Preliminary results of proton beam therapy combined with weekly cisplatin intra-arterial infusion via a superficial temporal artery for treatment of maxillary sinus carcinoma.

OBJECTIVE: This study aimed to evaluate the efficacy and toxicity of proton beam therapy combined with cisplatin intra-arterial infusion via a superficial temporal artery as treatment for maxillary sinus carcinoma. METHODS: Twenty-six patients with confirmed maxillary sinus carcinoma were enrolled in this study from May 2009 to April 2011. Patients underwent proton beam therapy and intra-arterial infusion chemotherapy with cisplatin. RESULTS: The median total dose was 70.4 GyE per 32 fractions, and the median dose of cisplatin was 300 mg/body for six cycles of intra-arterial infusion. The 3-year overall survival rate was 58% for all patients (n = 26), 58% for patients with stage T4 disease (n = 12), 57% for patients with

Dosemetric Parameters Predictive of Rib Fractures after Proton Beam Therapy for Early-Stage Lung Cancer.

Proton beam therapy (PBT) is the preferred modality for early-stage lung cancer. Compared with X-ray therapy, PBT offers good dose concentration as revealed by the characteristics of the Bragg peak. Rib fractures (RFs) after PBT lead to decreased quality of life for patients. However, the incidence of and the risk factors for RFs after PBT have not yet been clarified. We therefore explored the relationship between irradiated rib volume and RFs after PBT for early-stage lung cancer. The purpose of this study was to investigate the incidence and the risk factors for RFs following PBT for early-stage lung cancer. We investigated 52 early-stage lung cancer patients and analyzed a total of 215 irradiated ribs after PBT. Grade 2 RFs occurred in 12 patients (20 ribs); these RFs were symptomatic without displacement. No patient experienced more severe RFs. The median time to grade 2 RFs development was 17 months (range: 9-29 months). The three-year incidence of grade 2 RFs was 30.2%. According to the analysis comparing radiation dose and rib volume using receiver operating characteristic curves, we demonstrated that the volume of ribs receiving more than 120 Gy3 (relative biological effectiveness (RBE)) was more than 3.7 cm(3) at an area under the curve of 0.81, which increased the incidence of RFs after PBT (P < 0.001). In this study, RFs were frequently observed following PBT for early-stage lung cancer. We demonstrated that the volume of ribs receiving more than 120 Gy3 (RBE) was the most significant parameter for predicting RFs.

High-dose proton beam therapy for stage I non-small cell lung cancer: Clinical outcomes and prognostic factors.

BACKGROUND: Evidence has suggested that radiation therapy with a lower dose per fraction may be a reasonable option for the treatment of centrally located non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the safety and efficacy of two proton beam therapy (PBT) protocols for stage I NSCLC and to determine prognostic factors. MATERIAL AND METHODS: This study included patients clinically diagnosed with stage I NSCLC. Based on the location of the tumor, one of the two PBT protocols was administered. Patients with peripherally located tumors were given 66 Gy relative biological dose effectiveness (RBE) over 10 fractions (Protocol A) while patients with centrally located tumors were given 80 Gy (RBE) over 25 fractions (Protocol B). RESULTS: Between January 2009 and May 2012, 56 eligible patients were enrolled (protocol A: 32 patients; protocol B: 24 patients). The three-year overall survival (OS), progression-free survival (PFS), and local control (LC) rates were 81.3% [95% confidence interval (CI) 75.9-86.7%], 73.4% (95% CI 67.2-79.6%), and 96.0% (95% CI 93.2-98.8%), respectively. There were no significant differences in outcomes between the two protocols. Late grade 2 and 3 pulmonary toxicities were observed in nine patients (13.4%) and one patient (1.5%), respectively; no grade 4 or 5 toxicities were observed. Sex, age, performance status, T-stage, operability, and tumor pathology were not associated with OS and PFS. Only maximum standardized uptake value (SUVmax; <5 vs. ≥5) was identified as a significant prognostic factor for OS and PFS. CONCLUSION: Both high-dose PBT protocols achieved high LC rates with tolerable toxicities in stage I NSCLC patients, and SUVmax was a significant prognostic factor.

