Diffuse large B-cell lymphoma with continuously elevated immunoglobulin M following treatment: a case report with pathologic, immunophenotypic, and molecular analyses.

A rare subtype of diffuse large B-cell lymphoma (DLBCL) has been reported to be accompanied by elevated immunoglobulin M (IgM) paraprotein in the serum at diagnosis, called as IgMs-DLBCL. The monoclonal IgM paraprotein disappears soon after treatment in most of these patients. Here, we described a DLBCL patient with continuously elevated IgM following therapy. A 59-year-old male was diagnosed with DLBCL (GCB subtype per Hans algorithm, stage IA) with involvement of the right cervical lymph node. After six cycles of immuno-chemotherapy with the R-CHOP regimen, complete metabolic remission was achieved, but an elevated level of serum IgM persisted. To investigate the origin of elevated IgM, pathologic, immunophenotypic, and molecular analyses of lymph node and bone marrow (BM) samples were performed pre- and post-treatment. BM infiltration of lymphoplasmacytic cells, and a typical immunophenotypic profile by flow cytometry supported the diagnosis of Waldenström macroglobulinemia (WM). The MCD subtype of DLBCL was identified by next-generation sequencing of the lymph node at initial diagnosis characterized by co-occurring point mutations in MYD88 L265P and CD79B. Additionally, two different dominant clonotypes of the immunoglobulin heavy chain (IGH) were detected in the lymph node and BM by IGH sequencing, which was IGHV 3-11*06/IGHJ 3*02 and IGHV 3-11*06/IGHJ 6*02, respectively, speculating to be two independent clonal origins. This study will provide a panoramic understanding of the origin or biological characteristics of DLBCL co-occurring with WM.

Long noncoding RNA SPRY4-IT1 acts as a miR-101-5p sponge to promote gastrointestinal stromal tumor progression by inhibiting ZEB1.

OBJECTIVES: Research on long noncoding RNAs (lncRNAs) has been conducted in different areas of oncology. Currently, the biological significance of lncRNAs and their regulatory features in gastrointestinal stromal tumors (GIST) remain largely unknown. We have previously identified SPRY4-IT1 overexpression in GIST through lncRNA sequencing of GIST tissues. Coincidentally, SPRY4-IT1 is an intron of the SPRY4 gene, and SPRY4 is specifically highly expressed in GIST. Thus the aim of the present study was to investigate the role of lncRNA SPRY4-IT1 in GIST pathogenesis. METHODS: Herein, we screened for SPRY4-IT1 and analyzed its possible phenotypes using Gene set enrichment analysis (GSEA). The phenotypes of GIST were verified using CCK-8, colony formation, and wound-healing assays. The ceRNA mechanism was determined by the location of lncRNA SPRY4-IT1, and its relationship to the Ago2 protein. The SPRY4-IT1/miR-101-5p/ZEB1 axis was predicted using online software and sequencing. Luciferase and pull-down assays were performed for verification. Pathway-associated and phenotype-associated proteins were detected by western blotting. RESULTS: Sequencing analysis revealed 117 differentially expressed lncRNAs in GIST and normal gastric tissue samples. Accordingly, SPRY4-IT1 was screened out and its phenotype was predicted by GSEA. Mechanistically, SPRY4-IT1 was identified as a competing endogenous RNA (ceRNA) that downregulated miR-101-5p and upregulated ZEB1, which activated extracellular signal-regulated kinase (ERK) signaling to stimulate GIST proliferation, invasion, and epithelial-mesenchymal transition. Although this effect was regulated by a negative feedback loop through SPRY4, it was still controlled by SPRY4-IT1. CONCLUSIONS: In GIST, we revealed a ceRNA mechanism by which SPRY4-IT1 modulates ZEB1 by sponging miR-101-5p, eventually driving tumor cell proliferation, migration, and epithelial-mesenchymal transition (EMT).

