The "GU-GU-RU" project to eliminate discrimination related to the health effects of the Fukushima nuclear accident.

BACKGROUND: Although 12 years have passed since Great East Japan Earthquake and following Fukushima nuclear accident, approximately 40% of Japanese citizen still believe that the current radiation exposure in Fukushima residents will likely/ very likely to cause genetic effects of radiation. This incorrect understanding could continue unexpected discrimination and prejudice towards those from Fukushima now and in the future. In order to provide updated knowledge and eliminate rumors related to radiation, Japanese Ministry of the Environment has launched "GU-GU-RU" project in 2021 with consisting of five sections. OBJECTIVE: (1) To discuss the objectives and effects of the "GU-GU-RU" project (results after the first year), (2) to present administrative measures that may be effective in the long-term to prevent unjustified discrimination and prejudice, and (3) to eliminate rumors in the event of future large-scale disasters, including radiation disasters. METHODS: We showed the contents of each sections carried out under the project and observed the result of first-year activities in each section. RESULTS: Among the programs, the "Radiation College" has steadily produced positive results, with nearly 1,300 students participating and 50 students sharing their thoughts and ideas. In addition, the project has adopted strategies such as creating and broadcasting a TV program and collaborations with manga, which are expected to have a significant impact on society. CONCLUSIONS: Compared to previous efforts on disseminating information related to health effect of radiation exposure, the "GU-GU-RU" project has taken a different approach in providing primary data of radiation and its health effects, which could become a better understanding of health effects of radiation for the general public, in order to eliminate rumors that may lead unjustified discrimination and prejudice.

Development of an HDR-BT QA tool for source position verification.

PURPOSE: This study aimed to develop a high-dose-rate brachytherapy (HDR-BT) quality assurance (QA) tool for verification of source positions, and to report on its effectiveness. METHODS: We fabricated a cuboid phantom measuring 30 × 30×3 cm3 with spaces to embed Fletcher-Williamson tandem and ovoid applicators. Lead-based, cylindrically shaped radiopaque markers, which scatter radiation and blacken the Gafchromic® RTQA2 films placed on the applicators, were inserted into the phantom to determine the applicator tip and reference source positions. A three-dimensional image-guided brachytherapy (3D-IGBT) plan was generated, and the source positions on the film and radiation treatment planning system (RTPS) were verified with the tool. Source position errors were evaluated as the distance in the applicator axis direction between the source position and the center position of two radiopaque marker pairs. RESULTS: Source position errors on the film and RTPS were in good agreement with one another and were all within 0.5 mm for all applicators. Offset values of each applicator were in good agreement with the value determined in treatment planning (6 mm). The expanded measurement uncertainty of our QA tool was estimated to be 0.87 mm, with a coverage factor k of 2. CONCLUSIONS: Our new HDR-BT QA tool developed for comprehensive source position verification will be useful for cross checking actual source positions and planned source positions on the RTPS.

FGFR Signaling as a Candidate Therapeutic Target for Cancers Resistant to Carbon Ion Radiotherapy.

Radiotherapy is an essential component of cancer therapy. Carbon ion radiotherapy (CIRT) promises to improve outcomes compared with standard of care in many cancers. Nevertheless, clinicians often observe in-field recurrence after CIRT. This indicates the presence of a subset of cancers that harbor intrinsic resistance to CIRT. Thus, the development of methods to identify and sensitize CIRT-resistant cancers is needed. To address this issue, we analyzed a unique donor-matched pair of clinical specimens: a treatment-naïve tumor, and the tumor that recurred locally after CIRT in the same patient. Exon sequencing of 409 cancer-related genes identified enrichment of somatic mutations in FGFR3 and FGFR4 in the recurrent tumor compared with the treatment-naïve tumor, indicating a pivotal role for FGFR signaling in cancer cell survival through CIRT. Inhibition of FGFR using the clinically available pan-FGFR inhibitor LY2874455 sensitized multiple cancer cell lines to carbon ions at 3 Gy (RBE: relative biological effectiveness), the daily dose prescribed to the patient. The sensitizer enhancement ratio was 1.66 ± 0.17, 1.27 ± 0.09, and 1.20 ± 0.18 in A549, H1299, and H1703 cells, respectively. Our data indicate the potential usefulness of the analytical pipeline employed in this pilot study to identify targetable mutations associated with resistance to CIRT, and of LY21874455 as a sensitizer for CIRT-resistant cancers. The results warrant validation in larger cohorts.