Clinical results of proton beam therapy for twenty older patients with esophageal cancer.

BACKGROUND: In an aging society, increasing number of older patients are diagnosed with esophageal cancer. The purpose of this study was to assess the clinical efficacy and safety of proton beam therapy for older patients with esophageal cancer. PATIENTS AND METHODS: Older patients (age: ≥ 65 years) newly diagnosed with esophageal cancer between January 2009 and June 2013 were enrolled in this study. All patients underwent either proton beam therapy alone or proton beam therapy with initial X-ray irradiation. Toxicities were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: Twenty patients were eligible for this study and all completed the treatment. The median age was 78 years (range: 65-89 years) and the median follow-up time was 26.5 months (range: 6-62 months). Seven patients had lymph node metastases and 10 had stage II/III cancer. The median dose of proton beam therapy was 72.6 Gy relative biological dose effectiveness (RBE) (range: 66-74.8 Gy [RBE]) for proton beam therapy alone and 33 Gy (RBE) (range: 30.8-39.6 Gy [RBE]; total dose range: 66.8-75.6 Gy [RBE]) for proton beam therapy with initial X-ray irradiation. The 2-year overall survival rate was 81.8% (95% confidence interval [CI]: 62.4%-100%), and the 2-year local control rate was 89.4% (95% CI: 75.5%-100%). Grade 2 or 3 toxicities occurred in some cases; however, no grade 4 or 5 toxicity was observed. CONCLUSIONS: High-dose (66-75.6 Gy [RBE]) proton beam therapy without chemotherapy was an efficacious and safe treatment for older patients with esophageal cancer.

Dosimetric Comparison Study of Proton Therapy Using Line Scanning versus Passive Scattering and Volumetric Modulated Arc Therapy for Localized Prostate Cancer.

BACKGROUND: The proton irradiation modality has transitioned from passive scattering (PS) to pencil beam scanning. Nevertheless, the documented outcomes predominantly rely on PS. METHODS: Thirty patients diagnosed with prostate cancer were selected to assess treatment planning across line scanning (LS), PS, and volumetric modulated arc therapy (VMAT). Dose constraints encompassed clinical target volume (CTV) D98 ≥ 73.0 Gy (RBE), rectal wall V65 < 17% and V40 < 35%, and bladder wall V65 < 25% and V40 < 50%. The CTV, rectal wall, and bladder wall dose volumes were calculated and evaluated using the Freidman test. RESULTS: The LS technique adhered to all dose limitations. For the rectal and bladder walls, 10 (33.3%) and 21 (70.0%) patients in the PS method and 5 (16.7%) and 1 (3.3%) patients in VMAT, respectively, failed to meet the stipulated requirements. The wide ranges of the rectal and bladder wall volumes (V10-70) were lower with LS than with PS and VMAT. LS outperformed VMAT across all dose-volume rectal and bladder wall indices. CONCLUSION: The LS method demonstrated a reduction in rectal and bladder doses relative to PS and VMAT, thereby suggesting the potential for mitigating toxicities.

Heat stress activates ER stress signals which suppress the heat shock response, an effect occurring preferentially in the cortex in rats.

Although heat stress induces a variety of illnesses, there have been few studies designed to uncover the molecular mechanisms underlining the illnesses. We here demonstrate that heat activates ER stress, which inhibits heat shock responses (HSR) via translational block. In heat-stressed rats, ER stress responses, as represented by eIF2α phosphorylation and XBP1 splicing, occurred mainly in the cortex, where the HSR was substantially inhibited. Heat exposure also activated ER stress signals in primary cortical neurons. Since HSF1 knockdown enhanced heat-induced ER stress and subsequent cell death, HSR inhibition in turn augments ER stress, implying a vicious spiral of both stresses. Taken together, heat-induced ER stress impairs the HSR and enhances cell damage, thereby manifesting its unique effect on heat stress.

