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The application of chemotherapy in non‐small cell lung cancer (NSCLC) is limited by the toxicity to normal cells and the development of multi‐drug resistance. Targeted chemotherapy using cytotoxic analogs against specific receptors on cancer cells could be a less toxic and more efficacious approach. We identified that the expressions of somatostatin receptor (SSTR) 2 and 5 in tumor tissues from NSCLC patients were higher than those in the adjacent normal tissues by immunohistochemistry, and therefore, cytotoxic somatostatin analogues might be applied for SSTRs‐mediated targeted therapy against NSCLC. Two cytotoxic analogs, paclitaxel‐octreotide (PTX‐OCT) and 2paclitaxel‐octreotide (2PTX‐OCT), were synthesized by linking one or two molecules of paclitaxel to one molecule of somatostatin analog octreotide. PTX‐OCT and 2PTX‐OCT significantly inhibited the growth and induced apoptosis of SSTR2‐ and SSTR5‐positive A549 cells, compared with the control (p, Targeted cytotoxic somatostatin analogs paclitaxel‐octreotide (PTX‐OCT) conjugates inhibited the growth and induced apoptosis of A549 cells in a SSTRs‐mediated manner, whereas they were less toxic to H157 (SSTRs‐negative) cells. PTX‐OCT and PTX‐2OCT significantly reverse paclitaxel resistance, with no or lower induction of MDR genes such as MDR‐1, MRP‐1, and BCRP than paclitaxel in vitro.

Objective: This phase 3 study aimed to test equivalence in efficacy and safety for QL1101, a bevacizumab analogue in Chinese patients with untreated locally advanced non-squamous non-small cell lung cancer (NSCLC). Methods: Eligible patients were randomly assigned 1:1 to receive carboplatin and paclitaxel in combination with either QL1101 or bevacizumab, 15 mg/kg every 3-week for 6 cycles. This was followed by maintenance treatment with single agent QL1101 every 3-week. The primary end-point was objective response rate (ORR), with secondary end-points being progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs). Results: Of 675 patients, 535 eligible patients were randomized to the QL1101 group (n = 269) and bevacizumab group (n = 266). ORRs were 52.8% and 56.8%, respectively, for the QL1101 and bevacizumab groups, with an ORR hazard ratio 0.93 (95% confidence interval: 0.8–0131.1). The PFS, OS, DCR, and AEs were comparable between the 2 groups, which remained the same after stratification according to epidermal growth factor receptor mutation or smoking history. Conclusions: QL1101 showed similar efficacy and safety profiles as compared to bevacizumab among Chinese patients with untreated locally advanced non-squamous NSCLC.

Background There is a lack of targeted therapeutic options for squamous cell lung cancer (SCC). Accelerated hypertension is an issue with many targeted therapies for lung cancer. This study aimed to analyze the efficacy of anlotinib, based on progression‐free survival (PFS) and overall survival (OS) in patients with SCC, stratified by hypertension and Eastern Cooperative Oncology Group (ECOG) score. Methods This was a post hoc analysis of a multicenter, double‐blind, phase III ALTER0303 randomized controlled trial. Only patients with SCC were included. The occurrence of hypertension during the study period was defined according to CTCAE 4.03. OS and PFS were the primary and secondary endpoints, respectively. The patients were stratified according to hypertension and ECOG score, respectively. Results The median PFS in the patients who developed hypertension was longer than in those who did not (7.2 (95% CI: 3.5–11.0) versus 3.2 (95% CI: 1.2–5.3) months, p = 0.001; HR (95% CI), 0.4 (0.2–0.8)). In the ECOG 0 patients, the median PFS in the patients who developed hypertension versus those who did not was 5.6 vs. 1.8 months, respectively (Figure 2(d)). In the ECOG 1 patients, the median PFS in the patients who developed hypertension versus those who did not was 7.0 (95% CI: 3.0–11.0) vs. 4.8 (95% CI: 1.2–8.5) months (p = 0.043). No statistically significant differences were found in OS in the stratified analyses. Conclusions The occurrence of hypertension might be a clinical indicator predicting the efficacy of third‐line anlotinib treatment in patients with SCC., In SCC patients who received third‐line anlotinib treatment, the median PFS was longer in patients who developed hypertension than in those who did not. Our results suggest that the occurrence of hypertension during treatment might be a clinical indicator predicting the efficacy of third‐line anlotinib in patients with SCC.

Background Treatment options for refractory metastatic colorectal cancer (mCRC) were limited. Anlotinib is a novel multitarget tyrosine kinase inhibitor. ALTER0703 study was conducted to assess efficacy and safety of anlotinib for patients with refractory mCRC. Materials and Methods This was a multicenter, double-blinded, placebo-controlled, randomized phase III trial involving 33 hospitals in China. Patients had taken at least two lines of therapies were 2:1 randomized to receive oral anlotinib (12 mg/day; days 1–14; 21 days per cycle) or placebo, plus best supportive care. Randomization was stratified by previous VEGF-targeting treatments and time from diagnosis to metastases. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL), and safety. Results A total of 419 patients (anlotinib: 282; placebo: 137) were treated from December 2014 to August 2016. The median PFS was improved in anlotinib group (4.1 months; 95% confidence interval [CI], 3.4–4.5) over placebo group (1.5 months; 95% CI, 1.4–1.5), with a hazard ratio (HR) of 0.34 (95% CI, 0.27–0.43; p < .0001). However, median OS was similar between two groups (8.6 months; 95% CI, 7.8–9.7 vs. 7.2 months; 95% CI, 6.2–8.8; HR, 1.02; p = .870). Improvements of ORR and DCR were observed in anlotinib over placebo. The most common grade ≥ 3 anlotinib related adverse events were hypertension (20.92%), increased γ-GT (7.09%), and hand-foot skin reaction (6.38%). Conclusion Anlotinib was tolerated in Chinese patients with refractory mCRC. Although OS did not reach significant difference, anlotinib still provided clinical benefits by substantially prolonged PFS in these patients. Implications for Practice In this randomized clinical trial that included 419 patients with refractory metastatic colorectal cancer, substantial prolonged in progression-free survival was noted in patients who received anlotinib compared with those given placebo. Improvements on objective response rate and disease control rate was also observed in anlotinib group. However, overall survival was similar between the two groups. In a word, in third-line or above treatment of Chinese patients with refractory metastatic colorectal cancer, anlotinib provided clinical benefit by significantly prolonged progression-free survival.

Summary Background Therapeutic options for advanced neuroendocrine tumours (NETs) are limited. We investigated the efficacy and safety of surufatinib (HMPL-012, sulfatinib) in patients with extrapancreatic NETs. Methods SANET-ep was a randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 24 hospitals across China. Patients (aged 18 years or older) with unresectable or metastatic, well differentiated, extrapancreatic NETs, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression on no more than two types of previous systemic regimens were enrolled. Patients were centrally randomly assigned (2:1) using stratified block randomisation (block size 3) via an interactive web response system to receive oral surufatinib at 300 mg per day or matching placebo. Randomisation was stratified by tumour origin, pathological grade, and previous treatment. Patients, investigators, research staff and the sponsor study team were masked to treatment allocation. Crossover to the surufatinib group was allowed for patients in the placebo group at disease progression. The primary endpoint was investigator-assessed progression-free survival, which was analysed in the intention-to-treat population. A preplanned interim analysis was done at 70% of predicted progression-free survival events. This study was registered with ClinicalTrials.gov , NCT02588170 . Follow-up is ongoing. Findings Between Dec 9, 2015, and March 31, 2019, 198 patients were randomly assigned to surufatinib (n=129) or placebo (n=69). Median follow-up was 13·8 months (95% CI 11·1–16·7) in the surufatinib group and 16·6 months (9·2–not calculable) in the placebo group. Investigator-assessed median progression-free survival was 9·2 months (95% CI 7·4–11·1) in the surufatinib group versus 3·8 months (3·7–5·7) in the placebo group (hazard ratio 0·33; 95% CI 0·22–0·50; p Interpretation Progression-free survival was significantly longer in patients given surufatinib compared with patients given placebo, and surufatinib has a favourable benefit-to-risk profile in patients with progressive, advanced, well differentiated extrapancreatic NETs. Our results suggest that surufatinib might be a new treatment option for this population. Funding Hutchison MediPharma.

