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// Lei Chang 1 and Ruixia Guo 1 1 Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China Correspondence to: Lei Chang, email: nancy_lei7985@163.com Keywords: cervix cancer, radiotherapy, chemotherapy, efficacy, network meta-analysis Received: November 24, 2016 Accepted: February 15, 2017 Published: April 20, 2017 ABSTRACT Background: Cervix cancer was the second most common cancer in female. However, there was no network meta-analysis (NMA) comparing the efficacy of the multiple chemotherapeutic interventions combined with radiation therapy in patients after operation. Methods: Randomized controlled trials were retrieved from PubMed, Embase and Cochrane Library. Overall survival (OS), recurrence-free survival (RFS), incidence of recurrence and distant metastasis were the main outcomes, particularly 5-year OS and PFS were considered as primary outcomes. Furthermore, the hazard ratio (HR) or odds ratio (OR) and their 95% credible intervals (CrIs) were extracted. The surface under cumulative ranking curve (SUCRA) was also used in this NMA. Results: A total of 39 eligible trials with 8,952 patients were included and 22 common chemotherapies were evaluated in this meta-analysis. For OS, cisplatin+fluorouracil+hydroxyurea, fluorouracil+mitomycin C, cisplatin and cisplatin+fluorouracil were better than placebo. As for RFS, cisplatin+fluorouracil, fluorouracil+mitomycin C, and cisplatin alone had the significant superiority compared with placebo. In terms of incidence of recurrence, the optimal drug combination was cisplatin+ifosfamide (0.93) based on SUCRA. Moreover, epirubicin (OR = 0.28, 95% CrI: 0.08-0.91) was the only one had the distinguished potency in reducing the occurrence of distant metastasis with a SUCRA rank probability of 0.88. Conclusion: We recommended cisplatin+fluorouracil+hydroxyurea and cisplatin+docetaxel for their good efficacy in long term survival. Meanwhile, the combination of multiple drugs with different mechanisms worked better.

// Aida Kiviniemi 1, 2 , Maria Gardberg 3 , Katri Kivinen 4 , Jussi P. Posti 5 , Ville Vuorinen 5 , Jussi Sipila 6, 7 , Melissa Rahi 5 , Matti Sankinen 5 and Heikki Minn 8 1 Department of Radiology, Medical Imaging Center of Southwest Finland, Turku University Hospital and University of Turku, Turku, Finland 2 Turku PET Center, Turku University Hospital and University of Turku, Turku, Finland 3 Department of Pathology, Turku University Hospital and University of Turku, Turku, Finland 4 TYKSLAB, Laboratory of Molecular Genetics, Turku University Hospital, Turku, Finland 5 Division of Clinical Neurosciences, Department of Neurosurgery, Turku University Hospital and University of Turku, Turku, Finland 6 Department of Neurology, North Karelia Central Hospital, Joensuu, Finland 7 Division of Clinical Neurosciences, Department of Neurology, Turku University Hospital and University of Turku, Turku, Finland 8 Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland Correspondence to: Aida Kiviniemi, email: aida.kiviniemi@utu.fi Keywords: glioma, somatostatin receptor, oligodendroglioma, IDH mutation, prognosis Received: February 20, 2017 Accepted: April 03, 2017 Published: April 13, 2017 ABSTRACT Somatostatin receptor subtype 2A (SSTR2A) is a potential therapeutic target in gliomas. Data on SSTR2A expression in different glioma entities, however, is particularly conflicting. Our objective was to characterize SSTR2A status and explore its impact on survival in gliomas classified according to the specific molecular signatures of the updated WHO classification. In total, 184 glioma samples were retrospectively analyzed for SSTR2A expression using immunohistochemistry with monoclonal antibody UMB-1. Double staining with CD68 was used to exclude microglia and macrophages from analyses. SSTR2A staining intensity and its localization in tumor cells was evaluated and correlated with glioma entities and survival. Diagnoses included 101 glioblastomas (93 isocitrate dehydrogenase (IDH) -wildtype, 3 IDH -mutant, 5 not otherwise specified (NOS)), 60 astrocytomas (22 IDH -wildtype, 37 IDH -mutant, 1 NOS), and 23 oligodendrogliomas (19 IDH -mutant and 1p/19q-codeleted, 4 NOS). SSTR2A expression significantly associated with oligodendrogliomas (79% SSTR2A positive) compared to IDH -mutant or IDH -wildtype astrocytomas (27% and 23% SSTR2A positive, respectively), and especially glioblastomas of which only 13% were SSTR2A positive ( p < 0.001, Fisher’s exact test). The staining pattern in glioblastomas was patchy whereas more homogeneous membranous and cytoplasmic staining was detected in oligodendrogliomas. Positive SSTR2A was related to longer overall survival in grade II and III gliomas (HR 2.7, CI 1.2–5.8, p = 0.013). In conclusion, SSTR2A expression is infrequent in astrocytomas and negative in the majority of glioblastomas where it is of no prognostic significance. In contrast, oligodendrogliomas show intense membranous and cytoplasmic SSTR2A expression, which carries potential diagnostic, prognostic, and therapeutic value.

Subclonal heterogeneity and clonal selection influences disease progression in chronic lymphocytic leukemia (CLL). It is therefore important that therapeutic decisions are made based on an understanding of the CLL clonal architecture and its dynamics in individual patients. Identification of cytogenetic abnormalities by FISH remains the cornerstone of contemporary clinical practice and provides a simple means for prognostic stratification. Here, we demonstrate that multiplexed-FISH can enhance recognition of CLL subclonal repertoire and its dynamics during disease progression, both in patients and CLL patient-derived xenografts (PDX). We applied a combination of patient-specific FISH probes to 24 CLL cases before treatment and at relapse, and determined putative ancestral relationships between subpopulations with different cytogenetic features. We subsequently established 7 CLL PDX models in NOD/Shi-SCID/IL-2Rγctm1sug/Jic (NOG) mice. Application of multiplexed-FISH to these models demonstrated that all of the identified cytogenetic subpopulations had leukemia propagating activity and that changes in their representation during disease progression could be spontaneous, accelerated by treatment or treatment-induced. We conclude that multiplexed-FISH in combination with PDX models have the potential to distinguish between spontaneous and treatment-induced clonal selection, and therefore provide a valuable tool for the pre-clinical evaluation of novel therapies.

// Jae Moon Gwak 1, 2 , Milim Kim 3 , Hyun Jeong Kim 3 , Min Hye Jang 4 , So Yeon Park 1, 3 1 Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea 2 Green Cross Laboratory, Yongin, Republic of Korea 3 Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea 4 Department of Pathology, Yeungnam University Medical Center, Daegu, Republic of Korea Correspondence to: So Yeon Park, email: sypmd@snu.ac.kr Keywords: Oct4, breast cancer, cancer stem cell, prognosis, tamoxifen resistance Received: September 20, 2016 Accepted: March 21, 2017 Published: March 31, 2017 ABSTRACT The transcription factors of embryonic stem cells, such as Oct4, Sox2, Nanog, Bmi1, and Klf4, are known to be associated with stemness, epithelial–mesenchymal transition and aggressive tumor behavior. This study was designed to evaluate the clinicopathological significance of their expression in breast cancer. Immunohistochemistry for Oct4, Sox2, Nanog, Bmi1, and Klf4 was performed in 319 cases of invasive breast cancer. The relationship between the expression of these markers and clinicopathologic features of the tumors, including breast cancer stem cell phenotype and epithelial–mesenchymal transition marker expression, and their prognostic value in breast cancer, were analyzed. Expression of Oct4 and Sox2 was commonly associated with high histologic grade and high Ki-67 index in the whole group and in the hormone receptor-positive subgroup. On the other hand, expression of Nanog, Bmi1, and Klf4 was inversely correlated with aggressive features of the breast cancer. Oct4 expression was associated with ALDH1 expression but not with epithelial–mesenchymal transition marker expression. In survival analysis, Oct4 expression was independently associated with poor prognosis in the whole group and in the hormone receptor-positive subgroup, but not in hormone receptor-negative subgroup. Particularly, Oct4 expression was associated with poor clinical outcome in patients with hormone receptor-positive breast cancer treated with tamoxifen. Our results indicate that Oct4 expression is associated with aggressive features, ALDH1 expression, tamoxifen resistance and poor clinical outcomes in hormone receptor-positive breast cancer, and thus may be useful as a predictive and prognostic marker in this subgroup of breast cancer.

