Mean heart dose-based normal tissue complication probability model for pericardial effusion: a study in oesophageal cancer patients.

We investigated the normal tissue complication probability (NTCP) of the incidence of pericardial effusion (PCE) based on the mean heart dose (MHD) in patients with oesophageal cancer treated with definitive chemoradiotherapy. The incidences of PCE in any grade (A-PCE) and symptomatic PCE (S-PCE) were evaluated separately. To identify predictors for PCE, several clinical and dose-volume parameters were analysed using a receiver operating characteristic (ROC) curve and multivariate regression analysis. To validate its clinical applicability, the generated NTCP model was compared to the Lyman-Kutcher-Burman (LKB) model. Among 229 eligible patients, A-PCE and S-PCE were observed in 100 (43.7%) and 18 (7.9%) patients, respectively. MHD showed a preferable area under the curve (AUC) value for S-PCE (AUC = 0.821) and A-PCE (AUC = 0.734). MHD was the only significant predictor for A-PCE; MHD and hypertension were selected as significant factors for S-PCE. The estimated NTCP, using the MHD-based model, showed excellent correspondence to the LKB model in A-PCE and S-PCE. The NTCP curve of A-PCE was gentler than that of S-PCE and had no threshold. The MHD-based NTCP model was simple but comparable to the LKB model for both A-PCE and S-PCE. Therefore, the estimated NTCP may provide clinically useful parameters for predicting PCE.

Thymoma-associated T-cell immunodeficiency after radiotherapy: A case report.

Acquired immunodeficiency in thymoma (Good's syndrome) without hypogammaglobulinemia is a rare condition. Here we describe the case of a 29-year-old Japanese woman with thymoma-associated T cell immunodeficiency after radiation therapy. She was admitted to the hospital with refractory pneumonia, which resulted from as T cell immunodeficiency, as revealed through low peripheral lymphocytes and oral candidiasis triggered through radiotherapy and required long-term antimicrobial therapy. Although radiotherapy is commonly administered for thymoma, our findings suggest that physicians should consider carrying out lymphocyte counts during thymoma treatment.

2-Nitroimidazoles induce mitochondrial stress and ferroptosis in glioma stem cells residing in a hypoxic niche.

Under hypoxic conditions, nitroimidazoles can replace oxygen as electron acceptors, thereby enhancing the effects of radiation on malignant cells. These compounds also accumulate in hypoxic cells, where they can act as cytotoxins or imaging agents. However, whether these effects apply to cancer stem cells has not been sufficiently explored. Here we show that the 2-nitroimidazole doranidazole potentiates radiation-induced DNA damage in hypoxic glioma stem cells (GSCs) and confers a significant survival benefit in mice harboring GSC-derived tumors in radiotherapy settings. Furthermore, doranidazole and misonidazole, but not metronidazole, manifested radiation-independent cytotoxicity for hypoxic GSCs that was mediated by ferroptosis induced partially through blockade of mitochondrial complexes I and II and resultant metabolic alterations in oxidative stress responses. Doranidazole also limited the growth of GSC-derived subcutaneous tumors and that of tumors in orthotopic brain slices. Our results thus reveal the theranostic potential of 2-nitroimidazoles as ferroptosis inducers that enable targeting GSCs in their hypoxic niche.

Antifungal Agent Luliconazole Inhibits the Growth of Mouse Glioma-initiating Cells in Brain Explants.

Imidazole antifungal compounds exert their antipathogenic effects through inhibition of sterol biosynthesis. These drugs have also recently been identified as candidate anticancer agents for several solid tumors including glioblastoma. However, their effects on glioma-initiating cells (GICs), i.e., glioma cells with stemlike properties that are able to initiate tumors, remain unclear. Consequently, we examined the effects of the optically active imidazole compound luliconazole on mouse GICs and GIC-based tumors. Luliconazole impaired in a concentration-dependent manner the growth of spheres formed by GICs in vitro. In contrast to the inhibitory effects of ionizing radiation and temozolomide on sphere growth, that of luliconazole was attenuated by the addition of exogenous cholesterol. Exposure to luliconazole of brain slices derived from mice with orthotopic GIC implants for 4 days in culture resulted in a marked increase in the number of tumor cells positive for cleaved caspase-3, but without a similar effect on normal cells. Furthermore, in brain slices, luliconazole inhibited the expansion of GIC-based tumors and the parenchymal infiltration of tumor cells. Our findings therefore indicate that luliconazole effectively targets GICs, thereby providing further support for the antitumorigenic effects of imidazole antifungal compounds.

Vasodilator oxyfedrine inhibits aldehyde metabolism and thereby sensitizes cancer cells to xCT-targeted therapy.

