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Time dependence of relative biological effectiveness (RBE) of carbon ions for skin damage was investigated to answer the question of whether the flat distribution of biological doses within a Spread-Out Bragg peak (SOBP) which is designed based on in vitro cell kill could also be flat for in vivo late responding tissue. Two spots of Indian ink intracutaneously injected into the legs of C3H mice were measured by calipers. An equieffective dose to produce 30% skin contraction was calculated from a dose–response curve and used to calculate the RBE of carbon ion beams. We discovered skin contraction progressed after irradiation and then reached a stable/slow progression phase. Equieffective doses decreased with time and the decrease was most prominent for gamma rays and least prominent for 100 keV/μm carbon ions. Survival parameter of alpha but not beta in the linear-quadratic model is closely related to the RBE of carbon ions. Biological doses within the SOBP increased with time but their distribution was still flat up to 1 year after irradiation. The outcomes of skin contraction studies suggest that (i) despite the higher RBE for skin contracture after carbon ions compared to gamma rays, gamma rays can result in a more severe late effect of skin contracture. This is due to the carbon effect saturating at a lower dose than gamma rays, and (ii) the biological dose distribution throughout the SOBP remains approximately the same even one year after exposure. [ABSTRACT FROM AUTHOR]

The goal of this work was to clarify the effect of carbon-ion beams on reduction of the metastatic potential of malignant melanoma using in vitro and in vivo techniques. We utilized a 290 MeV/u carbon beam with a 6-cm spread-out Bragg-peak (SOBP), 137Cs γ rays or 200 kVp X rays for irradiation, and in vitro murine melanoma B16/BL6 cells that were implanted into C57BL/6J mice. The metastatic abilities (migration, invasion and adhesion) were suppressed by carbon ion treatment at all doses that were tested, whereas invasion and migration tended to increase after X-ray irradiation at low dose. Biological effects of carbon ions increased with linear energy transfer (LET) for both cell killing and metastatic abilities, although the effects were more pronounced for migration and invasion. mRNA expression of E-cadherin was significantly downregulated with low-dose photon exposures, but increased with dose or LET. Expression of Mel-CAM and L1-CAM was upregulated after low-dose photon exposure, but decreased with dose, especially after carbon-ion treatment. Conversely, these molecules showed a reversal in expression changes, especially after low-dose photon exposure. Cell-cell adhesion may be an important contributor to the antimetastatic effect of carbon ion treatment. The number of lung metastases after local tumor irradiation significantly decreased with increased dose and LET, with carbon ions being more effective than γ rays. Integrating dose-response curves to examine the relationship between cell killing and lung metastasis clearly showed that carbon ions inhibit lung metastasis more efficiently than photons at the iso-effective level of cell killing. Thus, carbon ions were more effective than photon beams, not only at killing tumor cells, but also at inhibiting metastatic spread caused by tumor cells that survived irradiation. [ABSTRACT FROM AUTHOR]

This cross-sectional study aimed to determine the utility of ultrasonography with improved resolution using a high-frequency probe for dialysis-related carpal tunnel syndrome (CTS). This study targeted 125 hemodialysis patients at our hospital. A 12 MHz probe was placed on the carpal tunnel area to identify the median nerve. The compression rate of the nerve was calculated by measuring the smallest diameter of the compressed nerve and largest diameter of the unaffected part. To quantify CTS symptoms, we determined the presence of Tinel's sign, measured pinch strength, and used questionnaires to assess numbness and pain. The association of these clinical data with the compression rate was examined. Mean compression rate was 12.1 ± 1.1%. The compression rate cutoff value for those positive with Tinel's sign was 25%, (sensitivity and specificity were 0.80 and 0.91, respectively), and that for those with a history of CTS surgery was 25% (sensitivity and specificity were 0.67 and 0.89, respectively). Multiple regression analysis identified duration of dialysis, β2-microglobulin(β2-Mg) concentration, positivity for Tinel's sign, history of CTS surgery, and pinch strength as independent compression rate determinants. Notably, compression rates were significantly higher in patients with a ≥4-year duration of dialysis and a β2-Mg level of 20 mg/L or more. The compression rate of the median nerve measured by an improved ultrasound device significantly correlated with clinical symptoms, medical history, and serological features associated with dialysis-related CTS. Because ultrasonography is non-invasive, the examination might be a simple method especially for early diagnosis of dialysis-related CTS. [ABSTRACT FROM AUTHOR]

