Published papers

In order to assess the clinical outcome and prognostic factors of patients with nasopharyngeal carcinoma (NPC) who were initially treated in the Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine between 1997 and 2006, statistical analyses were performed based on the patient medical records. Cause-specific survival (CSS) and disease-free survival (DFS) in all cases (stage I to IV, n = 32) and advanced cases (stage III and IV, n = 22) were estimated using the Kaplan-Meier method. The independent prognostic values of the clinical and therapeutic factors were determined using multivariate Cox proportional hazards models. Results: The 5-year CSS/DFS were 43.4%/34.8% in all cases and 34.596/29.8% in advanced cases. Multivariate analysis revealed that, in all cases, the independent prognostic factors for CSS were age ≥ 61 vs. ≤60, risk ratio (RR) =5.717, p = 0.006), T-stage (3/4 vs. 1/2, RR = 6.957, p = 0.004), and the use of platinum agents (unused vs. used, RR = 3.911, p = 0.012), whereas those for DFS were T-stage (3/4 vs. 1/2, RR=3.499, p = 0.019) and the use of platinum agents (unused vs. used, RR=2.947, p = 0.028). In advanced cases, the use of platinum agents alone was significant for both CSS (RR = 4.503, p = 0.023)and DFS (RR=4.218, p = 0.014). The patients who received neoadjuvant chemotherapy (NAC) showed better CSS and DFS than the patients who did not (p = 0.066 and p = 0.025, respectively) in a univariate analysis (Log-rank test), although no significant difference was seen between these groups in the multivariate analysis. Conclusion: The advantage of the administration of platinum agents in the treatment of NPC was statistically corroborated even in our study with its small sample size. As agents combined with chemoradiotherapy, the efficacy of do-cetaxel alone did not seem comparable to that of platinum agents. The docetaxel-CDDP-5-FU regimen applied as NAC was suggested to be possibly beneficial for advanced cases of NPC.

Background: Inducible activation of nuclear factor (NF)-B is one of the principal mechanisms through which resistant prostate cancer cells are protected from radiotherapy. We hypothesised that inactivation of inducible NF-B with a novel NF-B inhibitor, DHMEQ, would increase the therapeutic effects of radiotherapy.Methods:PC-3 and LNCaP cells were exposed to irradiation and/or DHMEQ. Cell viability, cell cycle analysis, western blotting assay, and NF-B activity were measured. The antitumour effect of irradiation combined with DHMEQ in vivo was also assessed.Results:The combination of DHMEQ with irradiation resulted in cell growth inhibition and G2/M arrest relative to treatment with irradiation alone. Inducible NF-B activity by irradiation was inhibited by DHMEQ treatment. The expression of p53 and p21 in LNCaP, and of 14-3-3 in PC-3 cells, was increased in the combination treatment. In the in vivo study, 64 days after the start of treatment, tumour size was 85.1%, 77.1%, and 64.7% smaller in the combination treatment group than that of the untreated control, DHMEQ-treated alone, and irradiation alone groups, respectively.Conclusion:Blockade of NF-B activity induced by radiation with DHMEQ could overcome radio-resistant responses and may become a new therapeutic modality for treating prostate cancer.

Purpose: We investigated the incidences of pericardial and pleural effusions after definitive radiotherapy with or without concurrent chemotherapy were analyzed retrospectively. Methods: One hundred and forty-seven patients with esophageal cancer received definitive radiotherapy or concurrent chemoradiotherapy (CCR). Follow-up chest Computed Tomography scans were reviewed to detect pericardial and pleural effusions. Adverse events were graded according to the Radiation Therapy Oncology Group Common Toxicity Criteria. Results: The median follow-up was 34 (range, 6 to 84) months. Numbers of eligible patients evaluated for pericardial and pleural effusions were 107 and 101, respectively. Pericardial effusions exceeding grade 1 and grade 2 toxicities were observed in 46 (43%) and 15 (14%) patients, respectively. The corresponding numbers for pleura! effusions were 44 (44%) and 18 (18%). Onset of effusion ranged from 1 to 65 months after treatment. Multivariate analysis identified radiation field width of the mediastinum exceeding 8 cm as a significant risk factor for both pericardial and pleural effusions. Age and field length exceeding 20 cm were identified as independent risk factors for pleural effusion. Conclusions: Pericardial and pleural effusions after radiotherapy or CCR are occasionally recognized as adverse events in patients with esophageal cancer. The mediastinal radiation field width can be a simple indicator for predicting those adverse events.

