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Pathogens are capable of hijacking immune defense mechanisms, thereby creating a tolerogenic environment for hypermutated malignant cells that arise within the site of infection. Immune checkpoint–oriented immunotherapies have shown considerable promise. Equally important, the epigenetic reprogramming of an immune-evasive phenotype that activates the immune system in a synergistic manner can improve immunotherapy outcomes. These advances have led to combinations of epigenetic- and immune-based therapeutics. We previously demonstrated that Porphyromonas gingivalis isolated from esophageal squamous cell carcinoma (ESCC) lesions represents a major pathogen associated with this deadly disease. In this study, we examined the mechanisms associated with host immunity during P. gingivalis infection and demonstrated that experimentally infected ESCC responds by increasing the expression of B7-H4 and lysine demethylase 5B, which allowed subsequent in vivo analysis of the immunotherapeutic effects of anti–B7-H4 and histone demethylase inhibitors in models of chronic infection and immunity against xenografted human tumors. Using three different preclinical mouse models receiving combined therapy, we showed that mice mounted strong resistance against P. gingivalis infection and tumor challenge. This may have occurred via generation of a T cell–mediated response in the microenvironment and formation of immune memory. In ESCC subjects, coexpression of B7-H4 and KDM5B correlated more significantly with bacterial load than with the expression of either molecule alone. These results highlight the unique ability of P. gingivalis to evade immunity and define potential targets that can be exploited therapeutically to improve the control of P. gingivalis infection and the development of associated neoplasia.

Supplementary figures and tables.

Oral and esophageal squamous cell carcinomas harbor a diverse microbiome that differs compositionally from precancerous and healthy tissues. Though causality is yet to be definitively established, emerging trends implicate periodontal pathogens such as Porphyromonas gingivalis as associated with the cancerous state. Moreover, infection with P. gingivalis correlates with a poor prognosis, and P. gingivalis is oncopathogenic in animal models. Mechanistically, properties of P. gingivalis that have been established in vitro and could promote tumor development include induction of a dysbiotic inflammatory microenvironment, inhibition of apoptosis, increased cell proliferation, enhanced angiogenesis, activation of epithelial-to-mesenchymal transition, and production of carcinogenic metabolites. The microbial community context is also relevant to oncopathogenicity, and consortia of P. gingivalis and Fusobacterium nucleatum are synergistically pathogenic in oral cancer models in vivo. In contrast, oral streptococci, such as Streptococcus gordonii, can antagonize protumorigenic epithelial cell phenotypes induced by P. gingivalis, indicating functionally specialized roles for bacteria in oncogenic communities. Consistent with the notion of the bacterial community constituting the etiologic unit, metatranscriptomic data indicate that functional, rather than compositional, properties of the tumor-associated communities have more relevance to cancer development. A consistent association of P. gingivalis with oral and orodigestive carcinoma could have diagnostic potential for early detection of these conditions that have a high incidence and low survival rates.

Oesophageal cancer is the most common gastrointestinal malignancy in China and one of the major causes of death due to cancer worldwide. The occurrence of oesophageal cancer is a multifactor, multistage, and multistep process influenced by heredity, the environment, and microorganisms. Specifically, bacterial infection may be involved in the process of tissue carcinogenesis by directly or indirectly influencing tumour occurrence and development. Porphyromonas gingivalis is an important pathogen causing periodontitis, and periodontitis can promote the occurrence of various tumours. An increasing number of studies to date have shown that P. gingivalis plays an important role in the occurrence and development of oesophageal cancer. Overall, exploring how P. gingivalis promotes oesophageal cancer occurrence and development and how it affects the prognosis of these patients is of great importance for the diagnosis, prevention, and treatment of this type of cancer. Herein, the latest progress is reviewed.

KN026 is a novel human epidermal growth factor receptor 2 (HER2)-targeted bispecific antibody that binds two distinct domains of HER2. We report the safety and efficacy results of the phase 2 trial in patients with advanced HER2-expressing gastric or gastroesophageal junction cancer who failed from at least one prior line of standard treatment.In this open-label, multicentre, phase 2 trial, eligible patients were enrolled in the high-level HER2 cohort or low-level HER2 cohort and assigned to receive KN026 10 mg/kg (once a week), 20 mg/kg (once every two weeks) or 30 mg/kg (once every three weeks) intravenously. The primary end-points were the objective response rate (ORR) and duration of response assessed according to Response Evaluation Criteria in Solid Tumours (version 1.1).Between 17th June 2019 and 23rd August 2021, 45 patients were enrolled and received at least one dose of KN026, including 27 patients in the high-level HER2 cohort, 14 patients in the low-level HER2 cohort and four patients who had no HER2 expression. The ORR in the high-level HER2 cohort was 56% (95% confidence interval [CI] 35%-76%), with a durable response duration of 9.7 months (95% CI 4.2-not evaluable); while for the patients with low-level HER2, the ORR was 14% (95% CI 2%-43%). The most frequent ≥ grade 3 treatment-emergent adverse events were gastrointestinal disorders (five patients, 11%). No drug-related deaths were reported.KN026 showed a favourable safety profile and promising anti-tumour activity. Our results support further studies evaluating KN026 and the combination treatment with other active drugs in patients with advanced gastric or gastroesophageal junction cancer having high-level HER2 expression.

