[Studies of the Various Chronic Kidney Failure Rat Models and Hemodialysis Mini-pig Model for the Evaluation of Anti-hyperphosphatemia Drugs].

Animal models of chronic kidney failure (CKF) have been developed for the pharmacodynamic evaluation of various phosphate binders that are used clinically to treat hyperphosphatemia in patients with chronic kidney disease. However, these models represent different disease states and severities, depending on the experimental conditions and are not clearly defined for pharmacological evaluation. In addition, experimental models have not yet been established for artificial dialysis. The purpose of this study was to confirm the utility of the various rat models of CKF and the mini-pig model of hemodialysis as models of hyperphosphatemia for pharmacodynamic evaluation. Various rat models of pre-dialysis CKF (oral adenine dosing, 5/6 resection, and ligation nephrectomy model) were evaluated through determinations of serum and urinary parameters (osmolality, creatinine, and phosphorus), pathological observations of kidney, and the phosphorus-absorbing properties of lanthanum carbonate (La) formulations. The rat and mini-pig models were compared based on each evaluation index. In the oral adenine dosing model, serum phosphorus increased markedly and the area under the serum phosphorus concentration-time curve (phosphorus AUC) decreased in a dose-dependent manner with the administration of La formulations. In contrast, a significant decrease in serum phosphorus AUC, a prolongation of the dialysis interval, and an improvement in dialysis efficiency were observed after administration of La formulations to the mini-pig hemodialysis model. Furthermore, the results of bioequivalence studies between two La formulations (Fosrenol and SW670, a generic formulation) suggested that the rat and mini-pig models are useful and precise as pre-dialysis and dialysis models, respectively.

Combined Ventilation and Perfusion Imaging Correlates With the Dosimetric Parameters of Radiation Pneumonitis in Radiation Therapy Planning for Lung Cancer.

PURPOSE: The purpose of this study was to prospectively investigate clinical correlations between dosimetric parameters associated with radiation pneumonitis (RP) and functional lung imaging. METHODS AND MATERIALS: Functional lung imaging was performed using four-dimensional computed tomography (4D-CT) for ventilation imaging, single-photon emission computed tomography (SPECT) for perfusion imaging, or both (V/Q-matched region). Using 4D-CT, ventilation imaging was derived from a low attenuation area according to CT numbers below different thresholds (vent-860 and -910). Perfusion imaging at the 10th, 30th, 50th, and 70th percentile perfusion levels (F10-F70) were defined as the top 10%, 30%, 50%, and 70% hyperperfused normal lung, respectively. All imaging data were incorporated into a 3D planning system to evaluate correlations between RP dosimetric parameters (where fV20 is the percentage of functional lung volume irradiated with >20 Gy, or fMLD, the mean dose administered to functional lung) and the percentage of functional lung volume. Radiation pneumonitis was evaluated using Common Terminology Criteria for Adverse Events version 4.0. Statistical significance was defined as a P value of <.05. RESULTS: Sixty patients who underwent curative radiation therapy were enrolled (48 patients for non-small cell lung cancer, and 12 patients for small cell lung cancer). Grades 1, 2, and ≥3 RP were observed in 16, 44, and 6 patients, respectively. Significant correlations were observed between the percentage of functional lung volume and fV20 (r=0.4475 in vent-860 and 0.3508 in F30) or fMLD (r=0.4701 in vent-860 and 0.3128 in F30) in patients with grade ≥2 RP. F30∩vent-860 results exhibited stronger correlations with fV20 and fMLD in patients with grade ≥2 (r=0.5509 in fV20 and 0.5320 in fMLD) and grade ≥3 RP (r=0.8770 in fV20 and 0.8518 in fMLD). CONCLUSIONS: RP dosimetric parameters correlated significantly with functional lung imaging.

Results of sequential chemoradiotherapy for intracranial germinoma.

PURPOSE: To evaluate the efficacy of sequential chemoradiotherapy (CRT) for intracranial germinoma by long-term follow-up. MATERIALS AND METHODS: We retrospectively evaluated 23 consecutive intracranial germinoma patients without spinal dissemination, who had been treated by sequential CRT. All patients except for one were biopsied or surgically resected before treatment and all patients received both cranial and spinal magnetic resonance imaging. Three cycles of induction chemotherapy composed of etoposide and platinum agents were administered. The prescription of radiotherapy was 24 Gy per 12 fractions. No patients received spinal irradiation. RESULTS: All patients accomplished CRT and achieved complete remission. No severe acute and late toxicities were observed. Median follow-up time was 11.8 years. The 5- and 10-year overall survival rates were 100 and 100 %, and relapse-free survival rates were 96 and 89 %, respectively. Three patients developed intracranial recurrence and all of them were successfully salvaged by additional CRT. All patients were alive without disease at final follow-up. CONCLUSION: Treatment of 24 Gy of sequential CRT for intracranial germinoma might be promising as an alternative to radiotherapy alone. Spinal irradiation may not be necessary for patients who had no spinal dissemination and who were treated with CRT.

