UNASSIGNED: Radiotherapy (RT) can be used to reduce symptoms and maintain open airways for patients with non-small cell lung cancer when systemic treatment is not sufficient. For some patients, tumor control is not achieved due to radioresistance. Concurrent inhibition of epidermal growth factor receptors has been proposed as a strategy to overcome radioresistance but may increase toxicity. We performed a randomized trial to assess the efficacy, tolerance, and quality of life of concurrent erlotinib and palliative thoracic RT for patients with advanced non-small cell lung cancer.
UNASSIGNED: Patients were randomized 1:1 to RT alone (arm A) or in combination with erlotinib (arm B). A computed tomography (CT) scan at baseline and one at 4-12 weeks after inclusion was used to evaluate treatment response. Adverse events were registered during treatment and the subsequent 30 days. Health-related quality-of-life questionnaires were completed by the patients at baseline, weeks 2, 6, and 20.
UNASSIGNED: A total of 114 patients were included. Of the 74 patients with CT scans available for evaluation of treatment effect, there were no significant differences in tumor size reduction between the two groups: median 14.5% reduction in the control arm A and 17.0% in the erlotinib arm B (p = 0.68). Overall survival was not significantly different between the two treatment arms: 7.0 and 7.8 months in arm A and arm B, respectively (log-rank p = 0.32). There was no significant increase in adverse events in the experimental arm, other than what is expected from erlotinib treatment alone. Overall, patients reported similar quality of life in both treatment arms.
UNASSIGNED: Concurrent erlotinib and palliative thoracic RT for patients with advanced non-small cell lung cancer was well tolerated but did not improve the efficacy of the RT.
UNASSIGNED: ClinicalTrials.gov, identifier NCT02714530.

UNASSIGNED: Patients with failure after primary radiotherapy (RT) for head and neck squamous cell carcinoma (HNSCC) have a poor prognosis. This study investigates pattern of failure after primary curatively intended IMRT in a randomized controlled trial in relation to HPV/p16 status.
UNASSIGNED: Patients with HNSCC of the oral cavity, oropharynx (OPSCC), hypopharynx or larynx were treated with primary curative IMRT (+/-cisplatin) and concomitant nimorazole between 2007 and 12. Of 608 patients, 151 had loco-regional failure within five years, from whom 130 pairs of scans (planning-CT and diagnostic failure scan) were collected and deformably co-registered. Point of origin-based pattern of failure analysis was conducted, including distance to CTV1 and GTV, and estimated dose coverage of the point of origin.
UNASSIGNED: Of 130 patients with pairs of scans, 104 (80 %) had at least one local or regional failure site covered by 95 % of prescribed dose and 87 (67 %) of the failures had point of origin within the high-dose CTV (CTV1). Of failures from primary p16 + OPSCC, the majority of both mucosal (84 %) and nodal (61 %) failures were covered by curative doses. For p16- tumors (oral cavity, OPSCC p16neg, hypopharynx and larynx), 75 % of mucosal and 66 % of nodal failures were high-dose failures.
UNASSIGNED: Radioresistance is the primary cause of failure after RT for HNSCC irrespective of HPV/p16 status. Thus, focus on predictors for the response to RT is warranted to identify patients with higher risk of high-dose failure that might benefit from intensified treatment regimens.

