Clinicopathological features and prognostic factors of gastric intermediate-risk gastrointestinal stromal tumor after surgical resection: a retrospective study / 中华病理学杂志

Objective: To investigate the clinicopathological features, treatment and prognosis of gastric intermediate-risk gastrointestinal stromal tumor (GIST), so as to provide a reference for clinical management and further research. Methods: A retrospective observational study of patients with gastric intermediate-risk GIST, who underwent surgical resection between January 1996 and December 2019 at Zhongshan Hospital of Fudan University, was carried out. Results: Totally, 360 patients with a median age of 59 years were included. There were 190 males and 170 females with median tumor diameter of 5.9 cm. Routine genetic testing was performed in 247 cases (68.6%, 247/360), and 198 cases (80.2%) showed KIT mutation, 26 cases (10.5%) showed PDGFRA mutation, and 23 cases were wild-type GIST. According to "Zhongshan Method"(including 12 parameters), there were 121 malignant and 239 non-malignant cases. Complete follow-up data were available in 241 patients; 55 patients (22.8%) received imatinib therapy, 10 patients (4.1%) experienced tumor progression, and one patient (PDGFRA mutation, 0.4%) died. Disease-free survival (DFS) and overall survival rate at 5 years was 96.0% and 99.6%, respectively. Among the intermediate-risk GIST, there was no difference in DFS between the overall population, KIT mutation, PDGFRA mutation, wild-type, non-malignant and malignant subgroups (all P>0.05). However, the non-malignancy/malignancy analysis showed that there were significant differences in DFS among the overall population (P<0.01), imatinib treatment group (P=0.044) and no imatinib treatment group (P<0.01). Adjuvant imatinib resulted in potential survival benefit for KIT mutated malignant and intermediate-risk GIST in DFS (P=0.241). Conclusions: Gastric intermediate-risk GIST shows a heterogeneous biologic behavior spectrum from benign to highly malignant. It can be further classified into benign and malignant, mainly nonmalignant and low-grade malignant. The overall disease progression rate after surgical resection is low, and real-world data show that there is no significant benefit from imatinib treatment after surgery. However, adjuvant imatinib potentially improves DFS of intermediate-risk patients with tumors harboring KIT mutation in the malignant group. Therefore, a comprehensive analysis of gene mutations in benign/malignant GIST will facilitate improvements in therapeutic decision-making.

Clinicopathological features and prognosis of gastrointestinal stromal tumors with KIT/PDGFRA gene "homozygous mutation": a multicenter retrospective cohort study / 中华胃肠外科杂志

