GATIS score for predicting the prognosis of rectal neuroendocrine neoplasms: A Chinese multicenter study of 12-year experience.

BACKGROUND: There is currently a shortage of accurate, efficient, and precise predictive instruments for rectal neuroendocrine neoplasms (NENs). AIM: To develop a predictive model for individuals with rectal NENs (R-NENs) using data from a large cohort. METHODS: Data from patients with primary R-NENs were retrospectively collected from 17 large-scale referral medical centers in China. Random forest and Cox proportional hazard models were used to identify the risk factors for overall survival and progression-free survival, and two nomograms were constructed. RESULTS: A total of 1408 patients with R-NENs were included. Tumor grade, T stage, tumor size, age, and a prognostic nutritional index were important risk factors for prognosis. The GATIS score was calculated based on these five indicators. For overall survival prediction, the respective C-indexes in the training set were 0.915 (95% confidence interval: 0.866-0.964) for overall survival prediction and 0.908 (95% confidence interval: 0.872-0.944) for progression-free survival prediction. According to decision curve analysis, net benefit of the GATIS score was higher than that of a single factor. The time-dependent area under the receiver operating characteristic curve showed that the predictive power of the GATIS score was higher than that of the TNM stage and pathological grade at all time periods. CONCLUSION: The GATIS score had a good predictive effect on the prognosis of patients with R-NENs, with efficacy superior to that of the World Health Organization grade and TNM stage.

A combined pre- and intra-operative nomogram in evaluation of degrees of liver cirrhosis predicts post-hepatectomy liver failure: a multicenter prospective study.

Background: Adequate evaluation of degrees of liver cirrhosis is essential in surgical treatment of hepatocellular carcinoma (HCC) patients. The impact of the degrees of cirrhosis on prediction of post-hepatectomy liver failure (PHLF) remains poorly defined. This study aimed to construct and validate a combined pre- and intra-operative nomogram based on the degrees of cirrhosis in predicting PHLF in HCC patients using prospective multi-center's data. Methods: Consecutive HCC patients who underwent hepatectomy between May 18, 2019 and Dec 19, 2020 were enrolled at five tertiary hospitals. Preoperative cirrhotic severity scoring (CSS) and intra-operative direct liver stiffness measurement (DSM) were performed to correlate with the Laennec histopathological grading system. The performances of the pre-operative nomogram and combined pre- and intra-operative nomogram in predicting PHLF were compared with conventional predictive models of PHLF. Results: For 327 patients in this study, histopathological studies showed the rates of HCC patients with no, mild, moderate, and severe cirrhosis were 41.9%, 29.1%, 22.9%, and 6.1%, respectively. Either CSS or DSM was closely correlated with histopathological stages of cirrhosis. Thirty-three (10.1%) patients developed PHLF. The 30- and 90-day mortality rates were 0.9%. Multivariate regression analysis showed four pre-operative variables [HBV-DNA level, ICG-R15, prothrombin time (PT), and CSS], and one intra-operative variable (DSM) to be independent risk factors of PHLF. The pre-operative nomogram was constructed based on these four pre-operative variables together with total bilirubin. The combined pre- and intra-operative nomogram was constructed by adding the intra-operative DSM. The pre-operative nomogram was better than the conventional models in predicting PHLF. The prediction was further improved with the combined pre- and intra-operative nomogram. Conclusions: The combined pre- and intra-operative nomogram further improved prediction of PHLF when compared with the pre-operative nomogram. Trial Registration: Clinicaltrials.gov Identifier: NCT04076631.

Doxorubicin resistance induces IL6 activation in the colon cancer cell line LS180.

Despite improvements in the development of drugs for the treatment of cancer, drug resistance remains a major obstacle. In colon cancer, following an initially promising response, patients develop drug resistance, which impacts the efficacy and halts the response of cancerous cells towards drugs. In the present study, a phosphatase and tensin homolog (PTEN) knockdown model of LS180 cells, doxorubicin-resistant models of LS180 cells as well as doxorubicin-resistant LS180 (PTEN) knockdown model were established. The present study demonstrated that doxorubicin resistance led to the activation of interleukin (IL)6 signalling pathway which was enhanced by knockdown of PTEN. There was also an increase in the levels of IL8 and IL2 which were further enchanced by knockdown of PTEN. Doxorubicin resistance also led to an increase in the population of cancer stem cells in LS180 and shPTEN-treated LS180 cells. Notably, doxorubicin resistance also induced epithelial to mesenchymal transition and increased the formation of mammospheres. Furthermore, the present study also reported that IL6 receptor antibody not only decreased IL6 levels but also led to a significant decreased number of cancer stem cell like population and mammosphere formation. In conclusion, in the present study it was demonstrated that doxorubicin resistance led to activation of IL6 signalling pathway which was further elevated by the knockdown of PTEN in the colon cancer cell line LS180. Thus, inhibiting the IL6 loop may provide an alternative pathway to tackle doxorubicin resistance.

