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// Hua Zhang 1, 2, * , Xuexia Liu 3, * , Lei Chen 4, * , Li Cai 5 , Ning Li 3 , Peng Zhu 3 , Jian Chen 3 , Xicheng Song 1 , Guojun Li 2, 6 1 Department of Otolaryngology-Head and Neck Surgery, Yuhuangding Hospital of Qingdao University, Yantai, China 2 Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Department of Central Laboratory, Yuhuangding Hospital of Qingdao University, Yantai, China 4 Department of Clinical Laboratory, Yuhuangding Hospital of Qingdao University, Yantai, China 5 Department of Pathology, Yuhuangding Hospital of Qingdao University, Yantai, China 6 Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA * These authors have contributed equally to this work and are considered co-first authors Correspondence to: Xicheng Song, email: songxicheng@126.com Guojun Li, email: gli@mdanderson.org Keywords: peroxiredoxin 3, laryngeal squamous cell carcinoma, Hep-2 cell line, oxidative stress Received: November 10, 2016 Accepted: November 22, 2016 Published: December 09, 2016 ABSTRACT Peroxiredoxin (PRDX) proteins are involved in carcinogenesis. PRDX3, which is predominantly localized in mitochondria and up-regulated in several human cancers, seems to confer increased treatment resistance and aggressive phenotypes. This study examined the expression profile of PRDX3 and its possible clinical value in laryngeal squamous cell carcinoma (LSCC). The expression of PRDX3 in LSCC samples was confirmed by Western blotting and further analyzed by immunohistochemistry in LSCC samples of different clinical pathological stages. The results showed that up-regulated expression of PRDX3 was observed in LSCC and associated with poor differentiation (P < 0.01), primary tumor location, N category and tumor stage (P < 0.05). Knockdown of PRDX3 in the Hep-2 laryngeal carcinoma epithelial cell line significantly enhanced Hep-2 cells’ apoptosis and inhibited their proliferation and migration. Taken together, our results suggest that PRDX3 has substantial clinical impact on the progression of LSCC and shed new light on the role of PRDX3 in treatment resistance and aggressive phenotypes in LSCC.

// Hao Feng 1 , 2 , Tobias S. Schiergens 2 , Zhi-hai Mao 1 , Jingkun Zhao 1 , 2 , Xiaohui Shen 1 , Ai-Guo Lu 1 and Wolfgang E. Thasler 3 1 Department of Digestive Surgery, Ruijin Hospital, Shanghai Jiao-tong University School of Medicine, Shanghai, China 2 Department of General, Visceral, Transplant, and Vascular Surgery, University Hospital of Ludwig Maximilian University of Munich, Munich, Germany 3 Department of General and Visceral Surgery, Red Cross Hospital of Munich, Munich, Germany Correspondence to: Ai-guo Lu, email: // Hao Feng, email: // Keywords : laparoscopy; rectal cancer; operative risk; Cr-POSSUM system; complications Received : July 20, 2016 Accepted : October 17, 2016 Published : December 09, 2016 Abstract BACKGROUND: It is still controversial about the treatment strategy for rectal cancer patients with elevated operative risk and elder rectal cancer patients. METHODS: This study presented a retrospective single center experience in rectal cancer proctectomy for high operative risk patients. High operative risk patient was defined as Cr-POSSUM > 5% combined with associated risk factors. 220 in 1477 consecutive patients met the inclusion criteria. RESULTS: 132 patients were selected (66:66) after propensity score matching. The total complication rate between conventional open rectal resection (71 %) and laparoscopic surgery (41%) was significantly different ( p = 0.0005). There is a significantly positive correlation between open surgery and advanced Dindo Classification ( p = 0.02). Cr-POSSUM is positively correlated with Dindo Classification ( p = 0.01). There was no significant difference in survival rate among stage I~II, different age groups or different Cr-POSSUM score sub-groups. However, stage III-IV tumor patients in laparoscopic group experienced improved overall survival rate. ( p < 0.0001). For patients with preoperative pulmonary or renal disease, patients in laparoscopic group also had better long term prognosis ( p = 0.03, p = 0.049). CONCLUSIONS: The results demonstrate the potential advantages of laparoscopic rectal cancer resection for high operative risk patients, especially for the patients with preoperative respiratory or renal disease and stage III cancer.

// Xiangyun Deng 1, 2, 3 , Ying Zhang 1, 2, 3 , Dapeng Li 2, 3 , Xiaoling Zhang 2, 3 , Hui Guo 1, 2, 3 , Fei Wang 1, 2, 3 , Xiugui Sheng 2, 3 1 School of Medicine and Life Sciences, University of Jinan, Jinan 250022, Shandong, People’s Republic of China 2 Shandong Academy of Medical Sciences, Jinan 250000, Shandong, People’s Republic of China 3 Shandong Cancer Hospital Affiliated to Shandong University, Jinan 250117, Shandong, People’s Republic of China Correspondence to: Xiugui Sheng, email: shengxiugui@163.com Keywords: cervical cancer, tumor >2 cm, abdominal radical trachelectomy, sentinel lymph node, oncological outcomes Received: March 01, 2016 Accepted: November 21, 2016 Published: December 03, 2016 ABSTRACT Accuracy of prediction of pelvic lymph node status using sentinel lymph node biopsy (SLNB), and outcomes of SLNB-guided abdominal radical trachelectomy (ART) were assessed. Patients with stage IB1 (Figure 2009) cervical cancer and with tumors >2 cm were enrolled. Prior to fertility-sparing surgery 99mTc-labeled phytate was administered. SLNs were intraoperatively identified, excised, and assessed using fast-frozen sections. Systematic bilateral pelvic lymphadenectomy with or without para-aortic lymphadenectomy was subsequently undertaken. The SLN detection rate was 91.8% (45/49 patients); 8.2% (4/49) had radical hysterectomies because of metastatic primary SLNs. All SLNs received routine immunopathological examination to detect micrometastasis. Sensitivity, accuracy, and false negative rates were 100%, 100%, and 0%, respectively. ART was successfully completed in 45 patients (median follow-up, 61 [range, 4–149] months). Three of the 45 (6.7%) were lost to follow-up; two relapsed and one died of tumor progression. Overall 3-year survival and progression-free survival rates were 97.6% and 95.2%, respectively. Of the 19 patients who attempted to conceive after surgery, five achieved pregnancy, and one had a live birth in the third trimester. We concluded that SLNB using 99mTc-labeled phytate can accurately assess pelvic node status. SLNB-guided ART is safe and feasible in patients selected for fertility-sparing procedures.

// Haiyan Zheng 1 , Baohua Yang 2 , Dedong Xu 4 , Wenbo Wang 2 , Jie Tan 3 , Liyuan Sun 3 , Qinghua Li 3 , Li Sun 3 , Xuewei Xia 2, 3 1 Department of Neurosurgery, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, 322000, Zhejiang, China 2 Department of Neurosurgery, Guilin Medical University, Affiliated Hospital, Guilin, 541001, China 3 Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, 541001, China 4 Department of Neurosurgery, Hainan General Hospital, Haikou, 570311, China Correspondence to: Xuewei Xia, email: xxw7456@163.com Keywords: glioma, immunotherapy, staphylococcal enterotoxin B, interleukin-9, T helper-9 cell Received: June 20, 2016 Accepted: December 05, 2016 Published: December 16, 2016 ABSTRACT The effects of Staphylococcal enterotoxin B (SEB) on regulation of immune response have been recognized; whether SEB can enhance the effects of immunotherapy on glioma remains to be investigated. This study tests a hypothesis that administration with SEB enhances the effects of specific immunotherapy on glioma growth in mice. In this study, a glioma-bearing mouse model was developed by adoptive transfer with GL261 cells (a mouse glioma cell line). The mice were treated with the GL261 cell extracts (used as an Ag) with or without administration of SEB. We observed that treating glioma-bearing mice with the glioma Ag and SEB induced glioma-specific Th9 cells in both glioma tissue and the spleen. Treating CD4 + CD25 − T cells with SEB increased p300 phosphorylation, histone H3K4 acetylation at the interleukin (IL)-9 promoter locus, and increased the IL-9 transcriptional factor binding to the IL-9 promoter. Treating CD4 + CD25 − T cells with both SEB and glioma Ag induced glioma-specific Th9 cells. The glioma-specific Th9 cells induced glioma cell apoptosis in the culture. Treating the glioma-bearing mice with SEB and glioma Ag significantly inhibited the glioma growth. In conclusion, SEB plus glioma Ag immunotherapy inhibits the experimental glioma growth, which may be a novel therapeutic remedy for the treatment of glioma.

// Bin Zhang 1,2,* , Yuhao Dong 1,2,* , Jing Liu 1,2 , Zhouyang Lian 1,2 , Long Liang 1,2 , Wenbo Chen 3 , Xiaoning Luo 1,2 , Shufang Pei 1,2 , Xiaokai Mo 1,2 , Lu Zhang 1,2 , Wenhui Huang 1,4 , Fusheng Ouyang 1,2 , Baoliang Guo 1,2 , Changhong Liang 1 and Shuixing Zhang 1 1 Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China 2 Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China 3 Department of Radiology, Huizhou Municipal Central Hospital, Huizhou, Guangdong, P.R. China 4 School of medicine, South China University of Technology, Guangzhou, Guangdong, P.R. China * These authors have contributed equally to this work Correspondence to: Shuixing Zhang, email: // Keywords : immunotherapy; chemotherapy; advanced pancreatic cancer; adverse events; overall survival Received : July 15, 2016 Accepted : December 12, 2016 Published : December 15, 2016 Abstract There are limited data on the safety and efficacy of immunotherapy for patients with advanced pancreatic cancer (APC). A meta-analysis of single-arm trials is proposed to assess the efficacy and safety of immunotherapy for APC. Eighteen relevant studies involving 527 patients were identified. The pooled disease control rate (DCR), overall survival (OS), progression free survival (PFS), and 1-year survival rate were estimated as 59.32%, 7.90 months, 4.25 months, and 30.12%, respectively. Subgroup analysis showed that the pooled OS, PFS, and 1-year survival rate were significantly higher for autologous activated lymphocyte therapy compared with peptide-based vaccine therapy (OS: 8.28 months vs . 7.40 months; PFS: 6.04 months vs . 3.86 months; 1-year survival rate: 37.17% vs . 19.74%). Another subgroup analysis demonstrated that the pooled endpoints were estimated as obviously higher for immunotherapy plus chemotherapy compared with immunotherapy alone (DCR: 62.51% vs . 47.63%; OS: 8.67 months vs . 4.91 months; PFS: 4.91 months vs . 3.34 months; 1-year survival rate: 32.32% vs . 21.43%). Of the included trials, seven trials reported no treatment related adverse events , five trials reported (16.6 ± 3.9) % grade 3 adverse events and no grade 4 adverse events. In conclusion, immunotherapy is safe and effective in the treatment of APC.

// Mark de Mol 1, 2 , Brenda L. den Oudsten 3 , Mieke Aarts 4 and Joachim G.J.V. Aerts 1, 2 1 Department of Pulmonary Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands 2 Department of Pulmonary Medicine, Amphia Hospital, Breda, The Netherlands 3 Department of Medical and Clinical Psychology, Centre of Research on Psychological and Somatic Disorders (CoRPS), Tilburg University, Tilburg, The Netherlands 4 Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, The Netherlands Correspondence to: Joachim G.J.V. Aerts, email: j.aerts@amphia.nl Keywords: distress thermometer, health related quality of life, survival, cancer, chemotherapy Received: June 29, 2016 Accepted: November 14, 2016 Published: December 24, 2016 ABSTRACT Background: Depression and Health Related Quality of Life have been associated with prognosis in lung cancer. As the Distress Thermometer measures emotional problems and may share similarities with aspects of Health Related Quality of Life, we aimed to retrospectively assess the prognostic value of the Distress Thermometer in lung cancer patients treated with chemotherapy. Methods: Patients with stage III lung cancer who were treated at the day-care oncology unit with chemotherapy containing carboplatin from 2009 to 2014 and in whom a Distress Thermometer was performed at the time of the first cycle of chemotherapy were included in this study. Results: In total, one hundred and thirteen patients were included in the analysis. In the simple Cox regression analysis, overall survival did not significantly differ according to Distress Thermometer score. No significant differences in Distress Thermometer score according to stage, histology, (intended) treatment, age, sex, and comorbidity were observed. Also in a multivariable model the Distress Thermometer was not prognostic for overall survival, whereas sex and (intended) treatment was. Conclusions: In this study no prognostic value of the Distress Thermometer could be established in patients with stage III lung cancer treated with carboplatin. Further research is warranted to address this issue.