Tumor hypoxia is associated with resistance to radiotherapy and chemotherapy. In head and neck squamous cell carcinoma (HNSCC), nimorazole, an oxygen mimic, combined with radiotherapy (RT) enabled to improve loco-regional control (LRC) in some patients with hypoxic tumors but it is unknown whether this holds also for radiochemotherapy (RCTx). Here, we investigated the impact of nimorazole combined with RCTx in HNSCC xenografts and explored molecular biomarkers for its targeted use.
Irradiations were performed with 30 fractions in 6 weeks combined with weekly cisplatin. Nimorazole was applied before each fraction, beginning with the first or after ten fractions. Effect of RCTx with or without addition of nimorazole was quantified as permanent local control after irradiation. For histological evaluation and targeted gene expression analysis, tumors were excised untreated or after ten fractions. Using quantitative image analysis, micromilieu parameters were determined.
Nimorazole combined with RCTx significantly improved permanent local control in two tumor models, and showed a potential improvement in two additional models. In these four models, pimonidazole hypoxic volume (pHV) was significantly reduced after ten fractions of RCTx alone. Our results suggest that nimorazole combined with RCTx might improve TCR compared to RCTx alone if hypoxia is decreased during the course of RCTx but further experiments are warranted to verify this association. Differential gene expression analysis revealed 12 genes as potential for RCTx response. When evaluated in patients with HNSCC who were treated with primary RCTx, these genes were predictive for LRC.
Nimorazole combined with RCTx improved local tumor control in some but not in all HNSCC xenografts. We identified prognostic biomarkers with the potential for translation to patients with HNSCC.

Aerobic glycolysis is a metabolic mode of tumor cells different from normal cells that plays an important role in tumor proliferation and distant metastasis. Radiotherapy has now become a routine and effective treatment for many malignancies, however, resistance to radiotherapy remains a major challenge in the treatment of malignant tumors. Recent studies have found that the abnormal activity of the aerobic glycolysis process in tumor cells is most likely involved in regulating chemoresistance and radiation therapy resistance in malignant tumors. However, research on the functions and mechanisms of aerobic glycolysis in the molecular mechanisms of resistance to radiotherapy in malignant tumors is still in its early stages. This review collects recent studies on the effects of aerobic glycolysis and radiation therapy resistance in malignant tumors, to further understand the progress in this area. This research may more effectively guide the clinical development of more powerful treatment plans for radiation therapy resistant subtypes of cancer patients, and take an important step to improve the disease control rate of radiation therapy resistant subtypes of cancer patients.

Solid tumours may present hypoxic sub-regions of increased radioresistance. Hypoxia quantification requires of clinically implementable, non-invasive and reproducible techniques as positron emission tomography (PET). PET-based dose painting strategies aiming at targeting those sub-regions may be limited by the resolution gap between the PET imaging resolution and the smaller scale at which hypoxia occurs. The ultimate benefit of the usage of dose painting may be reached if the planned dose distribution can be performed and delivered consistently. This study aimed at assessing the feasibility of two PET-based dose painting strategies using two beam qualities (photon or proton beams) in terms of tumour control probability (TCP), accounting for underlying oxygen distribution at sub-millimetre scale.A tumour oxygenation model at submillimetre scale was created consisting of three regions with different oxygen partial pressure distributions, being hypoxia decreasing from core to periphery. A published relationship between uptake and oxygen partial pressure was used and a PET image of the tumour was simulated. The fundamental effects that limit the PET camera resolution were considered by processing the uptake distribution with a Gaussian 3D filter and re-binning to a PET image voxel size of 2 mm. Prescription doses to overcome tumour hypoxia were calculated based on the processed images, and planned using robust optimisation.Normal tissue complication probabilities and TCPs after the delivery of the planned doses were calculated for the nominal plan and the lowest bounds of the dose volume histograms resulting from the robust scenarios planned, taking into account the underlying oxygenation at submillimetre scale. Results were presented for the two beam qualities and the two dose painting strategies: by contours (DPBC) and by using a voxel grouping-based approach (DPBOX).In the studied case, DPBOX outperforms DPBC with respect to TCP regardless the beam quality, although both dose painting strategy plans demonstrated robust target coverage.

