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Additional file 1. Occurrence site and grade of reactive capillary endothelial proliferation.

Supplemental material, Supplementary_Information_for_TAM for A cohort study and meta-analysis of the evidence for consideration of Lauren subtype when prescribing adjuvant or palliative chemotherapy for gastric cancer by Kunning Wang, Enxiao Li, Rita A. Busuttil, Joseph C. Kong, Sharon Pattison, Joseph J. Y. Sung, Jun Yu, Emad M. El-Omar, Julie A. Simpson and Alex Boussioutas in Therapeutic Advances in Medical Oncology

Triple-negative breast cancer (TNBC) has a poor prognosis mainly due to insensitivity or resistance to standard anthracycline- and taxane-based chemotherapy, urgently calling for new adjuvants to reverse drug resistance. Dual-target murine double minute 2 (MDM2) and murine double minute X (MDMX) inhibitor has been proved to play a critical part against cancer, particularly focusing on the tremendous potential to enhance the efficacy of doxorubicin (DOX), however little was reported in TNBC. In the present study, we investigated the synergistic antitumor effect of the MDM2/MDMX inhibitor with DOX using three TNBC cell lines, two in situ transplantation tumor models and 214 clinical samples. We observed that the MDM2/MDMX inhibitor combined with DOX could not only inhibit cell vitality and migration and invasion abilities, but also highly inhibit tumor growth in TNBC nude mice. Besides, co-treatment of MDM2/MDMX inhibitor and DOX suppressed epithelial to mesenchymal transition (EMT) through increasing the TAK1-binding protein 1 (TAB1), transforming growth factor β-activated kinase 1 (TAK1) and p38 mitogen-activated protein kinase (MAPK) expression. Small interfering RNA-mediated TAB1 knockdown induced the EMT, desensitized cells to DOX and enhanced the migration and invasion abilities. High MDM2/MDMX expression was positively associated with weak TAB1 expression in 214 TNBC tumor tissues confirmed by immumohistochemical staining and MDM2/MDMX/TAB1 expression was significantly related to TNBC patient survival. These findings indicate that dual-target MDM2/MDMX inhibitor could increase the sensitization of doxorubicin and inhibit migration and invasion abilities in TNBC cells through p38 MAPK pathway activation caused EMT suppression and hence could be useful in TNBC treatments in future.

Summary Background Patients with advanced or metastatic oesophageal squamous cell carcinoma have poor prognosis and few treatment options after first-line therapy. We aimed to assess efficacy and safety of the anti-PD-1 antibody camrelizumab versus investigator's choice of chemotherapy in previously treated patients. Methods ESCORT is a randomised, open-label, phase 3 study of patients aged 18 to 75 years with a histological or cytological diagnosis of advanced or metastatic oesophageal squamous cell carcinoma done at 43 hospitals in China. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had progressed on, or were intolerant to, first-line standard therapy. Patients were randomly assigned (1:1) to camrelizumab (200 mg every 2 weeks) or chemotherapy with docetaxel (75 mg/m2 every 3 weeks) or irinotecan (180 mg/m2 every 2 weeks), all given intravenously. Central randomisation was done using the Randomization and Trial Supply Management system with block size randomly generated as four or six and stratified by disease and ECOG performance status. The primary endpoint was overall survival, assessed in randomised patients who had received at least one dose of treatment. Safety was assessed in all treated patients. The trial is registered with ClinicalTrials.gov , NCT03099382 , and is closed to new participants. Findings From May 10, 2017, to July 24, 2018, 457 (75%) of 607 screened patients were randomly assigned to treatment, of whom 228 received camrelizumab treatment and 220 received chemotherapy. As of data cutoff on May 6, 2019, with a median follow-up time of 8·3 months (IQR 4·1–12·8) in the camrelizumab group and 6·2 months (3·6–10·1) in the chemotherapy group, median overall survival was 8·3 months (95% CI 6·8–9·7) in the camrelizumab group and 6·2 months (5·7–6·9) in the chemotherapy group (hazard ratio 0·71 [95% CI 0·57–0·87]; two-sided p=0·0010). The most common treatment-related adverse events of grade 3 or worse were anaemia (camrelizumab vs chemotherapy: six [3%] vs 11 [5%]), abnormal hepatic function (four [2%] vs one [ Interpretation Second-line camrelizumab significantly improved overall survival in patients with advanced or metastatic oesophageal squamous cell carcinoma compared with chemotherapy, with a manageable safety profile. It might represent a potential option of standard second-line treatment for patients with oesophageal squamous cell carcinoma in China. Funding Jiangsu Hengrui Medicine.

Long Zou,1,2 Yinying Wu,1 Ke Ma,1 Yangwei Fan,1 Danfeng Dong,1 Ningyan Geng,2 Enxiao Li1 1Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 2Department of Gastroenterology, Shangluo Central Hospital, Shangluo, Shaanxi, People’s Republic of China Abstract: A novel molecular classification of gastric cancer by the Asian Cancer Research Group (ACRG) is a potential advance in diagnosis and treatment, and it helps to determine prognosis. The use of immunohistochemistry (IHC) rather than gene expression analysis to determine tumor subtypes was evaluated with the aim of determining the feasibility of using the ACRG molecular classification. A total of 69 esophagogastric junction (EGJ) carcinomas were classified as microsatellite instable (MSI, 17.40%, 12 of 69), microsatellite stable with markers of epithelial-to-mesenchymal transition (MSS/EMT, 18.84%, 13 of 69), microsatellite stable with active tumor protein 53 (MSS/TP53+, 27.53%, 19 of 69), and microsatellite stable with inactive TP53 (MSS/TP53-, 36.23%, 25 of 69). The molecular classification did not significantly correlate with anyone of the clinicopathological characteristics of the EGJ carcinoma patients, including age, gender, depth of tumor invasion, the presence of lymph node metastasis, histologic grade, and p-TNM stage of the American Joint Committee on Cancer (P>0.05). Kaplan–Meier survival analysis and log rank tests showed that molecular classification, histologic grade, p-TNM stage, and postoperative adjuvant chemotherapy were significantly associated with overall survival (OS; P

The present study aimed to investigate the clinicopathological significance of programmed cell death ligand-1 (PD-L1) and programmed cell death protein 1 (PD-1) expression in extrahepatic cholangiocarcinoma (ECC). PD-L1 and PD-1 expression was detected by immunohistochemical methods in 70 ECC formalin-fixed, paraffin-embedded tissue specimens and 50 para-carcinoma tissue specimens. The associations of PD-L1 and PD-1 expression with clinicopathological characteristics and prognosis of ECC patients were explored. Positive rates of PD-L1 and PD-1 expression were increased in ECC tissues compared with those in the corresponding para-carcinoma tissues. Besides, the expression of PD-L1 was correlated with the expression of PD-1 (P

