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Copper (Cu) is an essential trace element whose serum levels have been reported to act as an effective indicator of the efficacy of radiotherapy. However, little is known about the role of Cu in radiotherapy. In this study we aimed to determine this role and investigate the precise mechanism by which Cu or Cu-related proteins regulate the radiosensitivity of hepatocellular carcinoma (HCC).The expression and function of Cu and copper metabolism MURR1 domain 10 (COMMD10) were assessed via a Cu detection assay, immunostaining, real-time PCR, western blot, a radiation clonogenic assay and a 5-ethynyl-2'-deoxyuridine assay. Ferroptosis was determined by detecting glutathione, lipid peroxidation, malondialdehyde and ferrous ion (Fe) levels. The in vivo effects of Cu and COMMD10 were examined with Cu/Cu chelator treatment or lentivirus modification of COMMD10 expression in radiated mouse models.We identified a novel role of Cu in promoting the radioresistance of HCC cells. Ionizing radiation (IR) induced a reduction of COMMD10, which increased intracellular Cu and led to radioresistance of HCC. COMMD10 enhanced ferroptosis and radiosensitivity in vitro and in vivo. Mechanistically, low expression of COMMD10 induced by IR inhibited the ubiquitin degradation of HIF1α (by inducing Cu accumulation) and simultaneously impaired its combination with HIF1α, promoting HIF1α nuclear translocation and the transcription of ceruloplasmin (CP) and SLC7A11, which jointly inhibited ferroptosis in HCC cells. In addition, elevated CP promoted HIF1α expression by reducing Fe, forming a positive feedback loop.COMMD10 inhibits the HIF1α/CP loop to enhance ferroptosis and radiosensitivity by disrupting Cu-Fe homeostasis in HCC. This work provides new targets and treatment strategies for overcoming radioresistance in HCC.Radiotherapy benefits patients with unresectable or advanced hepatocellular carcinoma (HCC), but its effectiveness is hampered by radioresistance. Herein, we uncovered a novel role for copper in promoting the radioresistance of HCCs. This work has revealed new targets and potential treatment strategies that could be used to sensitize HCC to radiotherapy.

Background Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. Currently, there is limited knowledge of dysregulation of cellular proliferation and apoptosis that contribute to the malignant phenotype in HCC. Copper metabolism gene MURR1 domain 10 (COMMD10) is initially identified as a suppressor gene in the pathogenesis of HCC in our observations. Here we aimed to explore its function and prognostic value in the progression of HCC. Methods Functional experiments were performed to explore the role of COMMD10 in HCC. The molecular mechanisms of COMMD10 were determined by luciferase assay, immunofluorescence, and immunoprecipitation. The nomogram was based on a retrospective and multicenter study of 516 patients who were pathologically diagnosed with HCC from three Chinese hospitals. The predictive accuracy and discriminative ability of the nomogram were determined by a C‐index and calibration curve and were compared with COMMD10 and the Barcelona Clinic Liver Cancer (BCLC) staging system. The primary endpoint was overall survival (OS). Results COMMD10 expression was significantly lower in HCC than that in normal liver tissues. In vitro and in vivo experiments revealed that COMMD10 suppressed cell proliferation and induced apoptosis in HCC. Mechanistically, COMMD10 inhibits TNFα mediated ubiquitination of IκBα and p65 nuclear translocation through the combination of COMMD10‐N terminal to the Rel homology domain of p65, which inhibited NF‐κB activity and increased expression of cleaved caspase9/3 in HCC. Clinically, COMMD10 stratifies early‐stage HCC patients into two risk groups with significantly different OS. Additionally, the nomogram based on COMMD10 and BCLC stage yielded more accuracy than BCLC stage alone for predicting OS of HCC patients in three cohorts. Conclusions COMMD10 suppresses proliferation and promotes apoptosis by inhibiting NF‐κB signaling and values up BCLC staging in predicting OS, which provides evidence for the identification of potential therapeutic targets and the accurate prediction of prognosis for patients with HCC., 1. COMMD10 stabilizes IκBα protein by inhibiting ubiquitination and degradation of IκBα. 2. COMMD10 interacts with the Rel homology domain of p65 and suppresses the nuclear translocation of p65. 3. COMMD10/NF‐κB axis promotes apoptosis by modulating Bcl‐2/Bax/caspase‐9/3 pathway in hepatocellular carcinoma.