Mesenchymal glioblastoma stem cells (GSCs), a subpopulation in glioblastoma that are responsible for therapy resistance and tumor spreading in the brain, reportedly upregulate aldehyde dehydrogenase isoform-1A3 (ALDH1A3) which can be inhibited by disulfiram (DSF), an FDA-approved drug formerly prescribed in alcohol use disorder. Reportedly, DSF in combination with Cu2+ ions exerts multiple tumoricidal, chemo- and radio-therapy-sensitizing effects in several tumor entities. The present study aimed to quantify these DSF effects in glioblastoma stem cells in vitro, regarding dependence on ALDH1A3 expression. To this end, two patient-derived GSC cultures with differing ALDH1A3 expression were pretreated (in the presence of CuSO4, 100 nM) with DSF (0 or 100 nM) and the DNA-alkylating agent temozolomide (0 or 30 µM) and then cells were irradiated with a single dose of 0-8 Gy. As read-outs, cell cycle distribution and clonogenic survival were determined by flow cytometry and limited dilution assay, respectively. As a result, DSF modulated cell cycle distribution in both GSC cultures and dramatically decreased clonogenic survival independently of ALDH1A3 expression. This effect was additive to the impairment of clonogenic survival by radiation, but not associated with radiosensitization. Of note, cotreatment with temozolomide blunted the DSF inhibition of clonogenic survival. In conclusion, DSF targets GSCs independent of ALDH1A3 expression, suggesting a therapeutic efficacy also in glioblastomas with low mesenchymal GSC populations. As temozolomide somehow antagonized the DSF effects, strategies for future combination of DSF with the adjuvant standard therapy (fractionated radiotherapy and concomitant temozolomide chemotherapy followed by temozolomide maintenance therapy) are not supported by the present study.

UNASSIGNED: To examine the impact of epidermal growth factor receptor (EGFR) mutations on objective response to palliative lung radiotherapy in patients with metastatic non-small cell lung cancer (NSCLC).
UNASSIGNED: A multicentre retrospective study was conducted of patients with metastatic NSCLC diagnosed between March 2010 and June 2012 who received palliative radiotherapy to the chest. Patients included for study had baseline imaging and follow-up imaging 1-3 months after radiotherapy. The primary endpoint was 1-3 month local objective imaging response by the Response Evaluation Criteria in Solid Tumours (RECIST). Patients were divided into EGFR mutation positive (EGFR+) and EGFR wild type (WT) cohorts for analysis.
UNASSIGNED: There were 121 patients for study inclusion: 89 (74%) were EGFR WT and 32 (26%) were EGFR+. The response rate between EGFR WT and EGFR+ cohorts was not significantly different (49 vs. 63%, p = 0.21). On multivariate analysis, initiation of a tyrosine kinase inhibitor (TKI) after radiotherapy was associated with a higher rate of response (OR: 5.07, 95%CI: 1.08-23.69, p = 0.039) but EGFR mutation status was not. For the EGFR+ cohort, patients with disease progression after initial management on a TKI had a worse response rate compared to patients who were TKI-naïve before starting radiotherapy (30 vs. 77%, p = 0.018). Local control was not statistically different between the EGFR cohorts.
UNASSIGNED: The EGFR mutation status alone was not an independent predictor of objective radiographic response to palliative thoracic radiotherapy. Acquired resistance to TKI therapy may be associated with disease cross-resistance to palliative radiotherapy.

Background: For atypical meningiomas (AMs), the combination of gross total resection (GTR) and adjuvant radiotherapy (ART) is still a controversial therapeutic strategy to improve prognosis. This study analyzed the factors influencing the prognosis on AM patients treated with GTR + ART by investigating both clinical characteristics and the change in microRNA (miRNA) expression. Materials and Methods: Adult AM patients who were admitted to the Tiantan hospital from 2008 to 2015 and underwent GTR + ART were included. Patients who suffered recurrence within 3 years after operation were considered radioresistant, while the others were considered radiosensitive. Clinical characterizations were compared between these two groups. The microRNA (miRNA) expression was detected via miRNA microarray in 10 patients, five from the radiosensitive group and from the radioresistant group. Results: A total of 55 cases were included in this study. No significant difference was found in the clinical characteristics (gender, age, tumor location, tumor size, peritumoral brain edema, and Ki-67 index) between radiosensitive and radioresistant patients. We found seven significantly upregulated miRNAs (miR-4286, miR-4695-5p, miR-6732-5p, miR-6855-5p, miR-7977, miR-6765-3p, miR-6787-5p) and seven significantly downregulated miRNAs (miR-1275, miR-30c-1-3p, miR-4449, miR-4539, miR-4684-3p, miR-6129, miR-6891-5p) in patients resistant to radiotherapy. The differentially expressed miRNAs were enriched mostly in the fatty acid metabolic pathways (hsa00061, hsa01212) and transforming growth factor beta signaling pathway (hsa04350). Conclusion: For AM patients treated with GTR + ART, the changes in miRNA expression discovered in this study may be a potential predictor of individual sensitivity to adjuvant radiotherapy. Further research is needed regarding the predictive power and mechanism by which these miRNAs influence prognosis.