// Zheling Chen 1 , Yinghong Ren 2 , Xianglin L. Du 3 , Jiao Yang 1 , Yanwei Shen 1 , Shuting Li 1 , Yunying Wu 1 , Meng Lv 1 , Danfeng Dong 1 , Enxiao Li 1 , Wei Li 4 , Peijun Liu 5 , Jin Yang 1 and Min Yi 1, 6 1 Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China 2 Department of Internal Medicine, Shangluo Central Hospital, Shangluo, Shaanxi, People’s Republic of China 3 Department of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas School of Public Health, Houston, TX, USA 4 Weapon Industry Health Research Institute, Xian, Shaanxi, People’s Republic of China 5 Department of Translational Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China 6 Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Correspondence to: Min Yi, email: myi@mdanderson.org Jin Yang, email: yangjin@mail.xjtu.edu.cn Keywords: esophageal cancer, the united states, survival, incidence rate, ethnicity Received: February 12, 2017 Accepted: March 06, 2017 Published: March 30, 2017 ABSTRACT Objectives: This study was performed to identify the differences in incidence, clinicopathological features, and survival in esophageal cancer among ethnic groups in the United States and to determine the reasons for the differences. Result: A total of 49,766 patients were included. Black and Asian groups had a higher proportion of squamous cell carcinoma (ESCC) (85.5% and 75.4%, respectively) and mid-esophagus tumor (43.2% and 37.7% respectively) than the non-Hispanic white and Hispanic white groups. The incidences of ESCC in all ethnic groups declined since 1973, especially in black males. At the same time, incidences of esophageal adenocarcinoma (EAC) dramatically increased in white males since 1973. And incidences of ESCC and EAC were the lowest and stable in Asian female. Multivariable models showed that patients who were male, or black, or had larger tumors, or positive lymph nodes had an increased risk of death from esophageal cancer, while patients with ESCC or diagnosed after 2005 or treated with surgery had a lower likelihood of death. For ESCC, the black patients had the lowest DSS, while for EAC there were no significant differences in DSS among the ethnic/racial groups. Materials and Method: From the Surveillance, Epidemiology, and End Results Program database, patients diagnosed with esophageal cancer from 1998-2013 were identified. Differences in incidences, clinicopathological features, treatments, and disease-specific survival (DSS) in four broad racial/ethnic groups were compared. Conclusion: Histological type distribution between racial groups could be an important consideration in the incidence and the survival trend but other factors could also have an effect.

Background: The evidence base for optimum third-line therapy for metastatic colorectal cancer (mCRC) is not conclusive. Recent studies have demonstrated the efficacy of regorafenib as third-line therapy in mCRC. This indirect meta-analysis compared the efficacy and safety of regorafenib with other available third-line therapies for mCRC. Methods: A literature search for randomized controlled trials (RCTs) was conducted in PubMed, Embase, and Cochrane Library for studies evaluating the efficacy and safety of fruquintinib, regorafenib, TAS-102, and nintedanib as third-line therapies in patients with mCRC. Overall survival (OS) and progression-free survival (PFS) were the primary outcomes, while objective response rate (ORR) and safety were the secondary outcomes. Hazard ratio (HR) and relative risk (RR) with their respective 95% confidence interval (CI) were used for analysis of survival, clinical response, and safety data. An adjusted indirect meta-analysis with placebo as the common comparator was performed. Results: We identified eight RCTs comparing regorafenib (two studies), fruquintinib (two studies), TAS-102 (three studies), and nintedanib (one study) against placebo. The OS with regorafenib was significantly better when compared with nintedanib (HR = 0.66; 95% CI: 0.45, 0.95, p = 0.02) but was similar to that of fruquintinib (HR = 1.01; 95% CI: 0.67, 1.52, p = 0.94) and TAS-102 (HR = 0.97; 95% CI: 0.68, 1.38, p = 0.88). The PFS and ORR for regorafenib were slightly better than those of TAS-102 (PFS: HR = 0.86, 95% CI: 0.54, 1.37, p = 0.5; ORR: RR = 1.13, 95% CI: 0.11, 11.05, p = 0.92) and nintedanib (PFS: HR = 0.68, 95% CI: 0.42, 1.10, p = 0.12; ORR: not reported) but were lower than those for fruquintinib (PFS: HR = 1.53, 95% CI: 0.93, 2.52, p = 0.08; ORR: RR = 0.68269, 95% CI: 0.045, 10.32, p = 0.79). Safety analysis showed that the RR of adverse events (AEs) was lesser in patients treated with regorafenib in comparison with that in patients treated with fruquintinib, but was similar to that in patients treated with nintedanib and TAS-102. Conclusion: Regorafenib has efficacy similar to that of TAS-102 and better safety when compared with fruquintinib. Considering the mechanism of action of regorafenib, which targets multiple factors in the angiogenic pathway, it could be an ideal option for treatment in the beyond second-line setting.

This study examined the tumor expression of programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) in patients with GEP-NEN. This study aims to reveal the relationship of their expression with clinicopathological characteristics and prognosis.PD1 and PD-L1 expression in tumors from 120 GEP-MEN patients was evaluated using immunohistochemistry. The correlations of the expression of PDL1/PD1 and clinicopathological features were assessed.Immunohistochemical staining indicated that PD-L1 was expressed in the tumor cells of 52.5% patients with GEP-NENs, and PD-L1 expression was positively correlated with the World Health Organization (WHO) classification, American Joint Committee on Cancer (AJCC) stage, lymphatic metastasis and prognosis. Meanwhile, PD-1 was expressed in tumor infiltrating lymphocytes within 55.8% tumor samples, and PD-1 expression was positively correlated with AJCC stage and GEP-NENs prognosis. Moreover, survival analysis indicated that the overall median survival of patients with PD-L1/PD-1-positive tumors significantly differed from that of patients with PD-L1/PD-1-negative tumors. Multivariate analysis confirmed that AJCC stage and Chromogranin A expression in tumor tissues were independent prognostic factors for overall survival. In conclusion, PDL1 was an independent prognostic factor for patients with GEP-NENs. Our results suggested that patients with GEP-NENs might be appropriate for PD1/PDL1-targeted therapy.Our findings show that the expression of PD-L1 and PD-1 correlates with patient prognosis, and may thus serve as potential pathological prognostic markers of GEP-NENs. Immunotherapy using PD-1/PD-L1 inhibitors may be a promising strategy for GEP-NENs patients with PD-L1/PD-1 positively expressed.

Background Mitochondrial shape is dynamically changed by fusion and fission processes in cells, and dysfunction of this process has become one of the emerging hallmarks of cancer. However, the expression patterns and biological effects of mitochondrial fission and fusion proteins in pancreatic cancer (PC) are still unclear. Methods The expressions of mitochondrial fission and fusion proteins were first evaluated by quantitative reverse transcription polymerase chain reaction and western blot analysis in both PC cell lines and tissue samples. In addition, the biologic functions of the differentially expressed proteins in PC cell growth and metastasis both in vitro and in vivo and their potential underlying mechanisms were systematically explored. Results We first found that DRP1 was substantially upregulated in PC cell lines and tissue samples mainly due to the downregulation of miR-29a, which contributed to the poor survival of PC patients. DRP1 promoted the growth and metastasis of PC cells both in vitro and in vivo by inducing G1-S cell cycle transition and matrix metalloproteinase 2 secretion. Mechanistic investigations revealed that increased DRP1 upregulation-mediated mitochondrial fission and subsequently enhanced aerobic glycolysis were involved in the promotion of growth and metastasis by DRP1 in PC cells. Conclusions Our findings demonstrate that mitochondrial fusion protein DRP1 plays a critical oncogenic role in PC cells by enhancing aerobic glycolysis, which could serve as a novel therapeutic target for PC treatment.