Objective: To investigate the clinicopathological features of gastrointestinal stromal tumor (GIST) with KIT/PDGFRA "homozygous mutation", the efficacy of targeted therapy and the prognosis. Methods: A retrospective cohort study and propensity score matching were used. "Homozygous mutation" was defined as the detection of KIT/PDGFRA gene status of GIST by Sanger sequencing, which showed that there was only mutant gene sequence in the sequencing map, lack of wild-type sequence or the peak height of mutant gene sequence was much higher than that of wild-type gene sequence (> 3 times). "Heterozygous mutation" was defined as the mutant gene sequences coexisted with wild type gene sequences, and the peak height was similar (3 times or less). The clinicopathological data and follow-up information of 92 GIST patients with KIT/PDGFRA "homozygous mutation" were collected from 4 hospitals in Shanghai from January 2008 to May 2021 (Renji Hospital, Shanghai Jiaotong University School of Medicine: 70 cases; Zhongshan Hospital, Fudan University: 14 cases; Changhai Hospital, Naval Military Medical University: 6 cases and Ruijin Hospital, Shanghai Jiaotong University School of Medicine: 2 cases). Patients with perioperative death, other malignancies, and incomplete clinicopathological information were excluded. The clinicopathological features of the patients and the efficacy of targeted drug therapy were observed and analyzed. The efficacy was evaluated using Choi criteria, which were divided into complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). In addition, a total of 230 patients with high-risk GIST with "heterozygous mutation" in exon 11 of KIT gene and 117 patients with recurrent or metastatic GIST with "heterozygous mutation" in exon 11 of KIT gene were included. The propensity score matching method was used to match GIST patients with "heterozygous" and "homozygous" mutations in exon 11 of KIT gene (1∶1) for survival analysis. The disease-free survival (DFS) between two groups of high-risk GIST patients who underwent complete surgical resection were compared. And progression-free survival (PFS) in patients with recurrent or metastatic GIST were compared. Results: Of the 92 GIST cases with KIT/PDGFRA "homozygous mutation", 58 were males and 34 were females, with a median onset age of 62 (31-91) years. Primary GIST 83 cases. Primary high-risk GIST (53 cases), metastatic GIST (21 cases) and recurrent GIST (9 cases) accounted for 90.2% (83/92). There were 90 cases of KIT gene"homozygous mutation" (exon 11 for 88 cases, exon 13 for 1 case, exon 17 for 1 case), and 2 cases of PDGFRA gene "homozygous mutation" (exon 12 for 1 case, exon 18 for 1 case). The median follow-up time was 49 (8-181) months. Among the 61 cases of primary localized GIST undergoing complete surgical resection, 2 cases were intermediate-risk GIST, 5 cases were low-risk GIST, and 1 case was very low-risk GIST, of whom 1 case of intermediate-risk GIST received 1-year adjuvant imatinib mesylate (IM) therapy after operation, and no tumor recurrence developed during the follow-up period. The remaining 53 cases were high-risk GIST, and follow-up data were obtained from 50 cases, of whom 22 developed tumor recurrence during follow-up. Of 9 patients directly receiving neoadjuvant targeted therapy (IM or avapritinib), 5 had complete imaging follow-up data, and the evaluation of efficacy achieved PR. Of all the 92 GIST cases with KIT/PDGFRA "homozygous mutation", 50 (54.4%) had tumor metastasis or tumor recurrence or progression during follow-up, and 12 (13.0%) died of the tumor. Survival analysis combined with propensity score showed that in 100 cases of high-risk GISTs with complete resection, GISTs with "homozygous mutation" in exon 11 of KIT gene had shorter disease-free survival (DFS) than GISTs with "heterozygous mutation" in exon 11 of KIT gene (median DFS: 72 months vs. 148 months, P=0.015). In 60 cases of recurrent or metastatic GISTs with KIT gene exon 11 mutation, IM was used as the first-line treatment, and the progression-free survival (PFS) of GISTs with "homozygous mutation" was shorter compared to GISTs with "heterozygous mutation" (median PFS: 38 months vs. 69 months, P=0.044). The differences were statistically significant. Conclusions: "Homozygous mutation" in KIT/PDGFRA gene is associated with the progression of GIST. The corresponding targeted therapeutic drugs are still effective for GIST with KIT/PDGFRA gene "homozygous mutation". Compared with GIST patients with "heterozygous mutation" in KIT exon 11, GIST patients with "homozygous mutation" in KIT exon 11 are more likely to relapse after surgery and to develop resistance to IM. Therefore, it is still necessary to seek more effective treatment methods for this subset of cases.

Adherence to adjuvant with therapy imatinib in patients with gastrointestinal stromal tumor: a national multi-center cross-sectional study / 中华胃肠外科杂志