Long-term results of definitive concurrent chemoradiotherapy for patients with esophageal submucosal cancer (T1bN0M0).

BACKGROUND: The long-term outcomes of definitive concurrent chemoradiotherapy for patients with esophageal submucosal cancer without regional and distant metastasis were retrospectively analyzed. METHODS: Patients with histologically confirmed esophageal submucosal cancers without regional and distant metastasis who received definitive concurrent chemoradiotherapy from 2001 to 2011 were included. Radiation therapy of a median total dose of 60 Gy/30 fractions (range, 54-66 Gy) with elective nodal irradiation of 40 Gy was combined concurrently with 5-furuorouracil-based chemotherapy. RESULTS: Thirty-six patients (33 men and 3 women) aged from 45 to 80 years (median, 67 years) were assessed. All patients had squamous cell carcinoma. With a median follow-up time of 61 months, the 5-year overall survival, disease-free survival, and locoregional failure-free survival rates were 86 % [95 % confidence interval (CI), 74-99 %], 59 % (95 % CI, 42-77 %), and 90 % (95 % CI, 79-100 %), respectively. Late toxicities of grade 3 pleural effusion in 2 patients, grade 4 pericardial effusion in 1 patient, and grade 5 pneumonitis in 1 patient were observed. Metachronous esophageal cancer was observed in 8 patients (22 %). Among them, 6 patients with mucosal legions were salvaged by endoscopic resection. CONCLUSION: Our long-term results of concurrent chemoradiotherapy (CCRT) for patients with esophageal submucosal cancer showed acceptable toxicities and favorable locoregional control and survivals while maintaining organ preservation.

[Stereotactic body radiotherapy].

Stereotactic body radiotherapy(SBRT)is defined as the management and delivery of image-guided high-dose radiation therapy with tumor ablative intent within a short course of treatment. SBRT was more effective than 3D-CRT. In the phase II JCOG0403 trial for T1N0M0 non-small-cell lung cancer, the 3-year overall survival rate was 76% for operable patients and 59.9% for inoperable patients. Several authors reported the treatment results in various dose-fractionation schedules. However, the optimal dose, fractionation regimen, and the dose reference method are yet to be determined. Clinical trial s comparing SBRT and sublobar resection were planned but too few cases were enrolled to provide definitive evidence. SBRT for hepatocellular carcinoma(HCC) is a standard treatment option for patients who are ineligible for resection or radiofrequency ablation. A phase II trial for untreated non-metastatic primary HCC is ongoing in Japan which is expected to provide more supporting evidence.

Long-term results of radiation oncology seminar for medical students and residents held between 1995 and 2011: career paths of the participants.

PURPOSE: The radiation oncology seminar for medical students and residents was initiated by the Japanese Society for Therapeutic Radiology and Oncology (JASTRO) with the aim of increasing the numbers of radiation oncologists. We investigated the long-term results related to the career paths of the program participants. METHODS: This study enrolled 531 individuals who were medical students and residents at the time of program participation, between 1995 and 2011. We surveyed participants with regard to their affiliation status with the Japan Radiological Society (JRS) and JASTRO and whether they were board-certified radiation oncologists. RESULTS: Forty-two percent of the participants were members of JRS and 26.4 % were members of JASTRO. The membership status with JASTRO was investigated in program participants from 2004 to 2009, and comparison by status revealed that 30.1 % of medical students and 47.2 % of residents were members, with a significant difference (p = 0.013). As high as 92.3 % of the participants in the 1995-2001 cohort who had joined JRS and JASTRO were board-certified radiation oncologists. CONCLUSION: This program has greatly contributed to increasing the numbers of radiation oncologists. Because residents had a higher rate of affiliation than medical students, it is necessary to share information with not only medical universities, but also teaching hospitals.

Clinical results of external beam radiotherapy alone with a concomitant boost program or with conventional fractionation for cervical cancer patients who did not receive intracavitary brachytherapy.