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

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

Gimeracil, an inhibitor of dihydropyrimidine dehydrogenase, inhibits the early step in homologous recombination.

Gimeracil (5-chloro-2, 4-dihydroxypyridine) is an inhibitor of dihydropyrimidine dehydrogenase (DPYD), which degrades pyrimidine including 5-fluorouracil in the blood. Gimeracil was originally added to an oral fluoropyrimidine derivative S-1 to yield prolonged 5-fluorouracil concentrations in serum and tumor tissues. We have already reported that gimeracil had radiosensitizing effects by partially inhibiting homologous recombination (HR) in the repair of DNA double strand breaks. We investigated the mechanisms of gimeracil radiosensitization. Comet assay and radiation-induced focus formation of various kinds of proteins involved in HR was carried out. siRNA for DPYD were transfected to HeLa cells to investigate the target protein for radiosensitization with gimeracil. SCneo assay was carried out to examine whether DPYD depletion by siRNA inhibited HR repair of DNA double strand breaks. Tail moments in neutral comet assay increased in gimeracil-treated cells. Gimeracil restrained the formation of foci of Rad51 and replication protein A (RPA), whereas it increased the number of foci of Nbs1, Mre11, Rad50, and FancD2. When HeLa cells were transfected with the DPYD siRNA before irradiation, the cells became more radiosensitive. The degree of radiosensitization by transfection of DPYD siRNA was similar to that of gimeracil. Gimeracil did not sensitize DPYD-depleted cells. Depletion of DPYD by siRNA significantly reduced the frequency of neopositive clones in SCneo assay. Gimeracil partially inhibits the early step in HR. It was found that DPYD is the target protein for radiosensitization by gimeracil. The inhibitors of DPYD, such as gimeracil, could enhance the efficacy of radiotherapy through partial suppression of HR-mediated DNA repair.

Japanese structure survey of radiation oncology in 2007 with special reference to designated cancer care hospitals.

BACKGROUND AND PURPOSE: The structure of radiation oncology in designated cancer care hospitals in Japan was investigated in terms of equipment, personnel, patient load, and geographic distribution. The effect of changes in the health care policy in Japan on radiotherapy structure was also examined. MATERIAL AND METHODS: The Japanese Society of Therapeutic Radiology and Oncology surveyed the national structure of radiation oncology in 2007. The structures of 349 designated cancer care hospitals and 372 other radiotherapy facilities were compared. RESULTS: Respective findings for equipment and personnel at designated cancer care hospitals and other facilities included the following: linear accelerators/facility: 1.3 and 1.0; annual patients/linear accelerator: 296.5 and 175.0; and annual patient load/full-time equivalent radiation oncologist was 237.0 and 273.3, respectively. Geographically, the number of designated cancer care hospitals was associated with population size. CONCLUSION: The structure of radiation oncology in Japan in terms of equipment, especially for designated cancer care hospitals, was as mature as that in European countries and the United States, even though the medical costs in relation to GDP in Japan are lower. There is still a shortage of manpower. The survey data proved to be important to fully understand the radiation oncology medical care system in Japan.

A dosimetry study of the Oncoseed 6711 using glass rod dosimeters and EGS5 Monte Carlo code in a geometry lacking radiation equilibrium scatter conditions.

