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Neuro-Oncology  2014;16(Suppl 3):iii36.
BACKGROUND: (blind field) METHODS: Glioma cell lines (U251, LN229 and LN428) were irradiated with and without Mirin and then clonogenicity, apoptosis, and cell cycle change were examined. Western blot analysis was performed to determine the relative potency of Mirin to inhibit the radioresistance, through the signaling activity of AKT. We also examined the levels of H2AX phosphorylation (γH2AX), which is a marker of DNA double-strand breaks (DSBs) using Western blot. RESULTS: Glioblastoma cells pretreated with Mirin demonstrated an enhanced sensitivity to radiation. FACS analysis revealed that Mirin and radiation caused the glioma cells to accumulate in the G2/M-phase of the cell cycle and the combination of these two treatments further increased the G2/M fraction of the glioma cells. Mirin significantly enhanced radiation-induced apoptotic cell death. Also, Mirin blocked the basal and increase of radiation-induced AKT phosphorylation. We observed that the combination of Mirin and radiation increased persistence of γH2AX at 24 h suggesting the inhibition of DNA DSBs repair. CONCLUSIONS: These results indicate that Mirin can effectively enhance glioma cell radiosensitivity. It suggests that Mirin is a potent radiosensitizer for treating glioma cells. SECONDARY CATEGORY: n/a.
PMCID: PMC4144599
2.  Combination of 5α-reductase inhibitor with combined androgen blockade (CAB) as a novel cytoreductive regimen before prostate brachytherapy: Ultra-CAB 
We report a first case of using a 5α-reductase inhibitor (5ARI) and combined androgen blockade (CAB) as a cytoreductive regimen before prostate brachytherapy. Prostate volume reduction with CAB is limited to approximately 40% in most cases, making it difficult to meet anatomical constraints to perform these procedures in cases with large prostate volume. With the added administration of 5ARI, further volume reduction can be expected. Here, we describe this cytoreductive regimen used in a 63 year-old prostate cancer patient who became eligible to receive brachytherapy after dutasteride (0.5 mg daily) was added to CAB and prostate volume reduction of 57% was achieved.
PMCID: PMC4446383  PMID: 26069888
Combined androgen blockade (CAB); ultra-combined androgen blockade (UCAB); dutasteride; brachytherapy; 5α-reductase inhibitor; prostate cancer
3.  Continuous low-dose irradiation by I-125 seeds induces apoptosis of gastric cancer cells regardless of histological origin 
Cancer Biology & Therapy  2013;15(1):81-88.
The efficacy of conventional radiation therapy for gastric cancer is controversial. In this study, we evaluated the in vitro and in vivo effects of continuous low-dose-rate irradiation by I-125 seeds on different histological types of gastric cancer cell lines. Three human gastric cancer cell lines (MKN74, MKN45, and NUGC4) were treated with or without continuous low-dose irradiation by I-125 seeds in vitro and in vivo. Cell viability, apoptosis, caspase-3 assay, and cell-cycle distribution were examined in vitro. Body weight and tumor volumes of BALB/c nude mice bearing MKN74, MKN45, and NUGC4 gastric cancer xenografts were measured, and in vivo cell proliferation and apoptosis assays were performed by Ki67 and TUNEL staining, respectively. Continuous low-dose-rate irradiation by I-125 seeds reduced cell viability and induced cell apoptosis through the activation of caspase-3, and led to the accumulation of cells in the G2/M phase in vitro. It also suppressed the growth of gastric cancer xenografts in nude mice, while inhibiting cell proliferation and inducing apoptosis as demonstrated by Ki67 and TUNEL staining. Therefore, our data suggest that continuous low-dose-rate irradiation by I-125 seeds could be a promising new option for gastric cancer treatment, regardless of histological origin.
PMCID: PMC3938526  PMID: 24149371
I-125 seed irradiation; gastric cancer; apoptosis; cell cycle; caspase
5.  Combined brachytherapy and external beam radiotherapy without adjuvant androgen deprivation therapy for high-risk prostate cancer 
To report the outcomes of patients treated with combined iodine-125 (I-125) brachytherapy and external beam radiotherapy (EBRT) for high-risk prostate cancer.