Objective: To analyze the current adherence to imatinib in patients with gastrointestinal stromal tumors (GIST) in China and its influencing factors. Methods: A cross-sectional survey was conducted. Study period: from October 1, 2020 to November 31, 2020. Study subjects: GIST patients taking imatinib who were diagnosed and treated in public tertiary level A general hospitals or oncology hospitals; those who had not been pathologically diagnosed, those who never received imatinib, or those who had taken imatinib in the past but stopped afterwards were excluded. The Questionnaire Star online surgery platform was used to design a questionnaire about the adherence to adjuvant imatinib therapy of Chinese GIST patients. The link of questionnaire was sent through WeChat. The questionnaire contained basic information of patients, medication status and Morisky Medication Adherence Scale. Results: A total of 2162 questionnaires from 31 provinces, autonomous regions, and municipalities were collected, of which 2005 were valid questionnaires, with an effective rate of 92.7%. The survey subjects included 1104 males and 901 females, with a median age of 56 (22-91) years old. Working status: 609 cases (30.4%) in the work unit, 729 cases (36.4%) of retirement, 667 cases of flexible employment or unemployment (33.3%). Education level: 477 cases (23.8%) with bachelor degree or above, 658 cases (32.8%) of high school, 782 cases (39.0%) of elementary or junior high school, 88 cases (4.4%) without education. Marital status: 1789 cases (89.2%) were married, 179 cases (8.9%) divorced or widowed, 37 cases (1.8%) unmarried. Two hundred and ninety-four patients (14.7%) had metastasis when they were first diagnosed, including 203 liver metastases, 52 peritoneal metastases, and 39 other metastases. One thousand eight hundred and sixty-nine patients underwent surgical treatment, of whom 1642 (81.9%) achieved complete resection. The median time of taking imatinib was 25 (1-200) months. Common adverse reactions of imatinib included 1701 cases (84.8%) of periorbital edema, 1031 cases (51.4%) of leukopenia, 948 cases (47.3%) of fatigue, 781 cases (39.0%) of nausea and vomiting, 709 cases (35.4%) of rash, and 670 cases (33.4%) of lower extremity edema. The score of the Morisky Medication Adherence Scale showed that 392 cases (19.6%) had poor adherence, 1023 cases (51.0%) had moderate adherence, and 590 cases (29.4%) had good adherence. Univariate analysis showed that gender, age, work status, economic income, residence, education level, marriage, the duration of taking medication and adverse reactions were associated with adherence to adjuvant imatinib therapy (all P<0.05). Multivariate analysis showed that female (OR=1.264, P=0.009), non-retirement (OR=1.454, P=0.001), monthly income ≤4000 yuan (OR=1.280, P=0.036), township residents (OR=1.332, P=0.005), unmarried or divorced or widowed (OR=1.362, P=0.026), the duration of imatinib medication >36 months (OR=1.478, P<0.001) and adverse reactions (OR=1.719, P=0.048) were independent risk factors for poor adherence to adjuvant imatinib. Among patients undergoing complete resection, 324 (19.7%) had poor adherence, 836 (50.9%) had moderate adherence, and 482 (29.4%) had good adherence. Meanwhile, 55 patients with good adherence (11.4%) developed recurrence after surgery, 121 patients with moderate adherence (14.5%) developed recurrence, 61 patients with poor adherence (18.8%) developed recurrence, and the difference was statistically significant (P=0.017). Conclusions: The adherence to adjuvant therapy with imatinib in Chinese GIST patients is relatively poor. Females, non-retirement, monthly income ≤4000 yuan, township residents, unmarried or divorced or widowed, the duration of imatinib medication >36 months, and adverse reactions are independently associated with poor adherence of GIST patients. Those with poor adherence have a higher risk of recurrence after surgery. Positive interventions based on the above risk factors are advocated to improve the prognosis of patients with GIST.