Rationale Tenosynovial giant cell tumor (TGCT) is a neoplastic, inflammatory disease with a benign but aggressive course that often presents as localized (TGCT-L) and diffuse (TGCT-D) forms based on the growth pattern and clinical behavior. For TGCT-L, simple excision of the diseased synovial tissue is the preferred treatment option, while for TGCT-D, adequate synovectomy is usually tricky but is essential. However, approximately 44% of TGCT-D cases will relapse after surgery alone. Thus, the optimal treatment strategy in patients with TGCT-D is evolving, and standalone surgical resection can no longer be regarded as the only treatment. The previous studies have shown that postoperative adjuvant radiotherapy can reduce recurrence in TGCT, especially in patients with incomplete synovectomy. Patient concerns In the first case, a 54-year-old male presented with recurrent pain and swelling of the right knee with a protracted disease course (≥10 years). The other patient is a 64-year-old male who developed swelling, pain, abnormal bending, and limited movement of the left knee without obvious inducement. Diagnoses Clinical and imaging examinations can provide a definitive diagnosis, and pathology is the gold standard. TGCT-D was confirmed by postoperative pathology. After the operation, the patients underwent an MRI re-examination and showed that the lesions of the knee were not completely resected. Interventions Arthroscopic synovectomy was performed on the patients, and postoperative pathology was confirmed as TGCT-D. Because of incomplete synovectomy, the 2 cases received image-guided, intensity-modulated radiotherapy (IG-IMRT) after the operation. Outcomes The follow-up time was 1 year, no evidence of disease progression was found in MRI. No obvious adverse effects associated with radiotherapy were detected during the follow-up period. Lessons These cases and reviews illustrate the necessity of radiotherapy for TGCT-D and that IG-IMRT is a safe and effective method for treating TGCT-D of the knee.

// Jian Guan 1, * , Yue Zhang 1, * , Qinyang Li 1 , Yaowei Zhang 1 , Lu Li 1 , Min Chen 1 , Nanjie Xiao 1 , Longhua Chen 1 1 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China * These authors have contributed equally to this work Correspondence to: Jian Guan, email: guanjian5461@163.com Longhua Chen, email: chenlh5461@163.com Keywords: cisplatin, head and neck, cancer, therapy, meta-analysis Received: January 11, 2016 Accepted: August 22, 2016 Published: September 02, 2016 ABSTRACT Purpose: This study was performed to compare the efficacies and acute toxicities in weekly- and three weekly- cisplatin based concurrent chemoradiotherapy (CCRT) for advanced HNC patients. Results: 779 patients of 10 studies were eligible. No difference in the 2-, 3-year OS or 1-, 2-year LRFS was observed, whereas patients in three weekly CCRT arm tended to have a better 5-year OS (HR=1.79, 95%C 0.97-3.31, p=0.06). Weekly arm seemed to show less gastrointestinal toxicities (RR=0.59, 95%CI 0.34-1.02, p=0.06), but similar hematologic toxicity compared to three weekly arm. Subgroup analysis displayed more grade ≥3 mucositis (RR=1.72, p=0.01), and more chemotherapy related delay/interrupt (RR=2.68, p

