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Background Microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) tumours have a high response rate to immunotherapy. Antitumour activity and safety of serplulimab, a novel humanised anti-PD-1 monoclonal antibody, were evaluated in this phase II study. Methods In this ongoing, single-arm, open-label, phase II trial, patients with previously treated unresectable or metastatic MSI-H/dMMR solid tumours received intravenous serplulimab 3 mg/kg every 2 weeks for up to 52 cycles. The primary endpoint was objective response rate (ORR) assessed by an independent radiological review committee per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included additional efficacy measures, safety, and tolerability. Results As of 9 January 2021, 108 patients were enrolled, and 68 patients with confirmed MSI-H solid tumours were included in the main efficacy analysis population (MEAP). The median follow-up duration in the MEAP was 7.7 months, with an ORR of 38.2% (95% confidence interval, 26.7–50.8). Of the 108 patients, grade ≥3 treatment-emergent adverse events were reported in 53 (49.1%) patients; immune-related adverse events occurred in 52 (48.1%) patients. Conclusions Serplulimab demonstrates a durable antitumour effect and a manageable safety profile in previously treated patients with MSI-H solid tumours. Serplulimab is a promising tissue-agnostic treatment for previously treated MSI-H solid tumours. Trial registration NCT03941574.

Apatinib, a highly selective inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2), inhibits the angiogenesis of tumours. The function and mechanism of apatinib in oesophageal squamous cell carcinoma (ESCC) remain unknown. In present study, we found that the development of ESCC in patients was controlled by treatment of combination of apatinib and a chemotherapeutic drug. Moreover, apatinib efficiently promotes cell apoptosis, inhibits cell proliferation, invasion, epithelial-mesenchymal transition (EMT) and activity of the Akt/mTOR pathway in ESCC cells. Western blot analysis showed that apatinib significantly increased vimentin protein levels, decreased Bcl2, matrix metalloproteinase 9 (MMP9), E-cadherin, p-Akt and p-mTOR protein levels in ESCC cells. Furthermore, apatinib enhanced chemosensitivity of cytotoxic drugs paclitaxel (TAX), 5-fluorouracil (5-FU) and cisplatin (DDP) by upregulating expression of vimentin protein, and downregulating expression of Bcl2, MMP9 and E-cadherin protein in vitro. Compared with single-agent groups, the combination of apatinib with each chemotherapeutic drug significantly repressed tumour growth and angiogenesis through blocking the expression of Ki67 and VEGFR-2 in vivo. Taken together, apatinib efficiently inhibits cell growth through blocking Bcl2 and Akt/mTOR pathway, and suppresses metastasis via inhibiting MMP9 and EMT in ESCC cells. Apatinib promoted antitumour effect of chemotherapeutic agents through promoting cell apoptosis and inhibiting EMT and angiogenesis in ESCC.

Background Pucotenlimab is a novel recombinant humanized anti-PD-1 (Programmed death-1) monoclonal antibody, which belongs to the human IgG4/kappa subtype, and can selectively block the binding of PD-1 with its ligands PD-L1 and PD-L2. Methods In this phase 2 trial, patients with locally advanced or metastatic melanoma who had failed conventional treatment (chemotherapy, targeted therapy, interferon, IL-2, et al.) were recruited. The patients were administrated with Pucotenlimab of 3 mg/kg every 3 weeks until disease progression, intolerable toxicity, or treatment discontinuation for any other reasons. The primary endpoint was the overall response rate (ORR). The secondary endpoints were disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and toxicity. Results One-hundred and nineteen patients were enrolled and followed up for 19.32 (ranging from 15.901 to 24.608) months by the cutoff date of July 30th, 2021. The ORR was 20.17% (24/119, 95% CI, 13.370%-28.506%) based on both independent review committee (IRC) and the investigator’s assessment per RECIST v1.1. The median PFS were 2.89 (95% CI, 2.037–4.074) months and 2.46 (95% CI, 2.004–4.008) months based on IRC and investigator’s assessment, respectively, per RECIST v1.1. The median OS was 16.59 (95% CI, 13.963–26.973) months. Treatment-related adverse events (TRAEs) occurred in 77.3% (92/119) of the patients. The incidence of Grade ≥ 3 TRAEs was 15.1% (18/119). In addition, none of the patients died because of TRAEs. As for biomarker analysis, Eotaxin (CCL11) and MCP-1 (CCL2) were related to treatment response, while TNF-α and VEGF were related to treatment failure. Conclusions Pucotenlimab as a ≥ 2nd line therapy showed promising efficacy and tolerable toxicity for patients with locally advanced or metastatic melanoma. Trial registration Clinicaltrials.gov Identifier: NCT04749485 (registered retrospectively on 11/02/2021).

