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We conducted a nationwide survey of tomotherapy for malignant pleural mesothelioma (MPM) in Japan. Fifty-six facilities were surveyed and data on 31 patients treated curatively between 2008 and 2017 were collected from 14 facilities. Twenty patients received hemithorax irradiation after extrapleural pneumonectomy (EPP) (first group). Five patients received irradiation without EPP (second group), while six received salvage radiotherapy for local recurrence (salvage group). Among the seven patients not undergoing EPP, five (four in the second group and one in the salvage group) were treated with lung sparing pleural irradiation (LSPI) and two with irradiation to visible tumors. Two-year overall survival (OS) rates in the first and second groups were 33% and 60%, respectively (median, 13 vs 30 months, P = 0.82). In the first and second groups, 2-year local control (LC) rates were 53 and 67%, respectively (P = 0.54) and 2-year progression-free survival (PFS) rates were 16% and 60%, respectively (P = 0.07). Distant metastases occurred in 15 patients in the first group and three in the second group. In the salvage group, the median OS was 18 months. Recurrence was observed in the irradiated volume in four patients. The contralateral lung dose was higher in LSPI than in hemithorax irradiation plans (mean, 11.0 ± 2.2 vs 6.1 ± 3.1 Gy, P = 0.002). Grade 3 or 5 lung toxicity was observed in two patients receiving EPP and hemithorax irradiation, but not in those undergoing LSPI. In conclusion, outcomes of EPP and hemithorax irradiation were not satisfactory, whereas LSPI appeared promising and encouraging.

Background and purpose Intensity-modulated radiation therapy (IMRT) is increasingly applied in concurrent chemoradiotherapy (CCRT) for locally-advanced non-small cell lung cancer (NSCLC), with improvement of target coverage and better sparing of normal tissue. IMRT tends to have a larger low-dose irradiation volume than 3D conformal radiotherapy, but the incidence of and risk factors for pneumonitis remain unclear, especially following the approval of durvalumab. Materials and methods We retrospectively reviewed the records of NSCLC patients treated by CCRT using IMRT at seven Japanese institutions. Primary outcomes were incidence of symptomatic pneumonitis and progression-free survival (PFS). Multivariate logistic regression analysis was used to identify risk factors for ≥grade 2 pneumonitis. Results Median follow-up from the start of CCRT was 14.3 months (n = 107 patients; median age 70 years, 29% female). Median lung V5 and V20 was 49.2% and 19.5%, respectively. Durvalumab was administered to 87 patients (81%). Pneumonitis developed in 95 (89%) patients of which 53% had grade 1, 28% grade 2, 6.5% grade 3, and 0.9% grade 4. Durvalumab had been discontinued in 16 patients (18.4%) due to pneumonitis. By multivariate analysis, age ≥70 years, male sex, and V5 ≥58.9% were identified as significantly associated with ≥grade 2 pneumonitis (p = 0.0065, 0.036 and 0.0013 respectively). The median PFS from the start of CCRT was not reached (95% CI, 14.2 months to not reached) in patients receiving durvalumab. Conclusion CCRT using IMRT followed by durvalumab was generally effective and tolerable; V5

Background Technological developments have led to an increased usage of external-body radiotherapy (RT) for the treatment of hepatocellular carcinoma (HCC). Transcatheter arterial chemoembolization (TACE) may be required later in patients treated with RT because of the high recurrence rate and multinodular presentation of HCC. However, despite the risk of liver function impairment, the cumulative liver damage correlated with TACE following a hepatic RT has not been adequately assessed. Purpose To evaluate the feasibility of TACE following RT for HCC. Materials and methods Sixty-seven patients with HCC who underwent TACE after RT were retrospectively evaluated between 2012 and 2018. We assessed increases in Child–Turcotte–Pugh (CTP) by ≥2 points at 1 month, the incidence of major complications, survival duration, and short-term mortality within 6 months after TACE. Furthermore, we evaluated the predictive factors for liver function impairment and short-term mortality. Results Eight patients experienced a CTP increase ≥2 points at 1 month. There were no cases of liver abscesses or bilomas. Nine patients died within 6 months following TACE. The mean liver dose (MLD) was a significant predictor of liver function impairment at 1 month ( p = 0.042). Low liver functional reserve, distant metastasis ( p = 0.037), MLD ( p = 0.046), TACE type ( p = 0.025), and TACE within 3 months following RT ( p = 0.007) were significant predictors of short-term mortality. Conclusions Despite the feasibility of TACE following RT, clinicians should pay attention to impaired pretreatment liver function, following high dose RT, and the short duration between RT and TACE.

Aim:CyberKnife is the most advanced form of stereotactic body radiotherapy (SBRT) system that uses a robotic arm to deliver highly focused beams of radiation; however, a limitation is that it only irradiates from ceiling to floor direction. In patients with posterior lungs tumour who are positioned supine, normal lung tissue may suffer undesirable radiation injuries. This study compares the treatment planning between the prone set-up and the supine set-up for lung cancer in CyberKnife SBRT to decrease normal lung dose to avoid radiation side effects.Materials and methods:A human phantom was used to generate 108 plans (54 for prone and 54 for supine) using the CyberKnife planning platform. The supine and prone plans were compared in terms of the dosimetric characteristics, delivery efficiency and plan efficiency.Results:For posterior targets, the area of low-dose exposure to normal lungs was smaller in the prone set-up than in the supine set-up. V10 of the lungs was 7·53% and 10·47% (p < 0·001) in the anterior region, and 10·78% and 8·03% (p < 0·001) in the posterior region in the supine and prone set-up plans, respectively.Conclusions:The comparison between the prone set-up and the supine set-up was investigated with regard to target coverage and dose to organs at risk. Our results may be deployed in CyberKnife treatment planning to monitor normal tissue dose by considering patient positioning. This may assist in the design of better treatment plans and prevention of symptomatic radiation pneumonitis in lung cancer patients.

Introduction: Intensity-modulated radiation therapy (IMRT) has become a popular choice for breast cancer treatment. We aimed to evaluate and compare the robustness of each optimization method used for breast IMRT using TomoTherapy.Methods: A retrospective analysis was performed on 10 patients with left breast cancer. For each optimization method (clipping, virtual bolus, and skin flash), a corresponding 50 Gy/25 fr plan was created in the helical and direct TomoTherapy modes. The dose-volume histogram parameters were compared after shifting the patients anteriorly and posteriorly. Results: In the helical mode, when the patient was not shifted, the median D1cc (minimum dose delivered to 1 cc of the organ volume) for breast skin for the clipping and virtual bolus plans were 52.2 (interquartile range: 51.9–52.6) and 50.4 (50.1–50.8) Gy, respectively. After an anterior shift, the D1cc of the breast skin for the clipping and virtual bolus plans was 56.0 (55.6–56.8) and 50.9 (50.5–51.3) Gy, respectively. When the direct mode was used without shifting the patient, the D1cc of the breast skin for the clipping, virtual bolus, and skin flash plans were 52.6 (51.9–53.1), 53.4 (52.6–53.9), and 52.3 (51.7–53.0) Gy, respectively. After shifting anteriorly, D1cc of the breast skin for the clipping, virtual bolus, and skin flash plans was 55.6 (54.1–56.4), 52.4 (52.0–53.0), and 53.6 (52.6–54.6) Gy, respectively. Conclusions: The clipping method is not sufficient for breast IMRT. The virtual bolus and skin flash methods were more effective optimization methods according to our analyses.

