Elevated ASF1B Promotes Apoptosis in Gastric Tumour Cells Through the Bax/Bcl-2-p53 Pathway and is Related to a Good Prognosis

Background: Previous studies have shown that ASF1B, a H3-H4 histone chaperone, plays a key role in cancer. However, the prognostic relevance and mechanism of ASF1B in patients with gastric cancer (GC) are not clear. Therefore, we explored the prognostic role of ASF1B in gastric cancer and explored its biological function.Methods: From the bioinformatics perspective, R software was used for prognostic correlation analysis, Gene Set Enrichment Analysis (GSEA) and Weighted Gene Coexpression Network Analysis (WGCNA) were used to screen related differential genes, and R software was used for Gene Oncology（GO）functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. In vitro, CCK-8 colorimetric assays and wound healing assays were used to evaluate the cell proliferation and migration abilities. The mechanism was investigated by western blot and cell functional assays.Results: Bioinformatics analysis showed that ASF1B was highly expressed in gastric cancer and that its expression was negatively correlated with T stage and prognosis. Cox regression analysis showed that ASF1B could be used as an independent prognostic factor in gastric cancer. The module genes were identified by WGCNA, and the genes related to ASF1B expression were identified by a PPI coexpression network construction. GO analysis showed enrichment in the terms positive regulation of cell cycle, DNA integrity checkpoint, regulation of double strand break repair, and signal transduction of p53; KEGG analysis showed enrichment in the p53 signalling pathway. GSEA showed that ASF1B was highly enriched in gene sets such as p53 signalling pathway, base excision repair, homologous recombination, and mismatch repair. TIMER analysis showed that the expression of ASF1B was closely related to the key genes of p53 apoptosis. In vitro experiments showed that ASF1B gene knockdown enhanced the proliferation and migration of gastric cancer cells and inhibited gastric cancer cell apoptosis by downregulating P53/Bax and upregulating the expression of the Bcl-2 protein.Conclusions: ASF1B may be an independent prognostic factor in gastric cancer. Downregulation of ASF1B promotes the proliferation and invasion of gastric tumour cells and is related to poor prognosis.

Perforated gastric cancer: a critical appraisal

Gastric cancer perforation is a life-threatening condition that accounts for less than 5% of all gastric cancer patients and typically requires emergency surgery. However, preoperative diagnosis is difficult and management has a dual purpose: to treat peritonitis and to achieve a curative resection. The optimal surgical strategy is still unclear and prognosis remains poor. A search of the literature was performed using MEDLINE databases (Pubmed, EMBASE, Web of Science and Cochrane) using terms such as “perforated gastric cancer”, “perforated gastric cancer and surgery”, “perforated gastric tumour” and “gastric cancer perforated”. Case reports, other reviews, non-english written papers and papers written before 2010 were excluded. Eight articles published between 2010 and 2020 matched the inclusion criteria for this review. Perforated gastric cancer was more prevalent in elderly males. Distal stomach was most frequently involved. Preoperative diagnosis was uncommon. Mortality rates ranged from 2 to 46%. Patients able to receive an R0 resection demonstrated better long-term survival compared with patients who had simple closure procedures. Laparoscopic procedure was mentioned only in one study. In an emergency situation, curative RO resection should always be offered in patients without multiple adverse factors. A surgical strategy using laparoscopic local repair as first step of surgery to resolve the peritonitis followed by a radical open or laparoscopic gastrectomy with lymphadenectomy could be considered. A balance between emergency and oncological needs should drive the surgical choice on a case by case basis.

Targeting the PI3K and MAPK pathways to improve response to HER2-targeted therapies in HER2-positive gastric cancer

Background Aberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). The role of PI3K or MEK inhibitors in sensitising HER2-positive GCs to trastuzumab or in overcoming trastuzumab resistance is unclear. Methods Using mass spectrometry-based genotyping we analysed 105 hotspot, non-synonymous somatic mutations in PIK3CA and ERBB-family (EGFR, ERBB2, ERBB3 and ERBB4) genes in gastric tumour samples from 69 patients. A panel of gastric cell lines (N87, OE19, ESO26, SNU16, KATOIII) were profiled for anti-proliferative response to the PI3K inhibitor copanlisib and the MEK1/2 inhibitor refametinib alone and in combination with anti-HER2 therapies. Results Patients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months). Mutations in PIK3CA were only identified in HER2-negative tumours, while ERBB-family mutations were identified in HER2-positive and HER2-negative tumours. Copanlisib had anti-proliferative effects in 4/5 cell lines, with IC50s ranging from 23.4 (N87) to 93.8 nM (SNU16). All HER2-positive cell lines except SNU16 were sensitive to lapatinib (IC50s 0.04 µM–1.5 µM). OE19 cells were resistant to trastuzumab. The combination of lapatinib and copanlisib was synergistic in ESO-26 and OE-19 cells (ED50: 0.83 ± 0.19 and 0.88 ± 0.13, respectively) and additive in NCI-N87 cells (ED50:1.01 ± 0.55). The combination of copanlisib and trastuzumab significantly improved growth inhibition compared to either therapy alone in NCI-N87, ESO26 and OE19 cells (p < 0.05). Conclusions PI3K or MEK inhibition alone or in combination with anti-HER2 therapy may represent an improved treatment strategy for some patients with HER2-positive GC, and warrants further investigation in a clinical trial setting.

