No abstract

Mini-patient-derived xenograft (mini-PDX) is a novel, rapid and accurate method used to assess in vivo drug susceptibility. In the present study, a mini-PDX combined with next-generation sequencing (NGS) was used to guide the individualized treatment of a patient with metastatic a-fetoprotein-producing and human epidermal growth factor receptor 2 (HER-2) amplified gastric cancer (GC). Tumor cells were isolated from the tumor tissue obtained from gastroscopic biopsy, transferred into capsules and implanted into severe combined immunodeficiency mice to determine their sensitivity to various drug regimens. NGS was also performed to assess the mutation spectrum of the cells. The results were analyzed to select the most appropriate treatment regimen for the patient. The mini-PDX model confirmed that the patient's tumor was sensitive to a combination regimen of irinotecan and tegafur-gimeracil-oteracil (S-1). Fluorescence in situ hybridization assay of the tumor tissue confirmed HER-2 amplification. The NGS results indicated ERBB2 amplification, and tumor protein P53 [c.659A>G (p.Y220C)], ataxia-telengiectasia mutated [c.125A>G (p.H42R)] and MutS homolog 6 [c.3254C(8>7) (p.F1088Sfs*2)] mutation, in which UGT1A1*28, TA6/7 (rs8175347) was a mutant heterozygote. After six courses of treatment with a regimen comprising 300 mg irinotecan on day 1 + 40 mg S-1 twice daily on days 2-15 + 350 mg trastuzumab once-every 3 weeks, the patient continued with S-1 treatment for 4 courses and trastuzumab for 1 year. The patient retained progression-free survival status at the 32-month follow-up. Thus, the mini-PDX model combined with the NGS rapidly assessed drug sensitivity in a patient with GC and revealed key genetic mutations. However, the proposed technique requires further research to confirm its potential in the individualized treatment of patients with refractory malignancies.

Background Atherosclerosis (AS) is a chronic inflammatory disease, as a main cause leading to vascular diseases worldwide. Although increasing studies have focused on macrophages in AS, the exact relating mechanism is still largely unclear. Our study aimed to explore the pathogenic role and diagnostic role of macrophage autophagy related genes (MARGs) in AS. Methods All datasets were downloaded from Gene Expression Omnibus database and Human Autophagy Database. The differential expression analysis and cross analysis were performed to identify candidate MARGs. GO and KEGG enrichment analyses were conducted to obtain the functional information. Moreover, we analyzed the correlation between target gene and macrophage polarization in AS. The correlation between target gene and plaque instability, different stages of AS were also analyzed. Results Compared with normal samples, a total of 575 differentially expressed genes (DEGs) were identified in AS samples. A total of 12 overlapped genes were obtained after cross-analysis of the above 575 DEGs and autophagy related genes (ARGs). Then, 10 MARGs were identified in AS samples, which were significantly enriched in 22 KEGG pathways and 61 GO terms. The expression of HSPB8 was significantly down-regulated in atherosclerotic samples compared with normal samples (with largest fold change). Meanwhile, the proportion of M-CSF in low HSPB8 expression AS group was higher than high expression AS group. Furthermore, the expression of HSPB8 was negatively correlated with most inflammatory factors. Conclusion The downregulation of MARG HSPB8 probably involves in the M2 macrophage polarization in AS samples. HSPB8 is a promising diagnostic marker for AS patients.

Background: Chemotherapy is the main treatment strategy for patients with advanced HER2-negative gastric cancer(GC); yet, many patients do not respond well to treatment. This study evaluated the sensitivity of a mini patient-derived xenograft (MiniPDX) animal model in patients with HER2-negative intermediate-advanced GC . Methods: In this single-arm, open-label clinical study, we consecutively recruited patients with HER2-negative advanced or recurrent GC from September 2018 to July 2021. Tumor tissues were subjected to MiniPDX drug sensitivity tests for screening individualized anti-tumor drugs; appropriate drug types or combinations were selected based on drug screening results. The primary endpoints were progression-free survival (PFS) and safety, and the secondary endpoints were overall survival (OS) and objective response rate (ORR). Results: A total of 17 patients were screened, and 14 eligible patients were included.The median follow-up time was 9 (2-34) months. The median PFS time was 14.1 (2-13) months, the median OS time was 16.9 (2-34) months, ORR was 42.9% (6/14), and DCR was 92.9% (13/14). The most common treatment-related adverse events (TRAE) were fatigue (14 (100%)), anorexia (13 (93%)) and insomnia (12 (86%)), and the most common grade 3 or worse TRAE was fatigue (6 (43%)), and anorexia (6 (43%)). The occurrence rate of myelosuppression, nausea and vomiting, abnormal liver enzymes, and other grade 3-4 chemotherapy adverse reactions were relatively low, and no grade 5 treatment-related adverse events occurred. Conclusion: Screening of GC/GJC first-line chemotherapy regimens and targeted drugs based on the MiniPDX animal model showed relatively good tumor activity and good safety.

Background Chemotherapy is the main treatment strategy for patients with advanced HER2-negative gastric cancer (GC); yet, many patients do not respond well to treatment. This study evaluated the sensitivity of a mini patient-derived xenograft (MiniPDX) animal model in patients with HER2-negative intermediate-advanced GC. Methods In this single-arm, open-label clinical study, we consecutively recruited patients with HER2-negative advanced or recurrent GC from September 2018 to July 2021. Tumor tissues were subjected to MiniPDX drug sensitivity tests for screening individualized anti-tumor drugs; appropriate drug types or combinations were selected based on drug screening results. The primary endpoints were progression-free survival (PFS) and safety, and the secondary endpoints were overall survival (OS) and objective response rate (ORR). Results A total of 17 patients were screened, and 14 eligible patients were included.The median follow-up time was 9 (2–34) months. The median PFS time was 14.1 (2–34) months, the median OS time was 16.9 (2–34) months, ORR was 42.9% (6/14), and DCR was 92.9% (13/14). The most common treatment-related adverse events (TRAE) were fatigue (14 (100%)), anorexia (13 (93%)) and insomnia (12 (86%)), and the most common grade 3 or worse TRAE was fatigue (6 (43%)), and anorexia (6 (43%)). The occurrence rate of myelosuppression, nausea and vomiting, abnormal liver enzymes, and other grade 3–4 chemotherapy adverse reactions were relatively low, and no grade 5 treatment-related adverse events occurred. Conclusion Screening HER2-negative medium-advanced GC/GJC chemotherapy regimens and targeted drugs based on MiniPDX animal models showed good tumor activity and safety.