peroxide was eliminated by the administration of sodium pyruvate, only the PE of SaOS2FM(H) increased. The combination of BSO and NO (NOR4 or isosorbide 5-mononitrate) administration synergistically decreased PE in both cell lines. These findings suggest that changes in cellular adhesion properties correlate with the balance between increased hydrogen peroxide levels and decreased superoxide radical levels. This is the first report to indicate that PE and cellular adhesion properties change bidirectionally according to the levels of MnSOD overexpression: first increasing then decreasing as MnSOD activity increases. Our results indicate that PE changes might be decided by the balance between two cytotoxic compounds (decreased superoxide radical levels and increased hydrogen peroxide levels), and that NO loading and increased hydrogen peroxide synergistically reduce PE and cellular adhesion.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

A phantom has previously been developed containing carrageenan, agarose and gadolmium chloride (called CAG phantom) for MRI with 1.5T. T-1 and T-2 relaxation times of this phantom are independently changeable by varying concentrations of relaxation-time modifiers to simulate relaxation times of the various types of human tissues. The CAG phantom has a T, value of 202-1904 ms and a T-2 value of 38-423 ins, when the GdCl3 concentration is varied from 0-140 mumol/kg and the agarose concentration is varied from 0-1.6%. A new phantom has now been developed (called CAGN phantom), made by adding an electric conductive agent, NaCl, to the CAG phantom for use in the areas of MRI and hyperthermia research. Dielectric properties of the CAGN phantom were measured and the results of experiments were expressed by the Cole-Cole equation in the frequency range of 5-130 MHz. The relationship between the conductivity of the CAGN phantom and the concentration of NaCl was expressed by a linear function in the frequency range of 1-130 MHz. The linear function involves a parameter of frequency and, when the frequency is 10 MHz, the conductivity of the CAGN phantom can be changed from 0.27-1.26 Sm-1 by increasing the NaCl concentration from 0-0.7%. The CAGN phantom developed can be employed in basic experiments for non-invasive temperature measurement using MRI and as a loading phantom for MRI with up to 3 T.

DOI： 10.1080/0265673042000199277

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

Cepharanthin (CEP) is a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata. CEP is reported to inhibit drug resistance by inhibiting P-glycoprotein, a drug efflux pump, and recently to induce apoptosis. In the present study, we examined the effects of CEP as an inhibitor of adriamycin (ADR) resistance on ADR-induced apoptosis and necrosis. First, we established p53-deficient ADR-resistant osteosarcoma cell lines, SaOS(2)-AR and SaOS(2) F-AR. Resistant cells showed a higher level of intracellular glutathione peroxidase activity than parent cells. P-glycoprotein was overexpressed in resistant cells. The intracellular ADR level of resistant cells was lower than that of parent cells. One mug/ml CEP eliminated the degradation of intracellular ADR of resistant cells; that is, to a level equivalent to that of the parent cells. CEP of 0.5 mug/ml, which was not cytotoxic when used alone, significantly increased the ADR sensitivity of resistant cells, to a level similar to the parent cell level. Isosorbide 5-mononitrate, a potential nitric oxide-generation agent, combined with CEP further increased the ADR sensitivity of resistant cells, indicating a synergistic effect of CEP and isosorbide 5-mononitrate on ADR cytotoxicity. Time-lapse microscopic observation revealed that ADR dominantly induced apoptosis much more than necrosis for both parent and resistant cells, and that the use of 0.5 mug/ml CEP with ADR synergistically accelerated apoptosis in resistant cells. Finally, we clarified the property by which CEP synergistically accelerates ADR-induced apoptosis. This property might be a new mechanism that explains how CEP overcomes ADR resistance.

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

Cepharanthine (Cc) is a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata. In our previous study, Cc significantly enhanced thermosensitivity and thereby reduced thermotolerance in vitro, and intraperitoneal injection of Cc slightly enhanced thermosensitivity in vivo. In the present study, we investigated Cc's effect in vitro on the pattern of cell death after heating and the effect of intra-tumoral injection of Cc on in vivo thermosensitivity using a mouse fibrosarcoma, FSa-II, and C3H/He mice. Cc significantly enhanced the in vitro thermosensitivity of FSa-II cells with heating at 44degreesC, with increased Cc concentration. Time-lapse microscopic observation of individual cells confirmed that Cc treatment hastened both apoptosis (specifically, apoptotic budding) and necrosis (as indicated by staining with propidium iodide). Staining with annexin V-enhanced green fluorescent protein indicated that Cc used concomitantly with heating significantly increased the proportion of cells in the early stage of apoptosis. Cc combined with heating also significantly increased the proportion of cells with high intracellular caspase-3 activity, as detected by a substrate of caspase-3, PhiPhiLux-G(1)D(2). The intra-tumoral injection of Cc, followed by heating at 44degreesC, significantly delayed in vivo tumor growth, and this delay increased in a Cc concentration-dependent manner. Cc injected 30 min before heating delayed tumor growth more than Cc injected immediately before heating. These findings suggest the potential of Cc as a thermosensitizer to increase apoptosis of tumor cells.

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

Using a pEYFP-Nuc vector, which contains nucleic acid sequences of a nuclear localization signal, we established a Jurkat-YN cell line that expressed enhanced yellow fluorescent protein (EYFP) in the nucleus. We observed three-dimensional and time-lapse changes in nuclear morphology of Jurkat-YN cells during Fas-induced apoptosis using a confocal laser scanning microscope. The nuclear forms visualized by EYFP were almost equal in quality to those visualized by SYTO59, a nucleic acid stain for living cells. Three-dimensional deformities in the nuclear form were observed during apoptosis before chromatin condensation became apparent, indicating these deformities are characteristic morphological changes of the early stage of apoptosis. In conclusion, the pEYFP-Nuc vector is a useful tool in the time-lapse observation of nuclear morphology of living cells during apoptosis.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

A new tissue-equivalent MRI phantom based on carrageenan gel was developed. Carrageenan gel is an ideal solidifying agent for making large, strong phantoms in a wide variety of shapes. GdCl3 was added as a T-1 modifier and agarose as a T-2 modifier. The relaxation times of a very large number of samples were estimated using 1.5-T clinical MRI equipment. The developed phantom was found to have a T-1 value of 202-1904 ms and a T-2 value of 38-423 ms when the GdCl3 concentration was varied from 0-140 mumol/kg and the agarose concentration was varied from 0-1.6% in a carrageenan concentration that was fixed at 3%. The range of measured relaxation times covered those of all types of human tissue. Empirical formulas linking the relaxation time with the concentration of the modifier were established to enable the accurate and easy calculation of the modifier concentration needed to achieve the required relaxation times. This enables the creation of a phantom having an arbitrary combination of T-1 and T-2 values and which is capable of retaining its shape. Magn Reson Med 50:1011-1017, 2003. (C) 2003 Wiley-Liss, Inc.

DOI： 10.1002/mrm.10619

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It has been shown that hyperthermia can enhance the cytotoxicity of some chemotherapeutics. However, the most effective agent(s) at elevated temperatures have yet to be determined. A previous study suggests that the drug of choice at elevated temperatures may be different from that at the physiological temperature, and that the alkylating agents may be most effective at elevated temperatures. To further investigate these possibilities, the effect of chemotherapeutic agents were compared. These agents were cyclophosphamide, ifosfamide, melphalan, cis-diamminedichloroplatinum (II), 5-fluorouracil, mitomycin C and bleomycin. Three tumours ( mammary carcinoma, osteosarcoma and squamous cell carcinoma) were used. They were transplanted into the feet of C3H/He mice. When tumours reached 65 mm(3) a test agent was injected intraperitoneally. Tumours were immediately heated at 41.5degreesC for 30 min, and the tumour growth (TG) time was studied for each tumour. Using the TG times, the TG-50 (the time required for one-half of the total number of the treated tumours to reach the volume of 800 mm(3) from 65 mm(3)) was calculated. Subsequently, the tumour growth delay time (GDT) and the thermal enhancement ratio (TER) were obtained. The GDT was the difference between the TG-50 of treated tumours and that of non-treated control tumours. The TER was the ratio of the GDT of a group treated with an agent at 41.5degreesC to that of a group treated with the agent at room temperature. Results showed that the top three effective agents tested at 41.5degreesC were solely alkylating agents-CY, IFO and L-PAM-for each kind of tumour. A GDT of cisplatin was smaller than those of the alkylating agents. The smallest TER, 1.1, was observed for 5-fluorouracil, which was given for mammary carcinoma, and for mitomycin C, which was given for squamous cell carcinoma. It could be concluded that the alkylating agents at elevated temperatures might be the drugs of choice for many types of tumours. The possible mechanisms of thermal enhancement associated with these agents are discussed.

DOI： 10.1080/0265673021000035235

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Using a new system developed by us for acquiring microscopic images automatically, we compared the morphological changes that apoptotic cells undergo with changes in the staining pattern of annexin V-enhanced green fluorescent protein (AV-EGFP) and propidium iodide (PI) in individual cells. Jurkat cells were treated with 5 mM CaCl2 alone, anti-Fas antibody and heating at 42 degrees C for 30 min or 46 degrees C for 60 min, and then were incubated in medium with 5 mM CaCl2. Time-lapse DNA fragmentation analysis and morphological observation revealed that the anti-Pas antibody and heating at 42 degrees C for 30 min induced typical apoptosis in the cells, and heating at 46 degrees C for 60 min induced typical necrosis. Time-lapse observation of individual cells stained with AV-EGFP and PI confirmed that apoptotic cells were stained at first with AV-EGFP alone, and thereafter also with PI when the cellular membrane ruptured and the cell underwent secondary necrosis. Most of the cells which underwent necrosis were stained simultaneously with AV-EGFP and PI. There was a significant time interval between the staining of individual cells with AV-EGFP, indicating apoptosis, and staining of these cells with PI, which indicated the occurrence of secondary necrosis. These results suggest that time-lapse examinations are necessary to distinguish apoptosis, secondary necrosis and necrosis in cells from one another. This study presents direct evidence that apoptotic cells undergo secondary necrosis, which could be recognized with PI.

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

The relationship between spontaneous apoptosis and overexpression of manganese superoxide dismutase (MnSOD) gene was examined in vivo. The mouse fibrosarcoma cells expressing high MnSOD activities due to transfection with the human MnSOD cDNA (SOD-H), or the fibrosarcoma cells transfected with the selectable marker alone (NEO), were transplanted into immune-deficient Fox Chase SCID C.B-17/Icr-scid Jcl mice. Apoptosis in tumors was visually quantified by the in situ end-labeling method. The number of apoptotic cells in the SOD-H tumors was significantly less than that in the NEO tumors. The tumor growth time of the SOD-H tumors to grow from 34 to 500 mm in one-half of the mice was slightly longer than that of the NEO tumors, but the difference was not statistically significant. These results suggest that overexpression of MnSOD gene is involved in the suppression of spontaneous apoptosis, without a resultant alteration in the tumor growth.

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

Cepharanthin (Ce) is a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata. The results of our previous in vitro study indicated that Ce reduces thermotolerance by enhancing thermosensitivity. In the present study, we investigated the in vitro and in vivo effects of Ce on thermosensitivity and thermotolerance using a murine mammary carcinoma, MCa, and C3H/HeN mice. Ce enhanced the thermosensitivity of MCa cells for heating at 44 degrees C not only in vitro but also in vivo. The in vivo enhancement ratio +/- SD of Ce at 100 mg/kg for heating at 44 degrees C was 1.3+/-0.3. The fractionated heat treatments at 44 degrees C for 30 and 60 min with an interval time of 0-6 days resulted in the development of remarkable thermotolerance and the expression of heat shock protein 70 in MCa tumors after the first heating. Ce at 100 mg/kg given immediately after the first heating increased the expression of heat shock protein 70 in MCa tumors, and did not reduce the development of thermotolerance. Ce given immediately before the first or second heating also did not inhibit the thermotolerance. The results of this study suggest that Ce enhances the thermosensitivity of MCa tumors as a thermosensitizer, but that this mild thermosensitizing property of Ce might be insufficient to conquer the remarkable thermotolerance in MCa tumors that develops after the first heating.

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Language：English   Publisher：TAYLOR & FRANCIS LTD  

It has been demonstrated in vitro and in vivo that hyperthermia can enhance the cytotoxicity of some chemotherapeutic agents. This paper summarizes the authors' own laboratory studies on the effect of chemotherapeutic agents given at elevated temperatures, experimental results obtained using animal tumour systems in other laboratories, and clinical trials of thermochemotherapy reported in literature. The in vivo studies have demonstrated that the thermal enhancement of cytotoxicity of many chemotherapeutic agents is maximized at mild temperatures such as at 40.5-43 degrees C. Comparison of in vitro and in vivo results using five agents show that the in vivo thermal enhancement increases with an increase in the activation energy obtained in the temperature range between 40.5 and 43.0 degrees C. A summary of experimental results obtained by various investigators indicates a potentially wide variation in the thermal enhancement of a given agent among the different types of tumours and suggests potential agents useful at moderately elevated temperatures. In vivo studies on nine different agents indicate that the drug(s) of choice at physiological temperatures may not be the drug(s) of choice at elevated temperatures. It is also shown that drug concentration in the target must be high for sufficient thermal enhancement. Clinical trials of thermochemotherapy have employed various heating methods, including local heating, hyerthermic perfusion and whole body hyperthermia. Extensive trials have been made in the treatment of melanoma and soft tissue sarcoma in the extremity. Hyperthermic isolated perfusion with chemotherapeutic(s) provides much higher drug concentration than a systemic drug administration in the target(s), resulting in a high tumour response rate and an increased survival of the patients. It is of interest that the most successful agent used in the treatment of both melanomas and sarcomas is melphalan and is the drug of choice at moderately elevated temperatures among the nine agents tested in the in vivo studies. Current results using the tumour necrosis factor with melphalan are impressive. In several institutes, techniques have been developed to uniformly heat the localized tumour, but studies are needed to find an agent effective at elevated temperatures to each type of tumours and to establish the methods for obtaining a sufficient drug concentration in the target tissue.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

Purpose: To investigate the significance of hypoxic cells, reoxygenation and repopulation for the outcome of fractionated radiotherapy of a slow-growing subline of a murine fibrosarcoma and to compare the results with those previously obtained from the original fast-growing tumor.
Materials and methods: A slow-growing subline, 457-O, was obtained among the tumors that recurred after a single irradiation to the third generation isotransplants of a mouse fibrosarcoma, FSa-II. The single cell suspensions were transplanted into the mouse foot and when the tumors reached an average diameter of 4 mm, they were subjected to one to 20 equal daily gamma-ray doses given in air (A) or under hypoxic conditions (H). The TCD50 (50% tumor control radiation dose) was calculated according to the tumor control frequency within 180 days. The linear-quadratic plus time model was fitted to these data by logistic regression analysis.
Results: The volume doubling time of the 457-O tumors was similar to 2.2 times slower than that of the original FSa-II tumors. The TCD50(H) (single dose) was 52.3 Gy and increased with an increasing number of fractions to a TCD50(H) (20 doses) of 90.8 Gy This increase of 38.5 Gy was much smaller than that of 149 Gy for the original FSa-II. The TCD50(A) (single dose) and TCD50(A) (20 doses) were 41.3 and 50.6 Gy, respectively. This small difference of 9.3 Gy contrasted with a significant increase of 52.9 Gy for the FSa-II.
Discussion: These results suggested no repopulation of 457-O tumor clonogens during the course of up to 20 daily doses, while the original FSa-II tumor cells repopulated substantially. Hypoxic clonogens in the slow-growing tumor reoxygenated but some fractions remained critical.
Conclusion: The present data together with those obtained from the fast-growing FSa-II suggested that hypoxic clonogens were critical for the outcome of fractionated radiotherapy. Repopulation was insignificant in this slow-growing tumor during five to 20 daily doses. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.

DOI： 10.1016/S0167-8140(98)00010-3

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT JOURNAL ONCOLOGY  

The tumor metastatic ability and tumorigenicity of the mouse fibrosarcoma cell line (FSa-II) were significantly reduced due to overexpression of manganese superoxide dismutase (MnSOD) as reported previously. We investigated changes in the in vitro basic character of FSa-II cells transfected with the human MnSOD cDNA which was employed in the previous studies. FSa-II and the control vector-transfected cell line NEO, had no detectable MnSOD activity. SOD-H, into which MnSOD cDNA was transfected, is the cell line with high MnSOD activity. The malignant phenotype, characterized by serum-independence, was suppressed with elevated MnSOD activity. A quantitative comparison of transferrin receptor (TfR) by flow cytometry showed the amount of TfR on the membrane of SOD-H cells to be significantly less than that on the membrane of NEO cells. The amount of CD44 expression on SOD-H cells was almost the same as that on NEO cells. The results of this study suggest that the overexpression of MnSOD is related to suppression of the malignant phenotype and that changes of iron metabolism may play an important role in this process.

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We have examined the tumorigenicity and the level of extracellular matrix proteins in fibrosarcoma cells expressing low (SOD-L) and high (SOD-H) MnSOD activities as well as the fibrosarcoma cells transfected with the selectable marker alone (NEO). When the cells derived from each tumor cell line were injected into syngeneic mice., the number of tumor cells required to make a tumor in one-half of the mice (TD50) was markedly increased in MnSOD-transfected cells. The decrease in the tumorigenicity of the MnSOD-transfected cells was associated with an increase in the fibronectin level. These results support the hypothesis that MnSOD is a new type of tumor-suppressor gene.

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Purpose: It has been shown that thermochemotherapy (TC) given prior to radiation reduces the number of clonogens, with a resultant decrease in the tumor control radiation dose. The purpose of this article was to investigate using an animal tumor model how this clonogen reduction affects subsequent fractionated radiotherapy, including repopulation of surviving clonogens, and whether the induction TC can increase the therapeutic gain factor (TGF).
Methods and Materials: The single-cell suspensions prepared from the fourth-generation isotransplants of a spontaneous fibrosarcoma, FSa-II, were transplanted into the C3Hf/Sed mouse foot. TC was given by heating tumors at 41.5 degrees C for 30 min immediately after an intraperitoneal injection of cyclophosphamide (200 mg/kg) when tumors reached an average diameter of 4 mm. Fractionated radiotherapy (R) with equally graded daily doses was initiated 24 h after TC either in air (A) or under hypoxic conditions (H). The 50% tumor control dose (TCD50) and the radiation dose to induce a score 2.0 reaction (complete epilation with fibrosis) in one-half of irradiated animals, RD50(2.0), were obtained, and the TGF was calculated. Our previous results on the fractionated radiotherapy using the same tumor system served as controls.
Results: The TCD50(A, single dose) and TCD50(H, single dose) following TC+R were 52.2 and 57.3 Gy, respectively, which were 14.0 and 20.4 Gy lower than those following radiation alone. The TCD50(A, TC+R) increased only slightly when the number of fractions was increased from one to 10 doses, and all TCD(50)s were significantly lower than the TCD50(A, R alone). Both TCD50(H, TC+R) and TCD50(H, R alone) increased consistently from a single dose to 20 doses, but all TCD50(H, TC+R) were significantly lower than the TCD50(H, R alone). Regarding the normal tissue reaction, the RD50 values both following TC+R and R alone increased consistently from a single dose to 20 daily doses. However, the RD50(TC+R) and RD50(R alone) for each corresponding number of fractions was not significantly different, resulting in the TGFs significantly &gt;1.0 for combined TC+R treatments, with the exception of 20 daily doses given in air.
Conclusion: The induction TC decreased the TCD50 values substantially without altering the RD50 for a late reaction, resulting in an significant increase in the TGF. These results encourage the use of TC as an induction treatment prior to fractionated radiotherapy. (C) 1997 Elsevier Science Inc.