Unusual gastric tumour in an adolescent: primary gastric teratoma

Gastric teratoma is a rare entity beyond infancy and usually presents as a slow-growing asymptomatic abdominal mass. There are a few published reports of these tumours seen in patients beyond the age of 1 year. In resource-constrained population, these masses are usually neglected because of minimal symptoms associated with these tumours. We report a case of a 14-year-old adolescent who was diagnosed to have a large primary gastric teratoma and underwent en bloc excision with wedge resection of the stomach. A systematic review to identify the previously reported cases of primary gastric teratoma in patients of over the age of 1 year in last 50 years yielded only five articles. A high index of suspicion for primary gastric teratomas in young children and adolescents presenting with asymptomatic large abdominal masses would help treat these patients with a curative intent and excellent treatment outcomes.

Metastasis of cutaneous squamous cell carcinoma to the stomach: a rare entity

Metastatic spread of cutaneous squamous cell carcinoma (cSCC) to the gastrointestinal tract is a rare entity. A 63-year-old woman with a history of poorly controlled HIV and a recurrent cSCC on the right temple presented with functional decline, ascites and shortness of breath. A CT scan showed widespread metastatic malignancy involving lung, pleura, heart, stomach, liver, retroperitoneum and soft-tissue. In the case presented here, an upper endoscopy revealed a submucosal lesion in the stomach. Biopsies described the lesion as a poorly differentiated SCC. Comprehensive genomic profiling yielded striking molecular similarities between the gastric tumour and the patient’s prior cSCC. It confirmed the origin of the disease and excluded spread from an occult primary. This case adds to the limited literature on gastrointestinal metastases of cSCC and serves as a reminder that non-AIDS-defining cancers are on the rise in the HIV-population.

Coexpression of Matrix Metalloproteinase-7 and Tissue Inhibitor of Metalloproteinase-1 as a Prognostic Biomarker in Gastric Cancer

Background. Degradation of the extracellular matrix (ECM), an essential step in tumour invasion and metastasis, is mainly dependent on the activities of both matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). This study aimed to explore whether expression of MMP-7 and TIMP-1 alone and in combination can be used as a prognostic marker for gastric cancer (GC). Method. A total of 285 patients who had undergone tumourectomy for GC were included. Gastric tumour tissues were stained immunohistochemically to evaluate expression of MMP-7 and TIMP-1. Results. Expression of MMP-7 was associated with tumour N stage and neural invasion. Multivariate Cox regression analysis suggested that expression of MMP-7 or TIMP-1 alone cannot serve as an indicator of patient prognosis; however, coexpression of MMP-7 and TIMP-1 was found to be an independent predictive factor of overall survival in patients with GC (HR=1.74, 95% CI: 1.08-2.80). The results of stratified analysis also showed that the predictive value of MMP-7 and TIMP-1 coexpression was stronger in patients with N3 stage disease and not receiving chemotherapy. Conclusions. In conclusion, coexpression of MMP-7 and its inhibitor TIMP-1 in gastric tumour tissues is a potential prognostic marker for GC. Greater knowledge of protein expression will lead to new paradigms and possible improvements in therapeutics.

Multiple hepatoid gastric adenocarcinoma: A case report and literature review

Background Hepatoid gastric adenocarcinoma (HGAC) is a rare gastric malignancy that exhibits the characteristics of differentiated hepatocellular carcinoma and gastric adenocarcinoma. Most cases of HGAC are also accompanied by an elevated serum alpha-fetoprotein (AFP) concentration. Here, we report a rare case of HGAC involving two primary lesions.Case presentation A 61-year-old man presented at our institution with the complaint of upper abdominal pain. An examination revealed a significantly elevated serum AFP concentration. Abdominal computed tomography revealed a gastric tumour with enlarged peripheral lymph nodes and a cavernous haemangioma in the right anterior hepatic lobe. The patient underwent distal gastrectomy, and postoperative histopathology revealed two hepatoid gastric adenocarcinomas. Immunohistochemically, the tumours were positive for AFP, hepatocyte and chromogranin A (CgA), with a Ki67 index >90%. Following a postoperative diagnosis of HGAC, the patient was treated with a chemotherapy regimen of oxaliplatin combined with capecitabine. At the 6-month follow-up, the patient’s serum AFP concentration returned to the normal level. No signs of recurrence were detected.Conclusions Compared with other gastric cancers, HGAC tends to be more malignant and invasive, with a poor prognosis. These tumours are also prone to liver metastasis,but for which without liver metastasis may have a better prognosis. We hope that our experience with this extremely rare case of HGAC involving two different primary lesions without liver metastasis, as well as our literature review and summary of the etiological mechanism, pathological features, treatment and prognosis, will help improve the diagnosis and treatment of HGAC.