Details of a Researcher - Shigematsu, Naoyuki

Papers - Shigematsu, Naoyuki

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Novel parameter predicting grade 2 rectal bleeding after iodine-125 prostate brachytherapy combined with external beam radiation therapy

Shiraishi Yutaka, Hanada Takashi, Ohashi Toshio, Yorozu Atsunori, Toya Kazuhito, Saito Shiro, Shigematsu Naoyuki

International Journal of Radiation Oncology Biology Physics 87 ( 1 ) 182 - 187 2013.09

ISSN 0360-3016

Purpose: To propose a novel parameter predicting rectal bleeding on the basis of generalized equivalent uniform doses (gEUD) after ¹²⁵I prostate brachytherapy combined with external beam radiation therapy and to assess the predictive value of this parameter. Methods and Materials: To account for differences among radiation treatment modalities and fractionation schedules, rectal dose-volume histograms (DVHs) of 369 patients with localized prostate cancer undergoing combined therapy retrieved from corresponding treatment planning systems were converted to equivalent dose-based DVHs. The gEUDs for the rectum were calculated from these converted DVHs. The total gEUD (gEUD_sum) was determined by a summation of the brachytherapy and external-beam radiation therapy components. Results: Thirty-eight patients (10.3%) developed grade 2+ rectal bleeding. The grade 2+ rectal bleeding rate increased as the gEUD_sum increased: 2.0% (2 of 102 patients) for <70 Gy, 10.3% (15 of 145 patients) for 70-80 Gy, 15.8% (12 of 76 patients) for 80-90 Gy, and 19.6% (9 of 46 patients) for >90 Gy (P=.002). Multivariate analysis identified age (P=.024) and gEUD_sum (P=.000) as risk factors for grade 2+ rectal bleeding. Conclusions: Our results demonstrate gEUD to be a potential predictive factor for grade 2+ late rectal bleeding after combined therapy for prostate cancer.

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Comparison of preplanning and intraoperative planning for I-125 prostate brachytherapy

Yoshida Kayo, Ohashi Toshio, Yorozu Atsunori, Toya Kazuhito, Nishiyama Toru, Saito Shiro, Hanada Takashi, Shiraishi Yutaka, Shigematsu Naoyuki

Japanese Journal of Clinical Oncology 43 ( 4 ) 383 - 389 2013.04

ISSN 0368-2811

Objective: To compare two widely used permanent prostate brachytherapy techniques, preplanning and intraoperative planning, based on postimplant dosimetry, toxicity and biochemical outcomes. Methods: Between 2003 and 2006, 665 men with localized prostate cancer were treated with permanent interstitial implantation. The first 227 consecutive men were treated with the preplanning technique, followed by 438 men treated with the intraoperative technique. Late toxicity was scored by the Common Terminology Criteria for Adverse Events v.4.0. Biochemical failure was defined as a prostate-specific antigen increase of more than 2 ng/ml above the nadir value excluding a benign bounce. Univariate and multivariate analyses were performed to identify the variables associated with biochemical failure-free survival. Results: Postimplant target coverage was similar in the two groups, with a small difference in risk organ doses. Mean V100 was 96.3 vs. 96.7% (P = 0.205), D90 was 119.6 vs. 119.4% (P = 0.884), urethral D10 was 157.5 vs. 146.1% (P = 0.010), rectal V100 was 0.57 vs. 0.43 cc (P = 0.002) in the preplanning and intraoperative planning groups, respectively. Acute and late Grade 3 genitourinary and gastrointestinal toxicities were , <1% for both methods. The 5-year biochemical failure-free survival rate was 95.4% for the preplanning and 94.0% for the intraoperative planning group (P = 0.776). Multivariate analysis revealed Gleason score, biopsy positive rate and V100 to be predictors of biochemical failure-free survival, while the planning technique was not significant. Conclusion: This large-scale analysis of high-quality implants revealed similar postimplant dosimetry, toxicity profiles and biochemical failure-free survival for the preplanning and intraoperative planning methods.