Aim:To modify the final dose delivered to superficial tissues and to modulate dose distribution near irradiated surface, different boluses are used. Air gaps often form under the bolus affecting dose distribution. This study aimed to evaluate the effect of an air gap under the bolus radiation on dose delivery.Materials and methods:To evaluate the impact of the air gap, both helical tomotherapy (HT) and direct tomotherapy (DT) were performed in a simulation study.Results:The maximum dose to bolus in DT plans was bigger than that used in HT plans. The maximum dose delivered to the bolus depended on the air gap size. However, the maximum dose to bolus in all HT plans was within the acceptable value range. Acceptable value was set to up to 107% of the prescription dose. In the simulation performed in this study, the acceptable air gap under bolus was up to 15 mm and below 5 mm in HT and DT plans, respectively.Conclusions:HT technique is a good choice, but DT technique can be also used if the bolus position can be reproduced accurately. Thus, the reproducibility of the bolus position between planning and treatment is very important.

Purpose Real-time tracking systems of moving respiratory targets such as CyberKnife, Radixact, or Vero4DRT are an advanced robotic radiotherapy device used to deliver stereotactic body radiotherapy (SBRT). The internal target volume (ITV) of lung tumors is assessed through a fiducial marker fusion using four-dimensional computed tomography (CT). It is important to minimize the ITV to protect normal lung tissue from exposure to radiation and the associated side effects post SBRT. However, the ITV may alter if there is a change in the position of the fiducial marker with respect to the tumor. This study investigated the relationship between fiducial marker position and the ITV in order to prevent radiation exposure of normal lung tissue, and correct target coverage. Materials and methods This study retrospectively reviewed 230 lung cancer patients who received a fiducial marker for SBRT between April 2015 and September 2021. The distance of the fiducial marker to the gross tumor volume (GTV) in the expiratory (d(ex)) and inspiratory (d(in)) CT, and the ratio of the ITV/V(GTV(ex)), were investigated. Results Upon comparing each lobe, although there was no significant difference in the d(diff) and the ITV/V(GTV(ex)) between all lobes for d(ex) < 10 mm, there was significant difference in the d(diff) and the ITV/V(GTV(ex)) between the lower and upper lobes for d(ex) ≥ 10 mm (p < 0.05). Moreover, there was significant difference in the d(diff) and the ITV/V(GTV(ex)) between d(ex) ≥10 mm and d(ex) < 10 mm in all lung regions (p < 0.05). Conclusion The ITV that had no margin from GTVs increased when d(ex) was ≥10 mm for all lung regions (p < 0.05). Furthermore, the increase in ITV tended to be greater in the lower lung lobe. These findings can help decrease the possibility of adverse events post SBRT, and correct target coverage.

Aim To investigate tumour motion tracking uncertainties in the CyberKnife Synchrony system with single fiducial marker in liver tumours. Background In the fiducial-based CyberKnife real-time tumour motion tracking system, multiple fiducial markers are generally used to enable translation and rotation corrections during tracking. However, sometimes a single fiducial marker is employed when rotation corrections are not estimated during treatment. Materials and methods Data were analysed for 32 patients with liver tumours where one fiducial marker was implanted. Four-dimensional computed tomography (CT) scans were performed to determine the internal target volume (ITV). Before the first treatment fraction, the CT scans were repeated and the marker migration was determined. Log files generated by the Synchrony system were obtained after each treatment and the correlation model errors were calculated. Intra-fractional spine rotations were examined on the spine alignment images before and after each treatment. Results The mean (standard deviation) ITV margin was 4.1 (2.3) mm, which correlated weakly with the distance between the fiducial marker and the tumour. The mean migration distance of the marker was 1.5 (0.7) mm. The overall mean correlation model error was 1.03 (0.37) mm in the radial direction. The overall mean spine rotations were 0.27° (0.31), 0.25° (0.22), and 0.23° (0.26) for roll, pitch, and yaw, respectively. The treatment time was moderately associated with the correlation model errors and weakly related to spine rotation in the roll and yaw planes. Conclusions More caution and an additional safety margins are required when tracking a single fiducial marker.

BackgroundConcurrent chemoradiotherapy (CCRT) followed by durvalumab is the standard of care for unresectable locally advanced non-small cell cancer (LA-NSCLC). However, a major concern about the administration of durvalumab after CCRT is whether the incidence of symptomatic radiation pneumonitis (RP) increases. In the present analysis, we report the initial results of CCRT followed by durvalumab in patients with LA-NSCLC in a real-world setting with a focus on predictive factors for symptomatic RP. MethodsPatients who were pathologically diagnosed with NSCLC and initiated treatment with CCRT followed by durvalumab between July 2018 and December 2019 were eligible for this study. Patients were included if they completed the planned CRT course and were administered at least one course of durvalumab. We retrospectively investigated the preliminary survival outcome and incidence and predictive factors for symptomatic RP. ResultsOf the 67 patients who were scheduled to receive CCRT, 63 completed the entire CCRT course. Of these patients, 56 proceeded to consolidation with durvalumab. The median time to eternal discontinuation of durvalumab was 9.7 months. The cumulative proportions of patients who exhibited symptomatic RP were 30, 40 and 44% at 3, 6 and 12 months, respectively. In multivariate analyses, the pulmonary fibrosis score and lung V40 were significant predictive factors for symptomatic RP (p < 0.001, HR: 7.83, 95% CI: 3.38-18.13, and p = 0.034, HR: 3.17, 95% CI: 1.09-9.19, respectively). ConclusionsThe pulmonary fibrosis sore and lung V40 are significant predictive factors for symptomatic RP. We should be cautious about the administration of durvalumab for patients with subclinical pulmonary fibrosis. To the best of our knowledge, this is one of the first reports showing the predictive value of high dose volumes to the lung in patients with LA-NSCLC who receive CCRT followed by durvalumab.

Background Although rare, cytomegalovirus (CMV) reactivation can be lethal in patients with cancer. However, the criteria for the prevention of cytomegalovirus reactivation during cancer treatment are unclear. This study aimed to identify factors associated with CMV reactivation in patients with esophageal cancer who were receiving chemoradiotherapy. Methods This retrospective study included esophageal cancer patients receiving definitive or palliative chemoradiotherapy during April 2013–March 2020. Patients with fever during chemoradiotherapy underwent a systemic work‐up to detect the primary focus of infection, and CMV antigenemia was assessed in cases of unidentifiable infection. Results Among 132 patients (80.3% male, median age 69 years [range, 39–86 years]), 124 received 5‐fluorouracil plus cisplatin and 8 received oxaliplatin–5‐fluorouracil–levofolinate chemotherapy. Overall, 19 patients had CMV reactivation, 37 had other infections, and 76 had no identified infection (groups 1, 2, and 3, respectively). Median minimum lymphocyte counts were 81.0/µl (interquartile range: 52.0–144.0/µl), 120.0/µl (81.0–162.5/µl), and 185.5/µl (120.5–328.0/µl) in groups 1, 2, and 3, respectively, with counts being significantly lower in groups 1 and 2 than in group 3 (p, CMV reactivation is not rare in esophageal cancer patients receiving chemoradiotherapy and is associated with minimum lymphocyte counts. CMV reactivation should be considered in differential diagnosis when a patient receiving chemoradiotherapy presents with a marked decrease in the lymphocyte count.