Background: Hepatocellular carcinoma (HCC) patients diagnosed with the same clinic stage by Barcelona Clinic Liver Cancer (BCLC) system show different prognosis due to coexistence of inflammation and tumor heterogeneity. Here, we aimed to seek for inflammation-related molecular biomarkers for accurately predicting diagnosis and prognosis of HCC. Methods: In this multicenter and retrospective analysis, we included 516 patients with HCC from three Chinese hospitals: Nanfang Hospital (Guangzhou, China), Zhujiang Hospital (Guangzhou, China) and Yuebei Hospital (Shaoguan, China). COMMD10 was screened out from inflammation-induced HCC using real-time PCR analysis. Nomogram based on COMMD10 and BCLC stage was established and validated. The predictive accuracy and discriminative ability of the nomogram was determined by concordance index and calibration curve. The primary endpoint was overall survival (OS). In vitro and in vivo assays were performed to investigate the role of COMMD10 in HCC. The potential molecular mechanisms of COMMD10 were determined by luciferase assay, immunofluorescence, immunoprecipitation. Findings: The nomogram based on COMMD10 and BCLC stage yielded more accuracy than BCLC stage alone for predicting OS of HCC patients in multicenter cohorts. COMMD10 can stratify early-stage HCC (BCLC stage 0 and A) patients into two risk groups with significantly different OS. Mechanistically, COMMD10 suppressed proliferation in vitro and in vivo by interacting with Rel homology domain of p65 and potentiating apoptosis by modulating Bcl-2/Bax/caspase-9/3 pathway in HCC. Interpretation: COMMD10 is a powerful prognostic biomarker and values up BCLC staging to predict OS for HCC, especially for identifying early-stage HCC patients who could benefit from individual therapy. Funding Statement: This work was supported by the National Natural Science Foundation of China [NO.81672992,81602685]; the Natural Science Foundation of Guangdong Province [NO. 2017A030313486]. Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: This study was approved by the Ethics Committee of Nanfang Hospital of Southern Medical University, and all participants provided written informed consent prior to surgery. It also conforms to the provisions of the Declaration of Helsinki.

// Jian Guan 1, * , Qinyang Li 1, * , Yue Zhang 1 , Nanjie Xiao 1 , Min Chen 1 , Yaowei Zhang 1 , Lu Li 1 , Longhua Chen 1 1 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China * These authors have contributed equally to this work Correspondence to: Jian Guan, e-mail: guanjian5461@163.com Longhua Chen, e-mail: chenlh5461@163.com Keywords: carboplatin, cisplatin, meta-analysis, head and neck, cancer Received: August 05, 2015 Accepted: January 01, 2016 Published: January 09, 2016 ABSTRACT Purpose: This study was performed to compare the efficacies and toxicities of cisplatin (CDDP)- and carboplatin (CBDCA)-based chemotherapy (CT) in patients with SCCHN. Methods: The search strategy included Pubmed, Science Direct, the Cochrane Library, and the China National Knowledge Internet Web. Statistical analyses were performed using RevMan 5.2. The primary endpoint was overall survival (OS) with secondary endpoints of locoregional control (LRC) and grade≥3 toxicity. Results: Overall, 12 studies and 1165 patients were included. CDDP-based CT significantly improved 5-year OS (HR=0.67, 95% CI, 0.49 to 0.91; P =0.01) compared to the CBDCA group. No difference in the 3-year OS/LRC was observed, but a subgroup analysis showed a better 3-year OS in the CDDP arm for non-nasopharynx carcinoma (non-NPC) SCCHN (HR=0.66, 95% CI, 0.48 to 0.91; P =0.01). The CDDP-based CT was associated with more gastrointestinal toxicities (RR=4.58; P =0.005) and nephrotoxicity (4/110=3.6%) compared to the CBDCA group, but fewer anemia, leukopenia and thrombocytopenia with RRs of 0.27, 0.71, and 0.28 respectively. Conclusions: Patients with CDDP-based CT can achieve a higher OS, but there is no significant difference in LRC. The CDDP-based CT is associated with fewer hematological toxicities but more gastrointestinal toxicities and nephrotoxicity compared to the CBDCA arm.