Circular RNAs (circRNAs) are a class of noncoding RNAs with covalently single-stranded closed loop structures derived from back-splicing event of linear precursor mRNAs (pre-mRNAs). N6-methyladenosine (m

BACKGROUND: The effect of Porphyromonas gingivalis (Pg) infection on oesophageal squamous cell carcinoma (ESCC) prognosis, chemotherapeutic efficacy, and oesophageal cancer cell apoptosis resistance and proliferation remain poorly understood. METHODS: Clinicopathological data from 312 ESCC oesophagectomy patients, along with the computed tomography imaging results and longitudinal cancerous tissue samples from a patient subset (n = 85) who received neoadjuvant chemotherapy (NACT), were analysed. Comparison of overall survival and response rate to NACT between Pg-infected and Pg-uninfected patients was made by multivariate Cox analysis and Response Evaluation Criteria in Solid Tumours v.1.1 criteria. The influence of Pg on cell proliferation and drug-induced apoptosis was examined in ESCC patients and validated in vitro and in vivo. RESULTS: The 5-year overall survival was lower in Pg-positive patients, and infection was associated with multiple clinicopathological factors and pathologic tumour, node, metastasis stage. Of the 85 patients who received NACT, Pg infection was associated with a lower response rate and 5-year overall survival. Infection with Pg resulted in apoptosis resistance in ESCC and promoted ESCC cell viability, which was confirmed in longitudinal cancerous tissue samples. Pg-induced apoptosis resistance was dependent on fimbriae and STAT3. CONCLUSIONS: Pg infection is associated with a worse ESCC prognosis, reduced chemotherapy efficacy, and can potentiate the aggressive behaviour of ESCC cells.

Transcription-induced chimeric RNAs are an emerging area of research into molecular signatures for disease biomarker and therapeutic target development. Despite their importance, little is known for chimeric RNAs-relevant roles and the underlying mechanisms for cancer pathogenesis and progression. Here we describe a unique ASTN2-PAPPA(antisense) chimeric RNA (A-P-as chiRNA) that could be the first reported chimeric RNA derived from the splicing of exons and intron antisense of two neighboring genes, respectively. Aberrant A-P-as chiRNA level in ESCC tissues was associated with tumor progression and patients' outcome. In vitro and in vivo studies demonstrated that A-P-as chiRNA aggravated ESCC metastasis and enhanced stemness through modulating OCT4. Mechanistic studies demonstrated that ERK5-mediated non-canonical PAF1 activity was required for A-P-as chiRNA-induced cancer malignancy. The study defined an undocumented function of chimeric RNAs in aggravating cancer stemness and metastasis.

Smoking is one of the most impactful lifestyle-related risk factors in many cancer types including esophageal squamous cell carcinoma (ESCC). As the major component of tobacco and e-cigarettes, nicotine is not only responsible for addiction to smoking but also a carcinogen. Here we report that nicotine enhances ESCC cancer malignancy and tumor-initiating capacity by interacting with cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) and subsequently activating the JAK2/STAT3 signaling pathway. We found that aberrant CHRNA7 expression can serve as an independent prognostic factor for ESCC patients. In multiple ESCC mouse models, dextromethorphan and metformin synergistically repressed nicotine-enhanced cancer-initiating cells (CIC) properties and inhibited ESCC progression. Mechanistically, dextromethorphan non-competitively inhibited nicotine binding to CHRNA7 while metformin downregulated CHRNA7 expression by antagonizing nicotine-induced promoter DNA hypomethylation of CHRNA7. Since dextromethorphan and metformin are two safe FDA-approved drugs with minimal undesirable side-effects, the combination of these drugs has a high potential as either a preventive and/or a therapeutic strategy against nicotine-promoted ESCC and perhaps other nicotine-sensitive cancer types as well.