DOI： 10.1016/S0360-3016(97)00037-0

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

We report the results of phase I/II studies of preoperative multidisciplinary treatment of 14 patients with soft tissue sarcoma using hyperthermia from November 1990 to April 1995. The preoperative treatment was conducted with thermo-radio-chemotherapy in 11 cases of stage III, and with thermo-radiotherapy as well as thermo-chemotherapy in three cases of stages I and II. Hyperthermia was carried out twice a week with totals ranging from 4 to 14 times (average: 8.4 times); each session lasted 60 min. Radiotherapy was administered four or five times per week, and the dose was 1.8-2Gy/fraction, with a total of 30-40 Gy in a four week period. Chemotherapy was mainly in the form of MAID regimen (2-mercaptoethanesulphonic acid (mesna), adriamycin, ifosfamide and dacarbazine). The tumors were surgically resected in all patients after completing the preoperative treatment. The efficacy rate, as expressed by the percentage of either tumors in which reduction rate was 50% or more, or tumors for which post-treatment contrast enhanced CT image revealed low density volumes occupying 50% or more of the total mass, was 71% (ten of the 14 tumors). The mean tumor necrosis rate in the resected specimens was 78%. The tumor necrosis rate was significantly high (P &lt;0.05) in patients whose Time greater than or equal to 42 degrees C was of long duration. Postoperative complications were observed in six patients; among these, two patients developed wound infection that required surgical treatment as a complication of surgery performed in the early stage following the preoperative treatment. After a mean postoperative follow-up of 27 months, distant metastasis occurred in four patients resulting in three fatalities. The three-year cumulative survival rate was 64.3%. No local recurrence was observed in any patient during the follow-up, thus confirming our hypothesis that preoperative multidisciplinary treatment has an excellent local efficacy. We think that it would be valuable to conduct, at many facilities, phase III studies on the treatment of soft tissue sarcoma by a combination of surgery and preoperative multidisciplinary treatment using hyperthermia, paying close attention to the interval between these two modalities.

DOI： 10.18926/AMO/30776

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

The effect of hyperthermia on the cytotoxicity of 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]-tetrahydro-2H-1 ,3,2-oxazaphosphorine-2-oxide, ifosfamide (IFO) was investigated in vivo. Tumours were early generation isotransplants of a spontaneous C3Hf/Sed mouse fibrosarcoma, FSa-II. The tumour cell suspensions containing similar to 2 x 10(5) cells were transplanted into the dorsal site of the C3Hf/Sed mouse foot. Hyperthermia was given by immersing the tumour-bearing foot into a constant temperature water bath set at 41.5 degrees C for 0-90 min when tumours reached 34mm(3). IFO was administered ip immediately before hyperthermia. Tumour response was studied by the tumour growth (TG) time assay; namely, the TG time or the time for one-half of the treated tumours to reach 700mm(3) from the initial treatment day was determined and the dose-response curve was fittted between the TG time and IFO dose. The anti-tumour effect of IFO was enhanced at this elevated temperature. The thermal enhancement ratio (TER) or the ratio of the slope of dose-response curve at 41.5 degrees C to that of dose-response curve without hyperthermia was relatively small for a short treatment time of 30 min. This TER was smaller for IFO than the TERs for cyclophosphamide (CY) and BCNU which had been studied in our laboratory. However, the TER for IFO increased greatly with a prolongation of treatment time from 30 to 90 min, and exceeded the TER for CY. The TERs were 1.5, 2.6 and 3.6 for heating time of 30, 60, and 90 min, respectively, indicating that a long treatment time such as 90 min at moderately elevated temperatures could result in a substantial enhancement of the antitumour effect of IFO.

DOI： 10.3109/02656739709056436

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

This study investigated the in vitro and in vivo radiation response of tumor cells transfected with human manganese superoxide dismutase (MnSOD) cDNA. A major objective was to test the potential tumor suppressive effect of MnSOD in vivo. Tumor cells studied were an in vitro Line derived from a murine spontaneous fibrosarcoma, FSa-II, which expressed an undetectable MnSOD activity. These cells were transfected with pSV2-NEO plasmid (NEO line) or cotransfected with MnSOD plasmid plus pSV2-NEO plasmid (SOD lines) as described previously. The cell lines used were SOD-L and SOD-H, which expressed, respectively, low and high MnSOD activities after transfection, and NEO and parental FSa-II controls. Both SOD-L and SOD-H cell lines were slightly more resistant to ionizing radiation than were the two control cell lines when irradiated in vitro in the presence of oxygen. The dose-modifying factors calculated at the survival level of 0.01 were 1.13 and 1.15 for the SOD-L and SOD-H cells, respectively. To investigate potential tumor suppressive effects, animal tumors of 4 mm diameter were irradiated in vivo under hypoxic conditions, and the radiation dose to control one-half of the irradiated tumors (TCD50) was determined for each tumor. The TCD(50)s obtained on the basis of the tumor control rate in 120 days after irradiation were substantially lower for the SOD-H and SOD-L tumors compared to the NEO tumors. They were 22.9, 28.6, and 47.5 Gy for SOD-H, SOD-L and NEO tumors, respectively. To analyze these data, survival curves were obtained for hypoxic cells by irradiating NEO and SOD-H tumors under hypoxic conditions in vivo and assaying in vitro. Analysis of these curves suggests that the decrease in the TCD(50)s of SOD tumors is attributable to the reduced tumorigenicity in these tumors. The hypoxic cell survival curves also showed that SOD did not protect cells from radiation in the absence of oxygen. Electron microscopy showed no morphological differences between these cells. These results suggest that the fraction of tumorigenic cells could be reduced by expression of MnSOD, resulting in a substantial decrease in the TCD50.

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Between November 1984 and August 1992 we used hyperthermotherapy in six cases of local recurrence of rectal cancer. Hyperthermotherapy was performed on the average 8.7 times (range: 3-18) for each patient for 60 min each. All patients underwent combined radiotherapy and received a mean radiation dose of 42.5 Gy (range: 9-60 Gy). Five patients underwent heating within 1 h after irradiation and one patient simultaneously with the irradiation. Four patients underwent combined chemotherapy and two patients immunotherapy. Before the treatment all patients had painful lesions, but pain decreased posttherapeutically in five patients. Performance status improved in two patients. High carcinoembryonic antigen levels prior to the therapy in four patients decreased in all cases after treatment. Posttherapeutical computed tomograms revealed only minor response or no changes. After the treatment, four patients died of exacerbations of recurrent tumors and one patient of distant metastases. The patient who underwent simultaneous radiohyperthermotherapy is presently alive, in August 1992, 38 months after initiation of the treatment. The 50 % survival time after initiation of the treatment was 25 months (range: 10-38 months). Hyperthermotherapy combined with radiotherapy, chemotherapy and/or immunotherapy was useful for the alleviation of pain in patients who developed local recurrence after surgery, and improved survival after recurrences can be expected.

DOI： 10.18926/AMO/31557

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Simultaneous radiohyperthermotherapy (SRH) is a combined hyperthermia-radiation therapy in which irradiation is given during heating. Mutual interference between the high energy radiotherapy system (Toshiba LMR-15A) and the 13.56 MHz capacitive heating system (Omron HEH-500C) was tested with phantom materials prior to a clinical trial with SRH. The energy and flatness of irradiation were not affected by the heating system within the range of clinical use. The high energy radiotherapy system did not affect the increase or distribution of temperature during simultaneous treatment. The results of this phantom study indicated that these apparatuses would not produce clinically significant mutual interference during SRH. A clinical trial was performed on a 57-year-old woman with postoperative recurrence of rectal cancer. This is the first reported clinical case treated with true SRH in which external irradiation was administered during mid capacitive heating. Twelve SRH treatments were performed on the recurrent lesion at a frequency of twice a week for six weeks using the apparatuses described above. There was a significant reduction in pain after treatment. The tumor marker carcinoembryonic antigen (CEA) level decreased after treatment. On CT images taken after treatment, the tumor site became a low density area which indicated necrosis. There were no side effects. These results suggest that further clinical study of SRH should be performed to clarify its advantages.

DOI： 10.18926/AMO/32638

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BACKGROUND: The association between sarcopenia and prognosis in patients with locally advanced non-small cell lung cancer (NSCLC) undergoing trimodality therapy, consisting of preoperative concurrent chemoradiotherapy and surgery, has not been reported. Therefore, we aimed to investigate the association of sarcopenia and fat mass with prognosis after trimodality therapy. METHODS: To assess sarcopenia, the psoas muscle mass was measured. Using computed tomography data, including third lumbar vertebra level images, psoas muscle mass and visceral and subcutaneous fat mass were measured. Additionally, body mass indices, and visceral/subcutaneous fat ratio, obtained by dividing the visceral fat index by the subcutaneous fat index, were calculated. We investigated the relationship between these parameters and overall survival. RESULTS: Ninety-nine eligible patients were included. In the univariate analysis, age, clinical stage, tumor location, psoas muscle index, and visceral/subcutaneous fat ratio were significant prognostic factors for overall survival (P = 0.008, P = 0.04, P = 0.04, P = 0.02, and P = 0.02, respectively). In the multivariate analysis, age and psoas muscle index were significant prognostic factors for overall survival (P = 0.01 and P = 0.03, respectively). The 5-year overall survival rates for the high and low psoas muscle index groups were 79.6% [95% confidence interval (CI), 67.1-94.5%] and 66.2% (95% CI, 54.1-81.1%), respectively; whereas, the 10-year overall survival rates were 61.9% (95% CI, 42.0-91.4%) and 25.3% (95% CI, 8.6-74.2%), respectively. CONCLUSION: Sarcopenia was related to poor overall survival in patients with locally advanced NSCLC undergoing trimodality therapy. Assessment of body composition prior to treatment may provide important information for formulating rational therapeutic strategies.

DOI： 10.1007/s10147-021-01927-7

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DOI： 10.1038/s41598-021-93955-6

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We intended to investigate whether muscle and adipose masses were associated with prognosis among patients with stage III non-small-cell lung cancer (NSCLC) who were undergoing chemoradiotherapy (CCRT). We retrospectively explored data of patients with stage III NSCLC who underwent definitive CCRT (≥ 60 Gy) between January 2004 and March 2018 at our hospital. We examined the relationship of overall survival (OS) with body mass index (BMI), skeletal muscle index (SMI), psoas muscle index (PMI), visceral adipose tissue index (VAI), subcutaneous adipose tissue index (SAI), and visceral-to-subcutaneous adipose tissue area ratio (VSR) using log-rank tests for the univariate analysis and Cox proportional hazard models for the multivariate analysis. Overall, 16, 32, and 12 patients had stage IIIA, IIIB, and IIIC NSCLC, respectively. The total radiotherapy dose ranged from 60 Gy/30 fractions to 66 Gy/33 fractions. In the univariate analysis, the performance status (PS), BMI, and SMI were associated with OS, whereas the PMI, VAI, SAI, and VSR were not. In the multivariate analysis, the PS and SMI were associated with OS. The hazard ratios and 95% confidence intervals were 2.91 and 1.28-6.64 for PS, and 2.36 and 1.15-4.85 for SMI, respectively. The 1, 3, and 5-year OS rates were 92.1%, 59.6%, and 51.0% in patients with high SMI, and 63.6%, 53.8%, and 17.9% in patients with low SMI, respectively. The SMI correlated with prognosis in our study population, whereas adipose mass did not. Therefore, sarcopenia should be considered while predicting the OS in such patients.

DOI： 10.1038/s41598-021-91449-z

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Palliative concurrent chemoradiotherapy (CCRT) is often administered to patients with stage III non-small cell lung cancer (NSCLC). We investigated the clinical outcomes of patients receiving palliative CCRT for NSCLC. Data of patients with NSCLC who underwent palliative CCRT (n=16), preoperative CCRT plus surgery (n=97), or definitive CCRT (n=48) were evaluated. In all groups, the concurrent chemotherapy regimens consisted of cisplatin and docetaxel. Rates of local control (LC), distant metastasis-free survival (DMFS), progression-free survival (PFS), overall survival (OS), and prognosis were compared. The 2-year rates of LC, DMFS, PFS, and OS in 16 patients who underwent palliative CCRT were 44.4%, 12.5%, 12.5%, and 18.8%, respectively. Univariate analysis showed that palliative CCRT was associated with poor LC (p<0.001), DMFS (p<0.001), PFS (p<0.001), and OS (p<0.001) outcomes in patients who completed CCRT as a preoperative treatment and poor LC (p=0.01), DMFS (p=0.003), PFS (p=0.04), and OS (p=0.004) outcomes in patients who were considered for definitive CCRT. Although there were some long-term survivors, the clinical outcomes of palliative CCRT were significantly inferior to those of the ideal treatments. Therefore, careful determination of the appropriate treatment indications and further studies are warranted.

DOI： 10.18926/AMO/62218

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The aim of this study was to investigate whether volumetric positron emission tomography (PET) parameters are prognostic predictors in stage III non-small cell lung cancer patients receiving definitive concurrent chemoradiotherapy (CCRT) with cisplatin/docetaxel. Cases involving definitive CCRT were reviewed retrospectively, and the maximum standardized uptake value, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were calculated. The relationships between these PET parameters and prognosis were analyzed. MTV and TLG were significant predictors of distant metastasis-free survival (DMFS) (p = 0.0003 and 0.0005, respectively) and progression-free survival (PFS) (p = 0.001 and 0.0007, respectively). The three-year DMFS rates in patients with low and high MTV were 13.3% and 64.6%, respectively, and the corresponding values in those with low and high TLG were 13.3% and 65.2%, respectively. The three-year PFS rates in patients with low and high MTV were 13.3% and 57.8%, respectively, and the corresponding values in patients with low and high TLG were 13.3% and 57.8%, respectively. However, MTV and TLG were not predictors of local control or overall survival. We demonstrated that volumetric PET parameters were predictors of patients receiving definitive CCRT. Our findings contradict the findings of previous reports and warrant further research to validate them.

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BACKGROUND: Stereotactic body radiation therapy (SBRT) is an established therapy for medically inoperable early-stage non-small cell lung cancer (NSCLC). Many elderly patients are medically inoperable owing to comorbidities. Therefore, SBRT may be a useful therapy for elderly patients. However, the application of SBRT for patients aged ≥ 80 years has not been completely elucidated. Therefore, this study aimed to assess the clinical utility of SBRT for elderly patients aged ≥ 80 years with pathologically proven early-stage NSCLC. METHODS: We retrospectively evaluated the data of patients aged ≥ 80 years with pathologically proven primary NSCLC who underwent SBRT at our institution between January 2009 and March 2020. Treatment outcomes and toxicities were analyzed. We used the Kaplan-Meier method to estimate survival curves and the log-rank test to compare the survival curves. We performed univariate and multivariate Cox regression analyses. p-values < 0.05 were regarded significant. RESULTS: Sixty-four patients (65 lesions) were included, and the median follow-up period was 38.7 (range 3.5-95.7) months. The median age was 82.9 (range 80.0-94.8) years. Sixteen patients were medically operable, and 48 patients were medically inoperable. The prescribed dose of SBRT was either 48 Gy in four fractions or 60 Gy in 10 fractions. The median survival time was 60.0 months (95% confidence interval, 43.5-71.1). The 1-, 3-, and 5-year local control, cancer-specific survival, progression-free survival, and overall survival rates were 98.4%, 98.4%, 81.0%, and 88.9%; 90.1%, 93.7%, 58.9%, and 68.3%; and 87.4%, 83.5%, 38.2%, and 47.5%, respectively. Multivariate analysis revealed that inoperability and solid nodules were the predictors of poor overall survival after SBRT in elderly patients. Two patients (3.1%) had grade 3 radiation pneumonitis, and one patient (1.6%) had grade 5 radiation pneumonitis. CONCLUSIONS: SBRT was feasible in patients aged ≥ 80 years with NSCLC. It achieved good local control with minimal toxicity. SBRT may be beneficial in elderly patients with early-stage NSCLC.

DOI： 10.1186/s13014-021-01769-7

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The purpose of the present study was to clarify whether positron emission tomography/computed tomography (PET/CT) volumetric parameters were prognostic predictors of non-small cell lung cancer (NSCLC) treatment in patients who had undergone preoperative concurrent chemoradiotherapy (CCRT) and surgery. In the present study, retrospectively surveyed the data of patients with NSCLC who underwent preoperative CCRT and surgery at Okayama University Hospital (Okayama, Japan) between April 2006 and March 2018. The maximum standardized uptake value (SUVmax) and volumetric parameters, including metabolic tumor volume (MTV) and total lesion glycolysis (TLG), were calculated using PET/CT and the percentage decrease (Δ) in each parameter value post-CCRT. The SUVmax threshold for defining MTV was set at 2.5. Furthermore, the association between survival and PET parameter values was analyzed. A total of 52 patients were included in the present study. The median follow-up period was 50.65 months. In univariate analysis, ΔTLG was identified to be a significant predictor of progression-free survival (PFS; P=0.03). The 5-year PFS rates were 48.6 and 76.6% for patients with low ΔTLG and high ΔTLG, respectively. High ΔTLG was indicative of a higher overall survival rate (P=0.08). The present results suggest that ΔTLG calculated using PET/CT is a prognostic predictor of NSCLC treated using preoperative CCRT and surgery, and may help physicians determine treatment strategies.

DOI： 10.3892/mco.2021.2235

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AIM: To investigate whether muscle and adipose mass are associated with radiation pneumonitis (RP) in patients with non-small cell lung cancer undergoing preoperative concurrent chemoradiotherapy. PATIENTS AND METHODS: We calculated body mass index and determined skeletal muscle, psoas muscle, visceral adipose tissue (VAI), and subcutaneous adipose tissue indices, and visceral-to-subcutaneous adipose tissue area ratio for patients using computed tomography. We examined their relationship with grade 2 or more RP. RESULTS: Among 94 patients, 28 experienced grade 2 or more RP. On multivariate analysis, only VAI was associated with grade 2 or more RP (all p=0.026). The 6-month incidence rates of grade 2 or more RP were 21.4% and 36.8% in patients with VAI <39 and ≥39 cm 2 /m 2 , respectively. CONCLUSION: High visceral adipose mass is associated with grade 2 or more RP in patients undergoing preoperative concurrent chemoradiotherapy. Measuring visceral adipose mass may help to predict RP occurrence. Further studies are needed to validate our findings.