AIM: To assess the reliability of web-based version of ocular surface disease index in Chinese (C-OSDI) on clinically diagnosed dry eye disease (DE) patients.METHODS: A total of 254 Chinese participants (51%male, 129/254; mean age: 27.90±9.06y) with DED completed paper- and web-based versions of C-OSDI questionnaires in a randomized crossover design. Ophthalmology examination and DED diagnosis were performed prior to the participants being invited to join the study. Participants were randomly designated to either group A (paper-based first and web based second) or group B (web-based first and paper-based second). Final data analysis included participants that had successfully completed both versions of the C-OSDI. Demographic characteristics, test-retest reliability, and agreement of individual items, subscales, and total score were evaluated with intraclass correlation coefficients(ICC), Spearman rank correlation, Wilcoxon test and Rasch analysis.RESULTS: Reliability indexes were adequate, Pearson correlation was greater than 0.8 and ICCs range was 0.827to 0.982; total C-OSDI score was not statistically different between the two versions. The values of mean-squares fit statistics were very low compared to 1, indicating that the responses to the items by the model had a high degree of predictability. While comparing the favorability72% (182/254) of the participants preferred web-based assessment.CONCLUSION: Web-based C-OSDI is reliable in assessing DED and correlation with the paper-based version is significant in all subscales and overall total score. Web based C-OSDI can be administered to assess individuals with DED as participants predominantly favored online assessment.

Purpose RC48 contains the novel humanized anti-HER2 antibody hertuzumab conjugated to MMAE via a cleavable linker. A phase I study was initiated to evaluate the toxicity, MTD, PK, and antitumor activity of RC48 in patients with HER2-overexpressing locally advanced or metastatic solid carcinomas, particularly gastric cancer. Patients and methods This was a 2-part phase I study. Successive cohorts of patients received escalating doses of RC48 (0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, and 3.0 mg/kg). Dose expansion proceeded at the dose of 2.0 mg/kg Q2W. The efficacy and safety set included all patients who received at least one dose of RC48. Results Fifty-seven patients were enrolled, the MTD was unavailable due to termination of 3.0 mg/kg cohort; 2.5 mg/kg Q2W was declared the RP2D. RC48 was well tolerated, the most frequent grade 3 or worse TRAEs included neutropenia (19.3%), leukopenia (17.5%), hypoesthesia (14.0%), and increased conjugated blood bilirubin (8.8%). Four deaths occurred during the whole study, three of which were believed to be related to RC48. Overall, ORR and DCR were 21.0% (12/57) and 49.1% (28/57). Notably, patients who were HER2 IHC2+/FISH- responded similarly to those who were IHC2+/FISH+ and IHC3+, with ORRs of 35.7% (5/14), 20% (2/10), and 13.6% (3/22), respectively. In patients who were pretreated with HER2-targeted drugs, RC48 also showed promising efficacy, with ORR of 15.0% (3/20) and DCR of 45.0% (9/20). Conclusion RC48 was well tolerated and showed promising antitumor activity in HER2-positive solid tumors, including gastric cancer with HER2 IHC 2+/FISH- status. Clinical trial information NCT02881190.

Background Currently, there are no randomized trials on the effect of antiangiogenic therapy in patients with esophageal squamous cell carcinoma (ESCC). The following study investigated the efficacy and safety of anlotinib in patients with advanced ESCC who were previously treated with chemotherapy. Methods This randomized, placebo‐controlled, double‐blind phase 2 trial (NCT02649361) was conducted in 13 Chinese hospitals. Eligible patients were adults with histologically confirmed recurrent or metastatic ESCC who were previously treated with chemotherapy, and were randomly assigned (2:1) to receive oral anlotinib 12 mg or placebo on days 1–14 (repeated every 21 days). The primary endpoint was progression‐free survival (PFS). Results One hundred and sixty‐five patients were randomly assigned to the anlotinib (n = 110) or the placebo (n = 55) arm. Median PFS was 3.02 months (95% CI 2.63–3.65) in the anlotinib group and 1.41 months (95% CI 1.38–1.41) in the placebo group (hazard ratio 0.46 [95% CI 0.32–0.66]; p, Anti‐angiogenic multi‐target inhibitor anlotinib significantly improved PFS and DCR compared with placebo in this study. Our findings demonstrated that angiogenesis targeting therapy might be an efficient therapeutic target in advanced or metastatic ESCC.

The benefit of systemic treatment in esophageal squamous cell carcinoma (ESCC) which has progressed after chemotherapy is still uncertain. Anlotinib (AL3818) is a novel multi-target TKI, inhibiting tumor angiogenesis and proliferation. A phase II trial (NCT02649361) has demonstrated that anlotinib has a durable antitumor activity with a manageable adverse event profile in refractory metastatic ESCC. This study (NCT03387904) aimed at comparing the effects and safety of Anlotinib Plus Irinotecan versus Irinotecan in patients with ESCC. Methods We conducted a prospective randomized, multicenter, phase II trial to compare the efficacy of Anlotinib Plus Irinotecan with Irinotecan in recurrent ESCC patients who had resistance to platinum or taxane-based chemotherapy. Eligible patients were adults with pathologically confirmed recurrent ESCC, and 82 patients were randomized 1:1 to Irinotecan (65 mg/m2/day 1 and day 8) with or without anlotinib (12 mg qd day 1 to 14) of a 21-day cycle till progression or intolerable. The primary endpoint is the disease control rate (DCR) and progression-free survival (PFS) and the secondary end points are objective response rate (ORR) and overall survival (OS). Results Between 13/1 2019 and 20/1 2020, a total of 43 patients were enrolled and randomly assigned to either the anlotinib plus irinotecan (n = 22) or the irinotecan group (n = 21).The mPFS was longer in trial group than in control group (89 days vs 66 days, HR = 0.447, P = 0.055). The Disease control rate (DCR) was 54.5% in trial group and 38.1% in the control group. The treatment-related adverse events (>10%) were fatigue (59.1%), nausea (50.0%), decreased appetite (36.4%), hoarseness (27.3%), thyroid-stimulating hormone elevation (22.7%), diarrhea (9.1%), and decreased lymphocytes count(9.1%) in trial group. Grade 3 AEs included fatigue (4.5% vs 4.8%), nausea (4.5% vs 0%) and diarrhea (4.5% vs 0%) in two groups. Conclusion Anlotinib plus irinotecan was similarly tolerable but prolonged PFS compared to irinotecan monotherapy as a second-line treatment in patients with recurrent ESCC.