// Lei Zhang 1 , Ying Mu 2 , Anqi Zhang 3 , Jiaping Xie 2 , Shuangfeng Chen 3 , Fang Xu 4 , Weihua Wang 3 , Yingxin Zhang 3 , Shaoda Ren 3 and Changhui Zhou 3 1 Institute of Hematopathy, Henan Provincial People’s Hospital, Zhengzhou, Henan Province, China 2 Department of Gastroenterology, Liaocheng People’s Hospital, Liaocheng Clinical School of Taishan Medical University, Liaocheng, Shandong Province, China 3 Department of Central Laboratory, Liaocheng People’s Hospital, Liaocheng Clinical School of Taishan Medical University, Liaocheng, Shandong Province, China 4 Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province, China Correspondence to: Changhui Zhou, email: zhouchanghui008@163.com Shaoda Ren, email: zslrsd@163.com Keywords: cytokine-induced killer cells, dendritic cells, colorectal cancer, immunotherapy, meta-analysis Received: November 23, 2016 Accepted: March 17, 2017 Published: March 29, 2017 ABSTRACT Purpose: To systematically evaluate the efficacy and safety of Cytokine-induced killer cells/dendritic cells-cytokine induced killer cells (CIK/DC-CIK) immunotherapy in treating advanced colorectal cancer (CRC) patients. Results: 29 trials including 2,610 CRC patients were evolved. Compared with chemotherapy alone, the combination of chemotherapy with CIK/DC-CIK immunotherapy significantly prolonged the overall survival rate (OS) and disease-free survival rate (DFS) (1–5 year OS, P 0.05). Materials and Methods: Clinical trials reporting response or safety of CIK/DC-CIK immunotherapy treating advanced CRC patients and published before September 2016 were searched in Cochrane Library, EMBASE, PubMed, Wanfang and CNKI database. Research quality and heterogeneity were evaluated before analysis. Pooled analyses were performed using random or fixed-effect models. Conclusions: The combination of CIK/DC-CIK immunotherapy and chemotherapy prolong CRC patients’ survival time, enhanced patients’ immune function and alleviates the adverse effects caused by chemotherapy.

// Jee Yeon Kim 1 , In Ja Park 1 , Hyeong Ryul Kim 2 , Dong Kwan Kim 2 , Jong Lyul Lee 1 , Yong Sik Yoon 1 , Chan Wook Kim 1 , Seok-Byung Lim 1 , Jung Bok Lee 3 , Chang Sik Yu 1 and Jin Cheon Kim 1 1 Department of Colon and Rectal Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea 2 Department of Thoracic and Cardiovascular Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea 3 Department of Clinical Epidemiology and Biostatistics, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea Correspondence to: In Ja Park, email: ipark@amc.seoul.kr Keywords: colorectal cancer, pulmonary metastasectomy, disease free survival Received: December 15, 2016 Accepted: March 12, 2017 Published: March 28, 2017 ABSTRACT Purpose: We aimed to compare disease-free survival after pulmonary metastasectomy to that after hepatic metastasectomy, and to identify prognostic factors after pulmonary metastasectomy. Results: Between 2005 and 2015, 129 patients underwent resection of isolated metachronous lung metastases from colorectal cancer. Three-year DFS after pulmonary metastasectomy was similar to that after hepatic metastasectomy (50.7% vs. 45.5%, respectively; p=0.58). Rectal cancer (hazard ratio [HR]: 2.04, 95% confidence interval [CI]: 1.09–3.79; p=0.03) and ≥2 metastases (HR: 2.17, 95% CI: 1.28–3.68; p=0.004) were independent adverse risk factors associated with disease-free survival after pulmonary metastasectomy on multivariate analysis. Three-year DFS for colon vs. rectal cancer patients was 72.5% vs. 42.6%, respectively (p=0.04). The number of lung metastases was an independent risk factor for DFS after pulmonary metastasectomy in rectal cancer patients. Patients and Methods: Patients who underwent lung metastasectomy after curative resection of colorectal cancers were investigated. Disease-free survival (DFS) after pulmonary metastasectomy was compared to that after hepatic metastasectomy, which has a relatively well-known prognosis. Multivariate Cox proportional hazards analysis was performed to identify clinical variables predictive of survival after pulmonary metastasectomy. Conclusions: Disease-free survival rates after resection of lung vs. liver metastases arising from colorectal cancers are similar. However, lung metastases specifically from rectal cancers produce poorer DFS rates. Primary tumor location must be considered for pulmonary metastasis treatment and follow-up in colorectal cancer patients.

// Tomohiro Fujiwara 1, 2, 3 , Koji Uotani 1 , Aki Yoshida 1 , Takuya Morita 1 , Yutaka Nezu 3 , Eisuke Kobayashi 4 , Akihiko Yoshida 5 , Takenori Uehara 1 , Toshinori Omori 1 , Kazuhisa Sugiu 1 , Tadashi Komatsubara 1 , Ken Takeda 6 , Toshiyuki Kunisada 7 , Machiko Kawamura 8 , Akira Kawai 4 , Takahiro Ochiya 3 , Toshifumi Ozaki 1 1 Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 2 Center of Innovative Medicine, Okayama University Hospital, Okayama, Japan 3 Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan 4 Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan 5 Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan 6 Department of Intelligent Orthopaedic System, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 7 Department of Medical Materials for Musculoskeletal Reconstruction, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 8 Department of Hematology, Saitama Cancer Center, Saitama, Japan Correspondence to: Tomohiro Fujiwara, email: tomomedvn@gmail.com Keywords: microRNA, liquid biopsy, osteosarcoma, biomarker, prognosis Received: September 24, 2016 Accepted: February 27, 2017 Published: March 23, 2017 ABSTRACT Background: Emerging evidence has suggested that circulating microRNAs (miRNAs) in body fluids have novel diagnostic and prognostic significance for patients with malignant diseases. The lack of useful biomarkers is a crucial problem of bone and soft tissue sarcomas; therefore, we investigated the circulating miRNA signature and its clinical relevance in osteosarcoma. Methods: Global miRNA profiling was performed using patient serum collected from a discovery cohort of osteosarcoma patients and controls and cell culture media. The secretion of the detected miRNAs from osteosarcoma cells and clinical relevance of serum miRNA levels were evaluated using in vitro and in vivo models and a validation patient cohort. Results: Discovery screening identified 236 serum miRNAs that were highly expressed in osteosarcoma patients compared with controls, and eight among these were also identified in the cell culture media. Upregulated expression levels of miR-17-5p and miR-25-3p were identified in osteosarcoma cells, and these were abundantly secreted into the culture media in tumor-derived exosomes. Serum miR-25-3p levels were significantly higher in osteosarcoma patients than in control individuals in the validation cohort, with favorable sensitivity and specificity compared with serum alkaline phosphatase. Furthermore, serum miR-25-3p levels at diagnosis were correlated with patient prognosis and reflected tumor burden in both in vivo models and patients; these associations were more sensitive than those of serum alkaline phosphatase. Conclusions: Serum-based circulating miR-25-3p may serve as a non-invasive blood-based biomarker for tumor monitoring and prognostic prediction in osteosarcoma patients.

// Chengrun Du 1 , Hongmei Ying 1 , Youwang Zhang 1 , Yafang Huang 2 , Ruiping Zhai 1 and Chaosu Hu 1 1 Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China 2 Department of Ultrasound, Fudan University Shanghai Cancer Center, Shanghai, P.R. China Correspondence to: Hongmei Ying, email: yinghongmei2011@sina.com Keywords: retropharyngeal nodes, undifferentiated squamous cell carcinoma, transoral sonography-guided fine-needle aspiration, primary unknown, radiotherapy Received: September 18, 2016 Accepted: February 21, 2017 Published: March 18, 2017 ABSTRACT Background and Objective: To evaluate treatment outcomes for patients with retropharyngeal metastatic undifferentiated squamous cell carcinoma (SCC) from an unknown primary site. Methods: From January 2005 to January 2015, patients who presented with enlarged retropharyngeal nodes underwent transoral sonography-guided fine-needle aspiration to confirm histology. Those with metastatic undifferentiated SCC with unknown primary tumors were treated with radical radiotherapy to nasopharyngeal mucosa plus bilateral neck. Chemotherapy was administered for patients staged N2-3. Endpoints included metastatic nodes control, the appearance of primary tumor, overall survival and treatment-related toxicities. Results: A total of 49 patients were recruited into this study. Retropharyngeal and cervical nodal disease was controlled in 96% of all patients. The incidence of occult primary cancer appearance was 8%. No primary cancer other than of the nasopharynx was detected during the course of follow-up. Ten patients developed distant metastases. The 5-year overall survival, progression-free survival, regional relapse free survival, distant metastasis free survival were 79.6%, 61.1%, 83.4%, 73.8%, respectively. Common late adverse effects included xerostomia (57%) and hearing impairment (35%). Conclusion: Radical radiotherapy to both the nasopharynx and bilateral neck can achieve excellent outcome with mild toxicities for patients with retropharyngeal metastatic undifferentiated squamous cell carcinoma from an unknown primary site.

Metastasis is a major cause of mortality for cancer patients and remains as the greatest challenge in cancer therapy. Driven by multiple factors, metastasis may not be controlled by the inhibition of single target. This study was aimed at assessing the hypothesis that drugs could be rationally combined to co-target critical DNA, RNA and protein molecules to achieve "saturation attack" against metastasis. Independent actions of the model drugs DNA-intercalating doxorubicin, RNA-interfering miR-34a and protein-inhibiting sorafenib on DNA replication, RNA translation and protein kinase signaling in highly metastatic, human osteosarcoma 143B cells were demonstrated by the increase of γH2A.X foci formation, reduction of c-MET expression and inhibition of Erk1/2 phosphorylation, respectively, and optimal effects were found for triple-drug combination. Consequently, triple-drug treatment showed a strong synergism in suppressing 143B cell proliferation and the greatest effects in reducing cell invasion. Compared to single- and dual-drug treatment, triple-drug therapy suppressed pulmonary metastases and orthotopic osteosarcoma progression to significantly greater degrees in orthotopic osteosarcoma xenograft/spontaneous metastases mouse models, while none showed significant toxicity. In addition, triple-drug therapy improved the overall survival to the greatest extent in experimental metastases mouse models. These findings demonstrate co-targeting of DNA, RNA and protein molecules as a novel therapeutic strategy for the treatment of metastasis.