In prostate stereotactic body radiation therapy (SBRT), hydrogel spacers are increasingly used. This study aimed to perform a dosimetry comparison of treatment plans using CyberKnife (CK), commonly used for prostate SBRT, Helical TomoTherapy (HT), and TrueBeam (TB) in patients with hydrogel spacer implantations. The data of 20 patients who received hydrogel spacer implantation for prostate SBRT were retrospectively analyzed. The prescription dose was 36.25 Gy in five fractions to 95% of the planning target volume (PTV; D95). The conformity index (CI), gradient index (GI), homogeneity index (HI), and dose‐volume histogram (DVH) were analyzed for the three modalities, using the same PTV margins. The monitor unit (MU) and the beam‐on‐time (BOT) values were subsequently compared. The CI of TB (0.93 ± 0.02) was significantly superior to those of CK (0.82 ± 0.03, p

Purpose The CyberKnife Xsight Lung Tracking (XLT) and 1-View tracking systems can synchronize beam targeting to a visible lung tumor with respiratory motion during irradiation without requiring internal fiducial markers. The systems use a correlation model that relates external marker positions to tumor positions as well as a prediction model that predicts the target's future position. In this study, the correlation and prediction model uncertainties related to the CyberKnife fiducial-free tumor tracking system were evaluated using clinical log data. Methods and materials Data from 211 fractions in 42 patients with lung tumors were analyzed. Log files produced by the CyberKnife Synchrony system were acquired after each treatment; the mean correlation and prediction errors for each patient were calculated. Additionally, we examined the tracking tumor-related parameters and analyzed the relationships between the model errors and tracking tumor-related parameters. Results The overall means ± standard deviations (SDs) of the correlation errors were 0.70 ± 0.43 mm, 0.36 ± 0.16 mm, 0.44 ± 0.22 mm, and 0.95 ± 0.43 mm for the superoinferior (SI), left-right (LR), anteroposterior (AP), and radial directions, respectively. The overall means ± SDs of the prediction errors were 0.13 ± 0.11 mm, 0.03 ± 0.02 mm, 0.03 ± 0.02 mm, and 0.14 ± 0.11 mm for the SI, LR, AP, and radial directions, respectively. There were no significant differences in these errors between the XLT and 1-View tracking methods. The tumor motion amplitude was moderately associated with the correlation error and strongly related to the prediction error in the SI and radial directions. Conclusions Clinical log data analysis can be used to determine the necessary margin sizes in treatment plans to compensate for correlation and prediction errors in the CyberKnife fiducial-free lung tumor tracking system. The tumor motion amplitude may facilitate margin determination.

The treatment of brainstem metastases remains a challenge as the brainstem itself is considered a neurological organ at risk. We aimed to investigate the efficacy and safety of CyberKnife hypofractionated stereotactic radiotherapy (HFSRT) for brainstem metastases, and to examine the balance between efficacy and safety for the management of neurological symptoms. A total of 26 lesions [pons (n = 18), medulla (n = 4) and midbrain (n = 4)] in 20 patients treated with CyberKnife hypofractionated stereotactic radiotherapy were retrospectively analyzed. The total radiation doses (18–30 Gy) were delivered in 3 or 5 equal fractions. The median follow-up was 6.5 (range, 0.5–38.0) months. The 6- and 12-month local control rates were 100% and 90%, respectively. Symptomatic failures, defined as the worsening and appearance of neurological symptoms due to the brainstem lesion after CyberKnife HFSRT, were observed in 6 patients [local failure (n = 1) and adverse events (n = 5). The symptomatic control and overall survival rates were 90% and 72% (after 6 months), respectively, and 76% and 53% (after 12 months), respectively. Longer symptomatic control was associated with site of lesion origin, and longer overall survival was associated with a graded prognostic assessment score of >2. To our knowledge, this is the second study to investigate the efficacy and safety of CyberKnife HFSRT for brainstem metastases. The local control rate was comparable with that of prior stereotactic radiosurgery studies. We propose a new evaluation criterion—‘symptomatic control’—to evaluate the efficacy and safety of brainstem radiotherapy.

The purpose of this study is to identify the suitable leaf margin for liver stereotactic body radiotherapy (SBRT) with flattening filter-free (FFF) beams, as compared with that with flattening filter (FF) beams. SBRT treatment planning for 10 patients with liver cancer was performed using 10-MV FFF and FF beams obtained from a Varian TrueBeam (Varian Medical Systems, Palo Alto, CA) linear accelerator. Each plan was generated with the leaf margin to the planning target volume (PTV) ranging from -3 to 5 mm. The prescription dose at D95 (dose covering 95% of the volume) was 48 Gy in 4 fractions to the PTV. The following dosimetric parameters were evaluated quantitatively: homogeneity index (HI), conformity index (CI), gradient index (GI), the normal liver receiving a dose greater than or equal to 20 Gy (V20), and the mean normal liver dose. The HI for FFF and FF beams increased as the leaf margin decreased. The leaf margins that achieved the best CI and GI were 0.1 and -0.3 mm for FFF beams, and 0.1 and -0.9 mm for FF beams. The liver V20 and the mean liver dose reached their minimum values at leaf margins of -0.8 and 0.0 mm for FFF beams, and -0.8 and 0.0 mm for FF beams. The suitable leaf margin for SBRT planning did not differ significantly for FFF and FF beams. Our data showed that, for both FFF and FF beams, a leaf margin of 0 or -1 mm was optimal for liver SBRT planning in terms of both target coverage and normal tissue sparing.