Purpose: To determine the dose-dependent relative biological effectiveness (RBE) for tumor prevalence in mice receiving single localized doses to their right leg of either carbon ions (15, 45 or 75 keV/μm) or 137Cs gamma rays. Methods and materials: A total of 1647 female C3H mice were irradiated to their hind legs with a localized dose of either reference gamma rays or 15, 45 or 75 keV/μm carbon-ion beams. Irradiated mice were evaluated for tumors twice a month during their three-year life span, and the dimensions of any tumors found were measured with a caliper. The tumor induction frequency was calculated by Kaplan-Meier analysis. Results: The incidence of tumors from 50 Gy of 45 keV/μm carbon ions was marginally higher than those from 50 Gy of gamma rays. However, 60 Gy of 15 keV/μm carbon ions induced significantly fewer tumors than did gamma rays. RBE values of 0.87 + 0.12, 1.29 + 0.08 or 2.06 + 0.39 for lifetime tumorigenesis were calculated for 15, 45 or 75 keV/μm carbon-ion beams, respectively. Fibrosarcoma predominated, with no Linear Energy Transfer (LET)-dependent differences in the tumor histology. Experiments measuring the late effect of leg skin shrinkage suggested that the carcinogenic damage of 15 keV/μm carbon ions would be less than that of gamma rays. Conclusions: We conclude that patients receiving radiation doses to their normal tissues would face less risk of secondary tumor induction by carbon ions of intermediate LET values compared to equivalent doses of photons. [ABSTRACT FROM AUTHOR]

Purpose: Respiration-gated irradiation for a moving target requires a longer time to deliver single fraction in proton radiotherapy (PRT). Ultrahigh dose rate (UDR) proton beam, which is 10-100 times higher than that is used in current clinical practice, has been investigated to deliver daily dose in single breath hold duration. The purpose of this study is to investigate the survival curve and relative biological effectiveness (RBE) of such an ultrahigh dose rate proton beam and their linear energy transfer (LET) dependence. Methods: HSG cells were irradiated by a spatially and temporally uniform proton beam at two different dose rates: 8 Gy/min (CDR, clinical dose rate) and 325 Gy/min (UDR, ultrahigh dose rate) at the Bragg peak and 1.75 (CDR) and 114 Gy/min (UDR) at the plateau. To study LET dependence, the cells were positioned at the Bragg peak, where the absorbed dose-averaged LET was 3.19 keV/μm, and at the plateau, where it was 0.56 keV/μm. After the cell exposure and colony assay, the measured data were fitted by the linear quadratic (LQ) model and the survival curves and RBE at 10% survival were compared. Results: No significant difference was observed in the survival curves between the two proton dose rates. The ratio of the RBE for CDR/UDR was 0.98±0.04 at the Bragg peak and 0.96±0.06 at the plateau. On the other hand, Bragg peak/plateau RBE ratio was 1.15±0.05 for UDR and 1.18±0.07 for CDR. Conclusions: Present RBE can be consistently used in treatment planning of PRT using ultrahigh dose rate radiation. Because a significant increase in RBE toward the Bragg peak was observed for both UDR and CDR, further evaluation of RBE enhancement toward the Bragg peak and beyond is required. [ABSTRACT FROM AUTHOR]

