Immune signature profiling identified prognostic factors for gastric cancer.

OBJECTIVE: Tumor microenvironment, especially the host immune system, plays a pivotal role in tumor initiation and progression. Profiling of immune signature within tumor might uncover biomarkers for targeted therapies and clinical outcomes. However, systematic analysis of immune-related genes in gastric cancer (GC) has not been reported. METHODS: Expressions of a total of 718 immune-related genes were generated in 372 stomach adenocarcinoma (STAD) patients from The Cancer Genome Atlas (TCGA) database using RNA-sequencing data. Integrated bioinformatics analyses were performed to identify prognostic factors as well. RESULTS: Survival analyses revealed 73 genes, which were significantly associated with patient's overall survival (OS). Taken together with clinicopathological parameters, we established a predictive model, containing 10 immune-related genes, which were NRP1, C6, CXCR4, LBP, PNMA1, TLR5, ITGA6, MICB, PBK and TNFRSF18, with powerful efficiency in distinguishing satisfactory or poor survival of STAD patients. Moreover, the top 3 ranked prognostic genes, NRP1, TGFß2 and MFGE8, were also significantly associated with patient's OS by an independent validation achieved from Kaplan-Meier plotter database. CONCLUSIONS: We profiled prognostic immune signature and established prognostic predictive model for GC, which could reflect immune disorders within tumor microenvironment, and also may provide novel predictive and therapeutic targets for GC patients in the near future.

Geo-Positioning Accuracy Improvement of Multi-Mode GF-3 Satellite SAR Imagery Based on Error Sources Analysis.

The GaoFen-3 (GF-3) satellite is the only synthetic aperture radar (SAR) satellite in the High-Resolution Earth Observation System Project, which is the first C-band full-polarization SAR satellite in China. In this paper, we proposed some error sources-based weight strategies to improve the geometric performance of multi-mode GF-3 satellite SAR images without using ground control points (GCPs). To get enough tie points, a robust SAR image registration method and the SAR-features from accelerated segment test (SAR-FAST) method is used to achieve the image registration and tie point extraction. Then, the original position of these tie points in object-space is calculated with the help of the space intersection method. With the dataset clustered by the density-based spatial clustering of applications with noise (DBSCAN) algorithm, we undertake the block adjustment with a bias-compensated rational function model (RFM) aided to improve the geometric performance of these multi-mode GF-3 satellite SAR images. Different weight strategies are proposed to develop the normal equation matrix according to the error sources analysis of GF-3 satellite SAR images, and the preconditioned conjugate gradient (PCG) method is utilized to solve the normal equation. The experimental results indicate that our proposed method can improve the geometric positioning accuracy of GF-3 satellite SAR images within 2 pixels.

Geometric Positioning Accuracy Improvement of ZY-3 Satellite Imagery Based on Statistical Learning Theory.

With the increasing demand for high-resolution remote sensing images for mapping and monitoring the Earth's environment, geometric positioning accuracy improvement plays a significant role in the image preprocessing step. Based on the statistical learning theory, we propose a new method to improve the geometric positioning accuracy without ground control points (GCPs). Multi-temporal images from the ZY-3 satellite are tested and the bias-compensated rational function model (RFM) is applied as the block adjustment model in our experiment. An easy and stable weight strategy and the fast iterative shrinkage-thresholding (FIST) algorithm which is widely used in the field of compressive sensing are improved and utilized to define the normal equation matrix and solve it. Then, the residual errors after traditional block adjustment are acquired and tested with the newly proposed inherent error compensation model based on statistical learning theory. The final results indicate that the geometric positioning accuracy of ZY-3 satellite imagery can be improved greatly with our proposed method.

[Clinicopathologic features and prognosis of 51 patients with α-fetoprotein-producing gastric cancer].

