Selection of Particle Beam vs. Photon Beam Radiation Therapy for HCC: Japanese Experience

( Hideyuki Sakurai ),( M Iizumi ),( S Shimizu ),( H. Numajiri ),( M. Mizumoto ),( K. Nakai ),( T. Okumura ) 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Radiation therapy (RT) using conventional fractionation has not been thought to be curative enough for hepatocellular carcinoma (HCC) and it has not been performed as a high priority in comparison to other standard treatments, such as surgery, percutaneous ablation and transcatheter approach. Because the liver is high sensitive to radiation, especially for patients with liver cirrhosis, non-irradiated normal liver volume must be preserved as much as possible when curative radiation is given for HCC. Since many technological progress has been made in radiation oncology in recent years, RTs are used as an important curative treatment option for liver cancer. Stereotactic body radiotherapy (SBRT), which is included in Japanese national health insurance system, is a technique to accurately concentrate doses three-dimensionally on the target with short-term irradiation of 1-2 weeks. This technique can be used for relatively small tumors less than 5 cm with about 90% local control. Recently, Hara K. et al. reported survival result of SBRT comparing radiofrequency ablation using propensity score analysis, and they concluded that SBRT appears to be an acceptable alternative treatment option for patients who are not candidates for RFA. In addition, in Japan, muticenter prospective study of SBRT for untreated solitary primary HCC, so called STRSPH study, is ongoing. Eligible patients are untreated solitary, Child-Pugh score ≦7, Diameter: 1-5cm, UICC 7th. T1, T2, T3bN0M0, performance status score of 0-2, and 20-85 year-old. The primary endpoint / number of cases of this study are 3-year overall survival / 60 cases. Particle beam therapy (PBT: proton beam therapy, heavy ion beam therapy) has unique character of radiation dose distribution, which is called Bragg peak. PBT can accumulate more dose to the target with minimizing normal liver dose. Primary liver tumor is an important indication that has been specified to be of the highest priority by the American Society for Radiology and Oncology (ASTRO). In fact, most of the studies on PBT for HCC are published by Japan, and rather highly evaluated abroad. Eighteen proton facilities and 6 heavy ion facilities are working now in Japan. The local control rate was approximately 90% and the 5-year survival rate was reported to be approximately 50%. According to the results of our hospital, PBT can control 90% of a large tumor of 10 cm or more. Clinical studies of PBT report favorable therapeutic effects, even for not only large tumors but also tumors in elderly patient. In addition, PBT has been clearly shown to play an important role in the treatment of HCC-related portal vein tumor thrombosis (PVTT). When applied as a curative treatment for bulky tumors with portal vein embolism, median survival time of 27 months has been obtained in our study. The clinical study comparing proton vs surgery, which is non-randomized trial using propensity score, is ongoing in Japan (JCOG1315C). Japanese Society for Radiation Oncology (JASTRO) defined identical rule for indication and treatment method in PBT for HCC, and the all data should be registered in the data-base since 2016. We are facing an aging society, although there are indications of surgery and other local treatment, the number of patients who choose curative radiation therapy due to aging and co-existing disease is increasing. But, the history of radical RT for HCC is still short, and sufficient consensus has not been obtained regarding the criteria for its therapeutic indication. RT may become an option for curative local treatment of HCC, but no specific role for RT has been described in the Japanese treatment guidelines. In the future, it is important to proceed with research to clarify the indication of curative radiation therapy, keeping in mind the comparison with other therapies.

Relationship of IGF-I mRNA Levels to Tissue Development in Chicken Embryos of Different Strains

Kita, K.,Noda, C.,Miki, K.,Kino, K.,Okumura, J. Asian Australasian Association of Animal Productio 2000 Animal Bioscience Vol.13 No.12

Insulin-like growth factor-I (IGF-I) mRNA levels in the eyes, heart, liver and breast muscle removed from dwarf egg-type, normal egg-type and normal meat-type chicken embryos at 7, 14 and 20 days of incubation were measured. There was no influence of chicken strain on IGF-I gene expression in the eyes and liver. The IGF-I gene expression in eyes increased significantly along with the incubation period. In the liver, IGF-I gene expression at 20 days of incubation was significantly higher than that at 14 days of incubation. In the muscle, the lowest value for IGF-I gene expression was observed in meat-type chicken embryos. Regression analysis revealed that IGF-I gene expression was significantly correlated to the weights of the eyes and liver, but not the muscle. We conclude that there is little influence of strain on tissue IGF-I gene expression in chicken embryos during incubation but that tissue development in chicken embryos is nevertheless at least partly regulated by the change in IGF-I gene expression.