Clinicopathological factors associated with HER2-positive gastric cancer: A meta-analysis.

BACKGROUND: The treatment of patients with advanced gastric cancer remains a most challenging task in the clinical practice. Recently, targeted therapies have significantly impacted the treatment strategy for many common malignancies. The use of trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), plus chemotherapy proved to improve median overall survival in patients with advanced gastric cancer, compared with chemotherapy alone in Trastuzumab for Gastric Cancer (ToGA) trial. However, the prognostic value of HER2 status in gastric cancer remains controversial. Therefore, the aim of this study was to investigate the clinical pathology significance of HER2 overexpression in resectable gastric cancer for selecting the right patients with gastric cancer who may benefit from trastuzumab treatment. METHODS: Publications reported the clinicopathological factors associated with HER2 status in gastric cancer from 2012 to 2017 were collected. The literature databases, such as "Cochrane Library", "Sciencedirect", "Springer", "PubMed", "Embase", were extensively searched to retrieve the clinical studies of HER2 expression in gastric cancer. The major outcomes measures were odds ratios (ORs) and their 95% CIs. Statistical analysis was carried out by Revman software 5.3. The Newcastle-Ottawa scale was used to assess the quality of evidence. RESULT: Fifteen studies met our inclusion criteria. This study demonstrated that the pooled OR for HER2 positivity was associated with being male (OR: 1.42; 95% CI: 1.23-1.64), well/moderately differentiated tumor (OR: 2.76; 95% CI: 1.72-4.45), and for intestinal-type tumor (OR: 0.31; 95% CI: 0.25-0.38). However, it had no correlation with depth of tumor (P = .07), venous invasion (P = .82), and lymphovascular invasion (P = .24). CONCLUSION: HER2-positive expression was associated with male gender, intestinal type, and well/moderate cell differentiation. We recommend that those gastric cancer patients who may benefit from trastuzumab treatment should be subjected to targeted therapies. However, detecting HER2 status may contribute to the target therapy for gastric carcinoma using trastuzumab. This would be strengthened by further studies incorporating comorbidity data, and outcomes from centralized programs.

Clinical application of entire gastrointestinal barium meal combined with multi-temporal abdominal films in patients with intestinal neuronal dysplasia type B.

OBJECTIVE: To report and evaluate the application of entire gastrointestinal barium meal combined with multi-temporal abdominal films in the diagnosis of patients with intestinal neuronal dysplasia type B (IND type B). METHODS: Thirty-six patients with symptoms of long-standing constipation were enrolled in this study. The study took place at the Department of General Surgery, Xiangyang Central Hospital, Hubei Province, China from July 2007 to October 2012. All of them had already been subjected to the tests of barium enema and anorectal manometry and were suspected to be IND type B, but were not confirmed by mucous membrane acetylcholinesterase determination. All underwent the entire gastrointestinal barium meal combined with multi-temporal abdominal films. The data was collected and then analyzed retrospectively. RESULTS: After entire gastrointestinal barium meal combined with multi-temporal abdominal films, 30 out of 36 cases in this group were diagnosed with intestinal neuronal diseases, and then were treated with appropriate surgical treatment. The postoperative pathological diagnosis was IND type B. The other 6 patients in this group still could not be diagnosed explicitly after the test; thus, we treated them with conservative treatment. CONCLUSION: Entire gastrointestinal barium meal combined with multi-temporal abdominal films has the advantage of being able to test the gastrointestinal transfer capabilities and to find physiological and pathological changes simultaneously. It could provide important proof for the diagnosis of patients with intestinal neuronal dysplasia type B.

[PTEN induces anoikis through its phosphatase activity in hepatocellular carcinoma cells].

OBJECTIVE: To investigate the effect and mechanisms of tumor suppressor gene PTEN on the induction of anoikis of hepatocellular carcinoma SMMC-7721 cells. METHODS: SMMC-7721 cells were transfected with GFP plasmids containing wild-type PTEN or phosphatase inactivating mutant PTEN (C124A-PTEN) in vitro; The PTEN expression and the phosphorylation levels of focal adhesion kinase (FAK) and protein kinase B (PKB/Akt) were detected by Western blotting; Flow cytometry assay and laser scanning confocal microscopy were used to analyze apoptosis in adherent and non-adherent cells. RESULTS: Compared with the control, PTEN expression in the cells transfected with wild-type PTEN increased to 248%, while the phosphorylation level of FAK and Akt decreased 65.2% and 89.1%, respectively; and the anoikis percentage increased from 9.5% to 31.3%. In the cells transfected with C124A-PTEN, neither the phosphorylation of FAK and Akt nor the anoikis percentage had obviously changed, although the PTEN expression enhanced dramatically in comparison with the control. CONCLUSION: Through its phosphatase activity, tumor suppressor gene PTEN can suppress the phosphorylation of FAK and Akt, and induce anoikis in hepatocellular carcinoma cells.