Changes in mitochondrial morphology by dysregulated mitochondrial fission-fusion proteins have been increasingly recognized as a hallmark of cancer. MiD49 (mitochondrial dynamics protein of 49 kDa) is a newly identified mitochondrial fission protein involved in the dynamic regulation of mitochondrial morphology. However, the expression pattern and biological functions of MiD49 in human cancers remain largely unexplored, especially in pancreatic cancer (PC). In the present study, the expression and clinical significance of MiD49 was firstly determined by RT-qPCR and western blot analyses in PC cell lines and tumor tissues. In addition, the biologic functions of MiD49 in PC cell growth and metastasis were investigated using gain- and loss-of-function assays both in vitro and in vivo. Moreover, the underlying mechanisms by which MiD49 regulates PC cell growth and metastasis were further explored. Our results showed that MiD49 was markedly downregulated in both PC cell lines and human PC specimens. Forced expression of MiD49 suppressed PC cell growth and metastasis both in vitro and in vivo, while knockdown of MiD49 exhibited the opposite effect. Mechanistic exploration demonstrated that the tumor-suppressive effect of MiD49 was mediated by decreased mitochondrial fission and subsequent reduced ROS production in PC cells. Our findings suggest a critical tumor-suppressive role played by MiD49 in pancreatic cancer.

Classification of CRC lung metastases. (DOC 33 kb)

2572 Background: The subsequent treatment choices are limited for the patients with advanced solid tumors who had failed the standard therapies. PD-1 blockade monotherapy demonstrated robust antitumor activity in patients with MSI-H/dMMR. The aim of this study is to identify the efficacy and safety of HX008, an anti-PD-1 monoclonal antibody, in patients with advanced MSI-H/dMMR solid tumors. Methods: Eligible patients were age ≥18 years with histologically/cytologically confirmed advanced MSI-H/dMMR solid tumors, who have failed at least one line of standard systemic therapy. MSI-H/dMMR status was assessed centrally. Patients received HX008 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed 9 weeks after the first treatment, then every 6 weeks for the first year of therapy, and every 12 weeks thereafter. The primary end point was objective response rate (ORR) per RECIST1.1. Results: One hundred patients were enrolled from October 2018 to December 2020, with a median age of 53 (range 20-74) years. All of the patients were ≥ second-line patients. The most common cancer types were colorectal cancer (N=74) and gastric cancer (N=10). Median follow-up is 8.97 (range 0.03-25.53) months at the time of data cutoff. Among 86 patients who had reached the initial response evaluation, there were 8 CR, 33 PR, 24 SD, 17 PD and 4 NE. ORR was 47.67% (95%CI 36.79%-58.73%), and DCR was 75.58% (95%CI 65.13%-84.20%). ORR and DCR for the 66 colorectal cancer patients were 50% (95%CI 37.43-62.57%) and 75.76% (95%CI 63.64-85.46%). Median PFS was not reached (95%CI 6.18-NR) for all enrolled patients, while the 6-month and 12-month PFS rates were 62.66% (95%CI 50.98%-72.31%) and 52.70% (95%CI 39.96%-63.94%), respectively. Median OS was not reached. Treatment-related adverse events occurred in 77 patients (77%). Twelve patients (12%) had grade 3 or 4 treatment-related adverse events and there were no grade 5 treatment-related adverse events. The grade 3 or 4 treatment-related adverse events with incidence >1% included anemia (2%) and leukopenia (2%). Immune-related adverse events were observed in 15 patients (15%), including hypothyroidism in 9 patients (all were grade 1-2), and hepatitis, hyperglycemia, myocarditis, creatin kinase/creatin kinase MB increased, hypopigmentation of the vulva, rash, each in 1 patient. Conclusions: HX008 as a ≥second-line therapy showed promising efficacy and a manageable safety profile in patients with MSI-H/dMMR advanced solid tumors. Clinical trial information: NCT03704246.

4111 Background: In the phase 3 SANET-p trial (NCT02589821), surufatinib significantly increased progression-free survival (PFS) compared with placebo in patients with progressive, well-differentiated (grade 1 or 2), advanced pancreatic neuroendocrine tumors (NETs). Here we report the relationship of Ki-67 and baseline Chromogranin A (CgA) on efficacy outcomes. Methods: A total of 172 patients with advanced pancreatic NETs were randomized to surufatinib or placebo in a 2:1 ratio. Investigator-assessed PFS and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 were used for the analysis. The post-hoc subgroup analyses were performed on Ki-67 subcategory: < 5% (n = 40 vs 21), 5-10% (n = 57 vs 31), > 10% (n = 16 vs 7), and baseline CgA subcategory: ≤ 2 times of upper limit of normal (ULN) (n = 59 vs 31), > 2 × ULN (n = 44 vs 24). Results: In the intent-to-treat population, surufatinib was superior to placebo, median PFS (mPFS) of 10.9 vs 3.7 months (mo) ( p = 0.0011), with a stratified hazard ratio (HR) of 0.491 (95% confidence interval [CI]: 0.319, 0.755). mPFS was statistically significantly longer in the surufatinib arm versus that in the placebo arm in subgroups of Ki-67 5-10% (11.0 vs 3.7 mo, HR = 0.33, p= 0.0002), Ki-67 > 10% (11.1 vs 2.8 mo, HR = 0.04, p = 0.0003) and CgA > 2 × ULN (11.0 vs 3.7 mo, HR = 0.36, p = 0.0036). There was numerical PFS improvement with surufatinib compared to placebo in subgroup of Ki-67 < 5% (9.3 vs 5.6 mo, HR = 0.91, p = 0.8015) and CgA ≤ 2 × ULN (9.4 vs 3.7 mo, HR = 0.61, p = 0.0809). ORRs in the subgroups of Ki-67 < 5%, 5-10%, and > 10% with surufatinib were 15.8%, 24.0% and 12.5% respectively. There was only one partial response in the placebo arm (with Ki-67 < 5%). ORRs in the subgroups of CgA ≤ 2 × ULN and > 2 × ULN with surufatinib were 18.9% and 21.4%, while also only one partial response in the placebo arm with CgA ≤ 2 × ULN. Conclusions: Surufatinib showed statistically significant and clinically meaningful improvement in PFS compared to placebo in patients with advanced, progressive, well-differentiated pancreatic NETs. From this exploratory analysis, surufatinib demonstrated benefit irrespective of Ki-67 expression levels or baseline CgA. Clinical trial information: NCT02589821.