Background The biological behavior of cells change after they develop drug resistance, and the degree of resistance will be affected by the tumor microenvironment. Here, we aimed to explore the changes in the biological behavior of tumors and to observe the differences in the release of cytokines and chemokines which can influence the tumor microenvironment. We also aimed to study how TKIs-resistant cell lines recruit macrophages to reduce the sensitivity of the cells following gefitinib administration. Methods We generated and maintained gefitinib-resistant cell lines to study the differences between gefitinib-sensitive cell lines according to clone formation, cell growth curve analysis, whole-exome sequencing, and qPCR ARRAY technology. We used the WNT/β-catenin inhibitor, WNT/β-catenin activator and overexpression β-catenin lentivirus to observe the changes in CCL2. M2 macrophages and gefitinib-resistant cell lines HCC827/GR were cocultured to detect the viability gefitinib for inducing cell death. Results The proliferation and migratory activities were much more pronounced in HCC827/GR cells. CCL2 expression was also enhanced and regulated by β-catenin in HCC827/GR. CCL2 promoted the chemotactic ability of M2 macrophages. M2 macrophages reduced the antitumor effect of gefitinib treatment by activating AKT/mTOR. Conclusions Gefitinib-resistant cell lines have stronger proliferation and migration capabilities, and attract macrophages by releasing more CCL2 to reduce the sensitivity of cells to gefitinib.

Background The aim of this study was to investigate whether tobacco extracts could regulate PD-L1 expression and enhance malignant biological differences in gefitinib-resistant cell lines. Methods We constructed gefitinib-resistant cells and observed the biological differences in gefitinib-resistant cells. The cells were stimulated with medium containing 5% volume of tobacco extract, and the change in PD-L1 expression and the mammalian target of rapamycin (mTOR) and p-mTOR expression in gefitinib-resistant cells treated with tobacco extracts was observed. We discussed the relationship between PD-L1 and mTOR. Results Tobacco extracts could promote PD-L1 expression in the cell line. Western blot analysis showed that mTOR and p-mTOR were significantly enhanced in gefitinib-resistant cell lines cultured in the tobacco extracts. The mTOR signaling pathway was involved in PD-L1 expression and in regulating the expression of cytokines IL-6 and IL-23. In addition, the tobacco extracts could promote macrophage migration via mTOR/IL-6. Conclusions PD-L1 can transmit inhibitory signals and reduce the proliferation of CD8 + T cells in lymph nodes. Tobacco extracts upregulate PD-L1 expression via mTOR/IL-6. These results imply that lung cancer patients should not smoke and stay away from a smoke environment.

Background Anlotinib showed significant survival benefits in advanced non‐small cell lung cancer (NSCLC) patients as a third‐ or further‐line treatment in the ALTER0303 trial. We aimed to evaluate the efficacy of anlotinib in patients with different histologies. Methods The ALTER0303 trial was a randomized, open‐label, phase 3 study of anlotinib in NSCLC patients previously treated with at least two lines of chemotherapy or a tyrosine kinase inhibitor (TKI) in 31 centers in China. Patients were randomly assigned at a 2:1 ratio to receive anlotinib (12 mg QD from days 1 to 14 of a 21‐day cycle) or placebo until progression or intolerable toxicity. The primary endpoint was overall survival (OS). We assessed the efficacy of anlotinib in histological subgroups in the full analysis set. Results In the ALTER0303 trial, 336 patients had the histological subtype of adenocarcinoma (ACC), 86 patients had the histological subtype of squamous cell carcinoma (SCC), and 15 patients had another subtype. In the ACC subgroup, the median OS time was significantly improved with anlotinib compared with placebo (9.6 months vs 6.9 months, P = .0051), as was the median progression‐free survival (PFS) time (5.5 months vs 1.4 months, P, In this study, we evaluated the efficacy of anlotinib as third‐ or further‐line treatment for patient with different histological types of NSCLC. In the ALTER0303 trial, 336 patients had the histological subtype of adenocarcinoma (ACC), 86 patients had the histological subtype of squamous cell carcinoma (SCC), and 15 patients had another subtype. Our findings suggest that anlotinib significantly improves PFS and OS in ACC patients and has a tendency to prolong survival in SCC patients.

With the advent of the era of big data, new technologies such as cloud computing and artificial intelligence are changing with each passing day. More and more science and technology are applied to the financial field, which greatly promotes a new round of prosperity and development of China’s financial market. However, because big data has the characteristics of fast spreading speed, wide penetration area, strong concealment, and difficulty in supervision, the integration of technology and finance in the era of big data will also generate some new risk problems. Based on this, this article starts with the connotation and characteristics of financial technology, summarizes the risk performance of financial technology, and proposes corresponding countermeasures, aiming to promote the healthy and stable development of China’s financial technology.

Background Anlotinib is a tyrosine kinase inhibitor inhibiting angiogenesis. This multicenter, randomized phase II trial aimed to investigate the efficacy and safety of anlotinib in comparison with sunitinib as first-line treatment for patients with metastatic renal cell carcinoma (mRCC). Materials and Methods Patients with mRCC from 13 clinical centers were randomly assigned in a 2:1 ratio to receive anlotinib (n = 90) or sunitinib (n = 43). Anlotinib was given orally at a dose of 12 mg once daily (2 weeks on/1 week off), and sunitinib was given orally at 50 mg once daily (4 weeks on/2 weeks off). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results The median PFS was similar with anlotinib and sunitinib (17.5 vs. 16.6 months, p > .05). The median OS (30.9 vs. 30.5 months, p > .05), ORR (30.3% vs. 27.9%), and 6-week DCR (97.8% vs. 93.0%) were similar in the two groups. Adverse events (AEs) of grade 3 or 4 were significantly less frequent with anlotinib than with sunitinib (28.9% vs. 55.8%, p Conclusion The clinical efficacy of anlotinib was similar to that of sunitinib as the first-line treatment for mRCC, but with a more favorable safety profile.

Background Larotinib is a new first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. This open-label, phase 1b study is aimed to evaluate the efficacy, safety of larotinib in patients with advanced esophageal squamous cell carcinoma (ESCC) with EGFR overexpression or amplification pretreated with one or more system regimens, and to recommend an appropriate dose for its further study. Methods Patients received larotinib orally at 3 doses (250, 300, 350 mg), once daily. Clinical response was evaluated every 8 weeks according to RECIST v1.1 criteria by both investigators and independent radiology review (IRC). Results 81 patients were enrolled. The investigator-assessed overall response rate (ORR) was 13.7% (10/73), all responses were observed in the 350 mg group of which ORR up to 20.0% (10/50), with 10 of them having EGFR overexpression and 4 having EGFR amplification. Per IRC assessment, ORR for all patients and 350 mg group were 13.9% (10/72) and 16.3% (8/50). In the 350 mg group, median overall survival (OS) and progression-free survival (PFS) were 8.0 (95% CI 4.9–10.2) months and 3.4 (95% CI 2.4–3.7) months, respectively. The most common treatment-related adverse events (TRAEs) were diarrhea, rash, and palmar-plantar erythrodysesthesia syndrome, elevated AST/ALT, vomiting, similarly with other EGFR TKIs. Conclusions Larotinib demonstrated promising antitumor activity and manageable safety profiles in patients with pre-treated advanced ESCC with EGFR overexpression or amplification, especially at the dose of 350 mg, which showed better efficacy and acceptable safety. A phase 3 study is underway on 350 mg larotinib in ESCC patients with EGFR overexpression. Trial registration This trial was retrospectively registered on 25/03/2019, NCT03888092. https://clinicaltrials.gov/ct2/show/NCT03888092.

This randomized, open-label, multi-center phase 2 study (ClinicalTrials.gov, number NCT03116152) assessed sintilimab, a PD-1 inhibitor, versus chemo in patients with advanced esophageal squamous cell carcinoma (ESCC) refractory to first-line (1L) chemotherapy. The primary endpoint was overall survival (OS), while exploratory endpoint was the association of biomarkers with treatment efficacy. The median OS in the sintilimab group was significantly prolonged compared with that of the chemotherapy group, (objective response rates 12.6% and 6.3 %, respectively). Incidence of treatment-related adverse events of grade 3–5 was lower with sintilimab than with chemotherapy (20.2 vs. 39.1 %). Patients with high TCR clonality and low mTBI showed the longest median OS (15.0 mo), while patients with low NLR at 6 wk post-treatment had a significantly prolonged median OS compared with those with high NLR. High expression of T-follicular helper cells or activated B-cell signature was significantly associated with longer progression-free survival in the sintilimab group.