OBJECTIVE: To analyze the clinicopathologic features and prognosis of α-fetoprotein (AFP)-producing gastric cancers (AFPGC). METHODS: Fifty-one serum AFP-positive patients with positive immunohistochemical staining of AFP in the primary lesions (study group) and sixty-five gastric cancer cases with normal AFP level (control group) treated in our department from January 2005 to December 2007 were included in this study. Their clinicopathologic features and follow-up data were statistically analyzed. RESULTS: Compared with the control group, the study group had a higher incidence of poorly differentiated adenocarcinoma (P=0.021) and liver metastasis (P=0.001) than that in the control group.The TNM stages in the study group were significantly higher than those in the control group (P=0.001). The 1-, 2-, and 5-year survival rates of the study group were 62.7%, 27.5% and 4.7%, respectively, and the median survival was 16 months, significantly lower than the 84.6%, 55.4%, 16.5%, and 30 months of the control group (P<0.001 for all). The serum AFP levels in the study group ranged from 58.63 µg/L to 12 100.00 µg/L, and could be classified into two groups:27 cases <500 µg/L, and 24 cases ≥500 µg/L. There was no significant difference of the immunohistochemical staining results between the two subgroups (P=0.912). CONCLUSIONS: AFPGC is a special type of gastric cancer with high degree of malignancy and poor prognosis. Monitoring of serum AFP level can earlier detect the progression of disease and give corresponding treatment.

KLF9­regulated FBXO31 inhibits the progression of endometrial cancer and enhances the sensitivity of endometrial cancer cells to cisplatin.

Endometrial cancer (EC) is one of the most common malignancies with an increasing annual incidence. F-box only protein 31 (FBXO31) plays a significant regulatory role in several types of cancer. The transcription factor Krüppel-like factor 9 (KLF9) of FBXO31 is reduced in EC as a tumor suppressor. However, their particular regulatory role and mechanism in EC have not been previously reported. Therefore, the UALCAN database was used to predict the expression levels of FBXO31 in EC. In addition, the regulatory effect of FBXO31 on EC cell proliferation, invasion, migration, apoptosis and cisplatin (DDP) sensitivity was investigated at the cellular level. The association between KLF9 and FBXO31 was predicted using the JASPAR database and verified by chromatin immunoprecipitation and luciferase reporter assays. Finally, the regulatory effects of KLF9 and FBXO31 overexpression or silencing were also explored. The results demonstrated that FBXO31 was poorly expressed in EC. Additionally, FBXO31 overexpression inhibited the malignant progression of EC cells and enhanced their sensitivity to DDP. Furthermore, KLF9 promoted FBXO31 transcription. Overall, the present study suggested that the KLF9-mediated regulation of FBXO31 could inhibit the progression of EC and enhance the sensitivity of EC cells to DDP.

Securinine inhibits carcinogenesis in gastric cancer by targeting AURKA-ß-catenin/Akt/STAT3 and the cell cycle pathway.

BACKGROUND: Gastric cancer (GC) is difficult to treat with currently available treatments. Securinine (SCR) has a lengthy history of use in the treatment of disorders of the nervous system, and its anticancer potential has been gaining attention in recent years. The aim of this study was to explore the repressive effect of SCR on GC and its fundamental mechanism. METHODS: The efficacy of SCR in GC cells was detected by MTT assays. Colony formation, flow cytometry and Transwell assays were used to assess the changes in the proliferation, apoptosis, cell cycle distribution, migration and invasion of GC cells after treatment. AGS (human gastric carcinoma cell)-derived xenografts were used to observe the effect of SCR on tumor growth in vivo. The molecular mechanism of action of SCR in GC was explored via RNA sequencing, bioinformatics analysis, Western blotting, molecular docking, and immunohistochemistry. RESULTS: SCR was first discovered to inhibit the proliferation, migration, and invasion of GC cells while initiating apoptosis and cell cycle arrest in vitro. It was also established that SCR has excellent anticancer effects in vivo. Interestingly, AURKA acts as a crucial target of SCR, and AURKA expression can be blocked by SCR. Moreover, this study revealed that SCR suppresses the cell cycle and the ß-catenin/Akt/STAT3 pathways, which were previously reported to be regulated by AURKA. CONCLUSION: SCR exerts a notable anticancer effect on GC by targeting AURKA and blocking the cell cycle and ß-catenin/Akt/STAT3 pathway. Thus, SCR is a promising pharmacological option for the treatment of GC.

