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// Zhi-Rui Zhou 1,2,3,* , Qing Han 3,* , Shi-Xiong Liang 3,4 , Xiao-Dong He 4 , Nu-Yun Cao 5 and Ying-Jie Zi 3 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, P.R.China 4 Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, P.R.China 5 College of Mathematics and Information Science, Guangxi University, Nanning, P.R.China * These authors have contributed equally to this paper Correspondence to: Shi-Xiong Liang, email: // Keywords : intensity modulated radiotherapy; normal tissue complication probability; radiation-induced lung injury; breast cancer Received : September 16, 2016 Accepted : October 24, 2016 Published : October 28, 2016 Abstract To investigate the relationship between dosimetric factors, including Lyman normal-tissue complication (NTCP) parameters and radiation-induced lung injury (RILI), in postoperative breast cancer patients treated by intensity modulated radiotherapy (IMRT). 109 breast cancer patients who received IMRT between January 2012 and December 2013 were prospectively enrolled. A maximum likelihood analysis yielded the best estimates for Lyman NTCP parameters. Ten patients were diagnosed with RILI (primarily Grade 1 or Grade 2 RILI); the rate of RILI was 9.17% (10/109). Multivariate analysis demonstrated that ipsilateral lung V 20 was an independent predictor ( P =0.001) of RILI. Setting V 20 =29.03% as the cut-off value, the prediction of RILI achieved high accuracy (94.5%), with a sensitivity of 80% and specificity of 96%. The NTCP model parameters for 109 patients were m=0.437, n =0.912, and TD 50 (1)=17.211 Gy. The sensitivity of the modified Lyman NTCP model to predict the RILI was 90% (9/10), the specificity was 69.7% (69/99), and the accuracy was 71.6% (78/109). The RILI rate of the NTCP 9.62% in patients with breast cancer was 23.08% (9/39), ( P =0.001). In conclusion, V 20 is an independent predictive factor for RILI in patients with breast cancer treated by IMRT; V 20 =29.03% could be a useful dosimetric parameter to predict the risk of RILI. The Lyman NTCP model parameters of the new value (m=0.437, n =0.912, TD50 (1) =17.211 Gy) can be used as an effective biological index to evaluate the risk of RILI.

// Qiong Yang 1,2,3,4,* , Fangxin Liao 1,3,4,* , Yuanyuan Huang 1,3,4 , Chang Jiang 1,3,4 , Shousheng Liu 1,3,4 , Wenzhuo He 1,3,4 , Pengfei Kong 1,3,4 , Bei Zhang 1,3,4 and Liangping Xia 1,3,4 1 VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P.R. China 2 Department of Oncology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, P.R. China 3 State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P.R. China 4 Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, P.R. China * These authors have contributed equally to this paper Correspondence to: Liangping Xia, email: // Bei Zhang, email: // Keywords : metastatic colorectal carcinoma, palliative local treatment, chemotherapy, propensity score matching, prognosis Received : November 11, 2015 Accepted : February 24, 2016 Published : March 15, 2016 Abstract We assessed the value of palliative local treatment of incurable metastatic lesions in colorectal cancer patients. Consecutive patients with metastatic colorectal cancer treated between 2003 and 2014 were retrospectively reviewed. Propensity score matching was used to create comparable palliative local treatment and chemotherapy alone groups ( n = 272 in each group). The primary endpoint was overall survival, which was calculated using Kaplan-Meier survival analyses. Factors possibly influencing survival were evaluated by univariate and subsequently by multivariate analyses. Palliative local treatment prolonged survival as compared with chemotherapy alone (38.73 vs . 19.8 months, p < 0.01). Univariate and subsequent multivariate analyses showed that primary stage IV at initial diagnosis; high CA199 level and LDH at the time of diagnosis were independent factors for a poor prognosis. Palliative local treatment improved survival better than chemotherapy alone in patients with 0, 1, 2, or 3 of the prognostic factors ( p < 0.01). Patients administered treatment for pulmonary metastases survived longer than those treated for metastases elsewhere (56.77 vs . 35.43 months, p = 0.01). Surgical treatment provided marginally longer survival than non-surgical treatment (44.87 vs . 35.43 months, p = 0.05). These findings suggest palliative local treatment has survival benefit for selected patients with incurable metastatic colorectal cancer.