A combination of external beam radiotherapy (EBRT) and intracavitary brachytherapy (ICBT) is well established as the standard radical radiotherapy (RT) for cervical cancer. However, it is sometimes necessary to perform EBRT alone for patients where ICBT is not feasible. For these patients, we initiated EBRT alone with three-dimensional conformal radiotherapy (3DCRT). The purpose of this study is to evaluate the results of EBRT alone without ICBT for patients with cervical cancer. Sixteen patients were treated with EBRT alone between 2002 and 2009. There were three stage IIB, six stage IIIB and seven patients with stage IVA disease. A total of 10 patients were treated with a median dose of 66 Gy with a median overall treatment time (OTT) of 40 days delivered by a concomitant boost (CCB), and a median dose of 60 Gy with a median OTT of 47 days was administered for six patients by conventional fractionation (CF). The 3-year overall survival (OAS) and local control (LC) rates were 43.8% and 75.0%, respectively. The 3-year LC rate was 90.0% for the CCB group, 50.0% for the CF group (P = 0.0692); 100% for OTT ≤42 days, 42.9% for OTT ≥43 days (P = 0.0095). No severe acute and late adverse effects were encountered for any of the patients. These outcomes suggest that EBRT with a CCB program may be a promising radical treatment for cervical cancer that provides better LC with minimal complications, especially in cases where ICBT cannot be performed.

Long-term outcomes of intraluminal brachytherapy in combination with external beam radiotherapy for superficial esophageal cancer.

BACKGROUND: The aim of this study was to assess the long-term outcomes of combining high-dose-rate intraluminal brachytherapy (IBT) with external beam radiotherapy (EBRT) for superficial esophageal cancer (SEC). METHODS: From 1992 to 2002, 87 patients with T1N0M0 thoracic esophageal cancer received IBT in combination with EBRT. Of these, 44 had mucosal cancer and 43 had submucosal cancer. For patients with tumor invasion within the lamina propria mucosa, IBT alone was performed (n = 27). IBT boost following EBRT was performed for patients with tumor invasion in the muscularis mucosa or deeper (n = 60). No patient received chemotherapy. RESULTS: The median follow-up time was 94 months. For mucosal cancer, the 5-year locoregional control (LRC), cause-specific survival (CSS) and overall survival (OS) rates were 75, 97 and 84%, respectively, and 49, 55 and 31%, respectively, for submucosal cancer. Tumor depth was a significant factor associated with LRC (p = 0.02), CSS (p < 0.001) and OS (p < 0.001) by univariate analysis. Multivariate analysis revealed that tumor depth was the only significant predictor for OS (p = 0.003). Late toxicities of grade 3 or higher in esophagus, pneumonitis, pleural effusion and pericardial effusion were observed in 5, 0, 0 and 1 patients, respectively. Grade ≥3 events of cardiac ischemia and heart failure after radiotherapy were observed in 9 patients, and history of heart disease before radiotherapy was the only significant factor (p = 0.002). CONCLUSION: There was a clear difference in outcomes of IBT combined with EBRT between mucosal and submucosal esophageal cancers. More intensive treatment should be considered for submucosal cancer.

[Concurrent chemoradiation experience of the local relapse of rectal cancer patients].

We have reported the concurrent chemoradiation experience of local relapse of rectal cancer patients. From October 2004 to January 2007 we have treated consecutive 10 patients with radiation and the concurrent chemotherapy by CPT-11+S-1. Of 10 lesions, 5(50%)had a complete response, 2(20%)a partial response, 3(30%)a stable disease, yielding an overall response rate of 70%. Three year survival and relapse free survival was 64% and 22 months, respectively. Four patients live without cancers, 3 patients died with cancers and 2 patients live with cancers. Three patients had acute complication(more than Grade 2)including 3 appetite losses. The concurrent chemoradiation is feasible for out-patients and seems to offer good results for the local relapse of rectal cancer patients.

Pathogenic potentials of glycoprotein C-negative syncytial mutants from rabbit T cells infected persistently with herpes simplex virus type 1.

Human T cell lymphotropic virus type I (HTLV-I)-transformed T cells of rabbits were infected persistently with Herpes simplex virus type 1 (HSV-1) strain KOS. These infected cells yielded syncytial mutants, either glycoprotein C (gC)-negative or -positive, which predominated over and replaced the wild-type virus in a long-term culture for 2 years. An alignment of nucleotide sequences showed multiple mutations in glycoprotein B (gB) and gC genes of these mutants, which are or may be responsible for the mutant phenotypes. One of four mutants analyzed produced extensively large syncytia and possessed point mutations within the cytoplasmic domain of gB. All four mutants possessed multiple point mutations in gC and two possessed single insertions which resulted in a frame shift, leading to the premature termination of the gC polypeptide chain. The supernatant of the 2-year culture of cells infected persistently, containing only gC-negative syncytial mutants, induced encephalitic symptoms in B/Jas inbred rabbits, when injected intravenously. One gC-negative syncytial isolate from an encephalitic lesion, together with those from the culture supernatant, were examined for pathogenic potential in vitro and in vivo. All these mutants were more cytotoxic and more susceptible to complement inactivation than the parental virus, and could infect and replicate in adrenal glands when injected intravenously into rabbits. Invasion into the central nervous system appeared to be blocked at the portal of entry, the adrenal gland, i.e., none exhibited neuroinvasive potential by itself. Syncytial gC-negative mutants could thus be pathogenic in rabbits.