// Zaixiang Tang 1, 2, 3, 4 , Qinghua Zeng 5 , Yan Li 4 , Xinyan Zhang 4 , Jinlu Ma 5, 6 , Mark J. Suto 5 , Bo Xu 5 , Nengjun Yi 4 1 Department of Biostatistics, School of Public Health, Medical College of Soochow University, Suzhou 215123, China 2 Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, 215123, China 3 Center for Genetic Epidemiology and Genomics, Medical College of Soochow University, Suzhou, 215123, China 4 Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35294, USA 5 Drug Discovery Division, Southern Research Institute, Birmingham, AL 35294, USA 6 Department of Radiation Oncology, The First Hospital, Xi’an Jiaotong University, Xi’an, Shanxi, 710061, China Correspondence to: Nengjun Yi, email: nyi@uab.edu Bo Xu, email: bxu@southernresearch.org , bxu@uab.edu Keywords: gene signature, radio-sensitivity, radiotherapy, survival prediction, sarcoma Received: September 27, 2016 Accepted: January 24, 2017 Published: March 15, 2017 ABSTRACT Adjuvant radiotherapy is an important clinical treatment option for the majority of sarcomas. The motivation of current study is to identify a gene signature and to predict radiosensitive patients who are most likely to benefit from radiotherapy. Using the public available data of soft tissue sarcoma from The Cancer Genome Atlas, we developed a cross-validation procedure for identifying a gene signature and predicting radiosensitive patients through. The result showed that the predicted radiosensitive patients who received radiotherapy had a significantly better survival with a reduced rate of new tumor event and disease progression. Strata analysis showed that the predicted radiosensitive patients had significantly better survival under radiotherapy independent of histologic types. A hierarchical cluster analysis was used to validate the gene signature, and the results showed the predicted sensitivity for each patient well matched the results from cluster analysis. Together, we demonstrate a radiosensitive molecular signature that can be potentially used for identifying radiosensitive patients with sarcoma.

// Cheng Chen 1, * , Linkun Hu 1, * , Ye Chen 1 , Jianquan Hou 1 1 Department of Urology, the First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China * These authors contributed equally to this work Correspondence to: Jianquan Hou, email: houjianquan@suda.edu.cn Keywords: urinary bladder neoplasms, histology, distant metastasis, prognosis, survival Received: December 14, 2016 Accepted: February 28, 2017 Published: March 10, 2017 ABSTRACT We aim to evaluate the prognostic effect of the histological sub-type in patients with metastatic bladder cancer based on the Surveillance Epidemiology and End Results database. A total of 2634 eligible patients were included. The histological subtypes were: transitional cell carcinoma (TCC; 75.2%); adenocarcinoma (3.3%); squamous cell carcinoma (SQCC; 4.1%); and small cell carcinoma (4.3%). A significant association of adenocarcinoma with better survival outcomes ( P < 0.015), and that of SQCC with worse outcomes ( P < 0.001) was observed. On multivariate analysis, adenocarcinoma was significantly associated with longer and SQCC with shorter survival time as compared to TCC. Overall, 1331 (50.5%) patients had a single metastatic site and 523 (19.9%) had multiple sites involved. Single-site metastasis had a better survival outcome than multiple metastases ( P < 0.001). Histological sub-type and presence of multiple metastatic sites are independent predictors of survival time. Prospective, in-depth research is needed to determine optimal therapeutic strategies for different histological subtypes of bladder cancer with different metastatic patterns.

// Angela Boros 1 , Ludovic Lacroix 2 , Benjamin Lacas 3, 8, 10 , Julien Adam 2 , Jean-Pierre Pignon 3, 8, 10 , Caroline Caramella 4 , David Planchard 5 , Vincent de Montpreville 6 , Eric Deutsch 1, 7, 9 , Antonin Levy 1 , Benjamin Besse 5, 7 , Cecile Le Pechoux 1 1 Radiation Oncology Department, Gustave Roussy, Villejuif, France 2 Biopathology Department, Gustave Roussy, Villejuif, France 3 Biostatistics and Epidemiolgy Unit, Villejuif, France 4 Imaging Department, Gustave Roussy, Villejuif, France 5 Medical Oncology Department, Gustave Roussy, Villejuif, France 6 Pathology Department, Marie Lannelongue, Le Plessis Robinson, France 7 Paris-Sud University, DHU TORINO, Paris, France 8 Paris-Saclay University, Paris, France 9 INSERM U1030, Villejuif, France 10 INSERM U1018, Villejuif, France Correspondence to: Benjamin Besse, email: Benjamin.BESSE@gustaveroussy.fr Keywords: locally advanced, non-small cell lung cancer, mutation, prognostic, chemotherapy Received: July 04, 2016 Accepted: February 15, 2017 Published: March 07, 2017 ABSTRACT Introduction: Chemo-radiation is standard treatment in locally advanced non-small cell lung cancers (NSCLC). The prognostic value of mutations has been poorly explored in this population. Results: Clinical data were collected from 190 patients and mutational profiles were obtained in 78 of them; 58 (74%) were males, 31 (40%) current smokers, 47/31 stage IIIA/IIIB and 40 (51%) adenocarcinoma. The following mutations were identified: EGFR 12% (9/78), KRAS 15% (12/78), BRAF 5% (3/65), PI3KCA 2% (1/57), NRAS 3% (1/32), and ALK+ (FISH) 4% (2/51). HER2 was not detected. Median follow-up was 3.1 years. Overall survival was evaluated by group; no significant differences were identified in median overall survival ( p = 0.21), with 29.4 months for the EGFR/ALK group ( n = 11), 12.8 months for other mutations ( n = 17), and 23.4 months for wild-type ( n = 50). The EGFR/ALK and other mutations groups had poorer median progression-free survival (9.6 and 6.0 months) compared to the wild-type group (12.0 months; multivariate hazard ratio 2.0 [95% CI, 0.9–4.2] and 2.8 [95% CI, 1.5–5.2] respectively, p = 0.003). Materials and Methods: We retrospectively reviewed all patients receiving radical treatment for locally advanced NSCLC in a single institution between January 2002 and June 2013. Next generation sequencing was performed on DNA from paraffin-embedded tissue. ALK rearrangements were detected by immunohistochemistry and/or FISH. Mutational prognostic value for Kaplan-Meier survival parameters was determined by log-rank tests and Cox proportional hazards models. Conclusions: Selected gene alterations may be associated with poorer progression-free survival in locally advanced radically treated NSCLC and their prognostic and/or predictive value merits further evaluation in a larger population.

// Grzegorz J. Korpanty 1, 2, * , Lawson Eng 1, * , Xin Qiu 3, * , Olusola Olusesan Faluyi 1 , Daniel J. Renouf 4 , Dangxiao Cheng 5 , Devalben Patel 5 , Zhuo Chen 5 , Brandon C. Tse 5 , Jennifer J. Knox 1 , Lorin Dodbiba 1 , Jennifer Teichman 1 , Abul Kalam Azad 1 , Rebecca Wong 6 , Gail Darling 7 , David Reisman 8 , Sinead Cuffe 1, # , Geoffrey Liu 1, 5, 9, # , Wei Xu 3, # 1 Princess Margaret Cancer Centre, Department of Medicine, University Health Network, Toronto, ON, Canada 2 Canadian Cancer Trials Group, Department of Medicine, Queens University, Kingston, ON, Canada 3 Princess Margaret Cancer Centre, Department of Biostatistics, University Health Network, Toronto, ON, Canada 4 Department of Medical Oncology, University of British Columbia and British Columbia Cancer Agency, Vancouver, BC, Canada 5 Princess Margaret Cancer Centre, Department of Medical Biophysics, University Health Network, Toronto, ON, Canada 6 Princess Margaret Cancer Centre, Radiation Medicine Program, University Health Network, Toronto, ON, Canada 7 Department of Surgery, Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, ON, Canada 8 Department of Medicine in the College of Medicine, Division of Hematology and Oncology, University of Florida, Gainesville, FL, USA 9 Department of Epidemiology, Dalla Lana School of Pubic Health, Toronto, ON, Canada * Co-first authors # Co-senior authors Correspondence to: Geoffrey Liu, email: Geoffrey.Liu@uhn.on.ca Keywords: chromatin remodeling, polymorphism, cancer prognosis, esophageal cancer, brahma Received: October 20, 2016 Accepted: February 22, 2017 Published: March 03, 2017 ABSTRACT Purpose: Brahma (BRM) is a critical catalytic subunit of the SWI/SNF chromatin remodeling complex; expression of BRM is commonly lost in various cancer types. BRM promoter polymorphisms (BRM-741; BRM-1321) are associated with loss of BRM expression, and with cancer risk/survival. We evaluated these two polymorphisms in the overall survival (OS) of esophageal adenocarcinoma (EAC) patients. Results: Of 270 patients, 37% were stage IV. Minor allele frequencies were 47−49%; 15% were double-homozygotes. When compared to the wild-type genotype, the homozygous variant of BRM-741 carried an adjusted OS hazard ratio (aHR) of 1.64 (95% CI:1.1−2.4); for BRM-1321, the aHR was 2.09 (95% CI:1.4−3.0). Compared to the double wild-type, carrying homozygous variants of both promoter polymorphisms (double-homozygote) yielded an aHR of 2.21 (95% CI:1.4−3.6). Directions/magnitudes of associations were similar in subsets by age, gender, smoking status, use of platinum agents, and disease stage, and for progression-free survival. Materials and Methods: In a cohort of EAC patients of all stages (84% male; median age of 64 years), two BRM polymorphisms were genotyped. Cox proportional hazards models, adjusted for known prognostic variables, estimated the association of polymorphisms with OS. Conclusions: BRM polymorphisms were associated with OS in EAC in this study. Validation studies are warranted.