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Detection of esophageal fiducial marker displacement during radiation therapy with a 2-dimensional on-board imager

Fukada Junichi, Hanada Takashi, Kawaguchi Osamu, Ohashi Toshio, Takeuchi Hiroya, Kitagawa Yuko, Seki Satoshi, Shiraishi Yutaka, Ogata Haruhiko, Shigematsu Naoyuki

International Journal of Radiation Oncology Biology Physics 85 ( 4 ) 991 - 998 2013.03

ISSN 0360-3016

Purpose: To quantify the interfraction displacement of esophageal fiducial markers for primary esophageal cancer radiation therapy. Methods and Materials: Orthogonal 2-dimensional (2D) matching records fused to vertebrae were analyzed in clinically staged T1/2N0 esophageal cancer patients undergoing endoscopic clipping as fiducial metal markers. Displacement of the markers between the digitally reconstructed radiographs and on-board kilovoltage images during radiation therapy was analyzed according to direction and esophageal site. Results: Forty-four patients, with 81 markers (10 proximal, 42 middle, and 29 distal), underwent 367 2D matching sessions during radiation therapy. The mean (SD) absolute marker displacement was 0.26 (0.30) cm in the right-left (RL), 0.50 (0.39) cm in the superior-inferior (SI), and 0.24 (0.21) cm in the anterior-posterior (AP) direction. Displacement was significantly larger in the SI than in the RL and AP directions (P<.0001). In the SI direction, mean absolute displacements of the distal, middle, and proximal esophagus were 0.67 (0.45) cm, 0.42 (0.32) cm, and 0.36 (0.30) cm, respectively. Distal esophagus displacement was significantly larger than those of the middle and proximal esophagus (P<.0001). The estimated internal margin to cover 95% of the cases was 0.75 cm in the RL and AP directions. In the SI direction, the margin was 1.25 cm for the proximal and middle esophagus and 1.75 cm for the distal esophagus. Conclusions: The magnitude of interfraction displacement of esophageal clips was larger in the SI direction, particularly in the distal esophagus, but substantial displacement was observed in other directions and at other esophageal sites. It is practical to take estimated movements into account with internal margins, even if vertebrae-based 2D matching is performed.

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Acceptable toxicity after stereotactic body radiation therapy for liver tumors adjacent to the central biliary system

Eriguchi Takahisa, Takeda Atsuya, Sanuki Naoko, Oku Yohei, Aoki Yousuke, Shigematsu Naoyuki, Kunieda Etsuo

International Journal of Radiation Oncology Biology Physics 85 ( 4 ) 1006 - 1011 2013.03

ISSN 0360-3016

Purpose: To evaluate biliary toxicity after stereotactic body radiation therapy (SBRT) for liver tumors. Methods and Materials: Among 297 consecutive patients with liver tumors treated with SBRT of 35 to 50 Gy in 5 fractions, patients who were irradiated with >20 Gy to the central biliary system (CBS), including the gallbladder, and had follow-up times >6 months were retrospectively analyzed. Toxicity profiles, such as clinical symptoms and laboratory and radiologic data especially for obstructive jaundice and biliary infection, were investigated in relation to the dose volume and length relationship for each biliary organ. Results: Fifty patients with 55 tumors were irradiated with >20 Gy to the CBS. The median follow-up period was 18.2 months (range, 6.0-80.5 months). In the dose length analysis, 39, 34, 14, and 2 patients were irradiated with >20 Gy, >30 Gy, >40 Gy, and >50 Gy, respectively, to >1 cm of the biliary tract. Seven patients were irradiated with >20 Gy to >20% of the gallbladder. Only 2 patients experienced asymptomatic bile duct stenosis. One patient, metachronously treated twice with SBRT for tumors adjacent to each other, had a transient increase in hepatic and biliary enzymes 12 months after the second treatment. The high-dose area >80 Gy corresponded to the biliary stenosis region. The other patient experienced biliary stenosis 5 months after SBRT and had no laboratory changes. The biliary tract irradiated with >20 Gy was 7 mm and did not correspond to the bile duct stenosis region. No obstructive jaundice or biliary infection was found in any patient. Conclusions: SBRT for liver tumors adjacent to the CBS was feasible with minimal biliary toxicity. Only 1 patient had exceptional radiation-induced bile duct stenosis. For liver tumors adjacent to the CBS without other effective treatment options, SBRT at a dose of 40 Gy in 5 fractions is a safe treatment with regard to biliary toxicity.

