The shift of the treatment strategy of gastrointestinal stromal tumor from the surgical perspective / 中华外科杂志

As tumors originated from mesenchymal tissue, gastrointestinal stromal tumors (GIST) has its own typical history. For the idea of treatment for GIST at different historical periods, the role and value of surgery for the treatment of GIST keep changing. Laparoscopy and endoscopy will have the role they deserved. With the understanding of pathogenesis of GIST, targeted chemotherapy will be more and more accurate and individualized. How to improve the overall therapeutic effect of GIST, especially for the patients with the high risk and drug-resistance, is the dilemma and challenges for the surgeons.

Research advances in the secondary resistance mechanism of imatinib in gastrointestinal stromal tumors / 中华胃肠外科杂志

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumors in the gastrointestinal tract. Though surgical resection is the only radical treatment, postoperative recurrence and metastasis often occur. The first-line therapy for the treatment of recurrent, metastatic and unresectable GIST is imatinib. More than 80% of patients can benefit from imatinib treatment, but half of patients will still have recurrence or metastasis within 2 years after treatment initiation, and secondary drug resistance is a major cause of disease progression. Therefore, adeep understanding of the mechanisms of secondary drug resistance will guide us to develop personalized therapeutic schedule in the future. This article describes the mechanism of IM secondary resistance from the aspects of gene alteration, abnormal activation of signal transduction pathway, autophagy, apoptosis and drug concentration. It is found that single drug therapy has certain limitations in patients with secondary resistance to IM. Using IM combined with downstream signaling molecule inhibitors, autophagy inhibitors, insulin-like growth factor 1 receptor (IGF-1R) inhibitors, heat shock protein 90 (HSP90) inhibitors, cytotoxic T lymphocyte - associated antigen - 4 (CTLA - 4) antibodies and mitochondrial inhibitors provide us new therapeutic ideas. However, these combination treatments are still in the research phase, and further trials are needed to confirm the safety and efficacy. With the gradual deepening of research on drug resistance mechanisms, it will provide more solutions to the current serious drug resistance problem.

Standardization of the endoscopic treatment for early gastric cancer / 中华胃肠外科杂志

With the increasing incidence of early gastric cancer, endoscopic treatment has been widely used. It has also played an important role in the diagnosis and treatment of gastric cancer. Therefore, it is very important to carry out standardized treatment with endoscopy. In theory, endoscopic resection can be performed in early gastric cancers which have no lymph node metastasis and also can be resected completely. Endoscopic therapy is absolutely indicated in macroscopically intramucosal differentiated carcinomas (pT1a) without ulcer or ulcer scar and with diameter ≤2 cm. The expanded indications are: (1) macroscopically intramucosal differentiated carcinomas (pT1a) without ulcer and with diameter >2 cm; (2) macroscopically intramucosal differentiated carcinomas (pT1a) with ulcer and with diameter ≤2 cm; (3) macroscopically intramucosal undifferentiated carcinomas (pT1a) without ulcer and with diameter ≤2 cm. Methods of preoperative evaluation include endoscopy, CT, and endoscopic ultrasonography (EUS). For tumor size greater than 3 cm and undifferentiated lesions, evaluation should be carried out carefully in order to avoid the underestimation of T staging. During endoscopic surgery, the extent, nature, and depth of the lesion should be clearly defined again, if necessary, assisted by staining endoscopy. In order to avoid complications such as bleeding and perforation, stanch bleeding and aspiration of gas should be performed promptly during the operation. After endoscopic resection, when pathology reveals positive margin of resected specimen, lesions invading deep submucosa, vascular involvement or peri-gastric lymph node metastasis, additional surgery should be recommended. Even if the patients have been evaluated as radical treatment, close follow-up is still necessary. Only when surgeons strictly obey the indications of endoscopic treatment, make the accurate evaluations for the patients before operation, undergo endoscopic operation carefully, and perform the follow up closely, the patients can be benefit from endoscopic therapy really.

Prevention and management of pseudoaneurysm after radical gastrectomy for gastric cancer / 中华胃肠外科杂志

With the promotion of standard radical resection of gastric cancer, the incidence of postoperative pseudoaneurysm is significantly increasing. Both the patient's own factors and iatrogenic factors are accoutable. Surgeons should clarify the causes of pseudoaneurysm, pay attention to the clinical symptoms and signs, and treat the patients appropriately. In order to avoid the occurrence of postoperative pseudoaneurysm, surgeons should carefully evaluate the preoperative conditions, perform precision operation and reduce the morbidity of postoperative infection and fistula.

