Protective effects of hydrogen gas inhalation on radiation-induced bone marrow damage in cancer patients: a retrospective observational study.

Although intensity-modulated radiation therapy (IMRT) has been developed as an alternative to conventional radiotherapy, reducing bone marrow damage is limited. Thus, a novel technology is needed to further mitigate IMRT-induced bone marrow damage. Molecular hydrogen (H2) was recently reported as a preventive and therapeutic antioxidant that selectively scavenges hydroxyl radical (·OH) and peroxynitrite (ONOO-). This observational study aimed to examine whether H2 gas treatment improves IMRT-induced bone marrow damage in cancer patients. The study was performed at Clinic C4 in Tokyo, Japan between May 2015 and November 2016. During this period, all enrolled patients received IMRT once per day for 1 to 4 weeks. After each time of IMRT, the patients of control group (n = 7, 3 men and 4 women, age range: 26-70 years) received mild hyperbaric oxygen therapy in health care chamber for 30 minutes, and the patients of H2 group (n = 16, 8 men and 8 women, age range: 35-82 years) received 5% H2 gas in health care chamber for 30 minutes once per day. Radiation-induced bone marrow damage was evaluated by hematological examination of peripheral blood obtained before and after IMRT, and the data were expressed by the ratio after to before treatment. The total number of radiation times and total exposure doses of radiation were similar between the control and H2 groups. IMRT with health care chamber therapy significantly reduced white blood cells and platelets, but not red blood cells, hemoglobin and hematocrit. In contrast, H2 gas treatment significantly alleviates the reducing effects of white blood cells and platelets (P = 0.0011 and P = 0.0275, respectively). Tumor responses to IMRT were similar between the two groups. The results obtained demonstrated that H2 gas inhalation therapy alleviated IMRT-induced bone marrow damage without compromising the anti-tumor effects of IMRT. The present study suggests that this novel approach of H2 gas inhalation therapy may be applicable to IMRT-induced bone marrow damage in cancer patients. The study protocol was approved by an Ethics Committee Review of Tokyo Clinic and Research Institute ICVS Incorporated (Tokyo, Japan) on February 1, 2019, and was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: UMIN000035864) on February 20, 2019.

Optimization of X-ray microplanar beam radiation therapy for deep-seated tumors by a simulation study.

A Monte Carlo simulation was applied to study the energy dependence on the transverse dose distribution of microplanar beam radiation therapy (MRT) for deep-seated tumors. The distribution was found to be the peak (in-beam) dose and the decay from the edge of the beam down to the valley. The area below the same valley dose level (valley region) was decreased with the increase in the energy of X-rays at the same beam separation. To optimize the MRT, we made the following two assumptions: the therapeutic gain may be attributed to the efficient recovery of normal tissue caused by the beam separation; and a key factor for the efficient recovery of normal tissue depends on the area size of the valley region. Based on these assumptions and the results of the simulated dose distribution, we concluded that the optimum X-ray energy was in the range of 100-300 keV depending on the effective peak dose to the target tumors and/or tolerable surface dose. In addition, we proposed parameters to be studied for the optimization of MRT to deep-seated tumors.

Clinical response of advanced cancer patients to cellular immunotherapy and intensity-modulated radiation therapy.

Patients afflicted with advanced cancers were treated with the intratumoral injection of autologous immature dendritic cells (iDCs) followed by activated T-cell infusion and intensity-modulated radiation therapy (IMRT). A second round of iDCs and activated T cells was then administered to patients after the last radiation cycle. This complete regimen was repeated for new and recurring lesions after 6 weeks of follow-up. One year post therapy, outcome analyses were performed to evaluate treatment efficacy. Patients were grouped according to both the number and size of tumors and clinical parameters at treatment initiation, including recurrent disease after standard cancer therapy, Stage IV disease, and no prior therapy. Irrespective of prior treatment status, 23/37 patients with ≤ 5 neoplastic lesions that were ≤ 3 cm in diameter achieved complete responses (CRs), and 5/37 exhibited partial responses (PRs). Among 130 individuals harboring larger and more numerous lesions, CRs were observed in 7/74 patients that had received prior SCT and in 2/56 previously untreated patients. Some patients manifested immune responses including an increase in CD8+CD56+ lymphocytes among circulating mononuclear cells in the course of treatment. To prospectively explore the therapeutic use of these cells, CD8+ cells were isolated from patients that had been treated with cellular immunotherapy and IMRT, expanded in vitro, and injected into recurrent metastatic sites in 13 individuals who underwent the same immunoradiotherapeutic regimens but failed to respond. CRs were achieved in 34 of 58 of such recurrent lesions while PRs in 17 of 58. These data support the expanded use of immunoradiotherapy in advanced cancer patients exhibiting progressive disease.

