Preoperative adjuvant therapy for locally advanced and recurrent/metastatic gastrointestinal stromal tumors: a retrospective study.

BACKGROUND: Preoperative imatinib mesylate therapy for gastrointestinal stromal tumors (GISTs) is controversial. This study aimed to explore the clinical efficacy and optimal duration of preoperative imatinib mesylate (IM) therapy in patients with locally advanced and recurrent/metastatic GISTs. METHODS: We retrospectively examined patients who received preoperative imatinib mesylate therapy from January 2013 to December 2018 at Xiangya Hospital, Central South University and the Second Xiangya Hospital of Central South University, China. Clinical data, including the results of tests for mutations in KIT and PDGFR, findings from regularly conducted re-examinations, abdominal-enhanced computed tomography/magnetic resonance imaging data, responses to imatinib, progression-free survival, and overall cancer-specific survival, were recorded. RESULTS: A total of 25 patients were enrolled in our study, including 18 with a locally advanced GIST and 7 with recurrent or metastatic GISTs. Their ages ranged from 22 to 70 years (M:F = 1.6:0.9), with a mean age of 50.48 ± 12.51 years. The tumor locations included the stomach (56.0%), rectum (16.0%), enterocoelic/retroperitoneal sites (12.0%), and the small intestine (12.0%). Based on testing for mutations in KIT and PDGFR, 22 patients received 400 mg/day KIT, and 3 patients received 600 mg/day PDGFR. The median duration of preoperative IM therapy was 8.96 ± 4.81 months, ranging from 3 to 26 months. According to the Choi criteria, 24 patients achieved a partial response (PR), and 1 patient had stable disease (SD). All patients underwent surgery after preoperative IM therapy, and no postoperative complications appeared. The 2-year PFS and 5-year PFS were 92% and 60%, respectively, and the total 5-year cancer-specific survival (CSS) was 92%. CONCLUSION: Preoperative imatinib therapy is feasible for locally advanced and recurrent/metastatic GISTs and can effectively shrink the tumor size, allow organ sparing, and avoid extensive organ resection. Moreover, the optimal duration of preoperative IM therapy in patients with locally advanced and recurrent/metastatic GISTs was 8.96 ± 4.81 months, ranging from 3 to 26 months, and gastric GISTs had a better response to preoperative IM therapy than did non-gastric GISTs.

Mutational separation and clinical outcomes of TP53 and CDH1 in gastric cancer.

BACKGROUND: Gastric cancer (GC) is a deadly tumor with the fifth highest occurrence and highest global mortality rates. Owing to its heterogeneity, the underlying mechanism of GC remains unclear, and chemotherapy offers little benefit to individuals. AIM: To investigate the clinical outcomes of TP53 and CDH1 mutations in GC. METHODS: In this study, 202 gastric adenocarcinoma tumor tissues and their corresponding normal tissues were collected. A total of 490 genes were identified using target capture. Through t-test and Wilcoxon rank-sum test, somatic mutations, microsatellite instability, and clinical statistics, including overall survival, were detected, compared, and calculated. RESULTS: The mutation rates of 32 genes, including TP53, SPEN, FAT1, and CDH1 exceeded 10%. TP53 mutations had a slightly lower overall occurrence rate (33%). The TP53 mutation rate was significantly higher in advanced stages (stage III/IV) than that in early stages (stage I/II) (P < 0.05). In contrast, CDH1 mutations were significantly associated with diffuse GC. TP53 is related to poor prognosis of advanced-stage tumors; nevertheless, CDH1 corresponds to a diffuse type of cancer. TP53 is exclusively mutated in CDH1 and is primarily affected by two distinct GC mechanisms. CONCLUSION: Different somatic mutation patterns in TP53 and CDH1 indicate two major mechanisms of GC.

Prognostic significance of preoperative lymphocyte to monocyte ratio in patients with signet ring gastric cancer.