DOI： 10.21873/cdp.10009

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BACKGROUND: Radiation pneumonitis (RP) is a major pulmonary adverse event of chest radiotherapy. The PACIFIC trial that identified durvalumab as an effective subsequent-line therapy after concurrent chemoradiotherapy (CCRT) found that patients with grade 2 or higher RP may have to be excluded from treatment under certain criteria. The purpose of this study was to investigate the relationship between grade ≥2 RP and the parameters of dose-volume histograms after CCRT with cisplatin/docetaxel for stage III non-small cell lung cancer and conduct a subset analysis of severe RP that can lead to the permanent discontinuation of treatment per the PACIFIC trial criteria to help determine treatment strategy. METHODS: We calculated the percentage of the lung volume received at least 5 Gy (V5) and 20 Gy (V20), the mean lung dose (MLD), and the lung volume spared from a 5 Gy dose (VS5) to the total lung volume. Factors affecting the incidence of grade ≥2 RP were identified; severe RP was defined as grade ≥3 as well as grade 2 RP that required ≥10 mg prednisolone for at least 12 weeks. RESULTS: This study included 45 patients. On univariate analysis, all parameters and total lung volume were found to be significant predictors of grade ≥2 RP (P = .001, .003, .03, .004, and .02, respectively). On multivariate analysis, V20 was a significant predictive factor of grade ≥2 RP (P = .007). Severe RP developed in 6 of 37 patients (16.2%) whose V20 values were 35% or lower. On univariate analysis, only V20 was a significant predictor of severe RP in these patients (P = .01). CONCLUSIONS: The best approach to reduce the rate of grade ≥2 RP is to maintain the V5, V20, MLD, and VS5 as low as possible during radiotherapy planning in patients receiving definitive CCRT with cisplatin/docetaxel.

DOI： 10.1002/cam4.3093

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BACKGROUND: The relationship between lung dose-volume histogram (DVH) parameters and radiation pneumonitis (RP) associated with induction concurrent chemoradiotherapy (CCRT) followed by surgery in patients with non-small cell lung cancer (NSCLC) is unclear, particularly when concerning irradiation of the whole lung prior to resection. We performed this study to identify factors associated with grade ≥ 2 RP in such patients. METHODS: Patients who received induction CCRT (chemotherapy: cisplatin and docetaxel; radiotherapy: 46 Gy/23 fractions) between May 2003 and May 2017 were reviewed. The mean lung dose (MLD) and the percentage of the lung volume that received ≥5 Gy (V5) and ≥ 20 Gy (V20) were calculated. Factors associated with the development of grade ≥ 2 RP were analyzed. RESULTS: One hundred and eight patients were included in this study, 34 (31.5%) of whom experienced grade ≥ 2 RP. A V20 ≥ 21%, an MLD ≥10 Gy, and a lower lobe tumor location were significant predictors of grade ≥ 2 RP on univariate analysis (p = 0.007, 0.002, and 0.004, respectively). Moreover, an MLD ≥10 Gy and lower lobe location were significant predictors of grade ≥ 2 RP on multivariate analysis (p = 0.026 and 0.0043, respectively). The cumulative incidence rates of grade ≥ 2 RP at 6 months were 15.7 and 45.6% in patients with MLDs < 10 Gy and ≥ 10 Gy, respectively, and were 23.5 and 55.6% in patients with upper/middle lobe- vs. lower lobe-located tumors, respectively. CONCLUSIONS: MLD and lower lobe location were predictors of grade ≥ 2 RP in patients who received induction CCRT. It is necessary to reduce the MLD to the greatest extent possible to prevent the occurrence of this adverse event.

DOI： 10.1186/s12885-019-6359-9

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BACKGROUND: Severe complications, such as eye damage and dysfunciton of salivary glands, have been reported after radiotherapy among patients with head and neck cancer. Complications such as visual impairment have also been reported after proton therapy with pencil beam scanning (PBS). In the case of PBS, collimation can sharpen the penumbra towards surrounding normal tissue in the low energy region of the proton beam. In the current study, we examined how much the dose to the normal tissue was reduced by when intensity-modulated proton therapy (IMPT) was performed using a multi-leaf collimator (MLC) for patients with maxillary sinus cancer. METHODS: Computed tomography findings of 26 consecutive patients who received photon therapy at Okayama University Hospital were used in this study. We compared D2% of the region of interest (ROI; ROI-D2%) and the mean dose of ROI (ROI-mean) with and without the use of an MLC. The organs at risk (OARs) were the posterior retina, lacrimal gland, eyeball, and parotid gland. IMPT was performed for all patients. The spot size was approximately 5-6 mm at the isocenter. The collimator margin was calculated by enlarging the maximum outline of the target from the beam's eye view and setting the margin to 6 mm. All plans were optimized with the same parameters. RESULTS: The mean of ROI-D2% for the ipsilateral optic nerve was significantly reduced by 0.48 Gy, and the mean of ROI-mean for the ipsilateral optic nerve was significantly reduced by 1.04 Gy. The mean of ROI-mean to the optic chiasm was significantly reduced by 0.70 Gy. The dose to most OARs and the planning at risk volumes were also reduced. CONCLUSIONS: Compared with the plan involving IMPT without an MLC, in the dose plan involving IMPT using an MLC for maxillary sinus cancer, the dose to the optic nerve and optic chiasm were significantly reduced, as measured by the ROI-D2% and the ROI-mean. These findings demonstrate that the use of an MLC during IMPT for maxillary sinus cancer may be useful for preserving vision and preventing complications.

DOI： 10.1186/s13014-019-1405-y

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Cutaneous angiosarcoma is a rare aggressive malignant tumor. Concurrent chemoradiation (CCRT) with maintenance chemotherapy using taxanes is one of the primary treatments. The aim of the present study was to retrospectively analyze the efficacy of CCRT with maintenance chemotherapy using taxanes in localized angiosarcoma of the scalp without cervical lymph node metastases. A total of 19 patients treated with radiation therapy for localized angiosarcomas of the scalp without cervical lymph node metastases were enrolled. The overall survival (OS), progression-free survival (PFS), and local control (LC) rates were calculated using Kaplan-Meier analysis. Univariate analyses were performed for various potential prognostic factors for OS, PFS, and LC. The median radiation dose was 70 Gy (range, 60-70 Gy), and the fractional dose was 2 Gy. Radiation therapy alone, radiation therapy + interleukin-2, surgery + CCRT with maintenance chemotherapy, CCRT with maintenance chemotherapy, and CCRT without maintenance chemotherapy were administered to 2, 4, 2, 9 and 2 patients, respectively. The 1- and 3-year OS, PFS, and LC rates were 88 and 52%, 47 and 33%, and 74 and 56%, respectively. CCRT with maintenance chemotherapy and surgery were significant prognostic factors for PFS (P=0.036 and 0.025, respectively). Therefore, CCRT with maintenance chemotherapy using taxanes might be effective in treating localized angiosarcomas of the scalp without cervical lymph node metastases.

DOI： 10.3892/mco.2019.1918

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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This study aimed to compare the interobserver variabilities in magnetic resonance imaging (MRI)/computed tomography (CT) fusion image-based post-implant dosimetry of permanent prostate brachytherapy (PPB) between 1.5-T and 3.0-T MRI. The study included 60 patients. Of these patients, 30 underwent 1.5-T MRI and CT 30 days after seed implantation (1.5-T group), and 30 underwent 3.0-T MRI and CT 30 days after seed implantation (3.0-T group). All patients received PPB alone. Two radiation oncologists performed MRI/CT fusion image-based post-implant dosimetry, and the interobserver variabilities of dose-volume histogram (DVH) parameters [dose (Gy) received by 90% of the prostate volume (prostate D90)], percentage of the prostate volume receiving at least the full prescribed dose (prostate V100), percentage of the prostate volume receiving at least 150% of the prescribed dose (prostate V150), dose (Gy) received by 5% of the urethral volume (urethral D5) and the urethral volume receiving at least 150% of the prescribed dose (urethral V150)] were retrospectively estimated using the paired Student's t test and Pearson's correlation coefficient. The Pearson's correlation coefficients of all DVH parameters were higher in the 3.0-T group than in the 1.5-T group (1.5-T vs 3.0-T: prostate D90, 0.65 vs 0.93; prostate V100, 0.62 vs 0.82; prostate V150, 0.97 vs 0.98; urethral D5, 0.92 vs 0.93; and urethral V150, 0.88 vs 0.93). In the paired Student's t test, no significant differences were observed in any of the DVH parameters between the two radiation oncologists in the 3.0-T group (0.068 ≤ P ≤ 0.842); however, significant differences were observed in prostate D90 (P = 0.004), prostate V100 (P = 0.011) and prostate V150 (P = 0.002) between the oncologists in the 1.5-T group. The interobserver variability of DVH parameters in the MRI/CT fusion image-based post-implant dosimetry analysis of brachytherapy was lower with 3.0-T MRI than with 1.5-T MRI.

DOI： 10.1093/jrr/rrz012

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To clarify the relationship between dose-volume histogram (DVH) parameters and radiation pneumonitis (RP) after surgery in cases of non-small cell lung cancer (NSCLC) treated with induction concurrent chemoradiotherapy (CCRT). Patients with NSCLC treated with induction CCRT (chemotherapy: cisplatin and docetaxel; radiotherapy: 2.0 Gy fractions once daily for a total of 46 Gy) before surgery were reviewed. We calculated the percentage of lung volume receiving at least 20 Gy (V20) and the mean lung dose (MLD) for the total lung volume and the lung remaining after resection. Factors affecting the incidence of RP at grade 2 or higher (≥ G2 RP) were analyzed. Eighteen of 49 patients (37%) experienced ≥G2 RP. The V20 and MLD for the lung remaining after resection (V20r and MLDr) were significant predictors according to the multivariate analysis (p=0.007 and 0.041, respectively). The incidence of ≥G2 RP was 8% in patients with V20r<10%, and 13% in patients with MLDr<5.6 Gy, respectively. The optimal approach to reduce the rate of postoperative RP in patients with induction CCRT for NSCLC is to keep the V20r below 10% and/or the MLDr below 5.6 Gy in the radiotherapy planning.

DOI： 10.18926/AMO/56249

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：(公社)日本アイソトープ協会  

放射活性のあるヨウ素を用いてコバルト-ブレオマイシンを標識し、その腫瘍局在特性について明らかにした。本検討では、担がんマウスに3-125I-ヨードベンジルコバルト-ブレオマイシン(3-125I-Bz-Co-BLM)を注入し、全身オートラジオグラムにより検出を行った。その結果、3-125I-Bz-Co-BLMを注入したマウスにおいて、全て同一の結果が認められ、腫瘍領域(背、大腿、頸部)、腎臓、肝臓および顔面への3-125I-Bz-Co-BLMの蓄積が確認された。本検討から、全身オートラジオグラムにより、3-125I-Bz-Co-BLMの腫瘍親和性は、腎臓および肝臓を除き、正常臓器より高いという従来の結果を裏付けることが確認された。

DOI： 10.3769/radioisotopes.66.307

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DOI： 10.1007/978-981-10-0719-4_36

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INFORMA HEALTHCARE  

This article is a redissemination of the previous Japanese Quality Assurance Guide guidelines. Specific absorption rate and temperature distribution were investigated with respect to various aspects including metallic implant size and shape, insertion site, insertion direction, blood flow and heating power, and simulated results were compared with adverse reactions of patients treated by radio frequency capacitive-type heating. Recommended guidelines for safe heating methods for patients with metallic implants are presented based on our findings.

DOI： 10.3109/02656736.2013.774059

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：John Wiley and Sons Ltd  

Purpose: A 3.0-T MRI phantom (called the CAGN-3.0T phantom) having human-equivalent relaxation times and human-equivalent conductivity was developed. Methods: The ingredients of the phantom are carrageenan (as a gelatinizer), agarose (as a T2-relaxation modifier), GdCl3 (as a T1-relaxation modifier), NaCl (as a conductivity modifier), and NaN3 (as an antiseptic). Numerous samples with varying concentrations of agarose, GdCl3, and NaCl were prepared, and T 1 and T2 values were measured using 3.0-T MRI. Results: The T1 values of the CAGN-3.0T phantom were unaffected by NaCl, while the T2 values were only slightly affected. Based on the measured data, empirical formulae were devised to express the relationships between the concentrations of agarose, GdCl3, and NaCl and the relaxation times. The formula for expressing the conductivity of the CAGN-3.0T phantom was obtained. Conclusions: By adjustments to the concentrations of agarose, GdCl3, and NaCl, the relaxation times and conductivity of almost all types of human tissues can be simulated by CAGN-3.0T phantoms. The phantoms have T1 values of 395-2601 ms, T2 values of 29-334 ms, and conductivity of 0.27-1.26 S/m when concentrations of agarose, GdCl3, and NaCl are varied from 0 to 2.0 w/w%, 0 to 180 μmol/kg, and 0 to 0.7 w/w%, respectively. The CAGN-3.0T phantom has sufficient strength to replicate the torso without using reinforcing agents, and can be cut with a knife into any shape. © 2013 American Association of Physicists in Medicine.

DOI： 10.1118/1.4790023

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IOS PRESS  

In proton density-weighted (PDW) MR imaging, the patterns of signal intensity vary depending on the imaged material, and change with the flip angle (FA) applied to the imaged material. The correlation between the pre-determined FA and the actual FA applied to imaged objects was investigated using 4 types of phantoms having different dielectric properties. PDW images were acquired using the spin-echo (SE) method and different pre-determined FA. Dependency of the signal intensity distribution in the phantom on the pre-determined FA differed among phantoms: patterns for water and 0.402 w/w% saline solution phantoms changed with the pre-determined FA, whereas those for olive oil and 4.02 w/w% saline solution phantoms were barely affected by the pre-determined FA. Causes of these phenomena were considered to be the differences between the pre-determined FA and the actual FA among the phantoms; differences were also influenced by the positioning of the phantom. Our study showed that the actual FA in the phantom is greater than the pre-determined FA in high permittivity media, whereas it is reduced by an increased conductivity of the media.

DOI： 10.3233/XST-130375

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Hypoxia-inducible factor-1 alpha (HIF-1 alpha) has been found to enhance tumor invasion and metastasis, but no study has reported its action in esophageal carcinoma. The goal of this study was to explore the probable mechanism of HIF-1 alpha in the invasion and metastasis of esophageal carcinoma Eca109 cells in vitro and in vivo. mRNA and protein expression of HIF-1 alpha, E-cadherin and matrix metalloproteinase-2 (MMP-2) under hypoxia were detected by RT-PCR and Western blotting. The effects of silencing HIF-1 alpha on E-cadherin, MMP-2 mRNA and protein expression under hypoxia or normoxia were detected by RT-PCR and Western blotting, respectively. The invasive ability of Eca109 cells was tested using a transwell chambers. We established an Eca109-implanted tumor model and observed tumor growth and lymph node metastasis. The expression of HIF-1 alpha, E-cadherin and MMP-2 in xenograft tumors was detected by Western blotting. After exposure to hypoxia, HIF-1 alpha protein was up-regulated, both mRNA and protein levels of E-cadherin were down-regulated and MMP-2 was up-regulated, while HIF-1 alpha mRNA showed no significant change. SiRNA could block HIF-1 alpha effectively, increase E-cadherin expression and inhibit MMP-2 expression. The number of invading cells decreased after HIF-1 alpha was silenced. Meanwhile, the tumor volume was much smaller, and the metastatic rate of lymph nodes and the positive rate were lower in vivo. Our observations suggest that HIF-1 alpha inhibition might be an effective strategy to weaken invasion and metastasis in the esophageal carcinoma Eca109 cell line.

DOI： 10.18926/AMO/48964

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Magnetic resonance imaging (MRI) visualization of metallic stent lumens is possible if the stent structure counteracts eddy currents in the lumen induced by the radio frequency magnetic field, B-1. To examine the effectiveness of various stent designs in counteracting eddy currents, we anchored eight copper stent models and 2 commercially available nickel-titanium alloy (Nitinol) stents in a gel phantom, perpendicular or parallel to the direction of B-1. A mesh stent lumen showed hypointensity irrespective of its alignment relative to B-1. A solenoid stent lumen showed hypointensity with the stent axis parallel to B-1, but it had the same signal intensity as outside the lumen when perpendicular to B-1. A Moebius stent lumen showed no signal reduction, irrespective of alignment relative to B-1. Lumens of the commercially available stents showed hypointensity regardless of alignment relative to B-1. Computer simulation revealed that the signal intensities of the stents corresponded to magnetic flux densities of B-1 in the stents, which are modified by the structure of the stent. While in vivo MRI viewing of a Moebius stent lumen is likely possible regardless of axis alignment, inherent structural weakness may be problematic. As a more practical choice, the solenoid stent is easier to manufacture and generates no hypointensive signal when the axis is parallel to B-0.