Clinicopathological features and prognosis of chronic gastric ulcer with early canceration / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To evaluate the clinicopathological features and prognosis of chronic gastric ulcer with early canceration in order to provide useful information for diagnosis and treatment strategies.</p><p><b>METHODS</b>A retrospective review of clinical data and prognosis from 43 patients of chronic gastric ulcer with early canceration from 2003 to 2010 was conducted. These data were compared with those with primary intra-mucosa gastric cancer (type I and II 275 cases, type III 68 cases).</p><p><b>RESULTS</b>In 43 cases of chronic gastric ulcer with early canceration, 30 cases (69.8%) were male, 22 cases (51.2%) were younger than 60 years old. Lesions located in the body or antrum of the stomach in 39 cases (90.7%), were less than 2 cm in 26 cases (60.5%), were undifferentiated type in 23 cases (53.5%), and developed lymph node metastasis in 4 cases (9.3%). Lesions of 4 cases of chronic gastric ulcer with early canceration located in the upper third of the stomach, while those of type III primary intra-mucosal gastric cancer all located in the lower two thirds, and the difference was statistically significant (P<0.01). Compared to type III and type I and II primary intra-mucosal gastric cancer, chronic gastric ulcer with early canceration did not differ in clinicopathological characteristics such as histological type, vascular or lymphatic invasion, and lymph nodes metastasis (all P>0.05). The median follow-up time was 57 months (range 16 to 98 months). The 5-year overall survival was 95.3% in chronic gastric ulcer with early canceration group, similar to that of type I, II (97.4%) or type III (94.5%) primary intra-mucosal gastric cancer group (P>0.05).</p><p><b>CONCLUSIONS</b>The clinicopathological features of chronic gastric ulcer with early canceration are similar to those of primary intra-mucosal gastric cancer. The prognosis is promising for those patients undergoing surgical treatment.</p>

Efficacy of neoadjuvant chemotherpy in patients with locally advanced gastric cancer / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy and safety of neoadjuvant chemotherapy in patients with locally advanced gastric cancer, and to analyze the relevant factors of recurrent death of gastric cancer after adjuvant chemotherapy.</p><p><b>METHODS</b>Clinical data of 49 patients who underwent neoadjuvant chemotherapy for locally advanced gastric cancer between July 2007 and June 2011 were reviewed. Preoperative staging was determined by endoscopic ultrasonography and abdominal computer tomography (CT) or magnetic resonance imaging (MRI). Chemotherapy was administered for regimen of two or three drugs. Prognostic factors were analyzed by univariate and multivariate analysis with Cox proportional hazard model.</p><p><b>RESULTS</b>The response rate was 33.3% (16/48) and disease control rate was 93.8% (45/48). Forty-four (89.8%, 44/49) patients received curative resection after neoadjuvant chemotherapy, among whom 90.9% (40/44) underwent D2 lymphadenctomy. Thirty-two cases had pathological response and 2 patients had pathological complete response. The average hospital stay was 11.6 days and 2 patients had longer hospitalization because of postoperative pancreatic complications. The toxicities were most in grade 1-2. All the patients were followed up postoperatively and the median follow-up was 21.6 months. Median progression-free survival was 29.6 (95%CI:24.0-35.2) months and median overall survival was 34.6 months (95%CI:29.8-39.4). Imaging response (P=0.038, RR=0.168, 95%CI:0.031-0.904) and pathological response (P=0.007, RR=0.203, 95%CI:0.064-0.642) were identified as independent prognostic factors with COX multivariate analysis.</p><p><b>CONCLUSIONS</b>Neoadjuvant chemotherapy has quite high disease control rate and R0 resecting rate for patients with locally advanced gastric cancer. Imaging response and pathological response are most important prognostic factors in those patients.</p>

Screening of differentially expressed microRNAs in borderline and malignant gastrointestinal stromal tumors / 中华病理学杂志

<p><b>OBJECTIVE</b>Gastrointestinal stromal tumors (GISTs) have a broad spectrum of biological behaviors ranging from benign, borderline and malignant. This study aimed to screen differentially expressed microRNAs (miRNAs) between malignant and borderline GISTs and to investigate the potential role of miRNAs in the malignant transformation of GISTs.</p><p><b>METHODS</b>Six GIST samples including borderline tumors (n = 3) and malignant tumors (n = 3) were collected based on the clinical and pathological characteristics. Total RNA was extracted, followed by miRNA microarray analysis to screen the differentially expressed miRNAs. The most significantly expressed 4 miRNAs were then chosen for further validation by real-time PCR in 22 additional GIST samples.</p><p><b>RESULTS</b>Direct comparison of malignant group versus borderline group revealed 14 significantly and differentially expressed miRNAs (P < 0.05, with a fold change of < 0.5 or > 2). Five miRNAs were up-regulated and nine were down-regulated in the malignant group. Four miRNAs (miR-221, miR-135b, miR-675(*) and miR-218) were most significantly and differentially expressed between the two groups. The differential expression of 2 miRNAs (miR-221 and miR-675(*)) were subsequently confirmed with good concordance by real-time PCR.</p><p><b>CONCLUSIONS</b>The differential miRNA expression profiles between two groups are revealed by miRNA microarray assay, and confirmed by real-time PCR. Among differentially expressed miRNAs, miR-221 and miR-675(*) might be related to the malignant transformation of GISTs, and have a potential value in predicting biological behavior of GISTs.</p>