// Xing Chen 1 , Geng Liu 1 , Kaiqiang Wang 1 , Guodong Chen 1 and Jinjin Sun 1 1 Department of Hepatopancreatobiliary Surgery, The Second Hospital of Tianjin Medical University, Tianjin, China Correspondence to: Jinjin Sun, email: jsun02@tmu.edu.cn Keywords: LAPC, neoadjuvant radiation, resection, CSS, SEER Received: February 24, 2017 Accepted: April 07, 2017 Published: May 23, 2017 ABSTRACT Background and aim: To compare cancer-specific survival (CSS) between patients who received neoadjuvant radiation followed by resection (NRR) and those who received upfront resection (UR) for locally advanced pancreatic cancer (LAPC). Methods: A total of 772 LAPC patients who underwent curative-intent surgical resection with or without neoadjuvant radiation from 2004 to 2013 were identified from the Surveillance, Epidemiology, and End Result (SEER) database. Propensity score matching (PSM) was conducted to eliminate possible bias. Kaplan-Meier method was used to analyze long-term outcome. Independent risk factors of CSS were predicted by Cox proportional hazards model. Subgroup analyses were done according to 5 variables. Results: The propensity score model matched 196 patients from the whole cohort. Neoadjuvant radiation was an independent predictor of CSS no matter before or after PSM. After PSM, the 1-, 3-, 5-year CSS rates of NRR group were 82.7%, 39.2% and 17.1%, while 64.3%, 19.9% and 12.4% for UR group. The median CSS for NRR group was 25 months, while 17 months for UR group. In subgroup analyses, CSS rates or median CSS of NRR group were still superior to those of UR group in married, unmarried, pancreatic adenocarcinoma, G1+G2, G3+G4, N0 stage, N1 stage and M0 stage subgroups, but no differences were found in other histological types and M1 stage subgroups. Other predictors of CSS included histological type, tumor grade and marital status. Conclusions: Neoadjuvant radiation followed by resection has a significant survival benefit compared with upfront resection in LAPC patients. Therapeutic strategy for LAPC patients should be further explored.

Borderline resectable pancreatic cancer (BRPC) is a potentially resectable disease but is associated with poorer survival compared to primary resectable disease. There has been no prospective trial that compare the efficacy of FOLFIRNOX and gemcitabine-based regimen for BRPC. Between February 2013 and December 2014, 18 patients with BRPC receiving FOLFIRINOX were reviewed retrospectively. For comparative analysis, data for all BRPC patients (n=18) in our previous phase 2 study of neoadjuvant fixed-dose rate-gemcitabine plus capecitabine were pooled. Patients received a median 6 cycles (range, 3-13) of FOLFIRINOX. Surgical resection was performed in 12 patients (67%) and R0 resection in 9 patients. Median progression-free survival (PFS) and overall survival (OS) were 16.8 (95% confidence interval [CI], 9.4-24.2) and 21.2 (95% CI, 14.2-28.2) months, respectively. Patients who underwent surgical resection showed significantly better PFS (p=0.01) and OS (p=0.003) than those unresected. In the exploratory analysis, patients receiving FOLFIRINOX showed significantly longer PFS compared to those receiving fixed-dose rate-gemcitabine plus capecitabine (median 16.8 months [95% CI, 9.4-24.2] vs. 6.5 months [1.6-11.3]; p = 0.04). There was a trend toward improved OS in patients who received FOLFIRINOX (median 21.2 months [95% CI, 14.2-28.2]) compared to those who received fixed-dose rate-gemcitabine plus capecitabine (13.6 months [11.8-15.4]; p=0.12). FOLFIRINOX was feasible and effective as neoadjuvant chemotherapy for patients with BRPC and may have improved efficacy compared to a gemcitabine-based regimen.