Molecular tumor markers hold considerable promise for accurately predicting the recurrence and progression of colorectal cancer (CRC) in patients. However, in the majority of cases, single marker analysis has been found to have low accuracy, and is of little practical use in clinical practice. The present study investigated the prognostic value of the combined detection of the protein expression of metastasis suppressor 23-H1 (Nm23-H1) and p53 using immunohistochemical analysis, and the mRNA expression levels were analyzed using reverse transcription-quantitative polymerase chain reaction in 110 cases of stage II and III CRC. The results revealed that the expression levels of Nm23-H1 in CRC tissues were lower, compared with those in normal tissues (χ2=18.249; P0.05). No significant correlation was observed between the expression of p53 and clinicopathological features (P>0.05). Patients with CRC with Nm23-H1(+)/p53(−) tumors had increased survival rates, with a five-year overall survival rate of 83.8% and a five-year disease-free survival rate of 70.2%. The five-year overall survival rates in other study cohorts were lower, compared with the Nm23-H1(+)/p53(−) group (P

This study was conducted to retrospectively analyze the clinical characteristics and survival of patients with extranodal natural killer-T cell lymphoma (ENKL) and compare different treatment regimens. The univariate analysis demonstrated that survival was worse for patients with extranasal primary tumors, Eastern Cooperative Oncology Group performance status (ECOG PS) scores of ≥2, International Prognostic Index (IPI) scores of 3-5, Ann Arbor stage III and IV disease, B symptoms, lymph node involvement and absence of radiotherapy. The Cox analysis demonstrated that ECOG PS score, stage, IPI, presence of B symptoms and radiotherapy were independent prognostic factors for overall survival (OS). The effect of diverse therapies on survival was then analyzed, and it was found that the 5-year survival rate of patients receiving chemoradiotherapy differed significantly from that of patients who received chemotherapy alone [hazard ratio (HR)=0.347, P=0.0203], but did not differ significantly from the survival of patients treated with radiotherapy alone (HR=1.534, P=0.6371). A subgroup analysis revealed a difference between the radiotherapy and non-radiotherapy groups for patients with extranasal-type stage III/IV disease. It was concluded that ECOG score, stage, IPI, presence of B symptoms and radiotherapy were independent prognostic factors for OS in patients with ENKL. The addition of radiotherapy achieved better outcomes compared with chemotherapy alone, but no difference was observed between chemoradiotherapy and radiotherapy. Patients with advanced-stage disease may also benefit from radiotherapy.

Yangwei Fan,1,* Ke Ma,1,* Chuying Wang,1 Jing Ning,1 Yuan Hu,1 Danfeng Dong,1 Xuyuan Dong,1 Qianqian Geng,2 Enxiao Li,1 Yinying Wu1 1Department of Medical Oncology, 2Department of Nuclear Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China *These authors contributed equally tothis work Purpose: Programmed death 1 (PD-1) receptor and its ligand, programmed death ligand-1 (PD-L1), play critical roles in the immune invasion of various tumors. This study aimed to explore the clinical significance of PD-L1/PD-1 expression in the progression of pulmonary neuroendocrine tumors (PNETs). Methods: The expression of PD-L1 and PD-1 in 80 patients diagnosed with PNETs were investigated. Immunohistochemical analysis was performed on 80 formalin-fixed paraffin-embedded tissue specimens from PNETs and 20 corresponding cancer-adjacent tissue specimens. Results: Tissues from PNETs had higher levels of PD-L1 (58.8%) and PD-1 (51.3%) compared to the cancer-adjacent tissues (25% and 20%, respectively). Meanwhile, PD-L1 expression was associated with PD-1 expression (P=0.007). PD-L1 expression was significantly associated with histological type (P=0.014) and tumor stage (P=0.014). Univariate analyses showed that the overall survival time of PNETs patients was significantly associated with PD-L1 expression in cancer cells (P=0.003), PD-1 expression in tumor-infiltrating lymphocytes (P=0.001), tumor node metastasis stage (P

Anginex is an artificial synthetic small molecule β-sheet-forming peptide shown to have anti-angiogenesis and antitumor effects in various solid tumors. However, its molecular mechanism remains largely unclear and efficient delivery methods for anginex remains to be developed. We report on the development of recombinant adeno-associated virus (rAAV2)-delivered anginex and the underlying mechanism of anti-angiogenesis and antitumor effects of anginex. We have successfully developed the rAAV2 vector to efficiently express anginex (rAAV2‑anginex). Transduction of rAAV2-anginex significantly induced apoptosis, and inhibited the proliferation, migration, invasion and tube formation of human umbilical vein endothelial cells in vitro. Western blot analysis revealed that rAAV2‑anginex inhibited the phosphorylation of Akt, while inducing the phosphorylation of JNK and activation of the NF-κB signaling pathway. In an in vivo CAM assay and xenograft model of SKOV3, rAAV2-anginex significantly reduced microvessel density (MVD) and vascular endothelial growth factor 165 (VEGF165), as demonstrated by immunohistochemistry analysis. Importantly, rAAV2-anginex inhibited tumor growth in an ovarian cancer SKOV3 cell nude mouse xenograft model. Our results suggest that rAAV2-anginex may inhibit tumor angiogenesis and growth through regulating Akt, JNK and NF-κB signaling pathways.

4613 Background: In the phase 3 study (SANET-ep, NCT02588170), surufatinib significantly prolonged progression free survival compared with placebo in patients with progressive, well-differentiated advanced extrapancreatic neuroendocrine tumors (epNETs) (ESMO 2019 Abs. LBA76). Here, we report the results of health-related quality-of-life (HRQoL) from this study. Methods: Eligible patients were randomized in a 2:1 ratio to receive surufatinib or placebo, 300 mg, orally, once daily, until disease progression or intolerable adverse events. Patient-reported outcome questionnaires, including the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the QLQ-G.I.NET-21, were collected at baseline, Day 15 of the first cycle (28 Days/cycle), and Day 1 of every cycle thereafter and at discontinuation. Time until definitive deterioration (TUDD) was defined as time from randomization to deterioration of 10 points in domain score compared with baseline score (without subsequent observations of deterioration of less than 10 point or any improvement as compared to baseline score), or death due to any cause. TUDD and mean change from baseline based on a longitudinal repeated measures analysis of each domain were analyzed retrospectively. Significance testing was at two-sided 0.05 without adjustment for multiplicity. Results: Of 198 pts randomized (surufatinib n = 129; placebo n = 69), 197 (99.5%) patients completed HRQoL questionnaires at baseline. The questionnaire compliance rate was >90% for most on-treatment assessments. The TUDD was significantly longer in the surufatinib arm versus the placebo arm in the dyspnea domain (hazard ratio [HR] 0.52, p = 0.0103) and social function scale (HR 0.58, p = 0.0222), while the TUDD of diarrhea was significantly shorter in the surufatinib arm compared to placebo (HR 2.68, p = 0.0074). There was no significant difference of TUDD in the remaining domains of QLQ-C30 and G.I.NET-21. There was also no significant difference of the mean change of scores from baseline by repeated measures in the domains between the two arms except diarrhea (increase of 14.0 points [95% CI 9.6, 18.4] in the surufatinib arm versus 2.1 points [95% CI -4.1, 8.4] in the placebo arm, p = 0.0007). Conclusions: Treatment with surufatinib resulted in superior efficacy, acceptable toxicity, while generally maintaining HRQoL, which support surufatinib as a treatment option in this patient population that was previously treated with available therapies for epNETs. Clinical trial information: NCT02588170 .