Efficacy analysis of targeted therapy combined with surgery in the treatment of recurrent and metastatic gastrointestinal stromal tumor / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate the efficacy of targeted therapy combined with surgery in the treatment of recurrent and metastatic gastrointestinal stromal tumor(GIST).</p><p><b>METHODS</b>Clinicopathological and followed-up data of 318 patients with recurrent and metastatic GIST admitted in Zhongshan Hospital between January 2000 and December 2015 were analyzed retrospectively. According to different treatment methods, the patients were divided into four groups: surgery group (operation alone, 44 cases), target therapy group (imatinib alone, 108 cases), target therapy combined with surgery group (imatinib plus operation, 139 cases), other therapy group (chemotherapy, Chinese medicine and others, 27 cases). The progression-free survival (PFS) and overall survival (OS) of four groups were compared.</p><p><b>RESULTS</b>The baseline informations, such as age, gender, primary site, et al, were not significantly different (all P>0.05), but the recurrent and metastatic site was significantly different among 4 groups (P=0.000). The medial PFS of surgery group, target therapy group, target therapy combined with surgery was 16(95%CI: 4.9 to 27.0) months, 44 (95%CI: 30.9 to 57.1) months, 35 (95%CI: 26.5 to 43.5) months, respectively, and the latter 2 groups had significantly longer PFS than surgery group(P=0.000), while no significant difference was found between target therapy group and target combined with surgery group (P=0.251). The median OS of surgery group, target therapy group, target therapy combined with surgery, and other therapy group was 24 (95%CI: 9.0 to 39.0) months, 69(95%CI: 40.8 to 97.2) months, 92(95%CI: 78.0 to 106.0) months, 12(95%CI: 9.5 to 14.5) months. Target therapy group and target therapy combined with surgery group had significantly longer OS than surgery and other therapy groups (P=0.000), while the target therapy combined with surgery group had significantly longer OS than target therapy group(P=0.028).</p><p><b>CONCLUSION</b>Target therapy combined with surgery can prolong the survival of recurrent and metastatic GIST patients.</p>

Comparative study of laparoscopic and open surgery for gastric gastrointestinal stromal tumors / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate the feasibility and short-term efficacy of laparoscopic resection of primary localized gastric gastrointestinal stromal tumors (GIST) by comparing with open surgery.</p><p><b>METHODS</b>Clinicopathological data of 167 gastric GIST patients undergoing operation in Zhongshan Hospital from June 2008 to December 2013 were retrospectively analyzed, among whom 55 received laparoscopic surgery and 112 underwent open surgery for primary local gastric GIST. Efficacy of different size and different location of GIST was compared between laparoscopic and open groups.</p><p><b>RESULTS</b>There was no conversion to open surgery in laparoscopy group. Compared with open surgery, laparoscopic resection for gastric GIST smaller than 5 cm or located at anterior wall, greater curvature, lesser curvature, was associated with similar operation time(P>0.05), but less blood loss, shorter post-hospital stay or flatus time(all P<0.05). The operative outcomes were similar between laparoscopic and open resection for gastric GIST bigger than or equal to 5 cm or located at posterior wall(all P>0.05), except the longer operation time in laparoscopy group(P<0.05). The incidence of postoperative complication did not differ between two groups. Laparoscopic group had 2 patients with gastroparesis and open group had 2 gastroparesis, 2 pulmonary infection, and 1 poor wound healing(all P>0.05), which all recovered after conservative treatment. During 7 to 84 months(median 35) of follow-up, no recurrence or hepatic metastasis was found in laparoscopy group, and 3 hepatic metastases in open group. There was no significant difference of recurrence-free survival between two groups(P>0.05).</p><p><b>CONCLUSION</b>Laparoscopic resection for gastric GIST is safe and effective in selected patients, especially for those with tumors smaller than 5 cm, or located at anterior wall, greater curvature, lesser curvature, whose short-term outcomes are better than open resection.</p>