The major cellular antioxidant glutathione (GSH) protects cancer cells from oxidative damage that can lead to the induction of ferroptosis, an iron-dependent form of cell death triggered by the aberrant accumulation of lipid peroxides. Inhibitors of the cystine-glutamate antiporter subunit xCT, which mediates the uptake of extracellular cystine and thereby promotes GSH synthesis, are thus potential anticancer agents. However, the efficacy of xCT-targeted therapy has been found to be diminished by metabolic reprogramming that affects redox status in cancer cells. Identification of drugs for combination with xCT inhibitors that are able to overcome resistance to xCT-targeted therapy might thus provide the basis for effective cancer treatment. We have now identified the vasodilator oxyfedrine (OXY) as a sensitizer of cancer cells to GSH-depleting agents including the xCT inhibitor sulfasalazine (SSZ). Oxyfedrine contains a structural motif required for covalent inhibition of aldehyde dehydrogenase (ALDH) enzymes, and combined treatment with OXY and SSZ was found to induce accumulation of the cytotoxic aldehyde 4-hydroxynonenal and cell death in SSZ-resistant cancer cells both in vitro and in vivo. Microarray analysis of tumor xenograft tissue showed cyclooxygenase-2 expression as a potential biomarker for the efficacy of such combination therapy. Furthermore, OXY-mediated ALDH inhibition was found to sensitize cancer cells to GSH depletion induced by radiation therapy in vitro. Our findings thus establish a rationale for repurposing of OXY as a sensitizing drug for cancer treatment with agents that induce GSH depletion.

Influence of Backscatter Radiation on Cranial Bone Fixation Devices.

Postoperative radiation can cause ulcer formation, leading to the denudation of skin over alloplastic materials. The influence of backscatter radiation from fixation devices has not been investigated. The aim of this study is to evaluate backscatter dose variations for different cranial bone fixation devices in an experimental model designed to simulate postoperative radiotherapy. The authors assessed the radiation backscatter doses associated with resorbable (PLLA-PGA) and titanium plates. The samples were irradiated with 6 and 10 MV photon beams from a linear accelerator. Measurements were obtained using an ionization chamber and radiochromic films cut from the same batch. As a result, the backscatter radiation of water and PLLA-PGA proportionally decreased as the depth increased. However, the backscatter radiation of the titanium plate increased just above the plate. This depth lies in the region of the scalp. Each material showed a dose of radioactivity that was higher at 10 MV than that at 6 MV. These devices showed a significant difference, which suggested that these materials amplified the dose compared with water at 6 MV. In conclusion, it is supposed that PLLA-PGA should be used to fix the cranium to decrease the potential for radiation ulcers.

Metabolic heterogeneity and plasticity of glioma stem cells in a mouse glioblastoma model.

Background: Glioblastomas have been shown to rely on glycolysis as an energy source. However, recent evidence suggests that at least a subset of glioma cells with stem cell-like properties can thrive on oxidative phosphorylation. It remains unclear whether both metabolic phenotypes support tumor propagation, if they are independent, and how stable they are. The present study investigated these questions with the use of isogenic murine glioma stem cells (GSCs). Methods: GSCs were established from tumors formed by Ink4a/Arf-null, H-RasV12-expressing glioma-initiating cells that differed in extracellular acidification potential. Metabolic characteristics of GSCs were determined by measurement of glucose, oxygen, and glutamine uptake, ATP content, and lactate production. Effects of metabolic inhibitors and changes in oxygen or nutrient availability on lactate production and tumorsphere growth were also determined. Results: GSCs were found either to consume more glucose and produce more lactate or to consume more oxygen and maintain a higher ATP content depending on the metabolic characteristics of the tumor cells of origin. The latter, mitochondrial-type GSCs increased lactate production after treatment with the oxidative phosphorylation inhibitor oligomycin or phenformin. Exposure to hypoxia also increased lactate production and expression of glycolysis-related enzymes and metabolites in mitochondrial-type GSCs in a reversible manner. Conclusions: Both glycolytic and mitochondrial-type energy production can sustain tumor propagation by isogenic GSCs. Whereas both phenotypes can be independent and stable, cells that rely on oxidative phosphorylation can also switch to a more glycolytic phenotype in response to metabolic stress, suggesting that plasticity is a further characteristic of GSC metabolism.

Influence of backscatter radiation on cranial reconstruction implants.

OBJECTIVE: We aimed to evaluate backscatter dose variations in different cranial bone implant materials in an experimental model designed to simulate post-operative radiotherapy. METHODS: We assessed the radiation backscatter doses associated with sheet- and mesh-type titanium plates and hydroxyapatite (HAP) samples (porosity: 35%, 50% and 85%). The samples were irradiated with 6- and 10-MV photon beams from a linear accelerator. Measurements were obtained using an ionization chamber and radiochromic films cut from the same batch. RESULTS: At 6 MV, the titanium sheet showed the highest peak for backscattered radiation, followed by (in decreasing order) HAP30%, HAP50%, titanium mesh and HAP85%. At 10 MV, HAP30% showed the highest peak, followed by HAP50%, titanium sheet, titanium mesh and HAP85%. The peaks were at different depths in the titanium and HAP samples. The thickness of the human scalp is approximately 7 mm; therefore, measurements were obtained 0-7 mm above the implants to assess the likely dose on the scalp. A comparison of the maximum dose on the scalp showed the titanium sheet had the highest dose at both 6 and 10 MV. CONCLUSION: The backscatter dose differed with the density of the material and the backscatter depth was different for each material. Advances in knowledge: Ulcer formation due to radiotherapy after brain tumour depends on not only radiation but also the implant material. Therefore, the density and type of implant material should be considered when planning radiotherapy and selecting bone reconstruction materials.