The study aimed to explore the correlation of epidermal growth factor receptor (EGFR) mutation with tumor node metastasis (TNM) stage in patients with non-small-cell lung cancer (NSCLC) who underwent positron emission tomography/computed tomography (PET/CT) scan. Patients diagnosed with NSCLC who underwent EGFR mutation status testing and PET/CT or PET/CT plus brain magnetic resonance imaging scan at initial diagnosis in Nanfang Hospital between July 2010 and June 2014 were consecutively enrolled. The correlation of EGFR mutation status with TNM stage and distant metastasis organs including brain, bone, liver, pleural, adrenals and contralateral lobe of lung were analyzed. A total of 401 patients were enrolled. Tumor size in EGFR mutation group was significantly smaller than the wild-type group (P

e20573 Background: This multi-center retrospective study was to determine whether the ΔCt value of Amplified Refractory Mutation System (ARMS) in EGFR mutated detection in tumors predicts the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC). Methods: A total of 108 NSCLC patients harbored an exon 19 deletion (19Del) or exon 21 L858R mutation detected by ARMS were enrolled. We identified patients with ΔCt

6035 Background: Cisplatin based chemoradiotherapy (CRT) is the standard treatment for advanced head and neck cancer (HNC), currently the recommended doses are 30-40 mg/m2 every week or 80-100mg/m2...

e22133 Background: EGFR mutation in NSCLC is a biomarker of tumor response to EGFR-TKI. However, lacking in sufficient tumor tissue has limitation to acquire EGFR mutation status in clinical practice. Previous studies showed that lower SUV was associated with better TKI treatment. The objective of this study was to predict EGFR mutation status of NSCLC patients based on a model consisting of 18F-fluorodeoxyglucose (FDG) uptake and supported by primary tumor size and smoking history. Methods: We retrospectively reviewed NSCLC patients undergoing EGFR mutation test and pretreatment PET/CT between March 2009 and December 2013. The relationship of EGFR mutations with both SUV uptake value of primary tumors and patient characteristics were evaluated, and a multivariate logistic regression analysis was constructed. The model was assessed by area under the receiver operating characteristic curve (AUC) and was prospectively validated during January to June 2014. Results: 316 patients meeting criteria were enrolle...

e19060 Background: NSCLC accounts for 85%-90%of lung cancers, in which brain metastases (BMs) occur in 20–40%of all NSCLC cases. WBRT is the standard treatment for BMs in NSCLC, which leads to a un...

6036 Background: The cisplatin (CDDP)-based CT is considered as the standard regimen for the treatment of moderate to advanced SCCHN. Recently, an alteration is made to carboplatin (CBDCA) because ...

e19121 Background: Epidermal growth factor receptor (EGFR) mutation status is one of the most critical factors for clinicians to develop multiple strategies in non-small cell lung cancer (NSCLC) pa...

e22254 Background: Copper metabolism MURR1 domain-containing10(COMMD10), a novel component of FCOMMD protein family, is a protein involved in multiple cellular pathways, including copper homeostasis, NF-κB and HIF signalling. However, its expression and role in HBV-related hepatocellular carcinoma remain unclear. Methods: The expression of COMMD10 was detected in clinical formalin-fixed paraffin-embedded (FFPE) hepatocellular carcinoma tissues by immunohistochemistry with clinicopathological analyses and determined in matched pairs of fresh frozen tissues by Quantitative Real time PCR or Western blot. Results: Immunohistochemistry staining was performed in 129 cases of clinical paraffin-embedded HCC tissues. The staining signal of COMMD10 was mainly observed in adjacent normal livers or cirrhotic livers. Meanwhile,no signals or only weak signals were detected in HCC tissues. Among 129 samples, 94 cases of them (72.9%) exhibited low-expression of COMMD10 (0 to 1+) and high-expression of COMMD10 (2+ to 3+) ...