Introduction: Radiotherapy, combined regimens as platinum-paclitaxel chemotherapy and/or endocrine therapy is an important adjuvant treatment after surgery for endometrial cancer (EC). While, the resistance to them remain unclear. In our study, to separate the characteristics of side population (SP) cells from EC cell lines, study the mechanism of Taxol-resistance, progestin resistance and radioresistanc, and provide the basic for EC. Methods: SP cells from EC cell lines HEC-1A, Ishikawa and RL95-2 were separated by Hoechst 33342 staining and flow cytometry analysis. The expression of breast cancer resistance protein (BCRP) in SP cells and non-SP cells from HEC-1A was examined by immunocytochemistry, and the radiation-resistant and Taxol-resistant characteristics of SP cells and non-SP cells were compared by MTS. Ishikawa, Ishikawa-SP, and Ishikawa-non-SP cells incubated with MPA were selected for cell apoptosis assays by using flow cytometry. The expression of caspase-3 was examined by immunocytochemistry, and autophagy was detected by MDC staining. Results: Small proportions of SP cells, namely, 1.44 ± 0.93%, 2.86 ± 3.09%, and 2.87 ± 1.29%, were detected in HEC-1A, Ishikawa and RL95-2, respectively. There was a stronger clone formation efficiency for the SP cells than for non-SP cells in HEC-1A [(6.02 ± 1.17) vs. (0.53±0.20)%, P = 0.001], and there was a significant difference in the rate of tumourigenicity between the SP cells and non-SP cells in HEC-1A (87.5 vs. 12.5%). There were higher levels of BCRP expression (P = 0.001) and resistance to Taxol and radiation (P < 0.05) in the SP cells than in non-SP cells. After MPA treatment, the apoptosis rates were significantly different among the Ishikawa, Ishikawa-SP and Ishikawa-non-SP groups [(4.64 ± 0.18)%, (4.01 ± 0.43)%, and (9.3 ± 0.67)%; (P = 0.05)], and the expression of Caspase-3 in the Ishikawa group was higher than that in Ishikawa-SP group. The autophagic activity of the Ishikawa-SP cells was the strongest, while the autophagic activity of Ishikawa-non-SP was the weakest. Conclusions: There is a significant enrichment in SP cells among different EC cell lines, and these SP cells be more resistant to Taxol, MPA and radiation therapy. The overexpression of BCRP among SP cells may be the cause of resistance to Taxol, progestin and radiotherapy, which may be related to apoptosis and autophagic activity.

BACKGROUND: Radiotherapy (RT) combined with a radiosensitizer represents an important treatment for head and neck squamous cell carcinoma (HNSCC). Only few chemotherapy agents are currently approved as radiosensitizers for targeted therapy. In this study, the potent cyclin-dependent kinase 4/6 (CDK4/6) inhibitor LEE011 was tested for potential to act as a radiosensitizer during RT.
METHODS: RT enhancement by LEE011 was assessed by in vitro clonogenic assay, flow cytometry, and western blot in a variety of HNSCC cell lines. The HNSCC cell line OML1 and its radiation-resistant clone OML1-R were used.
RESULTS: LEE011 induced cell-cycle arrest in SCC4/SCC25 cells during the G1/M phase through inhibition of retinoblastoma protein phosphorylation. LEE011 enhanced the effects of radiation in OML1 cells and overcame radiation resistance in OML1-R cells.
CONCLUSIONS: LEE011 is a potential radiosensitizer that can enhance the cytotoxic effects of RT. Clinical trials including LEE011 during RT for HNSCC should be considered.