Objectives: Anti-tumor necrosis factor (TNF) agents have been regarded as the most effective treatment for ankylosing spondylitis (AS) so far. However, economic factors limited the prescription of original biologicals in China. Yisaipu® is a biosimilar for etanercept as pre fill syringes (PFS), which has entered China’s national medical insurance catalog for more than 10 yr and was widely used because it greatly reduced the economic burden of AS patients. Yisaipu® is provided subcutaneous injection in hospital setting only. We collected clinical data of AS patients before, during and after COVID-19 epidemic, in an attempt to investigate the advantages and disadvantages of original biologicals and Yisaipu® during regular follow up and COVID-19 epidemic.Methods: AS patients who received original biologicals or Yisaipu® in our department for more than 1 yr were included in our study. General data, demographic characteristics, disease activity, quality of life and medical compliance were collected from regular visits. The patients were followed up through telephone interviews from April 20th to 27th, 2020 about the overall impact of the COVID-19 epidemic.Results: There was no significant difference in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score-CRP (ASDAS-CRP) between the two groups. Health Assessment Questionnaire for Spondyloarthropathies (HAQ-s) showed that Yisaipu® group was superior to original biological group in terms of eating, gripping and driving. In addition, the medical cost of Yisaipu® was lower than that of original biologicals. The overall impact of the COVID-19 epidemic on patients of original biological group was comparatively smaller than that on Yisaipu® group.Conclusions: Yisaipu® provided AS patients with an economical selection during regular follow-up, while original biologicals had certain advantages in the COVID-19 epidemic setting, including a longer time interval between two drug administrations and the self-injection dose form of medication.

AIM To investigate whether computed tomography (CT) radiomics can differentiate pancreatobiliary-type from intestinal-type periampullary carcinomas. MATERIALS AND METHODS CT radiomics of 96 patients (54 pancreatobiliary type and 42 intestinal type) with surgically confirmed periampullary carcinoma were assessed retrospectively. Volumes of interest (VOIs) were delineated manually. Radiomic features were extracted from preoperative CT images. A single-phase model and combined-phase model were constructed. Five-fold cross-validation and five machine-learning algorithms were utilised for model construction. The diagnostic performance of the models was evaluated by receiver operating characteristic (ROC) curves, and indicators included area under the curve (AUC), accuracy, sensitivity, specificity, and precision. ROC curves were compared using DeLong's test. RESULTS A total of 788 features were extracted on each phase. After feature selection using least absolute shrinkage and selection operator (LASSO) algorithm, the number of selected optimal feature was 18 (plain scan), nine (arterial phase), two (venous phase), 23 (delayed phase), 15 (three enhanced phases), and 29 (all phases), respectively. For the single-phase model, the delayed-phase model using the logistic regression (LR) algorithm showed the best prediction performance with AUC, accuracy, sensitivity, specificity, and precision of 0.89, 0.83, 0.80, 0.88, and 0.93, respectively. Two combined-phase models showed better results than the single-phase models. The model of all phases using the LR algorithm showed the best prediction performance with AUC, accuracy, sensitivity, specificity, and precision of 0.96, 0.88, 0.90, 0.93, and 0.92, respectively. CONCLUSION Radiomic models based on preoperative CT images can differentiate pancreatobiliary-type from intestinal-type periampullary carcinomas, in particular, the model of all phases using the LR algorithm.

Background Pain in AS is currently considered an inflammatory pain (IP). However, it was found that some patients still had the sensation of pain even without inflammation. Our study was to investigate whether ankylosing spondylitis (AS) pain has a neuropathic pain (NeP) component. Methods The study consisted of three parts. The first included 182 AS patients to assess neuropathic pain in AS patients. The second included63 patients to evaluate pain improvement after etanercept therapy. The third included 20 AS patients and 10 healthy controls (HCs) to detect serum neurotransmitters. Results We found out that 55 paitents (30.21%) had possible NeP, and 14 (7.70%) had definite NeP. There were significant differences between the groups with respect to nocturnal pain (NP), peripheral pain (PP), total back pain (TBP), BASDAI, ASDAS-CRP, HAD-A, HAD-D and BASDAI-fatigue but not CRP concentrations. Principal component analysis (PCA) of AS pain revealed that the weight of NeP was greater than PP in the first principal component (0.703 vs 0.639). Structural equation modelling (SEM) revealed that NeP altered disease activity (β = 0.62, P P P vs 9.98 ± 6.40, P = 0.067). Serum norepinephrine concentrations in patients with positive PDQ were greater than those in patients with negative PDQ and HC. Conclusions We conclude that NeP contributes to pain in AS patients.

Online public opinion has a strong social influence and spreads at a very fast speed. Public opinion analysis on financial public opinion reports is conducive to the relevant institutions to conveniently understand the public opinion of the event and make correct guidance and control, which is also conducive to the sustainable development of financial market. In this paper, subject model, emotion dictionary construction, public opinion analysis and other technologies are used to conduct a detailed study of financial related network public opinion, and a financial public opinion analysis model is designed. The model can effectively identify the emotional words in the text from the improved topic model, and then match the emotional words with the more comprehensive and perfect emotional dictionary in the financial field, calculate the emotional tendency value of the emotional words, so as to classify the financial text public opinion more accurately.

Background Postoperative hypothermia (PH) is a common physiological abnormality associated with increased morbidity and mortality after non-cardiac surgery. The incidence, risk factors of PH and its impact on early outcomes after total aortic arch replacement are not clear. Methods We conducted a retrospective cohort study in patients with acute type A aortic dissection who underwent total arch replacement from January 2013 to December 2016 at our institution. Basic variables, procedural and postoperative early outcomes were collected. Univariate and multivariate statistical analysis were performed for statistical interpretation. The early outcomes were compared between patients with or without PH. Results A total of 300 patients (age 53.8±11.5 years, female 63, 21.0%) with acute type A aortic dissection underwent total arch replacement. Forty-four patients (14.7%) developed PH. The independent risk factors of PH are age and the intraoperative lowest bladder temperature. There is no significant difference in major postoperative morbidity and mortality between patients with or without PH. Conclusions The incidence of PH after total arch replacement in acute type A aortic dissection is relatively low. The independent risk factors of PH in this population include age and the intraoperative lowest bladder temperature. With comprehensive rewarming strategy upon arrival at the ICU, the PH is easy to be corrected, and the adverse effect of transient PH on early outcomes after arch surgery is minimal.

Background Microsatellite stable (MSS) or mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is resistant to immune checkpoint inhibitors. However, a recent Japanese trial showed that regorafenib plus nivolumab had encouraging anti-cancer activity in MSS or pMMR mCRCs. Materials and methods We retrospectively reviewed the efficacy and safety data of combination therapy with regorafenib plus anti-PD-1 antibody in patients with refractory MSS or pMMR mCRC in the medical centers of Shandong Province in China. Results Twenty-three patients with MSS or pMMR mCRC received regorafenib plus anti-PD-1 antibody. Eighteen (78.3%) patients experienced stable disease as best response, five (21.7%) patients had progressive disease, and no partial response was observed. The disease control rate (DCR) was 78.3% (18/23), and the median progression-free survival (PFS) was 3.1 months (95% CI, 2.32-3.89). Four of five (80.0%) patients with progressive disease had baseline liver metastasis, while nine of 18 (50.0%) patients with stable disease displayed no liver metastasis. One patient receiving radiofrequency ablation treatment for liver and abdominal wall metastases prior to combination treatment experienced a remarkably prolonged PFS of 9.2 months with SD. Neither liver metastasis status nor previous exposure to regorafenib was associated with treatment outcome. Treatment-related grade 3 toxicities were observed in 5/23 (21.7%) patients. Conclusion No objective response was observed with the combination of regorafenib plus anti-PD-1 antibody, suggesting its little clinical activity in unselected Chinese patients with pMMR/MSS mCRC. Meanwhile, it exhibited some potential benefit in this cohort in terms of DCR and PFS. Adverse events were generally tolerable and manageable. Prospective studies with large sample sizes are needed to verify the findings. This combination strategy plus local ablative therapy might be worthy of further exploration.