// Jiwei Huang 1 , Yichu Yuan 1 , Yanqing Wang 1 , Jin Zhang 1 , Wen Kong 1 , Haige Chen 1 , Yonghui Chen 1 and Yiran Huang 1 1 Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Correspondence to: Yonghui Chen, email: cyh1488@163.com Yiran Huang, email: yrhuangrenji@163.com Keywords: upper tract, urothelial carcinoma, fibrinogen, platelet-to-lymphocyte ratio, prognosis Received: August 31, 2016 Accepted: November 09, 2016 Published: November 25, 2016 ABSTRACT Purpose: Hemostatic factors is thought to have a potentially significant role in progression and metastasis of malignant tumors. We investigated the prognostic value of preoperative plasma fibrinogen level and platelet-to-lymphocyte ratio (PLR) in localized upper tract urothelial carcinoma (UTUC). Materials and Methods: A total of 481 patients who underwent radical nephroureterectomy for localized UTUC (pTa-4N0M0) were identified between January 2002 and June 2013. Patients were assigned a F-PLR score of 0, 1, or 2 based upon the presence of elevated plasma fibrinogen level, an elevated PLR, or both. The association between F-PLR score and clinicopathological variables was analysed. Results: The optimal cut-off value of plasma fibrinogen and PLR for overall survival stratification was determined to be 4.22 and 241.2. Kaplan–Meier analysis revealed significant differences in cancer specific survival (CSS) and overall survival (OS) among patients with F–PLR scores of 0, 1 and 2. Multivariate analysis identified higher F–PLR score as an independent risk factor for CSS (P < 0.001) and OS (P < 0.001). The estimated c-index of the multivariate model for CSS and OS increased from 0.772 and 0.756 to 0.799 and 0.784 when F–PLR score added, which was higher than fibrinogen level, PLR or neutrophil-to-lymphocyte ratio added. Conclusions: Preoperative F-PLR score is a negative independent prognostic factor for survival outcomes in patients with localized upper tract urothelial carcinoma. Preoperative F-PLR score may become a useful biomarker, particularly because of its low associated cost and easy accessibility.

// Peipei Xing 1, 2, * , Jin Zhang 1, 2, * , Zhao Yan 2, 3, * , Gang Zhao 4 , Xubin Li 5 , Guowen Wang 1, 2 , Yun Yang 1, 2 , Jun Zhao 1, 2 , Ruwei Xing 1, 2 , Sheng Teng 1, 2 , Yulin Ma 1, 2 , Zhichao Liao 1, 2 , Zhiwu Ren 1, 2 , Chao Zhang 1, 2 , Xiuxin Han 1, 2 , Wei Zhang 6 , Kexin Chen 2, 7 , Ping Wang 2, 8 and Jilong Yang 1, 2 1 Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, People’s Republic of China 2 National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, People’s Republic of China 3 Pharmacological Research Center, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, People’s Republic of China 4 Department of Pathology, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, People’s Republic of China 5 Department of Radiology, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, People’s Republic of China 6 Department of Cancer Biology, Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, North Carolina 27157, USA 7 Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, People’s Republic of China 8 Department of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Jilong Yang, email: yangjilong@tjmuch.com Keywords: sarcoma, endostar, chemotherapy, progression free survival, clinical benefit response Received: June 11, 2016 Accepted: November 12, 2016 Published: November 24, 2016 ABSTRACT Purpose: This retrospective case-series study evaluated efficacy and safety of Endostar combined with chemotherapy in the treatment of advanced bone and soft tissue sarcomas in stage IV. Materials and Methods: Forty-seven patients diagnosed with stage IV bone and soft tissue sarcomas and treated with chemotherapy in Tianjin Medical University Cancer Institute & Hospital were reviewed. Of these patients, 23 patients were treated with Endostar plus chemotherapy (designated as combined group), and 24 patients received only chemotherapy (designated as control group). Progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and clinical benefit response (CBR) were analyzed to find the difference between these two groups with the purpose to investigate the role of Endostar in metastatic sarcomas. Results: Endostar combined with chemotherapy had significantly increased PFS. In the combined group and control groups, the median PFS (8.6 months versus 4.4 months) and the CBR (47.8% versus 16.7%) showed significant difference ( P = 0.032), while the median overall survival (11.7 months versus 10.6 months, P = 0.658) and the ORR (17.4% versus 8.3%, P = 0.167) showed no significant difference. The common grade 3-4 side effects for both groups were myelosuppression and transient elevation of transaminases. Conclusion: Endostar combined with chemotherapy had significant activity to increase the PFS and improve CBR in patients with advanced sarcomas, with tolerable side effects.

// Junwei Chen 1, 2, * , Lisha Lai 3, * , Qu Lin 4 , Wensou Huang 1, 2 , Mingyue Cai 1 , Kangshun Zhu 1, 5 , Mingsheng Huang 1, 2, 5 1 Department of Radiology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630 China 2 Department of Interventional Radiology, Ling-nan Hospital, Guangzhou, 510530 China 3 Department of Radiology, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, 510180 China 4 Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510180 China 5 Interventional Radiology Institute, Sun Yat-Sen University, Guangzhou, 510630 China * These authors contributed equally to this work Correspondence to: Mingsheng Huang, email: huangmsh@mail.sysu.edu.cn Keywords: hepatocellular carcinoma, transarterial chemoembolization, hepatic resection, prognostic factors Received: February 29, 2016 Accepted: November 11, 2016 Published: November 17, 2016 ABSTRACT To investigate the prognosis of transarterial chemoembolization (TACE) followed by hepatic resection (HR) in large/multifocal hepatocellular carcinoma (HCC), the medical records of consecutive HCC patients who underwent TACE between January 2006 and December 2010 were retrospectively analyzed. Patients who received TACE alone comprised the T group (61 patients), while those who received HR after TACE comprised the T+R group (49 patients). All the resections were successfully performed, and only one class V complication occurred. While liver function was altered from baseline within 1 week after HR, it recovered within 1 month. Overall survival (OS) of the T+R and T groups were compared, and sub-group analyses were performed based on baseline α-fetoprotein (AFP) levels, the reduction of AFP, and tumor response before HR. Overall survival (OS) in the T+R group was longer than in the T group (47.00 ± 2.87 vs. 20.00 ± 1.85 months, P 0.05). These patients may not benefit from the combined treatment. Our findings suggest HR after TACE is safe and effective for large/multifocal HCC, and prolongs OS when compared to TACE alone.

// Cuiling Zhou 1, * , Donglan Liu 2, * , Jie Li 3, * , Huanhuan Sun 1 , Xiaobin Zheng 4 , Shuncong Wang 1 , Guobin Hong 5 , Saradhi Mallampati 6 , Hongliu Sun 7 , Xiuling Zhou 1 , Zhibin Cheng 1 , Hongyu Zhang 1 , Haiqing Ma 1 1 Department of Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong 519000, China 2 Department of Gastroenterology, Cancer Hospital of Jiangxi Province, Nanchang, Jiangxi 330029, China 3 Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China 4 Department of Respiratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong 519000, China 5 Department of Radiology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong 519000, China 6 Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 7 Department of Pathology, University of Michigan, Ann Arbor, MI 48201, USA * These authors have contributed equally to this work Correspondence to: Haiqing Ma, email: mahaiqing@mail.sysu.edu.cn Hongyu Zhang, email: zdwyzhy@163.com Keywords: advanced non-small-cell lung cancer, overall survival, combination treatment of DC-CIKs, chemotherapy, meta-analysis Received: July 10, 2016 Accepted: November 07, 2016 Published: November 16, 2016 ABSTRACT This study was aimed to investigate the efficacy and safety of the combination treatment of dendritic cells co-cultured with cytokine-induced killer cells and chemotherapy for patients with advanced non-small-cell lung cancer (NSCLC). Literatures were searched from the Cochrane Library Central, PubMed, Web of Science and EMBASE. The primary endpoint of interest was overall survival (OS), and secondary endpoints were disease control rate (DCR) and progression free survival (PFS). Finally 7 trials published between January 2005 and March 2016 met inclusion criteria and totally 610 patients were enrolled. The combination group showed advance in DCR (RR = 1.31, 95% CI = 1.13-1.52, p = 0.0004), 1-year OS (RR = 1.18, 95% CI = 1.05-1.33, p = 0.007), and 2-year OS (RR = 1.37, 95% CI = 1.10-1.70, p = 0.005), with statistical significance. The proportions of CD3 + T cells ( p = 0.002), NK cells ( p = 0.02) and NKT cells ( p = 0.001) were significantly higher in the peripheral blood of combination group, compared with those of the control group. Moreover, adverse reactions were obviously decreased in the combination group. However, no significant difference was identified in ORR and PFS between two groups ( p > 0.05). In conclusion, the combination therapy was safe and applicable for patients with advanced NSCLC.

// Jianghai Zhao 1, * , Hui Zhang 1, * , Lunshou Wei 1 , Shuping Xie 1 , Zhimin Suo 1 1 Department of Gastroenterology, Huaihe Hospital of Henan University, Kaifeng, Henan, 475000, China * These authors have contributed equally to this work Correspondence to: Zhimin Suo, email: wenyuhuwy@126.com Keywords: unresectable hepatocellular carcinoma, transarterial chemoembolization, long-term efficacy, network meta-analysis Received: May 23, 2016 Accepted: October 12, 2016 Published: November 07, 2016 ABSTRACT A small proportion of hepatocellular carcinoma (HCC) patients are suitable for surgical resections and various minimally invasive procedures have been introduced as alternatives to surgical resections. However, the relative efficacy of minimally invasive procedures remains to be studied in the current literature. Several popular minimally invasive procedures (monotherapy or combined therapies) were selected for comparison and their relative long-term efficacy were determined by using the statistics of hazard ratio (HR) which evaluates the survival status of HCC patients in one, two, three and four years, respectively. Evidence were obtained from the current literature and synthesized by using the approach of conventional pairwise meta-analysis and network meta-analysis (NMA). Moreover, selected minimally invasive procedures were ranked according to their surface under the cumulative ranking curve (SUCRA) which was produced by NMA in conjunction with the Markov Chain Monte Carlo (MCMC) sampling method. HCC patients treated by combined minimally invasive procedures, particularly transcatheter arterial chemoembolization (TACE) + high intensity focused ultrasound (HIFU), TACE + radiofrequency ablation (RFA), TACE + radiotherapy (RT) and TACE + Sorafenib (SOR) exhibited a significant decrease in the HR compared to those with standard TACE (HR < 1). The combined minimally invasive procedure of TACE + HIFU appears to be the most preferable therapy. PEI seems to be less favorable than other minimally invasive procedures. Combined minimally invasive procedures may be more preferable than standard minimally invasive procedures. Percutaneous ethanol injection (PEI) may not provide adequate efficacy compared to other minimally invasive procedures for unresectable HCC patients.

