Early detection of hepatocellular carcinoma via no end-repair enzymatic methylation sequencing of cell-free DNA and pre-trained neural network.

BACKGROUND: Early detection of hepatocellular carcinoma (HCC) is important in order to improve patient prognosis and survival rate. Methylation sequencing combined with neural networks to identify cell-free DNA (cfDNA) carrying aberrant methylation offers an appealing and non-invasive approach for HCC detection. However, some limitations exist in traditional methylation detection technologies and models, which may impede their performance in the read-level detection of HCC. METHODS: We developed a low DNA damage and high-fidelity methylation detection method called No End-repair Enzymatic Methyl-seq (NEEM-seq). We further developed a read-level neural detection model called DeepTrace that can better identify HCC-derived sequencing reads through a pre-trained and fine-tuned neural network. After pre-training on 11 million reads from NEEM-seq, DeepTrace was fine-tuned using 1.2 million HCC-derived reads from tumor tissue DNA after noise reduction, and 2.7 million non-tumor reads from non-tumor cfDNA. We validated the model using data from 130 individuals with cfDNA whole-genome NEEM-seq at around 1.6X depth. RESULTS: NEEM-seq overcomes the drawbacks of traditional enzymatic methylation sequencing methods by avoiding the introduction of unmethylation errors in cfDNA. DeepTrace outperformed other models in identifying HCC-derived reads and detecting HCC individuals. Based on the whole-genome NEEM-seq data of cfDNA, our model showed high accuracy of 96.2%, sensitivity of 93.6%, and specificity of 98.5% in the validation cohort consisting of 62 HCC patients, 48 liver disease patients, and 20 healthy individuals. In the early stage of HCC (BCLC 0/A and TNM I), the sensitivity of DeepTrace was 89.6 and 89.5% respectively, outperforming Alpha Fetoprotein (AFP) which showed much lower sensitivity in both BCLC 0/A (50.5%) and TNM I (44.7%). CONCLUSIONS: By combining high-fidelity methylation data from NEEM-seq with the DeepTrace model, our method has great potential for HCC early detection with high sensitivity and specificity, making it potentially suitable for clinical applications. DeepTrace: https://github.com/Bamrock/DeepTrace.

Targeting KRAS-mutant stomach/colorectal tumors by disrupting the ERK2-p53 complex.

KRAS is widely mutated in human cancers, resulting in unchecked tumor proliferation and metastasis, which makes identifying KRAS-targeting therapies a priority. Herein, we observe that mutant KRAS specifically promotes the formation of the ERK2-p53 complex in stomach/colorectal tumor cells. Disruption of this complex by applying MEK1/2 and ERK2 inhibitors elicits strong apoptotic responses in a p53-dependent manner, validated by genome-wide knockout screening. Mechanistically, p53 physically associates with phosphorylated ERK2 through a hydrophobic interaction in the presence of mutant KRAS, which suppresses p53 activation by preventing the recruitment of p300/CBP; trametinib disrupts the ERK2-p53 complex by reducing ERK2 phosphorylation, allowing the acetylation of p53 protein by recruiting p300/CBP; acetylated p53 activates PUMA transcription and thereby kills KRAS-mutant tumors. Our study shows an important role for the ERK2-p53 complex and provides a potential therapeutic strategy for treating KRAS-mutant cancer.

Analysis of differentially expressed long non­coding RNAs revealed a pro­tumor role of MIR205HG in cervical cancer.

Cervical cancer is the fourth most common female malignancy for both incidence and mortality worldwide and is one of the major threats to women's health. The role of long non­coding RNAs (lncRNAs) in cervical cancer remains largely unknown. In the present study, the differentially expressed lncRNAs in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) tissues were retrieved form The Cancer Genome Atlas (TCGA) and were analyzed. The expression analysis of related genes was performed with GEPIA. The proliferation and migratory and invasive abilities of MIR205HG knockdown CESC cells were analyzed using Cell Counting Kit­8 and transwell assays. The expression of Ki­67 and p16 was detected by immunofluorescence. A total of 203 differentially expressed lncRNAs were identified. The results demonstrated that MIR205HG was overexpressed in CESC tissues. Furthermore, the genes related to MIR205HG were enriched in cancer­related pathways. MIR205HG knockdown significantly decreased the proliferation and migratory and invasive abilities of CESC cells. In addition, silencing of MIR205HG significantly decreased the expression of p16 in C­33 A cells. The expression of fibroblast growth factor receptor 3, thymidine phosphorylase and GTPase HRas was downregulated in MIR205HG knockdown CESC cells. These findings revealed some potential lncRNA candidates for cervical cancer research and suggested that MIR205HG may have a pro­tumor role in CESC.