Background Chimeric antigen receptor (CAR) T cell therapy has made significant progress in the treatment of blood cancers such as leukemia, lymphoma, and myeloma. However, the therapy faces many challenges in treating solid tumors. These challenges include physical barriers, tumor microenvironment immunosuppression, tumor heterogeneity, target specificity, and limited reactive cell expansion in vivo.Conventional CAR T cell therapy has thus far shown weak cell expansion in solid tumor patients and achieved little or no therapeutic responses. Here, we developed CAR T cells based on a novel CoupledCAR® technology to treat solid tumors. In contrast to conventional CAR T cells, CoupledCAR T cells significantly improved the expansion of the CAR T cells in vivo and enhanced the CAR T cells’ migration ability and resistance to immunosuppression by the tumor microenvironment. The enhanced migration ability and resistance allow the CAR T cells to infiltrate to tumor tissue sites and increase anti-tumor activities. Methods We designed a ‘CoupledCAR’ lentivirus vector containing a single-chain variable fragment (scFv) targeting human TSHR. The lentivirus was produced by transfecting HEK-293T cells with ‘CoupledCAR’ lentiviral vectors and viral packaging plasmids. Patient‘s CD3 T cells were cultured in X-VIVO medium containing 125U/mL 1interleukin-2 (IL-2), and transduced with ‘CoupledCAR’ lentivirus at certain MOI. Transduction efficiency and was evaluated at 7 to 9 days after ‘CoupledCAR’ lentivirus transduction, and quality controls for fungi, bacteria, mycoplasma, chlamydia, and endotoxin were performed. After infusion, serial peripheral blood samples were collected, and the expansion and the cytokine release of CART cells were detected by FACS and QPCR. The evaluation of response level for patients were performed at month 1,month 3,and month 6 by PET/CT. Results Specifically, we engineered CoupledCAR T cells with lentiviral vectors encoding an anti-GCC (guanylate cyclase 2C) CAR molecule. Furthermore, anti-GCC CAR T cells showed anti-tumor activities in vitro and in vivo experiments.To verify the safety and efficacy of CoupledCAR T cells for treating solid tumors, we conducted several clinical trials for different solid tumors, including seven patients with colorectal cancer. These seven patients failed multiple rounds of chemotherapy and radiotherapy. In the clinical trial, the patients were infused with autologous anti-GCC CoupledCAR T cells range from 4.9×105/kg to 2.9×106/kg. All patients using anti-GCC CoupledCAR T cells showed rapid expansion of CoupledCAR T cells and killing of tumor cells. Specifically, we observed that CoupledCAR T cells expanded significantly in the patients and infiltrated tumor tissue sites, demonstrating enhanced anti-tumor activities. PET/CT showed significant tumor shrinkage and SUV max declined, and the ongoing responses were monitored. Patient 3 achieved complete response and the best overall response rate (ORR, include complete remission, complete metabolic response, partial response, and partial metabolic response.) was 71.4% (5/7), complete remission (CR) rate was 14.3% (1/7). Conclusions The clinical data demonstrated that CoupledCAR T cells effectively expanded, infiltrated tumor tissue sites, and kill tumor cells in patients with colorectal cancer. We used immunotherapy to achieve complete remission in patients with advanced colorectal cancer for the first time. We are recruiting more colorectal cancer patients to further test the safety and efficacy of anti-GCC CoupledCAR T cells. Since our CoupledCAR® technology is a platform technology, we are expanding it to treat other solid tumors using different target tumor markers.

Background Acute type A aortic dissection with arch involvement is a life-threatening condition, which requires immediate surgical attention. Emergent total arch replacement and root reconstruction is a technically demanding operation with varying outcomes based on surgeon experience. The human factors in total arch replacement in the emergent setting have never been systematically investigated. The ability of surgeons with low volumes to achieve acceptable results in their start-up period is not known. Methods From January 2013 to December 2016, patients with acute type A aortic dissection who underwent emergent total arch replacement with three surgeons were enrolled. Basic characteristics, procedural and postoperative outcomes were collected. The time of critical surgical steps and operative mortality were calculated using descriptive statistics and cumulative SUM (CUSUM) analysis. Results A total of 300 patients (age 53.8±11.5 years, female 63, 21.0%) with acute type A aortic dissection underwent emergent total arch replacement. A total of 219 patients (73.0%) had root reinforcement, 295 patients (98.3%) underwent frozen elephant trunk repair. Mean circulatory arrest and cross-clamp times were 29.8±9.8 and 112.3±32.1 min, respectively. The operative mortality was 6.7%, the stroke rate was 4.0%. The mean length of postoperative ICU and hospital stays were 8.4±10.6 and 18.0±12.2 days, respectively. By CUSUM depictions, surgeons appeared to have different learning curves with regards to operative time. By CUSUM failure analysis on operative mortality, two newly appointed surgeons in their start-up period stayed in an acceptable range, while one senior surgeon with higher volumes experienced superior outcomes and better performance. Conclusions Although emergent total arch replacement for acute type A dissection is a complex scenario, surgeons well-trained in adult cardiac surgery are able to achieve acceptable results in their start-up period.

Lung cancer is the leading cause of cancer‐related death worldwide, with an estimated 1.2 million deaths each year. Despite advances in lung cancer treatment, 5‐year survival rates are lower than ~15%, which is attributes to diagnosis limitations and current clinical drug resistance. Recently, more evidence has suggested that epigenome dysregulation is associated with the initiation and progress of cancer, and targeting epigenome‐related molecules improves cancer symptoms. Interestingly, some groups reported that the level of methylation of histone 3 lysine 4 (H3K4me3) was increased in lung tumors and participated in abnormal transcriptional regulation. However, a mechanistic analysis is not available. In this report, we found that the SET domain containing 1A (SETD1A), the enzyme for H3K4me3, was elevated in lung cancer tissue compared to normal lung tissue. Knockdown of SETD1A in A549 and H1299 cells led to defects in cell proliferation and epithelial‐mesenchymal transition (EMT), as evidenced by inhibited WNT and transforming growth factor β (TGFβ) pathways, compared with the control group. Xenograft assays also revealed a decreased tumor growth and EMT in the SETD1A silenced group compared with the control group. Mechanistic analysis suggested that SETD1A might regulate tumor progression via several critical oncogenes, which exhibited enhanced H3K4me3 levels around transcriptional start sites in lung cancer. This study illustrates the important role of SETD1A in lung cancer and provides a potential drug target for treatment., SETD1A was increased in lung cancer tissues compared with adjacent nontumor tissues and inversely correlated with overall survival status. Further research showed that STED1A silencing resulted in defects in cancer growth and EMT in vitro and in vivo. Mechanistic analysis suggested that SETD1A might regulate multiple critical oncogenes in lung cancer via global H3K4me3 levels.

Summary Background Surufatinib showed superior efficacy in extrapancreatic neuroendocrine tumours (NETs) in the phase 3 SANET-ep study. In SANET-p, we aimed to assess the efficacy and safety of surufatinib in patients with advanced pancreatic NETs. Methods SANET-p was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study, done in 21 hospitals across China. Eligible patients were adults (aged 18 years or older) with progressive, advanced, well differentiated pancreatic NETs, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and progression on up to two kinds of previous systemic regimens for advanced disease. Patients were randomly assigned (2:1) via an interactive web response system to receive 300 mg of surufatinib or placebo, taken orally once per day in consecutive 4-week treatment cycles until disease progression, intolerable toxicity, withdrawal of consent, poor compliance, use of other antitumour medication, pregnancy, loss to follow-up, or if the investigator deemed discontinuation in the patient's best interest. Randomisation was done centrally using stratified block randomisation (block size three), stratified by pathological grade, previous systemic antitumour treatment, and ECOG performance status score. Patients, investigators, research staff, and the sponsor study team were masked to treatment allocation. Crossover to surufatinib was permitted for patients in the placebo group with disease progression. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, which included all patients in randomisation. A pre-planned interim analysis was done at 70% of the predicted progression-free survival events. This study is registered at ClinicalTrials.gov , NCT02589821 . Findings Between Feb 18, 2016, and Nov 11, 2019, of 264 patients who were screened, 172 (65%) patients were randomly assigned to receive surufatinib (n=113) or placebo (n=59). The median follow-up was 19·3 months (95% CI 9·3–19·4) in the surufatinib group and 11·1 months (5·7–35·9) in the placebo group. The median investigator-assessed progression-free survival was 10·9 months (7·5–13·8) for surufatinib versus 3·7 months (2·8–5·6) for placebo (hazard ratio 0·49, 95% CI 0·32–0·76; p=0·0011). The trial met the early stopping criteria at the interim analysis and was terminated on recommendation from the independent data monitoring committee. The most common grade 3 or worse treatment-related adverse events were hypertension (43 [38%] of 113 with surufatinib vs four [7%] of 59 with placebo), proteinuria (11 [10%] vs one [2%]), and hypertriglyceridaemia (eight [7%] vs none). Treatment-related serious adverse events were reported in 25 (22%) patients in the surufatinib group and four (7%) patients in the placebo group. There were three on-treatment deaths in the surufatinib group, including two deaths due to adverse events (gastrointestinal haemorrhage [possibly treatment-related] and cerebral haemorrhage [unlikely to be treatment-related]), and one death attributed to disease progression. One on-treatment death in the placebo group was attributed to disease progression. Interpretation Surufatinib significantly improves progression-free survival and has an acceptable safety profile in patients with progressive, advanced pancreatic NETs, and could be a potential treatment option in this patient population. Funding Hutchison MediPharma.

