Treatment of gastric cancer with dermatomyositis as the initial symptom: Two case reports and review of literature.

BACKGROUND: Dermatomyositis (DM) is a rare autoimmune disease involving the connective tissue. The association between DM and gastric cancer remains unclear. Patients with DM have an increased risk of cancer and higher mortality. It requires immunosuppressive therapy, heightened surveillance, and immunologic response to internal malignancy. CASE SUMMARY: Two cases of gastric cancer with DM as the first symptom in Zhongshan Hospital, Fudan University (Shanghai, China) were reported. Two patients had a typical skin rash. The rash in the first patient involved mainly bilateral upper limbs and neck, while the second patient manifested rash associated mainly with the face, neck, and back. Both manifested muscle weakness in the extremities and elevated serum creatine kinase. Radical resection of the tumor dramatically improved DM-related symptoms in the two patients. The literature review showed that gastric cancer is more commonly associated with DM in middle-aged and older male populations. CONCLUSION: The findings suggest the need for comprehensive screening for malignant tumors in patients with DM refractory to long-term pharmacotherapy or hormone manipulation.

Familial gastrointestinal stromal tumors with KIT germline mutation in a Chinese family: A case report.

BACKGROUND: Familial gastrointestinal stromal tumors (GISTs) is a rare autosomal dominant disorder characterized by an array of clinical manifestations. Only 35 kindreds with germline KIT mutations and six with germline PDGFRA mutations have been reported so far. It is often characterized by a series of manifestations, such as multiple lesions and hyperpigmentation. However, the effect of imatinib treatment in these patients is still uncertain. CASE SUMMARY: Here, we report two patients (father and daughter) in a Chinese family (for the first time) with germline KIT mutation, and described their pathology, genetics and clinical manifestations. A 25-year-old Chinese woman went to hospital because of abdominal pain, and computed tomography showed multiple tumors in the small intestine. Small pigmented spots appeared on the skin within a few months after birth. Her father also had multiple pigmented spots and a history of multifocal GISTs. Multiple GISTs associated with diffuse interstitial Cajal cells (ICCs) hyperplasia were positive for CD117 and DOG-1. Gene sequencing revealed a germline mutation at codon 560 of exon 11 (p.V560G) of KIT gene in these two patients. Imatinib therapy showed the long-lasting disease stability after resection. Remarkably, the hypopigmentation of the skin could also be observed. Luckily germline KIT mutation has not been identified yet in the 3-year-old daughter of the female patient. CONCLUSION: Diagnosis of familial GISTs depends on combination of diffuse ICCs hyperplasia, germline KIT/PDGFRA mutation, hyperpigmentation and family history.

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.

Early activated hepatic stellate cell-derived molecules reverse acute hepatic injury.

AIM: To test whether hepatic stellate cells (HSCs) at different activation stages play different roles in acetaminophen (APAP)-induced acute liver injury (ALI). METHODS: HSCs were isolated from mouse liver and cultured in vitro. Morphological changes of initiation HSCs [HSCs (5d)] and perpetuation HSCs [HSCs (p3)] were observed by immunofluorescence and transmission electron microscopy. The protective effects of HSC-derived molecules, cell lysates and HSC-conditioned medium (HSC-CM) were tested in vivo by survival and histopathological analyses. Liver injury was determined by measuring aminotransferase levels in the serum and by histologic examination of tissue sections under a light microscope. Additionally, to determine the molecular mediators of the observed protective effects of initiation HSCs, we examined HSC-CM using a high-density protein array. RESULTS: HSCs (5d) and HSCs (p3) had different morphological and phenotypic traits. HSCs (5d) presented a star-shaped appearance with expressing α-SMA at non-uniform levels between cells. However, HSCs (p3) evolved into myofibroblast-like cells without lipid droplets and expressed a uniform and higher level of α-SMA. HSC-CM (5d), but not HSC-CM (p3), provided a significant survival benefit and showed a dramatic reduction of hepatocellular necrosis and panlobular leukocyte infiltrates in mice exposed to APAP. However, this protective effect was abrogated at higher cell masses, indicating a therapeutic window of effectiveness. Furthermore, the protein array screen revealed that HSC-CM (5d) was composed of many chemokines and growth factors that correlated with inflammatory inhibition and therapeutic activity. When compared with HSC-CM (p3), higher levels of monocyte chemoattractant protein-1, macrophage inflammatory protein-1γ, hepatocyte growth factor, interleukin-10, and matrix metalloproteinase-2, but lower levels of stem cell factor and Fas-Ligand were observed in HSC-CM (5d). CONCLUSION: These data indicated that initiation HSCs and perpetuation HSCs were different in morphology and protein expression, and provided the first experimental evidence of the potential medical value of initiation HSC-derived molecules in the treatment of ALI.

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.

A phase II trial of Xeloda and oxaliplatin (XELOX) neo-adjuvant chemotherapy followed by surgery for advanced gastric cancer patients with para-aortic lymph node metastasis.

