Published papers

© 2019 The Author(s). Background: We aimed to evaluate the efficacy and safety of 5-fluorouracil-based neoadjuvant chemoradiotherapy (NACRT) in patients with resectable/borderline resectable pancreatic ductal adenocarcinoma (PDAC). Methods: This retrospective study investigated the clinicopathological features and > 5-year survival of patients with T3/T4 PDAC who underwent NACRT at our institute between 2003 and 2012. Results: Seventeen resectable and eight borderline resectable patients were included. The protocol treatment completion and resection rates were 92.0% and 68.0%, respectively. Two patients failed to complete chemotherapy owing to cholangitis or anorexia. Common grade 3 toxicities included anorexia (12%), neutropenia (4%), thrombocytopenia (4%), anemia (4%), and leukopenia (12%). Pathologically negative margins were achieved in 94.1% of patients who underwent pancreatectomy. Pathological response according to Evans' classification was grade IIA in 10 patients (58.8%), IIB in 5 patients (29.4%), and IV in 2 patients (11.8%). Postoperative pancreatic fistulas were observed in four patients (23.5%), delayed gastric emptying in one patient (5.9%), and other operative morbidities in four patients (23.5%). The 1-, 2-, 5-, and 10-year overall survival rates were 73.9%, 60.9%, 60.9%, and 39.1%, respectively (median follow-up period, 80.3 months). Conclusions: NACRT is tolerable and beneficial for resectable/borderline resectable PDAC, even in the long-term.

© 2018 Saito et al. This paper presents an extremely rare case of synovial sarcoma arising from the maxillary sinus, which resulted in a clinically complete response to chemotherapy. Synovial sarcoma is a rare soft tissue malignant tumor, most commonly affecting the extremities. While ∼10% occur in the head and neck region, synovial sarcoma of the sinonasal tract is extremely rare, with only 11 cases having been reported previously. As with other sarcomas, the standard treatment is complete resection while allowing for a safe margin, but this is often difficult in the head and neck area due to the complicated anatomy there. This makes the treat­ment of head and neck sarcoma challenging and leads to the need for a multimodal approach in advanced cases. However, the exact efficacy of chemotherapy is not well understood. In this report, we present a case of unresectable maxillary sinus synovial sarcoma that was success­fully treated by chemotherapy followed by radiation therapy. A 53-year-old Japanese man was referred to our hospital with a history of left nose obstruction over the previous couple of years. Computed tomography/magnetic resonance imaging revealed a tumor arising from the maxillary sinus that extended to adjacent tissues. A biopsy was performed, and the tumor was diagnosed as synovial sarcoma. Since the tumor was unresectable, neoadjuvant chemotherapy was administered. The response was excellent, and the tumor became undetectable under endoscopy and radiological imaging. This provided us with a clinical evaluation of “complete response”. The treatment was concluded with definitive radiotherapy and two more cycles of adjuvant chemotherapy. The patient remains free of disease 12 months after treatment. Synovial sarcoma of the head and neck is a rare entity; complete resection is the treatment of choice but (neo)adjuvant chemotherapy can be considered in unresectable cases, as we show here in the present case.

© 2018 Wolters Kluwer Health, Inc. All rights reserved. A 64-year-old man with castration-resistant prostate cancer received 223Ra injection to treat bone metastases. The patient underwent a 223Ra SPECT scan after the first 223Ra injection in which there was increased uptake all over the spine. Spine-to-background activity ratio in the patient was approximately three times greater than normal spine-to-background activity ratios in 223Ra SPECT obtained from the other patients. Eight days after the fifth injection, the patient exhibited a very poor neurologic examination and died of intracranial hemorrhage due to severe thrombocytopenia (platelet counts, 23,000/mm3). The extensive radiation to the spine may have enhanced myelophthisic process in this case.

