A 78-year-old man with a subepithelial lesion (SEL) in the gastric body and two carcinomas in the gastric antrum was referred to our hospital. Following a diagnosis of SEL, the patient was ...followed-up by esophagogastroduodenoscopy annually for 4 years. Although the SEL had increased in size over the years, histological evaluation of the forceps biopsies did not reveal any significant findings. We detected a hypoechoic mass in the submucosa by endoscopic ultrasonography, and suspected the lesion to be an aberrant pancreas or mesenchymal tumor. The patient first underwent endoscopic submucosal dissection for the 2 gastric cancers. Histological examination of the resected specimens revealed intramucosal well-differentiated tubular adenocarcinomas. Next, endoscopic ultrasound–guided fine-needle aspiration (EUS-FNA) was performed for the gastric SEL. Aspirated specimens revealed an adenocarcinoma with lymphocyte infiltration. The lesion was diagnosed as a gastric carcinoma with lymphoid stroma (GCLS). Subsequently, he underwent distal gastrectomy, and the surgical specimen was confirmed as GCLS corresponding to preoperative diagnosis. In addition, the adenocarcinoma cells were positive for Epstein–Barr (EB) virus-encoded small RNA-1 by in situ hybridization. Finally, the lesion was diagnosed as GCLS associated with EB virus. Thus, EUS-FNA is advantageous for diagnosing GCLS associated with EB virus.
To establish novel islet-based therapies, our group has recently developed technologies for creating functional neo-islet tissues in the subcutaneous space by transplanting monolithic sheets of ...dispersed islet cells (islet cell sheets). Improving cellular function and viability are the next important challenges for enhancing the therapeutic effects. This article describes the adenoviral vector-mediated gene transduction of dispersed islet cells under culture conditions. Purified pancreatic islets were obtained from Lewis rats and dissociated into single islet cells. Cells were plated onto laminin-5-coated temperature-responsive polymer poly(N-isopropylacrylamide)-immobilized plastic dishes. At 0 h, islet cells were infected for 1 h with either conventional type 5 adenoviral vector (Ad-CA-GFP) or fiber-modified adenoviral vector (AdK7-CA-GFP) harboring a polylysine (K7) peptide in the C terminus of the fiber knob. We investigated gene transduction efficiency at 48 h after infection and found that AdK7-CA-GFP yielded higher transduction efficiencies than Ad-CA-GFP at a multiplicity of infection (MOI) of 5 and 10. For AdK7-CA-GFP at MOI = 10, 84.4 ± 1.5% of islet cells were found to be genetically transduced without marked vector infection-related cellular damage as determined by viable cell number and lactate dehydrogenase (LDH) release assay. After AdK7-CA-GFP infection at MOI = 10, cells remained attached and expanded to nearly full confluency, showing that this adenoviral infection protocol is a feasible approach for creating islet cell sheets. We have shown that dispersed and cultured islet cells can be genetically modified efficiently using fiber-modified adenoviral vectors. Therefore, this gene therapy technique could be used for cellular modification or biological assessment of dispersed islet cells.
A 57-year-old woman with a medical history of undergoing Stanford type B acute aortic dissection 11 months before presented with hematemesis. A computed tomography (CT) scan revealed an aortic arch ...aneurysm, and she was diagnosed with aortoesophageal fistula (AEF). Then, thoracic endovascular aortic repair (TEVAR) was emergently performed, and it was successful in gaining stable hemodynamics. After the infection subsided, we performed three-staged esophageal reconstruction for a radical cure. She became able to eat, and she was discharged home from our hospital. In addition to bleeding due to fistula between the aorta and the esophagus, infection of the aortic wall is the main symptom of AEF. Esophagectomy, removal of infected arterial tissue, and revascularization with artificial blood vessel are necessary as radical treatments. There are reports describing that the post-operative mortality rate is 3.1% and the in-hospital mortality rate is 18.8%. AEF is still a disease with a not-so-high lifesaving rate. We report a case of AEF treated with three-staged esophageal reconstruction to reduce surgical invasion after TEVAR along with some literature reviews.
Abstract
AT-rich interactive domain 1A (ARID1A), which is a tumor suppressor gene, is frequently mutated in Epstein-Barr virus-positive gastric cancer EBV (+) GC. While most ARID1A mutations in GC ...are truncating mutations, leading to loss of ARID1A protein expression, epigenetic modifications appear to contribute to ARID1A deficiency in EBV (+) GC harboring wild-type ARID1A. Based on the significant role of epigenetic modifications in EBV (+) GC that contributes to ARID1A deficiency, the methylation status of ARID1A was evaluated in EBV-infected cells and GC patients using a publicly available microarray and the Cancer Genome Atlas (TCGA) database. EBV-encoded miRNAs that potentially target ARID1A were identified as an additional epigenetic modulator by computational prediction. In vitro experiments were conducted to evaluate how EBV-encoded miRNAs affected ARID1A mRNA and protein levels. In clinical GC samples, the expression of predicted miRNAs and ARID1A and the mutation status of ARID1A was evaluated. As results, ARID1A was not hypermethylated in EBV (+) GC samples or EBV-infected GC cells. EBV infection did not alter ARID1A mRNA levels, suggesting that ARID1A protein deficiency was caused by post-transcriptional gene silencing in ARID1A-WT EBV (+) GC. Overexpression of miR-BART11-3p and miR-BART12, which were identified as miRNAs that potentially bind ARID1A, suppressed ARID1A protein expression in MKN7 and NCI-N87 cells. Highly expressed miR-BART11-3p and miR-BART12 were correlated with decreased ARID1A levels in GC tumors which did not harbor ARID1A mutations. The present findings revealed that ARID1A expression was epigenetically regulated by miR-BART11-3p and miR-BART12 in EBV (+) GC.