Endoscopic management of early postoperative anastomotic hemorrhage / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>The study aimed to evaluate the efficacy of endoscopic therapy for early postoperative anastomotic hemorrhage.</p><p><b>METHODS</b>Fourteen patients experienced an episode of early postoperative anastomotic hemorrhage and were treated endoscopically from January 2005 to June 2010. The clinical data was analyzed retrospectively.</p><p><b>RESULTS</b>Fourteen patients(9 males and 5 females, median age 57.5 years, range 26-74 years) were diagnosed with postoperative hemorrhage between 6 hours to 14 days after surgery. The blood loss ranged from 500 to 1500 ml. Sclerosing agent injection, electrocoagulation, and hemoclips were attempted to control the bleeding. Endoscopic approach to control early postoperative anastomotic hemorrhage was successful in all the patients. No recurrent bleeding was observed during the follow-up. No complications associated with endoscopic therapy.</p><p><b>CONCLUSION</b>Endoscopic approach for the management of early postoperative anastomotic hemorrhage is feasible with high success rate and associated with no complications.</p>

Clinicopathological features and prognosis of cystic gastrointestinal stromal tumor / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate the clinicopathological and molecular genetic characteristics of gastrointestinal stromal tumor (GISTs) with significant cystic changes, and to assess their biological behavior.</p><p><b>METHODS</b>Clinicopathological features of 7 patients with cystic GISTs treated at the Zhongshan Hospital of Fudan University from February 2005 to January 2010 were summarized retrospectively. The mutations status of c-kit and PDGFR-α were analyzed.</p><p><b>RESULTS</b>There were 2 males and 5 females aged from 46 to 76 years old. Primary site of GISTs included stomach(n=4), duodenum(n=1), and small intestinal(n=2). Tumor size ranged from 6 to 16 cm with obviously cystic changes. Tumor cells were found in the solid components under microscope, of which epithelioid cell type were found in 4 case and spindle cell type in 3 cases. The mitotic figures were no more than 3/50 HPF in all the patients. According to the NIH criteria, 4 were high-risk and 3 were low-risk. Based on morphological characteristics, 3 cases were as borderline tumor, 3 moderate-risk, and 1 moderate-risk. Gene mutation of exon 11 of c-kit were identified in 3 cases. During the follow up ranging from 9 to 80 months, all the 7 patients had cancer-free survival.</p><p><b>CONCLUSION</b>The biological behavior of cystic GIST is indolent with a low risk of malignancy and favorable prognosis.</p>

