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Objective To elucidate tumor mutation profiles associated with outcomes of uterine cervical cancer (UCC) patients treated with definitive radiotherapy. Methods Ninety-eight patients with newly diagnosed and pathologically confirmed UCC (82 squamous cell carcinomas, 12 adenocarcinomas, and four adenosquamous carcinomas) who were treated with definitive radiotherapy were analyzed. DNA was extracted from pre-treatment tumor biopsy specimens. The exons of 409 cancer-related genes were sequenced using a next-generation sequencer. Genetic mutations were identified and analyzed for correlations with clinical outcome. Results Recurrent mutations were observed in PIK3CA (35.7%), ARID1A (25.5%), NOTCH1 (19.4%), FGFR3 (16.3%), FBXW7 (19.4%), TP53 (13.3%), EP300 (12.2%), and FGFR4 (10.2%). The prevalence of mutations in FGFR family genes (i.e., FGFR1–4) was almost as high (24.5%) as that in PIK3CA and ARID1A, both of which are well-studied drivers of UCC. Fifty-five percent (21 of 38) of the identified FGFR mutations were located in the FGFR protein tyrosine kinase domain. Five-year progression-free survival (PFS) rates for FGFR mutation-positive patients (n = 24) were significantly worse than those for FGFR mutation-negative patients (n = 74) (43.9% vs. 68.5%, respectively; P = 0.010). Multivariate analysis identified FGFR mutations as significant predictors of worse 5 year PFS (P = 0.005), independent of clinicopathological variables. Conclusions FGFR mutations are associated with worse PFS in UCC patients treated with definitive radiotherapy. These results warrant further validation in prospective studies.

Little information is available on the risk factors for nasolacrimal duct obstruction after radiotherapy for head and neck tumors. We investigated the incidence and predictive dosimetric parameters for nasolacrimal duct obstruction following carbon-ion radiotherapy for head and neck tumors.Twenty-eight patients with head and neck non-squamous cell carcinoma were analyzed in this single-institution prospective study. More than half of the tumors were located in the nasal cavity and maxillary sinus. Carbon-ion radiotherapy consisting of 57.6 or 64.0 Gy(relative biological effectiveness; RBE) in 16 fractions was administered. Nasolacrimal duct obstruction was recorded according to Common Terminology Criteria for Adverse Events version 4.0. Cutoff values were determined using receiver operating characteristic (ROC) curve analysis. VX indicates the volume irradiated with X Gy(RBE).The median follow-up period was 60.3 months. Incidences of Grade 1 and 2 nasolacrimal duct obstructions were 46% (13/28) and 7% (2/28), respectively; no Grade 3 or greater toxicities were recorded. Throughout the dose range, the volumes of the irradiated nasolacrimal ducts were significantly higher in the obstruction-positive patients than in the obstruction-negative patients (p 0.001 for V10, V20, V30, V40, V50, and V60). Cutoff values determined by the ROC curve analysis classified the obstruction-positive patients with an accuracy of96% over the entire range of V10-V60.The incidence and predictive dosimetric parameters for nasolacrimal duct obstruction after carbon-ion radiotherapy were demonstrated in a prospective cohort. These data should help optimize carbon-ion radiotherapy treatments for patients with head and neck tumors.