GPR120 induces regulatory dendritic cells by inhibiting HK2-dependent glycolysis to alleviate fulminant hepatic failure.

Fulminant hepatic failure (FHF) is a potentially fatal liver disease that is associated with intrahepatic infiltration of inflammatory cells. As the receptor of polyunsaturated long chain fatty acids, GPR120 can regulate cell differentiation, proliferation, metabolism, and immune response. However, whether GPR120 is involved in FHF remains unknown. Using Propionibacterium acnes (P. acnes)-primed, LPS-induced FHF in mice, we found that interference with GPR120 activity using pharmacological agonist attenuated the severity of the liver injury and mortality of FHF in mice, while a lack of GPR120 exacerbated the disease. GPR120 activation potently alleviated FHF and led to decreased T helper (Th) 1 cell response and expansion of regulatory T cells (Tregs). Interestingly, GPR120 agonist didn't directly target T cells, but dramatically induced a distinct population of CD11c+MHC IIlowCD80lowCD86low regulatory DCs in the livers of FHF mice. GPR120 was found to restrict HIF-1α-dependent glycolysis. The augmented HIF-1α stabilization caused by GPR120 antagonism or deletion could be attenuated by the inhibition of ERK or by the activation of AMPK. Through the analysis of the clinical FHF, we further confirmed the activation of GPR120 was negatively associated with the severity in patients. Our findings indicated that GPR120 activation has therapeutic potential in FHF. Strategies to target GPR120 using agonists or free fatty acids (FFAs) may represent a novel approach to FHF treatment.

Genetic variations in DNA repair gene NEIL1 associated with radiation pneumonitis risk in lung cancer patients.

BACKGROUND: Radiation pneumonitis (RP) is a common side effect in lung cancer patients who received radiotherapy. Our previous study found genetic variations in DNA repair gene NEIL1 may be a predictor of RP in patients with esophageal cancer. So, we hypothesis genetic variations in NEIL1 gene could affect the risk of RP in lung cancer patients following radiotherapy. METHODS: Genetic variations rs4462560 G>C and rs7402844 C>G in NEIL1 gene were genotyped in 174 lung cancer patients received radio(chemo)therapy. Luciferase assay, real-time PCR and Western blot were used to access the effect of the variants on NEIL1 in HELF and HEF cell lines which were transfected with plasmids containing rs4462560 G>C and rs7402844 C>G. RESULTS: Patients with rs4462560 CC genotype had a lower risk of RP grade ≥2 than GG genotype. Compared with the CC genotype, rs7402844 GG genotype was associated with an increased RP grade ≥2 risk. What is more, rs4462560 G decreased the relative luciferase activity of NEIL1 gene promoter compared with the negative control in vitro, while rs4462560 C can increase the relative luciferase activity. The mRNA and protein level of the NEIL1 gene in rs4462560 G were lower than rs4462560 C. CONCLUSIONS: Genetic variants of NEIL1 are associated with RP risk through regulation of NEIL1 expression and serve as independent biomarkers for prediction of RP in patients treated with thoracic radiotherapy.

Distinct genomic profile in h. pylori-associated gastric cancer.