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A prospective longitudinal survey of erectile dysfunction in patients with localized prostate cancer treated with permanent prostate brachytherapy

Matsushima Masashi, Kikuchi Eiji, Maeda Takahiro, Nakashima Jun, Sugawara Akitomo, Ando Toshiyuki, Mizuno Ryuichi, Nagata Hirohiko, Miyajima Akira, Shigematsu Naoyuki, Oya Mototsugu

Journal of Urology 189 ( 3 ) 1014 - 1018 2013.03

ISSN 0022-5347

Purpose: Few studies have evaluated changes in erectile function with time before and after prostate brachytherapy using the International Index of Erectile Function-15, a sensitive, validated tool for assessing male sexual dysfunction. In this prospective study we evaluated the natural history of erectile function after prostate brachytherapy without supplemental therapy (external beam radiotherapy, phosphodiesterase-5 inhibitors or androgen deprivation therapy) using the International Index of Erectile Function-15. Materials and Methods: We identified 119 patients who were followed at least 12 months after prostate brachytherapy between 2004 and 2010. Sexual and erectile function status were assessed before brachytherapy (baseline), and 3, 6, 12, 18, 24 and 36 months postoperatively using the International Index of Erectile Function-15. Results: Mean total International Index of Erectile Function-15 score, and scores on the erectile function, orgasmic function, sexual desire and intercourse satisfaction domains 3 months after brachytherapy were significantly lower than at baseline (p <0.05). They remained lower until 36 months after prostate brachytherapy. Erectile function was maintained 12 months after brachytherapy in 16 of the 48 men (33.3%) with a baseline erectile function domain score of 11 or greater. There was no significant difference in clinical features except the age of patients who maintained the erectile function domain score and their counterparts 12 months after brachytherapy. Multivariate analysis revealed that age 70 years or greater was the only predictive factor for deteriorating erectile function after brachytherapy (p = 0.035). Conclusions: Findings indicate a global decrease in all domains of the International Index of Erectile Function-15 score 12 months after prostate brachytherapy. Also, patient age may influence the preservation of brachytherapy related potency.

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Dosimetric effects of prone and supine positions on post-implant assessments for prostate brachytherapy

Ohashi Toshio, Momma Tetsuo, Yamashita Shoji, Kanai Kunimitsu, Watanabe Yusuke, Hanada Takashi, Shigematsu Naoyuki

Journal of Contemporary Brachytherapy 5 ( 3 ) 122 - 126 2013

ISSN 1689-832X

Purpose: 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. Results: 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 D_2cc 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. Conclusions: 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.

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Multiple myeloma relapse in the irradiated liver

Uetake Akiko, Takeda Atsuya, Shigematsu Naoyuki, Ikeda Eiji, Kametaka Minako, Ohashi Toshio, Kunieda Etsuo

Journal of Radiotherapy in Practice 11 ( 4 ) 271 - 273 2012.12

ISSN 1460-3969

We described a rare case of multiple myeloma in a 60-year-old man, in whom relapse limited to the irradiated area in the left lobe of the liver developed following radiotherapy for lesions in 11th and 12th thoracic spines. Immunohistochemical analysis revealed expression of hepatocyte growth factor (HGF) and hepatocyte growth factor receptor (c-Met) in the hepatocytes in the irradiated area of the liver. We speculate that the malignant plasma cells might have proliferated in response to local increase of HGF production in the irradiated liver. The role of HGF in the extraosseous spread of multiple myeloma and also under the experimental condition of hepatic transplantation is discussed.

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Chemoradiotherapy for advanced gastric cancer

Takahashi Tsunehiro, Saikawa Yoshiro, Fukuda Kazumasa, Wada Norihito, Kawakubo Hirofumi, Takeuchi Hiroya, Fukada Junichi, Kawaguchi Osamu, Takaishi Hiromasa, Shigematsu Naoyuki, Kitagawa Yuko

Japanese Journal of Cancer and Chemotherapy 39 ( 13 ) 2464 - 2468 2012.12

ISSN 0385-0684

In the US and Europe, chemoradiotherapy has become a standard treatment not only for head and neck cancer, esophageal cancer, pancreatic cancer, and rectal cancer, but also for gastric cancer. In particular, chemoradiotherapy has been established as an adjuvant therapy. In Japan, it has not been established as a standard treatment. Its indications are limited, and it is often performed as palliative care. Disadvantages of radiation therapy for gastric cancer include the difficulty of establishing the area to irradiate due to peristaltic movement, risk of perforation and ulceration from high-dose radiation, and ineffectiveness against adenocarcinoma with low radiosensitivity. In recent years, technological advancement of radiation therapy has enabled pinpoint accuracy in the treatment of primary gastric lesions and regional lymph nodes. There has been much anticipation that chemoradiotherapy will become a part of multidisciplinary treatment for advanced cancer. This report describes the current state of chemoradiotherapy for gastric cancer in Japan and overseas, and outlines our approach to locally advanced gastric cancer.