To characterise symptomatic intracranial plaque without substantial stenosis using three-dimensional (3D) high-resolution contrast-enhanced black-blood magnetic resonance imaging (BBMRI) and to determine plaque features associated with recent cerebrovascular events.The institutional review board approved this retrospective study. The case notes from patients with evidence of intracranial atherosclerosis in a large intracranial artery with preceding BBMRI were reviewed retrospectively. Symptomatic and asymptomatic plaques with substantial luminal stenosis (50%) were matched by plaque location and patient age. All MRI images were de-identified and interpreted by two neuroradiologists who were blinded to the history of symptoms. Qualitative analyses including the presence of intraplaque haemorrhage (IPH), eccentricity, surface irregularity, and grade of plaque enhancement were recorded. Quantitative analyses including normal wall index and degree of contrast enhancement were calculated. Multivariate regression analysis was performed to identify the association with cerebrovascular ischaemic events.A total of 38 pairs of symptomatic and asymptomatic plaques from 74 patients were analysed. Compared to asymptomatic plaques, symptomatic plaques demonstrated higher degree of contrast enhancement (29.77 ± 19.23 versus 18.21 ± 12.18%, p=0.039) and presence of IPH (26% versus 8%, p=0.032). No significant differences were detected regarding eccentricity, surface irregularity, and normal wall index. Events were associated with contrast enhancement (OR, 1.212; 95% confidence interval [CI], 1.086-1.352) after controlling for age, sex, cardiovascular risk factors, and stenosis degree. IPH was not associated with events.Contrast enhancement in the intracranial plaque without substantial stenosis is associated with previous events, and may serve as the vulnerable feature, thereby stratifying stroke risk not achievable by luminal stenosis.

Objectives Anlotinib is a novel multi-target tyrosine Kinase inhibitor that inhibits VEGFR2/3, FGFR1-4, PDGFD α/β, c-Kit and Ret. In the phase III ALTER-0303 trial (Clinical Trial Registry ID: NCT 02388919), anlotinib significantly improved overall survival versus placebo in advanced non-small-cell lung cancer (NSCLC) patients who had received at least two previous chemotherapy and epidermal growth factor receptor/anaplastic lymphoma kinase targeted therapy regimens. This study assessed quality of life (QoL) in these patients. Methods Patients were randomized (2:1) to anlotinib or placebo up to progression or intolerable toxicity. The QoL were assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the associated EORTC Quality of Life Lung Cancer Specific Module (QLQ-LC13) at baseline, end of cycle 1, end of every two cycles, and at the final visit. The analyses were conducted in the first 6 cycles. Differences in scores of 10 points or more between two arms or from baseline were considered clinically meaningful. Results A total of 437 patients were assigned to anlotinib (n = 294) and placebo (n = 143). The completion rates of the QoL questionnaires were from 69.9% to 97.0%. Mean scores of QLQ-C30 and QLQ-LC13 subscales were similar in the anlotinib and placebo arms at baseline. Compared to placebo, anlotinib improved role functioning, social functioning, dyspnea, insomnia, constipation and financial problems. Only sore mouth or tongue symptom was worse in the anlotinib arm than in the placebo arm. Conclusions Anlotinib improved quality of life versus placebo in advanced NSCLC patients who had received at least two previous chemotherapies. The QoL analyses provided evidence that anlotinib should be a choice for the third-line treatment or beyond in advanced NSCLC.

Objective: Anlotinib hydrochloride is a multitarget tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, c-Kit, and c-MET; therefore, it exhibits both antitumor and anti-angiogenetic activities. A phase III trial has shown that anlotinib improved progression-free survival (PFS) and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC), who presented with progressive disease or intolerance after standard chemotherapy. This study aimed to analyze the characteristics of patients receiving anlotinib treatment to determine the dominant populations who are fit for the treatment.Methods: Data were collected from March 2015 to January 2017 from a randomized, double-blind, placebo-controlled, multicenter, phase III trial of anlotinib (ALTER0303). A total of 437 patients were enrolled and randomly allocated (2:1) to the anlotinib and placebo groups. Kaplan–Meier analysis and log-rank test were performed to compare PFS and OS. Cox proportional hazards model was adopted for multivariate prognostic analysis. Results: Multivariate analysis indicated that high post-therapeutic peripheral blood granulocyte/lymphocyte ratio and elevated alkaline phosphatase levels were independent risk factors for PFS. Meanwhile, elevated thyroid-stimulating hormone, blood glucose, and triglyceride levels; hypertension; and hand–foot syndrome were independent protective factors of PFS. High post-therapeutic peripheral blood granulocyte/lymphocyte ratio, an Eastern Cooperative Oncology Group (ECOG) score ≥ 2, and the sum of the maximal target lesion length at baseline were independent risk factors of OS, and hypertriglyceridemia was an independent protective factor of OS. Conclusions: This study preliminarily explored the possible factors that affected PFS and OS after anlotinib treatment in patients with advanced refractory NSCLC, and the baseline characteristics of the therapeutically dominant populations were then identified.

Brain metastasis is synchronous to the diagnosis of renal cell carcinoma (RCC). The prognosis of brain metastasis in RCC with the current treatment options is dismissal. Therefore, we present a case of an elderly female patient with RCC showing a partial response of brain metastasis after 18 months of 600 mg once daily sorafenib treatment who underwent right-sided nephrectomy. Further, withdrawal of sorafenib resulted in psychiatric changes along with increased metastasis lesions, which were recovered upon resuming the treatment, proposing that oral sorafenib can be used safely and efficiently for treatment of brain metastasis in advanced RCC.

Background: The COVID-19 pandemic is not only a traumatic event, but a collective stressor unfolding over time, causing alarming implications for the mental health. This study aims to shed light on the mental health status of patients with rheumatic disease (RD) during the massive outbreak of COVID-19 in China, especially the prevalence and severity of post-traumatic stress disorder (PTSD) compared with the levels in healthy people. Methods: A questionnaire survey was conducted in a cross-sectional study of 486 RD patients and 486 healthy control subjects. We collected participants’ demographic and clinical characteristics and surveyed the prevalence and severity of PTSD and sleep quality in the samples using the PTSD Checklist for DSM-5 (PCL-5) and 4 items from the Pittsburgh Sleep Quality Index (PSQI). Findings: Compared with healthy control subjects (n=486), RD patients (n=486) had a higher prevalence of PTSD (12·1% vs. 4·1%; p

BACKGROUND: Lung cancer remains one of the deadliest cancers worldwide. The ALTER0303 trial revealed that anlotinib might be used as a third-line or further treatment in non-small cell lung cancer (NSCLC) patients. Meanwhile, the impact of previous therapy strategies on the efficiency of anlotinib still remains unknown. METHODS: The subgroup of patients in ALTER0303 were analyzed by using Kaplan-Meier estimates, Pearson χ(2), or Fisher’s exact test. RESULTS: There was no statistical significance on progression-free survival (PFS) and overall survival (OS) among patients in different previous antiangiogenic treatments groups. Patients in the chest radiotherapy (CRT) group had longer median PFS than the non-CRT group (5.93 vs. 4.63 m, P=0.027). Regardless of what kind of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI) and chemotherapy regimens were used previously, all patients gained longer PFS in the anlotinib group, while only patients treated with vinorelbine/platinum in the EGFR wild type group, pemetrexed/platinum, vinorelbine/platinum, and gefitinib in the EGFR mutation group, and EGFR TKI used as the first line group could benefit from anlotinib on OS. When the OS was calculated from the time of diagnosis to the death, anlotinib could have increased median OS about 6 months (33.8 vs. 27.8 m, P

Background: Ankylosing spondylitis (AS) is a rheumatic inflammatory disease with unknown etiology, and fatigue is one of the main systemic symptoms of AS. The aim of the current study was to explore the mechanism of AS-associated fatigue (ASF) from multiple aspects, including neuropsychological changes.Method: A total of 120 AS patients and 78 age- and sex-matched healthy individuals were recruited into the study. Fatigue was assessed by the fatigue item of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Multidimensional Assessment of Fatigue (MAF) scale. Anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HADS). The cortical thickness and subcortical gray matter volume were assessed using a Philips Achieva 3.0 T TX MRI scanner.Result: Of the 120 AS patients, 103 (85.8%) reported varying degrees of fatigue. Among these fatigue cases, 33 (32.0%) were in the severe fatigue group (BASDAI-Fatigue ≥ 5), and 70 patients (68.0%) were considered to be in the mild fatigue group (BASDAI-Fatigue > 0 but