Esophageal squamous cell carcinoma (ESCC) as a common malignancy is prevalent in East Asia and in eastern and southern Africa. Although pembrolizumab, nivolumab and camrelizumab are respectively recommended as second-line treatment for advanced ESCC due to improved overall survival (OS), objective response rate (ORR) was modest. New effective treatments are needed. Hence, the study of camrelizumab plus apatinib (VEGFR2 inhibitor) as second-line treatment for advanced ESCC was performed. Methods This ongoing phase II trial (NCT03736863) in six sites in China enrolled pts aged 18-75 with unresectable locally advanced, locally recurrent, or metastatic ESCC that progressed or were intolerant after first-line chemotherapy, and an ECOG performance status of 0-1. Pts received 200 mg camrelizumab intravenously every 2 weeks and apatinib 250 mg orally once per day in 4-week cycles until disease progression, unacceptable adverse events (AEs) or withdrawal of consent. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS) and OS. Results At data cutoff (Feb 28, 2021), 52 pts were enrolled, including 42 males and 50 with distant metastases, with the median age of 62 years. In the evaluable population of 39 pts, ORR without confirmation was 43.59% and DCR was 94.87%. The median duration of response was 6.9 months (95% CI 4.57–9.23). The median PFS was 6.8 month (95% CI 2.66–10.94). The 12-month overall survival was 52.2%. A total of 80.8% of pts had treatment-related AEs (TRAEs) with 46.2% of grade ≥ 3 TRAEs. The safety profile of camrelizumab and apatinib was consistent with other anti–PD-1 antibodies and angiogenesis inhibitors. Conclusion This is the first study that evaluates the combination anti–PD-1 antibody and anti-angiogenesis inhibitor as a second-line therapy for advanced ESCC. Camrelizumab plus apatinib showed encouraging clinical efficacy and acceptable safety. Further phase III randomized trials are warranted.

Systemic chemotherapy is the first choice for patients with advanced esophageal cancer. However, due to drug resistance and dose-limiting toxicity, a large number of patients in China have not been treated. A novel therapy based on programed death 1 (PD-1) inhibitors has been proved to be effective in advanced esophageal cancer.This article is a meta-analysis aiming to systematically evaluate the efficacy and safety of anti-PD-1 therapy in patients with esophageal cancer. Methods Data were collected from eligible studies searched from PubMed, Web of Science, Cochrane Library and Embase. Pooled hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) was estimated to assess the efficacy of PD-1 inhibitors versus chemotherapy, and pooled odds ratio (OR) was calculated for objective response rate (ORR). The analysis among patients tested with different PD-1 status was also performed to figure out the relationship between PD-1 status and efficacy of anti-PD-1 therapy. The OR for occurrence of treatment-related adverse effect was calculated to assess the safety of anti-PD-1 therapy. Results A total of 8 studies were analyzed. Compared with patients with chemotherapy, patients with anti-PD-1 therapy had a significant improvement in OS (HR = 0.80, 95% CI: 0.70–0.91, P = 0.001), but no significant relationship was observed in ORR (HR = 1.87, 95% CI: 0.82–4.25, P = 0.13) and PFS (HR = 0.94, 95% CI: 0.70–1.26, P = 0.67). A similar result was observed in esophageal squamous cell carcinoma (ESCC). The PD-L1 status has no obvious connection with the efficacy of anti-PD-1 therapy. The incidence of grade 3 to 5 treatment-related adverse effect(AE) in anti-PD-1therapy was distinctly lower than that in chemotherapy, but there is no statistical difference in all treatment-related AE. Conclusion Anti-PD-1 therapy significantly prolonged the OS when compared with chemotherapy, while no significantly difference in PFS and ORR for the population of esophageal cancer, ESCC， PD-L1 positive. Based on the analysis of grade 3 to 5 treatment-related adverse effect events, a lower risk was associated with the anti-PD-1 therapy versus chemotherapy.