[Radiotherapy and PD-L1 Expression].

The combination treatment of radiotherapy with anti-PD-1/PD-L1 antibody has been shown to significantly improve the clinical outcome of various cancers. Recent studies showthat radiotherapy has multiple functions in modifying the tumor microenvironment, by inducing both immunostimulation and immunosuppression. The upregulation of PD-L1 expression in cancer cells interferes with the effector functions of interacting T cells. Preclinical studies demonstrate that radiotherapy induces PD-L1 upregulation by 4 pathways; (1)IFN-γ signaling,(2)EGFR pathway,(3)DNA damage signaling pathway, and(4)cGAS-STING pathway. All of these mechanisms are involved in the upregulation of PD-L1 expression in cancer cells via JAK/STAT pathway. Because the PD-1/PD-L1 interaction has been shown to be one of the major mechanisms of cancer immune escape, which leads to treatment failure, anti-PD-1/PD-L1 antibody may improve the efficacy of radiotherapy by enhancement of anti-tumor activity. In addition, PD-L1 expression is one of the biomarkers of good response to anti-PD-1/ PD-L1 antibody. Therefore, the comprehensive understanding of the mechanism underlying PD-L1 expression in response to radiotherapy is important for the establishment of optimal combination strategy. This approach could help to provide the basis for the combined therapies and promote personalized immuno-radiotherapy, although the signaling of PD-L1 upregulation induced by radiotherapy in tumors could be intricately regulated. In this article, we review previous researches which revealed the mechanisms of PD-L1 upregulation induced by radiotherapy.

Tumor-specific CD8-positive T cell-mediated antitumor immunity is implicated in the antitumor effect of local hyperthermia.

PURPOSE: This study aimed to elucidate the contribution of T cell-mediated antitumor immunity in the antitumor effect of local hyperthermia (LH). MATERIALS AND METHODS: C57BL/6J mice were injected with the mouse lymphoma cell line, E.G7-OVA, in the right femur on day 0. LH was induced by immersing the right femur in a water bath at 42 °C for 60 min on day 7, followed by administration of anti-CD8 monoclonal antibodies (mAb) or anti-CTLA-4 mAb (days 8, 11, and 14). The effect of LH on tumor growth (TG) was assessed by measuring the duration until tumor volume reached 1000 mm3 and survival time. Tumor-specific T cell responses were measured using enzyme-linked immunospot (ELISpot) assay. RESULTS: TG with and without LH treatment was 9.0 ± 9.6 and 7.0 ± 1.6 days, respectively. TG was significantly slower with LH treatment (p = .01). The therapeutic effect of LH was mitigated by addition of anti-CD8 mAb (p < .05 for both TG and survival) compared with the untreated (control) group. Furthermore, addition of anti-CTLA-4 mAb did not significantly affect the therapeutic effect of LH. The ELISpot assay showed that the number of spots in the LH group (276.3 ± 14.5) was significantly greater than in the control group (59.0 ± 4.5, p < .001). CONCLUSION: CD8-positive T cell-mediated antitumor immunity significantly contributes to the antitumor effect of LH.

Prospective observational study of carbon-ion radiotherapy for non-squamous cell carcinoma of the head and neck.

To evaluate the efficacy and safety of carbon-ion radiotherapy for non-squamous cell carcinoma of the head and neck, 35 patients were enrolled in this prospective study. The primary end-point was the 3-year local control rate, and the secondary end-points included the 3-year overall survival rate and adverse events. Acute and late adverse events were evaluated according to the Common Terminology Criteria for Adverse Events, version 4.0. The median follow-up time for all patients was 39 months. Thirty-two and three patients received 64.0 Gy (relative biological effectiveness) and 57.6 Gy (relative biological effectiveness) in 16 fractions, respectively. Adenoid cystic carcinoma was dominant (60%). Four patients had local recurrence and five patients died. The 3-year local control and overall survival rates were 93% and 88%, respectively. Acute grade 2-3 radiation mucositis (65%) and dermatitis (31%) was common, which improved immediately with conservative therapy. Late mucositis of grade 2, grade 3, and grade 4 were observed in 11, one, and no patients, respectively. There were no adverse events of grade 5. Carbon-ion radiotherapy achieved excellent local control and overall survival rates for non-squamous cell carcinoma. However, the late mucosal adverse events were not rare, and meticulous treatment planning is required. Trial registration no. UMIN000007886.