2528 Background: Chimeric antigen receptor (CAR) T cell therapy has made significant progress in the treatment of blood cancers such as leukemia, lymphoma, and myeloma. However, the therapy faces many challenges in treating solid tumors. These challenges include physical barriers, tumor microenvironment immunosuppression, tumor heterogeneity, target specificity, and limited expansion in vivo. Methods: We designed a CAR lentivirus vector that consisted of a humanized CD19-specific single-chain variable fragment (scFv), a 4-1BB costimulatory domain, and a CD3ζ signaling domain.The lentivirus was produced by transfecting HEK-293T cells with CAR lentiviral vectors and viral packaging plasmids. Patient’s CD3 T cells was cultured in X-VIVO medium containing 125U/mL 1interleukin-2 (IL-2), and transduced with CAR lentivirus at certain MOI 24h after stimulated by anti-CD3/CD28 magnetic beads. Transduction efficiency was evaluated at 7 to 9 days after CAR lentivirus transduction, and quality controls for fungi, bacteria, mycoplasma, chlamydia, and endotoxin were performed. After infusion, serial peripheral blood samples were collected, and the expansion and the cytokine release of CART cells were detected by FACS and QPCR,respectively. The evaluation of response level for patients were performed at month 1,month 3,and month 6 by PET/CT. Results: We engineered CoupledCAR T cells with lentiviral vectors encoding an anti-GCC (guanylate cyclase 2C) CAR molecule. To verify the safety and efficacy of CoupledCAR-T cells for treating solid tumors, we conducted several clinical trials for different solid tumors, including seven patients with colorectal cancer. These seven patients failed multiple rounds of chemotherapy and radiotherapy. In the clinical trial, the metastatic colorectal cancer patients were infused with autologous anti-GCC CoupledCAR-T cells range from 4.9×105/kg to 2.9×106/kg. We observed that CoupledCAR-T cells expanded significantly in the patients and infiltrated tumor tissue sites, demonstrating enhanced anti-tumor activities. PET/CT showed significant tumor shrinkage and SUV max declined, and the ongoing responses were monitored. Patient 3 achieved complete response and the best overall response rate (ORR, include complete remission, complete metabolic response, and partial response.) was 57.1% (4/7), complete remission (CR) rate was 14.3% (1/7). Conclusions: In conclusion, the clinical data demonstrated that CoupledCAR-T cells effectively expanded, infiltrated tumor tissue sites, and kill tumor cells in patients with colorectal cancer. We used immunotherapy to achieve complete remission in patients with advanced colorectal cancer for the first time. We are recruiting more colorectal cancer patients to further test the safety and efficacy of anti-GCC CoupledCAR T cells. Since our CoupledCAR technology is a platform technology, we are expanding it to treat other solid tumors using different target tumor markers.

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.

The SS18-SSX1 fusion gene has been shown to play important roles in the development of synovial sarcoma (SS), but the underlying molecular mechanisms and its downstream target genes are still not clear. Here SHC SH2-domain binding protein 1 (SHCBP1) was identified and validated to be a novel downstream target gene of SS18-SSX1 by using microarray assay, quantitative real-time (qPCR) and western blot. Expression of SHCBP1 was firstly confirmed in SS cell line and SS tissues. The effects of SHCBP1 overexpression or knockdown on SS cell proliferation and tumorigenicity were then studied by cell proliferation, DNA replication, colony formation, flow cytometric assays, and its in vivo tumorigenesis was determined in the nude mice. Meanwhile, the related signaling pathways of SHCBP1 were also examined in SS cells. The results indicated that SHCBP1 was significantly increased in SS cells and SS tissues compared with adjacent noncancerous tissues. The expression of SHCBP1 was demonstrated to be positively correlated with the SS18-SSX1 level. Overexpression and ablation of SHCBP1 promoted and inhibited, respectively, the proliferation and tumorigenicity of SS cells in vitro. SHCBP1 knockdown also significantly inhibited SS cell growth in nude mice, and lowered the MAPK/ERK and PI3K/AKT/mTOR signaling pathways and cyclin D1 expression. Our findings disclose that SHCBP1 is a novel downstream target gene of SS18-SSX1, and demonstrate that the oncogene SS18-SSX1 promotes tumorigenesis by increasing the expression of SHCBP1, which normally acts as a tumor promoting factor.

The present study aimed to investigate the expression levels of tumor necrosis factor-α-induced protein 8 (TNFAIP8) in gastric adenocarcinoma. TNFAIP8 expression levels in gastric adenocarcinoma tissue samples (with and without lymph node metastasis), adjacent normal tissue samples and metastatic lymph node tissue samples were detected by immunohistochemistry. The correlation between TNFAIP8 expression levels and clinicopathological data and gastric adenocarcinoma prognosis was analyzed. The results demonstrated that TNFAIP8 expression in gastric adenocarcinoma tissue samples and metastatic lymph node tissue samples markedly increased at a rate of 47.2% (50/106) and 81.7% (49/60), respectively, as compared with the adjacent normal tissue samples in which no TNGFAIP8 expression was detected (0%). This increase in TNFAIP8 expression was statistically significant. TNFAIP8 expression rates in the primary tumors (60%, 36/60) of patients with lymph node metastasis were significantly higher compared with the primary tumors of patients without lymph node metastasis (30.4%, 14/46). TNFAIP8 expression was associated with an increase in the severity of TNM stage, tumor grade, vascular invasion, lymph node metastasis and serum CA72-4 levels. The overall survival rate of patients with gastric adenocarcinoma and high TNFAIP8 expression was poorer compared with patients with low TNFAIP8 expression, and TNFAIP8 expression was negatively correlated with patient prognosis. The results also demonstrated that TNFAIP8 was an independent prognostic marker in gastric adenocarcinoma (relative risk, 1.736; P=0.029). In conclusion, the results of the present study demonstrated that TNFAIP8 expression was associated with the occurrence, development and metastasis of gastric adenocarcinoma, and negatively correlated with the prognosis of patients with gastric adenocarcinoma. TNFAIP8 may therefore serve as a prognostic factor for gastric adenocarcinoma.

Observational studies assessing the association of dietary fat and risk of ovarian cancer yield discrepant results. Pertinent prospective cohort studies were identified by a PubMed search from inception to December 2015. Sixteen independent case-control and nine cohort studies on dietary fat intake were included, with approximately 900,000 subjects in total. Relative risks (RRs) with 95% confidence intervals were pooled using a random effects model. Heterogeneity, sensitivity analysis and publication bias were assessed; subgroup analysis and analysis stratified by EOC histology were conducted. The reported studies showed a significant increase of ovarian cancer risk with high consumption of total-, saturated-, and trans-fats, while serous ovarian cancer was more susceptible to dietary fat consumption than other pathological subtypes. No evidence of positive association between dietary fat intake and ovarian cancer risk was provided by cohort studies. Menopausal status, hormone replacement therapy, body mass index (BMI), and pregnancy times, modified the objective associations. In conclusion, the meta-analysis findings indicate that high consumption of total, saturated and trans-fats increase ovarian cancer risk, and different histological subtypes have different susceptibility to dietary fat.

65 Background: The efficacy of late line treatments for metastatic colorectal cancer (mCRC) is still limited. Antiangiogenic therapy is one of standard treatments in mCRC. Anlotinib is a multitarget tyrosine kinase inhibitor, mainly targets VEGFR1-3. This phase III trial was conducted to evaluate anti-tumor efficacy and safety of anlotinib monotherapy in refractory mCRC. Methods: Aged 18 years or older mCRC patients were enrolled in 33 Chinese hospitals. They had received at least 2 lines of chemotherapy based treatments; had ECOG PS 0-1and adequate bone marrow, liver and renal function. Enrolled patients were 2-to-1 randomly assigned into anlotinib or placebo group and stratified by previous VEGF-targeting therapy (y/n) and time from diagnosis to metastases (

Chimeric antigen receptor (CAR) T cell therapy has made significant progress in the treatment of blood cancers such as leukemia, lymphoma, and myeloma. However, the therapy faces many challenges in treating solid tumors. These challenges include physical barriers, tumor microenvironment immunosuppression, tumor heterogeneity, target specificity, and limited reactive cell expansion in vivo. Conventional CAR T cell therapy has thus far shown weak cell expansion in solid tumor patients and achieved little or no therapeutic responses. Here, we developed CAR T cells based on a novel CoupledCAR® technology to treat solid tumors. In contrast to conventional CAR T cells, CoupledCAR T cells significantly improved the expansion of the CAR T cells in vivo and enhanced the CAR T cells' migration ability and resistance to immunosuppression by the tumor microenvironment. The enhanced migration ability and resistance allow the CAR T cells to infiltrate to tumor tissue sites and increase anti-tumor activities. Specifically, we engineered CoupledCAR T cells with lentiviral vectors encoding an anti-GCC (guanylate cyclase 2C) CAR molecule. Furthermore, anti-GCC CAR T cells showed anti-tumor activities in vitro and in vivo experiments. To verify the safety and efficacy of CoupledCAR T cells for treating solid tumors, we conducted several clinical trials for different solid tumors, including seven patients with colorectal cancer. These seven patients failed multiple rounds of chemotherapy and radiotherapy. In the clinical trial, the patients were infused with autologous anti-GCC CoupledCAR T cells range from 4.9×10^5/kg to 2.9×10^6/kg. All patients using anti-GCC CoupledCAR T cells showed rapid expansion of CoupledCAR T cells and killing of tumor cells. Specifically, we observed that CoupledCAR T cells expanded significantly in the patients and infiltrated tumor tissue sites, demonstrating enhanced anti-tumor activities. PET/CT showed significant tumor shrinkage and SUV max declined, and the ongoing responses were monitored. Patient 3 achieved complete response and the best overall response rate (ORR, include complete remission, complete metabolic response, partial response, and partial metabolic response.) was 71.4% (5/7), complete remission (CR) rate was 14.3% (1/7). The clinical data demonstrated that CoupledCAR T cells effectively expanded, infiltrated tumor tissue sites, and kill tumor cells in patients with colorectal cancer. We used immunotherapy to achieve complete remission in patients with advanced colorectal cancer for the first time. We are recruiting more colorectal cancer patients to further test the safety and efficacy of anti-GCC CoupledCAR T cells. Since our CoupledCAR® technology is a platform technology, we are expanding it to treat other solid tumors using different target tumor markers . Disclosures Xiao: Innovative Cellular Therapeutics: Other: stockholder.