Introduction Biofilms protect bacteria from antibiotics and this can produce drug-resistant strains, especially the main pathogen of periodontitis, Porphyromonas gingivalis. Carbon quantum dots with various biomedical properties are considered to have great application potential in antibacterial and anti-biofilm treatment. Methods Tinidazole carbon quantum dots (TCDs) and metronidazole carbon quantum dots (MCDs) were prepared by a hydrothermal method with the clinical antibacterial drugs tinidazole and metronidazole, respectively. Then, TCDs and MCDs were characterized by transmission electron microscopy, UV-visible spectroscopy, infrared spectroscopy and energy-dispersive spectrometry. The antibacterial effects were also investigated under different conditions. Results The TCDs and MCDs had uniform sizes. The results of UV-visible and energy-dispersive spectrometry confirmed their important carbon polymerization structures and the activity of the nitro group, which had an evident inhibitory effect on P. gingivalis, but almost no effect on other bacteria, including Escherichia coli, Staphylococcus aureus and Prevotella nigrescens. Importantly, the TCDs could penetrate the biofilms to further effectively inhibit the growth of P. gingivalis under the biofilms. Furthermore, it was found that the antibacterial effect of TCDs lies in its ability to impair toxicity by inhibiting the major virulence factors and related genes involved in the biofilm formation of P. gingivalis, thus affecting the self-assembly of biofilm-related proteins. Conclusion The findings demonstrate a promising new method for improving the efficiency of periodontitis treatment by penetrating the P. gingivalis biofilm with preparations of nano-level antibacterial drugs.

Recent studies have revealed that Porphyromonas gingivalis is closely related to the occurrence and progression of esophageal squamous cell carcinoma (ESCC). However, the underlying mechanism of P. gingivalis in ESCC has not been well elucidated. To explore the mechanism of P. gingivalis infection in ESCC, cellular proliferation, invasion, and migration models of KYSE-30 and KYSE-150 cells infected by P. gingivalis at a multiplicity of infection (MOI) of 10 were established. The results showed that P. gingivalis infection could drastically increase the proliferation, invasion, and migration ability of ESCC. Furthermore, the results of high-throughput sequencing showed that miR-194 was considerably upregulated in infected cells compared with control cells, which was further verified by qRT-PCR. The inhibition or overexpression of miR-194 had a significant effect on KYSE-30 and KYSE-150 cell migration and invasion. Additionally, the levels of GRHL3 and PTEN were decreased in P. gingivalis-infected esophageal cancer cells compared with uninfected esophageal cancer cells. Furthermore, dual-luciferase experiments confirmed that GRHL3 is a direct target of miR-194. In addition, the GRHL3-related pathway was investigated, and the levels of GRHL3 and PTEN were downregulated while the level of p-Akt was upregulated after P. gingivalis infection. Taken together, these findings indicated that P. gingivalis might promote ESCC proliferation and migration via the miR-194/GRHL3/PTEN/Akt signaling axis.

Background. Immune infiltrates in the tumor microenvironment have established roles in tumor growth, invasion, and metastasis. However, the diagnostic and prognostic potential of immune cell signature in esophageal squamous cell carcinoma (ESCC) remains unclear. Results. The proportions of 22 subsets of immune cells from 331 samples including 205 ESCC and 126 normal esophageal mucosa retrieved from TCGA, GEO, and GTEx databases were deciphered by CIBERSORT. Nine overlapping subsets of immune cells were identified as important features for discrimination of ESCC from normal tissue in the training cohort by LASSO and Boruta algorithms. A diagnostic immune score (DIS) developed by XGBoost showed high specificities and sensitivities in the training cohort, the internal validation cohort, and the external validation cohort (AUC: 0.999, 0.813, and 0.966, respectively). Furthermore, the prognostic immune score (PIS) was developed based on naive B cells and plasma cells using Cox proportional hazards model. The PIS, an independent prognostic predictor, classified patients with ESCC into low- and high-risk subgroups in the internal validation cohort ( P = 0.038 ) and the external validation cohort ( P = 0.022 ). In addition, a nomogram model comprising age, N stage, TNM stage, and PIS was constructed and performed excellent ( HR = 4.17 , 95% CI: 2.22-7.69, P < 0.0001 ) in all ESCC patients, with a time-dependent 5-year AUC of 0.745 (95% CI: 0.644 to 0.845), compared with PIS or TNM stage as a prognostic model alone. Conclusion. Our DIS, PIS, and nomogram models based on infiltrated immune features may aid diagnosis and survival prediction for patients with ESCC.

