The Ki-67 index in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) may change throughout the disease course. However, the definitive effect of Ki-67 variability on GEP-NENs remains unknown. The aims of this study were to evaluate changes in Ki-67 levels throughout the disease course and investigate the role of Ki-67 index variability in GEP-NENs. Specimens with multiple pathologies were evaluated from 30 patients who were selected from 514 patients with GEP-NENs, being treated at Wuhan Union Hospital from July 2009 to February 2018. The Ki-67 index was evaluated among multiple specimens over the disease course. Univariable and multivariable Cox proportional hazards regression analyses were performed to assess the prognostic significance of various clinical and histopathologic features. Among the 514 patients with GEP-NENs, metastases were seen in 182 (35.41%). Among the 30 patients from whom specimens with multiple pathologies were obtained, 24 were both primary and metastatic specimens and six were specimens collected over the course of the disease. Changes in Ki-67 levels were detected in 53.3% of the patients, of whom 40% had up-regulated Ki-67 levels, and 13.3% had down-regulated Ki-67 levels. Kaplan–Meier survival analysis showed that the group with Ki-67 variability had a shorter overall survival (p = 0.0297). The Cox regression analysis indicated that Ki-67 variability (p = 0.038) was the only independent prognostic factor for overall survival. Our data suggest that patients with GEP-NENs and Ki-67 variability had a poorer prognosis. The re-assessment of Ki-67 at sites of metastasis or during the disease course might play a role in predicting the prognosis of patients with GEP-NENs. This finding could have implications for how GEP-NENs are monitored and treated.

Objectives: Bone marrow‐derived cells (BMDCs), especially mesenchymal stem cells (MSCs), may be involved in the development of Helicobacter pylori‐associated gastric cancer (GC) in mice, but the specific mechanism remains unclear, and evidence from human studies is lacking.Materials and Methods: To verify the role of BM‐MSCs in H pylori‐associated GC, green fluorescent protein (GFP)‐labelled BM‐MSCs were transplanted into the subserosal layers of the stomach in a mouse model of chronic H pylori infection. Three months post‐transplantation, the mice were sacrificed, and the gastric tissues were subjected to histopathological and immunofluorescence analyses. In addition, we performed fluorescence in situ hybridization (FISH) and immunofluorescence analyses of gastric tissue from a female patient with H pylori infection and a history of acute myeloid leukaemia who received a BM transplant from a male donor.Results: In mice with chronic H pylori infection, GFP‐labelled BM‐MSCs migrated from the serous layer to the mucosal layer and promoted GC progression. The BM‐MSCs differentiated into pan‐cytokeratin‐positive epithelial cells and α‐smooth muscle actin‐positive cancer‐associated fibroblasts (CAFs) by secreting the protein thrombospondin‐2. FISH analysis of gastric tissue from the female patient revealed Y‐chromosome‐positive cells. Immunofluorescence analyses further confirmed that Y‐chromosome‐positive cells showed positive BM‐MSCs marker. These results suggested that allogeneic BMDCs, including BM‐MSCs, can migrate to the stomach under chronic H pylori infection.Conclusions: Taken together, these findings imply that BM‐MSCs participate in the development of chronic H pylori‐associated GC by differentiating into both gastric epithelial cells and CAFs.