Gastric cancer is one of the most common and deadly cancer types. Currently, four subtypes have been identified with unique molecular alterations: Epstein-Barr virus (EBV)-positive, microsatellite instability (MSI), chromosomal instability (CIN), and genomic stable (GS) tumors. Notably, many gastric tumors are associated with the bacterium Helicobacter pylori but the genomic landscape of this subgroup of tumors remains largely unknown. Targeted sequencing covering 425 genes was performed retrospectively on 1703 gastric tumor tissues and matched normal blood samples. Nonsynonymous mutations, copy-number variation (CNV), and MSI status were called from human DNA reads; nonhuman DNA reads were mapped to NCBI microbial reference genome using Kraken and significant species were identified. Overall, 37 (2.76%) from a total of 1703 samples were EBV-positive, 200 (11.74%) samples were H. pylori-positive, and 10 samples were positive for both. Among the rest, 59 (3.46%) samples were MSI, 380 (22.31%) were CIN, and 1017 (59.72%) were GS. Most of the 200 H. pylori-positive samples tend to be genome stable (85.5%, p < 0.001) and microsatellite stable (95%, p = 0.04). Compared to 1017 GS tumors, mutations in AKT3, EPAS1, MLH1, and BKT and amplifications of NFE2L2, TERC, MCL1, and TOP1 were significantly enriched in H. pylori-positive tumors. And compared to EBV-positive tumors, mutations in PIK3CA, ARID1A, and PTEN were significantly depleted in H. pylori-positive subtype while TP53 mutations were enriched. This study characterized the unique genomic landscape of H. pylori-positive gastric tumors using targeted panel sequencing. The successful identification of DNA reads from infectious agents in tumor samples indicates that deep sequencing is a promising way to uncover characteristics of microbial environment in tumors.

Translational control of Bcl-2 promotes apoptosis of gastric carcinoma cells.

BACKGROUND: Anti-apoptotic protein Bcl-2 plays a substantial role in the carcinogenesis, whereas the regulation for Bcl-2 in gastric carcinoma (GC) is poorly understood. Specifically, a role of microRNA (miR)-383 in the control of Bcl-2 has not been shown in GC and thus addressed in the current study. METHODS: We investigated the levels of miR-383 and Bcl-2 in 50 GC specimens, and compared them with patients' clinical characteristics. Bioinformatics analyses and luciferase-reporter assay were applied for analyzing the relationship between Bcl-2 and miR-383. An CCK assay was used to determine the survival of Fluorouracil-treated GC cells, and apoptosis of GC cells was assessed by flow cytometric FITC Annexin V apoptosis detection assay and expression of apoptosis-associated proteins. RESULTS: The levels of miR-383 were lower while the levels of Bcl-2 levels were higher in GC specimens, compared to tissue from the adjacent non-tumor region. Low miR-383 and high Bcl-2 seemed to be associated with high malignancy and metastasis. In GC specimens, the levels of Bcl-2 and miR-383 inversely correlated. The overall survival of miR-383-low cases was poorer. Mechanistically, miR-383 targeted the 3'-UTR of Bcl-2 mRNA to inhibit its protein translation. Overexpression of miR-383 downregulated Bcl-2, resulting in reduced survival of Fluorouracil-treated GC cells. Similar conclusion was drawn through analysis of published database. CONCLUSION: MiR-383 reduces survival of Fluorouracil-treated GC cells through downregulating of Bcl-2.

Prognostic significance of C-MYC dysregulation in esophageal squamous cell carcinoma: a meta-analysis.

Aim: The clinicopathological and prognostic significance of C-MYC dysregulation (amplification or overexpression) in esophageal squamous cell carcinoma (ESCC) remains controversial. Therefore, we performed this meta-analysis to elucidate this relationship. Materials & methods: Available studies were retrieved from PubMed, Web of Science, EMBASE and the Cochrane Library, and ten studies with a total of 1432 patients were included in this meta-analysis. Results: Pooled results showed that C-MYC dysregulation was significantly associated with poor overall survival (hazard ratio: 1.405 [95% CI: 1.170-1.639]; p < 0.001) and lymph node metastasis (odds ratio: 1.798 [95% CI: 1.125-2.873]; p = 0.014). Subgroup analysis confirmed the results and more prominent predictive effects were observed in the C-MYC amplification group. Conclusion: C-MYC dysregulation is a promising biomarker for ESCC prognosis.