The prognostic value of rectal invasion for stage IVA uterine cervical cancer treated with radiation therapy.

BACKGROUND: The prognostic value of rectal invasion is still unclear in stage IVA cervical cancer. The objective of this study is to evaluate patient outcome and prognostic factors in stage IVA cervical cancer treated with radiation therapy. METHODS: A retrospective review of the medical records of patients treated with definitive photon radiation therapy for pathologically proven stage IVA cervical cancer between 1980 and 2010 was performed. Eligible patients for the present study were diagnosed with clinical stage IVA cervical cancer by cystoscopy or/and proctoscopy, and they received definitive radiation therapy consisting of a combination of external beam radiotherapy and high-dose-rate brachytherapy. All patients underwent CT scans of the abdomen and pelvis. RESULTS: Among the 67 stage IVA patients studied, 53 patients were stage IVA on the basis of bladder invasion, 7 according to rectal mucosal invasion, and 7 because of both bladder and rectal mucosal invasion. Median follow-up of all patients and surviving patients was 19 months (range, 2-235 months) and 114 months (range, 14-223 months), respectively. The 5-year local control (LC), disease-free survival (DFS), and overall survival (OS) rate were 55, 17, and 24%, respectively. Rectal invasion had significant impact on DFS, but bladder invasion had the opposite effect (p = 0.00006 and 0.005, respectively). There were significant differences of LC, DFS and OS rates between patients with and without rectal invasion (p = 0.006, 0.00006 and 0.05, respectively). CONCLUSIONS: Patients with stage IVA cervical cancer had poor prognosis, with 5-year survival of only 24%. Furthermore, in stage IVA, rectal invasion might be a worse prognostic factor than bladder invasion.

Clinical outcomes of carbon ion radiotherapy for locally advanced adenocarcinoma of the uterine cervix in phase 1/2 clinical trial (protocol 9704).

BACKGROUND: This study sought to evaluate the toxicity and efficacy of carbon ion radiotherapy (C-ion RT) for locally advanced adenocarcinoma of the uterine cervix in a phase 1/2 clinical trial. METHODS: The treatment consisted of whole-pelvic irradiation of 36.0 gray equivalents (GyE) in 12 fractions and local boost with dose escalation from 26.4 to 38.4 GyE in 8 fractions. The dose escalation was performed with careful observation of acute normal tissue responses. Total dose to the cervical tumor was 62.4 to 74.4 GyE in 20 fractions. RESULTS: Between April 1998 and February 2010, 58 patients were treated with C-ion RT in this clinical trial. The number of patients with stage IIB, IIIB, and IVA disease were 20, 35, and 3, respectively. Median tumor size was 5.5 cm (range, 3.0-11.8 cm). Twenty-seven patients had pelvic lymph node metastases. The median follow-up period was 38 months. All patients completed the treatment schedule. Grade 2 or higher late toxicity was found in 8 patients: 5 with bladder and 2 with small intestine grade 2 toxicities, and 1 patient had grade 4 rectal complication, which was surgically salvaged. The 5-year local control rate, local control rate including salvage surgery, and overall survival rate in all cases were 54.5%, 68.2%, and 38.1%, respectively. CONCLUSIONS: Dose escalation of C-ion RT for adenocarcinoma of the uterine cervix was accomplished without severe toxicities except in 1 case. Although the number of patients in this study was small, the results support continued investigation and analysis to confirm therapeutic efficacy.

Carbon ion radiotherapy for mesonephric adenocarcinoma of the uterine cervix: a case report.