PURPOSE: The aim of this study was to develop a dose calculation method which is applicable to the interseed attenuation and the geometry lacking the equilibrium radiation scatter conditions in brachytherapy. METHODS: The dose obtained from measurement with a radiophotoluminescent glass rod dosimeter (GRD) was compared to the dose calculated with the Monte Carlo (MC) code "EGS5," using the 125I source structure detailed in by Kennedy et al. The GRDs were irradiated with 125I Oncoseed 6711 in a human head phantom. The phantom was a cylinder made of 2 mm thick PMMA with a diameter of 18 cm and length of 16 cm. Some of the GRD positions were so close to the phantom surface that the backscatter margin was less than 5 cm, insufficient for photons. RESULTS: The EGS5 simulations were found to reproduce the relative dose distributions as measured with the GRDs to within 25% uncertainty in the geometry lacking the equilibrium radiation scatter conditions. The absolute value of the GRD measurement agreed with the American Association of Physicist in Medicine Task Group No 43 Updated Protocol (AAPM-TG43U1) formalism to within 3% of the reference point (r = 1 cm, theta = 90 degrees), where the TG43U1 is especially reliable because of the abundant data accumulation in composing the formalism. The factor to normalize the measured or calculated dose to the TG43U1 estimate at the reference point was evaluated to be 0.97 for the GRD measurement and 1.8 for the MC calculation, which uses the integration of the apparent activity with the time as the amount of disintegration during the irradiation. Also, F(r,theta) and g(r) estimated by this calculation method were consistent with those proposed in the TG43U1. CONCLUSIONS: The results of this investigation support the validity of both the MC calculation method and GRD measurement in this study as well as the TG-43U1 formalism. Also, this calculation is applicable to interseed attenuation and the geometry lacking the equilibrium radiation scatter.

Proton Therapy for Localized Prostate Cancer: Long-Term Results From a Single-Center Experience.

PURPOSE: Although proton therapy is controversial, it has been used to treat localized prostate cancer over the past 2 decades. The purpose of this study is to examine the long-term efficacy and toxicity of proton therapy for localized prostate cancer. METHODS AND MATERIALS: This was a retrospective observational study of 2021 patients from 2003 to 2014 at a single institution. Patients were classified using the risk groups defined by the National Comprehensive Cancer Network guidelines, version 4.2019. Ninety-eight percent of the patients received 74 Gy (relative biological effectiveness) in 37 fractions. Fifty-one and 6% of the patients received neoadjuvant and adjuvant androgen deprivation therapy, respectively. The outcomes were the time of freedom from biochemical relapse and the time to late toxicity by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. The outcomes were estimated using the Kaplan-Meier method and were analyzed using multivariable Cox proportional hazards models. RESULTS: The median follow-up period was 84 months (interquartile range, 60-110). The 5- and 10-year freedom from biochemical relapse rates were 100% and 100%, 99% and 88%, 93% and 86%, 90% and 79%, 88% and 68%, and 76% and 63% for the very low, low, favorable intermediate, unfavorable intermediate, high, and very high-risk groups, respectively. Patients with higher risk experienced biochemical relapse after shorter periods. The 5-year rates of grade 2 or higher late genitourinary and gastrointestinal toxicity were 2.2% and 4.0%, respectively. The results of multivariable analyses indicate that younger patients more often experienced biochemical relapse. CONCLUSIONS: This study demonstrates the favorable biochemical controls of proton therapy even in advanced localized prostate cancer patients with a low incidence of late toxicities, supporting the feasibility of conducting prospective clinical trials. The risk groups defined by the National Comprehensive Cancer Network guidelines, version 4.2019, are useful to classify patients with localized prostate cancer. Our findings might suggest the necessity to develop a treatment strategy that accounts for the patient's age.

Evaluation of the urethral α/ß ratio and tissue repair half-time for iodine-125 prostate brachytherapy with or without supplemental external beam radiotherapy.