© The Author(s) 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. We investigated long-term treatment outcomes and the feasibility of chemoradiotherapy consisting of daily-low-dose 5-fluorouracil and cisplatin (LDFP) chemotherapy plus radiotherapy for Stage I-II squamous cell esophageal cancer. Treatment records from the 2000 through 2008 period were reviewed retrospectively. Fractionated radiotherapy was performed with a total dose of 60 Gy delivered in 2 Gy per fraction. LDFP chemotherapy, as continuous infusion of 200 mg/m 2 5-fluorouracil combined with one hour infusion of 4 mg/m 2 cisplatin, was administered on the same days as radiotherapy. Survival was calculated by the Kaplan-Meier method. Survival, responses, failure patterns, and toxicities were evaluated. Seventy-six (47 stage I and 29 stage II) patients were analyzed with a median follow-up of 93.6 months. The 8-year overall survival (OS), progression-free survival (PFS) and cause-specific survival (CSS) rates were 63.4%, 49.8%, and 76.7%, respectively. The 8-year OS, PFS, and CSS for stage I and stage II patients were 71.0%/56.1%/82.9% and 45.2%/40.2%/66.6%, respectively. Sixty-eight patients (89.5%) completed the treatment regimen. A complete response (CR) was achieved in 68 patients (89.5%). Twenty-five patients (36.8%) experienced recurrence after CR. The failure patterns were (overlap included): local failure (n = 12), nodal metastasis (n = 12), distant metastasis (n = 3), details unknown (n = 2). Salvage therapy was performed for local failure; endoscopic therapy (n = 7) or surgery (n = 2). Six patients remain alive without relapse after salvage endoscopic therapy. Major Grade 3 or higher acute adverse events were leukopenia (22%), anorexia (17%), and esophagitis (11%). Major late toxicities (Grade 3 or 4) involved pericardial effusion (12%), pleural effusion (4%), and esophageal stenosis (3%). Chemoradiotherapy with LDFP provided favorable long-term survival with acceptable toxicity for Stage I-II squamous cell esophageal cancer. The tumor response was excellent, but close endoscopic follow-up is essential for detecting and treating local recurrence.

© 2018 The Author(s). Published by S. Karger AG, Basel. We report a patient with highly advanced gastric carcinoma who was treated successfully with chemoradiotherapy (CRT) comprising S-1 and cisplatin. The patient was a 71-year-old male who was diagnosed with advanced gastric carcinoma by esophagogastroduodenoscopy (EGD) by medical examination. EGD demonstrated type 3 advanced gastric carcinoma in the posterior wall of the upper gastric body. An abdominal computed tomography (CT) scan showed that the gastric wall was thickened due to gastric primary tumor, and large lymph nodes (LNs) including the lesser curvature LN, anterosuperior LN along the common hepatic artery and some para-aortic LNs were detected. The patient was diagnosed with stage IV advanced gastric carcinoma according to the Japanese classification of gastric carcinoma (cT4a, cN3, cM1 [para-aortic LN], cStage IV). Preoperative CRT was carried out in an attempt to downstage the disease. Remarkable reduction of the primary tumor and metastatic LNs was observed after initial CRT, and radiological examination determined that a partial response had been achieved. Adverse effects included grade 2 anorexia and grade 3 ALP elevation (919 U/ml). No grade 4 or more severe adverse event was observed. After CRT, although we recommended curative surgery, the patient refused surgical treatment and opted for conservative treatment. Thus, we continued S-1 oral administration for 1 year. Five months after beginning CRT, upper endoscopy showed that the tumor had maintained regression and scar formation, in which no cancer cells were detected by endoscopic biopsy. The patient is doing well and has maintained a clinical complete response for more than 42 months without curative surgery. CRT could be considered as an option for treatment of patients with locally advanced gastric carcinoma diagnosed as unresectable, or for those who refuse surgical treatment.

Purpose: To compare late genitourinary (GU) and gastrointestinal (GI) toxicity following different prostate cancer treatment modalities. Materials and methods: This study included 1084 consecutive prostate cancer patients treated with conventional radiotherapy, intensity-modulated radiotherapy (IMRT), permanent iodine-125 implantation (PI) alone, and PI combined with external beam radiotherapy (PI + EBRT). The effects of treatment- and patient-related factors on late grade. ≥. 2 (G2+) GU/GI toxicity risk were assessed. Results: The median follow-up was 43. months (range, 12-97. months). Compared to the PI + EBRT, there was significantly less G2+ GU toxicity in the conventional radiotherapy (hazard ratio [HR] = 0.39; 95% CI, 0.20-0.77) and the IMRT (HR = 0.45, 95% CI, 0.27-0.73). Compared to the PI + EBRT, there was significantly more G2+ GI toxicity in the IMRT (HR = 2.38; 95% CI, 1.16-4.87). In PI-related groups, prostate equivalent dose in 2. Gy fractions was a significant predictor of G2+ GU toxicity (p = 0.001), and the rectal volume receiving more than 100% of the prescribed dose was a significant predictor of G2+ GI toxicity (p = 0.001). Conclusion: The differences in the late G2+ GU/GI risk cannot be explained by the differences in treatment modalities themselves, but by the total radiation dose to the GU/GI tract, which had a causal role in the development of late G2+ GU/GI toxicity across all treatment modality groups.