// Fabrice Barlesi 1, 2 , Diane-Charlotte Imbs 2 , Pascale Tomasini 1 , Laurent Greillier 1 , Melissa Galloux 1 , Albane Testot-Ferry 1 , Melanie Garcia 3 , Xavier Elharrar 1 , Annick Pelletier 1 , Nicolas Andre 2, 4 , Celine Mascaux 1 , Bruno Lacarelle 2, 3 , Raouf El Cheikh 2 , Raphael Serre 2 , Joseph Ciccolini 2, 3 and Dominique Barbolosi 2 1 Aix Marseille University, APHM, Marseille Early Phases Cancer Trials Center CLIP, Marseille, France 2 Aix Marseille University, SMARTc Unit, INSERM U911, Marseille, France 3 Aix Marseille University, APHM, Department of Pharmacology, Marseille, France 4 Aix Marseille University, APHM, Department of Pediatric Hematology and Oncology, Marseille, France Correspondence to: Fabrice Barlesi, email: fabrice.barlesi@ap-hm.fr Keywords: lung cancer, mesothelioma, mathematical modeling, vinorelbine, metronomic Received: March 24, 2017 Accepted: April 19, 2017 Published: May 02, 2017 ABSTRACT Introduction: Using mathematical modelling allows to select a treatment’s regimen across infinite possibilities. Here, we report the phase I assessment of a new schedule for metronomic vinorelbine in treating refractory advanced NSCLC and mesothelioma patients. Results: Overall, 13 patients were screened and 12 were treated (50% male, median age: 68yrs), including 9 NSCLC patients. All patients received at least one week (3 doses) of treatment. At data cut-off, the median length of treatment was 6.5 weeks (1–32+). All the patients presented with at least one adverse event (AE) and six patients with a severe AE (SAE). One partial response and 5 stable diseases were observed. The median OS was 6.4 months (95% CI, 4.8 to 12 months). The median and mean vinorelbine’s AUC were 122 ng/ml*h and 159 ng/ml*h, respectively, with the higher plasmatic vinorelbine exposure associated with the best ORR (difference of AUC comparison between responders and non-responders, p-value 0.017). Materials and Methods: The mathematical modelling determined the administration of vinorelbine, 60 mg on Day 1, 30 mg on Day 2 and 60 mg on Day 4 weekly until progression, as the best schedule. Advanced NSCLC or mesothelioma patients progressing after standard treatment were eligible for the trial. NCT02555007. Conclusions: Responses with acceptable safety profile were observed in heavily pretreated NSCLC and mesothelioma patients using oral vinorelbine at this metronomic dosage based on a mathematic modeling. This study demonstrates the feasibility of this new type of approach, as mathematical modeling may help to rationally decide the better regimen to be clinically tested across infinite possibilities.

// Jianjun Liu 1, * , Mingxue Su 2, * , Shikai Hong 1, * , Hong Gao 1 , Xucai Zheng 1 and Shengying Wang 1 1 Department of Head, Neck, and Breast Surgery, Anhui Provincial Cancer Hospital, West Branch of Anhui Provincial Hospital, Hefei, China 2 Department of Infectious Disease Epidemiology, Lu’an People’s Hospital, Lu’an, China * These authors contributed equally to this work Correspondence to: Shengying Wang, email: Shengywang@163.com Keywords: nomogram, breast cancer, preoperative radiotherapy Received: February 22, 2017 Accepted: May 01, 2017 Published: May 18, 2017 ABSTRACT Background: To estimate survival in non-metastatic breast cancer patients who failed to achieve a pathological complete response (pCR) more effectively, we combined the clinicpathological characteristics after preoperative radiation therapy (pRT) and established a novel nomogram. Materials and Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 2,545 non-metastatic breast cancer patients who underwent pRT between 1998 and 2013. Based on the registries of patients, the primary cohort divided into training set ( n = 1,692) and validation set ( n = 853). Nomograms were established by training set and validated by validation set. Results: According to the multivariate analysis of training set, nomogram which combined age at diagnosed, marital status, location, grade, ER status, yp-T status, yp-N status and whether received breast conservation surgery (BCS) was developed. Calibration plots of the nomograms showed that the probability of DSS corresponded to actual observation closely. The C-index was 0.78 in validation set, which was significantly higher than that of yp-TNM staging system (0.75, p = 0.004). Conclusions: The proposed nomogram resulted in more–reliable DSS prediction for non-metastatic breast cancer patients in general population, it would be helpful in individualized survival prediction and better treatment allocation after pRT.