DOI： 10.18926/AMO/48559

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Objective. High-dose-rate (HDR) brachytherapy using a customized mold is a minimally invasive treatment for oral cancer; however, it is difficult to use this technique for buccal and lip cancers involving the commissura labiorum, owing to its anatomic form. The purpose of this study was to introduce an improved customized mold consisting of 2 pieces to allow the fixation of molds to these sites.
Study design. Five patients with buccal carcinoma and 1 patient with lip carcinoma were treated with this technique after external beam radiotherapy. One patient with neck metastasis underwent both neck dissection and partial tumor resection before HDR brachytherapy.
Results. At the end of the follow-up period, 5 patients had no tumor recurrence, and 1 patient had suffered local recurrence.
Conclusions. Our technique is a viable therapeutic option for patients with buccal and lip carcinomas for whom the therapeutic modalities are limited by age, performance status, and other factors. (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;113:118-125)

DOI： 10.1016/j.tripleo.2011.06.038

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS  

Purpose: A 3.0-T MRI phantom having human-tissue-equivalent relaxation times was developed.
Methods: The ingredients of the phantom are carrageenan (for gelatinization), GdCl(3) (as a T(1)-relaxation modifier), agarose (as a T(2)-relaxation modifier), and NaN(3) (as an antiseptic agent). Numerous samples with varying concentrations of GdCl(3) and agarose were prepared, and T(1) and T(2) were measured using 3.0-T MRI.
Results: Relaxation times of the phantom samples ranged from 395 to 2601 ms for T(1) values and 29 to 334 ms for T(2) values. Based on the measured results, empirical formulae were devised to express the relationships between the concentrations of relaxation modifiers and relaxation times.
Conclusions: Adjustment of GdCl(3) and agarose concentrations allows arbitrary setting of relaxation times, and the creation of a phantom that can mimic relaxation times of human-tissue. Carrageenan is considered the most suitable as a gelling agent for an MRI phantom, as it permits the relatively easy and inexpensive production of a large phantom such as for the human torso, and which can be easily shaped with a knife. (C) 2011 American Association of Physicists in Medicine. [DOI: 10.1118/1.3656077]

DOI： 10.1118/1.3656077

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コバルト-ブレオマイシンの腫瘍集積性を損なうことなく、本化合物に放射性ヨードを付加させる研究を行った。コバルト-ブレオマイシンデメチル-A2はブレオマイシンデメチル-A2溶液に塩化コバルトを加えて合成し、他方、3-125I-ヨードベンジルアルコールは非放射性のコバルト-ブレオマイシンのヨード原子を125Iで置換して標識した。コバルト-ブレオマイシンにP2I4を作用させて3-125I-ヨードベンジルアイオダイドを作った。3-125I-ヨードベンジル-コバルト-ブレオマイシンはコバルト-ブレオマイシンデメチル-A2に3-125I-ヨードベンジルアイオダイドを結合させることで合成した。3-125I-ヨードベンジルーコバルトブレオマイシンを担癌マウスに静注し、体内分布を調べたところ、コバルト-ブレオマイシンは腫瘍組織に、腎臓と肝臓を除く他の正常組織よりも多く集積していた。以上より、コバルト-ブレオマイシンはかなり強い腫瘍親和性を保持していることが示唆された。

DOI： 10.3769/radioisotopes.60.1

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CiNii Article

CiNii Books

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本ハイパーサーミア学会  

8MHz誘電型外部加温におけるステント装着患者の安全加温についての指針を以下に示す。1.食道にステントを挿入された患者の加温は、禁忌である。2.血管に挿入されたステントを装着した患者の加温は、原則安全に加温できる。3.血管以外に挿入されたステントを装着した患者の加温は、原則禁忌である。4.胆管にステントを挿入された患者の加温は、シミュレーション結果と比較しても、原則安全に加温できると考えられる。ただし、胆管ステントが閉塞した患者に対しては要注意である。初回加温時のパワー上昇については、患者の様子を観察しながら行うこと。5.ステントが長ければ長い程、過剰な温度上昇が発生する可能性がある。6.ステントの直径が大きければ大きい程、過剰な温度上昇が発生する可能性がある。7.ステントの軸方向が電界の方向に近い程、過剰な温度上昇が発生する可能性がある。(著者抄録)

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Language：Japanese   Publisher：岡山医学会  

放射線外照射治療を行った孤立性の限局性脈絡膜血管腫4例(全例男性、平均48.0歳)について報告した。眼科的症状は視力低下2例、中心暗点、変視症各1例で、漿液性網膜剥離を3例に認めた。X線のエネルギーは4MV:3例、10MV:1例、照射方法は左右対向二門照射1例、同側一門照射3例、1回線量2Gyで総線量は20Gy、照射期間は14〜16日であった。治療効果は、漿液性網膜剥離は3例全例で改善し、全例で視力・症状の改善を認めた。観察期間は3.7〜58.5ヵ月で、最も短い1例を除き腫瘍の縮小を認めた。早期合併症は視界のゆがみを1例に認めたが経過観察中に改善し、晩期合併症はなく、全例で再発は認めていない。脈絡膜血管腫に対する20Gy外照射は安全かつ有効な治療法と考えられた。

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Language：English   Publishing type：Research paper (international conference proceedings)  

Purpose: Four‐dimensional radiotherapy(4DRT) using respiratory gating system and other techniques to control patient breathing are useful for stereotactic body radiotherapy. However, treatment time in 4DRT also will be elongated by the degree of synchronization. In such a situation, the synchronization, internal margin and the target localization might have effects on the target as to tumor control probability. The purpose of this study was to investigate the relationship of biological effective dose(BED) between respiratory motion patterns, gate parameters and target positioning accuracies using a model based simulation. Method and Materials: A virtual square of dimension 512×512 matrices of interest FOVs were used in this simulation. The pseudo tumor was set on the virtual matrices. The motion of the sphere was modeled by a simple cosine curve, and a sinusoidal breathing curve simulated by mathematical equation. A minimal time interval and various motion parameters such as amplitudes, target volumes, and gate parameters were set in this simulation. Then the probability densities of the target in each parameters ware calculated. Using calculated data sets, BEDs for the target were determined by changing two modeled curves of motion, margins, and gate parameters, respectively. Results: Various patterns such as tumor size, motion function, amplitude, gate parameters and size of margins of BEDs for the target were calculated. The result showed that it depended upon target volume and gate parameter. The approximate equation of optimal internal margins for target volume of 99% BED coverage was also determined. Conclusion: In this study, we have calculated BED based optimal internal margins of the moving target. This study also showed a method of 4DRT taking into account BED. Further research is in progress to evaluate the effect of elongation of patient irradiation and shape of the target by gate parameter settings. © 2010, American Association of Physicists in Medicine. All rights reserved.

DOI： 10.1118/1.3468943

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Language：Japanese   Publisher：金原出版(株)  

Oligo-recurrenceの乳癌骨転移に対する放射線治療の意義を遡及的に検討した。1998年1月〜2003年3月までに乳癌原発巣が制御されており、放射線治療を受けた骨転移が単一部位の再発であった11例について調査した結果、再発時年齢(中央値)は49歳、再発までの期間(中央値)は44ヵ月、再発部位は腰椎4例、骨盤骨3例、その他4例であり、放射線治療における総線量(中央値)は40Gy、全治療期間(中央値)は28日、経過観察期間(中央値)は56ヵ月であった。11例中10例では照射部位の疼痛が制御され、3年生存率77.8%、5年生存率58.4%と長期生存しており、疼痛が再燃した1例は照射線量の最も低い症例であった。長期間の疼痛緩和には高線量の放射線治療に意義があると考えられた。

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Purpose: We conceived a 2-stage heating method to dissolve the ingredients of magnetic resonance (MR) imaging phantoms to overcome issues of uneven quality in conventional MR imaging phantoms, and we evaluated uniformity and the reproducibility of our method. Methods: We used a 3-liter capacity, column-shaped, enamel-coated porcelain container to produce a muscle-equivalent phantom (diameter, 160 mm
height, 100 mm
volume, 2 liters). The phantom contained: 1) carrageenan as a gelling agent
2) agarose as a T2 modifier
3) GdCl3 as a T1 modifier
4) NaN3 as an antiseptic
and 5) distilled water. We applied both direct heating and 2-stage heating of pre-soaked materials. We placed powdered materials directly into hot water for direct heating but soaked them in water one day before use (post-swelling) in 2-stage heating. The materials in the container were melted in a silicone oil bath of 120 or 140°C under various conditions, then allowed to gel by natural cooling. We observed the resulting gel phantoms macroscopically using a CCD camera and evaluated their uniformity by microscopy and MR imaging. Results: We found it necessary to raise the temperature inside the phantom to 100.0°C, to produce a uniform gel with stable homogeneity and few bubbles. Use of an enamel-coated porcelain container required setting the temperature of the oil bath at 140°C. Conclusion: A uniform and reproducible human tissue-equivalent phantom with few bubbles can be manufactured using our 2-stage heating method, which employs pre-soaking in a silicone oil bath at 140°C for 30 min. We then added the swollen carrageenan to the agarose solution, which heating the temperature to 140°C for 30 min while continuously stirring at 120 rpm, following with natural cooling.

DOI： 10.2463/mrms.7.131

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身体深部にRFエネルギーを収束するために、身体周囲にInductive Aperture-Type Applicator(IATA)を配置する方法を提案する。この方法においては、脂肪層を過熱することなく、身体中心部の発熱を最大にすることが、有限要素法による計算によって示された。直径0.30m高さ0.54mの脂肪-筋肉円柱状ファントムの周囲に開口面の高さが0.20m、または0.30mのIATAで取り囲み、それに13.56MHz、または27.12MHzの高周波電流を流した場合、計算結果は筋肉中心部の発熱が最大となることを示した。中心部の発熱は辺縁の極大値に比較して1.11〜1.27倍になった。脂肪の発熱は筋肉中心部の発熱に比較して20%程度にとどまった。(著者抄録)

DOI： 10.3191/thermalmed.23.133

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

O-6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme whose expression is controlled by its promoter methylation. A cell that expresses a low amount of MGMT is known to be more sensitive to the antiproliferative effects of alkylating agents. We have previously shown that the colorectal cancer patients treated with 5-fluorouracil (5-FU) as adjuvant chemotherapy had a better prognosis when the tumor revealed hypermethylation in its MGMT promoter. Therefore, we sought to investigate the relationship between the expression levels of MGMT and the antitumor effect of 5-FU in vitro by using two colon adenocarcinoma and four oral cancer cell lines with a variety of MGMT expression. We also investigated the effects of MGMT depletion by O-6-benzylguanine (O-6-BG), a potent inhibitor of MGMT. The 5-FU treatment uniformly depleted protein and mRNA expression of MGMT in all cell lines examined. Cell lines expressing low levels of MGMT were sensitive to 5-FU. On the other hand, cells expressing high levels of MGMT were less sensitive to 5-FU. The 5-FU treatment exhibited a better antiproliferative effect on the cells expressing high levels of MGMT by the pretreatment of O-6-BG. Depletion of MGMT by O-6-BG enhanced the antitumor effect of 5-FU. Assessment of the levels of MGMT expression in cancer cells and the control of its expression could contribute to the effective chemotherapy by 5-FU especially in patients who previously were considered as low-responsive individuals whose tumors have high levels of MGMT.

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We attempted to find a specific antigen of oral squamous cell carcinoma (SCC) cells that could be safely applied to gene therapy in the conservative clinical treatment of oral cancer. We performed subtraction using normal human keratinocyte cells, followed by selection using four oral SCC cell lines. We isolated three clones from poorly differentiated SCC cells and four from well-differentiated SCC cells. These seven clones adsorbed to the oral SCC cells at rates 10-100 times those of normal human keratinocyte cells. The three clones from the poorly differentiated SCC cells showed the same peptide sequence (LAPRTHP). Of the four clones from the well-differentiated SCC cells, three showed the same peptide sequence (FGTLPGT) and the fourth showed a different one (VTPNSTP). Each peptide sequence may recognize the material that exists specifically on the oral SCC cell cortex. We can expect applications not only for tumor-targeting treatment using a gene therapy virus vector but also for diagnosis using, as a tumor marker, the peculiar SCC surface material that these peptides recognize.

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We investigated the safety and efficacy of alternative and concurrent chemoradiotherapy with 5-FU/CDGP for head and neck cancer. From January 2003 to August 2005, 19 patients with head and neck squamous cell carcinoma were treated in our institution. Alternative chemoradiotherapy (ACRT) was performed for 8 cases of nasopharyngeal cancer. Concurrent chemoradiotherapy (CCRT) was performed for 11 cases of other head and neck cancer. Median total dose of radiotherapy was 63Gy. ACRT consisted of 5-FU at a dose of 500mg/m2 on days 1-5 and 28-32 and CDGP at a dose of 60mg/m2 on days 6 and 33. CCRT consisted of 5-FU at a dose of 500mg/m2 on days 1-4 and 28-31 and CDGP at a dose of 60mg/m2 on days 5 and 32. Median follow-up periods was 13 months. CR+PR was admitted in five cases (63%) with ACRT, and in 9 cases (82%) with CCRT. Non-hematological adverse effects of grade 3 were admitted in eight cases (100%) of ACRT, and in 9 cases (82%) of CCRT. Chemoradiotherapy attained good results and non-hematological adverse effects were able to be managed by preserved treatment. © 2006, Japan Society for Head and Neck Cancer. All rights reserved.

DOI： 10.5981/jjhnc.32.378

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Language：Japanese   Publisher：金原出版(株)  

皮膚原発悪性リンパ腫14症例を対象に,外照射の治療成績を検討した.B細胞系,T細胞系が各々7例であった.全生存率は2年88.9%,5年47.6%で,非再発生存率は2年55.6%,5年27.8%であった.照射後の再発は7例(50%)にみられ,B細胞系が2例(28.6%),T細胞系が5例(71.4%)で,T細胞系再発5例の80%に照射野内再発を認めた.再発後,4例に放射線治療を追加したところ,3例は生存中である.早期合併症は1例に両手足腫脹,両手関節部びらん,口唇炎,顔周囲皮膚炎を認め,照射を休止した.晩期合併症は1例に難治性放射線皮膚潰瘍を認め,下肢切断に至った.非再発生存率における有意な予後因子はリンパ節浸潤なし,初発時乳酸脱酸素酵素正常,初発,単一の照射部位数であった.皮膚原発悪性リンパ腫に対する放射線治療は再照射,即ち同一部位への複数回照射を行う頻度が高く,晩期合併症にも留意した照射が肝要だと思われた

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOCIETY NUCLEAR MEDICINE  

It is a diagnostic problem to distinguish thymic rebound or rebound thymic hyperplasia front thymic malignancy, but it is frequently made more difficult because most patients have had previous malignancies. Recently we evaluated a six-year-old girl with thymic rebound after chemotherapy for lymphoma, by both gallium-67 and thallium-201 scans. On gallium-67 scan, intensive uptake was seen in the anterior mediastinum. CT revealed a triangular-shaped, homogeneous mass in the anterior mediastinum. On early scan of thallium-201 study, slight accumulation was seen in the anterior mediastinum and was enhanced in delayed scans. Considering the clinical state and imaging results, thymic rebound after chemotherapy was the most likely diagnosis, and follow-up observation was done without therapy. During the course, there were no signs of relapse. Some reports have described both positive and negative thallium-201 accumulation in thymic rebound. Although more experience with similar cases is necessary, it is likely that thallium-201 also tends to accumulate in thymic rebound as well as gallium-67.

DOI： 10.1007/BF02985630

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Language：Japanese   Publisher：金原出版(株)  

症例1:51歳男.生検で悪性胸膜中皮腫と診断され,右胸膜外肺全摘術を施行した.術後は右胸腔へ放射線治療を行い,現在も生存中である.症例2:57歳男.左胸水貯留を認め,胸腔鏡下胸膜生検術で悪性胸膜中皮腫と診断された.左胸膜外肺全摘術を施行し,術後は左胸腔へ放射線治療を行った.術後7ヵ月に胸水中及び血中のヒアルロン酸高値を認め,再発が疑われ,その後,全身状態悪化で死亡した.両症例共に,急性有害反応でgrade 1の食道炎及び皮膚炎とgrade 2の低アルブミン血症が見られた

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The DNA repair enzyme, O-6-methylguanine-DNA methyltransferase (MGMT) modulates the effectiveness of alkylating agents. However, the relationship between MGMT and the sensitivities to other agents has not been explored. In the present study, the association between MGMT expression and the cellular sensitivity to the platinum agent, CDDP was examined in four human oral cancer cell tines. CDDP depleted MGMT protein and mRNA levels in all four cell tines. Two cell lines with low MGMT expression were sensitive to an alkylating agent, N-methyl-N'-nitro-N-nitrosoguanidine and CDDP, whereas two other cell tines with high MGMT expression were resistant to both agents. Furthermore, the addition of the MGMT inhibitor, O-6-benzylguanine (O-6-BG), invariably enhanced CDDP sensitivity. CDDP depleted MGMT expression, and CDDP sensitivity was enhanced by O-6-BG. These results provide valuable information about the relationship between MGMT expression and CDDP sensitivity in oral cancer chemotherapy. (c) 2005 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.oraloncology.2005.05.011

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS  

We previously developed two new MRI phantoms (called the CAG phantom and the CAGN phantom), with T1 and T2 relaxation times equivalent to those of any human tissue at 1.5 T. The conductivity of the CAGN phantom is equivalent to that of most types of human tissue in the frequency range of 1 to 130 MHz. In this paper, the relaxation times of human tissues are summarized, and the composition of the corresponding phantoms are provided in table form. The ingredients of these phantoms are carrageenan as the gelling agent, GdCl3 as a T1 modifier, a-arose as a T2 modifier, NaCl (CAGN phantom only) as a conductivity modifier, NaN3 as an antiseptic, and distilled water. The phantoms have T1 values of 202-1904 ms and T2 values of 38-423 ms when the concentrations of GdCl3 and agarose are varied from 0-140 mu mol/kg, and 0%-1.6%, respectively, and the CAGN phantom has a conductivity of 0.27-1.26 S/m when the NaCl concentration is varied from 0%-0.7%. These phantoms have sufficient strength to replicate a torso without the use of reinforcing agents, and can be cut by a knife into any shape. We anticipate the CAGN phantom to be highly useful and practical for MRI and hyperthermia-related research. (9) 2005 American Association of Physicists in Medicine.

DOI： 10.1118/1.2047807

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

We speculated whether or not the expression level of telomerase reverse transcriptase (hTERT) would be modulated by agents targeting epigenetics in oral cancer cell lines. Although hTERT is known to be targeted by epigenetic changes, it remains unclear how chemoagents targeting epigenetics work on hTERT transcription. In the present study, the epigenetic effects of the histone deacetylase (HDAC) inhibitor FR901228 on hTERT transcription in oral cancer cell lines were analyzed by RT-PCR. The mRNA expression of hTERT was upregulated after exposure to FR901228 in hTERT-negative Hep2 cells, and even SAS and KB cells expressed high levels of hTERT. Moreover, cotreatment of protein synthesis inhibitor cycloheximide (CHX) resulted in the induction of hTERT transcription by FR901228. This suggests that the induction of hTERT by FR901228 requires de novo protein synthesis to some extent and is more likely a direct than an indirect effect on epigenetic changes such as histone acetylation/deacetylation. We further examined the effect of FR901228 on c-myc protein, which is one of the main hTERT transcription activators. FR901228 repressed c-myc protein only in the absence of CHX, and depended on the enhancement of de novo protein synthesis. Our results indicate that c-myc protein is repressed indirectly by FR901228 but may not contribute to FR901228-induced hTERT transcription. The present study showed that the HDAC inhibitor FR901228 induced the hTERT gene by a complex mechanism that involved transcription factors other than c-myc, in addition to inhibition of histone deacetylation.

DOI： 10.1007/s00280-004-0976-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

The authors developed a phantom, designated as the CAGN phantom, compatible for MRI and hyperthermia that is useful in the fundamental studies of non-invasive MR thermometry. The ingredients of this phantom are carrageenan, GdCl3 as a T-1 modifier, agarose as a T-2 modifier, NaCl as a conductivity modifier, NaN3 as an antiseptic and distilled water. Another phantom that was developed, the CAG phantom, has relaxation times that are adjustable to those of any human tissue. To use this phantom for electromagnetic heating, NaCl was added to change the conductivity of the phantom and clarified the relationship between the conductivity and NaCl concentration. This study examined the relationship between relaxation times and NaCl concentration of the CAGN phantom. The results showed that both T-1 and T-2 values were affected by NaCl and the experimental results led to the empirical formulae expressing the relationship between the relaxation rates (1/T-1, 1/T-2) and the concentrations of GdCl3, agarose and NaCl. The appropriate concentrations of T-1 and T-2 modifiers were calculated from these empirical formulae when making a specified phantom that has the required relaxation times and NaCl concentration.