A Retrospective Case Series Of High-Intensity Focused Ultrasound (HIFU) In Combination With Gemcitabine And Oxaliplatin (Gemox) On Treating Elderly Middle And Advanced Pancreatic Cancer.

PURPOSE: This retrospective study was conducted to evaluate the safety and efficacy of high-intensity focused ultrasound (HIFU) ablation combined with Gemcitabine and Oxaliplatin (Gemox) for the treatment of middle and advanced pancreatic cancer in elderly patients. METHODS: Forty-seven patients with pancreatic cancer treated with HIFU and Gemox were evaluated for inclusion, and 38 cases were finally included. The primary endpoint was safety. Secondary endpoints included the response rate, the clinical benefit response (CBR), overall survival (OS), progression-free survival (PFS). RESULTS: After combination therapy of HIFU and Gemox, severe complications were rarely reported, and no treatment-related death occurred. The rate of three or four-degree myelosuppression was low, and no obvious impairment of hepatorenal function was observed. Pancreatitis and gastrointestinal injury did not occurred. The disease control rate (DCR) was estimated to be 76.3%, including complete remission (CR), partial remission (PR), stable disease (SD) in 1, 6, 22 cases, respectively. And the objective response rate (ORR) was 18.4%. The clinical benefit rate (CBR) was 68.4%, with the pain significantly relieved (P<0.01). The serum level of CA19-9 showed significant changes after HIFU treatment. The median overall survival (OS) was 12.5 months, with a 6-month and 12-month OS rate of 82.13% and 59.34%, respectively. Stratified analyses did not reveal any significant difference between patients in different stages. CONCLUSION: Elderly patients (≥ 60 years old) with pancreatic cancer would experience tolerable toxicity and obtain good clinical benefits from the combination therapy of HIFU ablation and Gemox.

Prognostic value and association of Lauren classification with VEGF and VEGFR-2 expression in gastric cancer.

Gastric cancer (GC) is one of the most common malignant tumors in the world. As anti-angiogenic therapy shows efficacy in the treatment of GC, but only works in certain patients, the identification of potential beneficiaries are urgently required in order to apply appropriate treatments. The Lauren classification demonstrates numerous differences in etiology, epidemiology and pathology; however, the association between Lauren classification and pro-angiogenic factors remains unclear. The present study aimed to investigate the clinicopathological factors associated with Lauren classification and the prognostic significance of Lauren classification and vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) expression in GC. Paraffin-embedded GC tissues and clinical information of 255 patients with GC were collected. The clinicopathological factors associated with Lauren classification were evaluated by Logistic regression analysis. Kaplan-Meier survival and Cox regression analyses were used to examine the prognostic significance of Lauren classification and of VEGF and VEGFR-2 expression in patients with GC. The results demonstrated that there was no association between Lauren classification and VEGF and VEGFR-2 expression. Furthermore, results from survival analysis demonstrated that Lauren classification (P=0.001) and Tumor-Node-Metastasis stage (stage II, P=0.002; stage III, P<0.001) were independent prognostic factors in GC. Following subgroup analysis based on Tumor-Node-Metastasis stage, Lauren classification was demonstrated to be an independent prognostic factor in patients with stage III GC (P=0.010) but not in patients with stage I or II GC. Furthermore, VEGFR-2 overexpression was an independent predictor of survival in intestinal-type GC (P=0.040) but not in diffuse-type GC. Taken together, these results indicate that Lauren classification may serve as an independent prognostic factor for patients with GC. In addition, although the expression of VEGF and VEGFR-2 was not associated with Lauren classification, VEGFR-2 overexpression may be considered as an independent prognostic factor in intestinal-type GC.

Integrated assessment of PD-L1 expression and molecular classification facilitates therapy selection and prognosis prediction in gastric cancer.