Dose volume histogram analysis of focal liver reaction in follow-up multiphasic CT following stereotactic body radiotherapy for small hepatocellular carcinoma.

PURPOSE: To investigate threshold dose (TD) of focal liver reaction (FLR) following stereotactic body radiotherapy (SBRT) for patients with hepatocellular carcinoma (HCC) and liver cirrhosis. MATERIALS AND METHODS: In consecutive 50 patients receiving SBRT for small HCC, 38 patients receiving SBRT and follow up >6 months, FLR on follow-up CT had been previously studied. Patients with good concordance between FLR and highly irradiated area were eligible. Dose volume histogram (DVH) was used to identify TDs for FLR. Clinical factors were analyzed for correlation with TDs. RESULTS: Of 24 eligible patients, 23 had Child-Pugh score A and 1 scored B. Presence of FLR peaked at a median of 6 (range; 3-12) months. The median and 95% confidential intervals of TDs of pre-contrast and portal-venous phase CT were 32.4 Gy (30.3-35.4) and 34.4 Gy (31.9-36.0), respectively. Each median coefficient representing the concordance was 74.9% (range; 55.8-98.0%) and 80.5% (range; 70.8-92.4%), respectively. No clinical factors significantly correlated with the TDs. CONCLUSION: We proposed 30 Gy/5 fractions as TD of FLRs following SBRT for patients with HCC and liver cirrhosis. This TD will enable us to predict injured liver volume and to avoid complication beforehand from toxicity. Further pathological and clinical studies, in addition to more practical and precise data of DVH, are needed to clarify the significance of FLRs.

The maximum standardized uptake value (SUVmax) on FDG-PET is a strong predictor of local recurrence for localized non-small-cell lung cancer after stereotactic body radiotherapy (SBRT).

BACKGROUND: The maximum standardized uptake value (SUVmax) of FDG-PET may predict local recurrence for localized non-small-cell lung cancer (NSCLC) after stereotactic body radiotherapy (SBRT). METHODS: Among 195 localized NSCLCs that were treated with total doses of either 40Gy or 50Gy in 5 SBRT fractions, we reviewed those patients who underwent pre-treatment FDG-PET using a single scanner for staging. Local control rates (LCRs) were obtained by the Kaplan-Meier method and a log-rank test. Prognostic significance was assessed by univariate and multivariate analyses. RESULTS: A total of 95 patients with 97 lesions were eligible. Median follow-up was 16.0months (range: 6.0-46.3months). Local recurrences occurred in 9 lesions. By multivariate analysis, only the SUVmax of a primary tumor was a significant predictor (p=0.002). Two years LCRs for lower SUVmax (<6.0; n=78) and higher SUVmax (⩾6; n=19) were 93% and 42%, respectively. In subgroups with T1b and T2, LCRs were significantly better for lower SUVmax than for higher SUVmax (p<0.0005 and p<0.01). In both subgroups that received 40Gy and 50Gy, LCRs were also significantly better for lower SUVmax than for higher SUVmax (p<0.001 and p<0.01). CONCLUSIONS: SUVmax was the strongest predictor for local recurrence. A high SUVmax may be considered for dose escalation to improve local control. Additional follow-up is needed to determine if SUVmax is correlated with regional recurrence, distant metastasis, and survival.

Stereotactic body radiotherapy (SBRT) for oligometastatic lung tumors from colorectal cancer and other primary cancers in comparison with primary lung cancer.

PURPOSE: To analyze local control of oligometastatic lung tumors (OLTs) compared with that of primary lung cancer after stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: Retrospective record review of patients with OLTs who received SBRT with 50Gy in 5 fractions. Local control rates (LCRs), toxicities, and factors of prognostic significance were assessed. RESULTS: Twenty-one colorectal OLTs, 23 OLTs from other origins, and 188 primary lung cancers were included. Multivariate analysis revealed only tumor origin was prognostically significant (p<0.05). The 1-year/2-year LCRs in colorectal OLTs and OLTs from other origins were 80%/72% and 94%/94%, respectively. The LCR in colorectal OLTs was significantly worse than that in OLTs from the other origins and primary lung cancers with pathological and clinical diagnosis (p<0.05, p<0.0001 and p<0.005). Among 44 OLT patients, Grades 2 and 3 radiation pneumonitis were identified in 2 and 1 patients, respectively. No other toxicities of more than Grade 3 occurred. CONCLUSION: SBRT for OLTs is tolerable. The LCR for OLTs from origins other than colorectal cancer is excellent. However, LCR for colorectal OLTs is worse than that from other origins. Therefore dose escalation should be considered to achieve good local control for colorectal OLTs.