// Junwu Zhao 1,2 , Zhenguang Li 2 , Yannan Cong 2 , Jinbiao Zhang 2 , Ming Tan 2 , Haixia Zhang 2 , Na Geng 2 , Mengfan Li 2 , Wenwen Yu 3 and Peiyan Shan 1 1 Department of Neurology, Qilu Hospital of Shandong University, Jinan, Shandong, China 2 Department of Neurology, Weihai Municipal Hospital, Weihai, Shandong, China 3 Department of Clinical Medicine (Neurology), Weifang Medical University, Weifang, Shandong, China Correspondence to: Peiyan Shan, email: // Keywords : rTMS, cognitive function, AD Received : September 12, 2016 Accepted : October 24, 2016 Published : November 03, 2016 Abstract Repetitive transcranial magnetic stimulation (rTMS) acts as a kind of widely-applied and non-invasive method in the intervention of some neurological disorders. This prospective, randomized, double-blind, placebo-controlled trial investigates the effect of rTMS on 30 cases of Alzheimer’s disease (AD) participants, who were classified into mild and moderate groups. Neuropsychological tests were carried out using the AD Assessment Scale-cognitive subscale (ADAS-cog), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and World Health Organization University of California-Los Angeles, Auditory Verbal Learning Test (WHO-UCLA AVLT) before, immediately after, and 6 weeks after the intervention. In this work, data from 30 AD patients revealed that there was no obvious interaction effect of time-by-group. The ADAS-cog, MMSE and WHO-UCLA AVLT score in the rTMS group was significantly improved compared with baselines at 6 weeks after treatment (all p

// Wei Guo 1 , Dehong Luo 1 , Xinyi Chen 2 , Meng Lin 1 , Lin Li 1 , Yanfeng Zhao 1 , Liang Yang 1 , Lei Hu 1 , Xinming Zhao 1 and Chunwu Zhou 1 1 Department of Diagnostic Radiology, Peking Union Medical College, Cancer Institute & Hospital, Chinese Academy of Medical Sciences, Beijing, China 2 Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China Correspondence to: Dehong Luo, email: // Keywords : chemo-radiotherapy, dynamic contrast-enhanced magnetic resonance imaging, larynx and hypopharynx carcinoma, semi-quantitative parameters Received : July 18, 2016 Accepted : October 22, 2016 Published : October 27, 2016 Abstract Purpose: This study is to investigate the use of dynamic contrast-enhanced magnetic resonance imaging in predicting early response to CRT (chemo-radiotherapy) in patients with larynx and hypopharynx carcinoma from primary tumors. Method: Sixty-two patients with larynx and hypopharynx carcinoma underwent two DCE-MRI studies: a baseline exam before any treatment and a post-treatment exam 3 weeks after CRT. At the end of treatment, patients were classified as responders, or non-responders according to the Response Evaluation Criteria in Solid Tumors criteria (RECIST). The time intensity curves (TIC) were extracted and processed to obtain time to peak (TTP), maximum slope of increase (MSI), maximum slope of decrease (MSD) and positive enhancement integral (PEI), and the semi-quantitative MRI parameters were compared and analyzed between the two groups. Results: Fifty-four and 8 patients were included the responder and non-responder groups. It was observed that the MSI, MSD, and PEI were significantly lower post-treatment than pre-treatment( P < 0.05). The pretreatment MSI, MSD, and PEI parameters of responders were significantly higher than those of non-responders ( P < 0.05). The post-treatment MSI, MSD, and PEI parameters of responders were significantly lower than those of non-responders ( P < 0.05). Based on ROC curve analysis, at a threshold of 154.81 for pretreatment MSI, the corresponding AUC, sensitivity, and specificity were 0.882, 89.3% and 73.5%, respectively. Conclusion: The semi-quantitative DCE-MRI may aid in the prediction of early response to CRT in patients with larynx and hypopharynx carcinoma.

Background Chemokine (C-C motif) ligand 21 (CCL21), a ligand of the chemokine (C-C motif) receptor 7, has recently been identified as an immuno-based anti-cancer molecule for its dendritic cells and T lymphocytes chemoattractant function. The aim of this study was to investigate prognostic values of CCL21 expression in metastatic renal cell carcinoma patients treated with targeted therapy. Methods This study included 111 patients with metastatic renal cell carcinoma receiving targeted therapy. CCL21 expression was analyzed by immunohistochemistry on tissue microarrays. Prognostic value of tumoral CCL21 expression and patients clinical outcomes were evaluated. RESULTS Kaplan-Meier method showed that low CCL21 expression was associated with shorter patient overall survival and progression-free survival (overall survival, P = 0.005; progression-free survival, P = 0.044). Further stratified analysis showed that low CCL21 expression was significantly associated with shorter overall survival in clear cell renal cell carcinoma patients (P = 0.017) and patients treated with sorafenib (P = 0.009). Low CCL21 expression was also an adverse independent risk factor for overall survival (hazard ratio, 2.106; 95% CI, 1.286-3.450; P = 0.003) and progression-free survival (hazard ratio 1.617; 95%CI 1.060-2.465; P = 0.026) in multivariate analyses. CCL21 expression was significantly associated with treatment best response to targeted therapy (P = 0.009). This molecule could also be combined with Heng risk model to increase its overall survival predictive accuracy. Conclusion Low CCL21 expression was a potential independent adverse prognostic biomarker for overall survival and progression-free survival for metastatic renal cell carcinoma patients treated with targeted therapy.

// Lin Zhou 1, * , Yuan Chang 1, * , Le Xu 2, * , Son Tung Nguyen Hoang 1 , Zheng Liu 3 , Qiang Fu 3 , Zongming Lin 1 , Jiejie Xu 3 1 Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China 2 Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China 3 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China * These authors have contributed equally to this work Correspondence to: Zongming Lin, email: zongminglin@gmail.com Jiejie Xu, email: jjxufdu@fudan.edu.cn Keywords: vascular mimicry, bladder cancer, recurrence, radical cystectomy, adjuvant chemotherapy Received: July 25, 2016 Accepted: October 04, 2016 Published: October 20, 2016 ABSTRACT Vascular mimicry (VM) refers to the plasticity of aggressive cancer cells forming de novo vascular networks, which promoted tumor metastasis. The aim of this study was evaluate the impact of VM on recurrence-free survival (RFS) in urothelial carcinoma of the bladder (UCB). Records from 202 patients treated with radical cystectomy (RC) for UCB at Zhongshan Hospital between 2002 and 2014 were reviewed. The presence of VM was identified by CD31-PAS double staining. Positive VM staining occurred in 19.3% (39 of 202) UCB cases, and it was associated with increased risks of recurrence (Log-Rank p

// Yoshio Nakamura 1, 3 , Shigehisa Kitano 2, * , Akira Takahashi 1 , Arata Tsutsumida 1 , Kenjiro Namikawa 1 , Keiji Tanese 3 , Takayuki Abe 4 , Takeru Funakoshi 3 , Noboru Yamamoto 2 , Masayuki Amagai 3 , Naoya Yamazaki 1, * 1 Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan 2 Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan 3 Department of Dermatology, Keio University School of Medicine, Tokyo, Japan 4 Department of Preventive Medicine and Public Health, Biostatistics Unit at Clinical Translational Research Center, Keio University School of Medicine, Tokyo, Japan * These authors have contributed equally to this work Correspondence to: Shigehisa Kitano, email: skitano@ncc.go.jp Keywords: nivolumab, metastatic melanoma, absolute lymphocyte count, absolute neutrophil count, early markers for outcome Received: June 07, 2016 Accepted: September 28, 2016 Published: October 15, 2016 ABSTRACT Background: An anti-programmed cell death protein 1 monoclonal antibody, nivolumab, is one of the most effective drugs for advanced melanoma. Tumor cell-derived or immune cell-derived markers and clinical predictors such as serum lactate dehydrogenase (LDH) and cutaneous adverse events, have already been described as prognostic factors for advanced melanoma treated with nivolumab. We sought to identify further clinical predictors that can be determined in routine clinical practice. Methods: We retrospectively analyzed clinical findings of 98 consecutive patients with unresectable stage III or IV melanoma treated with nivolumab, at the National Cancer Center Hospital or at Keio University Hospital, in Tokyo, Japan, between July 2014 and July 2016. These patients had been administered nivolumab at a dose of 2mg/kg every 3 weeks. Results: As for pretreatment prognostic factors, ECOG performance status (PS) ≥1, maximum tumor diameters of ≥30mm, elevated LDH and elevated C-reactive protein were significantly associated with poor overall survival (OS) (hazard ratio [HR] 0.29 [ P

Because many patients with unresectable basal cell carcinoma (BCC) are aged ≥65 years, this study explores the efficacy and safety of vismodegib in these patients with locally advanced (la) or metastatic (m) basal cell carcinoma (BCC) in the ERIVANCE BCC trial and the expanded access study (EAS).We compared patients aged ≥65 years to patients aged

// Chuanbao Zhang 1, * , Jiye Li 1, 2, 3, * , Haoyuan Wang 4 , Sonya Wei Song 1, 2, 3 1 Beijing Neurosurgical Institute, Capital Medical University, TiantanXili, Dongcheng District, Beijing 100050, China 2 Beijing Institute for Brain Disorders, Youanmen, Beijing, 100069, China 3 Center for Brain Disorders Research, Capital Medical University, Youanmen, Beijing, 100069, China 4 Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China * These authors contributed equally to this work Correspondence to: Sonya Wei Song, email: sonyasongbj2016@163.com , sonyasong@ccmu.edu.cn Keywords: immune system, tumor-infiltrating B cells, prognosis, biomarker, glioma Received: April 11, 2016 Accepted: September 27, 2016 Published: October 12, 2016 ABSTRACT High grade gliomas contribute to most brain tumor mortality. A few studies reported that the immune system affected glioma development, and immune biomarkers helped understand the disease and formulate effective immunotherapy for patients. Currently, no B lymphocyte-based prognostic signature was reported in gliomas. By applying 78 B cell lineage-specific genes, we conducted a whole-genome gene expression analysis in 782 high grade gliomas derived from three independent datasets by Cox regression analysis and risk score method for signature identification, and then used Gene Ontology, Gene Set Enrichment Analysis, and other statistical methods for functional annotations of the signature-defined differences. We developed a five B cell-associated gene signature for prognosis of high grade glioma patients, which is independent of clinicopathological and genetic features. The signature identified high risk patients suitable for chemoradiotherapy, whereas low risk patients should rule out chemotherapy with radiotherapy only. We found that tumors of TCGA Mesenchymal subtype and wild type IDH1 were preferentially stratified to the high risk group, which bore strong immunosuppressive microenvironment, while tumors of TCGA Proneural subtype and mutated IDH1 were significantly accumulated to the low risk group, which exhibited less immunosuppressive state. The five B cell-associated gene signature predicts poor survival of high risk patients bearing strong immunosuppression and helps select optimal therapeutic regimens for glioma patients.

Increasing evidence suggests that ion channels not only regulate electric signaling in excitable cells but also play important roles in the development of brain tumor. However, the roles of ion channels in glioma remain controversial. In the present study, we systematically analyzed the expression patterns of ion channel genes in a cohort of Chinese patients with glioma using RNAseq expression profiling. First, a molecular signature comprising three ion channel genes (KCNN4, KCNB1 and KCNJ10) was identified using Univariate Cox regression and two-tailed student's t test conducted in overall survival (OS) and gene expression. We assigned a risk score based on three ion channel genes to each primary Glioblastoma multiforme (pGBM) patient. We demonstrated that pGBM patients who had a high risk of unfavorable outcome were sensitive to chemotherapy. Next, we screened the three ion genes-based signature in different molecular glioma subtypes. The signature showed a Mesenchymal subtype and wild-type IDH1 preference. Gene ontology (GO) analysis for the functional annotation of the signature showed that patients with high-risk scores tended to exhibit the increased expression of proteins associated with apoptosis, immune response, cell adhesion and motion and vasculature development. Gene Set Enrichment Analysis (GSEA) results showed that pathways associated with negative regulation of programmed cell death, cell proliferation and locomotory behavior were highly expressed in the high-risk group. These results suggest that ion channel gene expression could improve the subtype classification in gliomas at the molecular level. The findings in the present study have been validated in two independent cohorts.

// Andrew D.J. Pearson 1 , Sara M. Federico 2 , Isabelle Aerts 3 , Darren R. Hargrave 4 , Steven G. DuBois 5 , Robert Iannone 6 , Ryan D. Geschwindt 6 , Ruixue Wang 7 , Frank G. Haluska 8 , Tanya M. Trippett 9 , Birgit Geoerger 10 1 Paediatric Drug Development Unit, Children and Young People’s Unit, Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom (Retired) 2 Department of Pediatric Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA 3 Department of Pediatric, Adolescent and Young Adult Oncology, Institut Curie, Paris, France 4 Haematology and Oncology Department, Great Ormond Street Hospital for Children, London, United Kingdom 5 Department of Pediatrics, University of California San Francisco School of Medicine, and Benioff Children’s Hospital, San Francisco, CA, USA (current affiliation: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA, USA) 6 Clinical Research, Merck & Co., Inc., North Wales, PA, USA 7 BARDS, MSD RD 18 were evaluable for dose-limiting toxicities. One dose-limiting toxicity (grade 3 increased alanine aminotransferase) occurred in 1 patient at 33 mg/m 2 . Dose escalation concluded at 33 mg/m 2 ; the maximum tolerated dose was not determined. The most common treatment-related adverse events (frequency ≥40%) were manageable grade 1–2 stomatitis, thrombocytopenia, hypertriglyceridemia, increased alanine aminotransferase, fatigue, hypercholesterolemia, anemia, and increased aspartate aminotransferase. Ridaforolimus exposure at 28 mg/m 2 and 33 mg/m 2 exceeded adult target levels. The RP2D for oral ridaforolimus in children was defined as 33 mg/m 2 . Four patients received at least 4 cycles; 2 with pineoblastoma and diffuse intrinsic pontine glioma had stable disease for 12 and 46 cycles, respectively. Conclusions: Ridaforolimus is orally bioavailable and well tolerated in children with advanced solid tumors. The RP2D (33 mg/m 2 , 5 days/week) exceeds the adult RP2D. The favorable toxicity and pharmacokinetic profiles may allow for combination therapy, a promising therapeutic option in pediatric malignancies.