Influence of Antisense IGFBP-2 Oligo Deoxynucleotide Administration on Tissue IGFBP-2 Gene Expression in Chicks

Nagao, K.,Osada, K.,Murai, A.,Okumura, J.,Kita, K. Asian Australasian Association of Animal Productio 2001 Animal Bioscience Vol.14 No.12

We have examined the influence of antisense oligo deoxynucleotide (ODN) of IGFBP-2 on tissue IGFBP-2 gene expression in chicks. Antisense IGFBP-2 ODN was directly injected into the liver or cerebroventricle. Control birds were injected with vehicle. The hepatic IGFBP-2 gene expression was decreased to approximately 30% of the control at 2 h after injection of antisense ODN. In the brain of chickens injected with antisense ODN, IGFBP-2 mRNA level did not change after 2 h of injection and decreased to approximately 60% of the control after 6 h of injection. These results showed that the expression of IGFBP-2 gene in the liver and brain was successfully suppressed by administrating antisense ODN and that hepatic IGFBP-2 gene expression was quickly suppressed by antisense ODN compared with the brain.

Influence of Refeeding of Protein, Carbohydrate and Fat on Hepatic Insulin-Like Growth Factor-I mRNA Level in Fasted Chicks

Kita, K.,Hangsanet, K.,Okumura, J. Asian Australasian Association of Animal Productio 1998 Animal Bioscience Vol.11 No.3

The influence of refeeding either protein, carbohydrate or fat on hepatic insulin-like growth factor-I (IGF-I) mRNA level in chicks which had been fasted for 2 days was examined. The hepatic IGF-I mRNA was measured by ribonuclease protection assay. Fasting reduced hepatic IGF-I mRNA levels to less than half of those in the fed control. When chicks were refed either a control, protein or carbohydrate diet, IGF-I mRNA levels significantly increased to those in the fed control until 2 hours of refeeding. Refeeding of fat did not alter hepatic IGF-I mRNA levels. The significant correlation between liver weight and hepatic IGF-I gene expression suggests that when chicks are refed after 2-d fasting, the acute increase in hepatic IGF-I gene expression brought about after refeeding may be partly regulated by the increase in liver protein metabolism.

Nutritional and Tissue Specificity of IGF-I and IGFBP-2 Gene Expression in Growing Chickens - A Review -

Kita, K.,Nagao, K.,Okumura, J. Asian Australasian Association of Animal Productio 2005 Animal Bioscience Vol.18 No.5