PURPOSE: Gastric cancer with para-aortic lymph node (PAN) involvement is regarded as advanced disease, and only chemotherapy is recommended from the guidelines. In unresectable cases, neoadjuvant chemotherapy could prolong survival if conversion to resectability could be achieved. METHODS: The study was a single-arm phase II trial. Patients who were diagnosed with gastric cancer and PAN involvement (Stations No. 16a2/16b1) were treated with capecitabine and oxaliplatin combination chemotherapy every 3 weeks for a maximum of six cycles. After every two cycles, abdominal computed tomographic scans were repeated to evaluate the response, and surgery was performed at the physician(')s discretion in patients with sufficient tumor response, followed by chemotherapy with the same regimen to complete a total of six cycles. The primary end point was the response rate of the preoperative chemotherapy. The secondary end points were R0 resection rate, progression-free survival (PFS), overall survival (OS), and adverse events. RESULTS: A total of 48 patients were enrolled. The response rate of the first-line chemotherapy was 49.0 %, and the clinical benefit response was 85.1 %. After a median of four cycles of chemotherapy, 28 patients received surgery (58.3 %). The median PFS and OS of all patients were 10.0 and 29.8 months, respectively. Patients in the surgery group had much longer PFS (18.1 vs. 5.6 mo, P = 0.001) and OS (not reached vs. 12.5 mo, P = 0.016) compared with those in the non-surgery group. CONCLUSIONS: For gastric cancer patients with PAN involvement, neoadjuvant chemotherapy with XELOX demonstrated a good response rate, and a sufficient R0 resection rate, with acceptable toxicities. Further study is needed to confirm the effectiveness of this regimen.

[Clinicopathological features and prognosis of chronic gastric ulcer with early canceration].

OBJECTIVE: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

[Screening of differentially expressed microRNAs in borderline and malignant gastrointestinal stromal tumors].

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[Efficacy of neoadjuvant chemotherpy in patients with locally advanced gastric cancer].

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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

BACKGROUND: Gastric 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. METHODS: A 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. RESULTS: The 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. CONCLUSIONS: This 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.

[Clinicopathological features and prognosis of cystic gastrointestinal stromal tumor].

OBJECTIVE: To investigate the clinicopathological and molecular genetic characteristics of gastrointestinal stromal tumor (GISTs) with significant cystic changes, and to assess their biological behavior. METHODS: 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. RESULTS: 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. CONCLUSION: The biological behavior of cystic GIST is indolent with a low risk of malignancy and favorable prognosis.

[Endoscopic management of early postoperative anastomotic hemorrhage].

OBJECTIVE: The study aimed to evaluate the efficacy of endoscopic therapy for early postoperative anastomotic hemorrhage. METHODS: 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. RESULTS: 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. CONCLUSION: Endoscopic approach for the management of early postoperative anastomotic hemorrhage is feasible with high success rate and associated with no complications.

[Adjuvant chemotherapy for gastric cancer: more drugs do not mean better efficacy].

OBJECTIVE: To compare oncologic outcomes between doublet and triplet adjuvant chemotherapy for gastric cancer patients undergoing radical resection. METHODS: 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. RESULTS: 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). CONCLUSION: Triplet adjuvant chemotherapy appears not to be associated with superior efficacy than doublet regimen for patients with gastric cancer after radical resection.

[Expression of MDR1 and KIT in imatinib-resistant gastrointestinal stromal tumor cells].

OBJECTIVE: To explore the relationship between imatinib resistance and genes MDR1 and KIT in gastrointestinal stromal tumor (GIST) cells. METHODS: 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. RESULTS: 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). CONCLUSIONS: Over-expression of gene MDR1 may be associated with imatinib resistance in GIST. KIT may not be involved in imatinib resistance.

[Study on clinicopathologic parameters of malignant behavior in gastrointestinal stromal tumors].

OBJECTIVE: To determinate the clinicopathologic parameters in predicting the malignant behavior of gastrointestinal stromal tumor (GIST). METHODS: 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. RESULTS: 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). CONCLUSIONS: The set of clinicopathologic parameters is useful in predicting the malignant behavior of GIST and prognosis.

[Risk factors for postoperative pancreatic leakage after D(2) resection of gastric cancer].

OBJECTIVE: To investigate the incidence of pancreatic fistula following D(2) gastrectomy and associated risk factors. METHODS: 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. RESULTS: 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. CONCLUSION: The incidence of pancreatic fistula following D(2) gastrectomy is high. Drainage tube is necessary to prevent serious complications.

[Da Vinci robot-assisted gastrectomy with lymph node dissection for gastric cancer: a case series of 9 patients].

OBJECTIVE: To evaluate the technical feasibility, effectiveness, and safety of robot-assisted gastrectomy(RAG) with lymphadenectomy using the Da Vinci system. METHODS: A total of 9 patients in our institute from March 17 to April 24 2010 underwent RAG. Clinicopathologic characteristics and surgical outcomes were summarized. RESULTS: 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. CONCLUSIONS: RAG with lymphadenectomy can be applied safely and effectively for patients with gastric cancer.

[Study on the mechanism of imatinib-induced resistance in gastrointestinal stromal tumors].

OBJECTIVE: To investigate the mechanism of imatinib mesylate (IM) induced-resistance in the patients with gastrointestinal stromal tumors (GISTs) and treated with imatinib. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Impact of KIT and PDGFRA gene mutations on prognosis of patients with gastrointestinal stromal tumors after complete primary tumor resection.

INTRODUCTION: To investigate the impact of KIT and PDGFRA gene mutations on the prognosis of gastrointestinal stromal tumors (GIST). MATERIAL AND METHODS: Tumor 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 DISCUSSION: The 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. CONCLUSION: The 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.