We aim to investigate the safety and efficacy of microwave ablation (MWA) combined with attenuated Salmonella typhimurium strain VNP20009 in treating hepatocellular carcinoma. Portions of tumor tissues were orthotopically implanted in the livers of 40 male rats weighed 150~200 g to establish tumor models. Three weeks later, the rats were randomly divided into four groups: (A) MWA plus VNP20009 group; (B) MWA group; (C) VNP20009 group; and (D) control group. Incomplete MWA was performed (20~30 W, 1~2 min) after the hepatic carcinoma was properly exposed. VNP20009 (about 1×107 cfu) was directly injected into the tumor immediately. MRI scans were performed to assess the tumor responses 7 and 14 days later, respectively. Micro CT was used to observe the lung metastases. After the animals were sacrificed or died, the tumors were cut off for the purpose of pathological and immunohistochemical analyses. The results showed that the mean tumor volumes of MWA plus VNP20009 group on the 7th and 14th day post treatment were obviously smaller than those of other groups (P < 0.05). Lung metastases rates were 20%, 60%, 30% and 100% in MWA plus VNP20009 group, MWA group, VNP20009 group and control group, respectively. The median survival of the rats in MWA plus VNP20009 group was distinctly longer than those in other groups (P < 0.05). In summary, MWA combined with VNP20009 produced better effects than MWA or VNP20009 alone in treating hepatic carcinoma. This strategy might have potential ability to decrease lung metastases and prolong the overall survival.

// Min He 1, * , Jia-Xin Zhang 1, * , Yi-Zhou Jiang 1 , Ying-Le Chen 1 , Hai-Yuan Yang 1 , Li-Chen Tang 1 , Zhi-Ming Shao 1 and Gen-Hong Di 1 1 Department of Breast Surgery, Key Laboratory of Breast Cancer, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China * These authors have contributed equally to this work Correspondence to: Gen-Hong Di, email: genhongdi@163.com Keywords: lymph node ratio, triple-negative breast cancer, prognosis Received: December 21, 2016 Accepted: March 29, 2017 Published: April 25, 2017 ABSTRACT Background: We aimed to evaluate the prognostic value of the lymph node ratio (LNR) in patients with axillary lymph node-positive triple-negative breast cancer (TNBC). Methods: The prognostic efficacy was investigated in the first cohort from the Surveillance, Epidemiology, and End Results (SEER) dataset (n=4114) and was further validated in an independent cohort from Fudan University Shanghai Cancer Center (n=417). Patients were classified into low-, medium- and high-risk LNR groups. Results: Multivariate analysis revealed that the LNR was an independent predictor of overall survival (hazard ratio (HR) for high-risk LNR: 3.24; 95% confidence interval (CI): 2.56 to 4.09) and breast cancer-specific survival (HR for high-risk LNR: 3.57; 95% CI: 2.76 to 4.62) in the SEER population and also for disease-free survival (HR for high-risk LNR: 4.29; 95% CI: 2.24-8.21) in the validation population. Subgroup analysis revealed that patient classification according to the LNR could discriminate among groups of patients with different survival rates based on pathological nodal (pN) staging. Conclusion: The LNR shows potential for use as an additional prognostic factor for TNBC patients with positive lymph node involvement. Considering the heterogeneity of TNBC, use of the LNR might allow for optimization of the pN staging system and should be considered when making treatment decisions.

// Fan Yang 1, * , Pei Yang 1, * , Chuanbao Zhang 1, * , Yongzhi Wang 2 , Wei Zhang 2 , Huimin Hu 1 , Zhiliang Wang 1 , Xiaoguang Qiu 3 and Tao Jiang 1, 2, 4, 5 1 Department of Molecular Pathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China 2 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 3 Department of Radiation Therapy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 4 China National Clinical Research Center for Neurological Diseases, Beijing, China 5 Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing, China * These authors have contributed equally to this work Correspondence to: Tao Jiang, email: taojiang1964@163.com Keywords: glioblastoma, prognosis, recursive partitioning analysis, molecular marker, MGMT Received: July 18, 2016 Accepted: December 16, 2016 Published: April 21, 2017 ABSTRACT Glioblastoma accounts for more than half of diffuse gliomas. The prognosis of patients with glioblastoma remains poor despite comprehensive and intensive treatments. Furthermore, the clinical significance of molecular parameters and routinely available clinical variables for the prognosis prediction of glioblastomas remains limited. The authors describe a novel model may help in prognosis prediction and clinical management of glioblastoma patients. We performed a recursive partitioning analysis to generate three independent prognostic classes of 103 glioblastomas patients from TCGA dataset. Class I (MGMT promoter methylated, age 59, KPS ≥70), class III (MGMT promoter unmethylation, age 54-58, KPS ≥70; MGMT promoter unmethylation, KPS