Background Real-world safety and effectiveness data for trastuzumab plus chemotherapy treatment of patients with HER2-positive metastatic gastric cancer (mGC) in China are lacking. Patients and Methods EVIDENCE was a prospective, multicenter, noninterventional registry study evaluating the safety and effectiveness of trastuzumab in five cohorts of Chinese patients with gastric cancer, stratified by HER2 status and trastuzumab treatment. Effectiveness was analyzed for cohorts I (HER2-positive, trastuzumab treated), II (HER2-positive, trastuzumab untreated), and IV (HER2-negative, trastuzumab untreated); trastuzumab-related adverse events (AEs) were analyzed for cohort I. Results Cohorts I, II, and IV included 174, 113, and 422 patients, respectively. Most patients received first-line chemotherapy (87.6%). Median overall survival (OS1) for first-line treatment was 22.3, 17.2, and 17.4 months in cohorts I, II, and IV, respectively. After excluding patients who had surgery, respective median OS1 was 19.9, 15.3, and 12.9 months. Respective first-line progression-free survival (PFS1) was 8.2, 6.9, and 6.2 months; and respective first-line response rates (RR) were 51.7%, 18.4%, and 32.8%. Cohort I was significantly favored over cohort II for propensity score–matched first-line median OS1 (hazard ratio [HR], 0.61), PFS1 (HR, 0.64), and RR (odds ratio, 4.93). Trastuzumab-related AEs, grade 3–5 AEs, serious AEs, and AEs with a fatal outcome occurred in 23.6%, 3.4%, 2.3%, and 0.6% of cohort I patients, respectively. Conclusion Safety profiles were consistent with those known for trastuzumab and chemotherapy; trastuzumab treatment improved outcomes. Our study provides real-world data supporting first-line trastuzumab plus chemotherapy in Chinese patients with HER2-positive mGC. Implications for Practice This prospective, noninterventional registry study aimed to provide safety and effectiveness data for the use of trastuzumab in combination with chemotherapy in Chinese patients with HER2-positive metastatic gastric cancer (mGC) from the real-world clinical setting. Trastuzumab plus first-line chemotherapy was shown to be safe and to improve outcomes when compared with patients treated with chemotherapy alone. Trastuzumab was effective within a range of treatment regimens; subgroup analysis showed that trastuzumab paired most effectively with the XELOX regimen. This study provides real-world clinical safety and effectiveness data supporting the use of trastuzumab in the treatment of Chinese patients with HER2-positive mGC.

miR‐516a‐3p has been reported to play a suppressive role in several types of human tumours. However, the expression level, biological function and fundamental mechanisms of miR‐516a‐3p in breast cancer remain unclear. In the present study, we found that miR‐516a‐3p expression was down‐regulated and Pygopus2 (Pygo2) expression was up‐regulated in human breast cancer tissues and cells. Through analysing the clinicopathological characteristics, we demonstrated that low miR‐516a‐3p expression or positive Pygo2 expression was a predictor of poor prognosis for patients with breast cancer. The results of a dual luciferase reporter assay and Western blot analysis indicated that Pygo2 was a target gene of miR‐516a‐3p. Moreover, overexpression of miR‐516a‐3p inhibited cell growth, migration and invasion as well as epithelial‐mesenchymal transition (EMT) of breast cancer cells, whereas reduced miR‐516a‐3p expression promoted breast cancer cell growth, migration, invasion and EMT. Furthermore, we showed that miR‐516a‐3p suppressed cell proliferation, metastasis and EMT of breast cancer cells by inhibiting Pygo2 expression. We confirmed that miR‐516a‐3p exerted an anti‐tumour effect by inhibiting the activation of the Wnt/β‐catenin pathway. Finally, xenograft tumour models were used to show that miR‐516a‐3p inhibited breast cancer cell growth and EMT via suppressing the Pygo2/Wnt signalling pathway. Taken together, these results show that miR‐516a‐3p inhibits breast cancer cell growth, metastasis and EMT by blocking the Pygo2/ Wnt/β‐catenin pathway.

Objective: To explore genes potentially co-expressed with cyclin E in gastric cancer and discover possible targets for gastric cancer treatment. Methods: The Cancer Genome Atlas (TCGA) stomach adenocarcinoma sequencing data were used to predict genes co-expressed with cyclin E. Co-expression genes predicted by cBioPortal online analysis with Pearson correlation coefficient ≥0.4 were analyzed by gene ontology (GO) enrichment annotation using the PANTHER online platform (Ver. 7). Interactions between proteins encoded by these genes were analyzed using the STRING online platform (Ver. 10.5) and Cytoscape software (Ver. 3.5.1). Genes displaying a high degree of connection were analyzed by transcription factor enrichment prediction using FunRich software (Ver. 3). The significant transcription factor and cyclin E expression levels and their impact on gastric cancer progression were analyzed by Western blotting and Kaplan-Meier survival curve analysis. Results: After filtering the co-expression gene prediction results, 78 predicted genes that included 73 protein coding genes and 5 non-coding genes with Pearson correlation coefficient ≥0.4 were selected. The expressions of the genes were considered to be correlated with cyclin E expression. Among the 78 genes co-expressed with cyclin E, 19 genes at the central of the regulatory network associated with cyclin E were discovered. Nuclear transcription factor Y subunit alpha (NF-YA) was identified as a significant transcription factor associated with cyclin E co-expressing genes. Analysis of specimen donors’ clinical records revealed that high expression of NF-YA tended to be associated with increased cyclin E expression. The expression of both was associated with progression of gastric cancer. Western blotting results showed that compared with normal tissues, NF-YA and cyclin E were highly expressed in tumor tissues (P < 0.001). Survival curve analysis clearly demonstrated relatively poor overall survival of gastric cancer patients with high cyclin E or high NF-YA expression level, compared to patients with low cyclin E or NF-YA expression (P < 0.05). Conclusions: NF-YA may promote gastric cancer progression by increasing the transcription of cyclin E and other cell cycle regulatory genes. NF-YA might be a potential therapeutically useful prognostic factor for gastric cancer. Key words: Cyclin E; Nuclear transcription factor Y subunit alpha; Oncogene; Gastric cancer