// Alexandre Escande 1 , Christine Haie-Meder 1 , Pierre Maroun 1, 2 , Sebastien Gouy 3 , Renaud Mazeron 1 , Thomas Leroy 4 , Enrica Bentivegna 3 , Philippe Morice 2, 3, 5 , Eric Deutsch 1, 2, 5 , Cyrus Chargari 1, 2, 5, 6, 7 1 Radiotherapy department, Brachytherapy Unit, Gustave Roussy Cancer Campus, Villejuif, France 2 Faculte de medecine PARIS Sud, universite Paris Sud, Universite Paris Saclay, France 3 Department of Surgery, Gustave Roussy, Villejuif, France 4 Radiotherapy Department, Oscar Lambret Comprehensive Cancer Center, Lille, France 5 INSERM1030, Gustave Roussy Cancer Campus, Villejuif, France 6 French Military Health Services Academy, Ecole du Val-de-Grâce, Paris, France 7 Institut de Recherche Biomedicale des Armees, Bretigny-sur-Orge, France Correspondence to: Cyrus Chargari, email: cyrus.chargari@gustaveroussy.fr Keywords: locally advanced cervical cancer, image-guided adaptive brachytherapy, prognostic factor, biomarkers, neutrophilia Received: June 27, 2016 Accepted: September 19, 2016 Published: October 04, 2016 ABSTRACT Objective: To study the prognostic value of leucocyte disorders in a prospective cohort of cervical cancer patients receiving definitive chemoradiation plus image—guided adaptive brachytherapy (IGABT). Results: 113 patients were identified. All patients received a pelvic irradiation concomitant with chemotherapy, extended to the para-aortic area in 13 patients with IVB disease. Neutrophilia and leukocytosis were significant univariate prognostic factors for poorer local failure-free survival ( p = 0.000 and p = 0.002, respectively), associated with tumor size, high-risk clinical target volume (HR-CTV) and anemia. No effect was shown for distant metastases but leukocytosis and neutrophila were both poor prognostic factors for in-field relapses ( p = 0.003 and p 7,500/μl ( p = 0.018) were independent factors for poorer survival without local failure, with hazard ratio (HR) of 3.1. Materials and methods: We examined patients treated in our Institution between April 2009 and July 2015 by concurrent chemoradiation (45 Gy in 25 fractions +/– lymph node boosts) followed by a magnetic resonance imaging (MRI)-guided adaptive pulse-dose rate brachytherapy (15 Gy to the intermediate-risk clinical target volume). The prognostic value of pretreatment leucocyte disorders was examined. Leukocytosis and neutrophilia were defined as a leukocyte count or a neutrophils count exceeding 10,000 and 7,500/μl, respectively. Conclusions: Neutrophilia is a significant prognostic factor for local relapse in locally advanced cervical cancer treated with MRI-based IGABT. This biomarker could help identifying patients with higher risk of local relapse and requiring dose escalation.

// Shih-Hsin Tu 1, 2, 3 , Yin-Ching Lin 4 , Chi-Cheng Huang 1, 5, 6 , Po-Sheng Yang 7, 8 , Hui-Wen Chang 9 , Chien-Hsi Chang 9 , Chih-Hsiung Wu 1, 10 , Li-Ching Chen 2, 3, 11 , Yuan-Soon Ho 4, 9, 12, 13 1 Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 2 Breast Medical Center, Taipei Medical University Hospital, Taipei, Taiwan 3 Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan 4 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan 5 School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan 6 Breast Center, Cathay General Hospital, Taipei, Taiwan 7 Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan 8 Department of Medicine, Mackay Medical College, New Taipei City, Taiwan 9 Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, Taiwan 10 Department of Surgery, En Chu Kong Hospital, New Taipei City, Taiwan 11 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 12 Comprehensive Cancer Center of Taipei Medical University, Taipei, Taiwan 13 School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan Correspondence to: Li-Ching Chen, email: d117094003@tmu.edu.tw Yuan-Soon Ho, email: hoyuansn@tmu.edu.tw Keywords: protein phosphatase Mg 2+ /Mn 2+ dependent 1F, breast cancer, smoking, α9-nicotinic acetylcholine receptor, p53 Received: August 15, 2016 Accepted: October 04, 2016 Published: October 18, 2016 ABSTRACT We previously demonstrated that the activation of α9-nicotinic acetylcholine receptor (α9-nAchR) signaling by smoking promotes breast cancer formation. To investigate the downstream signaling molecules involved in α9-nAChR-induced breast tumorigenesis, we used real-time polymerase chain reactions and Western blotting to assess expression of protein phosphatase Mg 2+ /Mn 2+ dependent 1F (PPM1F), a Ser/Thr protein phosphatase, in human breast cancer samples (n=167). Additionally, stable PPM1F -knockdown and -overexpressing cell lines were established to evaluate the function of PPM1F. The phosphatase activity of PPM1F in nicotine-treated cells was assessed through Western blotting, confocal microscopy, and fluorescence resonance energy transfer. Higher levels of PPM1F were detected in the breast cancer tissues of heavy smokers (n=7, 12.8-fold) greater than of non-smokers (n= 28, 6.3-fold) (**p=0.01). In vitro , nicotine induced PPM1F expression, whereas α9-nAChR knockdown reduced the protein expression of PPM1F. A series of biochemical experiments using nicotine-treated cells suggested that the dephosphorylation of p53 (Ser-20) and BAX (Ser-184) by PPM1F is a critical posttranslational modification, as observed in breast cancer patients who were heavy smokers. These observations indicate that PPM1F may be a mediator downstream of α9-nAChR that activates smoking-induced carcinogenic signals. Thus, PPM1F expression could be used for prognostic diagnosis or inhibited for cancer prevention and therapy.

// Maria Thomsen 1, 2 , Christian Kersten 3 , Halfdan Sorbye 4 , Eva Skovlund 5 , Bengt Glimelius 6 , Per Pfeiffer 7 , Julia S. Johansen 8 , Elin H. Kure 9 , Tone Ikdahl 10 , Kjell Magne Tveit 1, 2, 11 , Thoralf Christoffersen 12 , Tormod Kyrre Guren 1, 11 1 Department of Oncology, Oslo University Hospital, Oslo, Norway 2 Institute of Clinical Medicine, University of Oslo, Oslo, Norway 3 Department of Oncology, Southern Hospital Trust, Kristiansand, Norway 4 Department of Oncology, Haukeland University Hospital, University of Bergen, Bergen, Norway 5 Department of Public Health and General Practice, Norwegian University of Science and Technology, Trondheim, Norway 6 Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden 7 Department of Oncology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark 8 Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark 9 Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway 10 Akershus University Hospital, Nordbyhagen, Norway 11 K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway 12 Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway Correspondence to: Maria Thomsen, email: uxthmg@ous-hf.no Keywords: mCRC, IL-6, CRP, prognostic biomarker, survival Received: May 20, 2016 Accepted: September 19, 2016 Published: October 12, 2016 ABSTRACT Objectives: The aim was to explore the prognostic significance of IL-6 and markers of systemic inflammatory response (SIR), in particular C-reactive protein (CRP), in metastatic colorectal cancer (mCRC) patients, in the total study population and according to RAS and BRAF mutation status. Results: High levels of pretreatment serum IL-6 or CRP were associated with impaired outcome, in terms of reduced PFS and OS. Patients with low versus high serum IL-6 levels had median OS of 26.0 versus 16.6 months, respectively ( P < 0.001). Stratified according to increasing CRP levels, median OS varied from 24.3 months to 12.3 months, ( P < 0.001). IL-6 and CRP levels affected overall prognosis also in adjusted analyses. The effect of IL-6 was particularly pronounced in patients with BRAF mutation (interaction P = 0.004). Materials and Methods: IL-6 and CRP were determined in pre-treatment serum samples from 393 patients included in the NORDIC-VII trial, in which patients with mCRC received first line treatment. The effect of serum IL-6 and CRP on progression-free survival (PFS) and overall survival (OS) was estimated. Conclusions: High baseline serum consentrations of IL-6 or CRP were associated with impaired prognosis in mCRC. IL-6 and CRP give independent prognostic information in addition to RAS and BRAF mutation status.

// Hou-Qun Ying 1, 4, * , Hong-Xin Peng 2, 4, * , Bang-Shun He 4, * , Yu-Qin Pan 4 , Feng Wang 3, 4 , Hui-Ling Sun 4 , Xian Liu 4 , Jie Chen 4 , Kang Lin 4 , Shu-Kui Wang 4 1 Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China 2 Medical School of Southeast University, Nanjing 210009, Jiangsu, China 3 Department of Clinical Laboratory, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China 4 Central Laboratory, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, Jiangsu, China * These authors have contributed equally to this work Correspondence to: Shu-Kui Wang, email: shukuiwang@163.com Keywords: miRNA, colorectal cancer, polymorphism, clinical outcome Received: November 03, 2015 Accepted: September 25, 2016 Published: October 04, 2016 ABSTRACT Genetic variation within microRNA (miRNA) may result in its abnormal folding or aberrant expression, contributing to colorectal turmorigenesis and metastasis. However, the association of six polymorphisms (miR-608 rs4919510, miR-499a rs3746444, miR-146a rs2910164, pre-miR-143 rs41291957, pre-miR-124-1 rs531564 and pre-miR-26a-1 rs7372209) with colorectal cancer (CRC) risk, therapeutic response and survival remains unclear. A retrospective study was carried out to investigate the association in 1358 0-III stage resected CRC patients and 1079 healthy controls using Sequenom’s MassARRAY platform. The results showed that rs4919510 was significantly associated with a decreased susceptibility to CRC in co-dominant, allele and recessive genetic models, and the protective role of rs4919510 allele G and genotype GG was more pronounced among stage 0-II cases; significant association between rs531564 and poor RFS was observed in cases undergoing adjuvant chemo-radiotherapy in co-dominant, allele and dominant models; moreover, there was a positive association between rs7372209 and recurrence-free survival in stage II cases in co-dominant and over-dominant models; additionally, a cumulative effect of rs531564 and rs7372209 at-risk genotypes with hazard ratio at 1.30 and 1.95 for one and two at-risk genotypes was examined in stage II cases, respectively. Our findings indicated that rs4919510 allele G and genotype GG were protective factors for 0-II stage CRC, rs7372209 and rs531564 could decrease RFS in II stage individuals and resected CRC patients receiving adjuvant chemo-radiology.

Lymph node metastasis (LNM) is one of the major prognostic factors for esophageal squamous cell carcinoma (ESCC). However there is no consensus regarding the prognostic significance of the location of LNM. Therefore, a novel classification was proposed to identify the lymph node (LN) stations which may be useful in predicting prognosis. A total of 260 ESCC patients were enrolled in this prospective study. The prognostic values of LNM in different lymph node (LN) stations were evaluated by random survival forests (RSF). Their prognostic significance was examined by Cox regression and receiver operating characteristic curve (ROC). The three most frequently involved LN stations were station 16 (24.49%), station 1 (22.22%) and station 2 (21.05%). Stations 1, 2, 8M, 8L and 16 were grouped as dominant LN stations (DLNS) which showed higher values in predicting overall survival (OS) and disease-free survival (DFS) than the remaining LN stations, which we define as non-dominant LN stations (N-DLNS). LNM features of DLNS (number of positive LN stations, number of positive LNs and LN ratio), but not those from N-DLNS, served as independent prognostic factors (P

Immediate medical intervention is required after pelvic tumor radiotherapy to protect the radiosensitive intestine and also to mitigate tumor growth. Toll-like receptors (TLRs) have been shown to promote tissue repair processes. Here, we analyzed the effect observed upon combining the TLR2 agonist, peptidoglycan (PGN), with radiation therapy on tumors as well as intestinal tissue, both in vitro and in vivo. In contrast to radiotherapy alone, PGN when combined with ionizing radiation (IR) elicited enhanced antitumor effects and also reduced the IR-induced intestinal damage. Mechanistic studies showed that PGN first induced an IL13 response in the irradiated intestine, but was decreased in tumor cell models screened by Th1/Th2 FlowCytomix assay and validated by the application of IL13 and anti-IL13 neutralizing antibodies. Next, PGN stimulated Akt3, but not Akt1/2, as was verified by AKT1/2/3 plasmid transfection assay and in AKT1/2/3 knockout mice in vivo. Akt3 expression was inhibited in 20 μg/mL PGN-treated tumor cells and in 1.5 mg/kg PGN-treated mouse tumor models. However, Akt3 was raised via IL13 in the irradiated intestine and human intestinal cell line after the same treatment. Finally, PGN activated mTOR via IL13/AKT3 in the intestine and restored intestinal structure and function. As an adjuvant to radiotherapy, PGN inhibited tumorigenesis by suppression of mTOR activity. To summarize, the IL13/AKT3/mTOR pathway was lessened in PGN-treated irradiated tumors but was raised in the normal intestine tissue. This distinct effect of PGN on normal and tumor tissues during pelvic radiotherapy suggests that PGN may be a promising adjuvant therapy to radiation.