Objective: Gefitinib (N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine, Iressa) is an approved anticancer drug. In this study, we labeled gefitinib with carbon-11 and evaluated [(11)C]gefitinib to explore its specific binding in intact fibrosarcoma (NFSa)-bearing mice.Methods: [(11)C]Gefitinib was synthesized by the reaction of desmethyl precursor (1) with [(11)C]CH(3)I. In vitro uptake of [(11)C]gefitinib into NFSa, human-A431 epidermoid carcinoma, and Jurkat T cells was determined. Positron emission tomography (PET) imaging using [(11)C]gefitinib was performed for NFSa-bearing mice.Results: [(11)C]Gefitinib accumulated into NFSa cells with 2.1 uptake ratio (UR)/mg protein in cells. Addition of nonradioactive gefitinib decreased uptake in a concentration-dependent manner. [(11)C]Gefitinib also had high uptake (2.6 UR/mg protein) into epidermal growth factor receptor/tyrosine kinase (EGFR/TK)-rich A431 cells but low uptake (0.2 UR/mg protein) into EGFR/TK-poor Jurkat cells. In vivo distribution study on NFSa-bearing mice by the dissection method revealed that [(11)C]gefitinib specifically accumulated into the tumor. The ratio of radioactivity in tumors to that in blood and muscle as two comparative regions increased from 0.4 to 6.0 and from 0.6 to 5.0 during this experiment (0-60 min), respectively. PET for NFSa-bearing mice produced a clear tumor image, although high radioactivity was distributed throughout the body. Treatment with nonradioactive gefitinib (100 mg/kg) decreased uptake in the tumor. In vivo metabolite analysis demonstrated that [(11)C]gefitinib was stable in the tumor, liver, kidney, and blood.Conclusion: These results demonstrated the promising potential of [(11)C]gefitinib to serve as a PET ligand for in vivo imaging of NFSa-bearing mice. [ABSTRACT FROM AUTHOR]

To elucidate the effect of tumor oxygenation status on recovery from damage following γ-ray or accelerated carbon ion irradiation in vivo, including in quiescent (Q) cells. SCC VII tumor-bearing mice were continuously given 5-bromo-2′-deoxyuridine (BrdU) to label all proliferating (P) cells. They received γ-ray or accelerated carbon ion irradiation with or without tumor clamping for inducing hypoxia. Immediately after irradiation, cells from some tumors were isolated, or acute hypoxia-releasing nicotinamide was loaded to the tumor-bearing mice. For 9 h after irradiation, some tumors were kept aerobic or hypoxic. Then isolated tumor cells were incubated with a cytokinesis blocker. The response of Q cells was assessed in terms of the micronucleus frequency using immunofluorescence staining for BrdU. That of the total (=P + Q) tumor cells was determined from BrdU non-treated tumors. Clearer recovery in Q cells than total cells and after aerobic than hypoxic γ-ray irradiation was efficiently suppressed with carbon ion beams. Inhibition of recovery through keeping irradiated tumors hypoxic after irradiation and promotion of recovery by nicotinamide loading were observed more clearly with γ-rays, after aerobic irradiation and in total cells than with carbon ion beams, after hypoxic irradiation and in Q cells, respectively. Tumor oxygenation status following irradiation can manipulate recovery from radiation-induced damage, especially after aerobic γ-ray irradiation in total cells. Carbon ion beams are promising because of their efficient suppression of the recovery. [ABSTRACT FROM AUTHOR]

Purpose. To clarify the radiosensitivity of intratumor total and quiescent (Q) cells in vivo to accelerated carbon ion beams compared with γ-ray irradiation. Materials and methods. SCC VII tumor-bearing mice received a continuous administration of 5-bromo-2'-deoxyuridine (BrdU) to label all intratumor proliferating (P) cells. Then they received 290 MeV/u carbon ions or γ-rays. Immediately or 12 hours after the irradiation, the radiosensitivity of Q cells was assessed in terms of the micronucleus frequency using immunofluorescence staining for BrdU. That of the total (=P+Q) tumor cells was determined from the BrdU non-treated tumors based on the micronucleus frequency and clonogenic cell survival. Results. The apparent difference in radiosensitivity between total and Q cell populations under γ-ray irradiation was markedly reduced with carbon ion beam, especially with a higher linear energy transfer (LET) value. Clearer repair in Q cells than total cells through delayed assay under γ-ray irradiation was efficiently inhibited with carbon ion beams, especially with a higher LET. Conclusion. In terms of tumor cell-killing effect as a whole, including intratumor Q cells, carbon ion beams, especially with higher LET values, were very useful for suppressing the dependency on the heterogeneity within solid tumors as well as depositing radiation dose precisely. [ABSTRACT FROM AUTHOR]