Clinicopathological features of small gastrointestinal stromal tumors / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate the clinicopathological features of small gastrointestinal stromal tumors(GISTs) and to evaluate the efficacy of endoscopic therapy for GISTs.</p><p><b>METHODS</b>Clinicopathological and follow-up data of 418 patients with GISTs undergoing endoscopic therapy in the Zhongshan Hospital between January 2009 and July 2014 were analyzed retrospectively. All the cases were evaluated by the NIH risk classification and AIFP classification, and were grouped according to the tumor size and location. Nuclear atypia and mitotic count were used to evaluate the biological behavior of small GIST. Efficacy of endoscopic therapy was analyzed with follow-up data.</p><p><b>RESULTS</b>Out of 418 patients, GISTs located in the esophagus was 14(3.3%), in the stomach 389(93.1%), in the duodenum 5(1.2%), in the rectum 10(2.4%). A total of 412(98.6%) patients were mainly spindle cells, and mitosis was not found in 320(76.5%) patients. In 389 small stomach GIST, 245(58.6%) were in fundic region. Cases were divided into four groups according to the size and the result revealed the bigger the size, the more the mitotic count. Nuclear atypia in the 1.5-1.9 cm group was significantly higher compared to other groups. Cases were divided into four groups according to the location and the result revealed the mitotic count was not associated to the location. While the nuclear atypia of stomach GIST was significantly higher than that of esophageal GIST and the nuclear atypia of rectum GIST was significantly higher than that of other positions. The median follow-up was 32(4-69) months. One case(gastric fundus GIST, >1.5 cm) presented local recurrence 23 months after operation and underwent endoscopic resection again. No recurrence or metastasis was found in other patients.</p><p><b>CONCLUSIONS</b>Endoscopic resection technique is effective for small GISTs patients. The small GISTs with 0.4 cm diameter or less are often benign and should be followed up for long time. The small GISTs with 0.5 cm diameter or more possess the risk of malignancy, then surgical resection should be performed. Rectum small GISTs (except for 0.4 cm diameter or less) have worse biological behavior and should be removed.</p>

Clinicopathological analysis of 80 patients with duodenum gastrointestinal stromal tumors / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To explore the clinicopathological characteristics, efficacy, and prognostic factors for patients with duodenum gastrointestinal stromal tumor(GIST).</p><p><b>METHODS</b>Clinicopathological and follow-up data of 80 patients with duodenum GIST in the Zhongshan Hospital from January 2000 to December 2013 were analyzed retrospectively.</p><p><b>RESULTS</b>There were 38 male and 42 female patients with a median age of 54 years. The major symptoms were upper alimentary tract hemorrhage and abdominal pain. Thirty-nine patients received local tumor excision, 18 patients underwent segmental duodenectomy, 23 patients were subjected to pancreaticoduodenectomy, all these operations were R0 resection. Thirty patients received imatinib treatment after operation, and 11 among them had metastasis relapse. Recurrence-free survival rates of 1-, 3-, and 5-years were 96.2%, 90.6%and 78.6% retrospectively. Overall survival rates of 1-, 3-, and 5-years were 100%, 98.3% and 96.1%. Multivariate Cox analysis showed tumor size >5 cm, mitotic count >5 mitosis/50 HPF and intermediate/high NIH risk classification were associated with an increased risk of recurrence. The significant difference was not detected between the limited resection group and pancreaticoduodenectomy group in OS and RFS.</p><p><b>CONCLUSIONS</b>Surgery is still the main treatment for duodenum GIST. The surgical program is mainly determined by the location and size of tumor. Imatinib therapy should be used if necessary.</p>

Evaluation and endoscopic treatment of small and micro gastrointestinal stromal tumors / 中华胃肠外科杂志

The incidence of small and micro gastrointestinal stromal tumors is increasing significantly because of the enhanced health consciousness and advanced endoscopic technology. But there still is controversial in the biological behavior and clinical treatment of GIST. The treatment of the GIST with endoscopic technology has obvious advantages. This method can remove tumor and avoid significant trauma. In this paper, the biological behavior, clinical evaluation and endoscopic treatment of the GIST are discussed.