BACKGROUND: Mesonephric adenocarcinoma is an extremely rare subtype of uterine cervical cancer that is associated with a poor prognosis and for which a standardized treatment protocol has not been established. Carbon ion radiotherapy (CIRT) is an emerging radiotherapy modality that has been shown to have a favorable anti-tumor effect, even for tumors resistant to conventional photon radiotherapy or chemotherapy. However, there is no report on CIRT outcomes for mesonephric adenocarcinoma of the uterine cervix. CASE PRESENTATION: We treated a 47-year-old Japanese woman with mesonephric adenocarcinoma of the uterine cervix (T2bN0M0 and stage IIB according to the 7th edition of the Union for International Cancer Control and International Federation of Gynecology and Obstetrics, respectively) with CIRT combined with brachytherapy and concurrent chemotherapy. CIRT consisted of whole pelvic irradiation and boost irradiation to the gross tumor; 36.0 Gy (relative biological effectiveness [RBE]) in 12 fractions and 19.2 Gy (RBE) in 4 fractions, respectively, performed once a day, four times per week. Computed tomography-based image-guided adaptive brachytherapy was performed after completion of CIRT, for which the D90 (i.e., the dose prescribed to 90% of the target volume) for the high-risk clinical target volume was 20.4 Gy in a total of 3 sessions in 2 weeks. A weekly cisplatin (40 mg/m2) dose was administered concomitantly with the radiotherapy for a total of five courses. From 4 months post-CIRT, the patient developed metastasis of the lung, with a total of 10 lung metastases over 70 months; these lesions were treated on each occasion by photon stereotactic body radiotherapy and/or systemic therapy. At 8 years from initial treatment (i.e., 2 years after the last treatment), the patient is alive without any evidence of recurrence and maintains a high quality of life. CONCLUSIONS: This is the first report of CIRT for treatment of mesonephric adenocarcinoma of the uterine cervix. The present case indicates the potential efficacy of CIRT in combination with brachytherapy for treatment of this disease.

Combination of oligo-fractionated irradiation with nivolumab can induce immune modulation in gastric cancer.

BACKGROUND: Tumor-associated antigen (TAA)-specific CD8(+) T cells are essential for nivolumab therapy, and irradiation has been reported to have the potential to generate and activate TAA-specific CD8(+) T cells. However, mechanistic insights of T-cell response during combinatorial immunotherapy using radiotherapy and nivolumab are still largely unknown. METHODS: Twenty patients included in this study were registered in the CIRCUIT trial (ClinicalTrials.gov, NCT03453164). All patients had multiple distant metastases and were intolerance or had progressed after primary and secondary chemotherapy without any immune checkpoint inhibitor. In the CIRCUIT trial, eligible patients were treated with a total of 22.5 Gy/5 fractions/5 days of radiotherapy to the largest or symptomatic lesion prior to receiving nivolumab every 2 weeks. In these 20 patients, T-cell responses during the combinatorial immunotherapy were monitored longitudinally by high-dimensional flow cytometry-based, multiplexed major histocompatibility complex multimer analysis using a total of 46 TAAs and 10 virus epitopes, repertoire analysis of T-cell receptor ß-chain (TCRß), together with circulating tumor DNA analysis to evaluate tumor mutational burden (TMB). RESULTS: Although most TAA-specific CD8(+) T cells could be tracked longitudinally, several TAA-specific CD8(+) T cells were detected de novo after irradiation, but viral-specific CD8(+) T cells did not show obvious changes during treatment, indicating potential irradiation-driven antigen spreading. Irradiation was associated with phenotypical changes of TAA-specific CD8(+) T cells towards higher expression of killer cell lectin-like receptor subfamily G, member 1, human leukocyte antigen D-related antigen, T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain, CD160, and CD45RO together with lower expression of CD27 and CD127. Of importance, TAA-specific CD8(+) T cells in non-progressors frequently showed a phenotype of CD45RO(+)CD27(+)CD127(+) central memory T cells compared with those in progressors. TCRß clonality (inverted Pielou's evenness) increased and TCRß diversity (Pielou's evenness and Diversity Evenness score) decreased during treatment in progressors (p=0.029, p=0.029, p=0.012, respectively). TMB score was significantly lower in non-progressors after irradiation (p=0.023). CONCLUSION: Oligo-fractionated irradiation induces an immune-modulating effect with potential antigen spreading and the combination of radiotherapy and nivolumab may be effective in a subset of patients with gastric cancer.