Background and purpose Integrated analysis of existing radiosensitivity data obtained by the gold-standard clonogenic assay has the potential to improve our understanding of cancer cell radioresistance. However, extraction of radiosensitivity data from the literature is highly labor-intensive. To aid in this task, using deep convolutional neural networks (CNNs) and other computer technologies, we developed an analysis pipeline that extracts radiosensitivity data derived from clonogenic assays from the literature. Materials and methods Three classifiers (C1–3) were developed to identify publications containing radiosensitivity data derived from clonogenic assays. C1 uses Faster Regions CNN with Inception Resnet v2 (fRCNN-IRv2), VGG-16, and Optical Character Recognition (OCR) to identify publications that contain semi-logarithmic graphs showing radiosensitivity data derived from clonogenic assays. C2 uses fRCNN-IRv2 and OCR to identify publications that contain bar graphs showing radiosensitivity data derived from clonogenic assays. C3 is a program that identifies publications containing keywords related to radiosensitivity data derived from clonogenic assays. A program (iSF2) was developed using Mask RCNN and OCR to extract surviving fraction after 2-Gy irradiation (SF2) as assessed by clonogenic assays, presented in semi-logarithmic graphs. The efficacy of C1–3 and iSF2 was tested using seven datasets (1805 and 222 publications in total, respectively). Results C1–3 yielded sensitivity of 91.2% ± 3.4% and specificity of 90.7% ± 3.6%. iSF2 returned SF2 values that were within 2.9% ± 2.6% of the SF2 values determined by radiation oncologists. Conclusion Our analysis pipeline is potentially useful to acquire radiosensitivity data derived from clonogenic assays from the literature.

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.

Programmed cell death-1 (PD-1) and its ligand (programmed death-ligand 1, PD-L1) are key factors that regulate a cytotoxic immune reaction. Anti-PD-1 therapy provides significant clinical benefits for patients with cancer, even those with advanced-stage cancer. We have recently demonstrated that DNA damage signaling from DNA double-strand breaks (DSBs) promotes PD-L1 upregulation in cancer cells. In the present study, we aimed to investigate PD-L1 expression in primary normal human dermal fibroblasts (NHDFs) in response to DSBs. We demonstrated that PD-L1 expression in NHDFs is not upregulated after ionizing radiation (IR). In addition, interferon (IFN) regulatory factor 1 (IRF1) and signal transducer and activator of transcription 1 (STAT1) phosphorylation do not respond in NHDFs after IR. In contrast, IFNγ treatment upregulates PD-L1 and IRF1 expressions and STAT1 phosphorylation. The nonresponsiveness was also observed after treatment with other DNA-damaging agents, such as camptothecin and etoposide. Treatment with a histone deacetylase inhibitor (HDACi), which causes chromatin relaxation and restores gene silencing, upregulates PD-L1 without exogenous DNA damage; however, IR-dependent upregulation is not observed in NHDFs treated with HDACi. Taken together, our data suggest that DNA-damage signaling is insufficient for upregulating PD-L1 in NHDFs.

Creatine riboside (CR) is a novel metabolite of cancer metabolism. It is a urinary diagnostic biomarker of lung and liver cancer risk and prognosis. The level of CR is highly positive correlated in tumor and urine indicating that it is derived from human lung and liver cancers. A precise and sensitive ultra-pressure liquid chromatography-tandem mass spectrometry (UPLC-ESI-MS/MS) method was developed and validated for simultaneous quantification of the noninvasive biomarker CR, along with creatinine riboside (CNR), and their precursors creatine and creatinine, utilizing the labeled internal standard creatine riboside-(13)C,(15)N(2) (CR-(13)C,(15)N(2)). Chromatography was carried out on a hydrophilic interaction chromatography column under a gradient mobile phase condition. MRM transitions were monitored for CR (264.1 > 132.1, m/z), CNR (246.1 > 113.9, m/z), creatine (132.0 > 72.0, m/z), creatinine (114.0 > 85.8, m/z) and CR-(13)C,(15)N(2) (267.1 > 134.9, m/z) with a 11.0 min run time in the positive mode ionization. The calibration plot of the method was linear over the concentration range of 4.50–10,000 nM. Method validation was performed according to regulatory guidelines established for sensitivity, selectivity, calibration curve, stability at different storage conditions, reinjection reproducibility, ruggedness with acceptable accuracy, and precision. This assay was applied for the quantification of CR along with CNR, creatine and creatinine in a subset of urine and serum samples from the National Cancer Institute – Maryland (NCI-MD) cohort population controls and lung cancer cases. It can be standardized and used in multiple laboratories for cancer diagnosis and determining the efficacy of cancer therapy and monitoring cancer recurrence.