Kuntang Shen

Impact of KIT and PDGFRA Gene Mutations on Prognosis of Patients with Gastrointestinal Stromal Tumors After Complete Primary Tumor Resection

IntroductionTo investigate the impact of KIT and PDGFRA gene mutations on the prognosis of gastrointestinal stromal tumors (GIST).Material and MethodsTumor tissue from 184 patients with primary GIST was submitted to mutational analysis of exons 9, 11, 13, and 17 of the KIT gene and exons 12 and 18 of the PDGFRA gene. Clinical and pathological parameters were analyzed and correlated to the risk of recurrence and disease-free survival (DFS).Results and DiscussionThe authors found that somatic mutations were detected in 162 tumors (88.0%). Age, clinical stage, mitotic count, and tumor size were of prognostic relevance on both univariate and multivariate analysis. Five-year DFS was 41.9%. While the presence of a KIT or PDGFRA mutation per se was not associated with tumor recurrence and/or disease-free survival, exon 11 deletion and hemizygous mutation status were both independent factors highly predictive for poor survival.ConclusionThe authors conclude that KIT exon 11 deletions and somatic loss of the wild-type KIT identified patients with poor prognosis. Age, clinical stage, tumor size, and mitotic count were standard clinicopathologic features that significantly influenced the prognosis. Mutation type of the mitogen receptor c-kit has a potential for predicting the course of the disease and might contribute to management individualization of GIST patients.

Prognostic analysis of combined curative resection of the stomach and liver lesions in 30 gastric cancer patients with synchronous liver metastases

BackgroundGastric cancer with synchronous liver metastasis remains a clinical treatment challenge. There has been a longstanding debate on the question whether surgical resection could be beneficial to long-term survival. This study is to investigate the effectiveness and prognostic factors of combined curative resection of the stomach and liver lesions in gastric cancer patients with synchronous liver metastases.MethodsA total of 30 patients who underwent simultaneous curative gastric and liver resection from March 2003 to April 2008 were analyzed retrospectively. Univariate and multivariate analyses were performed to select independent factors for survival.ResultsThe overall 1-, 2-, 3- and 5-year survival rates of 30 patients were 43.3%, 30.0%, 16.7% and 16.7%, respectively, with a median survival of 11.0 months and 5 patients still living by the time of last follow-up. Single liver metastasis (p = 0.028) and an absence of peritoneal dissemination (p = 0.007) were significantly independent prognostic factors for these gastric cancer patients with synchronous liver metastases. Major adverse events were protracted stomach paralysis in 2 patients and pulmonary infection in another 2 patients, all of whom recovered after conservative treatment.ConclusionsThis descriptive study without control group found that patients with solitary liver metastasis and absence of peritoneal dissemination could have better survival benefit from simultaneous curative resection of the gastric cancer and liver metastases.

Bone marrow mesenchymal stem cells promote the repair of islets from diabetic mice through paracrine actions.

Transplantation of bone marrow mesenchymal stem cells (MSCs) has been shown to effectively lower blood glucose levels in diabetic individuals, but the mechanism has not been adequately explained. We hypothesized that MSCs exert beneficial paracrine actions on the injured islets by releasing biologically active factors. To prove our hypothesis, we tested the cytoprotective effect of conditioned medium from cultured MSCs on isolated islets exposed to STZ in vitro and on mice islets after the experimental induction of diabetes in vivo. We assessed islet regeneration in the presence of conditioned medium and explored the possible mechanisms involved. Transplantation of MSCs can ameliorate hyperglycemia in diabetic mice by promoting the regeneration of β cells. Both β cell replication and islet progenitors differentiation contribute to β cell regeneration. MSC transplantation resulted in increases in pAkt and pErk expression by islets in vivo. Treatment with MSC-CM promoted islet cell proliferation and resulted in increases in pAkt and pErk expression by islets in vitro. The MSC-CM-mediated induction of β cell proliferation was completely blocked by the PI3K/Akt inhibitor LY294002 but not by the MEK/Erk inhibitor PD98059. Together, these data suggest that the PI3K/Akt signal pathway plays a critical role in β cell proliferation after MSC transplantation.