BACKGROUND: The ratio of lymphocytes to monocytes (LMR) has been shown to be an effective predictor of gastric cancer prognosis. However, its predictive accuracy for signet ring gastric cancer is currently not well understood. AIM: To evaluate the prognosis predictive accuracy of preoperative LMR in signet ring gastric cancer. METHODS: A total of 212 signet ring gastric cancer patients admitted at the Xiangya Hospital of Central South University, Department of Gastrointestinal Surgery, from January 2012 to December 2016 were enrolled in the study. The prognosis predictive accuracy of preoperative LMR was explored based on the area under the receiver operating characteristic. Factors that significantly affect the survival of patients were identified using single factor analysis, and those that were independently associated with signet ring gastric cancer were identified through multivariate analysis. RESULTS: The results of the single factor analysis revealed a strong correlation between the survival of signet ring gastric cancer patients and several factors, including tumor invasion (χ2 = 49.726; P < 0.001), lymph node metastasis (χ2 = 30.269; P < 0.001), pTNM stage (χ2 = 49.322; P < 0.001), surgical approach (χ2 = 8.489; P = 0.004), age (t = -2.213; P < 0.028), carcinoembryonic antigen (CEA) (Z = -3.265; P = 0.001), platelet-to-lymphocyte ratio (Z = -2.196; P = 0.028), LMR (Z = -2.226; P = 0.026), ALB (t = 3.284; P = 0.001), prognostic nutritional index (t = -3.789; P < 0.001) and FIB (Z = -3.065; P = 0.002). Furthermore, the multivariate analysis further demonstrated that age (HR: 0.563, 95%CI: 0.363-0.873), tumor invasion depth (HR: 0.226, 95%CI: 0.098-0.520), pTNM stage (HR: 0.444, 95%CI: 0.255-0.771), preoperative CEA level (HR: 0.597, 95%CI: 0.386-8.790), and preoperative LMR level (HR: 1.776, 95%CI: 1.150-2.741) were independent factors influencing the prognosis of signet ring gastric cancer. CONCLUSION: In signet ring gastric cancer patients, a low preoperative LMR level predicts poor prognosis. The death risk ratio of the low LMR group compared to the high LMR group is 1.776.

Meta-analysis of laparoscopy-assisted distal gastrectomy with D2 lymph node dissection for gastric cancer.

BACKGROUND: To assess the value of laparoscopy-assisted distal gastrectomy with D2 dissection for treatment of gastric cancer. METHODS: We collected studies that have compared laparoscopy-assisted distal gastrectomy (LADG) and open distal gastrectomy (ODG) with D2 dissection for treatment of gastric cancer in the past 15 years. Data of interest for LADG and ODG were subjected to meta-analysis using a fixed-effect and random-effect model. RESULTS: We analyzed 8 studies that included 1,065 patients. There were significant differences in operating time, blood loss, time to first flatus and first eating, postoperative hospital stay, and postoperative complications between the LADG and ODG groups. Compared with the ODG group, blood loss and complications in the LADG group decreased, time to recovery of gastrointestinal function and hospitalization period were shorter, but operating time was longer. There were no significant differences in the number of harvested lymph nodes, mortality, and rate of recurrence between the groups. CONCLUSIONS: Compared with ODG, LADG with D2 dissection has the advantages of minimal invasion, faster recovery, and fewer complications, and it can achieve the same degree of radicality and short-term prognosis as ODG. The drawbacks are that the operating time is slightly longer and long-term prognosis is not clear.

Crystallization and preliminary X-ray crystallographic studies of human cyclophilin J.

Human cyclophilin J, a new member of the cyclophilin family, has been expressed and crystallized. Diffraction data have been collected to 2.0 A resolution and preliminary crystallographic studies have been completed. The space group of the crystals is P3(1)21, with unit-cell parameters a = b = 40.597, c = 170.732 A, alpha = beta = 90, gamma = 120 degrees.

Role of AFP mRNA expression in peripheral blood as a predictor for postsurgical recurrence of hepatocellular carcinoma: a systematic review and meta-analysis.

AIM: To identify the role of alpha-fetoprotein (AFP) mRNA expression in peripheral blood one week after surgery as a predictor for recurrence of hepatocellular carcinoma (HCC). METHODS: Published studies fulfilling the selection criteria were identified by searching several databases online. After a methodology assessment using a quality scale designed by European Lung Cancer Working Party, data in each research were aggregated by means of meta-analysis. RESULTS: Altogether 368 cases were included in the 9 selected studies, which fulfilled the selection criteria. The quality scores ranged from 35% to 84% with a median score of 55%. The 'design' subscore had the lowest median value (38%). By aggregating the data, a high chi2 value (77.576) was presented. The fail-safe number was 136 and 64 for P = 0.05 and 0.01, respectively. CONCLUSION: AFP mRNA expression in peripheral blood 1 wk after surgery correlated with the recurrence of HCC and was a good predictor for tumor recurrence.

2.6 A resolution crystal structure of the bacterioferritin from Azotobacter vinelandii.

The crystal structure of the bacterioferritin from Azotobacter vinelandii has been determined at 2.6 A resolution. Both the low occupancy of one iron ion in the dinuclear iron center and the deviation of its adjacent residue His130 from the center suggest migration of the iron ion from the dinuclear iron site to the inner nucleation site. The concerted movement of His130 and Glu47 may admit a dynamic gating mechanism for shift of the oxidized iron ion. Ba2+ binding to the fourfold channel implicates that the channel bears Fe2+ conductivity and selectivity to provide a route for iron access to the inner cavity during core formation.