HLX07 alone or combined with serplulimab, cisplatin and 5-fluorouracil for advanced esophageal squamous cell carcinoma: A phase 2 study.

BACKGROUND: The combination of anti-PD-1 antibody serplulimab and chemotherapy is considered standard first-line therapy for advanced esophageal squamous cell carcinoma (ESCC), but few later-line treatments are available. Here we evaluated the therapeutic efficacy of the recombinant, humanized anti-EGFR antibody HLX07 when used alone or together with serplulimab and chemotherapy against advanced ESCC. METHODS: This open-label, non-randomized, two-cohort, phase 2 trial involved patients 18-75 years old with histologically or cytologically confirmed locally advanced, unresectable, or metastatic ESCC, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients who had failed first-line immuno-chemotherapy or at least two lines of other systemic therapy received HLX07 monotherapy intravenously at a dose of 1,000 mg once every 2 weeks (Q2W). Patients with no prior systemic therapy received HLX07 (1,000 mg, day 1) and serplulimab (200 mg, day 1) intravenously Q2W for up to 2 years, concurrently with cisplatin (50 mg/m2, day 1) for up to 8 cycles and 5-fluorouracil (1,200 mg/m2, days 1-2) for up to 12 cycles intravenously Q2W. The primary endpoints were progression-free survival (PFS) and objective response rate (ORR). RESULTS: Overall, 50 patients were enrolled. In the HLX07 monotherapy group, ORR was 15.0% (3/20), and the median PFS was 1.5 months (95% confidence interval [CI], 1.3 to 3.7). The median duration of response was not reached, and the rate of patients showing an objective response lasting at least 6 months was 66.7% (95% CI, 5.4 to 94.5). Two (10.0%, 2/20) patients experienced grade 3-4 treatment-related adverse events (TRAEs), including hypomagnesemia, hypocalcemia, and fatigue. No patient experienced grade 5 TRAEs. In the HLX07 combination group, the ORR was 60.0% (18/30), and the median PFS was 7.8 months (95% CI, 3.3 to 9.1). Fourteen (46.7%, 14/30) patients experienced grade 3-4 TRAEs, and one (3.3%, 1/30) patient died due to serplulimab-related pneumonitis. CONCLUSIONS: HLX07 monotherapy and its combination with serplulimab and chemotherapy showed manageable toxicity and promising antitumor activity in patients with recurrent or metastatic ESCC. Randomized controlled trials are warranted to further establish the safety and efficacy of HLX07 against ESCC. TRIAL REGISTRATION: This trial was registered at Clinicaltrials.gov (NCT05221658).

A randomized phase 2 study of HLX22 plus trastuzumab biosimilar HLX02 and XELOX as first-line therapy for HER2-positive advanced gastric cancer.

BACKGROUND: Gastric cancer is the fifth most common cancer and the fourth most common cause of cancer death worldwide, yet the prognosis of advanced disease remains poor. METHODS: This was a randomized, double-blinded, phase 2 trial (ClinicalTrials.gov: NCT04908813). Patients with locally advanced/metastatic HER2-positive gastric/gastroesophageal junction cancer and no prior systemic antitumor therapy were randomized 1:1:1 to 25 mg/kg HLX22 (a novel anti-HER2 antibody) + HLX02 (trastuzumab biosimilar) + oxaliplatin and capecitabine (XELOX) (group A), 15 mg/kg HLX22 + HLX02 + XELOX (group B), or placebo + HLX02 + XELOX (group C) in 3-week cycles. Primary endpoints were progression-free survival (PFS) and objective response rate (ORR) assessed by independent radiological review committee (IRRC). FINDINGS: Between November 29, 2021, and June 6, 2022, 82 patients were screened; 53 were randomized to group A (n = 18), B (n = 17), and C (n = 18). With 14.3 months of median follow-up, IRRC-assessed median PFS was prolonged with the addition of HLX22 (A vs. C, 15.1 vs. 8.2 months, hazard ratio [HR] 0.5 [95% confidence interval (CI) 0.17-1.27]; B vs. C, not reached vs. 8.2 months, HR 0.1 [95% CI 0.04-0.52]). Confirmed ORR was comparable among groups (A vs. B vs. C, 77.8% vs. 82.4% vs. 88.9%). Treatment-related adverse events (TRAEs) were observed in 18 (100%), 16 (94.1%), and 17 (94.4%) patients, respectively. One (5.6%) patient in group C reported a grade 5 TRAE. CONCLUSIONS: Adding HLX22 to HLX02 and XELOX prolonged PFS and enhanced antitumor response in the first-line treatment of HER2-positive gastric cancer, with manageable safety. FUNDING: Shanghai Henlius Biotech, Inc.