// Junjie Zhao 1, 2, * , Weidong Xu 2, * , Minghui He 3 , Zhensheng Zhang 2 , Shuxiong Zeng 2 , Chong Ma 2 , Yinghao Sun 2 , Chuanliang Xu 2 1 Department of Urology, Yantai Yuhuangding Hospital, Yantai 264000, China 2 Department of Urology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, China 3 Cancer Research Department, BGI-Shenzhen, Yantian District, Shenzhen, Guangdong 518083, China * These authors have contributed equally to this work Correspondence to: Chuanliang Xu, email: xuchuanliang@vip.126.com Keywords: bladder cancer, tumor progression, IPO11, prognosis, whole-exome sequencing Received: July 10, 2016 Accepted: September 06, 2016 Published: ABSTRACT Non-muscle-invasive bladder cancer (NMIBC) often has a worse prognosis following its progression to muscle-invasive bladder cancer (MIBC), despite radical cystectomy with pelvic lymph node dissection combined with chemotherapy. Therefore, the discovery of novel biomarkers for predicting the progression of this disease and of therapeutic targets for preventing it is crucial. We performed whole-exome sequencing to analyze superficial tumor tissues (T sup ) and basal tumor tissues (T bas ) from 3 MIBC patients and identified previously unreported copy number variations in IPO11 that warrants further investigation as a molecular target. In addition, we identified a significant association between the absolute copy number and mRNA expression of IPO11 and found that high importin-11 expression was correlated with poor 3-year overall survival (OS), cancer-specific survival (CSS) and cancer-free survival (CFS) compared with low expression in the BCa patients. Importin-11 overexpression was also an independent risk factor for CSS and CFS in the BCa patients. Our study has revealed that IPO11 copy number amplification contributes to its overexpression and that these changes are unfavorable prognostic factors in NMIBC. Thus, IPO11 copy number amplification and importin-11 overexpression are promising biomarkers for predicting the progression and poor prognosis of patients with NMIBC.

// Haiyong Wang 1, 2 , Li Kong 2 , Chenyue Zhang 3 , Dawei Chen 2 , Hui Zhu 2 , Jinming Yu 2 1 School of Medicine, Shandong University, Jinan, 250012, China 2 Department of Radiation Oncology, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, 250117, China 3 Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China Correspondence to: Hui Zhu, email: drzhuhui@163.com Jinming Yu, email: sdzlyujinming@126.com Keywords: breast cancer, mastectomy, radiotherapy, positive lymph nodes, SEER Received: April 2, 2016 Accepted: September 12, 2016 Published: September 26, 2016 ABSTRACT Postmastectomy radiotherapy (PMRT) has become a standard adjuvant postoperative therapy for breast cancer patients with four or more positive lymph nodes. However, some studies have demonstrated that some subgroups of the breast cancer patients with four or more positive lymph nodes did not benefit substantially from PMRT. Therefore, it is of great necessity to identify whether all breast cancer patients with four or more positive lymph nodes who underwent modified radical mastectomy be treated with PMRT. In our study, we first established a prognostic model using the Surveillance Epidemiology and End Results (SEER) database between 1998 and 2001. Univariate and multivariate Cox models were used to assess the prognostic factors, and five risk factors individually associated with prognosis including AJCC stage, AJCC T, Grade, ER status, PR status. Prognostic index of PMRT were defined as the number of risk factor (NRF). The NRF scores correlated well with overall survival of PMRT even if the patients were in the sub-poor prognosis group. Then the prognostic model was validated using the SEER database between 2006 and 2009, and the same results were obtained. In conclusion, different from others studies, our study demonstrated that all patients with four or more positive lymph nodes after modified radical mastectomy need to be treated with PMRT ever if the patients belonged to AJCC T4 in a poor prognosis group.

// Wolfgang P. Fendler 1,2 , Svenja Reinhardt 1 , Harun Ilhan 1 , Andreas Delker 1 , Guido Boning 1 , Franz J. Gildehaus 1 , Christian Stief 3,4 , Peter Bartenstein 1,4 , Christian Gratzke 3,4 , Sebastian Lehner 1 and Axel Rominger 1 1 Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany 2 Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA 3 Department of Urology, Ludwig-Maximilians-University of Munich, Munich, Germany 4 Comprehensive Cancer Center, Ludwig-Maximilians-University of Munich, Munich, Germany Correspondence to: Wolfgang P. Fendler, email: // Keywords : mCRPC; PET; prostate cancer; PSMA; lutetium Received : March 20, 2016 Accepted : September 19, 2016 Published : September 24, 2016 Abstract Prostate cancer can be targeted by ligands to the prostate-specific membrane antigen (PSMA). We aimed to evaluate dosimetry, safety and efficacy of 177 Lu-PSMA-617 radioligand therapy (RLT) in patients with metastatic castration-resistant prostate cancer (mCRPC). Fifteen patients each received two cycles of 3.7 GBq ( n = 5) or 6.0 GBq ( n = 10) 177 Lu-PSMA-617 at an eight to ten weeks interval. For safety monitoring, each treatment was followed by dosimetry with serial quantitative SPECT as well as inpatient and outpatient recording of adverse events. Response to RLT was primarily determined by baseline to follow-up change in 68 Ga-PSMA PET/CT (RECIST1.1), as well as change in prostate-specific antigen (PSA), quality of life (QoL, FACT-P scale), and pain (Brief Pain Inventory) as secondary endpoints. Radiation dose delivered to the tumor (6.1 Gy/GBq) was six to twelve-fold higher than to critical organs (kidney left/right 0.5/0.6 Gy/GBq each, salivary glands 1.0 Gy/GBq). Total radiation dose per kidney did not exceed 23 Gy in any patient. Three patients had sub-acute and latent grade 3 events, i.e. anemia, leukocytopenia, and nausea. No acute events, grade ≥4 events or high grade events for salivary gland or kidney function were observed. After two RLT cycles, 4 (27%) patients had partial response, 6 (40%) had stable disease, and 5 (33%) had progressive disease according to RECIST. Any PSA decline was observed in 12/15 (80%) patients during RLT. Significant pain relief was documented in 7/10 (70%) symptomatic patients and QoL improved in 9/15 (60%) patients. 177 Lu-PSMA-617 therapy proved safe and indicated promising response rates for both objective and patient-reported outcomes in our small group of mCRPC patients.

The clinicopathologic relevance and prognostic value of tumor deposits in colorectal cancer has been widely demonstrated. However, there are still debates in the prognostic value of tumor deposits and the applicability of N1c category in rectal cancer with preoperative radiotherapy. In this study, rectal cancer with preoperative radiotherapy followed by resection of primary tumors registered in Surveillance, Epidemiology and End Results (SEER) database from 2010-2012 were analyzed. There were 4,813 cases eligible for this study, and tumor deposits were found in 514 (10.7%) cases. The presence of tumor deposits was significantly associated with some aggressive characteristics, including poorer tumor differentiation, more advanced ypT category, ypN category and ypTNM stage, distant metastasis, elevated carcinoembryonic antigen, higher positive rates of circumferential resection margin and perineural invasion (all P < = 0.001). Tumor deposit was also an independent negative prognostic factor for cancer-specific survival in rectal cancer with preoperative radiotherapy (adjusted HR and 95% CI: 2.25 (1.51 – 3.35)). N1c category had significant worse survival compared with N0 category (adjusted HR and 95% CI: 2.41 (1.24 – 4.69)). In conclusion, tumor deposit was a significant and independent prognostic factor, and the N1c category by the 7th edition of AJCC/TNM staging system was applicable in rectal cancer with preoperative radiotherapy.

// Gaochao Dong 1, * , Qiang Chen 2, 3, * , Feng Jiang 1, * , Decai Yu 4 , Qixing Mao 1, 2 , Wenjie Xia 1, 2 , Run Shi 1, 2 , Jie Wang 1 , Lin Xu 2, 1 1 Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China 2 Department of The Fourth Clinical College, Nanjing Medical University, Nanjing, Jiangsu, China 3 Department of Thoracic Surgery, Xuzhou Centre Hospital, Xuzhou, Jiangsu, China 4 Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical College, Nanjing, Jiangsu, China * These authors contributed equally to this work Correspondence to: Lin Xu, email: xulin83cn@gmail.com Keywords: diisopropylamine dichloroacetate, esophageal squamous cell carcinoma, ROS, radiosensitization Received: April 21, 2016 Accepted: August 24, 2016 Published: September 08, 2016 ABSTRACT Radiotherapy is generally applied in the treatment of esophageal squamous cell carcinoma (ESCC). However, the radioresistance of ESCC still remains an obstacle for the curative effect of this treatment. We hypothesized that diisopropylamine dichloroacetate (DADA), an inhibitor of pyruvate dehydrogenase kinase (PDK), might enhance radiosensitizationin resistant ESCC. The clonogenic survival assay revealed that DADA sensitized ESCC cells to radiotherapy in vitro ; furthermore, the combination of DADA and radiotherapy increased the expression of γ-H2AX, which is a hallmark of DNA double-strand breaks. Arrest at G2/M phase as well as the induction of apoptosis of ESCC cells were also observed in the cells treated with the combination of DADA and radiotherapy. Notably, xenograft tumor growth was significantly suppressed in vivo by combined radiotherapy and DADA administration. It has been proven that glycolysis is highly correlated with radioresistance, which could be reversed by the shift from glycolysis to mitochondrial oxidation. In our present study, we found that DADA could modulate oxidative phosphorylation as well as increase the intracellular levels of reactive oxygen species (ROS). Collectively, we concluded that DADA-induced intracellular ROS accumulation was identified as the key factor of radiotherapy sensitization of ESCC.

// Doo-Sik Kong 1,* , Do-Hyun Nam 1,* , Shin-Hyuk Kang 2 , Jae Won Lee 3 , Jong-Hee Chang 4 , Jeong-Hoon Kim 5 , Young-Jin Lim 6 , Young-Cho Koh 7 , Yong-Gu Chung 2 , Jae-Min Kim 8 and Choong-Hyun Kim 8 1 Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Department of Neurosurgery, College of Medicine, Korea University, Seoul, Korea 3 Department of Statistics, Korea University, Seoul, Korea 4 Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea 5 Department of Neurosurgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 6 Department of Neurosurgery, Kyunghee University Hospital, Seoul, Korea 7 Department of Neurosurgery, Konkuk University Medical Center, Seoul, Korea 8 Department of Neurosurgery, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea * These authors have contributed equally to this work Correspondence to: Choong Hyun Kim, email: // Keywords : immunotherapy, autologous cytokine-induced killer cell, glioblastoma Received : August 05, 2016 Accepted : September 23, 2016 Published : September 27, 2016 Abstract Purpose: Adoptive cell immunotherapy involves an ex vivo expansion of autologous cytokine-induced killer (CIK) cells before their reinfusion into the host. We evaluated the efficacy and safety of CIK cell immunotherapy with radiotherapy-temozolomide (TMZ) for the treatment of newly diagnosed glioblastomas. Experimental design: In this multi-center, open-label, phase 3 study, we randomly assigned patients with newly diagnosed glioblastoma to receive CIK cell immunotherapy combined with standard TMZ chemoradiotherapy (CIK immunotherapy group) or standard TMZ chemoradiotherapy alone (control group). The efficacy endpoints were analyzed in the intention-to-treat set and in the per protocol set. Results: Between December 2008 and October 2012, a total of 180 patients were randomly assigned to the CIK immunotherapy ( n = 91) or control group ( n = 89 ). In the intention-to-treat analysis set, median PFS was 8.1 months (95% confidence interval (CI), 5.8 to 8.5 months) in the CIK immunotherapy group, as compared to 5.4 months (95% CI, 3.3 to 7.9 months) in the control group (one-sided log-rank, p = 0.0401). Overall survival did not differ significantly between two groups. Grade 3 or higher adverse events, health-related quality of life and performance status between two groups did not show a significant difference. Conclusions: The addition of CIK cells immunotherapy to standard chemoradiotherapy with TMZ improved PFS. However, the CIK immunotherapy group did not show evidence of a beneficial effect on overall survival.