PIK3C2A is a gene-specific target of microRNA-518a-5p in imatinib mesylate-resistant gastrointestinal stromal tumor

Imatinib mesylate resistance occurs in some patients with gastrointestinal stromal tumors (GISTs) during the course of treatment. In this study, we investigated the relationship between microRNAs (miRNAs) and imatinib-resistant GISTs, and the effect of miR-518a-5p on PIK3C2A in imatinib-resistant GISTs. A total of 20 matched-pair GIST samples from imatinib-resistant patients were included in the study. Each of the paired tumor specimens were from the same patient who had surgical removal of GISTs preimatinib and postimatinib treatment. Seven pairs of tissues were resected for microarray analysis, and the remaining 13 pairs were utilized for miRNAs analysis. Target genes were selected based on bioinformatics from multiple biological databases. Luciferase reporter assays were used to confirm the binding of miR-518a-5p to PIK3C2A 3′UTR. GIST882R-NC, 882R-miR-518a-5p-OE, and 882R-miR-518a-5p-KD cell lines were constructed using lentiviral vectors. miR-518a-5p and PIK3C2A expression in 882R-NC, 882R-OE, and 882R-KD cells was assessed by real-time PCR and western blotting. A cell counting kit was used to detect the influence of miR-518a-5p to cell proliferation. TUNEL staining was applied to detect the influence of miR-518a-5p to cell apoptosis. Microarray analysis showed that miR-518a-5p was downregulated in imatinib-resistant GISTs, and the expression of miR-518a-5p was confirmed with good concordance between real-time PCR and miRNA microarray results. Luciferase reporter assays indicated that miR-518a-5p bound to the PIK3C2A 3′UTR. Compared with 882R-OE, PIK3C2A expression was significantly increased in 882R-KD cells. MiR-518a-5p reduced 882R proliferation and promoted 882R apoptosis. In conclusion, PIK3C2A is a gene-specific target of miR-518a-5p in imatinib mesylate-resistant GISTs. Low expression of miR-518a-5p is likely to upregulate PIK3C2A and affect the cellular response to the drug, causing resistance to imatinib in GISTs.

MiR-320a downregulation is associated with imatinib resistance in gastrointestinal stromal tumors

Gastrointestinal stromal tumor (GIST) is one of the most common mesenchymal tumors of the gastrointestinal tract. Though imatinib improves the outcome, drug resistance remains the major problem for extending patient survival. Genetic mutation of the drug targets is the known mechanism for imatinib resistance. However, it cannot explain all of the phenomena of imatinib resistance, and numerous additional mechanisms have been proposed to account for imatinib resistance in various model systems. In this study, we applied the SYBR-green quantitative polymerase chain reaction-based array approach to screen the differentially expressed miRNAs between primary GIST patients and imatinib-resistant patients. The selected candidate miRNAs were validated in a cohort of 12 GIST patients. We found that low expression of miR-320a was correlated with short time to imatinib resistance, and proposed the potential mechanism of miR-320a for imatinib resistance.

Intra-abdominal inflammatory myofibroblastic tumor: Spontaneous regression

Inflammatory myofibroblastic tumors are usually treated by surgical resection. We herein report two cases of intra-abdominal inflammatory myofibroblastic tumors that were unresectable and underwent spontaneous regression without any treatment. Our case report and literature review show that regression is more common in the middle-aged and older male populations. Abdominal discomfort and fever were the most common symptoms, but the majority of patients had no obvious physical signs. There was no specific indicator for diagnosis. The majority of the lesions regressed within 3 mo and nearly all of the masses completely resolved within 1 year. We conclude that the clinical characteristics of inflammatory myofibroblastic tumors are variable and, accordingly, the disease needs to be subdivided and treated on an individual basis. Surgery is always the first-line treatment; however, for those masses assessed as unresectable, conservative therapy with intense follow-up should be considered.

Acute acalculous cholecystitis immediately after gastric operation: case report and literatures review.

Acute acalculous cholecystitis (AAC) is a rare complication of gastric surgery. The most commonly accepted concepts regarding its pathogenesis are bile stasis, sepsis and ischemia, but it has not been well described how to identify and manage this disease in the early stage. We report three cases of AAC in elderly patients immediately after gastric surgery, which were treated with three different strategies. One patient died 42 d after emergency cholecystectomy, and the other two finally recovered through timely cholecystostomy and percutaneous transhepatic gallbladder drainage, respectively. These cases informed us of the value of early diagnosis and proper treatment for perioperative AAC after gastric surgery. We further reviewed reported cases of AAC immediately after gastric operation, which may expand our knowledge of this disease.