Background: The association between the survival or efficacy of chemotherapy and the Lauren subtype of gastric cancer (GC) remains unclear. We aimed to clarify whether patients with different Lauren subtypes have different survival after treatment with systemic chemotherapy: intestinal gastric cancer (IGC) patients survived better than patients with mixed type gastric cancer (MGC) or diffuse gastric cancer (DGC) after treatment with systemic chemotherapy. Patients & methods: Relevant studies for the meta-analysis were identified through searching Pubmed, Embase, Cochrane and Ovid up to March 2020. We also included our own prospectively collected cohort of patients that were followed over a 10-year period. Sub-group and sensitivity analyses were also performed. Results: In our prospective cohort, the overall survival (OS) of IGC patients receiving systemic chemotherapy (chemoIGC) [median OS 5.01 years, interquartile range (IQR) 2.63–6.71] was significantly higher than that of DGC patients receiving the same chemotherapy (chemoDGC) (median OS 1.33 years, IQR 0.78–3.33, p = 0.0001). After adjusting for age, gender and cancer stage, there was a significant difference in OS in patients treated with chemotherapy based on the Lauren classification of GC {hazard ratio (HR) for OS of the IGC versus DGC 0.33, [95% confidence interval (CI), 0.17–0.65; p Conclusion: Our results support the consideration of Lauren subtype when prescribing systemic chemotherapy for GC, particularly for MGC or DGC, which may not benefit from chemotherapy. Lauren classification should be considered to stratify chemotherapy regimens to GC patients in future clinical trials, with particular relevance to MGC or DGC, which is more difficult to treat with current regimens.

Ribosomal protein S15A (RPS15A) has emerged as a novel oncogene of various human cancers. However, whether RPS15A is involved in pancreatic cancer remains unclear. In this study, we aimed to investigate the potential relevance of RPS15A in pancreatic cancer and elucidate the underlying regulatory mechanism. We found that RPS15A expression was significantly up-regulated in pancreatic cancer cell lines. RPS15A knockdown resulted in a decrease of cell proliferation and colony formation, and induced cell cycle arrest in G0/G1 phases of pancreatic cancer cells in vitro. In addition, RPS15A knockdown down-regulated β-catenin expression and blocked the activation of Wnt signaling. Notably, RPS15A was identified as a target gene of microRNA-519d-3p (miR-519d-3p), a tumor suppressive miRNA. Further data showed that miR-519d-3p negatively regulated RPS15A expression in pancreatic cancer cells. Moreover, miR-591d-3p expression was significantly decreased in pancreatic cancer cell lines and tissues and was inversely correlated with RPS15A expression. The overexpression of miR-519d-3p significantly inhibited the proliferation and Wnt/β-catenin signaling in pancreatic cancer cells, mimicking the similar effect of RPS15A knockdown. However, restoration of RPS15A expression partially reversed the antitumor effect of miR-519d-3p. Taken together, our results demonstrate that RPS15A knockdown or RPS15A inhibition by miR-519d-3p suppresses the growth of pancreatic cancer cells associated with the inhibition of Wnt/β-catenin signaling. Our study suggests that the miR-519d-3p/RPS15A/Wnt/β-catenin regulation axis plays an important role in the progression of pancreatic cancer and may serve as potential targets for treatment of pancreatic cancer.

Background Estrogen promotes breast cancer development and progression mainly through estrogen receptor (ER). However, blockage of estrogen production or action prevents development of and suppresses progression of ER-negative breast cancers. How estrogen promotes ER-negative breast cancer development and progression is poorly understood. We previously discovered that deletion of cell cycle inhibitors p16Ink4a (p16) or p18Ink4c (p18) is required for development of Brca1-deficient basal-like mammary tumors, and that mice lacking p18 develop luminal-type mammary tumors. Methods A genetic model system with three mouse strains, one that develops ER-positive mammary tumors (p18 single deletion) and the others that develop ER-negative tumors (p16;Brca1 and p18;Brca1 compound deletion), human BRCA1 mutant breast cancer patient-derived xenografts, and human BRCA1-deficient and BRCA1-proficient breast cancer cells were used to determine the role of estrogen in activating epithelial-mesenchymal transition (EMT), stimulating cell proliferation, and promoting ER-negative mammary tumor initiation and metastasis. Results Estrogen stimulated the proliferation and tumor-initiating potential of both ER-positive Brca1-proficient and ER-negative Brca1-deficient tumor cells. Estrogen activated EMT in a subset of Brca1-deficient mammary tumor cells that maintained epithelial features, and enhanced the number of cancer stem cells, promoting tumor progression and metastasis. Estrogen activated EMT independent of ER in Brca1-deficient, but not Brca1-proficient, tumor cells. Estrogen activated the AKT pathway in BRCA1-deficient tumor cells independent of ER, and pharmaceutical inhibition of AKT activity suppressed EMT and cell proliferation preventing BRCA1 deficient tumor progression. Conclusions This study reveals for the first time that estrogen promotes BRCA1-deficient tumor initiation and progression by stimulation of cell proliferation and activation of EMT, which are dependent on AKT activation and independent of ER. Electronic supplementary material The online version of this article (10.1186/s13058-018-0996-9) contains supplementary material, which is available to authorized users.

Figure S1. Characterization of mammary tumors developed in mutant mice in Balb/cB6 mixed background. Representative mammary tumors spontaneously developed in p18-/-;Brca1MGKO, p16-/-;Brca1MGKO and p18-/- mice were immunostained with the antibodies indicated. The representative cells are enlarged in the insets.

Figure S4. Estrogen promotes lung metastasis of Brca1-deficient mammary tumors. (A, B) Metastatic p18-/-;Brca1MGKO tumor cells were inoculated into the MFPs of NSG mice with either E2 or placebo supplement. When newly generated tumors reached maximum size allowed by the IACUC in 3â 6Â weeks, or the mice became moribund, lungs were dissected for analysis. Representative gross pictures (A) and H.E. staining (B) of lungs are shown.

Figure S6. Estrogen promotes EMT in Brca1-deficient tumor cells (A, B) p18-/-;Brca1MGKO type 1 (A) and p18-/- tumor cells (B) were treated with DMSO or E2 for the indicated time and analyzed by western blot. (C, D) p18-/-;Brca1MGKO type 2 tumor cells were treated with DMSO or 50 nM E2 for 2 h or 72 h, and then analyzed by FACS (C) and western blot (D). (E) SUM149 cells were treated with DMSO or 50 nM E2 for 72 h and analyzed by western blot.

Figure S3. Estrogen promotes Brca1-proficient and deficient mammary tumor initiation (A)Â Western blot analysis of mammary tumors regenerated by p18-/- or p18-/-;Brca1MGKO tumor cells with E2 supplement. (B) Representative gross pictures of p18-/- and p16-/-;Brca1MGKO tumors generated by transplantation. We transplanted 1 x 107 p18-/- or 6 x 104 p16-/-;Brca1MGKO tumor cells into MFPs of NSG mice with or without E2 supplement. Gross pictures were taken 6-7 weeks post-transplantation. (C) Representative H.E. staining of primary p18-/- tumors and tumors generated by p18-/- tumor cells with E2 supplement. Note the well-differentiated cells with glandular structure in both primary and regenerated tumors. (D) Representative H.E. staining of p16-/-;Brca1MGKO tumors generated in the presence or absence of E2 supplement. Note the poorly differentiated cells with increased fibroblast-like cells in the tumors with E2 treatment. Spindle cells (black arrows), cells with high nuclear-cytoplasm ratio (green arrows), mitotic cells (red arrows), and necrosis (yellow arrows) are indicated.