Between 2003 and 2009, I-125 permanent prostate brachytherapy plus EBRT was performed for 206 patients with high-risk prostate cancer. High-risk patients had prostate-specific antigen ≥ 20 ng/mL, and/or Gleason score ≥ 8, and/or Stage ≥ T3. One hundred and one patients (49.0%) received neoadjuvant androgen deprivation therapy (ADT) but none were given adjuvant ADT. Biochemical failure-free survival (BFFS) was determined using the Phoenix definition.
The 5-year actuarial BFFS rate was 84.8%. The 5-year cause-specific survival and overall survival rates were 98.7% and 97.6%, respectively. There were 8 deaths (3.9%), of which 2 were due to prostate cancer. On multivariate analysis, positive biopsy core rates and the number of high-risk factors were independent predictors of BFFS. The 5-year BFFS rates for patients in the positive biopsy core rate <50% and ≥50% groups were 89.3% and 78.2%, respectively (p = 0.03). The 5-year BFFS rate for patients with the any single high-risk factor was 86.1%, compared with 73.6% for those with any 2 or all 3 high-risk factors (p = 0.03). Neoadjuvant ADT did not impact the 5-year BFFS.
At a median follow-up of 60 months, high-risk prostate cancer patients undergoing combined I-125 brachytherapy and EBRT without adjuvant ADT have a high probability of achieving 5-year BFFS.
PMCID: PMC3904455  PMID: 24401540
Prostate cancer; Brachytherapy; High risk; Androgen deprivation therapy
6.  Phase I study of neoadjuvant chemoradiotherapy with S-1 plus biweekly cisplatin for advanced gastric cancer patients with lymph node metastasis: -KOGC04- 
In patients with highly advanced gastric cancer, the recurrence rate remains high and the prognosis disappointing. We previously reported a phase I study of a neoadjuvant chemoradiotherapy of S-1 plus weekly cisplatin. Although adequate safety and efficacy were reported, myelosuppression was frequently observed, leading to treatment delay in several cases. To decrease toxicity and improve efficacy, we planned a phase I study with a modified chemotherapy regimen with biweekly cisplatin.
Patients with advanced gastric cancer and lymph node metastasis who were treated by our institution between 2011 and 2012 were eligible for inclusion. The initial chemoradiotherapy schedule consisted of 6 weeks of S-1 orally administered on days 1–15 with an escalating dose of cisplatin administered on days 1 and 15. The starting dose (level 1) of cisplatin was 15 mg/m2, the second dose (level 2) was 20 mg/m2, and the third dose (level 3) was 25 mg/m2. Radiation of 40 Gy was administered in 20 fractions. After initial chemoradiotherapy, one cycle of combination chemotherapy with S-1 plus cisplatin was delivered. The second cycle was 42 days in duration and included S-1 administered on days 1–29 plus biweekly cisplatin administered on days 1, 15, and 29. After neoadjuvant treatment, a curative gastrectomy with extended (D2) lymph node dissection was planned.
Nine patients were enrolled. At level 3, one patient had dose-limiting grade 3 diarrhea. Another patient experienced grade 3 nausea and intended to discontinue the treatment. Overall, because 2 of 3 patients experienced dose-limiting toxicity at level 3, we confirmed level 3 (Cisplatin 25 mg/m2) as the maximum tolerated dose and level 2 (Cisplatin 20 mg/m2) as the recommended dose (RD). The response rate was 78%, and 8 patients underwent curative gastrectomy. Resected specimens showed a histological response in 6 patients (75%), including one with a pathological complete response.
In this phase I trial, RD of cisplatin was identified as 20 mg/m2. Generally, S-1 plus biweekly cisplatin can be given safely with concurrent radiation. We have initiated a multicenter phase II trial to further confirm the efficacy and safety of this approach.
Trial registration
PMCID: PMC3904203  PMID: 24398302
Gastric cancer; Neoadjuvant; Chemoradiotherapy; S-1; Cisplatin; Phase I
7.  Dosimetric effects of prone and supine positions on post-implant assessments for prostate brachytherapy 
Post-implant dosimetric assessment is essential for optimal care of patients receiving prostate brachytherapy. In most institutions, post-implant computed tomography (CT) is performed in the supine position. This study aimed to assess variability in dosimetric parameters with postural changes during acquisition of post-implant CT scans.