Impact of the number of lymph nodes dissected on the prognosis of G3 advanced gastric cancer / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To explore the risk factors associated with the prognosis in poorly differentiated(G3) advanced gastric cancer (AGC) and the effect of number of harvested lymph nodes on the prognosis.</p><p><b>METHODS</b>Clinical data of 484 patients with G3 advanced gastric cancer undergoing gastrectomy combined with lymphadenectomy in Zhongshan Hospital from December 2002 to October 2007 were retrospectively analyzed. The χ(2) test or Fisher's exact probability method was used to test measurement data. Survival was calculated using Kaplan-Meier method. Clinicopathological factors such as age, invasion depth, number of harvested lymph nodes, lymph node metastasis, ratio of metastatic lymph node, lymphatic vessels involvement were analyzed using the Cox regression model.</p><p><b>RESULTS</b>Number of lymph node dissected, lymph node metastasis, ratio of metastatic lymph node and lymphatic vessels involvement were significantly affected by groups of 15 lymph node dissected in G3 AGC patients (P<0.05). Invasion depth, number of lymph node dissected, lymph node metastasis, ratio of metastatic lymph node and lymphatic vessels involvement were significantly independent predictors of survival in G3 AGC patients (all P<0.05). Patients with at least 20 lymph nodes had a better survival rate than those with less than 20(P<0.01).</p><p><b>CONCLUSIONS</b>Invasion depth, number of harvested lymph nodes, lymph node metastasis, ratio of metastatic lymph node and lymphatic vessels involvement are important factors influencing the prognosis of G3 AGC. At least 20 lymph nodes should be recommended to ensure the quality of lymphadenectomy for gastric cancer.</p>

Role of exocrine cells in pancreatic enhancement using Mn-DPDP-enhanced MR imaging / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>To investigate role of exocrine cells in the pancreatic enhancement images at Manganese (II) N, N'-dipyridoxylethlenediamine-N, N'-diacetate 5, 5'-bisc (Mn-DPDP)-enhanced magnetic resonance (MR) imaging.</p><p><b>METHODS</b>Artificial pancreatic leakage was constructed in six dogs using a fistula tube inserted into the duodenum papillae. Pancreatic juice was collected before and after intravenous infusion of 2 ml/kg of Mn-DPDP at a rate of 2 - 3 ml/min. The Mn content of pancreatic juice was measured by atomic absorption spectroscopy. T(1)-weighted spin-echo images and T(1)-weighted spoiled phase gradient-echo (SPGR) images were obtained prior and approximately 30 min after the administration of Mn-DPDP at 1.5T.</p><p><b>RESULTS</b>The Mn content of pancreatic secretion increased 60.47 +/- 21.83 micro g/dl after the administration of Mn-DPDP (t = 6.785, P < 0.01). The signal/noise ratio (S/N) of the pancreas increased 53 percent +/- 49 percent and 62 percent +/- 44% on T(1)W spin echo images and SPGR images, respectively.</p><p><b>CONCLUSIONS</b>Exocrine cells of the pancreas can absorb manganese and excrete it through the pancreatic juice. Exocrine cells play an important role in the enhancement of the pancreas in MR imaging with Mn-DPDP.</p>

Mature insulin production by engineered non-beta cells / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>To pursue insulin and islet-transplantation replacement therapy for type 1 diabetes based on engineered human non-beta cells which secrete mature insulin.</p><p><b>METHODS</b>Human proinsulin cDNA was cloned from its genomic gene and mutated by overlap extension PCR, introducing furin consensus cleavage sequences (Arg-Xaa-Lys/Arg-Arg). An expression vector encoding a genetically modified human proinsulin cDNA was generated and transduced to Hela, 293, and L02 cells by lipofectin-mediated DNA transfection. Following G418 screening, the surviving L02 cells were selected and enriched. Insulin levels in the supernatant and cells were evaluated using radioimmunoassay and immunofluorescence staining.</p><p><b>RESULTS</b>Three sites in the insulin gene were mutated simultaneously. Insulin gene modified cells were able to express insulin at different levels: 8.45 - 188.00 microIU/24 h/2.0 x 10(6) Hela cells and 159.88 - 242.14 microIU/24 h/2.0 x 10(6) 293 cells for transient expression, and 2.56 - 61.95 microIU/24 h/2.0 x 10(6) from several L02 clones screened with G418. No insulin was released by control cells. Furthermore, immunofluorescence staining confirmed that proinsulin was stored as vacuoles in the cytoplasm of L02 cells.</p><p><b>CONCLUSION</b>A correctly mutated human proinsulin cDNA was obtained successfully, transfected and expressed efficiently in non-beta cells, lending support to the study of somatic gene therapy in diabetes mellitus.</p>