The lungs are the second most common site of metastasis for colorectal cancer (CRC) after the liver. Rectal cancer is associated with a higher incidence of lung metastases compared to colon cancer. In China, the proportion of rectal cancer cases is around 50%, much higher than that in Western countries (nearly 30%). However, there is no available consensus or guideline focusing on CRC with lung metastases. We conducted an extensive discussion and reached a consensus of management for lung metastases in CRC based on current research reports and the experts’ clinical experiences and knowledge. This consensus provided detailed approaches of diagnosis and differential diagnosis and provided general guidelines for multidisciplinary therapy (MDT) of lung metastases. We also focused on recommendations of MDT management of synchronous lung metastases and initial metachronous lung metastases. This consensus might improve clinical practice of CRC with lung metastases in China and will encourage oncologists to conduct more clinical trials to obtain high-level evidences about managing lung metastases. Electronic supplementary material The online version of this article (10.1186/s13045-019-0702-0) contains supplementary material, which is available to authorized users.

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.

BACKGROUND: The neutrophil to lymphocyte ratio (NLR) and red blood cell distribution width (RDW) play an important role in the prognosis of several cancers, but their prognostic value in patients with stage II–III gastric cancer (GC) is unclear. We aimed to evaluate the prognostic value of the RDW-NLR (R-NLR) score based on RDW and NLR in stage II–III GC patients after radical surgery. METHODS: Preoperative RDW and NLR clinicopathological data were retrospectively reviewed and analyzed from stage II–III GC patients who underwent radical gastrectomy. The optimal cut-off values for pre-RDW-variation coefficient (pre-RDW-cv) and pre-NLR were defined as 14.10% and 2.015, respectively. The R-NLR score was defined as 2 (both elevated RDW and NLR), 1 (one of these was elevated), or 0 (neither were elevated). Prognostic factors were identified by univariate and multivariate analyses. RESULTS: A total of 151 patients were included in this study, and 65 (43.05%), 54 (35.76%), and 32 (21.19%) patients had an R-NLR score of 0, 1 and 2, respectively. The preoperative R-NLR score was significantly correlated with tumor size and gender (all P0.05). Multivariate analysis demonstrated that the R-NLR score was independently correlated with OS [hazard ratio (HR), 1.527; P=0.007] and DFS (HR, 1.939; P=0.001). CONCLUSIONS: We validated the preoperative R-NLR score to be a promising predictor for stage II–III GC patients who have undergone radical gastrectomy.

Objective: In this post-hoc analysis, we evaluated anlotinib treatment-induced hypertension as a potential predictive factor of efficacy in esophageal squamous cell carcinoma (ESCC) patients. Methods: A total of 109 patients enrolled in the anlotinib group in a phase 2 trial were included. The tumor response was assessed by computed tomography at week 3, week 6, and then every 6 weeks until progressive disease was observed. The primary endpoint of the study was progression free survival (PFS). The secondary endpoints included overall survival (OS) and objective response rate (ORR). Results: In all patients, the median PFS was 3.02 months [95% confidence interval (CI): 2.63–3.65 months] and the OS was 6.11 months (95% CI: 4.40–7.79 months). The ORR was 7.34% (95% CI: 3.22%–13.95%). A total of 59 (54%) patients were diagnosed with treatment-induced hypertension (Group A), and the remaining patients (n = 50, 46%) were in Group B. Baseline prognostic factors were similar between the 2 groups. Patients in Group A had a longer PFS and OS and higher ORR. When stratifying patients using a previously known history of hypertension, treatment-induced hypertension was a predictor only for patients without previous hypertension, who had longer PFS [hazard ratio (HR): 0.40, 95% CI: 0.24–0.68] and OS (HR: 0.37, 95% CI: 0.21–0.67). Conclusions: We showed, for the first time, a correlation between treatment-induced hypertension and better prognoses in recurrent or metastatic ESCC patients treated with anlotinib, without a previously known history of hypertension. Treatment-induced hypertension may be a simple and low cost predictor for anlotinib antitumor efficacy in these patients, which may also reflect the intended target inhibition.

Background Hepatocellular carcinoma (HCC) is one of the cancers of highest incidence and mortality worldwide. Methods High-throughput screening was applied to find the most varied expressed LncRNA in primary hepatocellular carcinoma and explore the interaction network of it. Results We found that lncRNA-CR594175 was the lncRNA of most varied expression, which was lower in adjacent noncancerous tissues than in primary HCC, and was lower in primary HCC than in its metastases. Knockdown of CR594175 inhibited the proliferation and invasion of HCC cells HepG2. The mechanism study revealed that CR594175, as a RNA sponge, broke the negative regulation of CTNNB1 (Catenin, beta-1) by hsa-miR142-3p, and once CR594175 was silenced, the highly expressed hsa-miR142-3p regained its regulation on CTNNB1 and inhibited the proliferation and invasion through Wnt signaling pathway. Conclusions Our present study demonstrates for the first time that CR594175 silencing suppressed proliferation and invasion of HCC cells HepG2 in vivo and in vitro by restoring the negative regulation of CTNNB1 by hsa-miR142-3p, laying a solid theoretic base for using lncRNA-CR594175 as genetic therapy target for HCC and offering a reasonable explanation for inactivation of miRNA in difference tumors or tumor of different stages.