Material and methods
In total, 85 consecutive patients were enrolled in this study. Fifty-three patients underwent seed implantation alone, and the remaining 32 received a combination of seed implantation and external beam radiotherapy. For post-implant analyses, CT scans were obtained in two patient positions, supine and prone. To evaluate differences in dosimetric parameters associated with postural change, the dosimetric data obtained in the supine position were defined as the standard.
The median prostate volume was 22.4 ml in the supine and 22.5 ml in the prone position (p = 0.51). The median prostate D90 was 120.1% in the supine and 120.3% in the prone position, not significantly different. The mean prostate V100 was 97.1% in the supine and 97.0% in the prone position, again not significantly different. Median rectal V100 in supine and prone positions were 0.42 ml and 0.33 ml, respectively (p < 0.01). Rectal D2cc was also significantly decreased in the prone as compared with the supine position (median, 59.1% vs. 63.6%; p < 0.01). A larger post-implant prostate volume was associated with decreased rectal doses in the prone position.
Though there were no significant differences among prostate D90 assessments according to postural changes, our results suggest that post-implant rectal doses decreased in the prone position.
PMCID: PMC3797408  PMID: 24143145
prostate cancer; brachytherapy; post-implant; position; prone
8.  Comparison of the repair of potentially lethal damage after low- and high-LET radiation exposure, assessed from the kinetics and fidelity of chromosome rejoining in normal human fibroblasts 
Journal of Radiation Research  2013;54(6):989-997.
Potentially lethal damage (PLD) and its repair (PLDR) were studied in confluent human fibroblasts by analyzing the kinetics of chromosome break rejoining after X-ray or heavy-ion exposures. Cells were either held in the non-cycling G0 phase of the cell cycle for 12 h, or forced to proliferate immediately after irradiation. Fusion premature chromosome condensation (PCC) was combined with fluorescence in situ hybridization (FISH) to study chromosomal aberrations in interphase. The culture condition had no impact on the rejoining kinetics of PCC breaks during the 12 h after X-ray or heavy-ion irradiation. However, 12 h after X-ray and silicon irradiation, cycling cells had more chromosome exchanges than non-cycling cells. After 6 Gy X-rays, the yield of exchanges in cycling cells was 2.8 times higher than that in non-cycling cells, and after 2 Gy of 55 keV/μm silicon ions the yield of exchanges in cycling cells was twice that of non-cycling cells. In contrast, after exposure to 2 Gy 200-keV/μm or 440-keV/μm iron ions the yield of exchanges was similar in non-cycling and cycling cells. Since the majority of repair in G0/G1 occurs via the non-homologous end joining process (NHEJ), increased PLDR in X-ray and silicon-ion irradiated cells may result from improved cell cycle-specific rejoining fidelity through the NHEJ pathway, which is not the case in high-LET iron-ion irradiated cells.
PMCID: PMC3823769  PMID: 23674607
heavy ion; PLDR (potentially lethal damage repair); premature chromosome condensation; FISH (fluorescence in situ hybridization); misrepair
9.  Predicting pubic arch interference in prostate brachytherapy on transrectal ultrasonography-computed tomography fusion images 
Journal of Radiation Research  2012;53(5):753-759.
We investigated the usefulness of the fusion image created by transrectal ultrasonography (TRUS) and large-bore computed tomography (CT) for predicting pubic arch interference (PAI) during prostate seed brachytherapy. The TRUS volume study was performed in 21 patients, followed by large-bore computed tomography of patients in the lithotomy position. Then, we created TRUS-CT fusion images using a radiation planning treatment system. TRUS images in which the prostate outline was the largest were overlaid on CT images with the narrowest pubic arch. PAI was estimated in the right and left arch separately and classified to three grades: no PAI, PAI positive within 5 mm and PAI of >5 mm. If the estimated PAI was more than 5 mm on at least one side of the arch, we judged there to be a significant PAI. Brachytherapy was performed in 18 patients who were evaluated as not having significant PAI on TRUS. Intra-operative PAI was observed in one case, which was also detected with a fusion image. On the other hand, intra-operative PAI was not observed in one case that had been evaluated as having significant PAI with a fusion image. In the remaining three patients, TRUS suggested the presence of significant PAI, which was also confirmed by a fusion image. Intra-operative PAI could be predicted by TRUS-CT fusion imaging, even when it was undetectable by TRUS. Although improvement of the reproducibility of the patients’ position to avoid false-positive cases is warranted, TRUS-CT fusion imaging has the possibility that the uncertainty of TRUS can be supplemented.