// Xiangdong Tian 1, * , Yanna Cao 1, * , Jingfu Wang 1 , Jie Yan 1 , Yao Tian 2 , Zhongyuan Li 1 , Huijuan Wang 1 , Xiaofeng Duan 1 , Yan Jin 1 , Qiang Zhao 1 1 Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China 2 Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Qiang Zhao, email: qiangzhao169@sina.com Keywords: neuroblastoma, high-risk, treatment, surgery extent, survival rate Received: November 16, 2016 Accepted: February 13, 2017 Published: March 07, 2017 ABSTRACT The current multidisciplinary treatment for patients with high-risk neuroblastoma (NB) is the common census. However, protocols and opinions are different in different regions and institutions. We aimed to assess the protocol formulated by Chinese Children’s Cancer Group study in 2009, and the impact of surgery extent was highlightly evaluated. Methods: This study enrolled patients with high-risk neuroblastoma between 2009 and 2014 in Department of Pediatric Oncology of Tianjin Medical University Cancer Institute and Hospital. The clinical characteristics of patients were illustrated and surgery extent was evaluated by the impact on survival rate. Results: The 3-year overall survival (OS) and progression-free survival (PFS) were 56.2% and 50.5%, respectively. LDH ( P

// Naoko Tsuyama 1 , Daisuke Ennishi 2 , Masahiro Yokoyama 3 , Satoko Baba 4 , Reimi Asaka 1, 4 , Yuko Mishima 3 , Yasuhito Terui 3 , Kiyohiko Hatake 3 and Kengo Takeuchi 1, 4 1 Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan 2 Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan 3 Department of Hematology Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan 4 Pathology Project for Molecular Targets, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan Correspondence to: Kengo Takeuchi, email: kentakeuchi-tky@umin.net Keywords: diffuse large B-cell lymphoma, CD5, CD8, aberrant expression, T-cell marker Received: October 20, 2016 Accepted: February 28, 2017 Published: March 23, 2017 ABSTRACT Expression of T-cell markers, generally investigated for immunophenotyping of T-cell lymphomas, is also observed in several types of B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL). We previously reported that CD5 expression in DLBCL is an inferior prognostic factor in the era of rituximab. However, data regarding the frequencies, histological relevance, and prognostic importance of T-cell markers other than CD5 are currently unavailable. In the present study, we comprehensively evaluated the expression of T-cell markers (CD2, CD3, CD4, CD5, CD7, and CD8) in 501 B-cell lymphomas, including 225 DLBCLs, by flow cytometry and subsequent immunohistochemistry. T-cell markers other than CD5, such as CD2, CD4, CD7, and CD8, were expressed in 27 (5%) patients, and notably, all of these cases were classified as large B-cell lymphoma subtypes: 25 DLBCLs and 2 intravascular large B-cell lymphomas. CD5 and other T-cell markers were expressed in 15% (31/225) and 10% (25/225) of DLBCL cases, respectively. Five of them co-expressed CD5 and other T-cell markers. Retrospectively analyzing the prognostic relevance of T-cell markers in 169 patients with primary DLBCL treated with rituximab-based chemotherapy, we showed that only CD5 was a strong predictor of poor survival. This study provides information about the occurrence of T-cell markers other than CD5 in B-cell lymphomas, their frequent histological subtypes, and their prognostic significance in DLBCL. CD5 was reconfirmed as a negative prognostic marker in DLBCL patients receiving rituximab-inclusive chemotherapy, whereas T-cell markers other than CD5 were found to have no impact on clinicopathological and survival analyses.

Programmed cell death ligand 1 (PD-L1) is a transmembrane protein that is expressed on tumor cells that suppresses the T cell-mediated immune response. Therapies targeting the PD-L1 pathway promote anti-tumor immunity and have shown promising results in some types of cancers. However, the functional and therapeutic roles of PD-L1 in osteosarcoma remain largely unknown. In this study, we found that PD-L1 protein was expressed in osteosarcoma cell lines and tissue microarray of patient tumors. Tissue microarray immunohistochemistry analysis showed that the overall and five-year survival rates of patients with high levels of PD-L1 expression were significantly shorter than patients with low levels. High levels of PD-L1 expression were also associated with metastasis in osteosarcoma patients. Furthermore, we applied the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system to target PD-L1 gene at the DNA level in osteosarcoma cell lines. We found that the expression of PD-L1 could be efficiently disrupted by CRISPR/Cas9 system and PD-L1 knockdown increased drug sensitivities for doxorubicin and paclitaxel. These results suggest that PD-L1 is an independent prognostic factor in osteosarcoma and that PD-L1 knockout by CRISPR/Cas9 may be a therapeutic approach for the treatment of osteosarcoma.

// Shenglei Li 1, * , Hongtao Liu 2, * , Changying Diao 1 , Xiaohui Wang 1 , Ming Gao 3 , Zongming Li 4 , Lijie Song 3 , Xianzheng Gao 1 , Jing Han 1 , Feng Wang 3 , Wencai Li 1 and Xinwei Han 4 1 Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 50000, China 2 Laboratory for Cell Biology, College of Life Sciences of Zhengzhou University, Zhengzhou, Henan, 450001, China 3 Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450000, China 4 Department of Interventional Therapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450000, China * These authors have contributed equally to this work Correspondence to: Feng Wang, email: wangangvv@yeah.net Xinwei Han, email: chenyueqinms@163.com Keywords: esophageal cancer, surgery, adjuvant therapies, chemotherapy, radiotherapy Received: September 09, 2016 Accepted: February 20, 2017 Published: March 14, 2017 ABSTRACT This network meta-analysis was conducted to assess whether the efficacy of surgery with adjuvant therapies, including radiotherapy (RT+S), chemotherapy (CT+S), and chemoradiotherapy (CRT+S) have better performance in esophageal cancer treatment and management. PubMed and EMBASE were used to search for relevant trials. Both conventional pair-wise and network meta-analyses were carried out. The surface under the cumulative ranking curve (SUCRA) was used to rank interventions based on the efficacy of the treatment method. As for 3-year overall survival (OS), CRT+S showed the highest efficacy (CRT+S vs. surgery: HR=0.81, 95% CrI =0.73-0.90; CRT+S vs. CT+S: HR=0.82, 95% CrI =0.70-0.95; CRT+S vs. RT+S: HR=0.77, 95% CrI =0.62-0.95). For disease-free survival, CRT+S showed efficacy over CT+S ((HR =0.70, 95% CrI =0. 59-0.83). In conclusion, CRT+S showed a better performance for survival outcomes and ranks best among all therapies. The results of our study can provide guidance for medical decisions and treatment options that may help clinical practitioners improve the efficacy of EC treatment.

// Xuan-zhang Huang 1, * , You Chen 2, * , Wen-jun Chen 1 , Xi Zhang 1 , Cong-cong Wu 1 , Chao-ying Zhang 1 , Shuang-shuang Sun 1 , Jian Wu 1 1 Department of Chemotherapy and Radiotherapy, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou City 325027, P.R. China 2 The Wenzhou Dental Hospital, Wenzhou City 325027, P.R. China * These authors contributed equally to this work Correspondence to: Jian Wu, email: wzzjian1@163.com. Keywords: radiotherapy, breast-conserving surgery, older, early breast cancer, breast ductal carcinoma in situ Received: October 22, 2016 Accepted: February 28, 2017 Published: March 08, 2017 ABSTRACT Background: There are no consistent agreements on whether radiotherapy after breast-conserving surgery (BCS) could provide local control and survival benefit for older patients with early breast cancer or breast ductal carcinoma in situ (DCIS). The present study aimed to evaluate the efficacy of radiotherapy after BCS in older patients with early breast cancer or DCIS. Results: Radiotherapy could reduce the risk of local relapse in older patients with early breast cancer. The 5-year AR of local relapse was 2.2% and 6.2% for radiotherapy and non-radiotherapy group, respectively, with low 5-year ARD of 4.0% and high NNT of 25. The 10-year AR of local relapse was 5.3% and 10.5% for radiotherapy and non-radiotherapy group, respectively, with the 10-year ARD of 5.2% and NNT of 20. However, radiotherapy could not improve survival benefits, including overall survival, cancer-specific survival, breast-cancer-specific survival, and distant relapse. Moreover, radiotherapy could reduce the risk of ipsilateral breast events in older patients with DCIS. Materials and Methods: PubMed and Embase database were searched for relevant studies. Hazard ratios (HRs), risk ratios (RRs), absolute risk (AR), absolute risk difference (ARD), and number needed to treat (NNT) were used as effect measures to evaluate the efficacy of radiotherapy in older patients. Conclusions: Our study indicates that radiotherapy could slightly reduce the risk of local relapse in older patients with favorable early breast cancer. However, radiotherapy cannot translate into significant survival benefits.