PURPOSE: To assess the correlation between postimplant dosimetric quantifiers and the genitourinary (GU) toxicity of low-dose rate brachytherapy for prostate cancer. METHODS AND MATERIALS: The minimum urethral dose (UD10, 30, and 90) and the percent volume of the urethra receiving the prescription dose (V100, V150) were calculated from the postimplant dose-volume histograms of 182 patients. We then calculated various urethral biologically equivalent doses (uBEDs) using different values of the α/ß ratio and tissue repair half-time (t1/2) and examined the correlations with GU toxicity. RESULTS: Common dosimetric quantifiers, such as UD90 (brachytherapy) + UD50 (external beam radiotherapy), showed no correlation with Grade ≥ 2 GU toxicity. There was a significant correlation between Grade ≥2 GU toxicity and uBED when the α/ß value was 0.5 or 1 Gy and t1/2 was 0.5-2.5 h. An uBED (α/ß = 1.0, t1/2 = 0.5) had the largest hazard ratio for GU toxicity, and it was also significantly correlated with Grade ≥ 2 GU toxicity according to multivariate analysis. CONCLUSIONS: We observed a significant correlation of uBED with GU toxicity when α/ß was 0.5 or 1.0 Gy and t1/2 was 0.5-2.5 h. As the simple formula we used has not been verified in basic experiments, more data are needed to validate our results.

IL12RB2 and ABCA1 genes are associated with susceptibility to radiation dermatitis.

PURPOSE: Severe acute radiation dermatitis is observed in approximately 5% to 10% of patients who receive whole-breast radiotherapy. Several factors, including treatment-related and patient-oriented factors, are involved in susceptibility to severe dermatitis. Genetic factors are also thought to be related to a patient's susceptibility to severe dermatitis. To elucidate genetic polymorphisms associated with a susceptibility to radiation-induced dermatitis, a large-scale single-nucleotide polymorphism (SNP) analysis using DNA samples from 156 patients with breast cancer was conducted. EXPERIMENTAL DESIGN: Patients were selected from more than 3,000 female patients with early breast cancer who received radiotherapy after undergoing breast-conserving surgery. The dermatitis group was defined as patients who developed dermatitis at a National Cancer Institute Common Toxicity Criteria grade of > or =2. For the SNP analysis, DNA samples from each patient were subjected to the genotyping of 3,144 SNPs covering 494 genes. RESULTS: SNPs that mapped to two genes, ABCA1 and IL12RB2, were associated with radiation-induced dermatitis. In the ABCA1 gene, one of these SNPs was a nonsynonymous coding SNP causing R219K (P = 0.0065). As for the IL12RB2 gene, the strongest association was observed at SNP-K (rs3790568; P = 0.0013). Using polymorphisms of both genes, the probability of severe dermatitis was estimated for each combination of genotypes. These analyses showed that individuals carrying a combination of genotypes accounting for 14.7% of the Japanese population have the highest probability of developing radiation-induced dermatitis. CONCLUSION: Our results shed light on the mechanisms responsible for radiation-induced dermatitis. These results may also contribute to the individualization of radiotherapy.

High-intensity focused ultrasound induced apoptosis with caspase 3, 8, and 9/6 activation in rat hepatoma.

PURPOSE: The purpose of the present study is to investigate anticancer efficacy and apoptosis confirmed by caspase under several exposure conditions of high-intensity focused ultrasound (HIFU). MATERIALS AND METHODS: Twenty-five rats with KDH-8 hepatoma were treated by HIFU at several acoustic energies to evaluate treatment efficacy. Apoptosis was examined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and Hoechst 33258 staining, and caspase 3, 8, and 9/6 activity was respectively assayed. RESULTS: The KDH-8 subcutaneous tumors were reduced by HIFU, and these rats survived longer than the nontreatment rats (P < 0.01). The minimal threshold of HIFU energy was 30 W × 1.0 s for tumor control and long-term survival. The tumors exposed to HIFU exhibited marked apoptotic features under conditions of less than 10 W × 1.0 s. In cultured KDH-8 cells, apoptosis was caused at less than 30 W × 1.0 s (P < 0.01), and more was induced as the energy went down. Caspase 3, 8, and 9/6 were more activated at low energy under 10 W × 1.0 s (P < 0.01), and caspase 8, which is death receptor dependent, was significantly more activated than caspase 9/6, which is mitochondria dependent (P < 0.01). CONCLUSION: HIFU-induced apoptosis in vivo and in vitro is one of the mechanisms for tumor control and is mediated by caspase 3, 8, and 9/6. The significantly greater activation of caspase 8 than of caspase 9/6 suggests that the apoptosis pathway induced by HIFU might be more mitochondria dependent than death receptor dependent. However, further examination will be needed.