Tumor angiogenesis and its clinical significance in pediatric malignant liver tumor.

AIM: To investigate the expression of vascular endothelial growth factor (VEGF) and microvascular density (MVD) count in pediatric malignant liver tumor and their clinical significances. METHODS: Fourteen children with malignant liver tumors including seven hepatocellular carcinomas (HCCs), five hepatoblastomas, one malignant mesenchymoma and one rhabdomyosarcoma were studied. Twelve adult HCC samples served as control group. All samples were examined with streptavidin-biotin peroxidase (SP) immunohistochemical staining for VEGF expression and MVD count. RESULTS: VEGF positive expression in all pediatric malignant liver tumors was significantly higher than that in adult HCC (0.4971+/-0.14 vs 0.4027+/-0.03, P<0.05). VEGF expression in pediatric HCC group was also markedly higher than that in adult HCC group (0.5665+/-0.10 vs 0.4027+/-0.03, P<0.01) and pediatric non-HCC group (0.5665+/-0.10 vs 0.4276+/-0.15, P<0.05). The mean value of MVD in pediatric malignant liver tumors was significantly higher than that in adult HCC (33.66+/-12.24 vs 26.52+/-4.38, P<0.05). Furthermore, MVD in pediatric HCC group was significantly higher compared to that in adult HCC group (36.94+/-9.28 vs 26.52+/-4.38, P<0.05), but there was no significant difference compared to the pediatric non-HCC group (36.94+/-9.28 vs 30.37+/-14.61, P>0.05). All 7 children in HCC group died within 2 years, whereas the prognosis in pediatric non-HCC group was better, in which two patients survived more than 5 years. CONCLUSION: Children with malignant liver tumors, especially with HCC, may have extensive angiogenesis that induces a rapid tumor growth and leads to a poor prognosis.

[PTEN induces apoptosis and up-regulates p53 expression in HepG2 cells].

OBJECTIVE: To investigate the effects of tumor suppressor gene PTEN on apoptosis and protein expression of p53 in HepG2 cells, as well as to explore its mechanisms. METHODS: HepG2 cells were transfected with GFP plasmids containing wild-type PTEN or G129E-PTEN and C124A-PTEN in vitro. Both the expression of wild-type p53 and the phosphorylation of protein kinase B (PKB/Akt) and focal adhesion kinase (FAK) were detected by Western blotting. Flow cytometry and confocal microscopy were used to analyze apoptosis of the transfected cells. RESULTS: Compared with the control, the expression of phosphorylated FAK and phosphoylated Akt were down-regulated in HepG2 cells transfected with wild-type PTEN (-65%, -93%) and G129E-PTEN (-65%, -35%), whereas the apoptosis percentage increased to (19.8+/-1.2)% and (9.2+/-0.6)%, and p53 expression was up-regulated by 120% and 50%, respectively. However, in the cells transfected with C124A-PTEN, neither the phosphorylation of FAK and Akt nor the apoptosis percentage and p53 expression had changed. CONCLUSION: PTEN can dephosphrylate FAK through its protein phosphatase activity, and suppress phosphorylation of Akt mainly through its lipid phosphatase activity. Consequently, it can induce apoptosis of HepG2 cells and up-regulate p53 expression.

Angiogenesis in rabbit hepatic tumor after transcatheter arterial embolization.

AIM: To investigate the effect of transcatheter arterial embolization (TAE) on angiogenesis of hepatic tumor. METHODS: Twenty New Zealand White rabbits were randomly divided into two groups of 10 each and VX2 carcinoma was implanted in the left medial lobes of the livers. Fourteen days later, a silicon catheter was inserted into the left hepatic artery of rabbit with VX2 hepatic tumor and infusion was performed via the hepatic artery using Lipiodol (the TAE group) or saline (the control group). Rabbits were sacrificed 7 d after treatment and tumor tissues were excised. Expression of vascular endothelial growth factor (VEGF) protein and microvessel density (MVD) of tumors were examined using immunohistochemistry. The staining intensity of VEGF was evaluated with a computer-assisted image-analyzer. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the VEGF mRNA expression of tumors. RESULTS: MVD was higher in the TAE group compared with the control group (28.6+/-10.6 vs 16.3+/-6.9, P<0.01). Expression of VEGF protein was enhanced after TAE. The staining intensity of VEGF in the TAE group was 0.162+/-0.018, significantly higher than in the control group (0.142+/-0.01, P<0.01). At mRNA level, VEGF165 mRNA was significantly higher in the TAE group compared with the control group (2.58+/-0.42 vs 1.99+/-0.21, P<0.001). MVD was well correlated to VEGF expression in both the TAE group (r=0.69, P<0.05) and the control group (r=0.72, P<0.05). CONCLUSION: TAE promotes the development of neovascularization of residual tumors through up-regulation of VEGF expression, possibly due to hypoxic insult.