Background Hepatocellular carcinoma (HCC) is one of the cancers of highest incidence and mortality worldwide. The proliferation and invasion of tumor cells are the main reason for poor prognosis after HCC surgery. Long non-coding RNA (lncRNA) has been shown to play a key role in the progression of HCC. LncRNA-CR594175 is one of the highly expressed lncRNAs in HCC tumors and their metastatic tumors that we have obtained by the High-throughput screening method. Methods To elucidate the role of lncRNA-CR594175 in regulating the proliferation and invasion of human hepatoma cell line, HepG2, we operated through lncRNA-CR594175 silencing to inhibit the progression of HCC, either through in vitro or in vivo experiments. Results We found that lncRNA-CR594175 was lower in adjacent non-cancerous tissues than in primary HCC, and was lower in primary HCC than in its metastasis. Silencing of lncRNA-CR594175 inhibited the proliferation and invasion of HepG2 cells and growth of subcutaneous tumors. The results revealed that lncRNA-CR594175, as a RNA sponge, broke the negative regulation of hsa-miR-142-3p on Catenin, beta-1 (CTNNB1), and once lncRNA-CR594175 was silenced, the hsa-miR142-3p regained its negative regulation on CTNNB1 which can promote HCC progression by activating the wnt pathway. Conclusions Our present study demonstrated for the first time that lncRNA-CR594175 silencing suppressed proliferation and invasion of HCC cells in vivo and in vitro by restoring the negative regulation of hsa-miR-142-3p on CTNNB1, laying a solid theoretical base for using lncRNA-CR594175 as genetic target therapy for HCC and offering a reasonable explanation for inactivation of miRNA in different tumors or in the tumor at different stages.

Long noncoding RNAs (lncRNAs) have been implicated in various biological processes and pathological conditions, including tumorigenesis. However, the exact roles of NEAT1 and its underlying mechanisms in non-small cell lung cancer (NSCLC) remain largely unclear. In the present study, lncRNA NEAT1 was detected to be significantly upregulated in NSCLC tissues and closely associated with advanced TNM stages, lymph node metastasis, distant metastasis, and poor prognosis. Further experiments revealed that lncRNA NEAT1 silencing inhibited cell proliferation and invasion in vitro. In addition, mechanistic analysis showed that lncRNA NEAT1 upregulated the miR-181a-5p-targeted gene HMGB2 through acting as a competitive “sponge” of miR-181a-5p. In conclusion, our study suggested that lncRNA NEAT1 plays an oncogenic role in NSCLC progression and provides potential mechanisms by which lncRNA NEAT1 contributes to this disease.

Background We compared efficacy and safety of paclitaxel/capecitabine therapy followed by capecitabine for maintenance (PACX) versus cisplatin/capecitabine therapy (XP) in advanced gastric cancer. Methods Multicenter, randomized, phase III trial was conducted in China (December 2009–February 2014). Adults (n = 320) with histologically confirmed, untreated metastatic/unresectable gastric or gastroesophageal junction adenocarcinoma; with ≥ 1 measureable lesions according to Response Evaluation Criteria in Solid Tumors 1.0 criteria; Karnofsky performance score ≥ 70 and life expectancy ≥ 3 months were randomized (1:1) to PACX or XP. PACX group received paclitaxel 80 mg/m2 intravenous on days 1 and 8; capecitabine 1000 mg/m2 orally BD on days 1–14, followed by a 7-day rest interval for 4 cycles, followed by maintenance capecitabine at same dosage/schedule until disease progression, unendurable adverse events or death. XP group received cisplatin intravenous 80 mg/m2 on day 1 and capecitabine at same dosage/schedule as PACX group per cycle for 6 cycles. Results Median progression-free survival (5.0 versus 5.3 months; hazard ratio [95% CI]: 0.906; 0.706–1.164; p = 0.44) and overall survival (12.5 versus 11.8 months; hazard ratio: 0.878 [0.685–1.125]; p = 0.30) were not significantly different between PACX and XP groups. Objective response rate was significantly higher (43.1 versus 28.8%; p = 0.012) and disease control rate was similar (77.5 versus 72.5%; p = 0.75) in PACX versus XP, respectively. Quality of life was significantly improved in PACX versus XP after three treatment cycles. Many treatment-related adverse events were significantly lesser in PACX than XP. Conclusions First-line chemotherapy with PACX is effective with milder toxicities in advanced gastric cancer, but could not replace XP. Electronic supplementary material The online version of this article (10.1007/s10120-018-0809-y) contains supplementary material, which is available to authorized users.