Background: 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.Methods: 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.Results: 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.Conclusions: 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: UMIN000008941. © 2014 Matsuda et al.; licensee BioMed Central Ltd.

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. © The Author 2013. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Therapeutic Radiology and Oncology.

Purpose We investigated clinical and treatment-related factors as predictors of symptomatic pericardial effusion in esophageal cancer patients after concurrent chemoradiation therapy. Methods and Materials We reviewed 214 consecutive primary esophageal cancer patients treated with concurrent chemoradiation therapy between 2001 and 2010 in our institute. Pericardial effusion was detected on follow-up computed tomography. Symptomatic effusion was defined as effusion ≥grade 3 according to Common Terminology Criteria for Adverse Events v4.0 criteria. Percent volume irradiated with 5 to 65 Gy (V5-V65) and mean dose to the pericardium were evaluated employing dose-volume histograms. To evaluate dosimetry for patients treated with two-dimensional planning in the earlier period (2001-2005), computed tomography data at diagnosis were transferred to a treatment planning system to reconstruct three-dimensional plans without modification. Optimal dosimetric thresholds for symptomatic pericardial effusion were calculated by receiver operating characteristic curves. Associating clinical and treatment-related risk factors for symptomatic pericardial effusion were detected by univariate and multivariate analyses. Results The median follow-up was 29 (range, 6-121) months for eligible 167 patients. Symptomatic pericardial effusion was observed in 14 (8.4%) patients. Dosimetric analyses revealed average values of V30 to V45 for the pericardium and mean pericardial doses were significantly higher in patients with symptomatic pericardial effusion than in those with asymptomatic pericardial effusion (P<.05). Pericardial V5 to V55 and mean pericardial doses were significantly higher in patients with symptomatic pericardial effusion than in those without pericardial effusion (P<.001). Mean pericardial doses of 36.5 Gy and V45 of 58% were selected as optimal cutoff values for predicting symptomatic pericardial effusion. Multivariate analysis identified mean pericardial dose as the strongest risk factor for symptomatic pericardial effusion. Conclusions Dose-volume thresholds for the pericardium facilitate predicting symptomatic pericardial effusion. Mean pericardial dose was selected based not only on the optimal dose-volume threshold but also on the most significant risk factor for symptomatic pericardial effusion. © 2013 Elsevier Inc.

We have studied the induction of chromosome aberrations in human fibroblasts exposed in G0/G1 to X-rays or heavy ions to study the influence of G1 cell cycle arrest. Confluent normal fibroblasts were exposed to X-rays or accelerated particles with different LET values and chromosome aberrations were investigated in the first G0/G1 and G2//M phase. The particles used here were 490MeV/nucleon Si, 500MeV/nucleon Fe, and 200MeV/nucleon Fe ions. Cells were subcultured 24h after exposure and premature chromosome condensation (PCC) was performed by fusion-induced method for analysis of G0/G1 cells, and chemically-induced method for analysis of G2 and metaphase cells. Chromosome damage was assessed in chromosomes 1 and 3 using whole chromosome fluorescence in situ hybridization (FISH). Cell cycle was analyzed by flow cytometry at different incubation times following subculture. After irradiation with 2Gy of high-LET particles, the yields of chromosome aberrations and fragments were significantly higher in G0/G1 phase than in G2/M phase, whereas similar yields of damage were measured in both phases after exposure to X-rays. In contrast, the yield of misrepair, assessed by the number of color junctions, was similar in the G0/G1 and G2/M phases after exposure to either X-rays or high-LET particles. The yields of chromosome aberrations, fragments, and color junctions in both the G0/G1 and the G2/M phases, increased with LET up to 200keV/μm, then decreased for 440keV/μm Fe particles. A good correlation was found between chromosome aberrations in both G0/G1 and G2/M cells and survival fractions after 2Gy of different LET radiations, although the slopes were steeper for the G0/G1 cells. Flow cytometry analysis indicated that high-LET particles induce more non cycling G0/G1 cells within 48h of subculture than X-rays, suggesting that chromosome aberrations scored at the G2/M phase may not accurately describe the true radiation effect. © 2013 Elsevier B.V.

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. © 2013 Elsevier Inc. All rights reserved.

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.

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.

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. © The Japan Esophageal Society and Springer 2012.

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%).

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.

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. © 2012 by The Keio Journal of Medicine.