Nutritional regulation of gene expression associated with growth and feeding behavior in avian species can become an important technique to improve poultry production according to the supply of nutrients in the diet. Insulin-like growth factor-I (IGF-I) found in chickens has been characterized to be a 70 amino acid polypeptide and plays an important role in growth and metabolism. Although it is been well known that IGF-I is highly associated with embryonic development and post-hatching growth, changes in the distribution of IGF-I gene expression throughout early- to late-embryogenesis have not been studied so far. We revealed that the developmental pattern of IGF-I gene expression during embryogenesis differed among various tissues. No bands of IGF-I mRNA were detected in embryonic liver at 7 days of incubation, and thereafter the amount of hepatic IGF-I mRNA was increased from 14 to 20 days of incubation. In eyes, a peak in IGF-I mRNA levels occurred at mid-embryogenesis, but by contrast, IGF-I mRNA was barely detectable in the heart throughout all incubation periods. In the muscle, no significant difference in IGF-I gene expression was observed during different stages of embryogenesis. After hatching, hepatic IGF-I gene expression as well as plasma IGF-I concentration increases rapidly with age, reaches a peak before sexual maturity, and then declines. The IGF-I gene expression is very sensitive to changes in nutritional conditions. Food-restriction and fasting decreased hepatic IGF-I gene expression and refeeding restored IGF-I gene expression to the level of fed chickens. Dietary protein is also a very strong factor in changing hepatic IGF-I gene expression. Refeeding with dietary protein alone successfully restored hepatic IGF-I gene expression of fasted chickens to the level of fed controls. In most circumstances, IGF-I makes a complex with specific high-affinity IGF-binding proteins (IGFBPs). So far, four different IGFBPs have been identified in avian species and the major IGFBP in chicken plasma has been reported to be IGFBP-2. We studied the relationship between nutritional status and IGFBP-2 gene expression in various tissues of young chickens. In the liver of fed chickens, almost no IGFBP-2 mRNA was detected. However, fasting markedly increased hepatic IGFBP-2 gene expression, and the level was reduced after refeeding. In the gizzard of well-fed young chickens, IGFBP-2 gene expression was detected and fasting significantly elevated gizzard IGFBP-2 mRNA levels to about double that of fed controls. After refeeding, gizzard IGFBP-2 gene expression decreased similar to hepatic IGFBP-2 gene expression. In the brain, IGFBP-2 mRNA was observed in fed chickens and had significantly decreased by fasting. In the kidney, IGFBP-2 gene expression was observed but not influenced by fasting and refeeding. Recently, we have demonstrated in vivo that gizzard and hepatic IGFBP-2 gene expression in fasted chickens was rapidly reduced by intravenous administration of insulin, as indicated that in young chickens the reduction in gizzard and hepatic IGFBP-2 gene expression in vivo stimulated by malnutrition may be, in part, regulated by means of the increase in plasma insulin concentration via an insulin-response element. The influence of dietary protein source (isolated soybean protein vs. casein) and the supplementation of essential amino acids on gizzard IGFBP-2 gene expression was examined. In both soybean protein and casein diet groups, the deficiency of essential amino acids stimulated chickens to increase gizzard IGFBP-2 gene expression. Although amino acid supplementation of a soybean protein diet significantly decreased gizzard IGFBP-2 mRNA levels, a similar reduction was not observed in chickens fed a casein diet supplemented with amino acids. This overview of nutritional regulation of IGF-I and IGFBP-2 gene expression in young chickens would serve for the establishment of the supply of nutrients to diets to improve poultry pro

Effects of Refeeding with a Protein-Free Diets Supplemented with Various Essential Amino Acids on the Plasma Insulin-Like Growth Factor-I Concentration in Fasting Young Chickens

Kita, K,Shibata, T.,Nagao, K.,Hwangbo, J.,Okumura, J. Asian Australasian Association of Animal Productio 2002 Animal Bioscience Vol.15 No.3

The effect of refeeding with various single essential amino acids on the recovery of plasma insulin-like growth factor-I (IGF-I) concentration in fasted young chickens was examined. Young chickens (29 days of age) were divided into 15 experimental groups. Chickens in one group were fed on the commercial diet ad libitum for 4 days. The remaining 56 chickens in 14 experimental groups were fasted. After 2 days of fasting, 52 chicks in 13 fasted groups were refed with one of the following experimental diets for 2 days. Eleven experimental diets were protein-free diets supplemented with one of 11 essential amino acids (Arg, Gly, His, Ileu, Leu, Met, Phe, Lys, Thr, Trp, Val). The remaining 2 experimental diets were a protein-free diet containing 11 essential amino acids and a protein-free diet not supplemented with amino acids. Birds in the remaining fasted group continued to be fasted for 2 days. Fasting for 2 days markedly reduced plasma IGF-I concentration. When fasted chickens were refed the protein-free diet containing either Gly alone or all essential amino acids, plasma IGF-I concentration was recovered to the level similar to that of fed chickens. Protein-free diet alone, however, failed to restore the reduced IGF-I concentration in plasma. Body weight loss modulated by feeding with protein-free diets supplemented with various single essential amino acids was associated with changes in plasma IGF-I concentrations. We concluded that body weight loss by feeding with a protein-free diet was lower than that of fasted chickens and that body weight loss associated with the decrease in plasma IGF-I concentration was modulated by feeding with protein-free diets containing various single essential amino acids.