Proton Beam Therapy for Locally Recurrent Parotid Gland Cancer.

The aim of this study was to evaluate the efficacy and safety of proton beam therapy for patients with locally recurrent parotid cancer. Between 2009 and 2012, ten patients with locally recurrent parotid gland cancer were treated with proton beam therapy (70.2 Gy equivalents in 32 fractions) with or without intra-arterial infusion chemotherapy of cisplatin (50 mg/body/week, for a total of 5-8 weeks). The median follow-up was 24 months (range 10-49 months). The 1-year overall survival and local control rates were 80 %, and the 3-year overall survival and local control rates were 60 %. None of the patients experienced grade 3-5 toxicities in the treatment or the follow-up periods. These findings suggest that proton beam therapy could be applied effectively and safely for patients with locally recurrent parotid gland cancer.

Tissue oxygenation in a murine SCC VII tumor after X-ray irradiation as determined by EPR spectroscopy.

PURPOSE: The goal of this study was to clarify the dynamics of oxygenation (partial pressure of oxygen, pO(2)) in SCC VII murine tumors in mice after X-ray irradiation. MATERIALS AND METHODS: Changes in pO(2) in tumors were measured by 1.2-GHz electron paramagnetic resonance (EPR) spectroscopy after they were exposed to various doses of irradiation. The pO(2) in tumors was followed for up to six days after irradiation at doses of 0, 5, 10, 15, and 20 Gy. Paramagnetic crystals were used as an oximetry probe and implanted into normal or tumor tissues in mice for prolonged periods. RESULTS: The pattern of tumor oxygen after a single dose of radiation with the 5-Gy dose was different from those with other doses (10, 15, and 20 Gy). After 5 Gy, pO(2) increased rapidly (P<0.01, Student's t test) and then returned to the level observed before irradiation by 12h (P<0.01). In contrast, after 10, 15, or 20 Gy, pO(2) increased rapidly by 6h after irradiation, continued to increase until at least 24h (P<0.01), and then gradually decreased. CONCLUSIONS: In tumors that received 5 Gy, post-irradiation increases in pO(2) at 4h after irradiation were detected by EPR oximetry (P<0.01) noninvasively.

Brachytherapy for oral tongue cancer: an analysis of treatment results with various biological markers.

OBJECTIVE: Low-dose-rate (LDR) brachytherapy is an effective treatment for tongue cancer. However, little is known about the biological mechanism underlying this therapy, characterized by delivery of continuous exposures of LDR irradiation. It is reported that lower microvessel density (MVD), lower Ki-67 index or higher expression of endogenous hypoxic markers such as carbonic CA IX and Glut-1 are related to the poor control of tumors treated with external irradiation. To elucidate the biological characteristics of LDR brachytherapy, we analyzed our results in cases of tongue cancer treated with LDR brachytherapy by using immunohistochemical stainings with antibodies against Ki-67 and MVD, Glut-1 and CA IX. METHODS: The prognostic value of Ki-67 index, MVD and the expression of CA IX and Glut-1 was assessed in 68 tongue cancers treated with LDR brachytherapy. The specimens were taken from tongue cancers before radiation therapy and immunohistochemical staining was performed. RESULTS: The local recurrence-free survival rates were significantly different between T1+T2 and T3 (P = 0.00067), but not between low and high Ki-67 indexes (P = 0.54), between low and high MVD (P = 0.071), low and high CA IX indexes (P = 0.062) or low and high Glut-1 indexes (P = 0.107). T stage, the size of the tumor was the only significant factor for local control in multivariate analyses (P = 0.0377). CONCLUSION: LDR could overcome the radioresistence of non-cycling and hypoxic cells; however, we cannot draw firm conclusions due to the limited number of patients.