// Xiao Yang 1,* , Peng Li 1,* , Xiaheng Deng 1,* , Hongquan Dong 2 , Yidong Cheng 1 , Xiaolei Zhang 1 , Chengdi Yang 1 , Jingyuan Tang 1 , Wenbo Yuan 1 , Xiaoting Xu 1 , Jun Tao 1 , Pengchao Li 1 , Haiwei Yang 1 , Qiang Lu 1 , Min Gu 1 and Zengjun Wang 1 1 Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China 2 Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China * These authors have contributed equally to this work Correspondence to: Qiang Lu, email: // Min Gu, email: // Keywords : upper tract urothelial carcinoma; perioperative treatment; network meta-analysis Received : December 23, 2015 Accepted : September 20, 2016 Published : September 24, 2016 Abstract Background: Perioperative treatments have been used to improve prognosis in patients with upper tract urothelial carcinoma (UTUC). However, optimal management remains unestablished. Methods: We searched the Embase, Web of Science and Cochrane databases for studies published before June 20, 2015. All included studies were categorised into three groups on the basis of the outcome reported (overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS)). Relative hazard ratios (HRs) for death were calculated using random-effects Bayesian network meta-analysis methods. We also ranked the three different treatments in terms of three outcomes. Results: A total of 31 trials with 8100 patients were included. Compared with the control, adjuvant chemotherapy (AC) could improve OS, DSS and RFS by 32% (HR 0.68, 95% CI 0.51-0.89), 29% (HR 0.71, 95% CI 0.54-0.89) and 51% (HR 0.49, 95% CI 0.23-0.85), respectively. We noted a marked prolongation of RFS in both intravesical chemotherapy (HR 0.32, 95% CI 0.09-0.69) as well as concurrent radiotherapy and intravesical chemotherapy (HR 0.32, 95% CI 0.03-0.97) than in the control. Neoadjuvant chemotherapy (NAC) showed a significant improvement in DSS relative to the control (HR 0.25, 95% CI 0.06-0.61) and a distinct advantage over AC (HR 0.36, 95% CI 0.08-0.90) or AR (HR 6.89, 95% CI 1.25-18.66). Conclusions: Our results showed that AC; intravesical chemotherapy; and concurrent radiotherapy and intravesical chemotherapy could improve the prognosis of UTUC patients. NAC was found to be more favourable for UTUC than AC in terms of DSS.

// Ran Tao 1 , Xiaodan Li 2 , Ruizhi Ran 3 , Zhihua Xiao 4 , Hongyue Zhang 1 , Hongyan Kong 1 , Qiqin Song 1 , Yu Huang 1 , Likui Wang 5 and Jiaquan Huang 1 1 Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China 2 Department of Infectious Diseases,The Central Hospital of Enshi Autonomous Prefecture, Enshi Clinical College of Wuhan University, Wuhan, Hubei, China 3 Department of Interal Medicine-Oncology, The Central Hospital of Enshi Autonomous Prefecture, Enshi Clinical College of Wuhan University, Wuhan, Hubei, China 4 Department of Medical Oncology, Hubei Cancer Hospital, Wuhan, Hubei, China 5 Savaid Medical School, University of Chinese Academy of Sciences Institute of Microbiology, Chinese Academy of Sciences, Beijing, China Correspondence to: Jiaquan Huang, email: // Keywords : unresectable hepatocellular carcinoma, transcatheter arterial chemoembolization, network meta-analysis Received : June 29, 2016 Accepted : September 21, 2016 Published : September 29, 2016 Abstract Hepatocellular carcinoma (HCC) is usually managed by the transcatheter arterial chemoembolization (TACE). However, this technique has been challenged since severe complications have been observed in clinical practices. As a result, clinicians have started to seek other minimally invasive surgeries with equivalent efficacy. The corresponding surgeries were assessed by the five outcomes: complete response (CR), partial response (PR), stable disease (SD), progression disease (PD) and objective response rate (ORR). Direct meta-analysis and network meta-analysis were performed and the results were represented by odds ratios (OR), 95% confidence and credential intervals. Furthermore, the value of surface under the cumulative ranking curve (SUCRA)was calculated to provide corresponding rankings.Seventeen studies were incorporated into the network meta-analysis which indicated that TACE + external-beam radiation therapy (EBRT) and drug-eluting beads (DEB) were better than TACE at controllingPD. TACE + EBRT demonstrated their advantages compared to TARE-90Y.However, network meta-analysis comparison showed no significant difference between the corresponding eight treatments with respect to CR, PR, SD and ORR. Moreover, the SUCRA suggested that TACE+EBRT were better than other treatments at treating unresectableHCC.Based on the present results of this network meta-analysis, TACE + EBRT was more effective than the other seven minimally invasive surgeries and therefore it is considered as the optimal treatment for HCC.

// Zhibin Bai 1,2* , Yaoping Shi 1,3* , Jianfeng Wang 1 , Longhua Qiu 1 , Eric J. Monroe 1 , Gaojun Teng 2 , Feng Zhang 1,** and Xiaoming Yang 1,** 1 Image-Guided Biomolecular Intervention Research, Section of Interventional Radiology, Department of Radiology, University of Washington School of Medicine, Seattle, WA, USA 2 Department of Radiology, Zhongda Hospital, Southeastern University, Nanjing, China 3 Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China * These authors made the equal contributions as the co-first author for this study ** These authors made the equal contributions for this study Correspondence to: Xiaoming Yang, email: // Keywords : radiofrequency, hyperthermia, chemotherapy, pancreatic cancer, local Received : April 06, 2016 Accepted : September 20, 2016 Published : September 27, 2016 Abstract Purpose: To investigate the technical feasibility of using ultrasound-guided intratumoral radiofrequency hyperthermia (RFH) to enhance local chemotherapy of rat orthotopic pancreatic cancers. Materials and Methods: Orthotopic pancreatic cancer masses were established by inoculating luciferase/mCherry labeled-pancreatic cancer cells into the pancreatic tails of Lewis model rats via a laparotomy approach. Twenty-four rats with pancreatic cancer and 24 mice with subcutaneous pancreatic cancer xenografts in four study groups ( n = 6/group) received various treatments: i) combination therapy of intratumoral MR imaging-heating-guidewire-mediated RFH (42 o C) plus local chemotherapy (gemcitabine); ii) intratumoral chemotherapy alone; iii) RFH alone; and (iv)phosphate-buffered saline (PBS). Transcutaneous ultrasound imaging was used to guide the treatment and subsequently follow changes in tumor sizes. Bioluminescence optical imaging was performed to follow photon signal changes. Sonographic and optical findings were correlated with histology at 14 days. Results: Optical imaging demonstrated a significantly decreased bioluminescence signal in mice with combination therapy group, compared with the other control groups (0.51±0.18 VS 1.6±0.4 VS 3.18±0.9 VS 3.5±0.96, p < 0.05). Ultrasound imaging showed the smallest tumor volumes of both mice and rat group with the combination therapy, compared with other control groups (0.62±0.16 VS 1.25±0.19 VS 2.28±0.25 VS 2.64±0.26, p < 0.05) and (0.75±0.18 VS 1.31±0.30 VS 1.61±0.28 VS 1.72±0.28, p < 0.05). Both imaging findings were confirmed by histologic correlation. Conclusion Intratumoral RFH can augment the chemotherapeutic effect in an orthotopic pancreatic cancer model.

// Bing Sun 1 , Zhou Huang 1 , Shikai Wu 1 , Lijuan Ding 1 , Ge Shen 1 , Lei Cha 2 , Junliang Wang 1 , Santai Song 3 1 Department of Radiotherapy, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China 2 Department of Science and Technology, Academy of Military Medical Sciences, Beijing 100071, China 3 Department of Breast Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China Correspondence to: Shikai Wu, email: skywu4923@sina.com Keywords: breast cancer, brain metastases, cyst, whole-brain radiotherapy, stereotactic radiosurgery Received: July 02, 2016 Accepted: September 05, 2016 Published: September 21, 2016 ABSTRACT Purpose: Brain metastasis (BM) with a cystic component from breast cancer is rare and largely uncharacterized. The purpose of this study was to identify the characteristics of cystic BM in a large cohort of breast cancer patients. Results: A total of 35 eligible patients with cystic BM and 255 patients with solid BM were analyzed. Three factors were significantly associated with an increased probability of developing cystic lesions: age at diagnosis ≤ 40 years, age at BM ≤ 45 years, and poor histological grade ( p < 0.05). Patients with cystic metastasis were also characterized by a larger metastasis volume, a shorter progression-free survival (PFS) following their first treatment for BM, and poor overall survival after BM ( p < 0.05). Multivariate analysis further demonstrated that local control of cystic BM was only potentially achieved for HER2-negative primary tumors ( p = 0.084). Methods: Breast cancer patients with parenchymal BM were reviewed from consecutive cases treated at our institution. Cystic BM was defined when the volume of a cystic lesion was greater than 50% of the aggregated volume of all lesions present. Clinicopathologic and radiographic variables were correlated with development of cystic lesions and with prognosis of cystic BM. Conclusions: This study shows that cystic BM from breast cancer, a special morphological type of BM, had worse prognosis than the more commonly observed solid BM. Younger age and low tumor grade were associated with the development of cystic lesions. Further comprehensive research and management of cystic BM are warranted to improve its poor prognosis.

// RenCui Quan 1, * , JiaXing Huang 1, * , HongTao Chen 2, * , YiFeng Liao 1 , WeiZe Lv 1 , Nan Chen 1 , JianJun Liu 3, 4 , HongYu Zhang 1 , DaZhi Xu 3, 4 1 Department of Medical Oncology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhu Hai, Guangdong Province, People’s Republic of China 2 Department of Laboratory, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhu Hai, Guangdong Province, People’s Republic of China 3 Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, China 4 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong Province, China * These authors have contributed equally to this work Correspondence to: HongYu Zhang, email: zdwyzhy@163.com DaZhi Xu, email: xudzh@sysucc.org.cn Keywords: adjuvant chemotherapy, radically resected, gastric cancer Received: February 20, 2016 Accepted: August 09, 2016 Published: September 01, 2016 ABSTRACT Background: We conducted the retrospective study to compare the efficacy of monotherapies versus two-drug regimens as postoperative chemotherapy for patients with radically resected gastric cancer. Result: At a median follow-up of 5.3 years, no significant difference in terms of OS was observed between two groups, neither before nor after matching. After matching, median DFS was statistically significant between group A and B (median, 67.5 vs 101.0 months, respectively; hazard ratio [HR], 0.65; 95% CI, 0.45 to 0.95; P =0.027), which meant doublets prolonged DFS. In subgroup analysis, the patients of stage III receiving doublet achieved better OS than those receiving monotherapy. People who received doublet and were less than 65 years old, or male patients, or in T4 stage, or in N2 stage, or receiving subtotal gastrectomy had better DFS than those with monotherapy. Method: A data set including 501 patients (monotherapy, n=107; doublet, n=394) was matched between the two groups (n=107 patients per group) using the propensity-matched study. The primary and secondary endpoint was overall survival(OS) and disease-free survival(DFS), respectively. Survival data was compared using the Kaplan-Meier method and Cox proportion hazards models for univariate and multivariate analyses. Conclusion: The dual regimens seemed not to add overall survival benefits to patients receiving curative gastrectomy, compared with single-agent fluoropyrimidine as postoperative chemotherapy. However, dual regimens showed better disease-free survival.