This study aimed to evaluate the efficacy of stereotactic body radiotherapy (SBRT) compared with three-dimensional conformal radiotherapy (3DCRT). Forty-three patients with portal vein tumor thrombosis (PVTT)/inferior vena cava tumor thrombosis (IVCTT) treated with SBRT (27 with CyberKnife (CK) and 16 with TrueBeam (TB)) from April 2013 to December 2014, and 54 treated with 3DCRT from June 2008 to March 2013 were evaluated. Dosimetric parameters, response to radiotherapy (RT) and survival outcomes were compared in total SBRT vs. 3DCRT, CK vs. 3DCRT and TB vs. 3DCRT, respectively. The median biologically effective dose 10 (BED10) values in total SBRT, CK, TB and 3DCRT were 73.4 Gy10, 75.0 Gy10, 60.5 Gy10 and 58.5 Gy10, respectively (P < 0.001 in total SBRT vs. 3DCRT, P < 0.001 in CK vs. 3DCRT, P = 0.004 in TB vs. 3DCRT). The tumor response rates were 67%, 70%, 62% and 46%, respectively (P = 0.04, P = 0.04, P = 0.25). The 1-year overall survival rates were 49.3%, 56.7%, 38.1% and 29.3%, respectively (P = 0.02, P = 0.02, P = 0.30), and the 1-year local progression rates were 20.4%, 21.9%, 18.8% and 43.6%, respectively (P = 0.01, P = 0.04, P = 0.10). The use of SBRT made it possible to achieve a higher BED10 compared with the use of 3DCRT. Improvements in local control and survival were achieved in the CK group and the total SBRT group. Our results suggest that SBRT may have the potential to be the standard RT technique for the treatment of PVTT/IVCTT.

Purpose of this study is to obtain dose-volume histogram (DVH) predictors and threshold values for radiation esophagitis caused by high-dose involved field radiotherapy (IFRT) with concurrent chemotherapy in patients with stage III non-small cell lung cancer (NSCLC). Thirty-two patients treated by 66 Gy/33 Fr, 72 Gy/36 Fr, and 78 Gy/39 Fr thoracic radiotherapy without elective nodal irradiation plus concurrent cisplatin and vinorelvine were reviewed. Acute radiation esophagitis was evaluated according to common terminology criteria for adverse events version 4.0, and correlations between grade 2 or worse radiation esophagitis and DVH parameters were investigated. Grade 0–1, 2, 3, and 4–5 of radiation esophagitis were seen in 11 (34.4%), 20 (62.5%), 1 (3.1%), and 0 (0%) of the patients, respectively. Multivariate analysis revealed that whole esophagus V35 is a predictor of radiation esophagitis (OR = 0.74 [95%CI; 0.60–0.91], p = 0.006). There is a significant difference (38.4% vs. 89.4%, p = 0.027) in the cumulative rates of acute esophagitis according to V35 values of more than 20% versus less. As compared with other factors concerning patient and tumor and treatment factors, V35 < 20% of the esophagus was an independent predictor (HR = 0.29 [95%CI; 0.09–0.85], p = 0.025). In conclusion, whole esophagus V35 < 20% is proposed in high-dose IFRT with concurrent chemotherapy for stage III NSCLC patients.

Purpose: To analyze the results of radical radiotherapy by electron beams for squamous cell carcinoma (SCC) of the eyelid and to find the possible prognostic factors. Materials and Methods: Records of 38 patients with histologically confirmed SCC of the eyelid who underwent electron beam radiation therapy between 1964 and 2010 in our institution were retrospectively reviewed. Median tumor size was 15 mm (range, 3–40 mm). T stage was T1 in three, T2a in six, T2b in 14, and T3a in 15 patients. Four patients had nodal metastasis. Of the 38 patients, 14 had relapsed disease after prior treatment. Median radiation dose was 60.0 Gy (range, 45.0– 70.4 Gy). Median follow-up was 72.5 months (range, 2.0–369 months). Results: 5-year local relapse-free, nodal relapse-free, distant metastasis-free and relapse-free rates for all patients were 71.8%, 77.5%, 90.6% and 58.0%, respectively. In seven patients, lymph node metastases occurred in 11 faciocervical regions. The 5-year overall survival was 79.5%. T stage and radiation dose expressed in EQD 2G ytended to have impacts on local control. Relapsed patients showed unfavorable local relapse-free rate, however this was without statistical significance. Of the 14 patients who died, 12 succumbed to concurrent diseases. Grade 3 or greater severe late morbidities (CTCAE ver4.0) were observed in nine patients. Due to the morbidities, two patients lost their vision. Conclusion: Radical radiotherapy for SCC of the eyelid yielded good results and could be a treatment option. Whether radiation-dose escalation could improve local control in advanced T stages and relapsed patients needs further study.

The main purpose of this study was to compare three different treatment plans for locally advanced cervical cancer: (i) the inverse-planning simulated annealing (IPSA) plan for combination brachytherapy (BT) of interstitial and intracavitary brachytherapy, (ii) manual optimization based on the Manchester system for combination-BT, and (iii) the conventional Manchester system using only tandem and ovoids. This was a retrospective study of 25 consecutive implants. The high-risk clinical target volume (HR-CTV) and organs at risk were defined according to the GEC-ESTRO Working Group definitions. A dose of 6 Gy was prescribed. The uniform cost function for dose constraints was applied to all IPSA-generated plans. The coverage of the HR-CTV by IPSA for combination-BT was equivalent to that of manual optimization, and was better than that of the Manchester system using only tandem and ovoids. The mean V100 achieved by IPSA for combination-BT, manual optimization and Manchester was 96 ± 3.7%, 95 ± 5.5% and 80 ± 13.4%, respectively. The mean D100 was 483 ± 80, 487 ± 97 and 335 ± 119 cGy, respectively. The mean D90 was 677 ± 61, 681 ± 88 and 513 ± 150 cGy, respectively. IPSA resulted in significant reductions of the doses to the rectum (IPSA D2cm(3): 408 ± 71 cGy vs manual optimization D2cm(3): 485 ± 105 cGy; P = 0.03) and the bladder (IPSA D2cm(3): 452 ± 60 cGy vs manual optimization D2cm(3): 583 ± 113 cGy; P < 0.0001). In conclusion, combination-BT achieved better tumor coverage, and plans using IPSA provided significant sparing of normal tissues without compromising CTV coverage.

Purpose To evaluate the effectiveness of episcleral 106ruthenium plaque therapy (RPT) in the management of retinoblastoma. Methods and Materials One hundred one RPTs were retrospectively analyzed that were performed in 90 eyes of 85 patients with retinoblastoma at National Cancer Center Hospital between 1998 and 2008. Each RPT had a corresponding tumor and 101 tumors were considered in the analysis of local control. Median follow-up length was 72.8 months. Median patient age at the RPT was 28 months. Median prescribed doses at reference depth and outer surface of the sclera were 47.4 Gy and 162.3 Gy, respectively. Results Local control rate (LCR) and ocular retention rate (ORR) at 2 years were 33.7% and 58.7%, respectively. Unilateral disease, International Classification of Retinoblastoma group C or more advanced at the first presentation or at the time of RPT, vitreous and/or subretinal seeding, tumor size greater than 5 disc diameter (DD), reference depth greater than 5 mm, dose rate at reference depth lower than 0.7 Gy/hour, dose at the reference depth lower than 35 Gy, and (biologically effective dose with an α/β ratio of 10 Gy) at the reference depth lower than 40 Gy10 were associated with unfavorable LCR. Two patients died of metastatic disease. Radiation complications included retinal detachment in 12 eyes (13.3%), proliferative retinopathy in 6 (6.7%), rubeosis iris in 2 (2.2%), and posterior subcapsular cataract in 23 (25.6%). Conclusion RPT is an effective eye-preserving treatment for retinoblastoma.