// Bigang Liu 1, * , Shuai Gong 1, 2, * , Qiuhui Li 1, 3 , Xin Chen 1, 3 , John Moore 1 , Mahipal V. Suraneni 1 , Mark D. Badeaux 1 , Collene R. Jeter 1 , Jianjun Shen 1 , Rashid Mehmood 3 , Qingxia Fan 2 and Dean G. Tang 1, 3, 4 1 Department of Molecular Carcinogenesis, University of Texas M.D Anderson Cancer Center, Science Park, Smithville, TX 78957, USA 2 Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China 3 Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA 4 Cancer Stem Cell Institute, Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China * These authors have contributed equally to this work Correspondence to: Dean G. Tang, email: Dean.Tang@Roswellpark.org Keywords: NanogP8, Nanog, prostate, prostate cancer, stem cells Received: February 13, 2017 Accepted: March 21, 2017 Published: April 18, 2017 ABSTRACT This project was undertaken to address a critical cancer biology question: Is overexpression of the pluripotency molecule Nanog sufficient to initiate tumor development in a somatic tissue? Nanog1 is critical for the self-renewal and pluripotency of ES cells, and its retrotransposed homolog, NanogP8 is preferentially expressed in somatic cancer cells. Our work has shown that shRNA-mediated knockdown of NanogP8 in prostate, breast, and colon cancer cells inhibits tumor regeneration whereas inducible overexpression of NanogP8 promotes cancer stem cell phenotypes and properties. To address the key unanswered question whether tissue-specific overexpression of NanogP8 is sufficient to promote tumor development in vivo , we generated a NanogP8 transgenic mouse model, in which the ARR 2 PB promoter was used to drive NanogP8 cDNA. Surprisingly, the ARR 2 PB-NanogP8 transgenic mice were viable, developed normally, and did not form spontaneous tumors in >2 years. Also, both wild type and ARR 2 PB-NanogP8 transgenic mice responded similarly to castration and regeneration and castrated ARR 2 PB-NanogP8 transgenic mice also did not develop tumors. By crossing the ARR 2 PB-NanogP8 transgenic mice with ARR 2 PB-Myc (i.e., Hi-Myc) mice, we found that the double transgenic (i.e., ARR 2 PB-NanogP8; Hi-Myc) mice showed similar tumor incidence and histology to the Hi-Myc mice. Interestingly, however, we observed white dots in the ventral lobes of the double transgenic prostates, which were characterized as overgrown ductules/buds featured by crowded atypical Nanog-expressing luminal cells. Taken together, our present work demonstrates that transgenic overexpression of NanogP8 in the mouse prostate is insufficient to initiate tumorigenesis but weakly promotes tumor development in the Hi-Myc mouse model.

BACKGROUND MicroRNAs (miRNAs) are a class of small non-coding RNAs that are strongly involved in various types of carcinogenesis, including hepatocellular carcinoma (HCC). This study aimed to clarify whether miR-4417 promotes HCC growth by targeting TRIM35 and regulating PKM2 phosphorylation. MATERIAL AND METHODS Online software, including TargetScan and miRanda, was used to predict the potential target of miR-4417. Real-Time PCR (qRT-PCR) and Western blot assays were performed to detect the expression levels of mRNA and protein, respectively. Cell proliferation was measured by MTT assay and apoptosis in A549 cells was examined by flow cytometry. RESULTS Bioinformatics reveal that TRIM35 mRNA contains 1 conserved target site of miR-4417. High level of miR-4417 and low levels of TRIM35 mRNA and protein were observed in HCC cells compared with a normal liver cell line. Biological function analysis showed that miR-4417 inhibitor inhibits cell proliferation and promotes apoptosis in HCC cells. Furthermore, we verified that TRIM35 is a functional target of miR-4417 by use of luciferase reporter assay, and TRIM35 overexpressing showed an elevation of proliferation and a reduction of apoptosis in HCC cells. We subsequently investigated whether miR-4417 and TRIM35 regulate HCC cell proliferation and apoptosis through PKM2 Y105 phosphorylation, and the results supported our speculation that miR-4417 targets TRIM35 and regulates the Y105 phosphorylation of PKM2 to promote hepatocarcinogenesis. CONCLUSIONS Our findings indicate that miR-4417 may function as an oncogene in HCC and is a potential alternative therapeutic target for this deadly disease.

Yan Yan,1,* Kun Zhou,2,* Liping Wang,1 Feng Wang,1 Xinfeng Chen,3 Qingxia Fan1 1Department of Oncology, 2Department of Thoracic Surgery, 3Department of Biotherapy Center, The First AffiliatedHospital of Zhengzhou University, Zhengzhou, People’s Republic of China *These authors contributed equally tothis work Objective: The main purpose of this study was to analyze the serum cathepsin B (CTSB) and cystatin C (CysC) levels in patients with esophageal carcinoma and their correlation with the clinical indices and prognosis. Methods: The serum levels of CTSB and CysC from 56 patients with esophageal carcinoma and 30 healthy donors were determined preoperatively by using enzyme-linked immunosorbent assay. The correlation between CTSB and CysC was evaluated by Spearman correlation coefficient test. Kaplan–Meier survival curves were plotted, while the survival rates were compared using the log-rank test. Univariate and multivariate analyses of prognostic factors for survival were performed using the Cox proportional hazard regression model with a 95% confidence interval. Results: CTSB (38.35±4.3 ng/mL) and CysC (703.96±23.6 ng/mL) levels were significantly higher in the sera of the patients than in controls. A significant correlation was observed between CTSB and CysC (r=0.754, P

