Search

Aim With the increased use of particle therapy for liver cancer, local recurrence after particle therapy increased. Salvage hepatectomy is an acceptable treatment option for local recurrence following particle therapy; however, its safety and effectiveness remain unclear. Therefore, this multi‐center study aimed to verify the feasibility and efficacy of salvage hepatectomy and assess clinical issues associated with its application. Methods We retrospectively assessed the perioperative outcomes, prognosis, and pathological characteristics of 15 patients who underwent salvage hepatectomy for local recurrence after particle therapy between 2006 and 2019. Results Hepatocellular carcinoma and metastatic liver tumors were noted in eight and seven patients, respectively. The mean total dose and number of fractions were 66.5 Gy and 12, respectively, and the mean interval between particle therapy and surgery was 30.1 months. Major hepatectomy was performed in seven cases. Moreover, the mortality rate was 0%, and surgical complications of Clavien‐Dindo grade IIIa or higher were observed in four cases (27%)—two bile leakages, one pleural effusion, and one refractory skin fistula. The median overall survival time and 5‐year overall survival rate after salvage hepatectomy were 29.9 months and 43.1%, respectively. Histological examination of the irradiated liver tissue surrounding the tumor showed sinusoidal dilatation, loss of hepatocyte, and fibrosis in most cases. Conclusion Salvage hepatectomy after particle therapy is a feasible therapy; however, the risk of refractory complications associated with particle therapy is relatively high. Therefore, the first‐line treatment for resectable liver cancer should be carefully determined considering second‐line treatment after local recurrence., This is the first study that verified feasibility and efficacy of salvage hepatectomy for local recurrence after particle therapy and indicated clinical issues and pathological features of this therapy. These data would be a guidepost for surgeons to treat such patients.

Introduction: Although the primary treatment option for hilar cholangiocarcinoma (HC) has been surgical resection, most patients present with unresectable advanced tumors at the time of diagnosis. Particle therapy (PT) holds great potential for HC, even though the anatomical proximity to the gastrointestinal tract prevents delivering a radical dose to the tumor. Space-making PT (SMPT), consisting of spacer placement surgery and subsequent PT, has been developed to minimize complications and maximize the therapeutic benefit of dose escalation for HC. This study aimed to conduct a dosimetric evaluation and examine the effectiveness of SMPT for the treatment of HC. Methods: Between 2007 and 2018, 12 patients with unresectable HC treated with SMPT were enrolled. The treatment outcomes and effectiveness of spacer placement surgery were evaluated through analyses of pre- and post-surgical parameters of dose-volume histograms. Results: All patients completed the planned SMPT protocol. The median survival time was 29.6 months, and the 1- and 3-year overall survival rates were 82.5% and 45.8%, respectively. The mean V95% value (volume irradiated with 95% of the planned treatment dose) of the gross tumor volume and clinical target volume after spacer placement surgery improved to 98.5% and 96.6% from preoperative values of 85.6% and 78.1%, respectively (p = 0.0196 and p = 0.0053, respectively). Grade 3 or higher adverse events after SMPT were seen in 6 patients. Discussion/Conclusion: SMPT led to improvements in dosimetric parameters and showed good feasibility and excellent outcomes. SMPT can be a promising novel alternative for unresectable HC.

Cancer cells often exhibit increased reactive oxygen species generation and altered redox regulation. The current study was conducted to investigate the biochemical and molecular events associated with redox alterations during chemical-induced malignant transformation and to evaluate their potential roles in radiation sensitivity. Immortalized nonmalignant human bronchial epithelial cells were exposed to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and a clone of cells exhibiting malignant behaviors was isolated and characterized. This clone initially exhibited an increase in cellular superoxide that eventually decreased after a long-term culture in vitro, associated with altered expression of antioxidant molecules, including an increase in thioredoxin-1 and manganese superoxide dismutase, and a decrease in glutathione peroxidase-1. These cells also showed a significant decrease in sensitivity to ionizing radiation, as demonstrated by less cell death in acute apoptosis analyses and long-term cell proliferation assays. Using biochemical redox modulation and siRNA approach, we showed that the increase in thioredoxin-1 played a significant role in conferring resistance to IR. Although there was a substantial increase in cellular glutathione, inhibition of glutathione synthesis did not increase IR sensitivity. Our study showed complex redox alterations during NNK-induced malignant transformation, and identified Trx-1 as a radiosensitivity modulator.