BACKGROUND AND PURPOSE An ATP-binding cassette (ABC) transporter, breast cancer resistance protein (BCRP)/ABCG2, limits oral bioavailability of sulphasalazine. Here we examined the effect of curcumin, the principal curcuminoid of turmeric, on oral bioavailability of microdoses and therapeutic doses of sulphasalazine in humans. EXPERIMENTAL APPROACH Effects of curcumin were measured on the ATP-dependent sulphasalazine uptake by hBCRP-expressing membrane vesicles and on oral bioavailability of sulphasalazine in wild-type and Bcrp(-/-) mice. Eight healthy Japanese subjects received an oral dose of sulphasalazine suspension (100 µg) or tablets (2 g) alone or after curcumin tablets (2 g). Uptake of sulphasalazine was studied in HEK293 cells transfected with the influx transporter (OATP)2B1. KEY RESULTS Curcumin was a potent hBCRP inhibitor in vitro (K(i) 0.70 ± 0.41 µM). Curcumin increased the area under the curve (AUC)(0-8) of plasma sulphasalazine eightfold in wild-type mice at 300 and 400 mg·kg(-1), but not in Bcrp(-/-) mice. Curcumin increased AUC(0-24) of plasma sulphasalazine 2.0-fold at microdoses and 3.2-fold at therapeutic doses in humans. Non-linearity of the dose-exposure relationship was observed between microdoses and therapeutic doses of sulphasalazine. Sulphasalazine was a substrate for OATP2B1 (K(m) 1.7 ± 0.3 µM). Its linear index (dose/K(m)) at the therapeutic dose was high and may saturate OATP2B1. CONCLUSIONS AND IMPLICATIONS Curcumin can be used to investigate effects of BCRP on oral bioavailability of drugs in humans. Besides the limited dissolution, OATP2B1 saturation is a possible mechanism underlying non-linearity in the dose-exposure relationship of sulphasalazine.

The purpose of this retrospective study is to investigate the impact of concurrent chemotherapy on definitive radiotherapy for the International Federation of Gynecology and Obstetrics (FIGO) IIIb cervical cancer. Between 2000 and 2009, 131 women with FIGO IIIb cervical cancer were treated by definitive radiotherapy (i.e. whole pelvic external beam radiotherapy for 40-60 Gy in 20-30 fractions with or without center shielding and concomitant high-dose rate intracavitary brachytherapy with 192-iridium remote after loading system for 6 Gy to point A of the Manchester method). The concurrent chemotherapy regimen was cisplatin (40 mg/m(2)/week). After a median follow-up period of 44.0 months (range 4.2-114.9 months) and 62.1 months for live patients, the five-year overall survival (OS), loco-regional control (LRC) and distant metastasis-free survival (DMFS) rates were 52.4, 80.1 and 59.9%, respectively. Univariate and multivariate analyses revealed that lack of concurrent chemotherapy was the most significant factor leading to poor prognosis for OS (HR = 2.53; 95% CI 1.44-4.47; P = 0.001) and DMFS (HR = 2.53; 95% CI 1.39-4.61; P = 0.002), but not for LRC (HR = 1.57; 95% CI 0.64-3.88; P = 0.322). The cumulative incidence rates of late rectal complications after definitive radiotherapy were not significantly different with or without concurrent chemotherapy (any grade at five years 23.9 vs 21.7%; P = 0.669). In conclusion, concurrent chemotherapy is valuable in definitive radiotherapy for Japanese women with FIGO IIIb cervical cancer.

This report describes the case of a 57-year-old woman with liver and bone metastases from malignant insulinoma, who was afflicted with severe hypoglycemia. Treatment of the liver metastases using octreotide, diazoxide and transarterial embolization failed to raise her blood glucose level and she required constant glucose infusion (about 1000 kcal/day) and oral feeding (about 2200 kcal/day) to avoid a hypoglycemic attack. Subsequently, 110 MBq (2.0 MBq/kg) of strontium-89 were administered by intravenous injection. Three weeks after the strontium-89 injection, we could reduce the dose of constant glucose infusion while maintaining a euglycemic status. Six weeks after the injection, the constant glucose infusion was discontinued. Although strontium-89 therapy is indicated for patients with multiple painful bone metastases, it was also useful as a means of inhibiting tumor activity and controlling hypoglycemia in this case. To our knowledge, this is the first report to provide evidence that strontium-89 can be useful in controlling intractable hypoglycemia in patients with malignant insulinoma with bone metastases.

Whether chemotherapy for systemic disease affects survival of patients with brain metastases or not has not been elucidated before. We performed comprehensive analysis of patients with newly-diagnosed brain metastases primarily treated with whole brain radiation therapy (WBRT) alone. Data from 134 patients with newly-diagnosed brain metastases primarily treated with WBRT from 2007 to 2008 was retrospectively reviewed. Univariate and multivariate analyses were performed to identify significant prognostic factors. Median survival time (MST) of this cohort from the start of WBRT was 5.7 months. MST of patients with RPA Class 1, 2 and 3 were 10.3, 7.8 and 2.2 months, respectively. Multivariate analysis revealed that karnofsky performance status (≥70, p

Purpose In the management of soft tissue sarcomas, perioperative radiation therapy has been used to reduce the risk of local recurrence after resection. However, a significance of postoperative high–dose rate brachytherapy (HDRBT) remains to be studied. Retrospective analysis was performed to elucidate the role of postoperative HDRBT. Methods and Materials Twenty-five patients with 26 soft tissue sarcoma lesions underwent postoperative HDRBT using 192 Ir remote afterloader without external beam radiation therapy. Ninety-two percent of the lesions were Grade 2 or 3 malignancies, and 50% were resected with positive surgical margins. The remaining 50% had very close margins. Fourteen lesions were treated for local recurrences after previous resections. Applicators of HDRBT were placed during the operation to include only the tumor bed excluding surgical scars. Applied dose was mainly 36 Gy/6 fractions/3 d b.i.d. Results Five-year local recurrence-free survival was 78.2% in all the 26 lesions. Recurrences were not seen within the treated volume of HDRBT. Two groups were defined according to the marginal status and number of previous operations. Group 1 was the lesions with a positive margin and foregoing resections. The remaining lesions were classified as Group 2. Five-year local recurrence-free survival was 43.8% and 93.3% in Group 1 and Group 2, respectively with a statistically significant difference ( p = 0.004). Conclusions Postoperative HDRBT was effective in controlling local lesions; but in Group 1 lesions, addition of a wide field external beam radiation therapy seems to be necessary to improve the local control rate.

To clarify the toxicity of palliative radiotherapy (RT) and its efficacy against bleeding of unresectable gastric cancer.Clinical data of 19 patients received palliative RT for bleeding from unresectable gastric cancer were reviewed. The median total dose and dose per fraction were 40 Gy (range 2-50 Gy) and 2.5 Gy (range 1.8-3 Gy).The treatment success rate was 68.4%. By using a tumor alpha/beta ratio of 10, biological effective dose of 50 Gy(10) or more was significantly correlated with treatment success (P = 0.040). The median event-free survival was 1.5 months after RT and the median overall survival from starting RT was 3.4 months. Grade 3 nausea and anorexia were recorded in 1 and 3 patients, respectively.Palliative RT was effective for hemostasis in patients with gastric cancer bleeding with minor adverse events.