DOI： 10.1080/0265673042000199268

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本ハイパーサーミア学会  

組織内加温や腔内加温は一般に内部電極と外部電極の2電極で行われる.しかしながら,一対の平面外部電極の間に内部電極を留置する方法も行なわれている.この2つの加温方法の発熱分布を比較するために,今回,内部電極に1個と外部に誘電型加温電極を2個使用し,合計3電極でSARシミュレーションを行った.その結果,3電極の場合と2電極の場合を比較すると,3電極法では加熱方向を制御でき,熱放散の少ない加温ができることが示唆された

DOI： 10.3191/thermalmedicine.20.241

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Maspin, which belongs to the serine protease inhibitor (serpin) superfamily, has been proposed as a potent tumor suppressor that inhibits cell motility, invasion, angiogenesis, and metastasis. In the present study, we examined the effects of 5-aza-2'-deoxycytidine (5-aza-dC), a demethylating agent, and FR901228, a histone deacetylase (HDAC) inhibitor, on maspin expression in oral cancer cell tines. The expression levels of maspin mRNA were divided into two groups, which was the maspin tow-expressed and high-expressed cell lines in the 12 oral cancer cell lines. The maspin promoter contained only a few methylated CpG sites in the maspin low-expressed cell lines. Moreover, the methylation status was not altered after 5-aza-dC treatment. However, the transcription of the maspin gene was clearly increased following 5-aza-dC treatment in a number of oral cancer cell tines. These results imply that an action of 5-aza-dC is separate from induction of promoter demethylation. Treatment with FR901228 resulted in a time-dependent stimulation of the re-expression of maspin mRNA as early as 4 h after treatment in the maspin downregulated cells. The re-expression of the maspin gene may contribute to the recuperation of biological functions linked to FR901228 such as an inhibitory effect on tumor angiogenesis and cell invasion. These results indicate that maspin and its target genes may be excellent leads for future studies on the potential benefits of FR901228, a HDAC inhibitor, in cancer therapy. (C) 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.oraloncology.2003.12.008

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Language：Japanese   Publisher：岡山大学医学部保健学科  

MRはX線のように形態画像を表示できる以外に,機能画像,代謝画像,術中画像を表示できることから,重要な撮像モダリティーであるが,成書にはその画像再構成法の具体的な記述はなされていない.そこで,ファントムを用いて具体的に画像を再構成することを試みた.まず矩形ファントムを用いてサンプリング時間の測定を行った.次にMRI MULTI-TEST PHANTOMをスキャンすることによりファントムのエコー信号を採取した.このエコー信号を矩形ファントムで求めたサンプリング時間ごとにサンプリングすることによりk-spaceを得た.このk-spaceから逆フーリエ変換を行うことにより画像の再構成を行った.得られた画像とMRI装置に表示された画像の比較を行い,画像が再現されていることを確認した

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本ハイパーサーミア学会  

BHK21細胞とtsAF8細胞を用いてprotein kinaseの阻害剤であるCalphostin CとH89の,温熱耐性の発現に及ぼす効果を検討した.その結果,いずれの細胞においてもCalphostin Cによって温熱耐性の発現が阻害された.H89では0.05μMの濃度では温熱耐性の発現が阻害されたが,2.5μMでは逆に発現が促進された.Calphostin CはPKCを特異的に阻害し,H89は主にPKAを阻害するが濃度が高くなるとPKGも阻害する.温熱耐性の発現はPKCとPKAにより阻害されるが,PKGによって促進されることが示唆された

DOI： 10.3191/thermalmedicine.19.187

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(公社)日本放射線腫瘍学会  

周囲組織に放射線障害を発生させずに病巣に十分な治癒線量を照射する目的で,放射線治療歴のある頭頸部再発癌症例31例に対して,ロボットを組み合わせた定位放射線治療装置であるCyberKnifeによる治療を行った.計画標的体積は2.6〜381.0cm3,総投与線量は15.0〜40.3Gyであった.観察期間は1.7〜22.4ヵ月で,評価は治療3ヵ月目までに行った.治療後の一次効果は奏効率74%,局所コントロール率94%であった.症状改善は,疼痛が8例中4例で消失,4例で軽減,2例は不変であった.鼻出血の2例は,1ヵ月目頃に消失した.急性有害反応は,粘膜炎が5例,頸部腫脹が1例に認められ,保存的治療を行った.転帰は,生存13例,原病死14例,他病死4例であった.原病死のうち7例の治療領域は制御されたが,他の7例は制御不能であった

DOI： 10.11182/jastro1989.15.139

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Language：Japanese   Publisher：(公社)日本医学放射線学会  

転移性脳腫瘍に対しリニアックを用いた定位放射線照射(STI)を施行した54症例(延べ照射部位118ヶ所)の治療成績より,大きな腫瘍または重要組織近傍に存在する腫瘍に対する分割照射(SRT)の安全性と有効性について検討を行った.治療後の一次効果は,1回照射(SRS),STI,SRTで有意差を認めなかった.再発率においても照射法による差を認めなかった.早期および晩期合併症の発生率に,照射法による有意差を認めなかった.単変量解析では年齢,KPS,活動性頭蓋病変の有無が,多変量解析では年齢,性別,活動性頭蓋病変の有無,癌の診断確定から照射迄の期間が有意な予後因子であった.治療効果および合併症においてSRSとの有意差はなく,転移性脳腫瘍に対するSRTは安全かつ有効な治療法であると考えられた

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Language：Japanese   Publisher：岡山大学医学部保健学科  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOCIETY NUCLEAR MEDICINE  

Background: Regional dysfunction demonstrated by Tc-99m-diethylenetriamine-penta-acetic acid-galactosyl human serum albumin (GSA) scintigraphy due to regional decrease in the portal venous flow has previously been reported. In this study, we call attention to the significance of unilateral portal venous flow decrease for preoperative hepatectomy simulation, and evaluate the hepatectomy simulation discrepancy between Tc-99m-GSA single-photon emission computed tomography (SPECT) and CT volumetry. Methods: Twenty-four hepatectomy candidates underwent preoperative hepatectomy simulation by both Tc-99m-GSA SPECT and CT volumetry. Both anatomical and functional resection ratios were calculated by means of CT volumetry and Tc-99m-GSA SPECT, respectively. The differences and ratios between anatomical and functional resection ratios were calculated in all patients, and compared in patients with and without unilateral portal venous flow decrease. Results: Anatomical resection ratios were 28.0 +/- 11.7 (mean standard deviation) in patients with unilateral portal venous flow decrease, and 42.1 +/- 15.7 in patients without unilateral portal venous flow decrease (p = 0.0127). Functional resection ratios were 14.7 +/- 12.8 in patients with unilateral portal venous flow decrease and 40.5 +/- 14.6 in patients without (p = 0.0004). The differences between anatomical and functional resection ratios were 13.0 +/- 7.9,in patients with unilateral portal venous flow decrease and 5.6 +/- 3.1 in patients without (p = 0.0099). The ratios between anatomical and functional resection ratios were 0.48 +/- 0.29 in patients with unilateral portal venous flow decrease and 0.86 +/- 0.10 in patients without (p = 0.0018). In 12 of the 13 patients with unilateral portal venous flow decrease, anatomical resection ratios were found to be larger than functional resection ratios, whereas this happened in only 6 of I I patients without unilateral portal venous flow decrease (p = 0.0063). Conclusion: Unilateral portal venous, flow decrease is suspected to be a major factor in the discrepancy between hepatectomy simulations with radionuclide receptor imaging and CT volumetry.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

We report on thermoradiotherapy combined with p53 gene therapy in the human salivary gland adenocarcinoma cell line HSG. HSG cells were successfully infected at a rate of 62.3% with MOIs of 20 of either AxCAip53 or AxCAiLacZ. The AxCAiLacZ did not inhibit the survival of the HSG cells. The survival fractions of AxCAip53-infected HSG cells were lower than those of the AxCAiLacZ-infected HSG cells, but there was no significant difference (p=0.30). AxCAip53 decreased the survival rates of thermotherapy (43degreesC; p=0.084 and 44degreesC; p=0.18), radiotherapy (6 Gy; p=0.20) and thermoradiotherapy (6 Gy plus 43degreesC; p=0.24 and 6 Gy plus 44degreesC; p=0.96), but there were no significant differences. In comparing the survival rates of thermoradiotherapy with those of thermotherapy and radiotherapy, thermoradiotherapy, regardless of the combination with p53 gene therapy, demonstrated actual survival rates lower than theoretical survival rates based on survival rates of thermotherapy multiplied by survival rates of radiotherapy. This result indicates that thermoradiotherapy is effective in the treatment of HSG cells. Thermoradiotherapy combined with p53 gene therapy was the most effective therapy among the combinations of therapies demonstrating that thermoradiotherapy combined with p53 gene therapy may be a useful, tool in the treatment of HSG cells.

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Authorship：Lead author  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：放射線生物研究会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

We reconstructed the recombinant p53-expressing adenovirus and examined its infections and effects in head and neck squamous cell carcinoma cell lines. Eight human head and neck squamous cell carcinoma cell lines were infected by the recombinant adenovirus harboring the lacZ gene (AxCAiLacZ) or the wild-type p53 gene (AxCAip53), and the effects were investigated. The eight cell lines were successfully infected by AxCAiLacZ at a level of more than 50%. The survival of all 8 squamous cell lines were inhibited in the range from 8 to 26.7% by only one treatment of the AxCAip53 infection. This result suggested that p53 gene therapy might become a useful tool in head and neck squamous cell carcinoma treatment.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：RADIOLOGICAL SOC NORTH AMERICA  

PURPOSE: To evaluate use of a short hook wire and suture system for preoperative localization of pulmonary nodular lesions.
MATERIALS AND METHODS: Percutaneous localization of 168 lesions was performed with computed tomographic (CT) guidance in 150 patients. Patients were classified into three groups: a 3-year early-learning experience of treatment of 40 lesions mainly in one institution (group A1), a more recent 4-year experience of treatment of 88 lesions in the same institution (group A2), and the roughly synchronous recent 3-year experience of treatment of 40 lesions in a different hospital (group B).
RESULTS: The hook wire was successfully placed without dislodgment in 146 patients, accounting for 164 (97.6%) of 168 lesions. Group A2 showed a success rate of 100%. There was no difference in patients among the three groups in regard to size of lesions or their distance from the pleural surface. In patients in groups A2 and B, the proportion of nodules with ground-glass opacity and primary lung carcinoma at CT was significantly greater than that in patients in group A1. In 168 placements, nonsymptomatic pneumothorax cases were observed in 54 (32.1%), hemorrhages into the lung were observed in 25 (14.9%), and hemorrhage into the pleural space was observed in one (0.6%). No patient complained of notable pain during or after the procedure, and no serious complication was experienced. Unsuccessful placement was caused by too shallow a puncture with the introducer needle.
CONCLUSION: This system with a flexible suture for preoperative localization has a high success rate. (C) RSNA, 2002.

DOI： 10.1148/radiol.2252011025

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

Thermoradiosensitivity of 8 cell lines of head and neck squamous cell carcinoma (HO-1-u-1, HSC2, HSC3, HSC4, SAS, KB, Hep2, and Ca9-22) was investigated. The differences of radiosensitivity between the cell line with the highest radiosensitivity and the cell line with the lowest radiosensitivity were 1.7-, 7.7-, and 41-fold at 2, 6 and 8 Gy, respectively. The differences between the cell line with the highest thermosensitivity and the cell line with the lowest thermosensitivity were 2.4-, 6.2- and 34.4-fold at 43 degreesC for 40, 60 and 100 min, and 2.6-, 4.9- and 127-fold at 44 degreesC for 20, 30 and 50 min, respectively. These findings indicated that there were large differences in both radiosensitivity and thermosensitivity among the 8 cell lines. There was a negative relationship between radiosensitivity and thermosensitivity (43 degreesC: r=-0.600, 44 degreesC: r=-0.848) in 7 of 8 cell lines, the exception being the HSC4 cell line, which was resistant to both therapies. Four of the 8 cell lines at 43 degreesC and 5 at 44 degreesC in the radiotherapy combined with thermotherapy showed actual survival rates smaller than the theoretical survival rates. Thus, thermoradiotherapy was deemed effective in the head and neck carcinoma cell lines, although 1 of 8 cell lines was resistant to both radiotherapy and thermotherapy.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

A 22-year-old woman with severe acute hepatitis underwent a Tc-99m galactosyl human serum albumin (GSA) scan. Intense accumulation was observed in the cephalic region of the right hepatic lobe, whereas the accumulation was reduced in the left lobe and the caudal region of the right lobe. A computed tomographic (CT) scan showed that the left lobe and the caudal region of the right posterior segment had atrophied and become hypodense, which were thought to represent post-necrotic scarring after massive hepatic necrosis. The relatively hyperdense region in the right lobe was slightly swollen and was thought to represent regenerating liver tissue or a "potato liver." Compared with the CT, the regions of elevated Tc-99m GSA accumulation correlated well with the areas of regenerating liver tissue, and the regions with reduced accumulation corresponded closely with the areas of postnecrotic scarring. On a Tc-99m phytate scan, unlike the Tc-99m GSA scan, the radiocolloid accumulation was intense in the left lobe and caudal region of the right lobe and reduced in the cephalic region of the right lobe. Together, the Tc-99m GSA scan and the Tc-99m phytate scan formed a set of exact "nega-posi" images. Biopsy specimens obtained during laparoscopy showed a few hepatocyte columns in the postnecrotic scarred left lobe. Severe disruption of the hepatocytes, prominent inflammatory cell infiltration, and obvious Kupffer cell hypertrophy and clustering were also observed.

DOI： 10.1097/01.RLU.0000020743.43414.67

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

The purpose of this study was to examine whether combined cisplatin and late course accelerated fractionation radiotherapy (LCAH) (the combined group) can confer a better outcome over LCAH alone in treating esophageal carcinoma. Eighty-one eligible patients were randomly entered into two groups: the LCAH alone group, and the combined group. There was a better outcome in the combined group compared to the LCAH group, but the difference was not significant. The combined therapy could significantly improve the survival rate and local control of the disease in the early stage, but not in the advanced stage, because of the possibility of invasion. More severe complications occurred in the combined group than in the LCAH group, but they were within tolerance. In conclusion, LCAH concomitant with cisplatin could improve the survival of patients with esophageal cancer, especially in the early stage, as long as the side effects of the treatment are within tolerable limits.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOCIETY NUCLEAR MEDICINE  

Objective: To compare the diagnostic capabilities of various serum thyroglobulin levels (To) and Tl-201 scintigraphy with regard to thyroid follicular lesions. Methods: We examined 80 thyroid follicular lesions (benign: 55, malignant: 25) in patients with nodular goiter for whom a pathological diagnosis was made based on surgical findings. To was measured by an I-125 (radioimmunoassay) method, In Tl-201 scintigraphy, 74 MBq of Tl-201 chloride was intravenously injected and imaged after 10 minutes (early image) and after 120 minutes (delayed image), and the scintigrarns were evaluated both visually and quantitatively, with special attention paid to the part of the nodule with the highest accumulation of Tl-201 chloride. The cutoff levels of To for categorizing the lesions as malignant were set at 40, 100, 300, 500, 1,000 and 2,500 mug/l. In Tl-201 scintigraphy, method I involved high uptake on both early and delayed images, method 2 involved high uptake on only the early image, and method 3 involved high uptake on only the early image or the same accumulation in comparison with the normal region on the early image, with no washout being quantitatively judged as indicative of malignancy. A summary index of overall test performance can be calculated as the area under the receiver operating characteristic (ROC) curve (Area (Az)). Likelihood ratios for several cutoff levels were also calculated. Results: In the diagnosis, Az of Tl-201 (0.95), was larger than that of Tg (0.65). The sensitivity and accuracy of To at each cutoff level (sensitivity: 4.0% to 76.0%, accuracy: 50.0%, to 72.5%) were lower than with Tl-201 scintigraphy (methods 1-3, sensitivity: 76.0-100%, accuracy: 77.5-88.8%). The likelihood ratio for the positive results of method 1 for Tl-201 scintigraphy, were greatest in the present study (13.9), and the likelihood ratio for the negative results of method 3 for Tl-201 scintigraphy, (0) was smallest in the present study. Conclusion: Diagnosis based on Tl-201 washout patterns in which quantitative evaluation is combined with visual evaluation appears to be more useful for the differentiation of malignant thyroid follicular lesions than diagnosis by Tg.

DOI： 10.1007/BF02993711

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：岡山大学医学部保健学科  

Propidium Iodide(PI)とbromodeoxyuridine(BrdU)でtsAF8細胞を二重染色し,フローサイトメトリーによって温熱耐性と細胞周期の関係の有無について調べた.tsAF8細胞を45℃20分の加温後34℃で培養すると,6時間後にはG1期の細胞が減少し,12時間後にはG2/M期への蓄積が見られた.しかし,加温後39.7℃で培養した場合には細胞周期の進行が殆ど見られなかった.BrdUの取込みは,加温せずに39.7℃で培養した場合には活発に行われ,45℃20分加温後34℃で培養した場合には,6時間後にはBrdUの取り込みは65.1%まで回復した.しかし,温熱耐性発現の抑制が観察される45℃20分加温後39.7℃で培養した場合には,BrdUの取込み量は6時間後に一時的に15.1%に回復するが,12時間後には取込み量はゼロとなった.温熱耐性と細胞周期との関係はtsAF8細胞においては見出されなかった

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

DOI： 10.5981/jjhnc1974.28.186

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Purpose: To evaluate the efficacy of radiotherapy for portal tumor emboli of hepatocellular carcinoma. Materials and Methods: Twenty-four patients with portal tumor emboli of hepatocellular carcinoma who were treated with radiotherapy from August 1995 to December 1999 were retrospectively studied. Patients were classified according to the degree of portal tumor emboli (Vp2: 3. Vp3: 14. Vp4: 7) and liver damage (A: 8, B: 11, C: 4. unknown: 1). The responses were classified as effective, no change, or progression. The liver function between pre- and post-radiotherapy was compared. Results: The responses were effective for 12 cases (75%) and no change for 4 cases (25%). Cause specific survival rate at 1 year and 50% survival time was 24.4% and 6.3 months, respectively. Cause specific survival rate at 1 year for liver damage A and Vp3 were 60% and 38% respectively. 50% survival time for liver damage A and Vp3 were 11 months and 11.3 months respectively. Prolongation of the prognosis over 6 months was observed in a few cases of liver damage B. Liver function with local irradiation was generally tolerable. Conclusions: Radiotherapy for portal tumor emboli of hepatocellular carcinoma was useful as one of multimodality treatments for advanced hepatocellular carcinoma. This treatment sometimes expected prolongation of the prognosis for hepatocellular carcinoma with portal tumor emboli. © 2002, Japanese Society for Therapeutic Radiology and Oncology. All rights reserved.

DOI： 10.11182/jastro1989.14.33

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

We report on thermochemotherapy in a human salivary gland adenocarcinoma cell line. Hyperthermia reduced the survival rate to 50 and 20% by heating at 43degreesC for 40 and 60 min, respectively, and is by itself useful in human salivary gland carcinoma treatment. Adriamycin, cisplatin, and mitomycin C can possible be used clinically, while bleomycin and 5-fluorouracil cannot, to treat this carcinoma. The optimal temperature was considered to be 41degreesC in adriamycin, 42degreesC in cisplatin, 37degreesC in mitomycin C, and 42degreesC in bleomycin in the thermochemotherapy. Thermochemotherapy is a useful tool in the treatment of human salivary gland carcinoma cells, but it is necessary to select the best anticancer drugs and the optimal temperature for optimal success using this treatment.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER-VERLAG  

We report two cases of bile duct stenosis due to portal cavernomas. Smooth stenoses were seen arising from both walls of the common bile duct on magnetic resonance (MR) cholangiopancreatography. On contrast-enhanced MR portography, peribiliary tortuous vessels were evident, indicating portal cavernomas. MR imaging can evaluate the biliary tree and portal systems noninvasively and was useful for evaluating this condition.