Role of surgery in patients with focally progressive gastrointestinal stromal tumors resistant to imatinib

The benefits of surgery for focally progressive gastrointestinal stromal tumor (GIST) during imatinib therapy are still in discussion. The aim of this study was to compare the outcomes of surgical resection of progressive lesions following tyrosine kinase inhibitor (TKI) therapy (S group) or TKI therapy alone (NS group) in GIST patients. We retrospectively investigated 57 patients with focally progressive GIST during imatinib therapy who were treated in Zhongshan hospital, Fudan University. Progression-free survival (PFS) and overall survival (OS) in the S group were significantly longer than those in the NS group. Among S group, the patients with R0 resection showed longer PFS than R2 resection; however, no difference was found between these two groups. Moreover, PFS and OS were not different in the NS-S group compared with S group. On multivariate analysis, surgery is an independent prognostic factor for longer PFS and OS. Our study supports the decision of treating GIST patients who were focally resistant to imatinib with surgery resection based on its benefit.

Efficacy of preoperative chemotherapy regimens in patients with initially unresectable locally advanced gastric adenocarcinoma: capecitabine and oxaliplatin (XELOX) or with epirubicin (EOX)

Purpose We assessed the effectiveness of EOX (capecitabine, oxaliplatin and epirubicin) compared with XELOX (capecitabine and oxaliplatin) as preoperative chemotherapy for initially unresectable locally advanced gastric cancer. Methods This is a prospective observational study. Patients with unresectable locally advanced gastric cancer were performed EOX regimen or XELOX regimen at the discretion of the investigators. They were assessed for response every 2 cycles by CT (computed tomography) scan. A multidisciplinary team reassessed resectability after 4 cycles. The primary endpoint was the response rate. Secondary end points included the R0 resection rate, survival and adverse events. Results From November 2008 to May 2015, 242 patients were enrolled; 112 of them were assigned to EOX regimen and 130 to XELOX regimen. The response rates were 33.0% and 33.8% respectively in EOX group and XELOX group (P = 0.997). After 4 cycles of chemotherapy, 63 patients (56.3%) in EOX group and 81 patients (62.3%) in XELOX group received radical operation (P = 0.408). There was no significant difference in progress-free survival (PFS, 12.0m vs. 15.4m, P = 0.925) and overall survival (OS, 25.7m vs. 29.0m, P = 0.783) in two groups. In addition, more adverse effects occurred in EOX group, such as more leucopenia (22.3% vs. 10.0%, P = 0.014), neutropenia (23.2% vs. 11.5%, P = 0.025), fatigue (11.6% vs. 3.8%, P = 0.041) and vomiting (10.7% vs. 2.3%, P = 0.015). Conclusions For unresectable locally advanced gastric cancer patients, XELOX regimen showed similar effects in response rate, radical resection rate and survival benefits, but with less toxicity effects.

Expanded endoscopic therapy criteria should be cautiously used in intramucosal gastric cancer.

Objective Accurate estimation of lymph node metastasis (LNM) in intramucosal gastric cancer is essential to select less invasive treatment options and even avoid surgery. The aim of this study was to evaluate combined clinicopathological features to predict the presence of LNM. Methods A retrospective review of data from 386 intramucosal gastric cancer patients who underwent gastrectomy with extended lymphadenectomy from 2003 to 2010 was conducted. The mutual relation between clinicopathological characteristics and LNM was analyzed. Results LNM was detected in 40 (10.4%) of the 386 patients. Histological type and vascular or lymphatic invasion presence showed a positive correlation with LNM occurrence by univariate analysis. Multivariate analysis revealed that histological type was the only factor associated with LNM. Combined clinicopathologic characteristics would be more predictable for LNM. We found no LNM when we used combined clinicopathological characteristics conforming to Japanese absolute indications for endoscopic therapy. The LNM rate was as high as 8.7% when Japanese expanded criteria were used. Univariate analysis in cancer conformity to expand endoscopic submucosal dissection (ESD) indication also revealed that the undifferential type was the only significant factor for LNM. Conclusions It was possible to predict intramucosal gastric cancer cases without LNM using combined clinicopathological characteristic analysis. Extended indication for ESD should be cautiously used for intramucosal gastric cancer patients.