Figure S8. E2 activates the AKT pathway in BRCA1 mutant PDX tumors, and inhibition of Akt suppresses proliferation of Brca1-deficient tumor cells. (A, B) Representative BRCA1 mutant PDX tumors treated with E2 or placebo were immunostained with the antibodies indicated. (C) p18-/-; Brca1MGKO type 2 tumor cells were treated with DMSO or 5Â nM E2 in the presence of different dosage of AZD5363. The number of viable cells were determined on day 1, day 3, and day 5; *p?

Figure S5. IHC analysis of ERa and EMT markers for tumors with or without E2 treatment. (A-C) Representative p18-/-;Brca1MGKO and p18-/- mammary tumors treated with E2 or placebo were immunostained with the antibodies indicated. Note the negative ERa staining in E2-treated p18-/-;Brca1MGKO tumors (B) and positive ERa staining in E2-treated p18-/- tumors (C).

Figure S7. Estrogen stimulates ER-positive cell proliferation that is blocked by 4OHT. MCF-7 cells were treated with DMSO and 5 nM E2 with or without 5 µM 4OHT. The number of viable cells was determined on day 1, day 3, and day 5 (A). Cells treated for 72 h were collected and analyzed by western blot (B); *p?

Figure S2. p18-/-;Brca1MGKO and p16-/-;Brca1MGKO tumor cells generate reproducible ER-negative Brca1-deficient mammary tumors. (A) A primary mammary tumor (donor tumor A) developed in a 15-month-old p16-/-;Brca1MGKO mouse was analyzed by FACS. As a control, tumor-free mammary glands from age-matched p16-/- mice were analyzed. Note a predominant CD24?+?CD29high population in the tumor. (B, C) We transplanted 6?Ă ?104 FACS-sorted Lin- cells from a p16-/-;Brca1MGKO tumor (donor tumor B) into MFPs of four NSG mice. Representative tumors generated were analyzed by IHC (B) and western blot (C). (D, E) Representative p18-/- and p18-/-;Brca1MGKO tumor cells were cultured and analyzed. MCF7 cells were used as a positive control of ERa expression. (F, G) We transplanted 1?Ă ?106 cultured p18-/-;Brca1MGKO tumor (donor tumor A) cells into MFPs of four NSG mice. Representative tumors generated were analyzed by IHC (F) and western blot (G). p18-/- tumors were used as control in (C) and (G).

HOXD10, a key regulator of cell-differentiated phenotype maintainence, has been demonstrated to be involved in the tumorigenesis of many human malignacies. However, the status of HOXD10 expression and its biological function in cholangiocellular carcinoma (CCC) remain to be clarified. In the present study, we investigated the clinical significance and biological functions of HOXD10 in CCC and found that the expression of HOXD10 and its downstream effector RHOC was significantly different in well-differentiated CCC tissues compared with poorly-differentiated lesions. We also observed a significant correlation between low HOXD10 and high RHOC expression levels and worse prognosis. The stable overexpression of HOXD10 by lentivirus vector significantly inhibited cell invasion partly by downregulating the expression of MMP2 and MMP9, and significantly increased early apoptosis in CCC cell lines and induced G1 phase cell cycle arrest, contributing to the inhibition of cell proliferation in vitro. Additionally, we demonstrated that the inactivation of the RHOC/AKT/MAPK pathway was involved in the tumor-suppressive functions of HOXD10 in CCC. These results suggested that HOXD10 may be a putative suppressor gene and can act as a prognostic marker and potentially a novel therapeutic target for CCC.

Background Among colorectal cancer (CRC) survivors, how the prior tumor location affects the risk of subsequent primary colorectal cancer (SPCRC) and the outcome of those suffering from SPCRC remain unknown. Methods CRC cases diagnosed from 1973 to 2012 were screened for SPCRC development using the Surveillance, Epidemiology, and End Results database. The relative risk of SPCRC was estimated using the standardized incidence ratio. Survivals were analyzed using the Kaplan–Meier and Cox regression model. Results The overall risk of SPCRC increased by 27% in CRC survivors compared to that of the general population. The risk increased in patients with both prior right colon cancer (RCC) and left colon cancer (LCC), and was concentrated in the first 5 years after the prior diagnosis, and among young patients. Among the 6701 SPCRC patients identified, patients with prior RCC were more likely to be elderly, female, and with more low or undifferentiated disease than those with prior LCC or rectal cancer (ReC). The overall survivals differed by both prior tumor location (P

// Yinying Wu 1 , Haiyang Liu 2 , Xianglin L. Du 3 , Fan Wang 1 , Jing Zhang 4 , Xiaohai Cui 4 , Enxiao Li 1 , Jin Yang 1 , Min Yi 1, 5 and Yunfeng Zhang 4 1 Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China 2 Department of Radiation Imaging, Shangluo Central Hospital, Shangluo, Shaanxi, People’s Republic of China 3 Department of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas School of Public Health, Houston, TX, USA 4 Second Department of Thoracic Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China 5 Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Correspondence to: Min Yi, email: myi@mdanderson.org Yunfeng Zhang, email: zyf100@xjtu.edu.cn Keywords: radiation therapy; neoadjuvant/adjuvant; disease specific survival; rectal cancer; tumor stage Received: June 20, 2017 Accepted: October 12, 2017 Published: November 06, 2017 ABSTRACT Objectives: The purposes of this study were to determine whether neoadjuvant or adjuvant radiotherapy affected disease-specific survival (DSS) in patients with rectal cancer and whether stratification by tumor stage affected the results. Results: 55.5% patients had neoadjuvant-radiotherapy (NRT), and 18.3% patients had adjuvant- radiotherapy (ART). Multivariable models showed that treatment type was independently associated with DSS. Patients with stages III/IV tumors who received ART plus chemotherapy had significantly worse DSS than did those who received NRT plus chemotherapy (NCRT) ( P = 0.03). Among patients with stage II tumors, those who received ART plus chemotherapy and those who received NCRT had similar DSS. Further stratification by risk group revealed that patients with stage IIIA tumors who received ART plus chemotherapy had significantly better DSS than did those who received NCRT ( P = 0.04). The ART plus chemotherapy and NCRT groups had similar DSS in patients with stage IIA tumors. Among high-risk patients (T3N+/T4), the NCRT group had significantly better DSS than did the ART plus chemotherapy group. Patients who underwent surgery only had the worst DSS of all the treatment groups. Materials and Methods: From the Surveillance, Epidemiology, and End Results database, patients diagnosed with stages II–IV rectal cancer from 2004–2014 were identified. Clinicopathologic features, treatments, and DSS in different treatment groups were compared. Conclusions: NCRT or ART plus chemotherapy can reduce deaths from rectal cancer. Patients with stage IIIA tumors will benefit most from ART plus chemotherapy, whereas NCRT should be recommended to patients with stages II, IIIB, or higher tumors.