Response of Muscle Protein Synthesis to the Infusion of Insulin-like Growth Factor-I and Fasting in Young Chickens

Kita, K.,Shibata, T.,Aman Yaman, M.,Nagao, K.,Okumura, J. Asian Australasian Association of Animal Productio 2002 Animal Bioscience Vol.15 No.12

In order to elucidate the physiological function of circulating IGF-I on muscle protein synthesis in the chicken under malnutritional conditions, we administrated recombinant chicken IGF-I using a osmotic mini pump to fasted young chickens and measured the rate of muscle protein synthesis and plasma metabolite. The pumps delivered IGF-I at the rate of $22{\mu}g/d\{300{\mu}g{\cdot}(kg\;body\;weight{\cdot}d)^{-1}\}$. Fractional rate of protein synthesis in the muscle was measured using a large dose injection of L-[$2,6-^3H$]phenylalanine. Constant infusion of chicken IGF-I did not affect plasma glucose level. Significant interaction between dietary treatment and IGF-I infusion was observed in plasma NEFA and total cholesterol concentrations. When chicks were fasted, IGF-I infusion decreased plasma NEFA and total cholesterol concentrations. On the other hand, IGF-I administration did not affect plasma levels of both metabolites. Fasting reduced plasma triglyceride concentration significantly. IGF-I infusion also decreased the level of plasma triglyceride. Plasma IGF-I concentration of young chickens was halved by fasting for 1 d. IGF-I infusion using an osmotic minipump for 1 d increased plasma IGF-I concentration in fasted chicks to the level of fed chicks. Fasting decreased body weight and the loss of body weight was significantly ameliorated by IGF-I infusion. There was a significant interaction between dietary treatment and IGF-I infusion in the fractional rate of breast muscle protein synthesis. There was no effect of IGF-I infusion on muscle protein synthesis in fed chicks. Muscle protein synthesis reduced by fasting was ameliorated by IGF-I infusion, but did not reach to the level of fed control. Muscle weight of fasted chicks infused with IGF-I was similar to fasted birds without IGF-I infusion, which suggests that muscle protein degradation would be increased by IGF-I infusion as well as protein synthesis in fasted chicks.

Influence of Chicken Embryo Extract on Protein Synthesis of Chicken Embryo Myoblasts Depends on Cell Density

Kita, K.,Hiramatsu, K.,Okumura, Jun-ichi Asian Australasian Association of Animal Productio 1998 Animal Bioscience Vol.11 No.6

The synergistic effect of fetal calf serum (FCS) and chicken embryo extract (CEE) on protein synthesis of chicken embryo myoblasts was examined. Myoblasts were derived from chicken embryo cultured for 14 days by trypsin digestion and cultured in 5% $CO^2/95%$ air at $37^{\circ}C$. When myoblasts were cultured at the low level of cell density (20-50% of well), CEE enhanced the ability of FCS to stimulate protein synthesis of myoblasts. However, there was no significant effect of CEE to stimulate protein synthesis of myoblasts cultured at high level of cell density (100% of well).

Measurements of the atmospheric neutrino flux by Super-Kamiokande: Energy spectra, geomagnetic effects, and solar modulation

Richard, E.,Okumura, K.,Abe, K.,Haga, Y.,Hayato, Y.,Ikeda, M.,Iyogi, K.,Kameda, J.,Kishimoto, Y.,Miura, M.,Moriyama, S.,Nakahata, M.,Nakajima, T.,Nakano, Y.,Nakayama, S.,Orii, A.,Sekiya, H.,Shiozawa, American Physical Society 2016 Physical Review D Vol.94 No.5