BACKGROUND: Bevacizumab is a monoclonal antibody (mAb) against vascular endothelial growth factor (VEGF) and used for treatments of various cancers. Due to the high costs of bevacizumab treatments, a biosimilar provides an affordable alternative therapy for cancer patients. METHODS: In this randomized, double-blind, multicenter, phase 3 study, locally advanced, metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC) patients with wild-type epidermal growth factor receptor were enrolled and randomized (1:1) into IBI305 or bevacizumab groups. Patients received 6 cycles of paclitaxel/carboplatin plus IBI305 or bevacizumab 15 mg/kg intravenously followed by IBI305 or bevacizumab 7.5 mg/kg maintenance until disease progression, unacceptable toxicity or death. The primary endpoint was confirmed objective response rate (ORR) by an independent radiological review committee (IRRC) and secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS) and safety. RESULTS: A total of 450 NSCLC patients were enrolled (224 in IBI305 group and 226 in bevacizumab group). ORRs were 44.3% for IBI305 and 46.4% for bevacizumab, and the ORR ratio was 0.95 (90% CI: 0.803 to 1.135), within the predefined equivalence margin of 0.75 to 1.33. No significant difference in PFS (7.64 vs. 7.77 m, P=0.9987) was observed between the 2 groups. Serious adverse events (AEs) occurred in 33.5% (75/224) of patients in the IBI305 group and 37.6% (85/226) in the bevacizumab group. AEs ≥ grade 3 were similar in the IBI305 and bevacizumab groups [84.4% (189/224) vs. 89.8% (203/226), P=0.085]. CONCLUSIONS: IBI305 is similar to bevacizumab in terms of efficacy and safety. TRIAL REGISTRATION: Clinicaltrials.org Identifier: NCT02954172. Registered on 3 November 2016. Https://clinicaltrials.gov/.

Purpose: The present study focused on exploring the associations of Porphyromonas gingivalis (P. gingivalis) infection and low Beclin1 expression with clinicopathological parameters and survival of esophageal squamous cell carcinoma (ESCC) patients, so as to illustrate its clinical significance and prognostic value.Methods: Immunohistochemistry (IHC) was used to detect P. gingivalis infection status and Beclin1 expression in 370 ESCC patients. The chi-square test was adopted to illustrate the relationship between categorical variables, and Cohen’s kappa coefficient was used for correlation analysis. Kaplan-Meier survival curves with the log-rank test were used to analyse the correlation of P. gingivalis infection and low Beclin1 expression with survival time. The effects of P. gingivalis infection and Beclin1 downregulation on the proliferation, migration and antiapoptotic abilities of ESCC cells in vitro were detected by Cell Counting Kit-8, wound healing and flow cytometry assays. For P. gingivalis infection of ESCC cells, cell culture medium was replaced with antibiotic-free medium when the density of ESCC cells was 70–80%, cells were inoculated with P. gingivalis at a multiplicity of infection (MOI) of 10.Result:P. gingivalis infection was negatively correlated with Beclin1 expression in ESCC tissues, and P. gingivalis infection and low Beclin1 expression were associated with differentiation status, tumor invasion depth, lymph node metastasis, clinical stage and prognosis in ESCC patients. In vitro experiments confirmed that P. gingivalis infection and Beclin1 downregulation potentiate the proliferation, migration and antiapoptotic abilities of ESCC cells (KYSE150 and KYSE30). Our results provide evidence that P. gingivalis infection and low Beclin1 expression were associated with the development and progression of ESCC.Conclusion: Long-term smoking and alcohol consumption causes poor oral and esophageal microenvironments and ESCC patients with these features were more susceptible to P. gingivalis infection and persistent colonization, and exhibited lower Beclin1 expression, worse prognosis and more advanced clinicopathological features. Our findings indicate that effectively eliminating P. gingivalis colonization and restoring Beclin1 expression in ESCC patients may contribute to preventation and targeted treatment, and yield new insights into the aetiological research on ESCC.

Chemotherapy resistance remains a major obstacle in the treatment of esophageal cancer. Previous researches have shown that an increase in exosomal PD-L1 expression was positively associated with a more advanced clinical stage, a poorer prognosis as well as drug resistance in patients with esophageal squamous cell carcinoma (ESCC). To explore the role of exosomal PD-L1 in ESCC, we performed bioinformatics analysis as well as several in vitro/in vivo functional experiments in a parental sensitive cell line EC-9706 and its derivative, a paclitaxel-resistant subline EC-9706R, and found that the exosomal PD-L1 from EC-9706R was higher than that from EC-9706. Moreover, exosomes from EC-9706R significantly increased invasion, migration and chemoresistance of EC-9706. Anti-PD-L1 treatment in combination with chemotherapy also led to reduced tumor burden in vivo. Inhibition of the release of exosomes by GW4869 or inhibition of STAT3 phosphorylation by stattic could effectively reverse the resistance to paclitaxel mediated by exosomal PD-L1. Furthermore, we found that PD-L1, miR-21, and multidrug resistance (MDR1) gene are involved in the process of exosomal transfer. Moreover, PD-L1 could enhance miR-21 expression by increasing the enrichment of STAT3 on miR-21 promoter. Our results suggested that exosomal PD-L1 may contribute to drug resistance to paclitaxel by regulating the STAT3/miR-21/PTEN/Akt axis and promote tumorigenic phenotype. This study provides a novel potential therapeutic approach to reverse chemoresistance and tumor progression through exosomal PD-L1 in ESCC patients.