Anti-PD-1 monoclonal antibody-resistant esophageal squamous cell carcinoma showing the abscopal effect: A case report with T-cell receptor/B-cell receptor repertoire analysis.

BACKGROUND: Several clinical trials of nivolumab have reported good results, including those in patients with advanced esophageal squamous cell carcinoma. However, the response rate of this drug remains poor. Notably, a rare phenomenon called abscopal effect refers to the regression of irradiated and nonirradiated distant tumors after local radiotherapy. Although the mechanism of this effect remains unclear, the antitumor immunity induced by radiotherapy is considered to be the most important factor. CASE: A 66-year-old man with recurrent nivolumab-resistant esophageal squamous cell carcinoma along with left-side cervical and abdominal para-aortic lymph node metastases was treated with a 40 Gy (10 fractions) dose of radiotherapy to the left-side cervical lymph node metastasis as a palliative treatment, which caused neck pain. In addition, nivolumab administration was resumed the day after completion of radiotherapy. Three months after radiotherapy, the irradiated lesion on the left neck had regressed to a scar-like lesion. Furthermore, the previously progressive abdominal para-aortic lymph nodes outside the irradiation area shrank (abscopal effect). T-cell receptor and B-cell receptor (TCR/BCR) repertoire analyses before and after radiotherapy revealed that radiotherapy led to changes in the TCR/BCR repertoire. CONCLUSION: Changes in the TCR/BCR repertoire may be a part of the mechanism underlying the abscopal effect. The findings of the present case suggest that the combination of immune checkpoint inhibitors and radiotherapy is a promising treatment approach even for patients with immune checkpoint inhibitor-resistant cancer.

Immunological Responses Associated With Neoadjuvant Therapy in the Tumor Microenvironment of Esophageal Squamous Cell Carcinoma.

BACKGROUND/AIM: Development of multidisciplinary therapies including immune checkpoint inhibitors for esophageal squamous cell carcinoma (ESCC) requires a clear understanding of immunological responses induced by chemotherapy with/without radiotherapy in the tumor microenvironment. PATIENTS AND METHODS: This is a retrospective analysis of paired pretreatment biopsy samples and surgically resected tumor samples of 49 patients who underwent radical surgery for ESCC with/without neoadjuvant therapy at Fukushima Medical University Hospital. The cohort included 30 patients treated with neoadjuvant chemotherapy (NAC), 11 treated with neoadjuvant chemoradiotherapy (NACRT), and eight who underwent surgery alone and did not receive neoadjuvant antitumor therapy. Chemotherapy included fluoropyrimidine- and platinum-based agents in all treated patients, and radiotherapy included 40 or 42 Gy administered in 20 or 21 fractions. Expression of CD8, human leukocyte antigen (HLA) class I-ABC, PD-L1, PD-L2, CEACAM-1, LSECtin, and p-STAT1, were determined using immunohistochemistry. RESULTS: The frequency of tumor-infiltrating CD8+ T cells was significantly increased by NAC (p<0.05), and the expression of HLA class I-ABC on tumor cells was significantly increased by NAC and NACRT (p<0.05). Furthermore, the ESCC cells expressed PD-L1, PD-L2, and CEACAM-1, whereas the expression of PD-L1 on ESCC cells was significantly correlated with the expression of p-STAT1 in ESCC cells (p<0.05). CONCLUSION: NAC and NACRT induced both positive and negative immunological responses in patients with ESCC. These results may be a part of basis for multidisciplinary therapy including immune checkpoint inhibitors for patients with advanced ESCC.

Phase I/II clinical trial of nivolumab in combination with oligo-fractionated irradiation for unresectable advanced or recurrent gastric cancer.