Prostate brachytherapy seed migration to a left varicocele

Sugawara Akitomo, Nakashima Jun, Kunieda Etsuo, Nagata Hirohiko, Mizuno Ryuichi, Seki Satoshi, Shiraishi Yutaka, Kouta Ryuichi, Oya Mototsugu, Shigematsu Naoyuki

Brachytherapy 11 ( 6 ) 502 - 506 2012.11

ISSN 1538-4721

Purpose: To report a rare case of seed migration to a left varicocele after transperineal interstitial prostate brachytherapy with loose iodine-125 (¹²⁵I) seeds. Methods and Materials: A 73-year-old man presented with a serum prostate-specific antigen level of 5.21ng/mL, Gleason score of 7 (3+4), and clinical T1c adenocarcinoma of the prostate. The patient underwent transperineal interstitial prostate brachytherapy with loose ¹²⁵I seeds followed by external beam radiation therapy. Two weeks after seed implantation, a followup pelvic radiograph was obtained. One month after seed implantation, a pelvic computed tomography scan for postimplant dosimetric analysis was carried out. Subsequent ultrasound examination of the scrotum was undertaken. Results: Two weeks after seed implantation, an anteroposterior pelvic radiograph showed that a migrated seed was overlapped by the scrotum. Postimplant pelvic computed tomography revealed that a seed had migrated to the left side of the scrotum. Subsequent ultrasound examination of the scrotum revealed that the patient had a left varicocele to which the seed had migrated. The patient had no symptoms related to the migrated seed. Conclusions: This is the first report of seed migration to a left varicocele after transperineal interstitial prostate brachytherapy with loose ¹²⁵I seeds. For the present case, we suggest that the seed moved from the prostate to the left varicocele through the pelvic veins, bypassing the systemic circulation.

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Impact of MRI-based postimplant dosimetric assessment in prostate brachytherapy using contrast-enhanced T1-weighted images

Ohashi Toshio, Momma Tetsuo, Yamashita Shoji, Nagatsuma Katsumi, Kanai Kunimitsu, Kitagawa Kazuhito, Takahashi Shinichi, Hanada Takashi, Yorozu Atsunori, Shigematsu Naoyuki

Brachytherapy 11 ( 6 ) 468 - 475 2012.11

ISSN 1538-4721

Purpose: To compare contrast-enhanced T1-weighted (CE-T1WI) magnetic resonance imaging (MRI) with computed tomography (CT) for postimplant dosimetry and seed recognition in prostate brachytherapy. Methods and Materials: A total of 245 patients who received ¹²⁵I prostate brachytherapy with or without external beam radiotherapy were enrolled. For postimplant analysis, CT and MRI scans were obtained at 1 month after seed implantation. For MRI-based dosimetry, T2-weighted images were fused with the CE-T1WI; the prostate was delineated on the T2-weighted images, and the seed detection was performed manually on the CE-T1WI. In CT-based dosimetry, the seed detection was essentially performed automatically. The dosimetric results obtained by MRI-based and CT-based dosimetry were compared. Results: The mean prostate D₉₀ (the minimum dose received by 90% of the prostate volume) estimated by MRI-based and CT-based dosimetry were 113% and 115%, respectively, with no significant difference. The mean prostate V₁₀₀ (the percent volume of the postimplant prostate receiving 100% of the prescribed dose) estimated by MRI-based and CT-based dosimetry were 95.2% and 95.8%, respectively, again with no significant difference. The mean prostate V₁₅₀ (the percent volume of the postimplant prostate receiving 150% of the prescribed dose) estimated by MRI-based and CT-based dosimetry were 52.8% and 57.0%, respectively (p<0.01). In all of the 35 patients (14%) in whom the MRI-based V₁₅₀ were at least 10% lower than the CT-based results, the seed detection by CT-based dosimetry was overestimated in highly seed-clustered areas or in the areas close to calcifications because of reconstruction artifacts in CT images. Conclusions: MRI-based dosimetry using CE-T1WI appears to be acceptable. Our results suggest that MRI-based dosimetry is a practical method for estimation of the higher dose distribution, especially if seeds are clustered together or when they are close to calcifications.