The effect of postmastectomy radiotherapy (PMRT) on T1-2 breast cancer patients with 1-3 positive axillary lymph nodes is controversial up to now. The purpose of this study was to evaluate the impact of postmastectomy radiotherapy for these patients. The prognostic factor effecting locoregional free-survival (LRFS) was also analyzed. In the retrospective clinical data of 1674 eligible patients, survival analysis was performed using the method of Kaplan-Meier and the log-rank test. Cox regression analysis was applied to identify the significant prognostic factors. We found PMRT increased 5-year LRFS (p=0.003), but could not improve 5-year disease-free survival or overall survival statistically. For patients without PMRT, multivariate analysis revealed that age, lymph node ratio and molecule subtype were risk factors effecting LRFS. To further analyze the role of PMRT, we grouped all the patients into low risk group (0 or 1 risk factor) and high risk group (2 or 3 risk factors) depending on these risk factors. We found that in low-risk group, PMRT increased only 5-year LRFS (p=0.012). However, in high-risk group, PMRT increased both 5-year LRFS (p=0.005) and 5-year disease-free survival (p=0.033), but could not improve 5-year overall survival statistically. Thus, these data provide the evidence that PMRT could improve LRFS for T1-2 breast cancer patients with 1-3 positive axillary lymph nodes. Additionally, PMRT could improve LRFS and disease-free survival for high risk patients. Age, lymph node ratio and molecule subtype were high risk factors effecting LRFS in our study.

// Juanjuan Li 1, * , Yue Xia 2, * , Qi Wu 1 , Shan Zhu 1 , Chuang Chen 1 , Wen Yang 1 , Wen Wei 1 and Shengrong Sun 1 1 Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China 2 Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China * These authors have contributed equally to this work Correspondence to: Shengrong Sun, email: sun137@sina.com Keywords: outcomes, inflammatory breast cancer, molecular subtypes, SEER program Received: January 20, 2017 Accepted: March 24, 2017 Published: April 19, 2017 ABSTRACT Background: The aim of this study was to evaluate the outcomes of patients with inflammatory breast cancer (IBC), with emphasis on the role of molecular subtypes and radiotherapy. Methods: A retrospective cohort study to investigate overall survival (OS) and breast cancer-specific mortality (BCSM) in patients with IBC was conducted using data obtained by the Surveillance, Epidemiology, and End Results (SEER) program from 2010–2013. Cox multivariate regression was used to calculate the adjusted Hazard Ratios (aHR). Results: 403 patients were eligible for this study. Patients in the group with hormone receptors (HR)+/HER2- subtype had an OS of 79.6% compared with 89.0 % in the group with (HR)+/HER2+ subtype and 76.8% in the HR-/HER2+ group and 62.9% in the triple-negative (TN) group. BCSM was 16.3% for the HR+/HER2- group, 9.8% for the HR+/HER2+ group, 21.7% for the HR-/HER2+ group, and 30.5% for the TN group. For distant metastases, the results showed that there was a high probability of bone metastasis in HR-positive groups, brain and liver metastasis in HER2-positive groups, and lung metastasis in the TN group. Multivariate analysis demonstrated that estrogen receptor and HER2 positivity were associated with better survival and that the TN subtype had a poorer OS and BCSM compared with other subtypes (P