Adjuvant chemotherapy for gastric cancer: more drugs do not mean better efficacy / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To compare oncologic outcomes between doublet and triplet adjuvant chemotherapy for gastric cancer patients undergoing radical resection.</p><p><b>METHODS</b>Patients with gastric cancer receiving adjuvant chemotherapy after radical resection from January 2004 to December 2008 were included. Doublet was defined as 5-FU 750 mg/m² (days 1-5) or capecitabine 1000 mg/m² (days 1-14) plus cisplatin 60 mg/m² (day 1) or oxaliplatin 130 mg/m² (day 1), while triplets had epirubicin 50 mg/m² (day 1) added. Chemotherapy was initiated 4-6 weeks after surgery, repeated every three weeks for 6 cycles. Patients were followed-up in the outpatient clinic until death or the most recent follow up(April 30, 2010). Cox proportional- hazard model and Chi-square test were used to test statistical difference.</p><p><b>RESULTS</b>A total of 316 patients (210 received doublets, 106 received triplets) had a median follow-up time of 47 months. Seventy-seven patients died at the end of the follow-up. Two groups were comparable except for age (median age of 57 in doublets, 51 in triplets, P<0.01). The two groups had similar disease-free survival (16 months vs. 23 months, P=0.656) and 3-year overall survival(59.6% vs. 64.8%, P=0.293). There was no significant difference in severe adverse side effects between the two groups (21.9% vs. 30.2%, P=0.107).</p><p><b>CONCLUSION</b>Triplet adjuvant chemotherapy appears not to be associated with superior efficacy than doublet regimen for patients with gastric cancer after radical resection.</p>

Study on clinicopathologic parameters of malignant behavior in gastrointestinal stromal tumors / 中华病理学杂志

<p><b>OBJECTIVE</b>To determinate the clinicopathologic parameters in predicting the malignant behavior of gastrointestinal stromal tumor (GIST).</p><p><b>METHODS</b>Eight hundred and forty cases of GIST were retrospectively reviewed. The tumors were classified as malignant if they met any of the following criteria: evidence of gross dissemination (including liver metastasis and/or peritoneal spread), evidence of microscopic dissemination (including lymph node metastasis, infiltration to vessels, fat tissue, nerves and/or mucosal tissue), or disease relapse. The remaining cases were provisionally classified as tumors of uncertain biologic behavior. A number of morphologic parameters were then evaluated under light microscopy and univariate and multivariate analyses were adopted for this study.</p><p><b>RESULTS</b>Histologic findings correlated with evidences of the following morphologic parameters were considered in accord with the criteria of the malignant behavior: mitotic count>or=10 per 50 high-power fields (P<0.01), muscle infiltration (P<0.01), coagulative necrosis (P<0.01), perivascular growth pattern (P=0.005) and remarkable nuclear atypia (P=0.014). Basing on the above criterion, 485 cases were re-classified as "malignant" and 355 cases "non-malignant". Follow-up data showed that the five-year disease-free survival and overall survival in the "non-malignant" group were 99.3% and 100% respectively, in contrast to 43.9% and 59.7% respectively in the "malignant" group (P<0.01).</p><p><b>CONCLUSIONS</b>The set of clinicopathologic parameters is useful in predicting the malignant behavior of GIST and prognosis.</p>

Da Vinci robot-assisted gastrectomy with lymph node dissection for gastric cancer: a case series of 9 patients / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To evaluate the technical feasibility, effectiveness, and safety of robot-assisted gastrectomy(RAG) with lymphadenectomy using the Da Vinci system.</p><p><b>METHODS</b>A total of 9 patients in our institute from March 17 to April 24 2010 underwent RAG. Clinicopathologic characteristics and surgical outcomes were summarized.</p><p><b>RESULTS</b>All operations were performed successfully without conversion to either open or laparoscopic approach. There were 5 total gastrectomies,2 distal gastrectomies, 1 proximal gastrectomy and 1 wedge gastrectomy with D(1) or D(2) lymphadenectomy. The total operative time was 150 to 440 minutes. Total blood loss ranged from 10 to 100 ml. The ranges of harvested lymph nodes were 19-24 for D(1) patients and 28-38 for D(2) patients. There was 1 case of postoperative gastric leakage, which were managed conservatively.</p><p><b>CONCLUSIONS</b>RAG with lymphadenectomy can be applied safely and effectively for patients with gastric cancer.</p>