The aim of this study was to clarify the radiosensitivity of intratumor total cells and quiescent (Q) cells in vivo to accelerated carbon ion beams compared with γ-ray irradiation. Squamous cell carcinoma (SCC) VII tumor-bearing mice received continuous administration of 5-bromo-2′-deoxyuridine (BrdU) to label all intratumor proliferating (P) cells. They then were exposed to carbon ions (290 MeV/u) or γ-rays. Immediately after and 12 h after irradiation, immunofluorescence staining for BrdU was used to assess the response of Q cells in terms of micronucleus frequency. The response of the total (P + Q) tumor cells was determined from the tumors not treated with BrdU. The apparent difference in radiosensitivity between total and Q cell populations under γ-ray irradiation was markedly reduced with carbon ion beams, especially with a higher linear energy transfer (LET) value. Clearer recovery in Q cells than in total cells through delayed assay under γ-ray irradiation was efficiently inhibited by carbon ion beams, especially those with a higher LET. In terms of the tumor cell-killing effect as a whole, including intratumor Q cells, carbon ion beams, especially with higher LET values, were extremely useful for suppressing the dependence on the heterogeneity within solid tumors as well as depositing the radiation dose precisely. [ABSTRACT FROM AUTHOR]

The effect of rolipram, a selective phosphodiesterase type 4 inhibitor, on the uptake of 18F-fluorodeoxyglucose (18F-FDG) in tumor tissue was examined in mice transplanted with NFSa fibrosarcoma. The uptake indexes of 18F-FDG in the heart, skeletal muscle and brain remarkably decreased after treatment with 3 mg/kg of rolipram (heart: 13%, skeletal muscle: 14%, brain: 31%), but fibrosarcoma tissue showed only a 50% reduction in the uptake index of 18F-FDG. The tumor/muscle ratio of radioactivity 30 min after 18F-FDG injection was consequently enhanced from 1.9 to 6.5 by rolipram. This indicates the possible use of rolipram to enhance the sensitivity of tumor detection, as well as characterization of tumors in 18F-FDG PET. [ABSTRACT FROM AUTHOR]

The effect of rolipram, a selective phosphodiesterase type 4 inhibitor, on the uptake of18F-fluorodeoxyglucose (18F-FDG) in tumor tissue was examined in mice transplanted with NFSa fibrosarcoma. The uptake indexes of18F-FDG in the heart, skeletal muscle and brain remarkably decreased after treatment with 3 mg/kg of rolipram (heart: 13%, skeletal muscle: 14%, brain: 31%), but fibrosarcoma tissue showed only a 50% reduction in the uptake index of18F-FDG. The tumor/muscle ratio of radioactivity 30 min after18F-FDG injection was consequently enhanced from 1.9 to 6.5 by rolipram. This indicates the possible use of rolipram to enhance the sensitivity of tumor detection, as well as characterization of tumors in18F-FDG PET. [ABSTRACT FROM AUTHOR]

Simple Summary: The treatment of hypoxic tumours continues to be one of the main challenges for radiation therapy. Minibeam radiation therapy (MBRT) shows a highly promising reduction of to-xicity in normal tissue, so that very heavy ions, such as Neon (Ne) or Argon (Ar), with extremely high LET, might become applicable to clinical situations. The high LET in the target would be unrivalled to overcome hypoxia, while MBRT might limit the side effects normally preventing the use of those heavy ions in a conventional radiotherapeutic setting. The work reported in this manuscript is the first experimental proof of the remarkable reduction of normal tissue (skin) toxicities after Ne MBRT irradiations as compared to conventional Ne irradiations. This result might allow for a renewed use of very heavy ions for cancer therapy. (1) Background: among all types of radiation, very heavy ions, such as Neon (Ne) or Argon (Ar), are the optimum candidates for hypoxic tumor treatments due to their reduced oxygen enhancement effect. However, their pioneering clinical use in the 1970s was halted due to severe side effects. The aim of this work was to provide a first proof that the combination of very heavy ions with minibeam radiation therapy leads to a minimization of toxicities and, thus, opening the door for a renewed use of heavy ions for therapy; (2) Methods: mouse legs were irradiated with either Ne MBRT or Ne broad beams at the same average dose. Skin toxicity was scored for a period of four weeks. Histopathology evaluations were carried out at the end of the study; (3) Results: a significant difference in toxicity was observed between the two irradiated groups. While severe da-mage, including necrosis, was observed in the broad beam group, only light to mild erythema was present in the MBRT group; (4) Conclusion: Ne MBRT is significantly better tolerated than conventional broad beam irradiations. [ABSTRACT FROM AUTHOR]