Chimeric RNAs (chiRNAs) play many previously unrecognized roles in different diseases including cancer. They can not only be used as biomarkers for diagnosis and prognosis of various diseases but also serve as potential therapeutic targets. In order to better understand the roles of chiRNAs in pathogenesis, we inserted human sequences into mouse genome and established a knockin mouse model of the tamoxifen-inducible expression of ASTN2-PAPPA antisense chimeric RNA (A-PaschiRNA). Mice carrying the A-PaschiRNA knockin gene do not display any apparent abnormalities in growth, fertility, histological, hematopoietic, and biochemical indices. Using this model, we dissected the role of A-PaschiRNA in chemical carcinogen 4-nitroquinoline 1-oxide (4NQO)-induced carcinogenesis of esophageal squamous cell carcinoma (ESCC). To our knowledge, we are the first to generate a chiRNA knockin mouse model using the Cre-loxP system. The model could be used to explore the roles of chiRNA in pathogenesis and potential targeted therapies.

BackgroundAs an endogenous extracellular vesicle, exosome is increasingly presenting its great potential in the field of drug delivery. However, it is the bottleneck to obtain a large number of uniform, stable and multi-component controllable exosomes with low cost and time. ResultsIn this study, we develop a novel targeted drug delivery system based on exosome-like nanovesicle by use of natural marine single-celled Dunaliella salina (DENV), the c(RGDyK) peptide has been conjugated to DENV surface to achieve the targeted delivery to esophageal cancer cells. Furthermore, miR-375 has been loaded into the cRGD-DENV through electroporation, and aPD-L1 has been conjugated onto its surface via Gly-PLGLAG-Cys peptide, a matrix metalloproteinase-2 (MMP-2)-cleavable peptide, which facilitates the release of aPD-L1 in tumor environment to achieve the high-efficiency combination of gene therapy and immunotherapy. Firstly, the engineered DENV delivery system was prepared and characterized. It exhibited a proper particle diameter (approximately 150 nm) with in vitro sustained release features in the presence of MMP-2/9. More importantly, the cRGD-DENV was effective, promoted selective delivery of cargo to the target site, and reduced nonspecific uptake, consequently, significantly inhibit tumor growth in vitro and in vivo. ConclusionThe specific nanocarrier delivery system provide a promising strategy for the rapid and large-scale production of functionalized exosome-like nanovesicle by adapting multifunctional peptides specifically targeted tumor.

Various genetic polymorphisms have been linked to lung cancer susceptibility and survival outcomes. Vitamin D (VD) regulates cell proliferation and differentiation, inhibits tumor growth and induces apoptosis. Observations from several previous studies including our own suggest that genetic polymorphisms in the VD pathway may be associated with lung cancer risk. The aim of this study is to assess if genetic polymorphisms in the VD pathway are associated with the prognosis of non-small cell lung cancer (NSCLC). Nine single nucleotide polymorphisms (SNPs) in five genes in the VD pathway were genotyped with the TaqMan assays in 542 patients with primary NSCLC, and the relationships between these SNPs and overall survival were evaluated. We found that SNP rs10741657 in the CYP2R1 gene was associated with the prognosis of NSCLC, especially in elderly patients and not being treated with chemotherapy. Some of the VD pathway-related genetic polymorphisms may influence the prognosis of NSCLC. More research is needed to further confirm the finding and test if VD supplements can be used for NSCLC treatment.

Pathogens are capable of hijacking immune defense mechanisms, thereby creating a tolerogenic environment for hypermutated malignant cells that arise within the site of infection. Immune checkpoint–oriented immunotherapies have shown considerable promise. Equally important, the epigenetic reprogramming of an immune-evasive phenotype that activates the immune system in a synergistic manner can improve immunotherapy outcomes. These advances have led to combinations of epigenetic- and immune-based therapeutics. We previously demonstrated that Porphyromonas gingivalis isolated from esophageal squamous cell carcinoma (ESCC) lesions represents a major pathogen associated with this deadly disease. In this study, we examined the mechanisms associated with host immunity during P. gingivalis infection and demonstrated that experimentally infected ESCC responds by increasing the expression of B7-H4 and lysine demethylase 5B, which allowed subsequent in vivo analysis of the immunotherapeutic effects of anti–B7-H4 and histone demethylase inhibitors in models of chronic infection and immunity against xenografted human tumors. Using three different preclinical mouse models receiving combined therapy, we showed that mice mounted strong resistance against P. gingivalis infection and tumor challenge. This may have occurred via generation of a T cell–mediated response in the microenvironment and formation of immune memory. In ESCC subjects, coexpression of B7-H4 and KDM5B correlated more significantly with bacterial load than with the expression of either molecule alone. These results highlight the unique ability of P. gingivalis to evade immunity and define potential targets that can be exploited therapeutically to improve the control of P. gingivalis infection and the development of associated neoplasia.