Background: Our previous study found that bone marrow-derived mesenchymal stem cells (BMSCs) promote Helicobacter pylori (H pylori)-associated gastric cancer (GC) progression by secreting thrombospondin-2 (THBS2). Extracellular vesicles (EVs) are important carriers for intercellular communication, and EVs secreted by BMSCs have been shown to be closely related to tumor development. The aim of this study was to investigate whether BMSC-derived microvesicles (MVs, a main type of EV) play a role in H. pylori-associated GC by transferring THBS2. Methods: BMSCs and THBS2-deficient BMSCs were treated with or without the supernatant of H. pylori for 12 h at a multiplicity of infection of 50, and their EVs were collected. Then, the effects of BMSC-derived MVs and THBS2-deficient BMSC-derived MVs on the GC cell line MGC-803 were assessed by in vitro proliferation, migration, and invasion assays. In addition, a subcutaneous xenograft tumor model, a nude mouse intraperitoneal metastasis model, and a tail vein injection metastasis model were constructed to evaluate the effects of BMSC-derived MVs and THBS2-deficient BMSC-derived MVs on GC development and metastasis in vivo. Results: BMSC-derived MVs could be readily internalized by MGC-803 cells. BMSC-derived MVs after H. pylori treatment significantly promoted their proliferation, migration and invasion in vitro (all P < 0.05) and promoted tumor development and metastasis in a subcutaneous xenograft tumor model, a nude mouse intraperitoneal metastasis model, and a tail vein injection metastasis model in vivo (all P < 0.05). The protein expression of THBS2 was significantly upregulated after H. pylori treatment in BMSC-derived MVs (P < 0.05). Depletion of the THBS2 gene reduces the tumor-promoting ability of BMSC-MVs in an H. pylori infection microenvironment both in vitro and in vivo. Conclusion: Overall, these findings indicate that MVs derived from BMSCs can promote H. pylori-associated GC development and metastasis by delivering the THBS2 protein.

The elderly population presents higher morbidity of H. pylori associated diseases in proximal stomach. The specific pathogenesis and mechanism have not been clearly addressed. The gastric environment for H. pylori colonization is dynamic with increasing age. The aim of present study is to investigate the correlation among the distribution of H. pylori, mucosal inflammation, gastric microenvironment and age. A total of 180 patients with dyspepsia symptoms were divided into young, middle-aged and elderly groups. Biopsies were obtained from each patient in five locations: great curvature (mid-corpus, mid-antrum), lesser curvature (mid-corpus, mid-antrum) and incisura angularis (IA), analyzed for H. pylori density, mucosal inflammation and histopathology. The infection rate of H. pylori increased linearly with age (p < 0.001) in corpus, but not in antrum and IA. The H. pylori density was significantly aggravated in IA (p = 0.002) and corpus (p < 0.001) in elderly patient, but not in antrum. The mucosa inflammation scores were consistent with the severity of H. pylori colonization among three age groups. In elderly patients, the pyloric glands present more frequently in corpus, comparing with young and middle-aged group. A significant positive correlation among aggravating severity of H. pylori infection, mucosal inflammation and pyloric metaplasia in corpus with increasing age (p < 0.001) was occurred. With increasing age, both topographic distribution of H. pylori and the expansion of pyloric glands increased in a distal-to-proximal gastric direction. Pyloric metaplasia in corpus was correlated with the risk of aggravated H. pylori colonization and associated inflammation in elderly population.

Neuroendocrine carcinomas (NECs) and mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) in the gastrointestinal (GI) tract are both rare and malignant; however, it is unclear whether their prognosis is the same. In this cross-sectional study, a total of 12,878 patients with NEC or MiNEN in the GI tract were reviewed retrospectively by searching the Surveillance, Epidemiology, and End Results (SEER) program database. Next, we compared the characteristics and survival between patients with NEC or MiNEN and further analyzed the prognostic factors for the patients. The data showed that patients with MiNEN had a worse prognosis as compared with patients with pure NEC in the small intestine (SI) and appendix, whereas there was no significant survival difference between NEC and MiNEN in the other parts of the GI system. On the whole, age ⩾55 years (p < 0.0001), male (p = 0.002), being diagnosed at TNM Stage II–IV (p < 0.0001) or not receiving surgical treatment (p < 0.0001) were the independent negative prognostic factors for NEC patients, whereas age ⩾55 years (p = 0.003), being diagnosed at TNM Stage III–IV (p < 0.001) or not receiving surgical treatment (p < 0.001) were identified as the independent negative prognostic factors for the MiNEN patients. Furthermore, when NECs or MiNENs were classified based on the primary tumor site, the results showed that the prognostic factors for NEC and MiNEN varied between the tumor sites. The prognostic differences between NECs and MiNENs in the GI tract are heterogeneous and site-related. Patients with appendiceal or SI MiNEN have a poorer prognosis than patients with pure appendiceal or SI NEC. Therefore, we should pay more attention to patients with MiNEN in the SI and appendix and monitor them more closely.