EZH2 suppresses insulinoma development by epigenetically reducing KIF4A expression via H3K27me3 modification.

Kinesin family member 4A (KIF4A), located in the human chromosome band Xq13.1, is aberrantly overexpressed in various cancers. Our study intended to assess the expression of KIF4A in insulinoma and to gain new insights into the molecular mechanisms of this rare disease. First, KIF4A was significantly recruited in pancreatic endocrine cells relative to other cell types. A significant correlation existed between the overexpression of KIF4A and the poor survival of pancreatic adenocarcinoma patients. As revealed by CCK-8, TUNEL assay, flow cytometry, wound healing, Matrigel-transwell, senescence-associated ß-galactosidase staining, ELISA, and subcutaneous tumor formation analysis in nude mice, knocking down KIF4A significantly inhibited the growth and metastasis of insulinoma cells in vivo and in vitro. Mechanistically, we observed that KIF4A promoter sequences had reduced H3K27me3 modifications, and decline in enhancer of zeste homolog-2 (EZH2) expression promoted KIF4A expression by reducing the modification, thus leading to insulinoma. Moreover, EZH2 knockdown-induced insulinoma cell proliferation was dependent on KIF4A overexpression since KIF4A knockdown eradicated shEZH2-induced proliferation of insulinoma cells. In summary, KIF4A was identified as a possible therapeutic target for insulinoma.

Safety and effectiveness of apatinib in elderly patients with metastatic gastric cancer: a sub-analysis from the large-scale, prospective observational study of apatinib for gastric cancer treatment in a real-world clinical setting (AHEAD-G202).

Background: Apatinib was shown to improve the survival of Chinese patients with refractory metastatic gastric cancer (mGC). As an orally administered drug, it has been widely used in elderly patients because the dosing schedule can be adjusted flexibly. However, data on the efficacy and safety of apatinib in elderly patients is scarce. The aim of this study was to evaluate the toxicity and effectiveness of apatinib for elderly patients with mGC in a real-world setting. Methods: Data from the sub-population of patients who were ≥65 years enrolled in the AHEAD-G202 trial were analyzed. Patients with mGC were prospectively registered and initially received ≤850 mg oral apatinib daily combined or not combined with chemotherapy, at the investigator's discretion. The primary endpoint was safety. The secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results: A total of 117 patients were included. There were 51 (43.59%) patients in the low-dose (250 mg) group, 60 (51.28%) patients in the mid-dose (425 to 500 mg) group, and 6 (5.13%) patients in the high-dose (850 mg) group according to the initial daily doses. Hypertension (6.84%) was the only grade 3-4 adverse event (AE) with a prevalence of more than 5% and across the low-dose (11.76%), mid-dose (3.33%) and high-dose group (0%). The median OS and PFS were 7.13 months (95% CI: 5.04 to 9.22 months) and 4.27 months (95% CI: 3.24 to 5.29 months), respectively. The OS and PFS were similar among the 65-74 and ≥75 years groups (χ2=1.406, P=0.306; χ2=0.378, P=0.066, respectively). The OS and PFS were also comparable among the 3 dose groups. Conclusions: Elderly patients with mGC can tolerate and benefit from apatinib therapy. A lower initial daily dosing strategy may be a suitable choice for elderly patients in clinical practice.

KLF7/VPS35 axis contributes to hepatocellular carcinoma progression through CCDC85C-activated ß-catenin pathway.