Few studies have reported progression-free survival (PFS) and overall survival (OS) of Metastatic spinal cord compression (MSCC) patients with primary hepatocellular carcinoma (HCC) following surgery and adjuvant therapies. Enrolled in this study were 155 MSCC patients with primary HCC who received surgery and adjuvant therapies between 2000 and 2015. Kaplan-Meier methods and Cox’s proportional hazards regression mode were performed to investigate the clinical features and prognostic factors affecting PFS and OS. The median PFS and OS was 7.0 months and 9.7 months, respectively. 92.9% patients responded well to surgery according to the Visual Analogue Scale, Frankel Score and postoperative complication occurrences. 68 (43.9%) patients who received circumferential decompression achieved better PFS than the remaining 87 (56.1%) patients who received laminectomy. Favorable outcomes were achieved after surgery during the perioperative period. Circumferential decompression was associated with better PFS than laminectomy. The postoperative Frankel Score E, Eastern Cooperative Oncology Group performance score of 1 or 2, no visceral metastasis, administration of postoperative radiation and the use of Sorafenib were found to be significant predictors of better PFS and OS. Patients who previously underwent resection of primary HCC with/without liver transplantation tended to have a better OS.

Fil: Massari, Noelia A. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Laboratorio de Radioisotopos; Argentina Fil: Massari, Noelia A. Universidad Nacional de la Patagonia San Juan Bosco. Facultad de Ciencias Naturales. Departamento de Inmunología; Argentina Fil: Nicoud, Melisa B. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Laboratorio de Radioisotopos; Argentina Fil: Nicoud, Melisa B. Pontificia Universidad Católica Argentina. Faculta de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Biología Tumoral e Inflamación; Argenitna Fil: Nicoud, Melisa B. Consejo Nacional de Investigaciones Científicas; Argentina Fil: Sambuco, Lorena. Instituto de Inmunooncología; Argentina Fil: Martinel Lamas, Diego J. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Laboratorio de Radioisotopos; Argentina Fil: Martinel Lamas, Diego J. Pontificia Universidad Católica Argentina. Faculta de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Biología Tumoral e Inflamación; Argenitna Fil: Martinel Lamas, Diego J. Consejo Nacional de Investigaciones Científicas; Argentina Fil: Herrero Ducloux, María V. Universidad Nacional de la Patagonia San Juan Bosco. Facultad de Ciencias Naturales. Departamento de Patología; Argentina Fil: Blanco, Horacio. Hospital Municipal de Oncología Marie Curie; Argentina Fil: Rivera, Elena S. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Laboratorio de Radioisotopos; Argentina Fil: Medina, Vanina Araceli. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Laboratorio de Radioisotopos; Argentina Fil: Medina, Vanina Araceli. Pontificia Universidad Católica Argentina. Faculta de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Biología Tumoral e Inflamación; Argenitna Fil: Medina, Vanina Araceli. Consejo Nacional de Investigaciones Científicas; Argentina Abstract: The aims of the work were to improve our knowledge of the role of H4R in melanoma proliferation and assess in vivo the therapeutic efficacy of histamine, clozapine and JNJ28610244, an H4R agonist, in a preclinical metastatic model of melanoma. Additionally, we aimed to investigate the combinatorial effect of histamine and gamma radiation on the radiobiological response of melanoma cells. Results indicate that 1205Lu metastatic melanoma cells express H4R and that histamine inhibits proliferation, in part through the stimulation of the H4R, and induces cell senescence and melanogenesis. Daily treatment with H4R agonists (1 mg/kg, sc) exhibited a significant in vivo antitumor effect and importantly, compounds reduced metastatic potential, particularly in the group treated with JNJ28610244, the H4R agonist with higher specificity. H4R is expressed in benign and malignant lesions of melanocytic lineage, highlighting the potential clinical use of histamine and H4R agonists. In addition, histamine increased radiosensitivity of melanoma cells in vitro and in vivo. We conclude that stimulation of H4R by specific ligands may represent a novel therapeutic strategy in those tumors that express this receptor. Furthermore, through increasing radiation-induced response, histamine could improve cancer radiotherapy for the treatment of melanoma.

Various trials and meta-analyses have reported conflicting results concerning the application of early goal-directed therapy (EGDT) for sepsis and septic shock. The aim of this study was to update the evidence by performing a systematic review and meta-analysis. Multiple databases were searched from initial through August, 2016 for randomized controlled trials (RCTs) which investigated the associations between the use of EGDT and mortality in patients with sepsis or septic shock. Meta-analysis was performed using random-effects model and heterogeneity was examined through subgroup analyses. The primary outcome of interest was patient all-cause mortality including hospital or ICU mortality. Seventeen RCTs including 6207 participants with 3234 in the EGDT group and 2973 in the control group were eligible for this study. Meta-analysis showed that EGDT did not significantly reduce hospital or intensive care unit (ICU) mortality (relative risk [RR] 0.89, 95% CI 0.78 to 1.02) compared with control group for patients with sepsis or septic shock. The findings of subgroup analyses stratified by study region, number of research center, year of enrollment, clinical setting, sample size, timing of EGDT almost remained constant with that of the primary analysis. Our findings provide evidence that EGDT offers neutral survival effects for patients with sepsis or septic shock. Further meta-analyses based on larger well-designed RCTs or individual patient data meta-analysis are required to explore the survival benefits of EDGT in patients with sepsis or septic shock.

// Yu Mao 1, * , Jian Hao 1, * , Zi-Qi Jin 2 , Yang-Yang Niu 3 , Xue Yang 1 , Dan Liu 1 , Rui Cao 4 , Xiong-Zhi Wu 4 1 Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China 2 Tianjin Medical University, Tianjin, 300070, China 3 Tianjin Children’s Hospital, Tianjin, 300134, China 4 Zhong-Shan-Men Inpatient Department, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China * These authors have contributed equally to this study and share first authorship Correspondence to: Xiong-Zhi Wu, email: wuxiongzhi@163.com Keywords: metastatic breast cancer, Chinese herbal medicine, network pharmacology, estrogen receptor, HSP90 Received: October 25, 2016 Accepted: January 22, 2017 Published: February 15, 2017 ABSTRACT Chinese Herbal Medicine (CHM) plays a significant role in breast cancer treatment. We conduct the study to ascertain the relative molecular targets of effective Chinese herbs in treating stage IV breast cancer. Survival benefit of CHM was verified by Kaplan-Meier method and Cox regression analysis. A bivariate correlation analysis was used to find and establish the effect of herbs in complex CHM formulas. A network pharmacological approach was adopted to explore the potential mechanisms of CHM. Patients in the CHM group had a median survival time of 55 months, which was longer than the 23 months of patients in the non-CHM group. Cox regression analysis indicated that CHM was an independent protective factor. Correlation analysis showed that 10 herbs were strongly correlated with favorable survival outcomes ( P

// Juan Zhou 1, * , San-Gang Wu 2, * , Jia-Yuan Sun 3, * , Xu-Lin Liao 4 , Feng-Yan Li 3 , Huan-Xin Lin 3 , Li-Chao Yang 5 , Zhen-Yu He 3 1 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, People’s Republic of China 2 Department of Radiation Oncology, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen 361003, People’s Republic of China 3 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, People’s Republic of China 4 Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Medical College, Xiamen University, Xiamen 361005, People’s Republic of China 5 Faculty of Basic Medicine, Medical College, Xiamen University, Xiamen 361005, People’s Republic of China * These authors contributed equally to this work Correspondence to: Li-Chao Yang, email: yanglichaoxmu@163.com Zhen-Yu He, email: hezhy@sysucc.org.cn Keywords: cervical cancer, positive lymph nodes, TNM, tumor histology, survival Received: November 07, 2016 Accepted: January 27, 2017 Published: February 09, 2017 ABSTRACT To determine the prognostic value of the number of positive lymph nodes (LNs) in cervical cancer and further stratify patients with positive LNs into multiple risk groups based on analysis of Surveillance Epidemiology and End Results (SEER) program. Patients with cervical cancer who undergo hysterectomy and had pathologically-confirmed positive LNs after lymphadenectomy were identified using the SEER database (1988-2012). Kaplan–Meier survival methods and Cox proportional hazards regression were performed. We included 2,222 patients with the median number of removed LNs and positive LNs was 22 and 2, respectively. Multivariable Cox analysis showed patients with > 2 positive LNs had poorer cause-specific survival (CSS) (hazard ratio [HR] 1.631, 95% confidence interval [CI] 1.382–1.926, P 2 positive LNs, respectively. The number of positive LNs had prognostic value in cervical squamous cell carcinoma or adenosquamous carcinoma, but not in cervical adenocarcinoma. The number of positive LNs is an independent risk factor for CSS and OS in cervical cancer. This new category might be helpful in better prognostic discrimination of node-positive early stage cervical cancer after hysterectomy.