Characteristics of index cancer among patients with single colorectal cancer and patients with SPCRC. (DOCX 25Â kb)

Median survival of SPCRC patients according to prior tumor location in stratified subgroups. (DOCX 35Â kb)

Standardized incidence ratio for SPCRC by latency among colorectal cancer survivors. (DOCX 29Â kb)

Standardized incidence ratio for SPCRC by anatomical sites of index colorectal cancer. (DOCX 27Â kb)

Tamoxifen and anastrozole are widely used as adjuvant treatment for early stage breast cancer, but their hepatotoxicity is not fully defined. We aimed to compare hepatotoxicity of anastrozole with tamoxifen in the adjuvant setting in postmenopausal breast cancer patients. Three hundred and fifty-three Chinese postmenopausal women with hormone receptor-positive early breast cancer were randomized to anastrozole or tamoxifen after optimal primary therapy. The primary end-point was fatty liver disease, defined as a liver–spleen ratio

e15122 Background: The microsatellite instability-high (MSI-H) phenotype confers good prognosis and greater response to immunotherapy in colorectal cancer(CRC). The mutational landscape of MSI-H CRC is unclear. This study was designed to illustrate the difference mutation profile between the MSI-H and microsatellite stable (MSS) CRC. Methods: Tumor tissue and matched blood samples from 40 patients with colorectal cancer were collected. Microsatellite instability (MSI) status were detected by PCR-amplified for five mononucleotide repeat markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27). Mutation profiles were sequenced by a cancer gene-targeted NGS panel. Results: The tumor mutation burden(TMB) of the MSI-H CRC patients was significantly higher than those MSS CRC patients. Compared with the MSS CRC, MSI-H CRC involved more genes and pathways. Furthermore, we found the copy number variation (CNV) was different between the two groups. The copy number instability (CNI) score of MSI-H CRC patients was significantly lower than those MSS CRC patients. MSI-H CRC patients showed a higher frequency of TP53 gene CNV gain compared with MSS CRC (41% (7/17) in MSI-H CRC versus 13% (3/23) in MSS CRC). Conclusions: The mutational landscape are different between the MSI-H and MSS colorectal cancer. Compared with MSS colorectal cancer, the MSI-H colorectal cancer patients have higher tumor mutation burden(TMB) and lower copy number instability (CNI) score. Keywords: colorectal cancer, microsatellite instability, tumor mutation burden, copy number instability. Abbreviations CRC, colorectal cancer; TMB, tumor mutation burden; MSI-H, The microsatellite instability-high; MSS, microsatellite stable; CNV, copy number variation.

// Ke Ma 1, * , Yangwei Fan 1, * , Xuyuan Dong 1 , Danfeng Dong 1 , Yuyan Guo 2 , Xin Wei 3 , Jing Ning 4 , Qianqian Geng 5 , Chuying Wang 1 , Yuan Hu 1 , Mengya Li 1 , Wenxia Niu 1 , Enxiao Li 1 and Yinying Wu 1 1 Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, P.R. China 2 Department of Medical Radiation Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, P.R. China 3 Department of Medical Oncology, Shaanxi Province People’s Hospital, Xi’an, Shaanxi 710068, P.R. China 4 Department of Obstetrics and Gynecology, Xi’an Third Hospital, Xi’an, Shaanxi 710068, P.R. China 5 Department of Nuclear Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, P.R. China * These authors have contributed equally to this work Correspondence to: Yinying Wu, email: shadowless_111@163.com , makeyfly@126.com Enxiao Li, email: doclienxiao@sina.com Keywords: MTA1, metastasis, epithelial to mesenchymal transition, NSCLC, AKT Received: August 10, 2016 Accepted: February 27, 2017 Published: March 21, 2017 ABSTRACT The present study assessed the role of metastasis-associated protein 1 (MTA1) in epithelial to mesenchymal transition (EMT) and metastasis in non-small-cell lung cancer (NSCLC) cells using a normal lung epithelium cell line, three NSCLC cell lines, a mouse NSCLC model, and 56 clinical NSCLC samples. We observed that MTA1 overexpression decreased cellular adhesion, promoted migration and invasion, and changed cytoskeletal polarity. MTA1 knockdown had the opposite effects. MTA1 overexpression decreased E-cadherin, Claudin-1, and ZO-1 levels and increased Vimentin expression in vitro and in vivo , through activation of AKT/GSK3β/β-catenin signaling. However, treatment with the AKT inhibitor MK2206 did not completely rescue effects associated with MTA1 expression changes, indicating that pathways other than the AKT/GSK3β/β-catenin pathway could be involved in MTA1-induced EMT. Compared with normal lung tissues, MTA1 expression was elevated in NSCLC patient tissues and was correlated with American Joint Committee on Cancer stage, T stage, lymphatic metastasis, and patient overall survival. Additionally, MTA1 expression was positively associated with p-AKT and cytoplasmic β-catenin levels. These findings indicate MTA1 promotes NSCLC cell EMT and metastasis via AKT/GSK3β/β-catenin signaling, which suggests MTA1 may be an effective anti-NSCLC therapeutic target.

Ras homolog family member C (RHOC) is important during the progression of several types of cancer, including prostate, breast and hepatocellular carcinoma. However, the function of RHOC in cholangiocellular carcinoma (CCC), a highly recurrent and metastatic carcinoma with poor prognosis, remains unclear. The aim of the present study was to investigate the involvement of RHOC in CCC tumor progression. RHOC expression levels were examined in CCC tissues and cells, and adjacent nontumorous bile duct tissues. The effects and molecular mechanisms of RHOC expression on cell migration and invasion were also investigated. The current study demonstrated that RHOC protein was frequently overexpressed in human CCC specimens and CCC cell lines. Downregulation of RHOC inhibited CCC cell invasion and migration partially via inhibition of matrix metalloproteinase 2, 3 and 9 expression. RHOC also modulated the expression of several epithelial-mesenchymal transition (EMT)-associated proteins, including E‑cadherin, vimentin, Slug and Snail, to promote to EMT progression. The present results demonstrated that RHOC is important for the invasion and migration of CCC through simultaneous regulation of MMPs and EMT‑associated protein, suggesting that RHOC is a potential molecular target for CCC treatment.

Tumor necrosis factor (TNF), an anti-angiogenic agent in cancer treatment, is limited to isolated limb perfusion due to systemic toxicities. We previously prepared a TNF mutant (rmhTNF) that significantly improved responses in lung cancer patients and exhibited a promising safety profile in phase I and II studies. To further investigate whether rmhTNF with standard chemotherapy provides a survival benefit, 529 patients with stage IIIB/IV non-small cell lung cancer (NSCLC) were randomly assigned to receive docetaxel plus carboplatin/cisplatin with rmhTNF (265) or chemotherapy alone (264). After four cycles of treatment, the median overall survival was 13.7 months in the chemotherapy plus rmhTNF group compared with 10.3 months in the chemotherapy group (hazard ratio (HR) 0.75, P = 0.001). The median progression-free survival in the chemotherapy plus rmhTNF group and the chemotherapy group was 8.6 and 4.5 months (HR 0.76, P = 0.001), respectively, with corresponding response rates of 38.5% and 27.7% (P = 0.008). Increased hyperpyrexia and pulmonary hemorrhage were associated with rmhTNF, but most effects were well tolerated. The results indicated that rmhTNF effectively potentiated chemotherapy in patients with advanced NSCLC and was comparable with bevacizumab, an angiogenesis inhibitor approved by the Food and Drug Administration (FDA) for NSCLC.