4511 Background: Patients (pts) with advanced esophageal squamous cell carcinoma (ESCC) refractory to first-line chemotherapy have limited treatment options. The study aims to evaluate the efficacy and safety of sintilimab, a PD-1 inhibitor, versus chemotherapy in these pts, and explore predictive value of PD-L1 and neutrophil-to-lymphocyte ratio (NLR) on efficacy of sintilimab. Methods: The open-label, multi-center phase 2 trial (NCT03116152) enrolled advanced ESCC pts refractory to first-line chemotherapy, and randomly assigned (1:1) them to receive sintilimab (200mg, Q3W) or chemotherapy (paclitaxel, 175mg/m2, Q3W; or irinotecan, 180mg/m2, Q2W), intravenously. The primary endpoint was overall survival (OS). Explorative endpoint were effects of PD-L1 and NLR on efficacy of sintilimab. Results: From May 16, 2017 to Aug 30, 2018, 190 pts were randomly assigned to sintilimab or chemotherapy (n = 95 per group). With the median follow-up of 7.2 months for sintilimab group and 6.2 months for chemotherapy group, the median OS in sintilimab was significantly higher than chemotherapy (7.2m vs. 6.2m, hazard ratio [HR] 0.70, P = 0.034). The objective response rate (ORR) was greater in sintilimab than chemotherapy with 12.6% vs. 6.3%, and the median duration of response was longer (8.3m vs. 6.2m). Incidences of treatment-related adverse events (TRAEs) of any grade (54.3% vs. 90.8%) and of grade 3-5 (20.2% vs. 39.1%) were both numerically less in sintilimab than in chemotherapy. The ORR in sintilimab versus chemotherapy in pts with tumor PD-L1 tumor proportion score (TPS) ≥1% and with TPS ≥10% were 20.2% vs. 0%, and 35.7% vs. 0%, respectively. In sintilimab group, pts with low NLR ( < 3) had a significant longer median OS (HR 0.54, P = 0.019) than with high NLR. Conclusions: Sintilimab was superior to chemotherapy with a significantly prolonged survival benefit and a favorable safety profile in pts with advanced ESCC refractory to first-line chemotherapy. High tumor PD-L1 expression (TPS ≥1% or ≥10%) might indicate more response benefit to sintilimab for these pts, and low NLR might be a positive predictive factor for sintilimab. Clinical trial information: NCT03116152 .

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 Anlotinib is an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, and stem cell factor receptor (c-Kit). In the phase III ALTER-0303 trial (Clinical Trial Registry ID: NCT 02388919), anlotinib significantly improved overall survival versus placebo in advanced non-small cell lung cancer patients who had received at least two previous chemotherapy and epidermal growth factor receptor/anaplastic lymphoma kinase targeted therapy regimens. This study summarized adverse event management in this trial. Methods Patients were randomized (2:1) to anlotinib or placebo up to progression or intolerable toxicity. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 and managed by investigators. Key strategies for preventing and managing the most common adverse events included patient education, supportive care, and dose modification. Results Between February 2015 and August 2016, 294 patients received anlotinib. A total of 170 (57.8%) patients received antihypertensive medications for hypertension, 53 (18.0%) patients received levothyroxine for hypothyroidism, 24 (8.2%) patients received fibrates for hypertriglyceridemia, 11 (3.7%) patients took cortisone cream for hand-foot syndrome, and 38 (12.9%) patients received anti-diarrheal medications for diarrhea. Dose reduction and drug discontinuation were required in 24 (8.16%) and 31 (10.54%) patients in the anlotinib group, respectively. Conclusion Anlotinb-related adverse events could be controlled by patient education, prophylactic measures, early and active intervention, and dose modification.

Background Mesenchymal stem cells (MSCs) possess powerful immunosuppression capacity. Transforming growth factor-β (TGF-β) is a well-known anti-inflammatory cytokine and plays an important role in various inflammatory processes. We hypothesized that TGF-β could synergize with MSCs in suppressing immune responses, and therefore established a mouse skin graft model to evaluate the effect of MSCs and MSCs combined with TGF-β on transplantation immunity in vivo. Methods Balb/c and C57BL/6 mice were used to establish the skin graft model. The recipients were divided into 3 groups and received intravenous bone marrow mesenchymal stem cells (BMSCs), BMSCs pretreated with TGF-β, and 0.9% saline solution, respectively. Skin graft survival time, pathological detection, the ratio of CD4+CD25+Foxp3+Treg cell of spleens, and the level of IFN-γ, IL-2, IL-10, and TGF-β expression were tested. Results The survival time of skin grafts were prolonged in both BMSC (12.5 ± 1.35 days) and BMSC-TGF-β (10.6 ± 1.90 days) recipients compared to the blank control recipients (8.0 ± 1.05 days). The ratio of CD4+CD25+Foxp3+Treg cell of spleens from BMSC and BMSC-TGF-β recipients was higher than that of the blank control, and the upregulated proliferation in the BMSC group occurred earlier and was prolonged compared to the BMSC-TGF-β group. The expression of IFN-γ and IL-2 was inhibited in both the BMSC and BMSC-TGF-β groups compared to the blank, while the expression of IL-10 and TGF-β was boosted. In contrast to the BMSC group, the BMSC-TGF-β group exhibited a weaker effect on the expression of cytokines. Conclusion TGF-β partially reversed the immunosuppressive effect of MSCs in vivo. This immunoregulatory feature may have potential applications for treating transplant rejection.

The transcription factor TAp73, a transcriptionally active isoform of p73, has high structure and function similaritieswith its homolog p53, therefore, are thought to be a cancer therapy candidate target. However, there is still a controversy about the tumor suppressor role of TAp73, since it has been found in numerous studies that TAp73 expression is elevated in different cancers. Thus, we take effort to clarify the influence of TAp73 on gastric cancer (GC) chemotherapy. Multiple cell lines of GC such as SNU-1, SNU-3, and AGS were applied to investigate expression of TAp73. Flow cytometry was utilized to detect apoptosis, revealing how TAp73 overexpression affected anticancer drug (ACD). Additionally, we explored how TAp73 overexpression influenced apoptotic cells of neoplastic tissues and tumor size of nude mice in vivo. Our results indicated that TAp73 was down-regulated in GC cells after chemotherapy drugs treatment. Besides, enforced expression of TAp73 affects chemotherapeutic drugs induced GC cell apoptosis, which is dependent on p53. The expression of TAp73 was regulated by its transcription factor, E2F1, in response to chemotherapy drugs. Our in vivo xenograft results also suggested that transfection of TAp73 affects the tumor suppression effect of 5-FU. Consequently, the findings of our study demonstrate that E2F1 and TAp73α are oncogenic and throw light upon the underlying mechanism of their role against apoptosis.

Background Gastric cancer (GC) is one of the most common cancers with high mortality globally. However, the molecular mechanisms of GC are unclear, and the prognosis of GC is poor. Therefore, it is important to explore the underlying mechanisms and screen for novel prognostic markers and treatment targets. Methods The genetic and clinical data of GC patients in The Cancer Genome Atlas (TCGA) was analyzed by weighted gene co-expression network analysis (WGCNA). Modules with clinical significance and preservation were distinguished, and gene ontology and pathway enrichment analysis were performed. Hub genes of these modules were validated in the TCGA dataset and another independent dataset from the Gene Expression Omnibus (GEO) database by t-test. Furthermore, the significance of these genes was confirmed via survival analysis. Results We found a preserved module consisting of 506 genes was associated with clinical traits including pathologic T stage and histologic grade. PDGFRB, COL8A1, EFEMP2, FBN1, EMILIN1, FSTL1 and KIRREL were identified as candidate genes in the module. Their expression levels were correlated with pathologic T stage and histologic grade, also affected overall survival of GC patients. Conclusion These candidate genes may be involved in proliferation and differentiation of GC cells. They may serve as novel prognostic markers and treatment targets. Moreover, most of them were first reported in GC and deserved further research.