Background Surgery is the gold standard treatment for local advanced disease, while definitive concurrent chemoradiotherapy (DCRT) is recommended for those who are medically unable to tolerate major surgery or medically fit patients who decline surgery. The primary aim of this trial is to compare the outcomes in Chinese patients with oesophageal squamous cell cancer with locally advanced resectable disease who have received either surgery or DCRT. Methods/design One hundred ninety-six patients with T1bN + M0 or T2-4aN0-2 M0 oesophageal squamous cell cancer will be randomised to the DCRT group or the surgery group. In the DCRT group, patients will be given intensity-modulated radiation therapy (IMRT) with 50 Gy/25 fractions and basic chemotherapy with 5-fluorouracil regimens. In the surgery group, patients will receive neoadjuvant chemoradiotherapy (NCRT) and standard oesophagectomy. Five years of follow-up will be scheduled for patients. The primary endpoints are 2-year/5-year overall survival; the secondary endpoints are 2-year/5-year progression-free survival, treatment-related adverse events and the patients’ quality of life. The main evaluation methods include oesophagoscopy, endoscopic ultrasonography and biopsy, oesophageal barium meal, computed tomography, positron emission tomography-computed tomography, blood tests and questionnaires. Discussion The preponderant oesophageal cancer pathology type is dramatically different in western Caucasian and Asian oesophageal cancer patients: Caucasian patients present with 80% adenocarcinomas, and Asians patients present with 95% squamous cell carcinomas. This phenomenon needs more in-depth studies to elucidate the differences in these populations. Based on the results of this study, we will show whether DCRT will benefit patients more than oesophagectomy. This study will contribute more evidence to the management of oesophageal squamous cell cancer. Trial registration ClinicalTrials.gov, NCT02972372. Registered on 26 November 2016. Electronic supplementary material The online version of this article (10.1186/s13063-019-3316-5) contains supplementary material, which is available to authorized users.

The highest incidence of esophageal squamous cell carcinoma (ESCC) occurs in China. Cancer stem cells play key roles for tumor progression. Gene amplified in squamous cell carcinoma 1 (GASC1) is essential to maintain self-renewal and differentiation potential of embryonic stem cells. This study aimed to reveal the effect and mechanism of GASC1 on ESCC stemness. The biological function of GASC1 in ESCC was evaluated both in vitro and in vivo. ChIP assay was performed to determine the molecular mechanism of GASC1 in epigenetic regulation of NOTCH1. We found that GASC1 expression was increased in poor differentiated ESCC cells and tissues. ESCC patients with a high level of GASC1 presented a significantly worse survival rate. GASC1 expression in purified ALDH+ ESCC cells was significantly higher than that in ALDH- cells. The stemness of ESCC was dramatically decreased after GASC1 blockade. Furthermore, blockade of GASC1 decreased NOTCH1 expression via increase of NOTCH1 promoter H3K9me2 and H3K9me3. Moreover, the impaired stemness after blockade of GASC1 could be reversed after transfection of NOTCH1 overexpression lentiviral vector. GASC1 promoted stemness in ESCC cells via NOTCH1 promoter demethylation. Therefore, GASC1/NOTCH1 signaling might be a potential therapeutic target for the treatment of ESCC patients.

Object Ovarian cancer is the primary cause of cancer-associated deaths among gynaecological malignancies. Increasing evidence suggests that microRNAs may be potential biomarkers for the diagnosis and prognosis of cancer. In this study, we conducted a systematic review and meta-analysis to summarize the global research and to evaluate the overall diagnostic accuracy of miRNAs in detecting ovarian cancer. Methods A systematic literature search was conducted for relevant studies through July 20, 2017, in English databases (CENTRAL, MEDLINE, and EMBASE), the Grey reference database and Chinese databases. Statistical analysis was conducted using OpenMetaAnalyst, STATA 14.0 and RevMan 5.3. Pooled sensitivity, specificity, and other parameters were used to assess the overall miRNA assay performance using a bivariate random-effects model (BRM). Meta-regression and subgroup analyses were performed to dissect the heterogeneity. Sensitivity analysis was performed to assess the robustness of our analysis, and the publication bias of the selected studies was assessed using Deeks’ funnel plot asymmetry test. Results Thirteen articles described 33 studies, including 1081 patients with ovarian cancer and 518 controls. The pooled results were as follows: sensitivity, 0.89 (95% CI: 0.84–0.93); specificity, 0.64 (95% CI: 0.56–0.72); positive likelihood ratio, 2.18 (95% CI: 1.89–2.51); negative likelihood ratio, 0.15 (95% CI: 0.11–0.22); and diagnostic odds ratio (DOR), 13.21 (95% CI: 9.00–19.38). We conducted subgroup analyses based on ethnicity, research design, and miRNA profiling and found that multiple miRNA panels were more accurate in detecting ovarian cancer, with a combined DOR of 30.06 (95% CI: 8.58–105.37). Conclusion Per the meta-analysis, circulating miRNAs may be novel and non-invasive biomarkers for detecting ovarian cancer, particularly multiple miRNA panels, which have potential diagnostic value as screening tools in clinical practice. Electronic supplementary material The online version of this article (10.1186/s13048-019-0482-8) contains supplementary material, which is available to authorized users.