Among the vitamin K (VK) compounds, VK3 exhibits distinct cytotoxic activity in cancer cells and is thought to affect redox cycling; however, the underlying mechanisms remain unclear. Here we demonstrate that VK3 selectively inhibits DNA polymerase (pol) gamma, the key enzyme responsible for mitochondrial DNA replication and repair. VK3 at 30 microM inhibited pol gamma by more than 80%, caused impairment of mitochondrial DNA replication and repair, and induced a significant increase in reactive oxygen species (ROS), leading to apoptosis. At a lower concentration (3 microM), VK3 did not cause a significant increase in ROS, but was able to effectively inhibit cell proliferation, which could be reversed by supplementing glycolytic substrates. The cytotoxic action of VK3 was independent of p53 tumor suppressor gene status. Interestingly, VK3 only inhibited pol gamma but did not affect other pol including human pol alpha, pol beta, pol delta, and pol epsilon. VK1 and VK2 exhibited no inhibitory effect on any of the pol tested. These data together suggest that the inhibition of pol gamma by VK3 is relatively specific, and that this compound seems to exert its anticancer activity by two possible mechanisms in a concentration-dependent manner: (1) induction of ROS-mediated cell death at high concentrations; and (2) inhibition of cell proliferation at lower concentrations likely through the suppression of mitochondrial respiratory function. These findings may explain various cytotoxic actions induced by VK3, and may pave the way for the further use of VK3.

SummaryReactive oxygen species (ROS) stimulate cell proliferation and induce genetic instability, and their increase in cancer cells is often viewed as an adverse event. Here, we show that such abnormal increases in ROS can be exploited to selectively kill cancer cells using β-phenylethyl isothiocyanate (PEITC). Oncogenic transformation of ovarian epithelial cells with H-RasV12 or expression of Bcr-Abl in hematopoietic cells causes elevated ROS generation and renders the malignant cells highly sensitive to PEITC, which effectively disables the glutathione antioxidant system and causes severe ROS accumulation preferentially in the transformed cells due to their active ROS output. Excessive ROS causes oxidative mitochondrial damage, inactivation of redox-sensitive molecules, and massive cell death. In vivo, PEITC exhibits therapeutic activity and prolongs animal survival.

This study retrospectively evaluated the efficacy and toxicity of particle therapy using carbon ions or protons for primary sacral chordomas.We evaluated 23 patients with primary sacral chordoma treated with carbon ion therapy (CIT) or proton therapy (PT) between July 2005 and June 2011 at the Hyogo Ion Beam Medical Center, Hyogo, Japan. The median patient age was 72 years. 14 patients were treated with 70.4 Gy equivalents (GyE) in 16 fractions and 9 were treated with 70.4 GyE in 32 fractions. CIT was used for 16 patients, and PT was used for 7 patients.The median follow-up period was 38 months. At 3 years, local control (LC), overall survival (OS) and progression-free survival (PFS) for all patients were 94%, 83% and 68%, respectively. The log-rank test revealed that male sex was significantly related to better PFS (p=0.029). No other factors, including dose fractionation and ion type, were significant for LC, OS or PFS. In nine patients, ≥ Grade 3 acute dermatitis was observed, and ≥ Grade 3 late toxicities were observed in nine patients. The 32-fraction protocol reduced severe toxicities in both the acute and late phases compared with the 16-fraction protocol.Particle therapy for patients with sacral chordoma showed favourable LC and OS. Severe toxicities were successfully reduced by modifying the dose fractionation and treatment planning in the later treatment era. Thus, this therapeutic modality should be considered useful and safe.This is the first study including both CIT and PT for sacral chordomas.

Esophageal adenocarcinoma (EAC) is a highly lethal cancer in western countries. EAC cells are believed to develop from esophageal epithelial cells through complex transformation processes involving inflammation and oxidative stress. The purpose of this study was to compare the redox status of malignant and nonmalignant esophageal epithelial cells and to test their responses to bile acid–induced oxidative stress and to treatment with honokiol (HNK), a natural product with anticancer activity. We demonstrated that esophageal adenocarcinoma cells express significantly higher levels of antioxidant molecules and were resistant to reactive oxygen species (ROS) stress induced by bile acid, but were sensitive to the cytotoxic action of HNK. Mechanistic study showed that HNK caused cancer cell death by disruption of mitochondrial transmembrane potential and was correlated with cyclophilin D (CypD) expression. Inhibition of CypD by cyclosporin A or abrogation of its expression by siRNA significantly suppressed the cytotoxicity of HNK, suggesting that CypD may be a key molecule that mediates the cytotoxicity. Our study suggests that the high antioxidant capacity in EAC cells confers on them the ability to survive the oxidative microenvironment in the reflux esophagus, and that HNK is a promising compound to kill the transformed cells preferentially. Antioxid. Redox Signal. 11, 1083–1095.