Objective: The aim of this study was to investigate significant clinical, tumour-related and dosimetric factors among patients with grade 0-1, grade 2 and grade 3 radiation pneumonitis (RP) after stereotactic body radiotherapy (SBRT) for lung tumours. Methods: Patients (n=128) with a total of 133 lung tumours treated with SBRT of 50 Gy in 5 fractions were analysed. RP was graded according to the Common Terminology Criteria for Adverse Events v.3.0. Significant factors were identified by univariate and multivariate analyses. Threshold dose-volume histograms (DVHs) were constructed to identify the incidence of RP. Results: The median follow-up period was 12 months (range, 6-45 months). In univariate analyses, gender, operability, forced expiratory volume in 1 s (FEV1), internal target volume, lung volumes treated with doses >5-30 Gy (V5-30) and mean lung dose were significant factors differentiating between grade 0-1 and grade 2 RP, and V15-30 were significant factors differentiating between grade 2 and grade 3. However, no factors were significant between grade 0-1 and grade 3 RP. Multivariate analysis showed that female gender, high FEV1 and high V15 were significant factors differentiating between grade 0-1 and grade 2 RP. Threshold DVH curves were created based on ≤5% and ≤15% risk of grade 2 RP among patients with grade 0-2 RP. Conclusions: Grade 0-2 RP was dose-volume dependent, and female gender and high FEV1 were significant predictive clinical factors for grade 2 RP among patients with grade 0-2 RP. However, incidences of V15-30 in grade 3 RP were significantly lower than those in grade 2 RP, and no significant clinical or tumour-related factors were found. Further studies are needed to identify the mechanism underlying the development of grade 3 RP after SBRT for lung tumours.

Disease relapse still greatly interferes with the success of allogeneic hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia (ALL). This study retrospectively evaluated the long-term safety and efficacy of a conditioning regimen consisting of total body irradiation (TBI; 12 Gy), cyclophosphamide (CY; 60 mg kg -1, two doses), and high-dose cytarabine (Ara-C; 2 g m -2; four doses) for patients with ALL. Fifty-five patients (median age: 31-years old) were evaluated. Stem cells were from human leukocyte antigen-identical siblings in 22 patients and from alternative donors in 33. There were no cases of early death before engraftment, and 100-day transplant-related mortality was 7.3%. With a median follow-up period of 9.6 years, 5-year overall and disease-free survival were 63.2% (95% CI: 46.5-79.9%) and 63.6% (95% CI: 47.1-80.1%) in patients with complete remission, respectively, both of which were significantly higher than the values of 27.3% (95% CI: 8.7-46.0%) and 22.7% (95% CI: 5.3-40.1%) for patients in advanced stages (P < 0.01). These results suggest that TBI and CY (TBI-CY) plus Ara-C could be a feasible and effective conditioning regimen for adult patients with ALL both in remission and in advanced stages, and a future study to compare this combination therapy with TBI-CY is required.

We would like to explain the effects of radiation on human health and discuss the actual effects of the contamination with radioactive material present in Tokyo. Currently, external exposure doses are within the allowable range in Tokyo and will have no adverse health effects on adults or children. As for internal exposure doses, there will likely be no problems as regards our ordinary dietary intakes. However, hot spots of Cs-134, Sr-90 and others should be monitored further.

A variety of reduced-intensity conditionings have been used in the reported studies of allogeneic hematopoietic stem cell transplantation (HSCT) for elderly patients with myeloid hematological malignancies. This study retrospectively analyzed the outcome of allogeneic HSCT for 10 patients aged 50 years or older with myeloid hematological malignancies after conditioning with fludarabine (125 mg/m(2)), melphalan (140 mg/m(2)) and total body irradiation (TBI; 8 Gy). Median age of the patients was 56.5 years, and diagnoses included acute myelogenous leukemia, advance myelodysplastic syndrome, and secondary myelofibrosis. Sources of stem cells were bone marrow from sibling (n=4) or unrelated donor (n=6). Both overall and disease-free survival rates were 40.0% (95% CI: 10.6~69.4%). Causes of death were relapse (n=2), fungal infection (n=2), and secondary malignancies (n=2). Because of a high incidence of transplant-related mortality, further refinement of this conditioning is required.

Purpose: To determine the rectal tolerance to Grade 2 rectal bleeding after I-125 seed brachytherapy combined with external beam radiotherapy (EBRT), based on the rectal dose-volume histogram. Methods and Materials: A total of 458 consecutive patients with stages T1 to T3 prostate cancer received combined modality treatment consisting of I-125 seed implantation followed by EBRT to the prostate and seminal vesicles. The prescribed doses of brachytherapy and EBRT were 100 Gy and 45 Gy in 25 fractions, respectively. The rectal dosimetric factors were analyzed for rectal volumes receiving >100 Gy and >150 Gy (R100 and R150) during brachytherapy and for rectal volumes receiving >30 Gy to 40 Gy (V30-V40) during EBRT therapy in 373 patients for whom datasets were available. The patients were followed from 21 to 72 months (median, 45 months) after the I-125 seed implantation. Results: Forty-four patients (9.7%) developed Grade 2 rectal bleeding. On multivariate analysis, age (p = 0.014), R100 (p = 0.002), and V30 (p = 0.001) were identified as risk factors for Grade 2 rectal bleeding. The rectal bleeding rate increased as the R100 increased: 5.0% (2/40 patients) for 0 ml; 7.5% (20/267 patients) for >0 to 0.5 ml; 11.0% (11/100 patients) for >0.5 to 1 ml; 17.9% (5/28 patients) for >1 to 1.5 ml; and 27.3% (6/22 patients) for >1.5 ml (p = 0.014). Grade 2 rectal bleeding developed in 6.4% (12/188) of patients with a V30 ≤35% and in 14.1% (26/185) of patients with a V30 >35% (p = 0.02). When these dose-volume parameters were considered in combination, the Grade 2 rectal bleeding rate was 4.2% (5/120 patients) for a R100 ≤0.5 ml and a V30 ≤35%, whereas it was 22.4% (13/58 patients) for R100 of >0.5 ml and V30 of >35%. Conclusion: The risk of rectal bleeding was found to be significantly volume-dependent in patients with prostate cancer who received combined modality treatment. Rectal dose-volume analysis is a practical method for predicting the risk of development of Grade 2 rectal bleeding.