Background: The purpose of this study was to compare the dose distributions and treatment delivery efficiency of volumetric modulated arc therapy (VMAT) with flattening filter free (FFF) beams (FFF-VMAT) against VMAT with flattening filter (FF) beams (FF-VMAT) and Helical TomoTherapy (HT) for head and neck cancer. Methods: Ten patients with nasopharyngeal and oropharyngeal cancer were chosen for this planning comparison study. Three treatment plans (dual arc FFF-VMAT, dual arc FF-VMAT, and HT) were created for each patient. The three prescription dose levels of the planning target volumes were 69.96, 60, and 54 Gy in 33 fractions, using the simultaneous integrated boost technique. Comparisons of the plan quality were performed by analyzing the homogeneity, conformity, dose to the organs at risk (OARs), the number of monitor units (MUs), and beam-on time (BOT) necessary for delivering the plans. Results: The target coverage and sparing of the OARs for FFF-VMAT were almost equivalent to those for FFVMAT and HT. Compared to FF-VMAT, FFF-VMAT and HT significantly increased the number of MUs. The BOTs were the same for FFF-VMAT and FF-VMAT but significantly increased for HT. Conclusion: We here present the first report of FFF-VMAT achieving a comparable plan quality with less delivery time to that of FF-VMAT and HT in head and neck cancer. FFF-VMAT is a highly efficient and feasible option for the treatment of head and neck cancer in clinical practice.

Purpose: To investigate the incidence and influencing factors of acute genitourinary (GU) and gastrointestinal morbidities in patients with prostate cancer treated with proton therapy. Methods and Materials: A total of 287 patients with histologically proven Stage cT1-T4N0M0 prostate cancer were treated with proton therapy between 2003 and 2004. Of these, 204 (71%) received neoadjuvant androgen suppression therapy. The patients were treated with 190–230-MeV protons using lateral-opposed techniques to a dose of 74 GyE. Dose–volume histogram analyses were performed. The incidence of acute morbidity was evaluated using the National Cancer Institute Common Toxicity Criteria, version 2.0. Clinical factors, including age, clinical target volume, initial prostate-specific antigen level, T stage, presence of diabetes mellitus, and the use of androgen suppression therapy, were investigated to determine whether those affected the incidence of acute GU morbidity. Results: None developed Grade 2 or higher acute gastrointestinal morbidity. In contrast, 111 (39%) and 4 (1%) patients experienced acute Grade 2 and Grade 3 GU morbidities, respectively. However, 87% of the patients were successfully relieved by the administration of a selective α-1 blocker. Multivariate analysis showed that a larger clinical target volume ( p = 0.001) and the use of androgen suppression therapy ( p = 0.017) were significant factors for the prediction of acute Grade 2-3 GU morbidity. Conclusion: In our experience with proton therapy, a low incidence of acute gastrointestinal morbidity was observed. In contrast, the incidence of acute GU morbidity was similar to that in other reports of photon radiotherapy. Additional follow-up is warranted to elucidate the long-term safety and efficacy of proton therapy for prostate cancer.

The National Institute of Health Sciences and 28 member companies of the Japan Pharmaceutical Manufacturers Association (JPMA) have conducted a validation study intended to examine whether or not lesions in the male reproductive organs noted in 4-week treatment studies can also be detected after 2-week treatment. In this study, lesions in the male reproductive organs after 2-week treatment were, therefore, compared with those after 4-week treatment. A total of 24 test substances was evaluated, these being nucleic acid modulators, cell division inhibitors, central hormonal modulators, hormonal drugs and their antagonists, other drugs and general chemicals. Among these substances, theophylline did not cause any appreciable lesions in the male reproductive organs even after 4-week treatment in the preliminary studies. With busulfan, data reported in the literature was not reproduced in the preliminary study and all animals died. Therefore, detailed examinations were not conducted for busulfan and theophylline. The remaining 22 test substances, when given to animals for 2 weeks at doses equal to or higher than for 4-week treatment, caused lesions similar to those noted after 4 weeks. It is evident from these findings that effects of pharmaceuticals on the male reproductive organs can be detected in most cases with 2-week treatment.

To assess whether or not male reproductive toxicity can be evaluated in a 2-week administration study, boric acid was administered daily by oral gavage to male Jcl:Wistar rats at dosage levels of 0, 300 and 500 mg/kg for 2 and 4 weeks, and the results obtained with the two different treatment schedules were compared. After a 2-week administration, decreased testis weights were observed in the 500 mg/kg group. Histopathologically, exfoliation of round spermatids, retention of step 19 spermatids and increased numbers of residual body-like structures in the seminiferous tubules and cell debris in the cranial epididymal ducts were observed in the 300 and 500 mg/kg groups. Distorted cytoplasmic lobes of step 19 spermatids, debris in the seminiferous tubules and focal atrophy of the seminiferous tubules with multinucleated giant cells formation and necrosis of spermatocytes were also observed in the 500 mg/kg group. After a 4-week administration, testis and epididymis weights were decreased in the 300 and 500 mg/kg groups. Histopathological changes in the 300 mg/kg group were similar to those found in the 300 and 500 mg/kg groups after a 2-week administration. Diffuse atrophy of the seminiferous tubules was additionally observed in the 500 mg/kg group. These results suggest that 2 weeks is a sufficient treatment period for the detection of the testicular toxicity caused by boric acid.

Brachytherapy plays a significant role in the management of cervical cancer, but the clinical significance of brachytherapy in the management of vaginal cancer remains to be defined. Thus, a single institutional experience in the treatment of primary invasive vaginal carcinoma was reviewed to define the role of brachytherapy. We retrospectively reviewed the charts of 36 patients with primary vaginal carcinoma who received definitive radiotherapy between 1992 and 2010. The treatment modalities included high-dose-rate intracavitary brachytherapy alone (HDR-ICBT; two patients), external beam radiation therapy alone (EBRT; 14 patients), a combination of EBRT and HDR-ICBT (10 patients), or high-dose-rate interstitial brachytherapy (HDR-ISBT; 10 patients). The median follow-up was 35.2 months. The 2-year local control rate (LCR), disease-free survival (DFS), and overall survival (OS) were 68.8%, 55.3% and 73.9%, respectively. The 2-year LCR for Stage I, II, III and IV was 100%, 87.5%, 51.5% and 0%, respectively (P = 0.007). In subgroup analysis consisting only of T2–T3 disease, the use of HDR-ISBT showed marginal significance for favorable 5-year LCR (88.9% vs 46.9%, P = 0.064). One patient each developed Grade 2 proctitis, Grade 2 cystitis, and a vaginal ulcer. We conclude that brachytherapy can play a central role in radiation therapy for primary vaginal cancer. Combining EBRT and HDR-ISBT for T2–T3 disease resulted in good local control.