PURPOSE: Targeting the PD-1/PD-L1 pathway has emerged as a novel therapy for cancer. To identify rational candidates for anti-PD-1/PD-L1 immunotherapy in gastric cancer (GC), the abundance of PD-L1 expression was evaluated on a kind of biomarker-based molecular classification for shaping prognosis and treatment planning. METHODS: One hundred and sixty-five GCs were classified into five subgroups using immunohistochemistry (IHC) and in situ hybridization (ISH) methods, based on a panel of seven markers (MLH1, PMS2, MSH2, MSH6, E-cadherin, P53, and Epstein-Barr virus mRNA). The expression of PD-L1 in GC tissues was analyzed immunohistochemically. RESULTS: The five categories (Epstein-Barr virus positivity, microsatellite instability, aberrant E-cadherin, aberrant P53 expression, and normal P53 expression) correspond to the reported molecular subgroups for similar proportions and clinicopathologic characteristics. Survival analysis indicated that subgroups with aberrant E-cadherin expression independently predicted a worse prognosis in GC patients (HR=2.51, P=0.010). The clinical and prognostic profiles produced by this stratification in nonintestinal-type GC were distinguishable from those in intestinal-type. Although PD-L1 was not a significant prognostic factor, that more frequent presence of PD-L1-positive in microsatellite instability tumors than other subtypes (P<0.010) hinted at a prolonged clinical course. Moreover, the lowest level of PD-L1 but the highest of Her2 was observed in the group of aberrant P53, namely it was suggested that there was a negative correlation between PD-L1 and Her2 overexpression. CONCLUSION: Different molecular subtypes in GC may have a tendency to react differently to anti-PD-L1/PD-1 immunotherapy or anti-Her2 therapy. A combination of PD-L1 expression and this cost-effective classification strategy would be helpful for predicting prognosis and promoting personalized therapy in clinical practice.

Fatty acid receptor GPR120 promotes breast cancer chemoresistance by upregulating ABC transporters expression and fatty acid synthesis.

BACKGROUND: Chemoresistance is the major cause of neoadjuvant treatment failure in breast cancer patients. Despite recent progress, the mechanism underlying chemoresistance remains to be further defined. METHODS: Expression of G protein-coupled receptor 120 (GPR120) was analyzed by immunohistochemistry in the biopsies of primary breast cancer who subsequently underwent preoperative neoadjuvant chemotherapy. In vitro and in vivo loss- and gain-of -function studies were performed to reveal the effects and related mechanism of GPR120 signaling pathway in the chemoresistance of breast cancer cells. FINDINGS: We identified that GPR120, a receptor for long-chain fatty acids, was important for the acquisition of chemoresistance in breast cancer cells. We showed that GPR120 expression was positively associated with clinical response to neoadjuvant chemotherapy in patients. In breast cancer cells, GPR120 enhanced the de novo synthesis of fatty acids that served as GPR120 ligands to activate GPR120 signaling via a feedback mechanism. Upregulated GPR120 signaling rendered cells resistant to epirubicin-induced cell death by upregulating ABC transporters expression and thus decreasing the intracellular accumulation of epirubicin. Akt/NF-κB pathway was responsible for the GPR120-mediated expression of ABC transporters leading to modulation of the concentration of chemotherapeutic drugs in cells. The functional importance of GPR120 in chemoresistance was further validated using epirubicin-treated tumor xenografts, in which we showed that blockade of GPR120 signaling with AH7614 or GPR120-siRNA significantly compromised chemoresistance. INTERPRETATION: Our results highlight that GPR120 might be a promising therapeutic target for breast cancer chemoresistance. FUND: National Natural Science Foundation of China, Ministry of Science and Technology of China, Program of Science and Technology Commission of Shanghai Municipality.

Prognostic value of the Glasgow prognostic score in colorectal cancer: a meta-analysis of 9,839 patients.