Risk factors for postoperative pancreatic leakage after D(2) resection of gastric cancer / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate the incidence of pancreatic fistula following D(2) gastrectomy and associated risk factors.</p><p><b>METHODS</b>A total of 132 consecutive cases of gastric cancer underwent D(2) gastrectomy between Jul 1, 2009 and Dec 2009. Amylase concentration of the drainage fluid and serum amylase concentration were tested on day 1, 4, 7 after operation. Univariate analyses were performed to evaluate the significance of various covariates as risk factors for the pancreatic fistula-related complications.</p><p><b>RESULTS</b>The incidence of pancreatic fistula was 17.4%. None of the following factors including age, gender, tumor location, tumor stage, N stage, range of resection, fistula output, and serum amylase were associated with pancreatic fistula.</p><p><b>CONCLUSION</b>The incidence of pancreatic fistula following D(2) gastrectomy is high. Drainage tube is necessary to prevent serious complications.</p>

Expression of MDR1 and KIT in imatinib-resistant gastrointestinal stromal tumor cells / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To explore the relationship between imatinib resistance and genes MDR1 and KIT in gastrointestinal stromal tumor (GIST) cells.</p><p><b>METHODS</b>The MDR1 and KIT mRNA level in GIST882-R and GIST882-S cells were detected by RT-PCR. Immunocytochemistry and Western blot were employed to detect P-gp and CD117 expression in GIST882-R and GIST882-S cells.</p><p><b>RESULTS</b>The relative expression of MDR1 mRNA was 0.321 + or - 0.033 in GIST882-R and 0.157 + or - 0.056 in GIST882-S cells, and the difference was statistically significant (P<0.05). The relative expression of KIT mRNA was 0.389 + or - 0.063 in GIST882-R and 0.339 + or - 0.067 in GIST882-S, and the difference was not statistically significant (P>0.05). The relative density of P-gp was 0.443 + or - 0.058 in GIST882-R and 0.237 + or - 0.094 in GIST882-S, and the difference was statistically significant (P<0.05). The relative density of CD117 was 0.744 + or - 0.123 in GIST882-R and 0.704 + or - 0.094 in GIST882-S, and the difference was not statistically significant (P>0.05).</p><p><b>CONCLUSIONS</b>Over-expression of gene MDR1 may be associated with imatinib resistance in GIST. KIT may not be involved in imatinib resistance.</p>

Study on the mechanism of imatinib-induced resistance in gastrointestinal stromal tumors / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate the mechanism of imatinib mesylate (IM) induced-resistance in the patients with gastrointestinal stromal tumors (GISTs) and treated with imatinib.</p><p><b>METHODS</b>Eight patients with GIST treated with IM developed secondary IM resistance. A total of 16 tumor samples (pre-IM therapy) and 11 tumor samples (post-IM treatment) were available. Exon 9, 11, 13, and 17 of c-kit gene as well as exon 12 and exon 18 of PDGFRA gene were sequenced.</p><p><b>RESULTS</b>In addition to the changes of baseline genotype, the IM-induced gene changes were concentrated in the kinase domain of c-kit gene in all 8 patients, 2 of them were located in the exon 13 of c-kit gene presenting with V654A, while 6 in exon 17 involving 816 and 820 to 823 codons.</p><p><b>CONCLUSION</b>The mechanism of imatinib mesylate resistance after initial treatment with this agent in gastrointestinal stromal tumors is a novel mutation development in kinase domain of c-kit.</p>