BACKGROUND: Although immune checkpoint inhibitors (ICI) targeting for PD-1 axis is a promising approach for advanced gastric cancer (GC) patients, the response rate is still limited. Induction of synergistic effect of irradiation with ICI targeting for the PD-1 axis can be an attractive strategy. The aim of this study was to assess the effect of the combination of irradiation with anti-PD-1 therapy for advanced GC. METHODS: We conducted a single-arm, phase I/II trial in GC patients treated with a combination of nivolumab and oligo-fractionated irradiation (22.5 Gy/5 fractions/5 days) (NCT03453164). Eligible patients (n = 40) had unresectable advanced or recurrent GC which progressed after primary and secondary chemotherapy with more than one lesion. The primary endpoint is the disease control rate (DCR) of non-irradiated target lesions and the secondary endpoints are the median survival time (MST), safety, and DCR of irradiated lesions. RESULTS: We observe that the DCR for the non-irradiated target as the abscopal effect is 22.5% (90% confidence interval (CI), 12.3-36.0), and the DCR for the irradiated lesion is 40.0% (90% CI, 26.9-54.2). The median survival time is 230 days (95% CI, 157-330), and grade 3 and higher adverse events (AEs) are observed in 16 patients (39 %) with no obvious additional AEs when adding irradiation. CONCLUSIONS: The present study suggests that the combination of nivolumab with oligo-fractionated irradiation has the potential to induce a promising anti-tumor effect for advanced GC.

Immunotherapy is a type of treatment that triggers the immune system to kill cancers. Combining immunotherapy with radiotherapy may enhance its effects. We evaluated this in a clinical trial in which we treated patients with advanced or recurrent cancers of the stomach (gastric cancer) with a combination of immunotherapy and radiotherapy. The combination was able to control disease in a subset of patients and was safe, with no obvious additional adverse effects when adding radiotherapy. The median survival time­at which point half of the patients treated are still alive­was 230 days. While these results are promising, larger, more rigorous studies are needed to determine whether this combination therapy is better than alternative approaches to treating advanced or recurrent gastric cancers.

Regional collaboration to improve quality of radiation therapy in Asia.

In Asia, several challenges hinder the delivery of high-quality cancer treatment, especially radiation therapy (RT). Many Asian countries face large-scale shortage of RT centres and treatment machines. Additionally, there is also a significant technological gap, with many RT centres in Asia still using outdated technology. There is an urgent need to improve radiation treatment quality in Asia. The Federation of Asian Organizations for Radiation Oncology (FARO) was set up to foster regional collaboration, which we believe can help to identify and solve some of these issues collectively. This report describes the background and rationale of starting FARO, and puts forth some of the early achievements of the group, including fact-finding and educational activities. Finally, we discuss future possibilities, including strategic proposals that may benefit the RT community and our patients in Asia.

Plan-Optimization Method for Central-shielding Pelvic Volumetric-modulated Arc Therapy for Cervical Cancer.

AIM: To establish a method of plan optimization in pelvic volumetric-modulated arc therapy (VMAT) for cervical cancer using the central-shielding (CS) principle. PATIENTS AND METHODS: We created external beam VMAT plans for eight cases with non-bulky stage I-IIb using the CS principle based on the Japanese standard guideline. Clinical target volumes (CTVs) for whole-pelvis (WP) irradiation were created using published guidelines, and CTVs for CS irradiation were created by subtracting the uterus corpus and 4 cm-wide regions centered at the cervix and vagina from the CTVs for WP irradiation. For plan optimization of CS irradiation, a 4-cm diameter cylindrical volume centered in the cervix and vagina was created as the volume receiving a high dose in brachytherapy, and the volume overlapping with the rectum was defined as the Ant-Rectum. Dose-volume histogram (DVH) parameters of two CS VMAT plans with and without (VMATOPT/VMATNO) dose optimization to the Ant-Rectum were compared. RESULTS: VMATOPT plans resulted in significantly lower DVH parameters of the Ant-Rectum and rectum compared to VMATNO plans. These were comparable to the DVH parameters of three-dimensional conformal radiotherapy (3DCRT) plans. Both VMAT plans resulted in significantly better coverage of planning target volumes than did the 3DCRT plans. CONCLUSION: In the implementation of IMRT/VMAT as the standard treatment for cervical cancer in Japan, our optimization method may be an essential step toward fully benefitting from the CS principle.

Phospho­STAT1 expression as a potential biomarker for anti­PD­1/anti­PD­L1 immunotherapy for breast cancer.