// Yujin Xu 1, 2 , Xiao Zheng 1, 2 , Xue Bai 3 , Pu Li 3 , Honglian Ma 1, 2 , Jin Wang 1, 2 , Xiao Hu 1, 2 and Ming Chen 1, 2 1 Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, China 2 Zhejiang Provincial Key Laboratory of Radiation Oncology, Hangzhou, 310022, China 3 Department of Radiation Physics, Zhejiang Cancer Hospital, Hangzhou, 310022, China Correspondence to: Ming Chen, email: chenming@zjcc.org.cn Keywords: non-small cell lung cancer, integrated boost intensity-modulated radiotherapy, local control, overall survival Received: March 03, 2017 Accepted: March 31, 2017 Published: April 13, 2017 ABSTRACT Objectives: To evaluate the clinical efficacy and toxicity of simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) for patients with locally advanced non-small cell lung cancer (NSCLC). Results: All patients completed definitive radiotherapy and 74 (85.1%) patients administrated platinum-based chemotherapy. The median radiation dose was 50.4Gy to PTV and 64.4 Gy simultaneously to the PGTV. The overall response rate (ORR) was 57.5% (50/87). The median duration of follow up was 24.6 months. The 1, 2, 3-year local control rate was 79.0%, 66.1%, and 60.5%, respectively. The 1, 2, 3-year overall survival (OS) rate was 89.7%, 56.7%, and 30.6%, respectively. Subgroup analysis showed that the median OS in concurrent chemoradiation (CCRT) was much better than non-CCRT (35.7 vs. 26.4 months) (HR: 0.52, 95% CI: 0.32–0.95, P = 0.033). Twenty-two (25.3%) patients experienced acute grade 3 esophagitis and 10 (11.5%) experienced acute grade ≥ 3 radiation pneumonitis. There were 2 (2.6%) late grade 3 pulmonary toxicity and no late grade ≥ 3 esophageal toxicity was observed. Materials and Methods: A total of 87 patients with locally advanced NSCLC who received SIB-IMRT from Jan. 2009 to Dec. 2012 in our hospital were retrospectively analyzed. Male accounted for 88.5%, with a median age of 61 years old. The SIB-IMRT plans were designed to deliver 50.4–64.0 Gy in 28–33 fractions (1.8–2.1 Gy/fraction) to PTV while simultaneously delivering 60.0–74.3 Gy in 28–33 fractions (2.0–2.5 Gy/fraction) to PGTV. Conclusions: SIB-IMRT, especially with concurrent chemotherapy, appears to be an effective and safe option to treat patients with locally advanced NSCLC. More prospective clinical studies should be warranted.

// Ping Zhu 1, 2 , Xianglin L. Du 1 , Guangrong Lu 2 and Jay-Jiguang Zhu 2 1 Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas Health Science Center at Houston (UTHealth), School of Public Health, Houston, TX 77030, USA 2 The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston (UTHealth), McGovern Medical School, and Memorial Hermann at Texas Medical Center, Houston, TX 77030, USA Correspondence to: Jay-Jiguang Zhu, email: jay.jiguang.zhu@uth.tmc.edu Keywords: glioblastoma (GBM), temozolomide, bevacizumab, overall survival, cancer registry Received: November 23, 2016 Accepted: March 20, 2017 Published: April 12, 2017 ABSTRACT Few population-based analyses have investigated survival change in glioblastoma multiforme (GBM) patients treated with concomitant radiotherapy-temozolomide (RT-TMZ) and adjuvant temozolomide (TMZ) and then bevacizumab (BEV) after Food and Drug Administration (FDA) approval, respectively. We aimed to explore the effects on survival with RT-TMZ, adjuvant TMZ and BEV in general GBM population based on the Surveillance, Epidemiology, and End Results (SEER) and Texas Cancer Registry (TCR) databases. A total of 28933 GBM patients from SEER (N = 24578) and TCR (N = 4355) between January 2000 and December 2013 were included. Patients were grouped into three calendar periods based on date of diagnosis: pre-RT-TMZ and pre-BEV (1/2000–2/2005, P1), post-RT-TMZ and pre-BEV (3/2005–4/2009, P2), and post-RT-TMZ and post-BEV (5/2009–12/2013, P3). The association between calendar period of diagnosis and survival was analyzed in SEER and TCR, separately, by the Kaplan-Meier method and Cox proportional hazards model. We found a significant increase in median overall survival (OS) across the three periods in both populations. In multivariate models, the risk of death was significantly reduced during P2 and further decreased in P3, which remained unchanged after stratification. Comparison and validation analysis were performed in the combined dataset, and consistent results were observed. We conclude that the OS of GBM patients in a “real-world” setting has been steadily improved from January 2000 to December 2013, which likely resulted from the administrations of TMZ concomitant with RT and adjuvant TMZ for newly diagnosed GBM and then BEV for recurrent GBM after respective FDA approval.