Summary On April 1, 2001, the Hyogo Ion Beam Medical Center (HIBMC) was opened as the first facility in the world to provide ion beam therapy using 2 types of beams, protons and carbon-ions. We will introduce the HIBMC, and report the results of the clinical study and general practice.

Objective: The aims of this study were to investigate the frequency of symptomatic radiation pneumonitis (RP) after CyberKnife lung stereotactic body radiotherapy (SBRT) and to evaluate predictive factors of symptomatic RP. Methods: 56 patients with peripheral non-small-cell lung cancer were treated using the CyberKnife® VSI™ System (Accuracy Inc., Sunnyvale, CA) between May 2013 and September 2015. Total radiation doses ranged from 48 to 56 Gy, as delivered in four equal fractions. Symptomatic RP was defined as a grade of ≥2. Predictive factors for symptomatic RP were evaluated using univariate and multivariate analyses. Results: With a median follow-up duration of 12.5 months (range, 3–27 months), symptomatic RP was observed in 6 (10.7%) of the 56 patients. In the univariate analysis, percent vital capacity (p 3.4% (p = 0.011) was identified as a significant predictive factor of symptomatic RP. Conclusion: The incidence of symptomatic RP after CyberKnife SBRT was almost identical to the incidences reported in the linear accelerator-based SBRT. A significant association was observed between a V25 >3.4% and the risk of developing symptomatic RP. Advances in knowledge: This is the first report that has investigated prognostic factors for symptomatic RP after CyberKnife SBRT for lung cancer. The newly developed scoring system may help to predict symptomatic RP.

Background There is no consensus on the indication for salvage chemoradiotherapy (CRT) after failure of primary chemotherapy for locally advanced pancreatic cancer (LAPC). Here we report on the retrospective analysis of patients who received salvage CRT after primary chemotherapy for LAPC. The primary objective of this study was to evaluate the efficacy and safety of salvage CRT after primary chemotherapy for LAPC. Methods Thirty patients who underwent salvage CRT, after the failure of primary chemotherapy for LAPC, were retrospectively enrolled from 2004 to 2011 at the authors’ institution. All the patients had histologically confirmed pancreatic adenocarcinoma. Results Primary chemotherapy was continued until progression or emergence of unacceptable toxicity. Eventually, 26 patients (87%) discontinued primary chemotherapy because of local tumor progression, whereas four patients (13%) discontinued chemotherapy because of interstitial pneumonitis caused by gemcitabine. After a median period of 7.9 months from starting chemotherapy, 30 patients underwent salvage CRT combined with either S-1 or 5-FU. Toxicities were generally mild and self-limiting. Median survival time (MST) from the start of salvage CRT was 8.8 months. The 6 month, 1-year and 2-year survival rates from the start of CRT were 77%, 33% and 26%, respectively. Multivariate analysis revealed that a lower pre-CRT serum CA 19–9 level (≤ 1000 U/ml; p = 0.009) and a single regimen of primary chemotherapy (p = 0.004) were independent prognostic factors for survival after salvage CRT. The MST for the entire patient population from the start of primary chemotherapy was 17.8 months, with 2- and 3-year overall survival rates of 39% and 22%, respectively. Conclusions CRT had moderate anti-tumor activity and an acceptable toxicity profile in patients with LAPC, even after failure of gemcitabine-based primary chemotherapy. If there are any signs of failure of primary chemotherapy without distant metastasis, salvage CRT could be a treatment of choice as a second-line therapy. Patients with relatively low serum CA19-9 levels after primary chemotherapy may achieve higher survival rates after salvage CRT. The strategy of using chemotherapy alone as a primary treatment for LAPC, followed-by CRT with salvage intent should be further investigated in prospective clinical trials. Trial registration 2011–136

BACKGROUND AND PURPOSE An ATP-binding cassette (ABC) transporter, breast cancer resistance protein (BCRP)/ABCG2, limits oral bioavailability of sulphasalazine. Here we examined the effect of curcumin, the principal curcuminoid of turmeric, on oral bioavailability of microdoses and therapeutic doses of sulphasalazine in humans. EXPERIMENTAL APPROACH Effects of curcumin were measured on the ATP-dependent sulphasalazine uptake by hBCRP-expressing membrane vesicles and on oral bioavailability of sulphasalazine in wild-type and Bcrp(-/-) mice. Eight healthy Japanese subjects received an oral dose of sulphasalazine suspension (100 µg) or tablets (2 g) alone or after curcumin tablets (2 g). Uptake of sulphasalazine was studied in HEK293 cells transfected with the influx transporter (OATP)2B1. KEY RESULTS Curcumin was a potent hBCRP inhibitor in vitro (K(i) 0.70 ± 0.41 µM). Curcumin increased the area under the curve (AUC)(0-8) of plasma sulphasalazine eightfold in wild-type mice at 300 and 400 mg·kg(-1), but not in Bcrp(-/-) mice. Curcumin increased AUC(0-24) of plasma sulphasalazine 2.0-fold at microdoses and 3.2-fold at therapeutic doses in humans. Non-linearity of the dose-exposure relationship was observed between microdoses and therapeutic doses of sulphasalazine. Sulphasalazine was a substrate for OATP2B1 (K(m) 1.7 ± 0.3 µM). Its linear index (dose/K(m)) at the therapeutic dose was high and may saturate OATP2B1. CONCLUSIONS AND IMPLICATIONS Curcumin can be used to investigate effects of BCRP on oral bioavailability of drugs in humans. Besides the limited dissolution, OATP2B1 saturation is a possible mechanism underlying non-linearity in the dose-exposure relationship of sulphasalazine.

To evaluate the effectiveness of episcleral ¹⁰⁶ruthenium plaque therapy (RPT) in the management of retinoblastoma.One hundred one RPTs were retrospectively analyzed that were performed in 90 eyes of 85 patients with retinoblastoma at National Cancer Center Hospital between 1998 and 2008. Each RPT had a corresponding tumor and 101 tumors were considered in the analysis of local control. Median follow-up length was 72.8 months. Median patient age at the RPT was 28 months. Median prescribed doses at reference depth and outer surface of the sclera were 47.4 Gy and 162.3 Gy, respectively.Local control rate (LCR) and ocular retention rate (ORR) at 2 years were 33.7% and 58.7%, respectively. Unilateral disease, International Classification of Retinoblastoma group C or more advanced at the first presentation or at the time of RPT, vitreous and/or subretinal seeding, tumor size greater than 5 disc diameter (DD), reference depth greater than 5 mm, dose rate at reference depth lower than 0.7 Gy/hour, dose at the reference depth lower than 35 Gy, and (biologically effective dose with an α/β ratio of 10 Gy) at the reference depth lower than 40 Gy(10) were associated with unfavorable LCR. Two patients died of metastatic disease. Radiation complications included retinal detachment in 12 eyes (13.3%), proliferative retinopathy in 6 (6.7%), rubeosis iris in 2 (2.2%), and posterior subcapsular cataract in 23 (25.6%).RPT is an effective eye-preserving treatment for retinoblastoma.