DOI： 10.1007/s00261-001-0038-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

Phosphatidylinositol 3 kinases (PI-3 kinases) play a crucial role in the inositol phospholipid signaling pathway. The effect of wortmannin. an inhibitor of PI-3 kinases, on the suppression of thermotolerance development was investigated in the temperature-sensitive cell line tsAF8. When wortmannin was added immediately after the preheating. the thermotolerance was suppressed, with this suppression being dose-dependent from 0.01 to 0.1 muM, but not dose-dependent from 0.1 to 20 muM. Our results suggest that PI-3 kinases might play an important role in thermotolerance development in tsAF8 cells.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

A preliminary study was conducted to evaluate the superior and inferior glenoid labra with abductive movement using an open-type MR unit in asymptomatic healthy volunteers. Both fast low angle shot (FLASH) and turbo spin echo (TSE) images were obtained to evaluate the shapes of both the superior and inferior labra, as well as to assess changes in signal at these sites. As the abduction angle was increased, the shape of the superior labrum changed from round or triangular to crescentic and a higher signal was frequently seen. At an abduction angle of 150 degrees, an increase in signal was seen in one-half of the superior labra; this increase was noted more frequently in volunteers over 40 years of age. In some of the superior labra, the increase in signal seen at 150 degrees abduction disappeared on subsequent images obtained at 0 degrees abduction. Hence, the increase in signal was considered to be a reversible change. The shape of the inferior labrum tended to change from crescentic to triangular or round. An increase in signal in the inferior labrum was unrelated to the abduction angle. Abductive kinematic studies using an open-type MR unit provides information about the morphology of the superior and inferior labra, as well as information about signal changes occurring at these sites.

DOI： 10.18926/AMO/31990

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：金原出版(株)  

術前に血清サイログロブリン測定,穿刺吸引細胞診(FNA),201Tlシンチグラフィの全てを施行し,手術で病理的組織診断が確定した結節性甲状腺腫74結節(男16,女58,14〜87歳)を対象とした.FNAでクラス3以上の場合はそのまま悪性と判定し,クラス2以下の場合は血清サイログロブリンのcut-off値を1000μg/lとする診断方法が最も優れた成績であった.結節性甲状腺腫の良悪性の鑑別診断は201Tlシンチグラフィ,特に早期像で高集積又は等集積で後期像にかけて洗い出しがみられないものを悪性と判定する基準のTl2法が有用であることが示唆された

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：(公社)日本放射線腫瘍学会  

経時的に4波長の蛍光顕微鏡像と明視野像を同時撮影し画像を自動取得できる新しい蛍光顕微鏡システムを作成した.培養装置付き倒立型顕微鏡にHoffman Modulation Contrast装置,培養システム,蛍光4波長自動切り替え装置,明視野/蛍光照明自動切り替えユニット,3CCDビデオカメラ及びコンピュータ自動画像取得ユニットを組み合わせてシステムを構築した.apoptosisとnecrosisの鑑別に対するAV及びpropidium iodide(PI)の二重染色法における経時的変化について例示した.ヒトT細胞由来の腫瘍細胞株であるJurkat細胞を抗Fas抗体処理後12時間で,95%の細胞がapoptosisに,3%の細胞がnecrosisとなった.又,apoptosisとなった細胞の56%がsecondary necrosisとなった.Apoptosisでは,明視野では典型的なbuddingがおこると共に,annexin V-enhanced green fluorescent protein(AV-EGFP)とPIの二重染色では初めにAV-EGFPのみで染色される

DOI： 10.11182/jastro1989.13.119

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

Effects of protein kinase C (PKC) inhibitors (H7, staurosporine, calphostin C) on thermotolerance development were investigated in temperature sensitive tsAF8 cells derived from Syrian hamster BHK21 cells. Cells were pre-heated at 45 degreesC for 20 min, incubated at 34 degreesC with PKC inhibitors for varying lengths of time, i.e. 1.25-10.0 h, and then heated at 45 degreesC for 30 min. Increasing survival fractions after the second heat treatment was inhibited by the treatment with H7 (40-160 muM), with staurosporine (0.05-1.0 muM), and with calphostin C (0.8, 1.2 muM) in a concentration dependent manner. When the concentrations of these PKC inhibitors were low, the restraint of increasing survival fractions was temporary, since survival fractions increased 3-7.5 h after pre-heating. However, the survival fractions were almost constant by the treatment with 160 muM H7 and 1.0 muM staurosporine. Induction of HSP72 after heat stress was investigated in tsAF8 and BHK21 cells. Cells were heated at 45 degreesC for 20 min and incubated at 34 or 39.7 degreesC (tsAF8), at 37 degreesC (BHK21). Intensity of intracellular fluorescence from HSP72 was measured by flow cytometry. HSP72 was induced in BHK21 cells, but there was no definite induction of HSP72 in tsAF8 cells at either 39.7 or 34 degreesC. These results suggest that PKC is related with the thermotolerance development in tsAF8 cells; however, HSP72 is not involved in the thermotolerance development in tsAF8 cells.

DOI： 10.1080/02656730010010667

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

Our previous study using a new microscopic system indicated that apoptotic cells undergo secondary necrosis during treatment with anti-Fas antibody and calcium. In this study, we compared the time-lapse appearance of apoptosis and secondary necrosis of Jurkat cells during treatment with anti-Fas antibody with and without calcium in individual cells. Apoptosis developed in 97% and 81% of cells during 36-hour-treatment with anti-Fas antibody with and without calcium, respectively. The apoptosis of Jurkat cells showed a characteristic pattern of time-lapse morphological change. Less than 1% of the apoptotic cells divided into apoptotic bodies. There was budding in all the other apoptotic cells, but no apoptotic bodies formed. We confirmed that secondary necrosis occurs in individual apoptotic cells during treatment with anti-Fas antibody. Neither the pattern of time-lapse morphological change nor the time interval between the beginning of apoptotic budding and secondary necrosis were related to the presence of calcium. This study clarified the characteristic pattern of time-lapse morphological change in Jurkat cells during treatment with anti-Fas antibody, and presented direct evidence that individual apoptotic cells undergo secondary necrosis. The presence of calcium did not affect the pattern of morphological change ol the time interval between the beginning of apoptotic budding and secondary necrosis.

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

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The sensitivity and N.P.V. by 201Tl scintigraphy which nodular uptake was higher and equal to normal thyroid tissue on early scan without quantitative washout were higher than those of FNA combined with the serum thyroglobulin level (sensitivity; 96.9%, 53.1-75.0%, N.P.V. 96.3%, 72.2-80.5%, respectively p<0.05). 201Tl scintigraphy is more useful for discrimination of benign and malignant thyroid nodules than fine- needle aspiration combined with serum thyroglobulin.

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本磁気共鳴医学会  

成分はカラギーナン,塩化マンガン,食塩,窒化ソーダ,そして水である.ファントムの成分がカラギーナン5wt%,塩化マンガン0.2mM,食塩0.19wt%,窒化ソーダ0.1wt%であるとき,1.5TにおけるT2は84.9ms,T1は429msである.この磁場強度に相当する周波数における導電率は0.769S/m,そして比誘電率は81.4である

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOCIETY NUCLEAR MEDICINE  

Nontumorous decrease in Tc-99m-GSA accumulation has not been well covered in the literature. Understanding of this phenomenon is, however, essential for accurate evaluation of regional hepatic function. Scintigrams (transaxial SPECT) of 269 patients who underwent Tc-99m-GSA liver scintigraphy were reviewed for the presence of nontumorous decreases in Tc-99m-GSA accumulation. Nontumorous decreases in Tc-99m-GSA accumulation were seen in 32 of 269 patients (12%). In 16 of the 32 patients (6%). nontumorous decreases in Tc-99m-GSA accumulation corresponded to regional decrease in portal venous How. The causes of such decrease in portal venous flow were portal thrombus of hepatocellular carcinomas in eight patients, portal venous stenosis or occlusion by hilar cholangiocarcinomas in five patients, inter alia. In eight patients (3%), the regions with decreased Tc-99m-GSA accumulation correlated with massive hepatic necrosis in fulminant hepatitis, scar in hepatitis, or confluent fibrosis in cirrhotic liver. In two patients (0.7%) with hilar cholangiocarcinomas, the possible causes of lobar decrease in Tc-99m-GSA accumulation were thought to be lobar decrease in portal venous Flow, lobar biliary stasis, or both. In four patients (1.5%), the exact causes of nontumorous decrease in Tc-99m-GSA accumulation could not be determined.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本ハイパーサーミア学会  

MRI装置と併用可能なRF interstitial型加温用の内部電極及び外部電極の材料及び形状について検討した.内部電極用試料として,鉄,チタン,モリブデン,タングステン,銅のコイル又はrodを用いた,外部電極用平板型試料として,銅箔及び溝を切り込んだ銅箔を用いた.試料を寒天ゲルに挟み,0.2T開放型MRIシステムを用いてT1強調画像,位相画像を採取した.その結果,銅が最もMRI画像に影響を与えないことが示された.内部電極としての弾性率及び密度を考慮した場合,モリブデンが電極材料として適していることが示された

DOI： 10.3191/thermalmedicine.16.159

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

The characteristic development of thermotolerance was examined in tsAF8 cells, which were temperature sensitive cell line derived from BHK21. tsAF8 cells lose RNA polymerase II activity and arrest in the G(1) phase of the cell cycle at the nonpermissive temperature of 39.5-40.6 degrees C. tsAF8 cells were pre-heated at 45 degrees C f or 20 min, incubated at 34 or 39.7 degrees C for different durations, and then heated again at 45 degrees C for 30 min. The cells were trypsinized immediately after the second heating to evaluate cell survival. As a result, thermotolerance was developed rapidly in the cells incubated at 34 degrees C. However, the survival rate of the cells incubated at 39.7 degrees C was almost constant. Thermotolerance of BHK21 cells, which were wild-type cells of tsAF8 cells, developed at 39.7 degrees C. These results suggest that thermotolerance may be inhibited in tsAF8 cells incubated at 39.7 degrees C, and that some metabolism which is inhibited in tsAF8 cells at 39.7 degrees C may be related to thermotolerance development.

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In this study, we examined the inhibitory effects on cell growth and the effects of quercetin on intracellular accumulation of adriamycin (ADR) in wild type Ehrlich ascites tumor cells (wild EAT cells) and their ADR-resistant strain. Quercetin strongly inhibited growth in both strains. Cell growth reached a plateau at 3.5 days in the wild type EAT cells and at 7 days in the ADR-resistant strain. The inhibitory concentration in 50% of the ADR-resistant cells on day 7 (24 mu M) was twice that of the wild type EAT cells on day 4 (12 mu M) after continuous treatment with quercetin. Quercetin decreased the ADR accumulation in the wild type cells but did not affect it in the ADR-resistant cells. Further quercetin did not affect the retention of ADR in either strain. These results indicated that qeurcetin decreased ADR accumulation without extruding ADR in the wild type EAT cells. ADR accumulation in the ADR-resistant cells treated with quercetin for 7 days was increased with increasing concentrations of quercetin. Moreover ADR accumulation in the ADR-resistant cells treated with 50 mu M quercetin for 7 days, increased to 186.6% and to 181.9% of that in untreated cells after 60 minutes and 120 minutes incubation, respectively, whilst it ina-eased to 70% from 37.5% of that in the wild type EAT cells after 60 minutes incubation. These findings indicated that quercetin might reverse ADR-resistance.

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In this study, we observed the influence of bovine calf serum (BCS) on the intracellular accumulation of adriamycin (ADR) in Ehrlich ascites tumor cells (wild type EAT cells) and their ADR-resistant strain. The ADR accumulation treated in the medium not containing BCS was S-fold of that containing 10% BCS. ADR incorporated into cells was not effluxed in the absence of the BCS, while it was rapidly effluxed for 30 minutes to about 20% of the amount incorporated into the cells in the presence of 20% BCS in both strains. This suggests that BCS remarkably decreases the ADR accumulation due to the promotion of ADR efflux. Further; the ADR accumulation dea eased with increasing concentrations of BCS in both strains. This indicates that BCS promotes the ADR efflux, dependeing on its concentrations. BCS was heated at 100 degrees C for 7 minutes and its protein contents were degenerated. Irs influence in the ADR accumulation of wild type and ADR-resistant strain was apparent. The ADR accumulation decreased with increasing concentrations of heated BCS in both strains, as well as in the untreated BCS. Thus, the protein content of the BCS did not affect ADR accumulation. Therefore, it is necessary to investigate which components of BCS affect the promotion of ADR efflux.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC NUCLEAR MEDICINE INC  

We assessed the ability of (TI)-T-201 planar scintigraphy and fine-needle aspiration (FNA) biopsy to differentiate malignant from benign lesions by comparing the findings of these techniques with those of surgical histopathology for 107 patients with 109 thyroid nodules. Methods: (TI)-T-201 (74 MBq) was injected intravenously, and an early image and a delayed image were acquired after 10 and 120 min, respectively for 10 min each. For (TI)-T-201 planar scintigraphy, accumulation of the tracer in the nodules was visually scored and the nodules were grouped. Group A showed high activity in both early and delayed images. Group B revealed high activity in only the early image. Group C showed activity in the early image equal to that in normal tissues. Quantitative calculation of the washout rate was less than 0 in group CI and 0 or higher in group CII. Group D revealed low activity in the early image and Variable activity in the delayed image. Three differential diagnosis methods were used for (TI)-T-201 planar scintigraphy: method 1, in which only group A was considered malignant; method 2, in which both group A and group B were considered malignant; and method 3, in which groups A, B and CI were considered malignant. FNA results were assessed and classified by experienced pathologists. Two differential diagnosis methods were used for FNA: method a, in which malignancy was assigned to class IV (probably malignant or higher), and method b, in which malignancy was assigned to class III (possibly malignant or higher). Results: Concerning (TI)-T-201 methods 1,2 and 3, sensitivity was 74.0%, 84.0% and 92.0%, respectively; specificity was 83.1%, 64.4% and 54.2%, respectively; and accuracy was 78.9%, 73.4% and 71.6%, respectively. For FNA, method a and method b had a sensitivity of 36.0% and 50.0%, respectively, and a specificity of 96.6% and 84.7%, respectively The accuracy of both methods was 68.8%. For follicular lesions, sensitivity ranged from 80.0% to 90.0% for (TI)-T-201 scintigraphy and from 10.0% to 30.0% for FNA. Conclusion: (TI)-T-201 planar scintigraphy was found to be easier to use and more accurate than FNA in the differentiation of diagnosis of benign and malignant thyroid nodules based on visual scoring combined with quantitative evaluation.

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In this study, we observed the intracellular accumulation and retention of calcein in Ehrlich ascites tumor cells (wild type EAT cells) and their adriamycin (ADR)-resistant strain to further study the mechanisms of ADR accumulation. In the wild type EAT cells, intracellular accumulation of calcein increased rapidly, but it was not incorporated into the cells in the ADR-resistant strain. This suggests that the efflux system or the inhibition system of influx, which does not exist in the wild type EAT cells, involves in the ADR- resistant strain. Calcein incorporated into the cells was effluxed from the cells in both strains at almost the same I ate. This suggests that the both strains may use a similar efflux system agaimt calcein. P-gp extrudes calcein-AM directly from the cell membrane, but not calcein. Calcein is effluxed by multidrug resistant protein (MRP) ol multispecific organic anion transporter (MOAT). Therefore, the mechanism which extrudes calcein of both strains, may be the other efflux system included MRP or MOAT apart from P-gp. In the same medium condition as treating in the calcein efflux experiments, about 20% amount of ADR incorporated into the cells was effluxed in the ADR-resistant cells, but not in the wild type cells. Since the efflux rates in the ADR differed from those in calcein in the same medium condidon, the mechanism of the ADR efflux might differ from that of calcein efflux in the ADR-resistant strain.

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

We developed a reliable system for the irradiation of xenografted tumors in mice which allows for accurate local irradiation under specific pathogen-free conditions. The system presented here consists of acrylic supports for mice and an acrylic box connected to a pump through 0.22 mu m pore-sized filters. Mice with xenotransplanted tumors growing on their right hind legs were set on the supports and put into the box in a laminar flow hood. The tumors of 7 mice were irradiated simultaneously with X-rays of 6 and 10 MV generated by a linear accelerator at a dose rate of 3.1-4.7 Gy/min. The air was ventilated through filters during irradiation in the closed box. Microorganism tests confirmed that no bacteria entered or left the box. One of the significant characteristics of this setup is that it allows for irradiation under conditions of acute hypoxia, which is obtained using an integrated tourniquet. The dose variation among 7 tumors was less than 1%. The rest of the mouse's body was shielded effectively by a half-field technique and a lead block. As a result, the whole body dose for the mice was 0-4% of the total dose absorbed by the tumor. Due to the high dose rate and the ability to irradiate 7 mice simultaneously under specific pathogen-free conditions, this new system can be considered a time-saving and valuable tool for radiation oncology research.

DOI： 10.18926/AMO/31638

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

We analyzed the influence of various parameters on the results of radiotherapy for T1 glottic cancer by assessing the outcomes of 60 patients with this cancer who received definitive radiotherapy between 1985 and 1994. Seven patients were treated with a cobalt-60 unit, and the other 53 with a linear accelerator (26 patients at 3-MV, 10 at 6-MV, and 17 at 10-MV). Of the 17 patients treated at 10-MV, 4 also received part of their treatment with a cobalt-60 unit. The total radiation dose ranged from 56 Gy to 70 Gy (mean, 61 Gy). The total radiation dose of 51 patients (85%) was 60 Gy. The factors found to influence local control were the strength of the radiation beam energy and whether or not there was gross tumor invasion of the anterior commissure. The local control I-ate was 71% in the patients treated with a 10-MV linear accelerator, 56% in those treated with a 6-MV linear accelerator and, 97% in those treated with a cobalt-60 unit or a 3-MV linear accelerator (P = 0.0173). The local control rate was 43% in the patients with gross anterior commissure invasion and 88% in those without (P = 0.0075). We conclude that low energy photon beams are more suitable for the treatment of early glottic cancers, especially if the lesion grossly invades the anterior commissure.