OBJECTIVE: Dysregulation of KLF7 participates in the development of various cancers, but it is unclear whether there is a link between HCC and aberrant expression of KLF7. The aim of this study was to investigate the role of KLF7 in proliferation and migration of hepatocellular carcinoma (HCC) cells. METHODS: CCK8, colony growth, transwell, cell cycle analysis and apoptosis detection were performed to explore the effect of KLF7, VPS35 and Ccdc85c on cell function in vitro. Xenografted tumor growth was used to assess in vivo role of KLF7. Chip-qPCR and luciferase reporter assays were applied to check whether KLF7 regulated VPS35 at transcriptional manner. Co-IP assay was performed to detect the interaction between VPS35 and Ccdc85c. Immunohistochemical staining and qRT-PCR analysis were performed in human HCC sampels to study the clinical significance of KLF7, VPS35 and ß-catenin. RESULTS: Firstly, KLF7 was highly expressed in human HCC samples and correlated with patients' differentiation and metastasis status. KLF7 overexpression contributed to cell proliferation and invasion of HCC cells in vitro and in vivo. KLF7 transcriptional activation of VPS35 was necessary for HCC tumor growth and metastasis. Further, co-IP studies revealed that VPS35 could interact with Ccdc85c in HCC cells. Rescue assay confirmed that overexpression of VPS35 and knockdown of Ccdc85c abolished the VPS35-medicated promotion effect on cell proliferation and invasion. Finally, KLF7/VPS35 axis regulated Ccdc85c, which involved in activation of ß-catenin signaling pathway, confirmed using ß-catenin inhibitor, GK974. Functional studies suggested that downregulation of Ccdc85c partly reversed the capacity of cell proliferation and invasion in HCC cells, which was regulated by VPS35 upregulation. Lastly, there was a positive correlation among KLF7, VPS35 and active-ß-catenin in human HCC patients. CONCLUSION: We demonstrated that KLF7/VPS35 axis promoted HCC cell progression by activating Ccdc85c-medicated ß-catenin pathway. Targeting this signal axis might be a potential treatment strategy for HCC.

An open label, multicenter, noninterventional study of apatinib in advanced gastric cancer patients (AHEAD-G202).

BACKGROUND: Apatinib has been proved to be effective and well tolerated among patients in phase II and III studies. Here, we evaluated the safety and effectiveness of apatinib in advanced gastric cancer patients in a real-world setting. METHODS: This study enrolled advanced gastric cancer patients who had progressed or relapsed despite systemic chemotherapy. The primary outcome was safety and the secondary outcomes included overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 337 patients were included. In total, 62 (18.4%), 102 (30.3%), and 173 (51.3%) patients received first, second, and third or higher line apatinib therapy, respectively. Grade 3/4 treatment-emergent adverse events (AEs) were infrequent (<5%), with hypertension (6.8%) being the only grade 3/4 AE occurring in more than 5% of the patients and across the low-dose (250 mg, 7.3%), mid-dose (425-500 mg, 6.1%), and high-dose group (675-850 mg, 2/15, 13.3%). The median OS and PFS were 7.13 months (95% CI, 6.17-7.93) and 4.20 months (95% CI, 4.60-4.77), respectively, and were comparable among the low-, mid-, and high-dose groups. CONCLUSION: Lower daily doses of apatinib achieved comparable OS and PFS versus higher daily doses of apatinib while maintaining a more benign safety profile in advanced gastric cancer patients. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02668380.

Safety and effectiveness of apatinib in patients with previously treated metastatic gastric cancer: a sub-analysis from the real-world study of apatinib for gastric cancer treatment (AHEAD-G202).