In the present study, we evaluated the mechanisms of programmed death ligand 1 (PD­L1) expression in the breast cancer microenvironment, focusing on the role of interferon­Î³ (IFN­Î³), and the clinical indications for anti­programmed cell death 1 (PD­1) /anti­PD­L1 immunotherapy. We evaluated PD­L1 expression in 4 breast cancer cell lines in the presence of 3 types of inhibitors, as well as IFN­Î³. The expression of phosphorylated signal transducer and activator of transcription 1 (p­STAT1), one of the IFN­Î³ signaling pathway molecules, was analyzed using immunohistochemistry (IHC) in relation to PD­L1 and human leukocyte antigen (HLA) class I expression on cancer cells and tumor­infiltrating CD8­positive T cells in 111 patients with stage II/III breast cancer. Using The Cancer Genome Atlas (TCGA) database, the correlation of the IFN­Î³ signature with PD­L1 expression was analyzed in breast invasive carcinoma tissues. As a result, the JAK/STAT pathway via IFN­Î³ was mainly involved in PD­L1 expression in the cell lines examined. IHC analysis revealed that the PD­L1 and HLA class I expression levels were significantly upregulated in the p­STAT1­positive cases. TCGA analysis indicated that the PD­L1 expression and IFN­Î³ signature exhibited a positive correlation. On the whole, these findings suggest that PD­L1 and HLA class I are co­expressed in p­STAT1­positive breast cancer cells induced by IFN­Î³ secreted from tumor infiltrating immune cells, and that p­STAT1 expression may be a potential biomarker for patient selection for immunotherapy with anti­PD­1/anti­PD­L1 monoclonal antibodies.

Dosimetric comparison of three-dimensional conformal radiotherapy versus volumetric-arc radiotherapy in cervical cancer treatment: applying the central-shielding principle to modern technology.

This study evaluated the feasibility of applying volumetric-arc radiotherapy (VMAT) in standard curative radiotherapy for non-bulky cervical cancer using the central-shielding principle. Whole-pelvis irradiation of 20 Gy and central-shielding pelvis irradiation of 30 Gy, both in 2 Gy fractions, were created using 3D conformal radiotherapy (3DCRT) with a standard midline block or VMAT. Composite dose distributions and DVH parameters were compared first in a simple phantom model and then in 10 clinical cases of Stage I-II cervical cancer. Whole-pelvis clinical target volumes (CTVs) were created from published guidelines for primary disease and lymph node regions, and CTVs for central-shielding irradiation were created by subtracting uterus corpus and 4 cm-wide regions centered at the cervical canal and vagina. In a phantom model, VMAT provided adequate dose coverage to the PTVs without excessive doses to the rectum or bladder compared with the 3DCRT plan. In the clinical cases, VMAT plans resulted in slightly but significantly better coverage of PTVs. The DVH parameters for the rectum and bladder were equivalent or lower for VMAT plans compared with the 3DCRT plans. In the bowel, V30Gy, V40Gy, and V50Gy were significantly lower in VMAT plans compared with in the 3DCRT plans (47.6% vs 61.0%, 29.8% vs 56.2% and 6.8% vs 21.1%, respectively). Based on these results, VMAT may be used in external-beam radiotherapy for early-stage cervical cancer by adopting the principle of central-shielding pelvis irradiation. Furthermore, VMAT is likely to reduce doses to the small bowel and may reduce gastrointestinal toxicities for these patients.

Incidence of organizing pneumonia after whole-breast radiotherapy for breast cancer, and risk factor analysis.

Radiation-induced organizing pneumonia (OP) reportedly occurs in ~2% of patients who receive whole-breast radiotherapy (WBRT). Though there are several reported risk factors, they remain unclear and controversial. We analyzed the incidence of and risk factors for OP after WBRT at our institution. We analyzed 665 breast cancer patients (with WBRT of 679 breasts) who underwent WBRT from October 2007 to September 2012 at our institution and were followed up for more than 1 year after completion of WBRT. Factors included in the analysis were age, the side affected, central lung distance (CLD), radiation dose, concurrent endocrine therapy, and chemotherapy. The median age was 56 years (range, 23-89 years). The sides affected were left, right and bilateral in 342, 309 and 14 patients, respectively. The median CLD was 1.1 cm (range, 0-3.0 cm). Concurrent endocrine therapy was performed in 236 patients, and chemotherapy was given in 215 patients; of these, 4 received concurrent chemotherapy. OP developed in nine patients (1.4%). The median time taken to develop OP after the completion of WBRT was 4 months (range, 2-12 months). All nine patients were treated with steroids, and symptoms promptly improved, except in two patients who relapsed. Statistical analysis revealed that only CLD (≥1.5 cm) was significantly associated with the development of OP (P = 0.004). In conclusion, the incidence of OP after WBRT was 1.4%, and CLD was a significant risk factor. In these patients, OP was controlled with steroid administration.