<P>A comprehensive study of the atmospheric neutrino flux in the energy region from sub-GeV up to several TeV using the Super-Kamiokande (SK) water Cherenkov detector is presented in this paper. The energy and azimuthal spectra, and variation over time, of the atmospheric nu(e) + (nu) over bar (e) and nu(mu) + (nu) over bar (mu) fluxes are measured. The energy spectra are obtained using an iterative unfolding method by combining various event topologies with differing energy responses. The azimuthal spectra depending on energy and zenith angle, and their modulation by geomagnetic effects, are also studied. A predicted east-west asymmetry is observed in both the nu(e) and nu(mu) samples at 8.0 sigma and 6.0 sigma significance, respectively, and an indication that the asymmetry dipole angle changes depending on the zenith angle was seen at the 2.2 sigma level. The measured energy and azimuthal spectra are consistent with the current flux models within the estimated systematic uncertainties. A study of the long-term correlation between the atmospheric neutrino flux and the solar magnetic activity cycle is performed, and a weak preference for a correlation was seen at the 1.1 sigma level, using SK-I-SK-IV data spanning a 20-year period. For several particularly strong solar activity periods, corresponding to Forbush decrease events, no theoretical prediction is available but a deviation below the typical neutrino event rate is seen at the 2.4 sigma level. The seasonal modulation of the neutrino flux is also examined, but the change in flux at the SK site is predicted to be negligible, and, as expected, no evidence for a seasonal correlation is seen.</P>

Two-stage partial melting and contrasting cooling history within the Higher Himalayan Crystalline Sequence in the far-eastern Nepal Himalaya

Imayama, T.,Takeshita, T.,Yi, K.,Cho, D.L.,Kitajima, K.,Tsutsumi, Y.,Kayama, M.,Nishido, H.,Okumura, T.,Yagi, K.,Itaya, T.,Sano, Y. Universitetsforlaget ; Elsevier Science Ltd 2012 Lithos Vol.134 No.-

The timing of partial melting and the pressure-temperature (P-T) paths in the High Himalayan Crystalline Sequence (HHCS) in far-eastern Nepal has been investigated using zircon chronology, rare earth element (REE) compositions, and P-T pseudosection analysis. Zircon from migmatites formed during Himalayan thermal events displays inherited magmatic core overgrown by two generations of metamorphic rims. The new rims are distinguished on the basis of their Tertiary ages, low MREE contents, and low Th/U ratios. The inner zircon rims from Sil+Grt+Bt+Kfs+Pl+Qtz and Ky+Sil+Grt+Bt+Ms+Pl+Qtz migmatites at different structural level of the HHCS display ages of c. 33-28Ma (Early Oligocene) and c. 21-18Ma (Early Miocene): these rims are characterized by flat MREE to HREE patterns and were overgrown by partial melt through muscovite dehydration melting under the stability of garnet, which occurred at P=c. 7-10kbar and T=c. 730-780<SUP>o</SUP>C, and at P=c. 8-14kbar and T=c. 720-770<SUP>o</SUP>C, respectively. The outer zircon rims are relatively enriched in HREE with respect to the inner rims and were overgrown at c. 27-23Ma (Late Oligocene) and at c. 18-16Ma (Early Miocene) during melt crystallization accompanying breakdown of garnet at P=c. 4-7kbar and T=c. 650-725<SUP>o</SUP>C. Early Miocene Ms-Bt leucogranites with two successively overgrown zircon rims at c. 18.3+/-0.3Ma and c. 16.3+/-0.2Ma were intruded into Early Oligocene migmatite hosts. Microstructural observations and the corresponding P-T conditions associated with the two generations of zircon rims indicate that the Early Oligocene and Early Miocene migmatites show relatively isobaric and nearly isothermal P-T paths during exhumation, respectively. The inferences are consistent with higher average cooling rates for the Early Miocene (c. 30-40<SUP>o</SUP>C/My) than the Early Oligocene (c. 15-25<SUP>o</SUP>C/My) migmatites, inferred from peak-T conditions and FT (c. 6Ma for both migmatites) and U-Pb zircon ages. The P-T-t paths of the two migmatites indicate that burial of the Early Miocene migmatites has been coeval with exhumation of the Early Oligocene migmatites, implying the formation of large-scale thrust within the HHCS.