Therapeutic response in patients with advanced malignancies treated with combined dendritic cell-activated T cell based immunotherapy and intensity-modulated radiotherapy.

Successful cancer immunotherapy is confounded by the magnitude of the tumor burden and the presence of immunoregulatory elements that suppress an immune response. To approach these issues, 26 patients with advanced treatment refractory cancer were enrolled in a safety/feasibility study wherein a conventional treatment modality, intensity modulated radiotherapy (IMRT), was combined with dendritic cell-based immunotherapy. We hypothesized that radiation would lower the tumor burdens, decrease the number/function of regulatory cells in the tumor environment, and release products of tumor cells that could be acquired by intratumoral injected immature dendritic cells (iDC). Metastatic lesions identified by CT (computed tomography) were injected with autologous iDC combined with a cytokine-based adjuvant and KLH (keyhole limpet hemocyanin), followed 24 h later by IV-infused T-cells expanded with anti-CD3 and IL-2 (AT). After three to five days, each of the injected lesions was treated with fractionated doses of IMRT followed by another injection of intratumoral iDC and IV-infused AT. No toxicity was observed with cell infusion while radiation-related toxicity was observed in seven patients. Five patients had progressive disease, eight demonstrated complete resolution at treated sites but developed recurrent disease at other sites, and 13 showed complete response at various follow-up times with an overall estimated Kaplan-Meier disease-free survival of 345 days. Most patients developed KLH antibodies supporting our hypothesis that the co-injected iDC are functional with the capacity to acquire antigens from their environment and generate an adaptive immune response. These results demonstrate the safety and effectiveness of this multimodality strategy combining immunotherapy and IMRT in patients with advanced malignancies.

A multiportal compensator system for IMRT delivery.

We have developed a multiportal compensator system for IMRT delivery, comprising a rotational compensator mount for a linac head, cylindrical compensator enclosures positioned in the mount, a vacuum-formed thermoplastic sheet with heavy alloy granules inside the enclosure, and a vacuum thermoforming device. The mount rotates like a revolver by a stepping motor, thus allowing automatic multiportal IMRT without exchanging compensators by human operators during treatment. The thermoforming device has servo-motor-driven 10 x 10 metal rod elements to actualize an arbitrary intensity profile. The thermoplastic sheet is preheated by a built-in biplanar heater and then it is placed over the rod elements. Subsequently, vacuum forming is performed through corner cutouts of the rod elements. After forced cooling down, the heavy alloy granules are fed into the formed sheet. Preliminary experiment using solid water phantoms and an x-ray film has shown that the intensity profile on the film agrees reasonably well with the desired profile.

Dynamic conical conformal radiotherapy using a C-arm-mounted accelerator: dose distribution and clinical application.

PURPOSE: The aim of this study was to solve anisotropy in the dose distributions from rotational conformal radiotherapy (RCRT) by using a C-arm-mounted accelerator. MATERIALS AND METHODS: The linac head was designed to move along the C-arm with a maximum angle of 60 degrees (from a vertical position toward the gantry). Simultaneous rotation of the gantry creates a dynamic conical irradiation technique. Dynamic conical conformal radiation therapy (Dyconic CRT) was developed by combining the technique with continuous motion of a multileaf collimator. Dose distributions were measured in phantoms using film densitometry and compared with conventional RCRT. Dose distributions in actual radiation therapy patients are also presented. RESULTS: Dyconic CRT enabled the precise delivery of noncoplanar beams without rotating the table. The measurements showed that three-dimensionally isotropic dose falloff was achieved with Dyconic CRT. Dose inhomogeneity in the sagittal direction with Dyconic CRT was compensated for by use of wedge filters. CONCLUSIONS: The drawbacks of the dose distributions produced by RCRT were overcome with the use of Dyconic CRT.