PMCID: PMC3430429  PMID: 22843359
prostate cancer; brachytherapy; seed implantation; pubic arch interference; fusion image
10.  Incidence of seed migration to the chest, abdomen, and pelvis after transperineal interstitial prostate brachytherapy with loose 125I seeds 
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.
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.
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.
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.
PMCID: PMC3206434  PMID: 21974959
Brachytherapy; 125I; Migration; Prostate cancer; Seed
11.  Radiation-sensitizing effect of low-concentration docetaxel on human esophageal squamous cell carcinoma cell lines 
Esophageal squamous cell carcinoma (ESCC) is more sensitive to radiation and chemotherapy than other cancers of the digestive system, and combined modality therapy may represent a promising treatment method. The radiation-sensitizing effect of docetaxel on ESCC cell lines was investigated. A colony formation assay was performed in which ESCC cell lines (TE2, TE3) and A431 were exposed to docetaxel (from 1.0×10−11 to 10−7 M) for 3 h to determine the concentration of docetaxel that was not able to kill individual cells (i.e., the non-cytocidal concentration). Individual cell lines were then exposed to the non-cytocidal concentration of docetaxel prior to, during, and after irradiation to determine whether the timing of docetaxel administration affected cell survival. In addition, flow-cytometry was performed, and the cell cycle was examined prior to and after docetaxel exposure to assess the mechanism of docetaxel as a radiation sensitizer. Docetaxel exhibited a concentration-dependent cytocidal effect, with a different IC50 for each cell type. Almost no cytocidal effect was observed at the following docetaxel concentrations: A431, ≤1.0×10−10 M; TE-2 and TE-3, ≤1.0×10−9 M. Concurrent treatment with docetaxel and radiation tended to decrease cell survival in all the cell lines compared with docetaxel or radiation alone. Cell survival was lowest when the cells were treated using X-ray irradiation after docetaxel exposure (p<0.05). Flow cytometry revealed that in all three cell lines, docetaxel exposure increased the G2/M cell fraction with a higher increase in the cell line that exhibited the highest radiosensitivity. This study demonstrated that the administration of docetaxel at a non-cytocidal concentration prior to radiotherapy produced a synergistic cell-killing effect in SCC cell lines.
PMCID: PMC3440770  PMID: 22977547
docetaxel; radiation-sensitizing effect; esophageal squamous cell carcinoma
12.  Preimplant factors affecting postimplant CT-determined prostate volume and the CT/TRUS volume ratio after transperineal interstitial prostate brachytherapy with 125I free seeds 
The aim was to identify preimplant factors affecting postimplant prostate volume and the increase in prostate volume after transperineal interstitial prostate brachytherapy with 125I free seeds.
We reviewed the records of 180 patients who underwent prostate brachytherapy with 125I free seeds for clinical T1/T2 prostate cancer. Eighty-one (45%) of the 180 patients underwent neoadjuvant hormonal therapy. No patient received supplemental external beam radiotherapy. Postimplant computed tomography was undertaken, and postimplant dosimetric analysis was performed. Univariate and multivariate analyses were performed to identify preimplant factors affecting postimplant prostate volume by computed tomography and the increase in prostate volume after implantation.
Preimplant prostate volume by transrectal ultrasound, serum prostate-specific antigen, number of needles, and number of seeds implanted were significantly correlated with postimplant prostate volume by computed tomography. The increase in prostate volume after implantation was significantly higher in patients with neoadjuvant hormonal therapy than in those without. Preimplant prostate volume by transrectal ultrasound, number of needles, and number of seeds implanted were significantly correlated with the increase in prostate volume after implantation. Stepwise multiple linear regression analysis showed that preimplant prostate volume by transrectal ultrasound and neoadjuvant hormonal therapy were significant independent factors affecting both postimplant prostate volume by computed tomography and the increase in prostate volume after implantation.
The results of the present study show that preimplant prostate volume by transrectal ultrasound and neoadjuvant hormonal therapy are significant preimplant factors affecting both postimplant prostate volume by computed tomography and the increase in prostate volume after implantation.
PMCID: PMC2954882  PMID: 20875137

Results 1-12 (12)