// Mark A. Currier 1 , Les Sprague 1 , Tilat A. Rizvi 2 , Brooke Nartker 1 , Chun-Yu Chen 1 , Pin-Yi Wang 1 , Brian J. Hutzen 1 , Meghan R. Franczek 1 , Ami V. Patel 2 , Katherine E. Chaney 2 , Keri A. Streby 1,3 , Jeffrey A. Ecsedy 4 , Joe Conner 5 , Nancy Ratner 2 and Timothy P. Cripe 1,3 1 Center for Childhood Cancer and Blood Diseases, Nationwide Children’s Hospital, The Ohio State University, Columbus, Ohio, USA 2 Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center; Cincinnati, Ohio, USA 3 Division of Hematology/Oncology/Blood and Marrow Transplantation, Nationwide Children’s Hospital, The Ohio State University, Columbus, Ohio, USA 4 Takeda Pharmaceuticals International Co, Cambridge, MA, USA 5 Virttu Biologics, Ltd, Biocity, Scotland, Newhouse, United Kingdom Correspondence to: Timothy P. Cripe, email: // Keywords : oHSV, Aurora A kinase, neuroblastoma, MPNST Received : November 07, 2016 Accepted : January 17, 2017 Published : February 02, 2017 Abstract Malignant peripheral nerve sheath tumor (MPNST) and neuroblastoma models respond to the investigational small molecule Aurora A kinase inhibitor, alisertib. We previously reported that MPNST and neuroblastomas are also susceptible to oncolytic herpes virus (oHSV) therapy. Herein, we show that combination of alisertib and HSV1716, a virus derived from HSV-1 and attenuated by deletion of RL1, exhibits significantly increased antitumor efficacy compared to either monotherapy. Alisertib and HSV1716 reduced tumor growth and increased survival in two xenograft models of MPNST and neuroblastoma. We found the enhanced antitumor effect was due to multiple mechanisms that likely each contribute to the combination effect. First, oncolytic herpes virus increased the sensitivity of uninfected cells to alisertib cytotoxicity, a process we term virus-induced therapeutic adjuvant (VITA). Second, alisertib increased peak virus production and slowed virus clearance from tumors, both likely a consequence of it preventing virus-mediated increase of intratumoral NK cells. We also found that alisertib inhibited virus-induced accumulation of intratumoral myeloid derived suppressor cells, which normally are protumorigenic. Our data suggest that clinical trials of the combination of oHSV and alisertib are warranted in patients with neuroblastoma or MPNST.

Renal cell carcinoma (RCC) management has undergone a major transformation over the past decade; immune checkpoint inhibitors are currently undergoing clinical trials and show promising results. However, the effectiveness of immune checkpoint inhibitors in patients with metastatic RCC (mRCC) is still limited. Lycorine, an alkaloid extracted from plants of the Amaryllidaceae family, is touted as a potential anti-cancer drug because of its demonstrative growth inhibition capacity (induction of cell cycle arrest and inhibition of vasculogenic mimicry formation). Moreover, T cell checkpoint blockade therapy with antibodies targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) has improved outcomes in cancer patients. However, the anti-tumor efficacy of combined lycorine and anti-CTLA-4 therapy remains unknown. Thus, we investigated a combination therapy of lycorine hydrochloride and anti-CTLA-4 using a murine RCC model. As a means of in vitro confirmation, we found that lycorine hydrochloride inhibited the viability of various RCC cell lines. Furthermore, luciferase-expressing Renca cells were implanted in the left kidney and the lung of BALB/c mice to develop a RCC metastatic mouse model. Lycorine hydrochloride and anti-CTLA-4 synergistically decreased tumor weight, lung metastasis, and luciferin-staining in tumor images. Importantly, the observed anti-tumor effects of this combination were dependent on significantly suppressing regulatory T cells while upregulating effector T cells; a decrease in regulatory T cells by 31.43% but an increase in effector T cells by 31.59% were observed in the combination group compared with those in the control group). We suggest that a combination of lycorine hydrochloride and anti-CTLA-4 is a viable therapeutic option for RCC patients.

// Chao Liu 1 , Shikai Wu 1 , Xiangying Meng 1 , Guangxian Liu 2 , Dongmei Chen 1 , Yang Cong 1 , Ge Shen 1 , Bing Sun 1 , Wei Wang 2 , Qian Wang 1 , Hongjun Gao 3 and Xiaoqing Liu 3 1 Department of Radiation Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China 2 Cancer Therapy Center, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China 3 Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China Correspondence to: Shikai Wu, email: // Keywords : T cells; lymphocyte subsets; stereotactic body radiation therapy; non-small cell lung cancer; immunotherapy Received : December 19, 2016 Accepted : January 27, 2017 Published : February 09, 2017 Abstract Background: Studies increasingly focus on the impact of radiotherapy on immunity; however, the role of peripheral cellular immunity prior to radiotherapy in cancer patients remains largely unknown. In this study, we investigated the predictive roles of lymphocyte subsets on tumor progression in non-small cell lung cancer (NSCLC) patients undergoing radiotherapy, and their expression in NSCLC patients at first relapse. Methods: We enrolled 70 NSCLC patients and 14 age- and sex-matched healthy donors and tested the lymphocyte subsets in their peripheral blood by flow cytometry. Among them, 40 newly diagnosed patients received radiotherapy and were enrolled to investigate the predictive value of lymphocyte subsets on tumor progression after radiotherapy by uni- and multivariate analyses; 30 patients at first relapse were included to evaluate the differences of lymphocyte subsets between them and first diagnosed patients and healthy volunteers. Results: Increased proportions of regulatory T cells, CD8+ T cells, and CD8+CD28- T cells and decreased CD4+ T cells and CD4/CD8 ratios were observed in NSCLC patients at first relapse compared to newly diagnosed patients. In the 40 first diagnosed patients undergoing radiotherapy, uni- and multivariate analyses showed that increased level of regulatory T cells correlated with poor progression-free survival (hazard ratio = 2.55 and 3.76, P = 0.022 and 0.010, respectively). Conclusions: Peripheral regulatory T cells were increased and independently predict tumor progression in NSCLC patients undergoing radiotherapy, suggesting the promising combination of radiotherapy and immunotherapy.

// Jinyao Li 1, 2, 3 , Adila Aipire 2 , Jinyu Li 2 , Hongge Zhu 1 , Yanping Wang 4 , Wenjia Guo 1 , Xiaoqin Li 1 , Jia Yang 1 , Chunling Liu 1 1 Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi 830011, China 2 College of Life Science and Technology, Xinjiang University, Urumqi 830046, China 3 XinJiang DingJu Biotech CO., LTD, Urumqi 830000, China 4 Bayin Guoleng Vocational and Technical College, Korla 841000, China Correspondence to: Jinyao Li, email: ljyxju@qq.com Jinyu Li, email: lijinyu234@163.com Chunling Liu, email: liudeyouxiang66@sina.com Keywords: λ-carrageenan, TLR4, dendritic cell-based vaccine, cancer immunotherapy, cellular responses Received: November 10, 2016 Accepted: January 24, 2017 Published: February 22, 2017 ABSTRACT In this study, we investigated the effect of λ-carrageenan on the maturation and function of dendritic cells (DCs) and its adjuvant effect on DC-based vaccine. We found that λ-carrageenan dose-dependently decreased the endocytosis of DCs, promoted DC maturation and increased cytokine production through TLR4 mediated signaling pathway. λ-carrageenan treatment also enhanced the ability of DCs in the stimulating allogenic splenocyte proliferation. In TC-1 tumor mouse model, HPV peptides pulsed λ-carrageenan-DC (HPV-CGN-DC) significantly inhibited tumor growth compared with control group. The frequencies of CD4 + and CD8 + T cells in spleens of tumor mice and their activation status were significantly increased in HPV-CGN-DC group, but the frequencies of natural regulatory T cells and CD11b + Gr-1 + cells were significantly decreased. Further, HPV-CGN-DC induced strong CD8 + T cell responses, which are negatively correlated with tumor volumes. The results suggested that λ-carrageenan promoted DC maturation through TLR4 signaling pathway and could be used as the adjuvant in DC-based vaccines.

// Zhi-Rui Zhou 1,2,3,* , Min Liu 3,* , Hui-Rong Lu 3 , Ye-Fei Li 3 , Shi-Xiong Liang 3,4 and Chun-Yan Zhang 5 1 Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China 3 Department of Radiation Oncology, Cancer Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P.R. China 4 Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, P.R. China 5 Department of Experimental Research, Cancer Hospital of Guangxi Medical University, Nanning, P.R. China * These authors have contributed equally to this work Correspondence to: Shi-Xiong Liang, email: // Chun-Yan Zhang, email: // Keywords : hepatocellular carcinoma, radiotherapy, cancer staging Received : September 20, 2016 Accepted : January 16, 2017 Published : January 28, 2017 Abstract There is no consensus on predicting prognosis for hepatocellular carcinoma patients undergoing radiotherapy. This study aims to evaluate the validity of different staging systems. Overall, 249 hepatocellular carcinoma patients were evaluated retrospectively. All patients were classified by different staging systems. The cumulative survival rates were calculated using the Kaplan-Meier method, and survival curves were compared using the log-rank test. Harrell’s concordance index (c-index) was calculated. The 1-, 3-, and 5-year overall survival rates were 58%, 31% and 20%, respectively. Significant differences in overall survival were observed between stages I and II of the Okuda staging system ( p =0.004), between scores of 3 and 4 of Cancer of the Liver Italian Program prognostic score ( p =0.009), between Chinese University Prognostic Index low-risk and intermediate-risk groups ( p =0.01), between 1 and 2 points of the Japan Integrated Staging score ( p =0.037), between stages III and IV of American Joint Committee on Cancer 1997 TNM staging system ( p =0.011), between stages II and III of American Joint Committee on Cancer 2002 TNM staging system ( p =0.026) and between stages I and II of Guangzhou 2001 staging system ( p =0.000). In conclusion, the Okuda staging system, Chinese University Prognostic Index, and Chinese Guangzhou 2001 staging system were more discriminative than the other staging systems in the prognostic stratification for hepatocellular carcinoma patients undergoing radiotherapy.