Hyogo Ion Beam Medical Center (HIBMC) is the world’s only facility to provide both proton and carbon-ion radiotherapy. Based on the characteristic, HIBMC conduct and investigate many comparative studies between proton radiotherapy and carbon-ion radiotherapy. In several comparative studies, we have the problem whether there are differences between proton and carbon-ion radiotherapy. We aimed to compare and clear cell biological effects in related to good clinical results in synchrotron-proton and carbon-ion beam, using radiological, cell biological and molecular biological approach. We mainly examined effects using human salivary gland cancer (HSG cells). Cells were irradiated from 2 to 6 points in each experiment along a 150 MeV, a 320 MeV carbon- ion and a linac 4MV X-ray. We examined cell viability and relative biological effectiveness (RBE) by colony formation assay and CCK-8 colorimetric assay. A linac 4MV X-ray was used as a reference. RBE values calculated from cell survival curve for proton in HSG cells at the dose that would reduce cell survival to 10% (D10) were 1.10 by colony formation assay and 1.29 by CCK-8 colorimetric assay. RBE values at a D10 for carbon-ion in HSG cells were 1.96 by colony formation assay and 1.90 by CCK-8 colorimetric assay. These results suggest that proton beam have greater deficiency on CCK-8 colorimetric reaction than cell growth process. We thought the problem in clinical particle therapy could be partly explained by the difference in the deficiency. Furthere, we examined DNA breaks by expression in phosphorylated protein of histone H2AX and generation of Reactive oxygen Species. We reported the effective results of synchrotron-proton and carbon-ion.

The purpose of this study is to investigate the treatment result for patient with pharyngeal region and to evaluate the difference between proton (PRT) and carbon ion radiotherapy (CRT). Thirty-three patients, 18 male and 15 female aged from 16 to 81 years underwent at the Hyogo Ion Beam Medical Center between May 2001 and August 2008. Twenty-two patients with nasopharyngeal and 11 with oropharyngeal cancer received PRT for a total prescribed doses of 65 GyE/26 Fr/5.2 weeks (2.5 GyE/ Fr) or CRT for 57.6 GyE/16 Fr/3.2 weeks (3.6 GyE/ Fr). The histology was adenoid cystic carcinoma in 17, squamous cell carcinoma in 6, malignant melanoma in 3, adenocarcinoma in 2, mucoepidermoid carcinoma in 2, and others in 3. The UICC TNM classification was T1 in 4, T2 in 9, T3 in 5, and T4 in 15, and N0 in 29, N1 in 3, and N2 in 1. One case diagnosed as M1 was nasopharyngeal adenoid cystic carcinoma accompanied by multiple lung metastasis. The tumor response was CR in 2, PR in 12, and NC in 14, with a response rate of 50%. The overall 3- and 5-year survival rates were 62 and 62% in all patients, respectively, and 81 and 81% in those with nasopharyngeal cancer. In contrast, none of patients with oropharyngeal cancer survived for 3 years. The 3- and 5-year local control rates were 79 and 79% in all patients, 84 and 84%, in patients with nasopharyngeal cancer, respectively, but slightly poor in those with oropharyngeal cancer, with 1- and 2-local control rates of 89 and 67%, respectively. There was no significant difference between the numbers of patients who underwent proton and carbon ion radiations. The differential use of proton and carbon ion radiation therapies is an unknown, and comparative studies are necessary.

The Hyogo Ion Beam Medical Center was established in May 2001, a leading project of the ‘Hyogo Cancer Strategy’. As its major characteristic, both proton and carbon ion beams can be generated. The accelerator is a synchrotron that can accelerate proton and carbon ion beams at a maximum of 230 and 320 MeV/u, respectively, and the maximum ranges in water are 300 and 200 mm, respectively. Three irradiation rooms installed with 45-degree, horizontal/vertical, and horizontal fixed ports can be used for carbon ion radiation therapy, and 2 gantry rooms can be additionally used for proton beams. Particle beam radiation therapy had been performed in 2,639 patients as of the end of March 2009. The diseases treated were prostate cancer, head and neck tumors, liver cancer, lung cancer, and bone soft tissue tumors, in decreasing order of frequency, and these 5 major diseases accounted for 87% of the cases. The outcomes surpassed those of surgical therapy, realizing cancer therapy without resection. As the current problems of particle beam radiation therapy, the effect of the differential use of proton and carbon ion beams is unclear, adverse events, such as skin disorders, may occur due to the limitation of the broad beam method, and the necessity to install large-scale devices is an obstacle to its dissemination. We are aiming at the development and clinical application of a laser-driven proton radiotherapy device in cooperation with the Japan Atomic Energy Agency.

