PurposeImmune checkpoint inhibitors plus antiangiogenic tyrosine kinase inhibitors may offer a first-line treatment for advanced hepatocellular carcinoma (HCC). In this phase 2 trial [registered with clinicaltrials.gov (NCT04052152)], we investigated the safety and efficacy of first-line anti-PD-1 antibody sintilimab plus antiangiogenic TKI anlotinib for advanced HCC.Methods and MaterialsPathologically-proven advanced HCC patients received sintilimab (200 mg) on day 1 and anlotinib (12 mg) once daily on days 1 to 14 every 3 weeks, with a safety run-in for the first six participants to assess dose-limiting toxicities (DLTs). The primary endpoints were safety and objective response rate (ORR) per RECIST v1.1.ResultsTwenty advanced HCC patients were enrolled. No DLTs occurred in the safety run-in. All patients had treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 8 (40.0%) patients, the most common being decreased platelet count (10.0%) and increased γ-glutamyl transferase (10.0%). No grade 4/5 TRAEs occurred. Five (25%) patients developed immune-related AEs. The ORR was 35.0% (95%CI 15.4%-59.2%) per RECIST v1.1 and 55.0% (95%CI 31.5%-76.9%) per modified RECIST. At data cutoff (March 31, 2021), the median progression-free survival was 12.2 months (95%CI, 3.8 to not reached). The median PFS was significantly longer in patients with lower LDH levels (not reached [NR], 95% CI, 8.7 to NR vs. higher LDH levels 5.2 months, 95% CI 3.4 to NR; P=0.020) and a CONUT score ≤2 (NR, 95% CI 5.1 to NR vs. CONUT score >2 6.2 months, 95% CI 1.8 to NR; P=0.020). Furthermore, patients showing tumor response had a significantly higher median proportion of CD16+CD56+ NK cells than patients who had stable or progressive disease (21.6% vs. 14.6%; P=0.026).ConclusionSintilimab plus anlotinib showed promising clinical activities with manageable toxicity as first-line treatment of advanced HCC.

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Gastric cancer (GC) is the third-leading cause of cancer mortality worldwide. The aim of this study was to develop a nomogram that estimates 1-year, 3-year, and 5-year survival probability of GC patients after D2 gastrectomy combined with adjuvant chemotherapy. The results showed that median age is 58 (range: 18-85) years in the training cohort and 59 (range: 32-85) years in the validation cohort. On multivariate analysis, four factors were found to be significantly associated with worse overall survival (OS): late TNM stage, positive resection margin, preoperative carcinoembryonic antigen (CEA) level, and single chemotherapy regimens compared with multiple chemotherapy regimens. All of these findings were validated in the validation cohort. Furthermore, the four factors were included in the final nomogram for the prediction of 1-year, 3-year, and 5-year survival probability, with accurate calibration and reasonable discrimination (C-index = 0.676 for training cohort, and C-index = 0.664 for validation cohort). The AUC values analyzed by the ROC analysis demonstrated a good predictive accuracy of the nomogram for OS (1-year, 3-year, and 5-year OS were 94.43%, 77.42%, and 73.03% in the training cohort, respectively; 96.95%, 81.54%, and 73.41% in the validation cohort, respectively). In conclusion, the proposed nomogram may be used to objectively and accurately predict survival probability of GC patients in a multi-institutional clinical setting.

Fusobacterium nucleatum infection plays vital roles in colorectal cancer (CRC) progression. Overexpression of microRNA‐4717‐3p (miR‐4717) was reported to be upregulated in F. nucleatum positive CRC tissues, however, the underlying mechanism is unknown. In this study, we found that miR‐4717 promoted CRC cell proliferation in vitro and growth of CRC in vivo following F. nucleatum infection. MicroRNA‐4717 suppressed the expression of mitogen‐activated protein kinase kinase 4 (MAP2K4), a tumor suppressor, by directly targeting its 3′‐UTR. Furthermore, we confirmed that methyltransferase‐like 3 (METTL3)‐dependent m6A methylation could methylate primary (pri)‐miR‐4717, which further promoted the maturation of pri‐miR‐4717, and METTL3 positively regulated CRC cell proliferation through miR‐4717/MAP2K4 pathways. In conclusion, F. nucleatum‐induced miR‐4717 excessive maturation through METTL3‐dependent m6A modification promotes CRC cell proliferation, which provides a potential therapeutic target and diagnostic biomarker for CRC.

Hepatocellular carcinoma (HCC) is one of the dominating tumors causing death due to lack of timely discovery and valid treatment. Abnormal increase of Rac GTPase activating protein 1 (RACGAP1) has been verified to be an oncogene in plenty tumors. The profound mechanism of RACGAP1 was rarely reported in HCC. In this study, we explored the function and mechanism of RACGAP1 in HCC through multiple analysis and experiments. RACGAP1 expression was up-regulated in HCC samples and the high expression of RACGAP1 was an independent prognostic risk factor for HCC patients. Meanwhile, RACGAP1 promoted developments of HCC both in vitro and in vivo. We verified that RACGAP1 promoted proliferation of HCC via PI3K/AKT/CDK2 and PI3K/AKT/GSK3β/Cyclin D1 signaling pathway. RACGAP1 accelerated the invasion and metastasis of HCC via phosphorylation of GSK3β and nuclear translocation of β-catenin. Furthermore, by luciferase reporter assay and Chromatin immunoprecipitation (ChIP) assay, we confirmed Recombinant GA Binding Protein Transcription Factor Alpha (GABPA) regulated the transcription of RACGAP1. All these findings revealed that RACGAP1 promotes the progression of HCC through a novel mechanism, which might be a new therapeutic target for HCC patients.