Background: The aim was to determine the incidence of seed migration not only to the chest, but also to the abdomen and pelvis after transperineal interstitial prostate brachytherapy with loose 125I seeds.Methods: We reviewed the records of 267 patients who underwent prostate brachytherapy with loose 125I seeds. After seed implantation, orthogonal chest radiographs, an abdominal radiograph, and a pelvic radiograph were undertaken routinely to document the occurrence and sites of seed migration. The incidence of seed migration to the chest, abdomen, and pelvis was calculated. All patients who had seed migration to the abdomen and pelvis subsequently underwent a computed tomography scan to identify the exact location of the migrated seeds. Postimplant dosimetric analysis was undertaken, and dosimetric results were compared between patients with and without seed migration.Results: A total of 19,236 seeds were implanted in 267 patients. Overall, 91 of 19,236 (0.47%) seeds migrated in 66 of 267 (24.7%) patients. Sixty-nine (0.36%) seeds migrated to the chest in 54 (20.2%) patients. Seven (0.036%) seeds migrated to the abdomen in six (2.2%) patients. Fifteen (0.078%) seeds migrated to the pelvis in 15 (5.6%) patients. Seed migration occurred predominantly within two weeks after seed implantation. None of the 66 patients had symptoms related to the migrated seeds. Postimplant prostate D90 was not significantly different between patients with and without seed migration.Conclusion: We showed the incidence of seed migration to the chest, abdomen and pelvis. Seed migration did not have a significant effect on postimplant prostate D90.

We previously reported a high incidence of kerato-conjunctivitis in patients receiving high-dose cytarabine following total body irradiation (TBI) as a conditioning for hematopoietic stem cell transplantation (HSCT) even on prophylaxis with topical corticosteroid. This study aimed to evaluate whether addition of eye rinse, which was designed to remove cytarabine from ocular surface, further reduces the incidence of kerato-conjunctivitis in the same setting. Seventy-six patients receiving cytarabine at a dose of 3 g/m 2 every 12 h for 4 days after receiving TBI (12 Gy) as conditioning for HSCT were evaluated. All patients received betamethasone sodium phosphate eye drops. Twenty-three patients were further instructed to rinse their eyes with sterile saline every 10-15 min during and for two additional hours after the completion of each cytarabine infusion. Among 23 patients with eye rinse, Grades 2-3 and 1-3 kerato-conjunctivitis were observed in 4 (17.4%) and 5 patients (21.7%), respectively. These incidences were significantly lower than those [35 (66.0%) and 41 (77.4%)] observed in 53 patients without eye rinse (P<0.001 and P<0.00001, respectively). These results strongly suggest that eye rinse effectively reduces the incidence and severity of cytarabine-induced kerato-conjunctivitis in HSCT recipients who receive high-dose cytarabine following TBI.

Background: The prognosis for advanced gastric cancer is poor, with surgery as the only treatment for resectable advanced gastric cancer. Therefore, treatment options that might improve the prognosis are needed. To that end, neoadjuvant chemoradiotherapy with S-1 and cisplatin (CDDP) was investigated. Patients and Methods: The chemotherapy schedule included one cycle repeated after 6 weeks. S-1 was administered orally every day on days 1-21 and CDDP was infused on days 1, 8 and 15. Radiation therapy was started concurrently with chemotherapy and repeated daily on days 1-5, 8-12, 15-19, and 22-26. Results: A total of 10 patients were recruited. The first four patients were entered into level 1 (CDDP, 20 mg/m2). The next six patients were entered into level 0 (15 mg/m2), because of dose-limiting toxicity (delaying the second course of chemotherapy in two patients) that had been observed at level 1. The maximum tolerated dose (MTD) of CDDP was 20 mg/m2. Seven patients underwent surgery and all had an R0 (no residual tumor) resection without surgical complications. Conclusion: Neoadjuvant chemoradiotherapy with S-1 and CDDP may cause surgery to be delayed, but shows promise for resectable advanced gastric cancer.