Phase I Study of Carbon Ion Radiotherapy and Image-Guided Brachytherapy for Locally Advanced Cervical Cancer.

A phase I study was performed to determine the recommended dose of carbon ion radiotherapy and 3D image-guided brachytherapy for histologically confirmed stage II (≥4 cm), III, or IVA cervical cancer. Dose-limiting toxicities (treatment-related toxicities occurring within three months from the start of carbon ion radiotherapy) included Grade 3 non-hematological toxicity, Grade 4 hematological toxicity, or interruption of treatment for more than two weeks due to treatment-related toxicities. Carbon ion radiotherapy consisted of whole-pelvic irradiation with 36.0 Gy (relative biological effectiveness) in 12 fractions and local boost with 19.2 Gy in four fractions for the primary site, and for positive lymph nodes. Three sessions of three-dimensional (3D) image-guided brachytherapy were administered after completion of carbon ion radiotherapy. Weekly cisplatin at a dose of 40 mg/m² was given concurrently. At a dose level of one, a total rectosigmoid D2cc dose between 67.2 Gy and 71.3 Gy at a biological equivalent dose of 2 Gy per fraction from carbon ion radiotherapy and 3D image-guided brachytherapy was prescribed. Six patients were enrolled into this dose level. No patients developed the pre-defined dose-limiting toxicities. For late toxicities, however, one patient developed Grade 3 rectal hemorrhage requiring transfusion at 10 months after treatment. The median survival time was 50.0 months for the five surviving patients. No further dose escalation was performed, and we determined the dose of level one as the recommended rectosigmoid dose. Although our results are preliminary, the study regimen encourages further investigation (registration: UMIN000013340).

Combination Therapy of Intravenously Injected Microglia and Radiation Therapy Prolongs Survival in a Rat Model of Spontaneous Malignant Glioma.

PURPOSE: The aim of this study was to investigate the efficacy of combination therapy with intravenously injected microglia (MI) and radiation therapy (RT) for malignant glioma in rats. METHODS AND MATERIALS: Transgenic rats expressing v-erbB and spontaneously developing malignant glioma were used. The rats were divided into 4 groups: control (n = 19), RT alone (n = 10), MI alone (n = 9), and combination MI and RT (MI + RT) (n = 10). Cranial x-ray irradiation (8 Gy per fraction; once per week) was performed at 50 and 51 weeks of age. Cultured rat microglial cells (5 × 106 cells/rat) were intravenously injected via the tail vein within 30 minutes after RT. RESULTS: No evidence of side effects, including thrombosis or graft-versus-host disease, was noted. Rats treated with RT alone, MI alone, MI + RT, and control survived 60.9, 56.3, 66.0, and 56.1 weeks, respectively. The survival period of MI + RT was significantly longer than that of control (P = .014), MI alone (P = .027), and RT alone (P = .049). Immunohistochemical analysis showed a significantly higher number of tumor-infiltrated MI in the RT alone (P = .041) and MI + RT groups (P = .014) compared with the control. Significantly more CD8-positive lymphocytes were observed in the MI + RT group (P = .049) compared with the control. A positive correlation was found between the number of MI and CD8-positive lymphocytes (R2 = 0.556). A positive correlation was also found between CD8-positive lymphocytes and survival periods (R2 = 0.460). CONCLUSIONS: MI + RT increased infiltrated MI and CD8-positive T cells and prolonged survival in transgenic rats that spontaneously developed malignant glioma. Combined immunocellular therapy and RT may provide a novel treatment strategy for malignant glioma.