[Clinical application of altered fractionation theory].

Altered fractionation schedules are based on two different concepts of radiobiology. One concept is that the radiation repair capability of cells in late responding tissues is higher than that of cells in acute responding tissues which include tumor tissues. Hyperfractionation utilizes this concept. The other concept is that accelerated repopulation of tumor cells occurs in a later period of radiation therapy. In order to overcome repopulation of tumor cells, accelerated hyperfractionation is proposed. These two concepts are independent and some fractionation methods include both concepts. Clinical results of altered fractionation schedules of radiation therapy could be predicted with a biological model (the linear quadratic model theory)for fractionated radiation. When this biological model is applied to tumors in which the tumor cell repopulation during radiotherapy period is negligible, the correction for tumor proliferation is required. Since the calculation of the biological effect dose with this model uses several assumptions, we should consider the biological effect dose as a crude approximation. Especially, in case of concomitant chemotherapy and altered fractionation, it is difficult to predict its results with a simple radiobiology model. The randomized trial is required to examine the significance of chemoradiotherapy using altered fractionation.

Wall composition analysis of the human hepatic artery by intravascular ultrasound.

PURPOSE: The purpose of this study was to elucidate the wall layer appearance of the human hepatic artery shown by intravascular ultrasound (IVUS). METHODS: We evaluated the wall layer appearance of 57 human hepatic arteries from 36 cadavers. The thickness of the inner high-echoic layer and the second low-echoic layer of the arteries was measured by IVUS, and it was compared with that of the arterial intima and media, respectively. RESULTS: The thickness of the inner high-echoic layer was 0.2 ± 0.1 mm and that of the second low-echoic layer was 0.4 ± 0.1 mm, on IVUS. However, the histological thickness of the intima was 120 ± 45 µm and that of the media was 258 ± 71 µm. The media of the hepatic artery correlated significantly with the second low-echoic layer on IVUS (r = 0.62, P < 0.01). The diameter of the vessels measured on IVUS correlated significantly with that of the histological specimens (r = 0.89, P < 0.01). CONCLUSION: From our results, the three layers of the hepatic artery detected with IVUS may correspond to the intima, media, and adventitia, respectively.

cDNA analysis of gene expression associated with DNA-dependent protein kinase activity.

DNA-dependent protein kinase (DNA-PK) is thought to play a pivotal role in DNA double-strand break repair. We recently demonstrated the association of DNA-PK activity in peripheral blood lymphocytes (PBL) with the incidence of chromosomal aberrations and the risk of cancer. In this study, we applied cDNA array technology to find the expression of genes which are associated with DNA-PK activity in PBLs with various levels of DNA-PK activity. Most genes correlated with DNA-PK activity involved cell cycle regulation. Moreover, the transcription factor E2F1, which plays an important role in cell cycle progression, exhibited strong correlation with the DNA-PK activity and Rbp130, which is considered a negative regulator of E2F, showed inverse correlation with DNA-PK activity. In silico promoter analyses showed the presence of at least one E2F binding site in the promoter regions of Ku70, Ku86, DNA-PKcs and genes associated with DNA-PK activity. In order to examine the relationship among the E2F1 expression, the expression of genes related with DNA-PK activity, and DNA-PK activity, we activated PMLs by PHA to progress the cell cycle. After PHA activation of PML, the expression of E2F1 and DNA-PK activity increased. The expression of most genes in PHA-stimulated PBLs had a similar relationship with DNA-PK activity to that without PHA stimulation. These results indicate that the E2F transcription factor may regulate the concerted expression of genes related with DNA-PK activity.