PURPOSE: The aim of this study was to perform a systematic review and meta-analysis to evaluate the value of the Glasgow prognostic score (GPS) or modified Glasgow prognostic score (mGPS) in patients with colorectal cancer (CRC). METHODS: A comprehensive medical literature search was performed using the online databases PubMed, Embase, Web of Science, and the Cochrane Library. After extracting basic characteristics and prognostic data from the included studies, overall survival (OS) and cancer-specific survival (CSS) were pooled as primary outcomes. Subgroup analyses were performed according to therapeutic strategies, models, cutoff values, regions, tumor, node, metastasis stages, sample size, and ages. RESULTS: Forty-three independent cohorts from 41 studies with 9,839 CRC patients were included in the present study. Correlation between GPS or mGPS and OS was analyzed in 32 cohorts of 7,714 patients, and 23 independent cohorts of 5,375 patients focused on the correlation between GPS or mGPS and CSS. The overall outcomes showed that patients with elevated GPS or mGPS were associated with poor OS (HR: 2.20, 95% CI: 1.88-2.57, P<0.001). Elevated GPS or mGPS also resulted in worse CSS (HR: 1.86, 95% CI: 1.59-2.17, P<0.001). The results of the subgroup analyses confirmed the overall outcomes. CONCLUSION: GPS or mGPS is an accurate prognostic predictor in patients with CRC. Patients with elevated pretreatment GPS or mGPS have a poor prognosis. Subgroup analyses confirmed the overall outcomes. Pretreatment GPS is a useful biomarker in the management of CRC.

The VEGFR-2 protein and the VEGFR-2 rs1870377 A>T genetic polymorphism are prognostic factors for gastric cancer.

OBJECTIVE: Angiogenesis is one of the key processes in the development of malignant tumors. The vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) signaling pathway regulates branching angiogenesis in cancer. In this study, we analyzed the associations of VEGF/VEGFR-2 proteins and VEGFR-2 genetic variations with the prognosis of gastric cancer (GC). METHOD: We collected the clinical information of patients with GC and extracted genomic DNA from paraffin-embedded tissues. Immunohistochemical methods were used to detect the expression of VEGF and VEGFR-2 in GC tissues. Four single nucleotide polymorphisms of VEGFR-2 were detected by the TaqMan assay. The Kaplan-Meier method and Cox regression model were applied to analyze the associations between clinicopathological characteristics, VEGFR-2 polymorphisms and GC prognosis. RESULTS: A total of 256 cases of GC were included in our study. VEGFR-2 (+) and VEGFR-2 (++/+++) protein expression levels were detected in 83 and 135 cases, respectively. High expression of the VEGFR-2 protein was associated with the poor prognosis of GC (log-rank test P = 0.026). No statistical significance was observed for the association between VEGF and the prognosis of GC. The VEGFR-2 rs1870377 A > T genetic polymorphism was discovered to be associated with the prognosis of GC (AA vs. AT, HR = 1.69, 95% CI = 1.06-2.68, P = 0.027). CONCLUSION: Our study suggested that the high expression of VEGFR-2, as well as the VEGFR-2 rs1870377 A > T genetic polymorphism, may be prognostic markers for GC.

The deubiquitinating enzyme UCHL1 is a favorable prognostic marker in neuroblastoma as it promotes neuronal differentiation.

BACKGROUND: Neuroblastoma (NB) is the most common pediatric solid tumor that originates from neural crest-derived sympathoadrenal precursor cells that are committed to development of sympathetic nervous system. The well differentiated histological phenotype of NB tumor cells has been reportedly associated with favorable patient outcome. Retinoic acid (RA) can effectively induce NB cell differentiation, thereby being used in the clinic as a treatment agent for inducing the differentiation of high-risk NB. However, the underlying molecular mechanisms of regulating differentiation remain elusive. METHODS: The correlation between clinical characteristics, survival and the deubiquitinating enzyme ubiquitin C-terminal hydrolase 1 (UCHL1) expression were assessed using a neuroblastic tumor tissue microarray, and then validated in three independent patient datasets. The different expression of UCHL1 in ganglioneuroblastoma, ganglioneuroma and NB was detected by immunohistochemistry, mass spectra and immunoblotting analysis, and the correlation between UCHL1 expression and the differentiated histology was analyzed, which was also validated in three independent patient datasets. Furthermore, the roles of UCHL1 in NB cell differentiation and proliferation and the underlying mechanisms were studied by using short hairpin RNA and its inhibitor LDN57444 in vitro. RESULTS: Based on our neuroblastic tumor tissue microarrays and three independent validation datasets (Oberthuer, Versteeg and Seeger), we identified that UCHL1 served as a prognostic marker for better clinical outcome in NB. We further demonstrated that high UCHL1 expression was associated with NB differentiation, indicated by higher UCHL1 expression in ganglioneuroblastomas/ganglioneuromas and well-differentiated NB than poorly differentiated NB, and the positive correlation between UCHL1 and differentiation markers. As expected, inhibiting UCHL1 by knockdown or LDN57444 could significantly inhibit RA-induced neural differentiation of NB tumor cells, characterized by decreased neurite outgrowth and neural differentiation markers. This effect of UCHL1 was associated with positively regulating RA-induced AKT and ERK1/2 signaling activation. What's more, knockdown of UCHL1 conferred resistance to RA-induced growth arrest. CONCLUSION: Our findings identify a pivotal role of UCHL1 in NB cell differentiation and as a prognostic marker for survival in patients with NB, potentially providing a novel therapeutic target for NB.