Tri-iodothyronine supplement protects gut barrier in septic rats.

AIM: To investigate the role of tri-iodothyronine supplement in protecting gut barrier in septic rats. METHODS: Twenty-two rats were randomized into three groups: sham group (n=6), sepsis group (n=8), and sepsis plus tri-iodothyronine (T(3)) group (n=8). Septic rat model was established through cecal ligation and puncture (CLP). After 5 h, sham and sepsis groups received saline, and the remaining group received T(3) intraperitoneally. Twenty-one hrs After CLP, intestinal permeability and serum free T(3) and T(4) were measured with fluorescence spectrophotometer and by radioimmunoassay, respectively. Intestinal ultrastructure and histologic morphology were observed under transmission electron microscopy (TEM) and light microscopy, respectively. RESULTS: After 21 h, septic symptoms and signs in sepsis plus T(3) group were milder than those in sepsis group. Serum FT(3) or FT(4) concentration in sepsis group was lower than that in sham group (1.59+/-0.20, 3.41+/-2.14 pmol/L vs 3.44+/-1.40, 9.53+/-3.39 pmol/L, P<0.05), and FT(3) concentration in sepsis plus T(3) group (3.40+/-1.65 pmol/L, P<0.05) was corrected. Portal concentration of fluorescein isothiocyanate-dextran (FITC-D) in sepsis group (2.51+/-0.56 mg/L) was higher than that in sham group (1.22+/-0.21 mg/L) (P<0.01), and in sepsis plus T(3) group (1.68+/-0.38 mg/L) it was decreased significantly(P<0.01). TEM and light microscopy showed that T(3) supplement preserved well ultrastructure and morphology of intestinal mucosa in septic rats. CONCLUSION: Tri-iodothyronine supplement protects gut barrier in septic rats.

Dickkopf-1 (DKK1) promotes invasion and metastasis of hepatocellular carcinoma.

BACKGROUND: Dickkopf-1 (DKK1) recently has been reported to be involved in the progress of hepatocellular carcinoma, but its concrete role is not clear. The objective of this study is to investigate the clinical significance, biological function and molecular mechanism of DKK1 in the invasion and metastasis of hepatocellular carcinoma. METHODS: The mRNA and protein expression levels of DKK1 in hepatocellular carcinoma were detected and its prognostic significance was assessed. The biological function of DKK1 in hepatocellular carcinoma was investigated by using wound healing, transwell invasion assay and hepatocellular carcinoma metastatic mouse model. RESULTS: DKK1 was predominantly elevated in hepatocellular carcinoma tissues, especially in tissue with vascular invasion. The increased DKK1 expression was correlated with multiple tumour nodes, high Edmondson-Steiner grade and vein invasion, as well as poor overall and disease-free survival of hepatocellular carcinoma. DKK1 could promote hepatocellular carcinoma cell invasion and metastasis in vitro and in vivo. Finally, a positive relationship of DKK1 expression with RhoA and JNK levels was found in both hepatocellular carcinoma cell lines and tissues, suggesting that DKK1 promotes invasion and metastasis of hepatocellular carcinoma possibly through the non-canonical Wnt pathway. CONCLUSIONS: Collectively, our findings suggest that DKK1 could serve as a novel prognostic marker and therapeutic target for hepatocellular carcinoma.

Purification and refolding of human alpha5-subunit (PSMA5) of the 20S proteasome, expressed as inclusion bodies in Escherichia coli.

The 20S proteasome is the central enzyme of nonlysosomal protein degradation in both the cytosol and nucleus. It is composed of 28 protein subunits which are arranged into four staggered heptameric rings. The outer rings consist of alpha-subunits which are responsible for binding of proteasome activators, inhibitors, and regulators. To better characterize human alpha5-subunit (PSMA5) of the 20S proteasome, we have established a high-efficiency Escherichia coli expression system. The DNA-coding sequence for the human PSMA5, which was subcloned into the vector pET-22b (+), has been expressed as inclusion bodies in E. coli BL21 (DE3). To produce the native PSMA5, straightforward protocols have been developed for refolding the human PSMA5 in the presence of surfactants using dilution refolding and size-exclusion chromatography matrix refolding methods. After refolding, recovery yields of about 20% were obtained, respectively, with purity above 95%. The human PSMA5 was detected by dynamic light scattering in refolding process, and the molecular weight of the final refolded product was measured using gel filtration chromatography, which indicates that the human PSMA5 exists mainly as tetramer.