Targeted therapies aimed at tumor vasculature are utilized in combination with chemotherapy to improve drug delivery and efficacy after tumor vascular normalization. Tumor vessels are highly disorganized with disrupted blood flow impeding drug delivery to cancer cells. Although pharmacologic anti-angiogenic therapy can remodel and normalize tumor vessels, there is a limited window of efficacy and these drugs are associated with severe side effects necessitating alternatives for vascular normalization. Recently, moderate aerobic exercise has been shown to induce vascular normalization in mouse models. Here, we provide a mechanistic explanation for the tumor vascular normalization induced by exercise. Shear stress, the mechanical stimuli exerted on endothelial cells by blood flow, modulates vascular integrity. Increasing vascular shear stress through aerobic exercise can alter and remodel blood vessels in normal tissues. Our data in mouse models indicate that activation of calcineurin-NFAT-TSP1 signaling in endothelial cells plays a critical role in exercise-induced shear stress mediated tumor vessel remodeling. We show that moderate aerobic exercise with chemotherapy caused a significantly greater decrease in tumor growth than chemotherapy alone through improved chemotherapy delivery after tumor vascular normalization. Our work suggests that the vascular normalizing effects of aerobic exercise can be an effective chemotherapy adjuvant.

// Yuhan Wang 1 , Yingying Han 1 , Qiang Weng 1 , Zhengrong Yuan 1 1 College of Biological Sciences and Technology, Beijing Forestry University, Beijing 100083, People’s Republic of China Correspondence to: Zhengrong Yuan, email: zryuan@bjfu.edu.cn Keywords: XPG, rs2296147, cancer, clinical outcomes, meta-analysis Received: May 24, 2016 Accepted: August 11, 2016 Published: August 29, 2016 ABSTRACT The Xeroderma pigmentosum complementation group G ( XPG ) rs2296147T>C polymorphism is suspected to associate with the clinical outcomes of cancer patients. However, the results are inconsistent. This meta-analysis aimed to evaluate the reliable predictive value of XPG rs2296147T>C polymorphism on clinical outcomes of cancer patients. A total of 11 eligible studies were enrolled in this meta-analysis. Our results indicated that the cancer patients with TT and CT genotypes were significantly associated with better respond rates when compared with the CC genotype (TT versus (vs.) CC: odds ratio (OR) = 2.05, 95% confidence intervals (CIs), 1.32-3.20, P = 0.002; TT+CT vs. CC: OR= 1.57, 95% CI, 1.14-2.17, P = 0.005). The TT genotype and/or T allele might be associated with higher survival time for cancer patients than the CC genotype and/or C allele. The cumulative meta-analyses showed an apparent beneficial objective response of TT genotype on cancer patients. In conclusion, this meta-analysis suggests that the XPG rs2296147T>C polymorphism is associated with the clinical outcomes of cancer patients. The XPG rs2296147T>C polymorphism might be a predictive factor of prognosis in cancers patients and contribute to individual treatment in the future.

// Francesca De Felice 1 , Daniela Musio 1 , Giovanni Luca Gravina 2 , Francesco Marampon 2 and Vincenzo Tombolini 1,3 1 Department of Radiotherapy, Policlinico Umberto I, “Sapienza” University of Rome, Rome, Italy 2 Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L’Aquila, L’Aquila, Italy 3 Spencer-Lorillard Foundation, Viale Regina Elena, Rome, Italy Correspondence to: Francesca De Felice, email: // Keywords : radiotherapy; stage I seminoma; surveillance; chemotherapy; orchiectomy Received : May 22, 2016 Accepted : August 13, 2016 Published : August 18, 2016 Abstract Aim : To report long term oncologic outcomes after adjuvant radiotherapy (RT) for stage I seminoma. Method: We reviewed the complete data set for all patients treated at our institute between 1988 and 2005 for stage I seminoma with adjuvant RT after radical orchiectomy . Results: A total of 85 patients were included. The median follow-up was 15 years. The 20-year overall survival (OS) and relapse free survival (RFS) were 92% and 96.3%, respectively. No severe acute and late complications were recorded. Overall 5.9% of patients had a second unrelated malignancy. Conclusion: Adjuvant RT is an efficacious and safe treatment in stage I seminoma.

To evaluate the safety and efficacy of combining Endostar antiangiogenic therapy with neoadjuvant chemotherapy for the treatment of stage IIIA (N2) NSCLC, we conducted a randomized, controlled, open-label clinical study of 30 NSCLC patients. Patients were randomly assigned to the test or control groups, which received either two cycles of an NP neoadjuvant chemotherapy regimen combined with Endostar or the NP regimen alone, respectively, at a 2:1 ratio. Efficacy was assessed after 3 weeks, and surgical resection occurred within 4 weeks, in the 26 patients who successfully completed treatment. While total response rates (RR) and clinical benefit rates (CBR) did not differ between the experimental groups, total tumor regression rates (TRR) were higher in the test group than in the control group. Median DFS and OS also did not differ between the test and control groups. Clinical perioperative indicators, including intraoperative blood loss, number of dissected lymph node groups, duration of postoperative indwelling catheter use, and time to postoperative discharge, were comparable in the test and control groups. Finally, hematological and non-hematological toxicities and postoperative pathological indicators, including down-staging ratio, complete resection ratio, and metastatic lymph node ratio, also did not differ between the groups. Overall, combining Endostar with NP neoadjuvant chemotherapy increased therapeutic efficacy without increasing adverse effects in stage IIIA-N2 NSCLC patients. This study is registered with ClinicalTrials.gov (number NCT02497118).

Alternating electric fields at an intermediate frequency (100~300 kHz), referred to as tumour-treating fields (TTF), are believed to interrupt the process of mitosis via apoptosis and to act as an inhibitor of cell proliferation. Although the existence of an antimitotic effect of TTF is widely known, the proposed apoptotic mechanism of TTF on cell function and the efficacy of TTF are controversial issues among medical experts. To resolve these controversial issues, a better understanding of the underlying molecular mechanisms of TTF on cell function and the differences between the effects of TTF alone and in combination with other treatment techniques is essential. Here, we report experimental evidence of TTF-induced apoptosis and the synergistic antimitotic effect of TTF in combination with ionizing radiation (IR). For these experiments, two human Glioblastoma multiforme (GBM) cells (U373 and U87) were treated either with TTF alone or with TTF followed by ionizing radiation (IR). Cell apoptosis, DNA damage, and mitotic abnormalities were quantified after the application of TTF, and their percentages were markedly increased when TTF was combined with IR. Our experimental results also suggested that TTF combined with IR synergistically suppressed both cell migration and invasion, based on the inhibition of MMP-9 and vimentin.

// Pei Yang 1,2,* , Chuanbao Zhang 2,* , Jinquan Cai 9 , Gan You 1,2 , Yinyan Wang 1,2 , Xiaoguang Qiu 3 , Shouwei Li 5 , Chenxing Wu 5 , Kun Yao 6 , Wenbin Li 7 , Xiaoxia Peng 10 , Wei Zhang 1,2 and Tao Jiang 2,4,8 1 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 2 Beijing Neurosurgical Institute, Capital Medical University, Beijing, China 3 Department of Radiation Therapy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 4 China National Clinical Research Center for Neurological Diseases, Beijing, China 5 Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China 6 Department of Pathology, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China 7 Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China 8 Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing, China 9 Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China 10 Department of Epidemiology and Biostatistics, School of Public Health and Family Medicine, Capital Medical University, Beijing, China * The first two authors contributed equally to this work Correspondence to: Wei Zhang, email: // Tao Jiang, email: // Keywords : high-grade glioma, young adult, radiation, temozolomide, survival Received : November 16, 2015 Accepted : August 22, 2016 Published : August 31, 2016 Abstract Purpose: Age is a major prognostic factor for malignant gliomas. However, few studies have investigated the management of gliomas in young adults. We determined the role of survival and treatment in young adults with advanced gliomas in a large population from the Chinese Glioma Genome Atlas (CGGA). Methods: This study included 726 adults (age ≥ 18) with histologically proven anaplastic glioma or glioblastoma multiforme (GBM). The overall and progression-free survival was determined in young (age < 50) and older groups (age ≥ 50). Results: The study included an older group (OP) of 264 patients and a younger group (YP) of 462patients. In the OP group with GBM and anaplastic glioma, patients treated with RT combined with temozolomide (TMZ) manifested significantly longer OS and PFS compared with patients assigned to RT alone (P < 0.05). In contrast, the YP group diagnosed with anaplastic glioma failed to show any survival advantage with RT plus TMZ compared with RT alone. Conclusions: We observed no survival benefit in young adults (age < 50) with anaplastic glioma when treated with TMZ combined with RT. Our findings warrant further investigation of younger patients diagnosed with anaplastic glioma treated with radiotherapy plus TMZ chemotherapy.

// Uwe Thiel 1 , Angela Wawer 1 , Irene von Luettichau 1 , Hans-Ulrich Bender 1 , Franziska Blaeschke 1 ,Thomas G.P. Grunewald 2 , Marc Steinborn 3 , Barbara Roper 4, 10, * , Halvard Bonig 5, 6 , Thomas Klingebiel 5 , Peter Bader 5 , Ewa Koscielniak 7 , Michael Paulussen 8 , Uta Dirksen 9 , Heribert Juergens 9 , Hans-Jochem Kolb 1 , Stefan E.G. Burdach 1, 10 1 Department of Pediatrics and Pediatric Oncology Center, Kinderklinik Munchen Schwabing, Stadtisches Klinikum Munchen und Klinikum rechts der Isar, Wilhelm Sander Sarcoma Unit, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany 2 Laboratory for Pediatric Sarcoma Biology, Institute of Pathology, LMU, Munich, Germany 3 Department of Radiology, Klinikum Schwabing, Stadtisches Klinikum Munchen, Munich, Germany 4 Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany 5 Department of Pediatric Hematology and Oncology, Universitatsklinikum Frankfurt, Frankfurt, Germany 6 Department of Transfusion Medicine and Immunohematology, Universitatsklinikum Frankfurt, Frankfurt, Germany 7 Department of Pediatric Oncology, Hematology and Immunology, Olgahospital, Klinikum Stuttgart, Stuttgart, Germany 8 Vestische Kinder- und Jugendklinik, Datteln, Universitat Witten/Herdecke, Datteln, Germany 9 Department of Pediatric Hematology and Oncology, Universitatsklinikum Munster, Munster, Germany 10 Munich Comprehensive Cancer Center, Munchen, Germany * Present address: Radiation Oncology Clinic, Klinikum Bogenhausen, Stadtisches Klinikum Munchen, Munich, Germany Correspondence to: Stefan E.G. Burdach, email: meta-eicess@lrz.tum.de Keywords: Ewing sarcoma, bone metastasis, bone marrow metastasis, allogeneic stem cell transplantation, high-dose chemotherapy Received: February 08, 2016 Accepted: June 30, 2016 Published: July 29, 2016 ABSTRACT Purpose: Advanced Ewing sarcomas have poor prognosis. They are defined by early relapse (

// Hong In Yoon 1,4 , Inkyung Jung 2 , Kwang-Hyub Han 3,4 and Jinsil Seong 1,4 1 Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Korea 2 Department of Biostatistics & Medical Informatics, Yonsei University College of Medicine, Seoul, Korea 3 Department of Internal Medicine, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Korea 4 Korean Liver Cancer Study Group, Seoul, Korea Correspondence to: Jinsil Seong, email: // Keywords : large hepatocellular carcinoma, radiotherapy, BCLC stage C, median survival time, propensity score matching Received : April 13, 2016 Accepted : June 17, 2016 Published : July 28, 2016 Abstract Background and aims: Clinical trials to determine the efficacy of radiotherapy (RT) in liver-confined but non-resectable Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) are scarce. We aimed to determine the benefit of RT in such tumors and investigated large HCC tumors. Methods: HCC data from the Korea Central Cancer Registry recorded from 2008 to 2010 were used. A total of 593 patients met our inclusion criteria; 67 were treated with RT while the remainder made up the non-RT group. Fifty-two RT recipients underwent combination treatments within 4 weeks after the first RT treatment, and were defined as the combination RT group. We performed propensity score matching (PSM) to compare the RT or combination RT groups with the non-RT group. The endpoint was overall survival (OS). Results: Median follow-up time for surviving patients was 48 months. After PSM, there was no difference in OS between the RT and non-RT groups or between the combination RT and non-RT groups. However, the combination RT group had a longer median survival time (MST) (10.7 vs. 6.9 months, respectively). Next, we conducted PSM between the combination RT and non-RT groups in patients with tumor sizes ≥10 cm; MST was significantly longer in the former group (10.1 vs. 5.4 months, respectively; bootstrap 95% confidence interval of the difference in MST: 0.2-11.8). Conclusions: As a combined modality, RT is a plausible therapeutic option for liver-confined but non-resectable BCLC stage C large HCC patients.