EBV-encoded miRNAs were specifically expressed in EBV-positive gastric cancer, and ARID1A expression was epigenetically regulated by miR-BART11-3p and miR-BART12, but not by DNA promotor hypermethylation, in EBV-positive gastric cancer.
A 70-year-old male patient was diagnosed with advanced gastric cancer with para-aortic lymph node metastasis. After diagnostic laparoscopy, the patient received 2 courses of neoadjuvant chemotherapy. ...Subsequently, distal gastrectomy, D2 plus para-aortic lymph node dissection, and Roux-en-Y reconstruction were performed. An enlarged lymph node(No. 16b2)was identified during surgery. The histopathological diagnosis revealed ypT4b, ypN3b, cM1(LYM; No. 16), Stage ⅣB. Chemotherapy with ramucirumab plus nab-paclitaxel was administered at 6 weeks postoperatively. However, after 2 courses of chemotherapy, the patient developed an abscess discharge from the wound, which was confirmed by an abdominal CT scan and diagnosed as an intra-abdominal abscess derived from duodenal perforation. The abscess was drained percutaneously. Subsequently, chemotherapy with nab-paclitaxel, nivolumab, and trifluridine/tipiracil hydrochloride was administered. After the appearance of brain metastases, the treatment was shifted to palliative care. The patient died 2 years and 7 months later from the primary disease.
Background
Chemotherapy has the potential to induce CD8
+
T-cell infiltration in the tumor microenvironment (TME) and activate the anti-tumor immune response in several cancers including esophageal ...squamous cell carcinoma (ESCC). The tumor cell-intrinsic cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway has been known as a critical component for regulating immune cell activation in the TME. However, its effect on the infiltration of immune cells induced by chemotherapy in the ESCC TME has not been investigated.
Methods
We examined the effect of the tumor-cell intrinsic cGAS–STING pathway on the infiltration of CD8
+
T cells induced by chemotherapy in ESCC using ESCC cell lines and surgically resected ESCC specimens from patients who received neoadjuvant chemotherapy (NAC).
Results
We found that chemotherapeutic agents, including 5-fluorouracil (5-FU) and cisplatin (CDDP), activated the cGAS–STING pathway, consequently inducing the expression of type I interferon and T-cell-attracting chemokines in ESCC cells. Moreover, the tumor cell-intrinsic expression of cGAS–STING was significantly and positively associated with the density of CD8
+
T cells in ESCC after NAC. However, the tumor cell-intrinsic expression of cGAS–STING did not significantly impact clinical outcomes in patients with ESCC after NAC.
Conclusion
Our findings suggest that the tumor cell-intrinsic cGAS–STING pathway might contribute to chemotherapy-induced immune cell activation in the ESCC TME.
Cancer-associated fibroblasts (CAFs) in the tumor microenvironment play an essential role in the tumor progression of esophageal squamous cell carcinoma (ESCC). The present study aimed to investigate ...the expression of CAF-related molecules, versican, periostin and lumican, in cancer stroma, to provide prognostic stratification for patients with ESCC after surgery. A total of 106 patients with ESCC who underwent curative esophagectomy without preoperative chemotherapy or radiotherapy were enrolled. The expression of CAF-related stromal proteins, including versican, periostin and lumican, was examined using immunohistochemistry, and the prognostic value was assessed by Kaplan-Meier survival analysis, and univariate and multivariate Cox regression models. The expression of versican, periostin and lumican was found specifically in the stromal component of ESCC. Kaplan-Meier analysis demonstrated that, compared with a low expression level, a high expression level of versican, periostin or lumican in the cancer stroma was significantly associated with worse relapse-free survival (RFS) and overall survival times in patients with ESCC. The prognostic values of stromal versican and lumican remained significant in a stratified analysis of stage I patients. Moreover, univariate and multivariate analysis revealed that high stromal versican or lumican expression was an independent prognostic factor for RFS in the patients. The present study demonstrated that CAF-related molecules, including versican, periostin and lumican, were expressed in the stroma of ESCC, and that stromal expression of versican and lumican in particular may have clinical utility as a prognostic biomarker for poor RFS in postoperative patients with ESCC.
Abstract
Background
Circulating tumor cells (CTCs) in patients with malignant tumors can be used as a prognostic marker. Recently the existence of mesenchymal CTCs have been detected by new methods. ...However, it has been not yet clarified how CTCs are associated with the treatment effects in esophageal cancer patients. We assessed CTCs in esophageal cancer patients and investigated the relationship between CTCs and treatment effect.
Methods
Seven patients who had potential of curative resection have been enrolled and peripheral blood samples (10ml) were collected before and after treatment. All patients received chemotherapy (5-FU and cisplatin) and four patients of them received as neoadjuvant therapy. Other patients received only chemotherapy and radiation therapy without operation. CTCs were analyzed using a Microfluidic Chip devise provide with the Nihon Gene Research Laboratories. This system can isolates CTCs from blood samples, based on their size and deformability differences from blood cells. Phenotypes of CTCs are determined by staining and scanning systems. A previous report revealed that this method had higher sensitivity for CTCs than conventional methods (the Cell Search system) in 61 metastatic breast cancer.
Results
Treatments effects were stable disease or better in all cases. Multiple CTCs were detected in all cases before treatment. Five patients had epithelial CTCs and others had only mesenchymal CTCs. Total number of CTCs after treatment whose data can be available decreased except for two cases. One patient had no CTC after treatment. Two cases have been currently analyzing.
Conclusion
CTCs may exist almost all patients of Stage II or more esophageal cancer. Decreasing the number of CTCs after treatment suggests some relationship between CTCs and treatment effect, and the accumulation of more cases is necessary.
Disclosure
All authors have declared no conflicts of interest.
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