Serum miR-331-3p predicts tumor recurrence in esophageal adenocarcinoma.

MicroRNAs (miRNAs) may contribute to the initiation and progression of cancer. The role of circulating miRNAs as predictors of recurrence in esophageal adenocarcinoma (EAC) has not been extensively explored. Here we measured the expressions of 167 miRNAs in serum samples from a discovery cohort of 72 EAC patients (32 patients with recurrence and 40 patients without). A rank sum test was performed to identify differentially expressed miRNAs. Cox regression model was applied to estimate the effect of miRNA expression on recurrence-free survival. The eligible miRNAs were then validated in an independent cohort of 329 EAC patients (132 patients with recurrence and 197 patients without). miR-331-3p was identified and confirmed to be differentially expressed between EAC patients with and without recurrence and associated with recurrence-free survival. In both cohorts, the expression of miR-331-3p was consistently decreased in patients with recurrence compared to those without (P < 0.05). Using patients with low expression of miR-331-3p as reference, those with high expression had HRs for recurrence of 0.45 (95% CI, 0.21-0.96, P = 0.040) and 0.55 (95% CI, 0.38-0.78, P = 0.001) in the discovery and validation cohorts, respectively. Therefore, serum miR-331-3p may be a useful biomarker for identifying EAC patients at high risk of recurrence.

Genetic Variants Within MTORC1 Genes Predict Gastric Cancer Prognosis in Chinese Populations.

Objective: Mammalian target of rapamycin complex 1 (mTORC1) plays an important role in maintaining proper cellular functions in gastric cancer (GC). Previous studies demonstrated genetic variants within mTORC1 genes were associated with GC risk. However, no studies reported the associations between genetic variants within mTORC1 genes and GC prognosis. Herein, we firstly assessed the associations of genetic variants of mTORC1 genes with overall survival (OS) of GC in Chinese populations. Methods: We genotyped eight single nucleotide polymorphisms (SNPs) in mTORC1 genes (i.e., rs2536 T>C and rs1883965 G>A for mTOR, rs3160 T>C and rs26865 A>G for MLST8, rs3751934 C>A, rs1062935 T>C, rs3751932 T>C and rs12602885 G>A for RPTOR) by the TaqMan method in 197 Chinese GC patients who had surgical resection in Xinhua Hospital. We conducted Kaplan-Meier survival plots and Cox hazards regression analysis to explore the associations of these SNPs with OS. Results: The single-locus analysis indicated that RPTOR rs1062935 T>C was associated with an increased risk of poor GC prognosis (CC vs. TT/TC: adjusted Hazard ratio (HR) = 1.71, 95% confidence interval (CI) = 1.04-2.82). The combined analysis of all eight SNPs showed that patients with more than three risk genotypes significantly increased risk of death (adjusted HR = 2.44, 95% CI = 1.30-4.58), when compared to those with three or less risk genotypes. Conclusions: Our findings indicated that genetic variants within mTORC1 genes may predict GC prognosis in Chinese populations. The results need to be validated in future studies with larger sample sizes.

Capecitabine/cisplatin versus 5-fluorouracil/cisplatin in Chinese patients with advanced and metastatic gastric cancer: Re-analysis of efficacy and safety data from the ML17032 phase III clinical trial.