Zerumbone has been reported to maintain the anti-cancer effects in many malignant cells. However, the effect and mechanism of Zerumbone on esophageal squamous cell carcinomas (ESCC) is rarely investigated. Here we report the inhibitory effect of Zerumbone (hereinafter referred to as ZER) on ESCC migration and the underlying molecular mechanism. ZER could inhibit the migration of human esophageal squamous cancer KYSE-30 cells and KYSE-150 cells. ZER induced Rac1 protein down-regulation in a dose- and time-dependent manner. The reduction of Rac1 protein was crucial for ZER-induced inhibition of cell migration, as Rac1 knockdown could enhance ZER-induced inhibition of cell migration. We further demonstrated that the decrease of Rac1 after ZER treatment is via proteasome-dependent degradation pathway, and ZER treatment drastically enhanced ubiquitination of Rac1, which finally caused Rac1 degradation. Collectively, our results indicated that ZER inhibits cell migration by suppressing Rac1 expression. This suppresion is achieved through promoting Rac1 ubiquitination and degradation. Thus, the study raises the possibility of ZER as a potential drug for ESCC due to its ability to inhibit cell migration.

4040 Background: Outcomes of second or later-line treatment for pts with advanced GC/GEJC remain inferior. KN026 is a novel HER2-targeted bispecific antibody composed of VH regions of trastuzumab and pertuzumab, targeting the HER2 juxtamembrane domain (IV) and the dimerization domain (II) simultaneously. KN026 has shown promising antitumor efficacy in preclinical and phase I studies. Here we present the results of KN026 monotherapy in previously treated, advanced HER2-expressing GC/GEJC. Methods: In this multi-center, single-arm, open-label, 2-cohort phase II study, adult pts with previously treated, advanced GC/GEJC were assigned into a HER2 high-level cohort (Cohort 1: IHC3+ or IHC 2+ ISH+) or a HER2 low-level cohort (Cohort 2: IHC 1+/2+ ISH- or IHC 0/1+ISH+). KN026 was given intravenously in 10 mg/kg QW, 20 mg/kg Q2W, or 30 mg/kg Q3W. Primary endpoints were objective response rate (ORR) and duration of response (DoR) assessed by investigators per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety outcomes. This trial is registered at ClinicalTrials.gov (NCT03925974). Results: At data cut-off (Oct. 29, 2021), 45 pts were enrolled and treated with KN026; 39 were eligible for response evaluation (25 pts in Cohort 1 and 14 pts in Cohort 2). In Cohort 1, ORR was 56% (95%CI 35%-76%) with 14 PR; the median DoR was 9.7 months (mo) (95%CI 4.2-not evaluable (NE)). At a median follow-up of 14.7 mo (95%CI 9.4-16.5), the median PFS was 8.3 mo (95%CI 4.2-11.4), and median OS was 16.3 mo (95% CI 11.0- NE). In Cohort 2, ORR was 14% (95%CI 2%-43%), with median DoR being 6.2 mo (95%CI 3.2-NE). At a median follow-up of 27.5 mo (95%CI 4.1-NE), the median PFS was 1.4 mo (95%CI 1.4-4.1), and median OS was 9.6 mo (95% CI 3.5-14.9). The table shows efficacy in Cohort 1 pts who have progressed on the prior trastuzumab treatment. KN026-related adverse events (TRAEs) were observed in 37 (82%) pts; the most common TRAEs (any grade) were increased aspartate aminotransferase (12, 27%), increased alanine aminotransferase (9, 20%), rash (7,16%), anemia (7,16%), and infusion-related reaction (7,16%). Four pts reported 5 grade 3 TRAEs, including infusion-related reaction, renal hydrocele, ureteral stenosis, increased blood pressure, and abnormal hepatic function (1 each). No grade 4 or 5 TRAEs occurred. Conclusions: KN026 monotherapy yielded promising efficacy with mild to moderate toxicities in pts with previously treated, advanced GC/GEJC. Further investigation is warranted. Clinical trial information: NCT03925974. [Table: see text]