// Tian-Zhu Yu 1, 2, * , Wen Zhang 1, 2, * , Qing-Xin Liu 1, 2, * , Wen-Hui Li 4, * , Jing-Qin Ma 1, 2 , Zi-Han Zhang 1, 2 , Min-Jie Yang 1, 2 , Jian-Hua Wang 1, 2 , Bing Chen 3 , Shao-Chong Zeng 3 , Jian-Jun Luo 1, 2 , Ling-Xiao Liu 1, 2 , Zhi-Ping Yan 1, 2 1 Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China 2 Shanghai Institute of Medical Imaging, Shanghai, China 3 Department of Radiotherapy, Zhongshan Hospital, Fudan University, Shanghai, China 4 Department of Interventional Radiology, Yancheng Third People’s Hospital, Southeast University, Yancheng, China * These authors have contributed equally to this work Correspondence to: Jian-Jun Luo, email: Luo.jianjun@zs-hospital.sh.cn Ling-Xiao Liu, email: Liu.lingxiao@zs-hospital.sh.cn Zhi-Ping Yan, email: Yan.zhiping@zs-hospital.sh.cn Keywords: hepatocellular carcinoma, main portal vein, tumor thrombus, endovascular brachytherapy, three-dimensional conformal radiotherapy Received: October 20, 2016 Accepted: December 27, 2016 Published: January 05, 2017 ABSTRACT Hepatocellular carcinoma (HCC) patients with main portal vein tumor thrombus have a median survival time of only about 4 months. We therefore compared the safety and efficacy of endovascular brachytherapy (EVBT) and sequential three-dimensional conformal radiotherapy (3-DCRT). From a cohort of 176 patients, we treated 123 with EVBT using iodine-125 seed strands (group A) and the remaining 53 with sequential 3-DCRT (group B). Overall survival, progression free survival and stent patency characteristics were compared between the two groups. Our analysis demonstrated a median survival of 11.7 ± 1.2 months in group A versus 9.5 ± 1.8 months in group B ( p = 0.002). The median progression free survival was 5.3 ± 0.7 months in groupA versus 4.4 ± 0.4 months in group B ( p = 0.010). The median stent patency period was 10.3 ± 1.1 months in group A versus 8.7 ± 0.7 months in group B ( p = 0.003). Therefore, as compared to sequential 3-DCRT, EVBT combined with portal vein stenting and TACE improved overall survival of HCC patients with main portal vein tumor thrombus.

Development of biocompatible/biodegradable materials with multiple functionalities via simple methods for cancer combination therapy has attracted great attention in recent years. Herein, paclitaxel (PTX), a popular anti-tumor chemotherapeutic drug, is used to induce the self-assembly of human serum albumin (HSA) pre-labeled with radionuclide I-131, obtaining 131I-HSA-PTX nanoparticles for combined chemotherapy and radioisotope therapy (RIT) of cancer. Such 131I-HSA-PTX nanoparticles show prolonged blood circulation time, high tumor specific uptake and excellent intra-tumor penetration ability. Interestingly, as revealed by in vivo photoacoustic imaging and ex vivo immunofluorescence staining, PTX delivered into the tumor by HSA-nanoparticle transportation can remarkably enhance the tumor local oxygen level and suppress the expression of HIF-1α, leading to greatly relieved tumor hypoxia. As the results, the combined in vivo chemotherapy & RIT with 131I-HSA-PTX nanoparticles in the animal tumor model offers excellent synergistic therapeutic efficacy, likely owing to the greatly modulated tumor microenvironment associated with PTX-based chemotherapy. Therefore, in this work, a simple yet effective therapeutic agent is developed for synergistic chemo-RIT of cancer, promising for future clinic translations in cancer treatment.

Nanoparticle-based theranostic agents have emerged as a new paradigm in nanomedicine field for integration of multimodal imaging and therapeutic functions within a single platform. However, the clinical translation of these agents is severely limited by the complexity of fabrication, long-term toxicity of the materials, and unfavorable biodistributions. Here we report an extremely simple and robust approach to develop highly versatile and biocompatible theranostic poly(vinyl alcohol)-porphyrin nanoparticles (PPNs). Through a “one-pot” fabrication process, including the chelation of metal ions and encapsulation of hydrophobic drugs, monodispersenanoparticle could be formed by self-assembly of a very simple and biocompatible building block (poly(vinyl alcohol)-porphyrin conjugate). Using this approach, we could conveniently produce multifunctional PPNs that integrate optical imaging, positron emission tomography (PET), photodynamic therapy (PDT), photothermal therapy (PTT) and drug delivery functions in one formulation. PPNs exhibited unique architecture-dependent fluorescence self-quenching, as well as photodynamic- and photothermal- properties. Near-infrared fluorescence could be amplified upon PPN dissociation, providing feasibility of low-background fluorescence imaging. Doxorubicin (DOX)-loaded PPNs achieved 53 times longer half-life in blood circulation than free DOX. Upon irradiation by near infrared light at a single excitation wavelength, PPNs could be activated to release reactive oxygen species, heat and drugs simultaneously at the tumor sites in mice bearing tumor xenograft, resulting in complete eradication of tumors. Due to their organic compositions, PPNs showed no obvious cytotoxicity in mice via intravenous administration during therapeutic studies. This highly versatile and multifunctional PPN theranostic nanoplatform showed great potential for the integration of multimodal imaging and therapeutic functions towards personalized nanomedicine against cancers.

Inflammatory breast cancer (IBC) is a virulent form of breast cancer, and novel treatment strategies are urgently needed. Immunohistochemical analysis of tumors from women with a clinical diagnosis of IBC (n = 147) and those with non-IBC breast cancer (n = 2510) revealed that, whereas in non-IBC cases cytoplasmic cyclin E was highly correlated with poor prognosis (P < 0.001), in IBC cases both nuclear and cytoplasmic cyclin E were indicative of poor prognosis. These results underscored the utility of the cyclin E/CDK2 complex as a novel target for treatment. Because IBC cell lines were highly sensitive to the CDK2 inhibitors dinaciclib and meriolin 5, we developed a high-throughput survival assay (HTSA) to design novel sequential combination strategies based on the presence of cyclin E and CDK2. Using a 14-cell-line panel, we found that dinaciclib potentiated the activity of DNA-damaging chemotherapies treated in a sequence of dinaciclib followed by chemotherapy, whereas this was not true for paclitaxel. We also identified a signature of DNA repair–related genes that are downregulated by dinaciclib, suggesting that global DNA repair is inhibited and that prolonged DNA damage leads to apoptosis. Taken together, our findings argue that CDK2-targeted combinations may be viable strategies in IBC worthy of future clinical investigation.

// Georgia Karpathiou 1 , Francois Casteillo 1 , Jean-Baptiste Giroult 2 , Fabien Forest 1 , Pierre Fournel 4 , Alessandra Monaya 1 , Marios Froudarakis 3 , Jean Marc Dumollard 1 , Jean Michel Prades 2 , Michel Peoc'h 1 1 Department of Pathology, North Hospital, University Hospital of St-Etienne, St-Etienne, France 2 Department of Head and Neck Surgery, North Hospital, University Hospital of St-Etienne, St-Etienne, France 3 Department of Pneumonology, North Hospital, University Hospital of St-Etienne, St-Etienne, France 4 Oncology Institute Lucien Neuwirth, St-Etienne, France Correspondence to: Georgia Karpathiou, email: gakarpath@yahoo.gr Keywords: PD-L1, CTLA4, macrophages, dendritic cells Received: July 15, 2016 Accepted: December 02, 2016 Published: December 27, 2016 ABSTRACT Background: Immune system affects prognosis of various malignancies. Anti-immune pathways like PD-L1 and CTLA4 are used by the tumor to overcome immune system and they serve as immunotherapy targets. The immune microenvironment of head-and-neck squamous cell carcinoma (SCCHN) has not been sufficiently studied. Patients and Methods: 152 SCCHN were immunohistochemically studied for the expression of CD3, CD8, CD57, CD4, granzyme b, CD20, CD163, S100, PD-L1, CTLA4 and CXCR4. Results: CD3, CD8, CD57 and stromal S100 higher density is a good prognostic factor (p=0.02, 0.01, 0.02, 0.03 respectively). CTLA4 tumor expression is a poor prognostic factor (p=0.05). The rest immune cells do not affect prognosis. CD3 and CD8 density does not correlate with clinicopathological factors or p16/p53 expression, while CD57 and CD4 higher density is associated with the absence of distant metastases (p=0.03 and 0.07, respectively). Higher CD20 and S100 density is associated with lower T stage (p=0.04 and 0.03, respectively). PD-L1 expression is higher in CD3, CD8, and CD163 infiltrated tumors and in histologically more aggressive tumors. Response to neoadjuvant chemotherapy is better in highly CD3 infiltrated tumors and in tumors with less intraepithelial macrophages. Conclusion: Rich T-lympocytic and dendritic cell response is a good prognostic factor in SCCHN, whereas tumors expressing CTLA4 show poor prognosis. PDL1 expression does not affect prognosis, but it is expressed in histologically more aggressive tumors and in T-cells rich tumors. Response to induction chemotherapy is better in tumors less infiltrated by macrophages and mostly infiltrated by T cells.