Apatinib, a VEGFR2 receptor tyrosine kinase inhibitor, showed survival benefits in Asian patients with heavily pretreated advanced gastric cancer. However, the adverse event (AEs) profile of apatinib has limited its use. Dosing schedules are used to alleviate toxicities despite no supportive evidence. This study aimed to analyze the toxicity and effectiveness of apatinib alone, especially with different dosing strategies in advanced gastric cancer patients under a real-world setting. Data from the subpopulation of patients who failed ≥2 chemotherapy regimens enrolled in the AHEAD-G202 trial were analyzed. The primary endpoint was safety. The secondary endpoints were overall survival (OS) and progression-free survival (PFS). Totally 120 patients were included into three groups by the initial daily doses: 43 (35.8%) patients in the low-dose (250 mg) group, 67 (55.8%) patients in the mid-dose (425 mg to 500 mg) group, and 10 (8.3%) patients in the high-dose (675 to 850 mg) group. Grade 3/4 treatment-emergent AEs were infrequent (<5%), with the most commonly reported grade 3/4 AEs being hand-foot syndrome (4.2%), hypertension (4.2%,), fatigue (4.2%), and difficulty in swallowing (4.2%) which gradually decreased among the high-, mid-, and low-dose groups. The median OS and PFS were 6.33 months (95% CI, 4.57-7.73) and 3.83 months (95% CI: 1.40-4.20), respectively and were comparable among the three doses groups. We found heavily pretreated advanced gastric cancer patients can tolerate and benefit from lower-doses of apatinib therapy. The lower initial daily dosing strategy represents an alternative approach for optimizing apatinib dosing in clinical practice.

Single nucleotide polymorphism rs2555639 in 15-PGDH and colorectal cancer metastasis.

PURPOSE: To investigate the correlation between metastasis of colon cancer and the single nucleotide polymorphism (SNP) rs2555639 in nicotinamide adenine dinucleotide (NAD)+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) (rs2555639). METHODS: We investigated the genotyping of peripheral blood genomic DNA in patients using the TaqMan probe method. The relationship between the genotype of 15-PGDH (rs2555639) and metastasis of colon cancer was analyzed. RESULTS: We noticed that rs2555639 TT polymorphism was significantly correlated with the susceptibility to colon cancer metastasis. Also, in the stratified analysis, we found similar results. CONCLUSION: Our data suggested that the rs2555639 T allele is associated with increased risk of metastasis of colon cancer, which can be used as an indicator for colon cancer metastasis.

Radiofrequency deep hyperthermia combined with chemotherapy in the treatment of advanced non-small cell lung cancer.

BACKGROUND: In the era of precision medicine, chemotherapy is still considered the cornerstone of treatment for lung cancer patients without gene mutations. How to reduce the toxicity and increase the efficiency of chemotherapy is worth exploring. This study aimed to investigate the curative effects and safety of hyperthermia combined with chemotherapy (HCT) for advanced patients with non-small cell lung cancer (NSCLC), especially those with malignant pleural effusion. METHODS: We retrospectively evaluated medical records of 93 patients with advanced NSCLC (stage IIIB-IV) from March 2011 to January 2014. The patients were divided into HCT and chemotherapy (CT) groups. The HCT group was treated with gemcitabine and cisplatin (GP) regimen combined with regional radiofrequency deep hyperthermia, while the CT group was treated with GP regimen only. Those with malignant pleural effusion extra underwent thoracentesis and intrapleural injection chemotherapy combined with hyperthermic or not. Clinical treatment results and adverse reactions were compared and analyzed after treatment. SPSS 19.0 software (SPSS Inc., USA) was used for statistical data processing. P values less than 0.05 were accepted to be statistically significant. RESULTS: Among the 93 patients, HCT group included 48 patients (16 patients with malignant pleural effusion), CT group included 45 patients (10 patients with malignant pleural effusion). There was no significant difference between the two groups in patient characteristics. The overall response rate (ORR) of pleural effusions was much better in HCT group than that in CT group (81.2% vs. 40.0%, P = 0.046). The patients in HCT group had lower incidence rate of weakness (12.5% vs. 46.7%, χ = 13.16, P < 0.001) and gastrointestinal (25.0% vs. 77.8%, χ = 25.88, P < 0.001) adverse reactions than that in CT group. The objective tumor response and survival showed no significant differences. CONCLUSIONS: Hyperthermia combined with chemotherapy might lead to the development of better therapeutic strategy for advanced NSCLC with malignant pleural effusion patients. Also, it could greatly reduce the chemotherapy toxic effects in the incidence of weakness and gastrointestinal adverse reactions in advanced NSCLC patients.