3577 Background: Dual blockade of immune checkpoint and angiogenesis is an effective strategy for multiple cancers. We initiated an open-label, multicenter phase II basket study to evaluate the antitumor activity and safety of camrelizumab (an anti-PD-1 antibody) plus famitinib (a receptor tyrosine kinase inhibitor) in patients (pts) with advanced solid tumors. Herein, we report the results from the metastatic colorectal cancer (mCRC) cohort. Methods: Pts with histologically confirmed mCRC, who had received previous irinotecan, oxaliplatin, and fluoropyrimidine combination chemotherapy, and progressed after ≥ 2 lines of systemic treatment were enrolled to receive camrelizumab (200 mg i.v. every 3 weeks) and famitinib (20 mg orally once daily). Primary endpoint was objective response rate (ORR) per RECIST version 1.1. Results: Between Jul 10, 2020, and Jul 12, 2021, of all the 44 mCRC pts enrolled, 14 (31.8%) pts had colon cancer (CC) and 30 (68.2%) pts had rectal cancer (RC). As of Nov 30, 2021, the median time from enrollment to data cutoff was 10.6 months (range, 4.7-16.7). The ORR was 13.6% (95% CI, 5.2-27.4) and the DCR was 45.5% (95% CI, 30.4-61.2) in all mCRC pts. Of them, no pts with CC achieved response; six pts with RC achieved PR, with the ORR of 20.0% (95% CI, 7.7-38.6) and the DCR of 46.7% (95% CI, 28.3-65.7). Pts with RC showed a median duration of response (DoR) of 7.1 months (95% CI, 2.3-not reached [NR]). The median overall survival (OS) was 15.2 months (95% CI, 7.2-NR) in pts with RC. Of all 44 mCRC pts, 28 (63.6%) had grade 3 or higher treatment related adverse events (TRAEs), mainly hypertension (25.0%), proteinuria (18.2%), decreased platelet count (11.4%), decreased neutrophil count (11.4%) and palmar-plantar erythrodysaesthesia syndrome (11.4%). Three (6.8%) pts discontinued any study treatment due to TRAEs. No grade 5 TRAE was reported. Conclusions: Camrelizumab plus famitinib appeared to show encouraging antitumor activity in pts with mCRC, especially in those with RC, and the safety profile of this combination regimen seemed to be manageable and consistent with single agent alone. Clinical trial information: NCT04346381. [Table: see text]

Mounting evidence suggests a causal relationship between specific bacterial infections and the development of certain malignancies. In this study, we examined the presence of Porphyromonas gingivalis (P. gingivalis) in oral-digestive tract tumors by immunohistochemistry (IHC) and PCR and analyzed the correlation between P. gingivalis detection and clinicopathological characteristics and prognosis of oral and esophageal carcinoma. The IHC results showed that the positive rates of P. gingivalis were 60.00, 46.00, 20.00, 6.67, and 2.86% in oral, esophagus, cardiac, stomach, and colorectal cancer tissues, respectively. Likewise, PCR results showed rates of 56.00, 42.00, 16.67, 3.33, and 2.86%, respectively. The two methods were consistent, and the kappa value was 0.806, P < 0.001. In addition, P. gingivalis expression was significantly correlated with lymph node metastasis and the clinical stages of oral and esophageal cancer (P < 0.05). The overall survival rate of the P. gingivalis undetected group (86, 50%) was significantly higher than that of the P. gingivalis detected group (57, 14%) for oral and esophageal cancer, respectively. In conclusion, the detection rate of P. gingivalis showed a decreasing trend in oral-digestive tract tumors. Detection with P. gingivalis was associated with poor prognosis for oral and esophageal cancer.

Highlights • P. gingivalis can be colonized in lung cancer tissues. • The microenvironment of cancerous tissues is more conducive to the survival of P. gingivalis than adjacent lung tissues. • Long term smoking and alcohol will more likely lead to P. gingivalis infections. • Effective clearance of P. gingivalis may prolong the survival time of lung cancer patients., A variety of pathogenic microorganisms can promote the occurrence and development of malignant tumors by colonizing in the body. It has been shown that Porphyromonas gingivalis (P. gingivalis) can be colonized for a long time in upper gastrointestinal tumors and is closely related to the occurrence and development of esophageal cancer in previous studies of our team. Because the esophagus and trachea are closely adjacent and P. gingivalis can instantly enter and colonize in cells, we speculate that P. gingivalis may be colonized in lung cancer cells through oral or blood, promoting the malignant progression of lung cancer. In this study, we investigated P. gingivalis infection in lung carcinoma tissues and adjacent lung tissues, and found that the colonization rate of P. gingivalis in carcinoma tissues was significantly higher than that in adjacent lung tissues. Therefore, we propose that the microenvironment of cancer cells is more conducive to the survival of P. gingivalis. Then, we analyzed the correlation between P. gingivalis infection and clinicopathological features and survival prognosis of patients with lung cancer. It was found that P. gingivalis infection was closely related to smoking, drinking, lymph node metastasis and clinical stage. Moreover, the survival rate and median survival time of patients with P. gingivalis infection were significantly shortened. Therefore, we put forward the view that long term smoking and drinking will cause a bad oral environment, increasing the risk of P. gingivalis infection, then P. gingivalis infection will promote the malignant progression of lung cancer.