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Result of salvage radiotherapy for post-operative PSA failure of prostate cancer

Sakayori M., Ohashi T., Fukada J., Shiraishi Y., Hanada T., Shigematsu N.

Japanese Journal of Clinical Radiology 57 ( 9 ) 1193 - 1199 2012.09

ISSN 0009-9252

Fifty-five patients with PSA failure were treated with salvage radiotherapy. Post-operative and postradiotherapy PSA failure was defined as the PSA elevation (nadir+0.2ng/ml) or the initiation of hormone therapy. The median follow-up period after salvage radiotherapy was 32 months (range ; l-67months). The 3-yrs biochemical free survival and overall survival rate was 66.7% and 100%. Result of salvage radiotherapy for post-operation PSA failure is good and only the dose was significant predictive factor (60Gy vs > 64Gy ; 53.9% vs 862%).

Initial experience of individualized chemoradiotherapy for superficial esophageal cancers based on the sentinel lymph node concept

Kaburagi Takuji, Takeuchi Hiroya, Fujii Hirofumi, Saikawa Yoshiro, Murakami Koji, Fukada Junichi, Shigematsu Naoyuki, Ozawa Soji, Ando Nobutoshi, Kitagawa Yuko

Esophagus 9 ( 3 ) 147 - 152 2012.09

ISSN 1612-9059

Background: Esophageal squamous cell carcinomas (ESCCs) invading the muscularis mucosae (T1a-MM) cause subclinical node metastasis in approximately 10 % of cases. When chemoradiotherapy (CRT) is administered to T1a-MM or deeper ESCC, prophylactic irradiation of areas with a risk of subclinical nodal metastasis may improve disease control. We had an opportunity for clinical observation of the status of lymph nodes in the patients whose hot spots in lymphoscintigraphy before CRT had been included within the irradiation field. Methods: We retrospectively investigated patients selected using following criteria: (1) cT1a-MM and cT1b without previous treatments, or pT1a-MM and pT1b cancers proved by previous endoscopic resections; (2) patients with neither clinical nodal nor distant metastasis; (3) patients whose hot spots detected by lymphoscintigraphy had been included within the irradiation fields. Lymphoscintigraphy had been examined with endoscopic injection of a radioisotope around the primary lesion before CRT. Results: Sixteen patients met the inclusion criteria. Of these patients [T1a-MM (4 cases), T1b-SM1 (2 cases), and T1b-SM2 (10 cases)], there were 9 definitive CRTs and 7 adjuvant CRTs after endoscopic resections. The median dose of irradiation was 60 Gy to the primary tumors and 46 Gy to the hot spots. All patients with definitive CRT achieved complete remission. At the median follow-up of 76.6 months, there was no lymph node recurrence. Conclusions: Prophylactic irradiation of the hot spots in lymphoscintigraphy may be effective. This result warrants further evaluation concerning the validity of irradiation field settings based on lymphoscintigraphic findings in patients with superficial ESCCs.

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Predicting pubic arch interference in prostate brachytherapy on transrectal ultrasonography-computed tomography fusion images.

Fukada Junichi, Shigematsu Naoyuki, Nakashima Jun, Ohashi Toshio, Kawaguchi Osamu, Oya Mototsugu

Journal of Radiation Research 53 ( 5 ) 753 - 759 2012.09

ISSN 0449-3060

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.