Detection and clinical significance of plasma vascular endothelial growth factor level in gastrointestinal stromal tumor patients / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate the clinical significance of plasma vascular endothelial growth factor (p-VEGF) levels in gastrointestinal stromal tumor (GIST) patients.</p><p><b>METHODS</b>The p-VEGF levels in 61 primary GIST patients, 18 patients with recurrence or metastasis, and 28 healthy blood donators (as control) were measured by enzyme-linked immunosorbent assay. Paired p-VEGF levels of pre- and post-treatment were obtained from 44 patients. One patient received 22 consecutive detections during the follow up.</p><p><b>RESULTS</b>Primary and recurrent GIST patients had higher p-VEGF levels than healthy controls [(145.31+/-45.58) ng/L, (145.72+/-52.73) ng/L vs (89.86+/-18.30) ng/L] (P<0.01). And there were no significant differences between primary patients and patients with recurrence or metastasis (P>0.05). Significant difference were found in the p-VEGF levels between pre- and post-treatment patients (P<0.01). Post-treatment p-VEGF levels decreased markedly both in 26 primary and 11 recurrent patients [(101.81+/-27.63) ng/L and (112.45+/-38.58) ng/L]. As for the patient with 22 consecutive detections during the follow up, p-VEGF levels the period of were higher before surgery and after recurrence, and lower two months after surgery and during Glivec therapy.</p><p><b>CONCLUSIONS</b>The p-VEGF level of GIST patients is significantly higher than that of healthy people, which will decrease markedly after effective management. Monitoring the p-VEGF level in GIST patients will be helpful to evaluate the therapeutic efficacy and predict the recurrence or metastasis.</p>

In vitro evidence for pancreatic lineage: Ngn3 positive cells are endocrine progenitors derived from cultured islets / 中华外科杂志

<p><b>OBJECTIVE</b>Further studies have been conducted to evaluate the roles of Ngn3 in adult islet maintenance and renewal.</p><p><b>METHODS</b>Islets were isolated from 6 - 8 week old male C57BL/6 mice. After common bile duct cannulation, the pancreas was resected and digested in collagenase V (2.5 mg/ml). Islets were then handpicked and 10 - 12 islets were plated in 60 mm culture dish and cultivated with RPMI-1640, which contained 12.5 mmol/L HEPES, 5.2 mmol/L glucose and 2% fetal bovine serum (FBS). Islet cells were analyzed by immunocytochemistry methods for A6, insulin, glucagon, nestin, Ngn3 and 5-bromo-2'-deoxy-uridine (BrdU).</p><p><b>RESULTS</b>The results of these studies indicated that less than 15 percent of proliferated islet cells were Ngn3 expressing cells, in which about one third of the Ngn3 positive cells co-expressed A6. The existence of Ngn3 in cultured islet cells is consistent with the results from other's findings both in embryogenesis and adult islet studies. A significant finding of our study is that the existence of A6 and Ngn3 co-expressing cells in the cultured islet. A6 is a marker for identifying bile duct epithelial cell oriented hepatic progenitor cells. Islet-derived A6 cells are possibly born in the adult pancreatic duct and migrate into islets. A6 cells co-express Ngn3 when these cells commit to endocrine lineage within the islets. More interestingly, islet-derived A6 positive cells have the potential to transdifferentiate into hepatic cells.</p><p><b>CONCLUSION</b>The presence of Ngn3(+) and A6(+) cells in the cultured islets suggests that the four established islet cell types arise from a common endocrine lineage residing within the adult islets. A6 and Ngn3 are useful markers for understanding intra-islet adult stem cell lineages in our future studies. This approach may allow for significant advances in understanding the IPC proliferation and differentiation, and open the possibility of using intra-islet adult stem cells for diabetes treatment.</p>

Imatinib mesylate STI571 therapy for five patients with advanced gastrointestinal stromal tumors / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To explore the therapeutic effect of STI571(imatinib mesylate) on advanced gastrointestinal stromal tumors (GISTs).</p><p><b>METHODS</b>Clinical data of 5 cases with advanced GISTs were analyzed retrospectively.</p><p><b>RESULTS</b>The expression of c- kit (CD117) was detected by immunohistochemical method in five patients with advanced GISTs . All patients failed to systematic chemotherapy or radiofrequency and operation because of extensive and multiple metastases (4 cases underwent 1 to 3 times of exploratory surgery). Tumor size was markedly decreased one to six months after STI571 given without serious drug- related side effects.</p><p><b>CONCLUSIONS</b>STI571 is an effective chemotherapy for advanced unresectable or metastatic GISTs. Inhibitor of the Kit signal- transduction pathway is a promising regimen that is different from conventional chemotherapy for advanced GISTs.</p>