Th17 cells are a new subset of CD4(+) T cells involved in the clearance of extracellular pathogens and fungi. Accumulating evidence suggests that Th17 cells and their signature cytokines have a pivotal role in the pathogenesis of multiple autoimmune-mediated inflammatory diseases. Here, we summarize recent research progress on Th17 function in the development and pathogenesis of autoimmune diseases. We also propose to identify new small molecule compounds to manipulate Th17 function for potential therapeutic application to treat human autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, inflammatory bowel disease, and multiple sclerosis.

Glycodelin is a kind of glycoprotein expressed in secretory endometrium, pregnancy deciduas, and amniotic fluid originally, which is vital for the maintenance of normal human reproductive activities. Recent researches have reported that glycodelin is specifically expressed in various malignancies, including female-specific cancers such as endometrial cancer, ovarian cancer and breast cancer, and non-gender specific cancers including lung cancer, and colon cancer, and glycodelin expression correlates with the diagnosis and prognosis of cancer patients. This review focuses on the expression of glycodelin in different cancers and its role in cancer development and progression. Glycodelin possesses the abilities to regulate cancer cell proliferation, differentiation, and invasion, promote cancer angiogenesis, and modulate the differentiation and function of immune cells including T cells, dendritic cells, monocyte-macrophages, natural killer cells and B cells participating in cancer development. The expression of glycodelin can be regulated by stromal cells, lysophosphatidic acid, histone deacetylase inhibitors, and relaxin. In summary, glycodelin is a promising biomarker for the diagnosis and prognosis of cancer patients, and depending on its distinct immunoregulatory effects, glycodelin can be a prospective target for cancer immunotherapy.

Background Dulanermin is a recombinant soluble human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that activates apoptotic pathways by binding to proapoptotic death receptor (DR) 4 and DR5. The purpose of this study was to evaluate the efficacy and safety of dulanermin combined with vinorelbine and cisplatin (NP) as the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Experimental design Patients were randomly assigned to receive NP chemotherapy (vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 30 mg/m2 on days 2 to 4) for up to six cycles plus dulanermin (75 μg/kg on days 1 to 14) or placebo every three weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was progression-free survival (PFS), and the secondary end points included objective response rate (ORR), overall survival (OS), and safety evaluation. Results Between October 2009 and June 2012, 452 untreated patients with stage IIIB to IV NSCLC were randomly assigned to receive dulanermin plus NP (n = 342) and placebo plus NP (n = 110). Median PFS was 6.4 months in the dulanermin arm versus 3.5 months in the placebo arm (hazard ratio (HR), 0.4034; 95% CI, 0.3181 to 0.5117, p

e20507 Background: In ALTER 0303, the common adverse reaction (AE) included hypertension (HTN) and hand foot syndrome (HFS). In this subgroup analysis, we aim to assess the relationship between common AEs and clinical benefit in anlotinib cohort. Methods: Eligible patients showed disease progression after second-line or further treatment were randomly assigned in a 2:1 ratio to receive 12 mg/day of anlotinib or placebo. The primary endpoint was overall survival (OS). This subgroup analysis was based on anlotinib cohort. Results: Patients with HTN had significantly improved median OS, median progress-free survival (PFS), objective response (ORR) and disease control rate (DCR) compared with patients without HFS in anlotinib cohort. Similarly, patients with HFS had better clinical outcomes in anlotinib cohort. Not surprisingly, patients occurred both HFS and HTN had more superior medium OS compared with only HFS, only HTN and neither HFS nor HTN. Conclusions: HTN or HFS is associated with better clinical outcomes in advanced NSCLC patients received anlotinib. Clinical trial information: NCT02388919. [Table: see text]

e20503 Background: As a promising multi-target tyrosine kinase inhibitor (TKI), anlotinib hydrochloride significantly improved overall survival (OS) and progression-free survival (PFS) in advanced NSCLC patients in the phase 3 trial (ALTER0303). Here, we demonstrated the efficacy of anlotinib in SCC patients with or without hypertension. Methods: Patients (n = 439) were randomized in a 2:1 ratio to receive anlotinib (12mg daily for 14 days in a 21 day cycle) or placebo. The primary endpoint was OS and second endpoints were PFS, ORR, DCR and QoL. The correlation between hypertension and efficacy (PFS and OS) was analyzed in SCC patients treated with anlotinib. Results: For different ECOG score (0 and 1) SCC patients (n = 46) in the anlotinib arm, the PFS was significantly improved in patients with hypertension in ECOG 1 group (7.00 vs 4.83 months, p = 0.043). There is no statistical difference in other subgroups. Moreover, for the SCC patients in anlotinib arm, PFS was significantly prolonged in patients with hypertension compared to the patients without hypertension (7.23 vs 3.23 months; HR = 0.36; 95% CI, 0.16–0.84; P = 0.001). However, the median OS of the patients with hypertension was numerically but not statistically longer than the patients without hypertension (13.93 vs 6.30 months; HR = 0.56; 95%CI, 0.26-1.22; P = 0.100). Conclusions: In the ALTER0303 trial, anlotinib significantly improved PFS with a potential benefit of OS for SCC patients with hypertension. And ECOG score does not affect the efficacy of anlotinib in SCC patients with or without hypertension. Clinical trial information: NCT02388919. [Table: see text]

Purpose To investigate the impact of the cytidine deaminase (CDA) A79C polymorphism on both the response to gemcitabine in non-small cell lung cancer (NSCLC) patients and the risk of hematologic toxicities in patients bearing any kind of cancer taking gemcitabine. Methods The PubMed and Embase databases were searched from the first available article to January 2013. Eligible studies included clinical trials that contained the keywords “gemcitabine” or “cytidine deaminase” and information about response rate of NSCLC patients or hematologic toxicities in patients with any kind of cancer. Relative risk (RR) of different genotypes and 95% confidence intervals (CI) were calculated. Results A total of 7 articles (623 patients from 6 studies) were included. The results showed that patients with wild type CDA (AA and AC) had a significantly lower rate of severe anemia than the homozygote mutant type CC (RR=0.308; 95%CI, 0.113-0.021, p=0.021). However, the rate of severe neutropenia, thrombocytopenia, and the response rate were identical between different CDA genotypes. Conclusion The A79C CDA polymorphism did not show a significant impact on the response rate to gemcitabine in NSCLC patients, while the wild type CDA genotype was indeed correlated to a lower rate of incidence of severe anemia in patients taking gemcitabine.

As one of the most aggressive human malignancies, pancreatic cancer is a leading cause of cancer-related deaths worldwide and only about 4% of patients will live 5 years after diagnosis. Eighty to approximately eighty-five percent of patients are diagnosed with an unresectable or metastatic disease, which is correlated with poor prognosis and low survival rate. Therefore, it is tremendously significant to exploit novel chemicals to prevent and treat pancreatic cancer. Previous research and clinical studies have demonstrated that many natural products derived from traditional Chinese medicine (TCM) such as camptothecin derivatives and vinca alkaloids could be effective antitumor compounds, hinting that TCM is a promising source for developing new antitumor drugs. In this report, we investigated the effects of bufalin, a primary active ingredient of the traditional Chinese medicine Chan-Su, on pancreatic cancer cell lines PANC-1 and CFPAC-1 and studied the underlying molecular mechanism. We found that exposure to bufalin could suppress the proliferation of pancreatic cancer cells time and dose dependently. We used flow cytometry to study the effects of bufalin on apoptosis and cell cycle distribution in PANC-1 and CFPAC-1 cells. The results indicated that bufalin could significantly induce both apoptosis and G2/M cell cycle arrest in pancreatic cancer cells. With western blotting, we found that the expression level of an antiapoptotic protein heat shock protein 27 (Hsp27) and its partner molecule p-Akt was decreased upon the treatment with bufalin. Besides, bufalin activated pro-caspase-3 and pro-caspase-9 and modulated the expression level of Bcl-2 and Bax. These data suggested that bufalin may trigger apoptosis by targeting Hsp27, which could inhibit apoptosis by interfering with key apoptotic proteins. The influence on the level of cylinB1, CDK1, and p21 was also observed after bufalin treatment, and the relationship between Hsp27 and the cell cycle-related proteins mentioned above deserves much more research. In addition, our data showed that bufalin could enhance the growth inhibition effect of gemcitabine in above pancreatic cancer cells. Taken together, bufalin might be worthy of further study for its potential as a therapeutic agent for pancreatic cancer treatment.