The application of neural networks to power converter control is discussed. In this system, the networks can get knowledge about the control rules for the inverter. The application of neural networks to the on-off pattern control of a pulse-width modulation (PWM) inverter is described. An example of application of a neural network to inverter control is given, along with simulation results. In the proposed system, the neural network is used to generate the on-off switching pattern of a three-phase PWM inverter. >

For fabricating efficient tandem solar cells, CuIn/sub x/Ga/sub 1-x/Se/sub 2/ thin films have been prepared on Si(100), Si(110) and Si(111) substrates in the temperature range (R.T./spl sim/400/spl deg/C) by RF sputtering. From EPMA analysis, these sputtered thin films are found to be nearly stoichiometric over the whole substrate temperature range, irrespective of the azimuth plane of the Si substrate. XPS studies showed that the compositional depth profile in these thin films is uniform. X-ray diffraction analysis indicated that all the thin films had a chalcopyrite structure. CuIn/sub x/Ga/sub 1-x/Se/sub 2/ thin films were strongly oriented along the (112) plane with increasing the substrate temperature, independent of the azimuth plane of the Si substrate, suggesting the larger grain growth.

Purpose/Objective(s): Bone and soft tissue sarcomas (BSTSs) have been considered to be radioresistant and the mainstay of the treatment is surgery. Particle therapy using carbon ions or protons has potential to be an alternative of surgery in the treatment of BSTSs because of the ability to deliver[for full text, please go to the a.m. URL], PTCOG 48; Meeting of the Particle Therapy Co-Operative Group

We report the demonstrated irradiation effect of laser-accelerated protons on human cancer cells. In vitro (living) A549 cells are irradiated with quasimonoenergetic proton bunches of 0.8–2.4 MeV with a single bunch duration of 15 ns. Irradiation with the proton dose of 20 Gy results in a distinct formation of γ-H2AX foci as an indicator of DNA double-strand breaks generated in the cancer cells. This is a pioneering result that points to future investigations of the radiobiological effects of laser-driven ion beams. Unique high-current and short-bunch features make laser-driven proton bunches an excitation source for time-resolved determination of radical yields.

Purpose: Recently several DVH parameters have been reported as useful indicators for the occurrence of radiation pneumonitis (RP) after thoracic radiotherapy. On the other hand, in the treatment of unresectable non-small cell lung cancer, recent RTOG report showed concurrent chemo-radiotherapy yielded better outcome with higher non-hematologic toxicity than sequential therapy. The purpose of this study is to clarify if percent of pulmonary volume irradiated exceeding 20Gy (V20) is associated with the incidence and grade of radiation pneumonitis (RP) in cases of advanced lung cancer treated with concurrent chemo-radiotherapy. Materials and Methods: Seventy-one patients with advanced lung cancer who were treated with conventionally fractionated radiotherapy concurrently with systemic chemotherapy from Jan 1999 to Sep 2000, and were followed more than three months were analyzed in this study. There were 58 males and 13 females and the median age was 67 (range 42-79). Sixty-five were NSCLC and other 6 were SCLC. Clinical stages were IIIA in 21, IIIB in 47, and IV in 3patients. Chemotherapy was given with radiotherapy concurrently in initial treatment in 65, and other 6 received induction chemotherapy followed by concurrent chemo-radiotherapy. Chemotherapy were consisted of cisplatin or carboplatin based regimens combined with taxane in 36, and other agents such as vinolerbine / CPT11 in 35patients. Radiotherapy was delivered in 1.8-2.0 Gy/fr qd to total doses of 48-66Gy (median 60Gy). RP were graded according to NCI-Common Toxicity Criteria Ver.2.0. The relationship between RP grade and V20 were analyzed. Univariate and multivariate analyses were performed to assess other patient and treatment related factors as well as V20. Results: The median follow-up period was 7.5 months (range 3-19 months). Grade 0, 1, 2, 3, 5 RP were observed in 16, 35,17, 1, 2 patients respectively. The mean V20 was 23.0% in all patients, while the mean V20 were 20.1, 22.0, 26.3, 27.0, and 34.5% in grade 0, 1, 2, 3, and 5 patients respectively. The six month cumulative incidences of RP greater than grade 2 were 8.7%, 18.3%, 51%, and 85% in patients whose V20 was 31% respectively (p

[This corrects the article DOI: 10.1039/D4SC05606J.]., (This journal is © The Royal Society of Chemistry.)