DOI： 10.18926/AMO/31630

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Language：Japanese   Publishing type：Research paper (bulletin of university, research institution)   Publisher：岡山大学医学部保健学科  

150KV X線,中性子線及び炭素線を照射したマウスNlH3T3細胞の生存率曲線のLD10から60Coγ線に対する生物学的効果比(RBE)を求めた.RBEは150KV X線では1.26,中性子線では2.44,炭素線(LET13,20,50,90,140,150,153,200keV/μm)ではそれぞれ1.41,1.47,2.22,2.61,1.61,2.05,1.57であった.LETとRBEの関係では100keV/μm付近にピークを認めた.150KV X線のLETは13keV/μm,中性子線のLETは70keVμmに相当した.60Coγ線の潜在性致死損傷からの回復(PLDR)は大きかった.炭素線照射でもPLDRが観察されるがLETが大きくなるとPLDRは減少したが,LET90keV/μmの炭素線でもPLDRが認められた

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

We observed modulation of the intracellular accumulation and retention of adriamycin (ADR) by metabolic inhibitors in Ehrlich ascites tumor cells (wild type EAT cells) and their ADR-resistant EAT strain. In the wild type EAT cells, ADR accumulation was increased by 0.2 mM of 2,4-dinitrophenol (2,4-DNP), 1 mM of sodium azide (NaN3) or 1 mM of potassium cyanide (KCN), which were the metabolic inhibitors and its efflux was inhibited by the metabolic inhibitors several fold. These results indicate that in wild type EAT cells, one of the mechanisms which increase the intracellular accumulation of ADR involve inhibition of efflux which may be inhibited by these metabolic inhibitors. In ADR-resistant EAT strain 2,4-DNP or KCN increased the ADR accumulation, but NaN3 did nor affect it. Further; ADR efflux in the ADR-resistant cells after incubation with the metabolic inhibitors were similar to that found in the control. These indicates that in the ADR-resistant cells, NaN3 does not affect ADR accumulation and retention, and that the increase in the ADR accumulation by KCN and 2,4-DNP was considered to be due to the influx rather than efflux. In addition, 2,4-DNP, NaN3 or KCN inhibited ADR efflux in the wild type GAT cells but not in the ADR-resistant EAT strain. These suggests that there is an efflux mechanism in the ADR-resistant EAT strain that involves an energy system that differs from the energy system in wild type EAT cells or does not depend on energy produced by the metabolic inhibitors.

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In the present study, the mechanism involved in the enhancement of adriamycin (ADR) accumulation by cepharanthin (CEP) and hyperthermia were examined. The accumulation of ADR and Fluo3 tan indicator of Ca2+) was increased by treatment with CEP. This suggests that ADR accumulation may increase due to increased influx of Ca2+). The ADR accumulation increased with increasing the KCI concentration in the presence of CEP when the KCI concentation was over 200 mM. This demonstrates that ADR accumulation increases with treatment with CEP and increasing the KCI concentration after the cell membrane potential reaches 0. ADR accumulation did not change with the extracellular pH in the absence of NaHCO3. CEP increased the ADR accumulation with increasing extracellular pH, regardless of NaHCO3. This suggests that CEP may affect the Hf flux, and consequently increase ADR accumulation regardless of NaHCO3. Further, it increased with increasing extracellular pH in the presence of NaHCO3, regardless of CEP It is thought that the interaction between H+ and HCO3- may cause increased ADR accumulation. ADR accumulation was decreased by DIDS and amiloride at 37 degrees C. ADR accumulation in the presence of amiloride at 45 degrees C was increased compared with that at 37 degrees C. However; the accumulation combined with amiloride and hyperthermia was lower than with treatment with ADR only at 37 degrees C. This indicates that ADR accumulation is decreasd by amiloride and increased by hyperthermia. ADR accumulation is further decreased by DIDS at 45 degrees C compared with 37 degrees C. This suggests that the H+ flux in hyperthermia is influenced by Cl-HCO3- exchanger but not Na+/H+ exchanger.

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To evaluate the role of combined hyperthermia and radiotherapy in the management of soft tissue sarcoma, a multi-institutional retrospective analysis was under taken by the JASTRO Hyperthermia Study Group. Clinical records of soft tissue sarcoma treated with thermoradiotherapy in three Japanese institutions were reviewed. In total 71 tumors were enrolled at this study. Thirty-eight male and 33 female. Main treatment sites were lower limbs(26) and pelvic cavities(15). Maximum tumor diameter was 11.6 ±6.6 cm and maximum tumor depth was 7.2 + 4 cm. Average radiation dose was 47.1 ±14.1 Gy and average heating sessions and average heating time were 7.1 ±3 and 47.8±7.5 min, respectively. Primary effect 1 month after combined treatment was CR in 8 tumors, PR in 25 tumors and NR in 38 tumors, and the overall response rate was 36 % (33/71 ). Local response rate according to radiation dose, 33 % at less than 30 Gy and 88 % at more than 60 Gy, respectively. Higher radiation dose showed higher response rate. Correlation between intra-tumor (maximum, average and minimum) temperature and local response was analyzed. No positive correlation was observed. The relation between various factors including tumor and treatment parameters and survivals were analysed. Multi-variate analysis showed that the treatment site (lower extremities), tumor volume less than 800 cm3, average heating time more than 45 min and no previous radiation history were statistically significant factors. © 1998, Japanese Society for Therapeutic Radiology and Oncology. All rights reserved.

DOI： 10.11182/jastro1989.10.69

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

The cytotoxic action of adriamycin is influenced by its intracellular accumulation. Therefore, it is important to clarify the mechanisms of adriamycin influx and efflux. In the present study, the influence of the extracellular KCl and Ca2+ concentration the extracellular pH and the presence of NaHCO3 on the ADR accumulation was investigated in order to study the mechanisms in ADR accumulation influenced by ions. The extracellular KCl concentration did not affect the intracellular ADR accumulation This suggests the cell membrane potential does not affect the ADR accumulation since it is influenced by the KCl concentration. The intracellular intensity of fluorescence of Fluo3 an indicator of Ca2+, increased between 0 and 20 mM of the extracellular concentration of Ca2+ ion. However; the ADR accumulation did not change between 0 and 20 mM of the extracellular concentration of Ca2+. This indicates that the extracellular concentration of Ca2+ does not affect the ADR accumulation under physiological conditions since 20 mM of Ca2+ is beyond normal physiological conditions. Further, the intracellular fluorescence of Fluo3 decreased as inn-easing the extracellular pH. In contrast, the ADR accumulation increased as increasing the extracellular pH. These suggest that the ADR accumulation increases as decreasing the intracellular Ca2+ as changing the extracellular pH- In wild type strain, the ADR accumulation did not change by the extracellular pH in the absence of NaHCO3, but increased as increasing the extracellular pH in the presence of NaHCO3. This suggests that the ADR accumulation in the wild type strain is influenced by NaHCO3 but the extracellular pH. In the ADR-resistant strain, the ADR accumulation decreased as increasing the extracellular pH regardless of NaHCO3. However, the accumulation of ADR increased as increasing the extracellular pH when the adjustment of pH was carried out with IN HCl. This suggests that Cl- may play an important role in the ADR influx in the ADR-resistant strain.

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Authorship：Last author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society for Therapeutic Radiology and Oncology  

DOI： 10.11182/jastro1989.10.161

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We present a case of endometrial carcinoma accompanied with mucinous cystadenoma in a 70-year-old postmenopausal woman treated with tamoxifen for breast cancer demonstrated by MR imaging. Tamoxifen therapy (20 mg/day) had been carried out for more than 11 years since the surgical procedure for the primary tumor. MR images showed a markedly enlarged uterus containing endometrial carcinoma, cystic atrophy of the endometrium, and a right adnexal mass with multicystic components of various signal intensities.

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Cepharanthin enhances the cytotoxicity of adriamycin by inhibiting its efflux incorporated into cancer cells. Therefore, it may also enhance accumulation of adriamycin, and then enhance toxicity by adriamycin in normal cells as well as in cancer cells. In this study, we first examined influence of cepharanthin on the accumulation of adriamycin in normal liver cells or spleen cells in vitro and in vivo. Cepharanthin lowered the accumulation of adriamycin in liver cells, in both in vitro and in vivo. In spleen cells, it enhanced adriamycin accumulation slightly in vitro, but did not affect that in vivo. Further, cepharanthin lowered the amount of adriamycin in plasma. This suggests that decreased levels of adriamycin in plasma may be one of factors in the decrease of adriamycin accumulation in liver cells. On the other hand cepharanthin enhanced the NK2280 accumulation used for an indicator of cell membrane potential for 60-100 minutes in liver cells, but did not change that in spleen cells. These suggest that the cell membrane potential may not affect the adriamycin accumulation in both cells since adriamycin accumulation increases with increasing accumulation of NK-2280. Moreover, no change in adriamycin efflux of liver cells was demonstrated by the treatment of cepharanthin. This indicates that the decrease in adriamycin accumulation in liver cells may not be due to the inhibition of adriamycin efflux. In conclusion, cepharanthin enhances adriamycin accumulation in cancer cells, but Cowers its accumulation in normal liver cells and does not affect that in spleen cells. Therefore, cepharanthin may be useful in cancer chemotherapy.

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The purpose of this study was to evaluate the characteristic findings of cervical carcinoma in dynamic MR imaging with a turbo-FLASH technique and to investigate the cause of the hyperintense rim surrounding the tumor on dynamic MR images by comparing them with the pathological findings in the resected specimens. Sixty consecutive patients with cervical carcinoma were included in this study. Dynamic MR imaging was performed with the rapid administration of Gd-DTPA using the turbo-FLASH technique. After dynamic MR imaging, T1-weighted spin echo (SE) images were obtained. Dynamic patterns of the lesions were investigated from images acquired in the early and late phases of dynamic MR imaging. The causes of the hyperintense rim were investigated by comparing dynamic MR images with the pathological findings. Most of the cervical carcinomas showed higher signal intensity than normal cervical stroma in the early phase of dynamic MR imaging. The pathological findings of the hyperintense rim on dynamic MR images differed according to the time of appearance of the hyperintense rim. Dynamic MR imaging with the turbo-FLASH technique, which shows high contrast between the lesion and normal cervical stroma, should be performed before obtaining contrast- enhanced T1-weighted SE images in patients with cervical carcinoma.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT-RAVEN PUBL  

Purpose: Our goal was to investigate the usefulness of dynamic MRI with the turbo-FLASH technique in estimating myometrial invasion by endometrial carcinoma.
Method: Forty-six patients with endometrial carcinomas were evaluated with pathologic correlation. Dynamic MRI was performed with the rapid administration of Gd-DTPA using the turbo-FLASH technique.
Results: The inner muscle layer showed more rapid contrast enhancement effects than the outer muscle layer even after menopause. Contrast-to-noise ratio between the inner muscle layer and endometrial carcinoma was maximum at similar to 50 s after administration of Gd-DTPA. In postmenopausal women, the accuracy in estimating myometrial invasion with T2-weighted images, contrast-enhanced T1-weighted images, and dynamic MRI was 66.7, 77.8, and 92.6%, respectively.
Conclusion: Dynamic MRI with the turbo-FLASH technique is considered to be a useful imaging method for the estimation of myometrial invasion by endometrial carcinoma, especially in postmenopausal patients.

DOI： 10.1097/00004728-199611000-00003

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The acquisition of resistance to anticancer drugs is an important problem in cancer chemotherapy. Ehrlich ascites tumor cells (wild type EAT cells) were grown in a medium containing 1 mu g/ml adriamycin (ADR) (ADR-resistant strain) and the cells that proliferated were established in our laboratory. Intracellular ADR accumulation and the killing effect of ADR in the ADR-resistant strain were markedly reduced compared with those of the wild type EAT cells. In this study, we initially observed thermosensitivity in both strains and found no difference in the thermosensitivity. These findings demonstrated that hyperthermic treatment was effective in the ADR-resistant strain as well as in the wild type EAT cells. On the other hand, thermotolerance is an important problem in the hyperthermic treatment of cancer. We next observed the thermotolerance of both strains and found that the thermotolerance in the ADR-resistant strain was greater than that in the wild type EAT cells, but the thermotolerance was almost restored within 24 hours. Furthermore, we investigated the influence of thermotolerance on the intracellular accumulation and killing effects of ADR in the wild type EAT cells. There was no difference in the intracellular ADR accumulation and the killing effect of ADR between non-thermoresistant cells and thermoresistant cells. These results suggested that hyperthermia was effective in the ADR-resistant cells either alone or combination with ADR.

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Uterine cirsoid aneurysm is uncommon. It is important to make a diagnosis of this disease preoperatively, because repeated curettages may induce life-threatening massive genital bleeding. We present a case of a 51-year-old woman with uterine cirsoid aneurysm in whom MRI and MRA were very useful for the preoperative diagnosis. The radiologic appearances on ultrasonography, CT, conventional SE MRI, MRA, dynamic MRI, and pelvic angiography are presented. Conventional SE T1-weighted and T2-weighted images demonstrated multiple flow voids in the uterus and bilateral adnexal regions, MRA demonstrated a cluster of distinct, tortuous, and coiled vascular channels in the pelvis. MRA could obtain images almost equal to angiography and was considered to be an excellent noninvasive imaging technique for the diagnosis of uterine cirsoid aneurysm.

DOI： 10.1097/00004728-199603000-00023

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Intracellular accumulation of adriamycin (ADR) has been reported to be influenced by cell membrane potential. We first evaluated intracellular accumulation of ADR and 3,3'-(di-n-hexyl)-2,2'-oxacarbocyanine iodide (NK-2280), an indicator of cell membrane potential, and found a good correlation between ADR and NK-2280 intracellular accumulation in several cell lines. This suggests that ADR accumulation may, be influenced by cell membrane potential ol the mechanisms of NK-2280 accumulation may be similar to those of ADR accumulation.
Next, we observed the influence of the Na+/H+ exchanger and Cl-/HCO3- exchanger on the intracellular accumulation of ADR and NK-2280, and found that ADR accumulation decreased with increasing concentrations of 3,5-diamino-6-chloro-N-(diaminomethylene)pyrazinecarboxamide (amiloride), an inhibitor of the Na+/H+ exchanger; and 4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid (DIDS), an inhibitor of the Cl-/HCO3- exchanger; however;NK-2280 accumulation was increased by amiloride, and decreased by DIDS. The increased accumulation of NK-2280 induced by amiloride may be due to the increased cell membrane potential caused by the inhibition of H+ ion efflux and Na+ ion influx due to the inhibition of the Na+/H+ exchanger The decreased accumulation of NK-2280 may be also due to the decreased cell membrane potential caused by the inhibition of CP ion efflux due to the inhibition of the Cl-/HCO3- exchanger by DIDS. However; the decreased rate caused by DIDS was greater than the increased rate caused by amiloride. Therefore, it is suggested that the decreased accumulation of NK-2280 by DIDS may be influenced by other factors apart from cell membrane potential. These results suggest that the Cl-/HCO3- exchanger may be related to both ADR accumulation, and NK-2280 accumulation, and that the Na+/H+ exchanger may be related to ADR accumulation, but not NK-2280. This suggests that the Cl-/HCO3- exchanger is of low selectivity.

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Authorship：Last author   Language：Japanese   Publisher：岡山大学医学部保健学科  

エールリッヒ腹水癌細胞とそのアドリアマイシン耐性細胞において蛍光pH指示薬2', 7'-bis-(2-carboxyethyl)carboxyfluorescein](BCECF)の蛍光量をフローサイトメトリーで測定することによって細胞内pHの検量曲線を作成することができた.このことより,これらの細胞においてBCECFの蛍光量で細胞内pHの変化を簡易に比較できることを示唆した.アミロライド[3, 5-diamino-6-chloro-N-(diaminomethylene)pyrazinecarboxamide],及びアミロライド誘導体MH-12-43[N-amidino-3-amino-6-chloro-5-(N-ethyliso-propylamino)pyrazinecarboxyamide]の細胞内pHへの影響をエールリッヒ腹水癌細胞で観察した.37℃では,0.5mMアミロライド,0.05mM MH-12-43により細胞内pHは減少し,42℃処理により更に減少した.42℃において,0.05mM MH-12-43による細胞内pHの減少は,0.5mMアミロライドによる減少より大きかった

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Adriamycin (ADR) is frequently used in the clinical treatment of cancer. ADR resistance is one of the most serious problems in cancer chemotherapy. Several factors have been demonstrated to be related to ADR resistance. Among these factors, the influx of ADR into cells and the efflux of ADR out of cells are important aspects of its effectiveness. In this study, we investigated the influence of FK506 on the ADR accumulation and retention in the ADR-resistant strain of Ehrlich tumor cells. The ADR accumulation in the ADR-resistant strain was about 40% of that of wild EAT cells. The addition of 50 mu M FK-506 on the ADR accumulation and retention in the ADR-resistant strain of Ehrlich tumor cells. The ADR accumulation in the ADR-resistant strain was about 40% of that of wild EAT cells. The addition of 50 mu m FK506 inhibited the efflux of ADR completely. ADR accumulation with the addition of 50 mu M FK-506 to the ADR-resistant strain was about 80% of that found in the wild strain. Thus, it was suggested that the increase in ADR accumulation by the ADR resistant strain by about 40%, when 50 mu m FK-506 was added might be due to complete inhibition of ADR efflux by P-glycoprotein, that the decrease of about 20% in ADR accumulation of the ADR-resistant strain compared to that in parent cells might be caused by problems with ADR influx. Therefore, it is necessary that the mechanisms which cause the decrease of ADR influx in the ADR-resistant strain be clarified.

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The influence of several oncogenes on drug resistance has recently been show by transfection studies. Therefore, we investigated the influence of transfection on adriamycin (ADR) in cell line transfected with several oncogenes accompanied with pSV2neo vector. There were differences in both the intracellular accumulation of ADR and its sensitivity among the transfectants rued in this study. There was a good cor? elation with the intracellular accumulation of ADR and its sensitivity (r=0.76, P=0.002). Further, there were no differences in the ADR efflux among the ras-family transfectants. Therefore, the changes in ADR sensitivity may be due to changes in ADR influx. On the other hand the ADR accumulation showed an increase of 1.14-2.29 fold by the treatment of 10 mu g/ml CEP. Moreover; the ADR accumulation showed an increase of 1.29-3.11 fold by hyperthermia at 42 degrees C. There was no significant difference in the ADR accumulation at 42 degrees C among the transfectants, suggesting that the influence on the ADR accumulation may be counteracted by hypethermia at 42 degrees C.