// Dieter Lemke 1, 2, 3 , Hans-Werner Pledl 1, 2, 3 , Markus Zorn 4 , Manfred Jugold 5 , Ed Green 1, 6 , Jonas Blaes 1, 2 , Sarah Low 1, 2, 3 , Anne Hertenstein 1, 2, 3 , Martina Ott 1, 6 , Felix Sahm 1, 7, 8 , Ann-Catherine Steffen 1, 2 , Markus Weiler 1, 2, 3 , Frank Winkler 1, 2, 3 , Michael Platten 1, 3, 6 , Zhen Dong 9, * , Wolfgang Wick 1, 2, 3, * 1 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany 2 Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany 3 Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany 4 Central Laboratory of Heidelberg University Hospital, German Cancer Research Center (DKFZ), Heidelberg, Germany 5 Core Facility Small Animal Imaging Center, German Cancer Research Center (DKFZ), Heidelberg, Germany 6 Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany 7 Department of Neuropathology, Institute of Pathology, University of Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany 8 Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany 9 Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China * These authors have shared senior authorship Correspondence to: Zhen Dong, email: dongz@tjh.tjmu.edu.cn Wolfgang Wick, email: wolfgang.wick@med.uni-heidelberg.de Keywords: dihydroartemisinin, glioblastoma, physical exercises (PE), therapy, physical exercise Received: May 11, 2016 Accepted: June 14, 2016 Published: July 20, 2016 ABSTRACT Influencing cancer metabolism by lifestyle changes is an attractive strategy as - if effective - exercise-induced problems may be less severe than those induced by classical anti-cancer therapies. Pursuing this idea, clinical trials evaluated the benefit of e.g. different diets such as the ketogenic diet, intermittent caloric restriction and physical exercise (PE) in the primary and secondary prevention of different cancer types. PE proved to be beneficial in the context of breast and colon cancer. Glioblastoma has a dismal prognosis, with an average overall survival of about one year despite maximal safe resection, concomitant radiochemotherapy with temozolomide followed by adjuvant temozolomide therapy. Here, we focused on the influence of PE as an isolated and adjuvant treatment in murine GB therapy. PE did not reduce toxic side effects of chemotherapy in mice administered in a dose escalating scheme as shown before for starvation. Although regular treadmill training on its own had no obvious beneficial effects, its combination with temozolomide was beneficial in the treatment of glioblastoma-bearing mice. As PE might partly act through the induction of reactive oxygen species, dihydroartemisinin - an approved anti-malarial drug which induces oxidative stress in glioma cells - was further evaluated in vitro and in vivo . Dihydroartemisinin showed anti-glioma activity by promoting autophagy, reduced the clonogenic survival and proliferation capacity of glioma cells, and prolonged the survival of tumor bearing mice. Using the reactive oxygen species scavenger n-acetyl-cysteine these effects were in part reversible, suggesting that dihydroartemisinin partly acts through the generation of reactive oxygen species.

// Jana Simova 1 , Olena Sapega 1 , Terezie Imrichova 2 , Ivan Stepanek 1 , Lenka Kyjacova 2 , Romana Mikyskova 1 , Marie Indrova 1 , Jana Bieblova 1 , Jan Bubenik 3 , Jiri Bartek 2, 4, 5 , Zdenek Hodny 2 , Milan Reinis 1 1 Immunology Unit, Czech Centre for Phenogenomics, BIOCEV and Department of Transgenic Models of Diseases, Institute of Molecular Genetics of the ASCR, v.v.i., Prague 14220, Czech Republic 2 Department of Genome Integrity, Institute of Molecular Genetics, v.v.i., Academy of Sciences of the Czech Republic, Prague 14220, Czech Republic 3 First Faculty of Medicine, Charles University in Prague, Prague 12000, Czech Republic 4 Danish Cancer Society Research Center, Copenhagen DK-2100, Denmark 5 Department of Medical Biochemistry and Biophysics, Science For Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institute, 17121 Solna, Sweden Correspondence to: Zdenek Hodny, email: hodny@img.cas.cz Milan Reinis, email: reinis@img.cas.cz Keywords: cellular senescence, cancer chemotherapy, docetaxel, IL-12, cell therapy Received: April 18, 2016 Accepted: May 29, 2016 Published: July 19, 2016 ABSTRACT Standard-of-care chemo- or radio-therapy can induce, besides tumor cell death, also tumor cell senescence. While senescence is considered to be a principal barrier against tumorigenesis, senescent cells can survive in the organism for protracted periods of time and they can promote tumor development. Based on this emerging concept, we hypothesized that elimination of such potentially cancer-promoting senescent cells could offer a therapeutic benefit. To assess this possibility, here we first show that tumor growth of proliferating mouse TC-1 HPV-16-associated cancer cells in syngeneic mice becomes accelerated by co-administration of TC-1 or TRAMP-C2 prostate cancer cells made senescent by pre-treatment with the anti-cancer drug docetaxel, or lethally irradiated. Phenotypic analyses of tumor-explanted cells indicated that the observed acceleration of tumor growth was attributable to a protumorigenic environment created by the co-injected senescent and proliferating cancer cells rather than to escape of the docetaxel-treated cells from senescence. Notably, accelerated tumor growth was effectively inhibited by cell immunotherapy using irradiated TC-1 cells engineered to produce interleukin IL-12. Collectively, our data document that immunotherapy, such as the IL-12 treatment, can provide an effective strategy for elimination of the detrimental effects caused by bystander senescent tumor cells in vivo .

// Ke-Da Yu 1, * , Lei Fan 1, * , Li-Xin Qiu 2, * , Hong Ling 1, * , Yi-Zhou Jiang 1 and Zhi-Ming Shao 1 1 Department of Breast Surgery, Shanghai Cancer Center and Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, P.R. China 2 Department of Medical Oncology, Shanghai Cancer Center and Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, P.R. China * These authors have contributed equally to this work Correspondence to: Ke-Da Yu, email: yukeda@163.com , yukeda@fudan.edu.cn Keywords: timing of adjuvant chemotherapy, breast cancer, survival, subtype Received: November 14, 2015 Accepted: May 17, 2016 Published: July 13, 2016 ABSTRACT Purpose: The optimal time from surgery to initiation of adjuvant chemotherapy of breast cancer is still controversial. We investigated the influence of time to adjuvant chemotherapy on survival outcomes according to breast cancer subtype. Results: Longer delay of initiation of adjuvant chemotherapy (≤4 weeks versus >8 weeks)) significantly decreased the DFS (adjusted hazard ratio [HR] of 1.86; 95% confidence interval [CI], 1.19-2.90) and OS (adjusted HR of 2.02; 95% CI, 1.10-3.71). However, a moderate delay (≤4 weeks versus 4-8 weeks) did not significantly influence the survival. We further investigated the effect of time to adjuvant chemotherapy (≤8 versus >8 weeks) on survival according to subtypes. Patients with luminal-A tumors who received delayed chemotherapy had no increased risk of recurrence (HR of 1.15; 95% CI, 0.54-2.43). In contrast, patients with luminal-B, triple-negative, or trastuzumab-untreated HER2-positive tumors would have decreased DFS because of delayed chemotherapy, with HR of 1.93 (95% CI, 1.10-3.34), 2.55 (95% CI, 1.25-5.18), and 2.41 (95% CI, 1.36-4.26), respectively. Methods: Operable women with stage I-IIIa breast cancer between 2003 and 2006 in our institution were included. 1,408 patients were divided into 3 groups according to the time to adjuvant chemotherapy: ≤4 weeks, 4-8 weeks, and >8 weeks. Disease-free survival (DFS) and overall survival (OS) were calculated. Conclusion: Longer delay of adjuvant chemotherapy was associated with worse survival and early initiation of adjuvant chemotherapy should be performed for patients with aggressive tumor subtypes.

// Aejaz Sayeed 1,2 , Huimin Lu 1,2 , Qin Liu 1,3 , David Deming II 1,2 , Alexander Duffy 1,2 , Peter McCue 4 , Adam P. Dicker 5 , Roger J. Davis 6,7 , Dmitry Gabrilovich 1,8 , Ulrich Rodeck 5,9 , Dario C. Altieri 1,10 and Lucia R. Languino 1,2,5 1 Prostate Cancer Discovery and Development Program, Philadelphia, PA, USA 2 Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA 3 Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA 4 Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA 5 Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA 6 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA 7 Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA, USA 8 Translational Tumor Immunology Program, The Wistar Institute, Philadelphia, PA, USA 9 Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA 10 Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA Correspondence to: Lucia R. Languino, email: // Keywords : TRAMP mice, prostate cancer, β1 integrins, FAK, insulin-like growth factor receptor Received : November 25, 2015 Accepted : June 15, 2016 Published : July 11, 2016 Abstract Radiation therapy is an effective cancer treatment modality although tumors invariably become resistant. Using the transgenic adenocarcinoma of mouse prostate (TRAMP) model system, we report that a hypofractionated radiation schedule (10 Gy/day for 5 consecutive days) effectively blocks prostate tumor growth in wild type (β1 wt /TRAMP) mice as well as in mice carrying a conditional ablation of β1 integrins in the prostatic epithelium (β1 pc-/- /TRAMP). Since JNK is known to be suppressed by β1 integrins and mediates radiation-induced apoptosis, we tested the effect of SP600125, an inhibitor of c-Jun amino-terminal kinase (JNK) in the TRAMP model system. Our results show that SP600125 negates the effect of radiation on tumor growth in β1 pc-/- /TRAMP mice and leads to invasive adenocarcinoma. These effects are associated with increased focal adhesion kinase (FAK) expression and phosphorylation in prostate tumors in β1 pc-/- /TRAMP mice. In marked contrast, radiation-induced tumor growth suppression, FAK expression and phosphorylation are not altered by SP600125 treatment of β1 wt /TRAMP mice. Furthermore, we have reported earlier that abrogation of insulin-like growth factor receptor (IGF-IR) in prostate cancer cells enhances the sensitivity to radiation. Here we further explore the β1/IGF-IR crosstalk and report that β1 integrins promote cell proliferation partly by enhancing the expression of IGF-IR. In conclusion, we demonstrate that β1 integrin-mediated inhibition of JNK signaling modulates tumor growth rate upon hypofractionated radiation.

// Jeong Il Yu 1,* , Hyebin Lee 5,* , Hee Chul Park 1 , Doo Ho Choi 1 , Yoon-La Choi 2 , In-Gu Do 6 , Hee Cheol Kim 3 , Woo Yong Lee 3 , Seong Hyeon Yun 3 , Yong Beom Cho 3 , Jung Wook Huh 3 , Yoon Ah Park 4 , Young Suk Park 4 , Joon Oh Park 4 , Seung Tae Kim 4 and Won Park 1 1 Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 3 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4 Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 5 Department of Radiation Oncology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea 6 Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea * These authors have contributed equally to this work as first authors Correspondence to: Won Park, email: // Keywords : rectal neoplasm, total mesorectal excision, radiotherapy, survivin, prognosis Received : May 05, 2016 Accepted : June 18, 2016 Published : July 06, 2016 Abstract Background & Aims: This study is designed to investigate the expression of survivin and p53 in human rectal cancer tissues and analyze associations between expression and clinical outcomes in terms of disease recurrence and survival duration. Results: During follow-up (median 119.0, range 6.6 to 161.3 months), tumor recurrence was detected in 50 patients (43.1%), and local recurrence developed as a first failure site in 13 patients (11.2%). Positive immunostaining of nuclear and cytoplasmic survivin was observed in about one quarter of patients, and about half of all patients had positive staining for p53. Both survivin and p53 were significant prognostic factors of disease-free survival in the univariate analyses, but only survivin remained a significant prognostic factor in the multivariate analysis. Methods: We performed a retrospective study with 116 locally advanced rectal cancer patients who underwent total mesorectal excision (TME) followed by postoperative concurrent chemo-radiation therapy (CCRT). Immunohistochemical staining was conducted using antibodies for survivin or p53, and their expression was analyzed using an individual score that combined the percentage of positive cells and staining intensity. Conclusions: Overexpression of nuclear and cytoplasmic survivin in locally advanced rectal cancer patients was associated with a higher recurrence rate in rectal cancer patients treated with TME followed by postoperative CCRT.