Preimplant factors affecting prostate D90 after transperineal interstitial prostate brachytherapy with loose ¹²⁵I seeds

Sugawara Akitomo, Nakashima Jun, Kunieda Etsuo, Nagata Hirohiko, Mizuno Ryuichi, Takeda Atsuya, Seki Satoshi, Shiraishi Yutaka, Kouta Ryuichi, Oya Mototsugu, Shigematsu Naoyuki

Keio Journal of Medicine 61 ( 3 ) 89 - 94 2012.09

ISSN 0022-9717

The dose received by 90% of the prostate volume (D90) is the key parameter of dosimetric analysis in prostate brachytherapy. The aim of this analysis was to identify preimplant factors affecting prostate D90 after transperineal interstitial prostate brachytherapy with loose ¹²⁵I seeds. We reviewed the records of 210 patients who underwent transperineal interstitial prostate brachytherapy with loose ¹²⁵I seeds for clinical T1/T2 prostate cancer at our institution. Patients who received supplemental external-beam radiation therapy were excluded. One hundred and nine patients (51.9%) received neoadjuvant hormonal therapy (NHT). One month after seed implantation, postimplant computed tomography and dosimetric analysis were performed. Univariate and multivariate analyses were carried out to identify preimplant factors affecting postimplant prostate D90. The postimplant prostate D90 values ranged from 123.3 to 234.1 Gy (mean ± standard error, 177.1 ± 1.4 Gy). Postimplant prostate D90 differed significantly between patients who had and had not undergone NHT (P = 0.001). In addition, simple regression analyses showed positive correlations with the estimated preimplant prostate D90, preimplant prostate volume by transrectal ultrasound (TRUS), total radioactivity, number of needles, and number of seeds. On stepwise multiple regression analysis, postimplant prostate D90 showed significant negative correlations with NHT and preimplant prostate volume by TRUS, and a significant positive correlation with total radioactivity. In conclusion, NHT, preimplant prostate volume by TRUS, and total radioactivity are significant preimplant factors affecting postimplant prostate D90 in prostate cancer patients treated with transperineal interstitial prostate brachytherapy with loose ¹²⁵I seeds.

Enhancement of radiosensitivity by a unique novel NF-B inhibitor, DHMEQ, in prostate cancer

Kozakai N., Kikuchi E., Hasegawa M., Suzuki E., Ide H., Miyajima A., Horiguchi Y., Nakashima J., Umezawa K., Shigematsu N., Oya M.

British Journal of Cancer 107 ( 4 ) 652 - 657 2012.08

ISSN 0007-0920

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.

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Statistical analysis of 32 patients with nasopharyngeal Carcinoma

Fujii Ryoichi, Imanishi Yorihisa, Tomita Toshiki, Sakamoto Koji, Shigetomi Seiji, Habu Noboru, Ootsuka Kuninori, Sato Yoichiro, Ozawa Hiroyuki, Yamashita Taku, Fujii Masato, Shigematsu Naoyuki, Ogawa Kaoru

Journal of Otolaryngology of Japan 115 ( 8 ) 773 - 782 2012.08

ISSN 0030-6622

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.

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Pericardial and pleural effusions after definitive radiotherapy for esophageal cancer

Fukada Junichi, Shigematsu Naoyuki, Ohashi Toshio, Shiraishi Yutaka, Takeuchi Hiroya, Kawaguchi Osamu, Kitagawa Yuko

Journal of Radiation Research 53 ( 3 ) 447 - 453 2012.05

ISSN 0449-3060

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.

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Comparison of clinical, tumour-relatedand dosimetric factors in grade 0-1, grade2 and grade 3 radiation pneumonitis after stereotactic body radiotherapy for lung tumours

Takeda A., Ohashi T., Kunieda Etsuo, Sanuki N., Enomoto T., Takeda T., Oku Y., Shigematsu N.

British Journal of Radiology 85 ( 1013 ) 636 - 642 2012.05

ISSN 0007-1285

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.

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Safety and efficacy of total body irradiation, cyclophosphamide, and cytarabine as a conditioning regimen for allogeneic hematopoietic stem cell transplantation in patients with acute lymphoblastic leukemia

Mori Takehiko, Aisa Yoshinobu, Kato Jun, Yamane Akiko, Nakazato Tomonori, Shigematsu Naoyuki, Okamoto Shinichiro

American Journal of Hematology 87 ( 4 ) 349 - 353 2012.04

ISSN 0361-8609

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.

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Clinical evidence of particle beam therapy

Shigematsu Naoyuki, Shiraishi Yutaka, Seki Satoshi, Fukada Junichi, Ohashi Toshio

International Journal of Clinical Oncology 17 ( 2 ) 75 - 78 2012.04

ISSN 1341-9625

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