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NIH3T3 cells and NIH3T3 cell lines, which were transfected with several oncogenes accompanied by pSV2neo vector, were observed for their survival rate when treated with commonly used anticancer drugs. The survival rates in the cell line transfected with the pSV2neo vector only did not differ significantly from that of parental NIH3T3 cells against bleomycin, nimustine and adriamycin, but it was significantly more resistant to cisplatin and more sensitive to mitomycin C. Therefore, the survival rate in each transfectant was compared with that in the pSV2neo transfectant. The Val-12, v-Ha-ras, v-int-2, v-erbB or v-abl transfectants accompanied by pSV2neo vector were significantly more sensitive to cisplatin than transfection with pSV2neo vector only. The Val-12, v-Ha-ras, v-int-2 and v-abl transfectants were significantly more sensitive, and the v-erbB transfectant more resistant to bleomycin than the pSV2neo transfectant. The v-int-2, v-erbB, frg, v-raf and v-myc transfectants were more sensitive, and the v-Ha-ras transfectant more resistant to nimustine than the pSV2neo transfectant. The N-ras, v-Ha-ras, v-sis, v-int, v-abl and v-myc transfectants were significantly more sensitive to adriamycin than the pSV2neo transfectant. The v-sis and v-int-2 transfectants were more sensitive, and the c-Ki-ras, Val-12, v-erbB and the v-src transfectants more resistant to mitomycin C than the pSV2neo transfectant. Thus there was no relationship between the drug sensitivity and the location of oncogenes, but the transfection was associated with either increased or decreased sensitivity to a number of commonly used anticancer drugs. Therefore, it may be important to take into consideration or overexpression of oncogenes in cancer chemotherapy.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD LONDON  

We compared adriamycin (ADR) accumulation with the intensity of intracellular fluorescence of 3,3'-(di-n-hexyl)-2,2'-oxacarbocyanine iodide (NK-2280), an indicator of cell membrane potential, after hyperthermia and examined the effects of cepharanthin (CEP) on the accumulation of ADR and NK-2280 in wild and ADR-resistant strains of Ehrlich ascites tumour (EAT) cells. Among wild 0.2 and 1-mu g ADR-resistant strains of EAT cells, intracellular accumulation of both ADR and NK-2280 decreased with an increase of ADR resistance. Hyperthermia at 42 degrees C and CEP induced a marked increase in accumulation of both ADR and NK-2280 in the ADR-resistant strains of EAT cells. The increase in ADR accumulation by hyperthermia and CEP is possibly due to an increase in the cell membrane potential and the inhibition of ADR efflux by CEP respectively. In the wild strain of EAT cells, we also evaluated the effect of extracellular pH change on ADR accumulation and the cell membrane potential and their alteration by hyperthermia and CEP. ADR accumulation decreased as pH decreased, but the cell membrane potential was not appreciably affected by pH change so far examined. Hyperthermia alone or combined with CEP significantly increased ADR accumulation in a pH range from 6.2 to 7.6. Hyperthermia increased the accumulation of ADR in the tumour cells, although its pH dependency was not completely resolved. CEP enhanced ADR accumulation more markedly in ADR-resistant cells than in wild-type cells. Therefore, the combination of hyperthermia and CEP may be very effective to increase the ADR cytotoxicity to ADR-resistant tumours.

DOI： 10.3109/02656739509004945

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We examined the influence of the extracellular pH, an inhibitor of Na+/H+ exchanger: 3,5-diamino-6-chloro-N-(diaminomethylene) pyrazinecarboxamide (amiloride), and an an inhibitor of Cl-/HCO3-: 4,4-diisothiocyanatostilbene-2,2-disulfonic acid (DIDS) on the accumulation of adriamycin (ADR) in Ehrlich ascites tumor cells and their adriamycin-resistant strain. A good correlation between the increases in ADR accumulation and the extracellular; pH was shown in the both strains The ADR accumulation decreased with an increasing concentration of amiloride or DIDS in both strains. These findings demonstrate that the influx of ADR was related closely to the efflux of H+ or to the activities of Na+/H+ ex-changer and Cl-/HCO3- exchanger. Therefore, raising the extracellular pH and enhancement of the activities of either Na+/H+ exchanger of Cl-/HCO3- exchanger may result in the potentiation of the cytotoxic effect of ADR through increase of ADR influx.

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：金原出版(株)  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

External capacitive heating is the usual method of electromagnetic wave heating, in which the tumor is caught and heated between two opposite applicators. Using a phantom, the authors developed and evaluated the performance of a new capacitive heating applicator designed for simultaneous radiohyperthermotherapy (SRH) in which the electron beam irradiation is provided from above an external capacitive heating applicator for the treatment of superficial and shallow-seated tumors. The trial applicator was constructed to fulfill the following conditions: 1. use of an electrode plate which does not affect the electron beam depth dose, 2. a uniform thickness to maintain flatness of the electron beam, and 3. a cooling function to prevent damage to normal skin tissue and enhance the therapeutic gain factor. This applicator was comprised of a 0.1-mm-thick copper electrode and a 5-mm-thick cooling chamber. The depth of the 80 % dose of the new applicator was 21 mm with a 9-MeV electron beam and 36 mm with a 15-MeV electron beam, which was comparable to the effect of a conventional irradiation bolus. The temperature distribution produced by the trial applicator was symmetrical on both sides from the center of the applicator. The 50 % specific absorption rate region was 6.4 cm wide at a depth of 1 cm from the phantom surface and 2.8 cm wide at a depth of 3 cm. There have been no previous reports on the development of an external capacitive heating applicator designed for the SRH of superficial and shallow-seated tumors; this is the first such report. SRH of these tumors can be performed simply, noninvasively and repeatedly by means of this new applicator.

DOI： 10.18926/AMO/31087

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We investigated the effects of amiloride and its derivative MH-12-43 on the thermosensitivity of adriamycin-resistant cells. Effects of hyperthermia at 42 degrees C were enhanced by 0.5 mM amiloride and 0.05 mM MH-12-43, which resulted in no decrease in survival rate by the treatment at 37 degrees C for 120 min. Therefore, the combination of hyperthermia and amiloride derivatives was effective in the adriamycin-resistant cells as well as wild type cells. Further, since the survival rates by the treatment with 0.05 mM MH-12-43 were markedly lower than those with 0.5 mM amiloride from hyperthermia at 42 degrees C, MH-12-43 might be more effective than amiloride.

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DOI： 10.3191/thermalmedicine.10.189

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(株)オンコロジア社  

natural human tumor necrosis factor-α(nTNF-α)とnatural human interferon-α(nIFN-α)の合剤のヒト由来大腸癌細胞株RPM 14788細胞におけるin vitroでの温熱増感作用を確認した。大腸癌術後の腹壁転移病巣にnTNF-α/nIFN-α計93×107Uの局所注入と各回60分,計37回の温熱療法とcarmofur計34,500mgの経口投与を併用したところ,造影CT上腫瘍内部に広範な低濃度域が出現して33%縮小し切除可能となった。摘出標本では造影CT上の低濃度域は広汎な凝固壊死で腫瘍細胞はみられなかった

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直腸癌術後の局所再発の4患者について,放熱線温熱療法併用中の,一時的な血清CEA上昇について検討した。放射線療法のみの患者ではCEAは上昇しなかった。CEAの上昇のピークは,温熱療法平均1.8回施行後で見られ,その値は温熱療法施行前の約1.5倍に達した。温熱療法前のCEA値が高い症例では,その上昇も高かった。42°C以上を維持できた時間が長い症例では,CEAの上昇の期間も長い傾向にあり,42°C以上の時間というのは,温熱療法の強さを反映していると考えられた。しかし,CEA上昇率は同時に加温した群と,照射後に加温した群では差異が認められなかった。CEA放出は,温熱療法に伴ってみられる現象であり,温熱療法の指標として今後検討する価値があると考える

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We performed a long-term follow-up of 4 patients with penile cancer who underwent hyperthermotherapy from August 1985 until August 1992. Hyperthermia was applied using a frequency of 350 MHz with a waveguide applicator twice a week for 60 min each for an average of 9.5 times (varying from 6 to 13 times). The total heating time that the temperature of urethra could be kept above 42-degrees-C, was 166 min on the average (ranging from 0 to 463 min). Two patients classified as stage I according to the Jackson classification and 1 patient classified as stage IV underwent combined radiotherapy and received an average radiation dose of 53 Gy (range, 40-70 Gy). Among these patients 2 underwent combined chemotherapy with bleomycin or peplomycin. Malignant cells disappeared posttherapeutically and in August 1992, after an average of 5 years and 9 months (varying from 4 years 6 months to 6 years 10 months), the patients were free of recurrences. The one patient on stage IV had extensive invasion of the abdominal wall, but still recovered completely. One patient on stage III underwent combined chemotherapy and hyperthermotherapy, but heating had obviously been insufficient. There was a residue of malignant cells after the treatment and we performed a penectomy. Regarding functional preservation of the penis a multidisciplinary therapy incorporating hyperthermotherapy can be expected to increase the curativity. This indicates that it could induce in an advanced case, where an operation would be difficult, complete remission.

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陰茎癌6例に温熱療法を施行し長期経過観察を行った。治療部位は4例が陰茎癌原発巣で,2例が陰茎癌鼠径リンパ節転移術後の再発巣であった。陰茎癌原発巣の治療では,放射線化学温熱療法を行ったstage 1,stage 4の各1例,放射線温熱療法を行ったstage 1の1例で,治療後腫瘍細胞が消失しCRとなり,平均5年9ヵ月間(4年6ヵ月〜6年10ヵ月)再発なく経過した。stage 4の1例は広範に腹壁浸潤していたが完全に治癒した。鼠径リンパ節転移術後の再発部の治療では,治療後腫瘍内部が広範な凝固壊死になったが,この周囲に腫瘍が残存し予後は不良であった。温熱療法を加えた集学的治療は陰茎癌原発巣の形態機能保存療法での根治性の増強と再発予防を期待でき,手術困難な進行例も完全寛解しうる有用な治療法と思われた

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DOI： 10.18926/amo/31569

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：岡山医学会  

NIH3T3細胞における塩化ベンザルコニウムの温熱耐性誘導能を調べた.1)塩化ベンザルコニウムの濃度上昇,接触時間延長とともに細胞毒性が増加した.0.002%塩化ベンザルコニウムの20分間処理にて,細胞の生存率は無処理細胞と比べて50%に減少した.2) 0.002%塩化ベンザルコニウムの20分間処理後の培養中に温熱耐性が誘導され,処理後15時間目に最大となり,以後徐々に消失した.処理後15時間目の45°C加温にて,対照群と比べてD0比で3.8倍の温熱耐性が出現した.3) 0.002%塩化ベンザルコニウムにて誘導される温熱耐性の大きさは,その処理時間が長くなるにしたがって大きくなった.以上の結果より,塩化ベンザルコニウム処理による細胞膜障害と温熱耐性誘導との間に関連性が示唆された

DOI： 10.4044/joma1947.105.1-2_43

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Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)  

CiNii Article

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society for Thermal Medicine  

Amilorid, 3, 5-diamino-6-chloro-N- (diaminomethylene) pyrazinecarboxamide, and its derivative MH-12-43, N-amidino-3-amino-6-chloro-5- (N-ethylisopropylamino) pyrazinecarboxamide, were studied for cytotoxicity, thermosensitivity and changes of intracellular pH (pH_i) in Ehrlich ascites tumor cells (EAT cells). Similar cytotoxicities were observed in MH-12-43 at lower concentrations than amiloride. After treatment with 0.5 mM amiloride or 0.05 mM MH-12-43 at 37°C for 120 min, no decrease in survival rate were shown. The effects of hyperthermia at 42°C were enhanced by amiloride and MH-12-43, and the more decrease in suvival rate with 0.05 mM MH-12-43 was observed rather than that with 0.5 mM amiloride from hyperthermia at 42°C. The treatment of 0.5 mM amiloride or 0.05 mM MH-12-43 reduced pH_i at 37°C, while the more reduction was observed by the treatment at 42°C. The reduction of pH_i by 0.05 mM MH-12-43 was more substantial than that of 0.5 mM amiloride at 42°C. These suggest that the enhancement in the hyperthermic effects by amiloride or MH-12-43 may be due in part to a decrease in pH_i.

DOI： 10.3191/thermalmedicine.9.310

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Language：Japanese   Publisher：Japanese Society for Thermal Medicine  

In the period from November 1984 until May 1993 hyperthermia was applied to seven patients with local recurrences of rectal cancer. For the heating we used a BSD made BSD-1000 for five patients and an Omron made HEH-500C for two patients. Hyperthermia was performed on the average 8.7 times (range : 3-18) for each patient for 60 minutes each. All patients underwent combined radiotherapy and received a mean radiation dose of 45 Gy (range : 9-60 Gy). Five patients underwent heating within 1 hour after irradiation and two patients simultaneously with the irradiation. Five patients underwent combined chemotherapy and two patients immunotherapy. Before the treatment all patients had painful lesions, but pain decreased posttherapeutically in six patients. Performance status improved in two patients. High carcinoembryonic antigen levels prior to the therapy in five patients decreased in all cases after treatment. Posttherapeutical computed tomograms revealed only minor response or no changes. After the treatment four patients died of exacerbations of recurrent tumors and two patients of distant metastases. The 50 % survival time after initiation of the treatment was 24 months. Hyperthermia combined with radiotherapy, chemotherapy and or immunotherapy was useful for the alleviation of pain in patients who developed local recurrence after surgery and could be expected to improve survival after recurrences.

DOI： 10.3191/thermalmedicine.9.281

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DOI： 10.18926/amo/31569

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：金原出版(株)  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

The effects of cepharanthin (Ce), glycyrrhizin (G), verapamil (V), and G plus V on induced thermotolerance in NIH3T3 cells were studied. Cells were heated with or without the drug at 45-degrees-C for 20 min (the first heating), incubated at 37-degrees-C for 12h (the incubation period), and heated again at 45-degrees-C for 0-210 min (the second heating). G and V were added throughout the experiment, while Ce was added throughout the experiment or during only the first or second heating, or the incubation period. The cells were harvested after the second heating to evaluate cell surival. In control experiments without any drug, thermotolerance developed and reached the highest peak in the cells incubated for 12h at 37-degrees-C. However, thermotolerance in the control cells was suppressed by incubating them at 0-degrees-C, but developed by subsequent incubation at 37-degrees-C. This suggests that the acquisition of thermotolerance by the cells required metabolic processes during the incubation at 37-degrees-C. When each drug was present throughout the experiment, only Ce or the combined use of G and V was effective in reducing thermotolerance. Thermotolerance was also suppressed in the presence of Ce during the second heating. These results indicate that Ce reduces thermotolerance by enhancing thermosensitivity rather than by inhibiting the development of thermotolerance.

DOI： 10.18926/AMO/32672

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society for Thermal Medicine  

DOI： 10.3191/thermalmedicine.8.1

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society for Thermal Medicine  

Simultaneous radiohyperthermotherapy (SRH) is a combined hyperthermia-radiation therapy in which radiation is given during heating. Mutual interference between the high energy radiotherapy system (Toshiba LMR-15A) and the 13.56MHz capacitive heating system (Omron HEH-500C) was examined using phantoms prior to clinical trials. Phantoms were irradiated and heated simultaneously at right angles. The energy and flatness of irradiation were measured using films and were not affected by the heating system within the range of clinical use. The temperature increase was measured with a thermocouple thermometer, and the temperature distribution was determined by liquid crystal thermometer. The high energy radiotherapy system did not affect the heating device set power, the temperature increase and distribution during simultaneous ti eatiiieiiL. This study clarified that these apparatuses work simultaneously without clinically significant mutual interference. SRH using these apparatuses can be safely applied to clinical study.

DOI： 10.3191/thermalmedicine.8.318

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society for Thermal Medicine  

An adriamycin (ADR) -resistant cell line derived from Ehrlich ascites tumor cells (wild EATC) was established in our laboratory. In this report, difference for thermosesitivity and thermotolerance between wild EATC and ADR resistant EATC were observed. ADR uptake and killing effect of ADR in thermoresistant-induced wild EATC in comparison with non-treated wild EATC also were evaluated.<BR>1) There was no difference for thermosensitivity between wild EATC and ADR resistant EATC.<BR>2) ADR resistant EATC showed bigger magnitude of thermotolerance than wild EATC.<BR>3) ADR uptake in thermoresistant-induced wild EATC showed no change in comparison with that in wild EATC. The killing effect of ADR also had no change in both cells.

DOI： 10.3191/thermalmedicine.8.291

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society for Thermal Medicine  

Simultaneous radiohyperthermotherapy (SRH) is a combined hyperthermia-radiation therapy in which radiation is given during heating. An in vitro study was performed on NIH3T3 cells using ⁶⁰Co γ-ray for irradiation and a water bath for heat treatment. The thermal enhancement ratio increased after simultaneous treatment compared to sequential treatment with heating for 90 min at 43°C and irradiation. Simultaneous treatment was more cytotoxic than sequential treatment with heating for 20 min at 45°C and irradiation of 6 Gy. A clinical trial was performed on a 57-year-old female with post-operative recurrence of rectal carcinoma. This is the first reported clinical case treated with true SRH in which external irradiation was administered during mid RE capacitive heating. Twelve SRH treatments were performed on the recurrent lesion at a frequency of twice a week for six weeks using the high energy radiotherapy system (Toshiba LMR-15A) and the 13.56MHz capacitive heating system (Omron HEH-500C). Average temperature at the time of irradiation in mid heating was 41.1°C. The patient received 60 Gy in 30 fractions over six weeks. There was a dramatic reduction in pain after treament. The tumor marker CEA level decreased after treatment. On CT images taken after treatment, the tumor site became a low density area which indicated necrosis. There were no side effects encountered. These results suggest that further clinical study of SRH should be performed to clarify its advantages.

DOI： 10.3191/thermalmedicine.8.326

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：岡山医学会  

NIH 3T3細胞を用いて,in vitroでの温熱耐性出現の時間経過にあたえるケルセチンの抑制効果を検討した.1) 37°Cでのケルセチンの殺細胞効果は,ケルセチンの濃度の増加(10 kg/mlおよび100 μg/ml)および接触時間の増加(12, 48および72時間)とともに増加したが,その程度は軽度であった.2)ケルセチン(10 μg/ml)自身の加温致死増感効果はみられなかった.3)ケルセチン(10 μg/ml)は37°Cでの指数増殖状態の細胞の増殖を72時間程度抑制した.4)ケルセチン(10 μg/ml)を45°C20分間初回加温後,2回目加温前の加温間隔時に投与することにより,温熱耐性の形成に要する時間経過の遅れがみられたが,一方,最終的に獲得される温熱耐性の形成の大きさに与える影響は少なかった.5)ケルセチン(10 μg/ml)は温熱耐性の消失の時間経過に影響を与えなかった

DOI： 10.4044/joma1947.103.7-8_973

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=1991&ichushi_jid=J00175&link_issn=&doc_id=19870035220024&doc_link_id=http%3A%2F%2Fousar.lib.okayama-u.ac.jp%2F14403&url=http%3A%2F%2Fousar.lib.okayama-u.ac.jp%2F14403&type=%89%AA%8ER%91%E5%8Aw%81F%89%AA%8ER%91%E5%8Aw%8Aw%8Fp%90%AC%89%CA%83%8A%83%7C%83W%83g%83%8A&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F80034_3.gif

Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：岡山医学会  

DOI： 10.4044/joma1947.101.11-12_1075

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=1989&ichushi_jid=J00175&link_issn=&doc_id=19870035100007&doc_link_id=http%3A%2F%2Fousar.lib.okayama-u.ac.jp%2F40798&url=http%3A%2F%2Fousar.lib.okayama-u.ac.jp%2F40798&type=%89%AA%8ER%91%E5%8Aw%81F%89%AA%8ER%91%E5%8Aw%8Aw%8Fp%90%AC%89%CA%83%8A%83%7C%83W%83g%83%8A&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F80034_3.gif

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.4044/joma1947.101.1-2_1

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Other Link： http://search.jamas.or.jp/link/ui/1990168645

Language：Japanese   Publishing type：Research paper (scientific journal)  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：放射線診療研究会  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：金原出版(株)  

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DOI： 10.4044/joma1947.99.7-8_1013

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Other Link： http://ousar.lib.okayama-u.ac.jp/metadata/15987

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHYSIOL CHEM PHYSICS MED NMR  

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