// Sheng Liming 1, 2 , Ji Yongling 1, 2 , Wu Qiner 3 , Du Xianghui 1, 2 1 Department of Radiotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China 2 Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology, Zhejiang, China 3 Department of Hyperthermia, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China Correspondence to: Du Xianghui, email: drduxianghui@gmail.com Keywords: esophageal cancer, regional hyperthermia, radiotherapy, prognosis Received: June 15, 2016 Accepted: November 24, 2016 Published: December 24, 2016 ABSTRACT To assess the efficacy and toxicity of Intensity-modulated radiotherapy (IMRT) and hyperthermia for upper and middle thoracic esophageal squamous cell carcinoma (UMT-ESCC) with supraclavicular lymph node metastasis. A total of 50 patients with UMT-ESCC with supraclavicular lymph node metastasis were evaluated in this retrospective study. All patients received IMRT. Hyperthermia was delivered simultaneously with irradiation, in 45 minutes twice a week for 5-6 weeks. Hyperthermia included supraclavicular lymph node metastasis. Forty-four patients (88.0%) received concurrent chemoradiotherapy based on cisplatin regimens. The most common types of hematological toxicities were anemia (62.0%) and leukopenia (60.0%). Most of these events were grade 1-2 and transient. The 3-year progression-free survival (PFS) rate and overall survival (OS) rate were 34.9% and 42.5%, respectively. Cox regression revealed that tumor length and number of supraclavicular lymph node metastasis were two independent predictors of OS (tumor length: HR=3.65, p=0.008; nodal stage: HR=8.07, p=0.019). The IMRT combined with supraclavicular regional hyperthermia has low toxicity and well tolerated with excellent local control in UMT-ESCC with supraclavicular lymph node metastasis.

Multiple myeloma (MM) is an incurable hematological malignancy, although bortezomib has markedly improved its outcomes. Growing clinical evidence indicates that enhancing induced natural killer (NK) or γδ T cells for infusion is useful in the treatment of MM. However, whether combination treatment with bortezomib and induced NK and γδ T cells further improves outcomes in MM, and how the treatments should be combined, remain unclear. Herein, we found that low-dose bortezomib did not suppress the viability of induced NK and γδ T cells, but did induce MM cell apoptosis. Importantly, low-dose bortezomib increased the expression of NKG2D and DNAM-1 ligands on MM cells, which sensitized the multiple myeloma cells to lysis by induced NK and γδ T cells. Our results suggested that combination treatment with low-dose bortezomib and induced NK or γδ T cells had a synergistic cytotoxic effect on MM cells. This study provided a proof of principle for the design of future trials and investigation of this combination therapeutic strategy for MM treatment.

// Christine C. Dobson 1, 2 , Thet Naing 1 , Shawn T. Beug 1 , Mame D. Faye 1 , Janelle Chabot 1 , Martin St-Jean 1 , Danielle E. Walker 1 , Eric C. LaCasse 1 , David F. Stojdl 1, 3 , Robert G. Korneluk 1, 3 , Martin Holcik 1, 4 1 Molecular Biomedicine Program, Apoptosis Research Centre, Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada 2 Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada 3 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada 4 Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada Correspondence to: Martin Holcik, email: martin@arc.cheo.ca Keywords: rhabdomyosarcoma, Smac mimetic, oncolytic virus, immunotherapy Received: June 20, 2016 Accepted: November 23, 2016 Published: December 10, 2016 ABSTRACT Rhabdomyosarcoma (RMS), a neoplasm characterized by undifferentiated myoblasts, is the most common soft tissue tumour in children. Therapeutic resistance is common in RMS and is often caused by acquired defects in the cellular apoptotic program. Smac mimetic compounds (SMCs) are a novel class of inhibitor of apoptosis (IAP) antagonists that are currently under clinical development as cancer therapeutics. We previously reported that cIAP1 is overexpressed in human primary RMS tumours and in patient-derived RMS cell lines where it drives resistance to apoptosis. In this study, we investigated whether inflammatory cytokine production triggered by activators of innate immunity synergizes with LCL161 to induce bystander killing of RMS cells in vitro and in vivo . Indeed, we show that innate immune stimuli (oncolytic virus (VSVΔ51-GFP), interferon γ (IFNγ), and tumour necrosis factor-like weak inducer of apoptosis (TWEAK)) combine with SMCs in vitro to reduce cell viability in the Kym-1 RMS cancer cell line. Other human RMS cell lines (RH36, RH41, RD, RH18, RH28, and RH30) and the murine RMS cell line 76-9 are resistant to treatment with LCL161 alone or in combination with immune stimulants in in vitro cell viability assays. In contrast, we report that the combination of LCL161 and VSVΔ51-GFP reduces tumour volume and prolongs survival in a 76-9 syngeneic murine model. Our results support further exploration of the combined use of IAP antagonists and innate immune stimuli as a therapeutic approach for RMS cancers.

// 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.

Integrating additive or synergistic antitumor effects that focus on distinct elements of tumor biology are the most rational strategies for cancer treatment. Treatments for breast cancer have increased overall survival, but remain limited by lack of efficacy in a subset of breast cancer patients. The real challenge is to define what elements of tumor biology make the most sense to be integrated. An emerging strategy is to consider a systems biology approach to impact multiple interactions in networks as compare with hitting a specific protein-protein interaction target. In this review, we consider how targeting tumor associated carbohydrate antigens (TACA) that are fundamental to signal pathways might be tailored to harness benefit from combination therapy of sustained immunity with chemotherapy. An approach we are developing makes use of a carbohydrate mimetic peptide (CMP) to induce polyspecific antibodies, which by their nature have numerous on and off target effects. Linking multi-target TACA recognition with mechanisms affecting tumor growth in the context of network heterogeneity and concepts of immune surveillance to tumor cells and the type of breast cancer patients that would benefit from such an approach provides a novel integrative treatment.

// 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.

The purpose of this study is to evaluate dose–volume histogram (DVH) predictors for the development of chronic gastrointestinal (GI) complications in patients with cervical cancer who have undergone postoperative concurrent chemotherapy and whole-pelvic radiation therapy (WPRT). The subjects were 135 patients who had undergone postoperative WPRT with concurrent nedaplatin-based chemotherapy between 2000 and 2014. Associations between selected DVH parameters and the incidence of chronic GI complications of G3 or higher were evaluated. Chronic GI complications of severity G3 occurred in 18 (13%) patients. Patients with GI complications had significantly greater V5–V45, mean dose and the generalized equivalent uniform dose (gEUD) of the small bowel loops, compared with those without GI complications. V30–V45, mean dose and gEUD of the bowel bag also showed significant differences between patients with and without GI complications. In contrast, no parameter for the large bowel loop was correlated with GI complications. Receiver operating characteristics curve analysis indicated that V30–V45 of the small bowel loops were better predictors than these respective parameters for the bowel bag. Next, patients were divided into four groups based on the median V15 and V40 of the small bowel loops. The group with both a high V15 and a high V40 showed a significantly higher probability of chronic GI complications. In conclusion, the small bowel loops are better predictors of chronic GI complications compared with the bowel bag, and a relatively high-dose volume (e.g. V40) of the small bowel loops is a useful predictor of chronic GI complications.

// 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.

Background We present the results of a Phase 2a randomized controlled trial investigating the safety, and secondary endpoints of subretinal rAAV.sFLT-1 gene therapy in patients with active wet age-related macular degeneration (wAMD). Methods All patients (n = 32), (ClinicalTrials.gov; NCT01494805), received ranibizumab injections at baseline and week 4, and thereafter according to prespecified criteria. Patients in the gene therapy group (n = 21) received rAAV.sFLT-1 (1 × 1011 vg). All patients were assessed every 4 weeks to the week 52 primary endpoint. Findings Ocular adverse events (AEs) in the rAAV.sFLT-1 group were mainly procedure related and self-resolved. All 11 phakic patients in the rAAV.sFLT-1 group showed progression of cataract following vitrectomy. No systemic safety signals were observed and none of the serious AEs were associated with rAAV.sFLT-1. AAV2 capsid was not detected and rAAV.sFLT-1 DNA was detected transiently in the tears of 13 patients. ELISPOT analysis did not identify any notable changes in T-cell response. In the rAAV.sFLT-1 group 12 patients had neutralizing antibodies (nAb) to AAV2. There was no change in sFLT-1 levels in bodily fluids. In the rAAV.sFLT-1 group, Best Corrected Visual Acuity (BCVA) improved by a median of 1.0 (IQR: − 3.0 to 9.0) Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline compared to a median of − 5.0 (IQR: − 17.5 to 1.0) ETDRS letters change in the control group. Twelve (57%) patients in the rAAV.sFLT-1 group maintained or improved vision compared to 4 (36%) in the control group. The median number of ranibizumab retreatments was 2.0 (IQR: 1.0 to 6.0) for the gene therapy group compared to 4.0 (IQR: 3.5 to 4.0) for the control group. Interpretation rAAV.sFLT-1 combined with the option for co-treatment appears to be a safe and promising approach to the treatment of wAMD. Funding National Health and Medical Research Council of Australia (AP1010405), Lions Eye Institute, Perth Australia, Avalanche Biotechnologies, Menlo Pk, CA, USA., Highlights • Subretinal injection of rAAV.sFLT-1 was found to be safe in 21 patients with wet age-related macular degeneration. • Visual acuity was maintained in gene therapy treated patients over the 52 week period. • The gene therapy treated group of patients had a trend towards fewer ranibizumab retreatments than the control group. Wet age-related macular degeneration (wAMD) is a common cause of vision loss in the elderly. We propose to use gene therapy to treat this disease. This study reinforces the findings from our Phase 1 study examining the safety of the delivery of rAAV.sFLT-1 by subretinal injection as a form of treatment of wAMD. The findings from this trial demonstrate that the surgical subretinal administration of rAAV.sFLT-1 has a favorable safety profile and that it can potentially be used in conjunction with current therapies to provide an improved outcome in the treatment of wAMD.

// 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.