// Thomas J. Schnoeller 1 , Florian Jentzmik 1, 2 , Andres J. Schrader 3 and Julie Steinestel 3 1 Department of Urology, Ulm University Medical Center, Ulm, Germany 2 Department of Urology, St. Elisabeth Hospital, Ravensburg, Germany 3 Department of Urology, Muenster University Medical Center, Muenster, Germany Correspondence to: Julie Steinestel, email: Julie.steinestel@ukmuenster.com Keywords: prostate cancer, tumor biology, biomarker, cholesterol, statin therapy Received: February 13, 2017 Accepted: March 14, 2017 Published: April 07, 2017 ABSTRACT Both cholesterol levels and the use of statins have been described to influence the development and prognosis of prostate cancer (PC). In this retrospective, cross-sectional analysis of consecutive cases from a tertiary referral center we evaluated an association between hypercholesterolemia (≥5.0mmol/l), the use of statins, and advanced/aggressive PC in 767 men with histologically confirmed, clinically localized PC awaiting radical prostatectomy. We found that patients with HCE (n=287, 37.4%) had a significantly higher incidence of poorly differentiated PC (Gleason score ≥7b, 81.1% vs. 4.9%), advanced local tumor stage (≥pT3, 57.7% vs. 22.2%), and nodal involvement (19.8% vs. 1.6%). Multivariate logistic regression analysis identified hypercholesterolemia as a risk factor for aggressive and/or advanced PC (OR 2.01, p

// Miao-Qun Xue 1 , Jun Liu 2 , Jian-Feng Sang 1 , Lei Su 1 and Yong-Zhong Yao 1 1 Department of General Surgery, Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China 2 Department of General Surgery, The Jiang Bei People’s Hospital of Nanjing, Nanjing 210048, China Correspondence to: Yong-Zhong Yao, email: cnyongzhongyao321@yeah.net Keywords: breast cancer, breast cancer stem cells, chemokine receptor, CXCR1, neo-adjuvant chemotherapy Received: October 12, 2016 Accepted: February 22, 2017 Published: April 06, 2017 ABSTRACT Objective: To investigate chemokine receptor CXCR1 expression characteristic in different breast tissues and analyze the relationship between CXCR1 expression changes in breast cancer tissue and efficacy of neo-adjuvant chemotherapy. Results: Chemokine receptor CXCR1 was lowly expressed in normal breast tissues and breast fibroadenoma, but highly expressed in breast cancer. It was significantly correlated with pathological stage, tumor cell differentiation, and lymph node metastasis ( P < 0.05). After neo-adjuvant chemotherapy, CXCR1 expression in breast cancer tissues decreased. Among these 104 breast cancer patients with different molecular subtypes, the survival rate with Luminal A was the highest, followed by the Luminal B breast cancer, TNBC was the worst. Materials and Methods: 104 cases with breast carcinoma, 20 cases with normal breast and 20 cases with breast fibroadenoma were included and followed up. Immunohistochemistry was used to detect the expression of CXCR1 in the various tissues. The relationship between the CXCR1 expression changes in breast cancer biopsies and surgical specimens, as well as the efficacy of neo-adjuvant chemotherapy, was analyzed. Conclusions: Chemokine receptor CXCR1 could be used as an indicator to predict benign or malignant breast disease, and it can even predict the malignancy degree of breast cancer, as well as its invasive ability and prognosis.

The aim of the present study was to compare the effectiveness of transarterial chemoembolization (TACE), TACE combined with Jie-du granules (JD), and TACE combined with sorafenib (SOR) for treating patients with unresectable hepatocellular carcinoma (HCC). For this purpose, we conducted a retrospective analysis of data from 266 consecutive patients with unresectable HCC who underwent TACE treatment at the Shanghai Hospital and Eastern Hepatic Surgery Hospital between Jan 2009 and Dec 2010. We prospectively analyzed patient survival and progression times as well as independent predictors, within a follow-up period of 86 months. Patients were divided into TACE-JD (n = 75), TACE-SOR (n = 124) and TACE (n = 67) groups. Median overall survival (OS) times being: TACE-JD, 21.43 months; TACE-SOR, 23.23 months; TACE, 13.97 months (TACE-SOR vs TACE, P < 0.001; TACE-SOR vs TACE-JD, P = 0.852; TACE-JD vs TACE, P < 0.001). The median times to progression (TTP) were as follows: TACE-JD, 8.67 months; TACE-SOR, 5.37 months; TACE, 4.57 months (TACE-SOR vs TACE, P = 0.479; TACE-SOR vs TACE-JD, P < 0.001; TACE-JD vs TACE, P < 0.001). Independent predictors of OS were treatment allocation, Child-Pugh class large tumor, albumin and extrahepatic metastasis. These findings show that patients with unresectable HCC who were administered TACE-JD survived significantly longer compared with those administered TACE or TACE-SOR.

// 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.

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.