Objectives: To evaluate the expression of P-glycoprotein (P-gp) and it’s effect on chemotherapy response in metastatic breast carcinoma. Methods: 46 postoperative patients with metastatic breast carcinoma were enrolled. P-gp expression was detected by SABC immunohistochemical method. These patients were treated with combined chemotherapy of cyclophosphamide, pirarubicin and 5-fluorouracil for at least two cycles. The relationship between P-gp expression and chemotherapeutic response was analyzed. Results: The positive rate of P-gp expression was 56.5%, the P-gp expression in the patients with lung or liver metastasis was higher than that in patients with skin or lymph node metastasis (P=0.049). The overall response rate was 58.1% in 43 patients; the response rate (89.5%) of the P-gp negative group was higher than that (30.0%) of the P-gp positive group (P

Current studies do not accurately evaluate the influence of tumor location on survival of colorectal cancer patients. This study aimed to explore whether tumor location could be identified as another high-risk factor in stage II colorectal cancer by using data identified from the Surveillance, Epidemiology, and End Results database. All colorectal cancer patients between 2004 and 2008 were grouped into three according to tumor location. Of 33,789 patients diagnosed with stage II colorectal cancer, 46.8% were right colon cancer, 37.5% were left colon cancer and 15.7% were rectal cancer. The 5-year cancer specific survivals were examined. Right colon cancer was associated with the female sex, older age (> 50), and having over 12 lymph nodes resected. Conversely, rectal cancer was associated with the male sex, patients younger than 50 years of age and insufficient lymph node resection. The characteristics of left colon cancer were between them and associated with Asian or Pacific Islander populations, T4 stage, and Grade II patients. The prognostic differences between three groups were significant and retained after stratification by T stage, histological grade, number of regional nodes dissected, age at diagnose, race and sex. Furthermore, the significant difference of location was retained as an independent high-risk parameter. Thus, stage II colorectal cancers of different locations have different clinic-pathological features and cancer-specific survivals, and tumor location should be recognized as another high-risk parameter in stage II colorectal cancer.

This study was conducted to investigate survival and prognostic factors for extrahepatic cholangiocarcinoma (ECC) following surgical resection and evaluate the effects of postoperative adjuvant therapy (AT) on overall survival (OS). We retrospectively collected clinical and pathological data between March, 2008 and December, 2013. The Kaplan-Meier method and the COX regression model were used to evaluate the OS and prognostic factors of 105 postoperative ECC patients, of whom 32 had received AT. The patients were stratified into seven risk subgroups and the survival rates were compared within each subgroup between patients who received AT and those who did not. The results demonstrated a median OS of 17.6 months, with 1- and 3-year survival rates of 67.9 and 19.5%, respectively, for the entire cohort. On univariate analysis, preoperative cholangitis, non-R0 surgical margins, poor differentiation grade, stage 3/4 and lymphatic metastasis were identified as adverse prognostic factors. AT was not significantly associated with improved OS. However, the subgroup analysis revealed that the effect of AT was significant only in the lymphatic metastasis group (median OS, 21.6 vs. 10.4 months; and 3-year OS, 16.6 vs. 0%, respectively; P=0.02). The survival curves of the AT and non-AT groups were significantly different only for node-positive patients. The COX regression model identified lymphatic metastasis, surgical margins and AT as independent prognostic factors for ECC. A negative resection margin may reduce the mortality rate following surgery by 47%. By contrast, lymph node metastasis was associated with a 2.18-fold higher mortality rate for ECC patients. Postoperative AT contributed to a 0.45-fold mortality rate compared to non-AT ECC patients. Therefore, we concluded that AT is a favorable prognostic factor for ECC patients and it may prolong the survival of patients with lymphatic metastasis. Our data suggest that postoperative AT should be recommended for node-positive ECC patients.

To guide clinicians in selecting treatment options for esophageal squamous cell carcinoma (ESCC) patients, reliable markers predictive of clinical outcome are desirable. This study analyzed the correlation of cyclophilin A (CypA) and matrix metalloproteinase 9 (MMP9) in ESCC and their relationships to clinicopathological features and survival. We immunohistochemically investigated 70 specimens of ESCC tissues using CypA and MMP9 antibodies. Then, the correlations between CypA and MMP9 expression and clinicopathological features and its prognostic relevance were determined. Significant correlations were only found in high level of CypA and MMP9 expression with tumor differentiation and lymph node status. Significant positive correlations were found between the expression status of CypA and that of MMP9. Overexpression of CypA and metastasis were significantly associated with shorter progression free survival times in univariate analysis. Multivariate analysis confirmed that CypA expression was an independent prognostic factor. CypA might be correlated with the differentiation, and its elevated expression may be an adverse prognostic indicator for the patients of ESCC. CypA/MMP9 signal pathway may be attributed to the malignant transformation of ESCC, and attention should be paid to a possible target for therapy. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1166551968105508 .

A rapid and sensitive method for determining aesculin of Cortex fraxini in rat was developed using high-performance liquid chromatography (HPLC) quadrupole time-of-flight (QTOF) tandem mass (MS/MS). Rat plasma was pretreated by fourfold methanol to remove plasma proteins. Chromatographic separation was performed on a reverse phase column. A tandem mass spectrometric detection with an electrospray ionization (ESI) interface was achieved using collision-induced dissociation (CID) under positive ionization mode. The MS/MS patterns monitored werem/z341.2716 →m/z179.1043 for aesculin andm/z248.3025 →m/z120.9130 for tinidazole (internal standard). The linear range was calculated to be 10.0–1500.0 ng/mL with a detection limit of 2.0 ng/mL. The inter- and intraday accuracy and precision were within ±7.0%. Pharmacokinetic study showed that aesculin was confirmed to be a one-compartment open model. The method is believed to have good linear range, high sensitivity and recoveries, and superior analytical efficiency. It will probably be an alternative for pharmacokinetic study of aesculin.

Ethnic disparities in lung and bronchial cancer diagnoses and disease-specific survival (DSS) rates in the United States are well known. However, few studies have specifically assessed these differences in Asian subgroups. The primary objectives of the retrospective analysis described herein were to identify any significant differences in clinicopathologic features, treatment, and survival rate between Asian lung cancer patients and lung cancer patients in other broad ethnic groups in the United States and to determine the reasons for these differences among subgroups of Asian patients with lung or bronchial cancer. We searched the Surveillance, Epidemiology, and End Results Program database to identify patients diagnosed with lung or bronchial cancer from 1990 to 2012. Differences in clinicopathologic features, treatment, and DSS rate in four broad ethnic groups and eight Asian subgroups were compared. The study population consisted of 849,088 patients, 5.2% of whom were of Asian descent. Female Asian patients had the lowest lung and bronchial cancer incidence rates, whereas male black patients had the highest rates. Asian patients had the best 5-year DSS rate. In our Asian subgroup analysis, Indian/Pakistani patients had the best 5-year DSS rate, whereas Hawaiian/Pacific Islander patients had the worst 5-year DSS rates. We found the differences in DSS rate among the four broad ethnic groups and eight Asian subgroups when we grouped patients by age and disease stage, as well. Asian patients had better DSS rates than those in the other three broad ethnic groups in almost every age and disease-stage group, especially in older patients and those with advanced-stage disease. In conclusion, we found that clinicopathologic features and treatment of lung and bronchial cancer differ by ethnicity in the United States, and the differences impact survival in each ethnic group.