Intravenous administration of human basic fibroblast growth factor (bFGF) for 2 weeks stimulated osteoblast proliferation and new bone formation in various skeletal bones in young and aged rats at dosage levels of 0.1 mg/kg/day and greater. Morphometry of the soft X-ray radiograms of cross sections of the tibia indicated about a 20% increase in the calcified bone area of the diaphysis at 0.1 mg/kg/day. The Ca and hydroxyproline contents showed statistically significant increases at this dosage. The new bone formation was found only on the endosteal side, and no periosteal bone formation was found. Similar systemic osteogenic potential was seen after intravenous administration of other growth factors of the FGF family, human acidic FGF and human heparin-binding secretory transforming protein-1. The above results suggest a potential therapeutic role for these growth factors in bone-loss diseases such as osteoporosis.

Purpose Data comparing the clinical outcomes of local brain radiotherapy (LBRT) and whole brain RT (WBRT) in patients with a single brain metastasis after tumor removal are limited. Patients and Methods A retrospective analysis was performed to compare the patterns of treatment failure, cause of death, progression-free survival, median survival time, and Karnofsky performance status for long-term survivors among patients who underwent surgery followed by either LBRT or WBRT between 1990 and 2008 at the National Cancer Center Hospital. Results A total of 130 consecutive patients were identified. The median progression-free survival period among the patients who received postoperative LBRT ( n = 64) and WBRT ( n = 66) was 9.7 and 11.5 months, respectively ( p = .75). The local recurrence rates (LBRT, 9.4% vs. WBRT, 12.1%) and intracranial new metastasis rate (LBRT, 42.2% vs. WBRT, 33.3%) were similar in each arm. The incidence of leptomeningeal metastasis was also equivalent (LBRT, 9.4% vs. WBRT, 10.6%). The median survival time for the LBRT and WBRT patients was 13.9 and 16.7 months, respectively ( p = .88). A neurologic cause of death was noted in 35.6% of the patients in the LBRT group and 36.7% of the WBRT group ( p = .99). The Karnofsky performance status at 2 years was comparable between the two groups. Conclusions The clinical outcomes of LBRT and WBRT were similar. A prospective evaluation is warranted.

In the first part of this study, we reported that the postmortem changes in rat kidneys at room temperature proceed most rapidly in the epithelial cells of the distal tubule and thick ascending limb of the loop of Henle, and that one of the factors which determine the rapidity of the postmortem changes at room temperature is the intensity of K-NPPase (Na, K-ATPase) activity. In the present study, the postmortem changes in rat kidneys maintained at 0°C for 20, 48, and 72hr after death were studied histopathologically, electron microscopically, and histo- and cytochemically to obtain further information on the mechanisms of postmortem changes. At 0°C, the postmortem changes in the distal tubules and thick ascending limb of the loop of Henle were delayed considerably, and only mild changes were observed electron microscopically even 72hr after death. Contrary to the results at room temperature, the postmortem changes in the proximal tubules were quicker than those in the distal tubules at 0°C, and the proximal tubules show obvious cytolysis 48hr or more after death. Electron microscopy revealed swelling of the lysosomes, and in enzyme cytochemistry, reaction products indicating ACPase activity increased in the cytoplasm around the lysosomes 48hr after death. These findings suggest that the lysosomal enzymes leak out from the lysosomes at least 48hr after death at 0°C. The lysosomal enzymes were considered to have activity even at 0°C, because ACPase activity could be detected cytochemically at 0°C in the lysosomes. The cytolysis observed in the proximal convoluted tubules at 0°C was not seen in the kidneys flushed with chlorpromazine, a membrane stabilizer, and was severe in the kidneys flushed with Triton X-100, a membrane labilizer. From these results, the postmortem cytolysis observed especially in the proximal convoluted tubules 48hr or more after death even at 0°C is considered to be autolysis caused by the lysosomal enzymes which leak out from the lysosomes. Together with the result of the previous part of this study, it is concluded that there are at least two biological factors which determine the rapidity of the postmortem changes in the cells of the rat kidney, the intensity of cellular Na, K-ATPase activity and the lability of the lysosomal membrane.

In the first part of this study, we reported that the postmortem changes in rat kidneys at room temperature proceed most rapidly in the epithelial cells of the distal tubule and thick ascending limb of the loop of Henle, and that one of the factors which determine the rapidity of the postmortem changes at room temperature is the intensity of K-NPPase (Na, K-ATPase) activity. In the present study, the postmortem changes in rat kidneys maintained at 0°C for 20, 48, and 72hr after death were studied histopathologically, electron microscopically, and histo- and cytochemically to obtain further information on the mechanisms of postmortem changes. At 0°C, the postmortem changes in the distal tubules and thick ascending limb of the loop of Henle were delayed considerably, and only mild changes were observed electron microscopically even 72hr after death. Contrary to the results at room temperature, the postmortem changes in the proximal tubules were quicker than those in the distal tubules at 0°C, and the proximal tubules show obvious cytolysis 48hr or more after death. Electron microscopy revealed swelling of the lysosomes, and in enzyme cytochemistry, reaction products indicating ACPase activity increased in the cytoplasm around the lysosomes 48hr after death. These findings suggest that the lysosomal enzymes leak out from the lysosomes at least 48hr after death at 0°C. The lysosomal enzymes were considered to have activity even at 0°C, because ACPase activity could be detected cytochemically at 0°C in the lysosomes. The cytolysis observed in the proximal convoluted tubules at 0°C was not seen in the kidneys flushed with chlorpromazine, a membrane stabilizer, and was severe in the kidneys flushed with Triton X-100, a membrane labilizer. From these results, the postmortem cytolysis observed especially in the proximal convoluted tubules 48hr or more after death even at 0°C is considered to be autolysis caused by the lysosomal enzymes which leak out from the lysosomes. Together with the result of the previous part of this study, it is concluded that there are at least two biological factors which determine the rapidity of the postmortem changes in the cells of the rat kidney, the intensity of cellular Na, K-ATPase activity and the lability of the lysosomal membrane.

We report a case of hepatocellular carcinoma (HCC), initially treated by carbon ions, then subsequently by protons for marginal recurrence. A 52-year-old man with stage II HCC was enrolled in the clinical study for carbon ion therapy. A total dose of 52.5 GyE in 8 fractions was delivered through a right lateral port for 13 days. Dynamic CT performed 7 months after the initiation of carbon ion therapy showed a decrease in the size of the tumor. Dynamic CT performed 12 months after the therapy revealed marginal recurrence of HCC accompanied with portal vein tumor thrombus (PVTT). Proton therapy of 66 GyE in 22 fractions was delivered through posterior and right lateral ports for 33 days. Dynamic CT performed 3 months after the initiation of proton therapy showed a regression of the recurrent tumor and disappearance of the PVTT. No serious adverse effects were observed during or after these two treatments. He was free from further recurrence 27 months after the initiation of the first carbon ion therapy. Both carbon ions and protons were effective with minimal side effects.