Lymphangioleiomyomatosis (LAM) is a progressive pulmonary disease that almost exclusively affects women. LAM cells migrate to the lungs, where they cause cystic destruction of lung parenchyma. Mutations in TSC1 or TSC2 lead to the activation of the mammalian target of rapamycin complex-1, a kinase that regulates growth factor-dependent protein translation, cell growth, and metabolism. Insulin-like growth factor binding protein 2 (IGFBP2) binds insulin, IGF1 and IGF2 in circulation, thereby modulating cell survival, migration, and invasion in neoplasms. In this study, we identified that IGFBP2 primarily localized in the nucleus of TSC2-null LAM patient-derived cells in vitro and in vivo. We also showed that nuclear accumulation of IGFBP2 is closely associated with estrogen receptor alpha (ERa) expression. Furthermore, estrogen treatment induced IGFBP2 nuclear translocation in TSC2-null LAM patient-derived cells. Importantly, depletion of IGFBP2 by siRNA reduced cell proliferation, enhanced apoptosis, and decreased migration and invasion of TSC2-null LAM patient-derived cells. More interestingly, depletion of IGFBP2 markedly decreased the phosphorylation of MAPK in LAM patient-derived TSC2-null cells. Collectively, these results suggest that IGFBP2 plays an important role in promoting tumorigenesis, through estrogen and ERalpha signaling pathway. Thus, targeting IGFBP2 may serve as a potential therapeutic strategy for women with LAM and other female gender specific neoplasms.

Competing endogenous RNA (ceRNA) is a newly proposed mechanism that describes a crosstalk among lncRNAs, mRNAs and their shared miRNAs. In this study, the role of miR-338-3p (miR-338) in the progression of esophageal cancer and its involve in the ceRNA regulatory circuit lncRNA-Snhg1/CST3 were explored. MiR-338 displayed a 30% decreased expression in esophageal squamous cell carcinoma tissues compared with the adjacent. Then, proto-oncogene CST3 was predicted and validated as a target gene of miR-338. Gain-and-loss-function experiments indicated that miR-338 suppressed expression of CST3 protein (also Cystatin C, CysC), promoted expression of apoptotic proteins caspase-8/3, attenuated esophageal carcinoma cell growth and induced its apoptosis. In addition, lncRNA-Snhg1 was significantly upregulated in esophageal carcinoma tissues and promoted esophageal carcinoma cell growth. Furthermore, our results from bioinformatics, luciferase reporter gene and RNA pull-down assays indicated that Snhg1 could be directly bound by miR-338. Snhg1 acted as a non-degradable sponge to relieve the suppression on CST3 caused by miR-338. In conclusion, lncRNA-Snhg1 promoted cell proliferation by acting as a non-degradable sponge for the tumor suppressor miR-338 in esophageal cancer cells.

Background Long noncoding RNA (lncRNA) has been implicated in numerous tumors, including pancreatic cancer (PC). However, the precise cellular roles and molecular mechanisms of lncRNA DIO3OS on PC development remains to be fully clarified. Methods We performed the meta-analysis on PC samples and non-tumor samples retrieved from the TCGA database, and measured the levels of DIO3OS in PC cell lines and a normal pancreatic duct epithelial cell line HPDE6-C7. Cell proliferation was evaluated via CCK-8 assay. Cell invasion in vitro was investigated by transwell assay. The RNA immunoprecipitation assay and luciferase reporter assay was utilized to confirm the putative miR-122-binding site in DIO3OS. The effects of DIO3OS on PC progression were tested using in vivo subcutaneous xenografts. Results Our results showed that DIO3OS was highly expressed in human PC tissues and PC cell lines. DIO3OS exhibited oncogenic properties in stimulating PC cell proliferation and invasion in vitro and promoting cancer growth in vivo. Through online predictive tools and functional experiments, we found that DIO3OS could bind directly to microRNA-122 (miR-122) and inhibited its expression, which functioned as a tumor suppressor in PC cells. We also verified that ALDOA was the direct target of miR-122, and the tumor suppressive effects caused by DIO3OS knockdown or miR-122 overexpression could be rescued by re-expression of ALDOA in PC cells. Conclusions Overall, our study suggested that lncRNA DIO3OS promotes PC cell growth and invasion by competing for miR-122 to modulate the expression of ALDOA. These findings yield a better understanding of the potential mechanisms by which gain of DIO3OS expression accelerates PC progression.

NRON mediates the degradation of tat protein to participate in HIV-1 infection. Interestingly, our study observed the down-regulation of NRON in triple-negative breast cancer (TNBC) tissues compared with paired adjacent healthy tissues. In contrast, lncRNA snaR was up-regulated in TNBC tissues and was inversely correlated with NRON. Expression levels of snaR increased, while expression levels of NRON decreased along with the increase of clinical stages. The snaR overexpression resulted in promoted cancer cell proliferation but did not significantly affect NRON expression. NRON overexpression inhibited cancer cell proliferation and down-regulated snaR. The snaR overexpression reduced the effects of NRON overexpression. We therefore conclude that NRON may down-regulate lncRNA snaR to inhibit cancer cell proliferation in TNBC.