AIM: To confirm non-inferiority and test potential superiority of capecitabine/cisplatin (XP) over 5-fluorouracil (5-FU)/cisplatin (FP) as first-line treatment for advanced gastric cancer (AGC) in Chinese patients. METHODS: In open-label phase III ML17032 trial, AGC (stage IIIA-IV) patients with or without metastases were randomized 1:1 to receive cisplatin (80 mg/m2 /day intravenous [IV] day 1) with either capecitabine (1000 mg/m2 /day oral [PO] twice daily [BID], days 1-14; XP) or 5-FU (800 mg/m2 /day continuous IV days 1-5; FP) every 3 weeks. The primary objective was to confirm the non-inferiority of XP over FP for progression-free survival (PFS). RESULTS: The intent-to-treat (ITT) population included 126 Chinese patients (XP-62, FP-64; 67.5% male, mean age 54.7 years). The primary analysis was performed on the per-protocol (PP) population (105 patients; XP-51, FP-54; 65.7% male). Median PFS in the XP and FP groups was 7.2 and 4.5 months, respectively. The adjusted hazard ratio (HR) for PFS was 0.52 (95% confidence interval [CI]: 0.32-0.83, P = 0.006). Unadjusted HR for PFS in the ITT population was 0.63 (95% CI, 0.42-0.94, P = 0.022). The most frequent drug-related grade 3/4 adverse events (AEs) were neutropenia (XP-20.7%, FP-17.7%) and gastrointestinal disorders (XP-19.0%, FP-19.4%). The overall incidence of grade 3/4 AEs (XP-43.1%, FP-46.8%), serious AEs (XP-1.7%, FP-3.2%), and AEs related to treatment discontinuation (XP-10.3%, FP-16.1%) were comparable. CONCLUSION: XP had a similar safety profile and may demonstrate superiority for PFS compared to FP as first-line treatment of Chinese patients with AGC (NCT02563054).

Correction to: Early presence of anti-angiogenesis-related adverse events as a potential biomarker of antitumor efficacy in metastatic gastric cancer patients treated with apatinib: a cohort study.

ABSTARCT: The original article [1] contains two errors in Table 2.

Early presence of anti-angiogenesis-related adverse events as a potential biomarker of antitumor efficacy in metastatic gastric cancer patients treated with apatinib: a cohort study.

BACKGROUND: Reliable biomarkers of apatinib response in gastric cancer (GC) are lacking. We investigated the association between early presence of common adverse events (AEs) and clinical outcomes in metastatic GC patients. PATIENTS AND METHODS: We conducted a retrospective cohort study using data on 269 apatinib-treated GC patients in two clinical trials. AEs were assessed at baseline until 28 days after the last dose of apatinib. Clinical outcomes were compared between patients with and without hypertension (HTN), proteinuria, or hand and foot syndrome (HFS) in the first 4 weeks. Time-to-event variables were assessed using Kaplan-Meier methods and Cox proportional hazard regression models. Binary endpoints were assessed using logistic regression models. Landmark analyses were performed as sensitivity analyses. Predictive model was analyzed, and risk scores were calculated to predict overall survival. RESULTS: Presence of AEs in the first 4 weeks was associated with prolonged median overall survival (169 vs. 103 days, log-rank p = 0.0039; adjusted hazard ratio (HR) 0.64, 95% confidence interval [CI] 0.64-0.84, p = 0.001), prolonged median progression-free survival (86.5 vs. 62 days, log-rank p = 0.0309; adjusted HR 0.69, 95% CI 0.53-0.91, p = 0.007), and increased disease control rate (54.67 vs. 32.77%; adjusted odds ratio 2.67, p < 0.001). Results remained significant in landmark analyses. The onset of any single AE or any combinations of the AEs were all statistically significantly associated with prolonged OS, except for the presence of proteinuria. An AE-based prediction model and subsequently derived scoring system showed high calibration and discrimination in predicting overall survival. CONCLUSION: Presence of HTN, proteinuria, or HFS during the first cycle of apatinib treatment was a viable biomarker of antitumor efficacy in metastatic GC patients.