Exon 11 homozygous mutations and intron 10/exon 11 junction deletions in the KIT gene are associated with poor prognosis of patients with gastrointestinal stromal tumors.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) with different types of mutations exhibit different clinical characteristics and prognosis. This study aimed to evaluate the prognostic value of mutations in KIT and PDGFRA in a large-scale cohort of GIST patients with current therapy including surgery and imatinib. METHODS: A total of 1163 patients diagnosed with GISTs between January 2006 and December 2018 were enrolled in this study. Mutation analysis was performed for exons 9, 11, 13, and 17 of KIT and exons 12 and 18 of PDGFRA. Mutations were grouped into 12 categories according to the gene, exon, and involved codons; they were analyzed considering the clinical characteristics, disease-free survival (DFS), and overall survival (OS) of patients with GISTs. RESULTS: In low-risk GISTs, we identified two predictors of worse DFS: tumor origin in the rectum and KIT exon 11 deletion involving two or more codons. In high-risk GISTs treated with R0 resection and imatinib, patients with KIT exon 11 homozygous mutations and KIT intron 10/exon 11 junction deletions demonstrated the highest recurrence rate, indicating that these mutations can be independent prognostic factors of DFS. The presence of KIT exon 11 homozygous mutations also independently influenced OS. CONCLUSION: Low-incidence mutations such as KIT exon 11 homozygous mutations or intron 10/exon 11 junction deletions in GISTs should be carefully evaluated to explore novel treatment strategies, as tumors with these mutations have a high recurrence rate and a very poor prognosis after surgery followed by imatinib adjuvant treatment.

Clinicopathologic characteristics, diagnostic clues, and prognoses of patients with multiple sporadic gastrointestinal stromal tumors: a case series and review of the literature.

BACKGROUND: Most sporadic gastrointestinal stromal tumors (GISTs) occur as solitary tumors, while multiple sporadic GISTs are extremely rare and often misdiagnosed as metastatic GISTs, leading to inappropriate treatment. This study aimed to investigate the clinicopathological characteristics, diagnostic clues, and prognoses of multiple sporadic GISTs. METHODS: Twenty-seven patients with multiple sporadic GISTs and 11 patients with metastatic GISTs mimicking sporadic GISTs were analyzed. The clinicopathological characteristics, genetic mutation types, and prognoses were summarized. In addition, 1066 cases of primary GISTs with a single lesion diagnosed at the same hospital were included as controls. RESULTS: Compared with 1066 cases of primary GIST with a single lesion, multiple sporadic GISTs occurred at an older age, were more common in women than in men, and were located mainly in the stomach. They were generally small in size, had a low mitotic index and were more often rated as very low risk/low risk. Mutation analysis of all available lesions revealed different KIT/PDGFRA mutation patterns among tumors from the same patients. No patient relapsed during the follow-up period. Among 11 patients with metastatic GISTs that mimicked multiple sporadic GISTs, multiple lesions from the same patient always had concordant pathological and mutational characteristics; namely, they carried an identical KIT/PDGFRA mutation, and the mitotic index was usually high. CONCLUSIONS: The prognoses of patients with multiple sporadic GISTs were not worse than those of patients with a single lesion of the same risk under the same treatment. When it was difficult to distinguish multiple sporadic GISTs from metastatic GISTs, multiple lesions in the same patient carried different KIT/PDGFRA mutation patterns, which supported tumor multiplicity, while the concordant hypermitotic phase in multiple lesions of GISTs suggested that the tumor was metastatic.

Ficolin-A/2, acting as a new regulator of macrophage polarization, mediates the inflammatory response in experimental mouse colitis.

Human ficolin-2 (FCN-2) and mouse ficolin-A (FCN-A, a ficolin-2-like molecule in mouse) are activators of the lectin complement pathway, present in normal plasma and usually associated with infectious diseases, but little is known about the role of FCN-A/2 in inflammatory bowel disease (IBD). In our present study, we found that patients with IBD exhibited much higher serum FCN-2 levels than healthy controls. In the dextran sulphate sodium-induced acute colitis mouse model, FCN-A knockout mice showed much milder disease symptoms with less histological damage, lower expression levels of pro-inflammatory cytokines [interleukin-6 (IL-6), IL-1ß and tumour necrosis factor-α (TNF-α)], chemokines (CXCL1/2/10 and CCL4) and higher levels of the anti-inflammatory cytokine IL-10 compared with wild-type mice. We demonstrated that FCN-A/2 exacerbated the inflammatory pathogenesis of IBD by stimulating M1 polarization through the TLR4/MyD88/MAPK/NF-κB signalling pathway in macrophages. Hence, our data suggest that FCN-A/2 may be used as a novel therapeutic target for IBD.

Long non-coding RNA LINC00628 functions as a gastric cancer suppressor via long-range modulating the expression of cell cycle related genes.

To discover new biomarkers for gastric cancer (GC) diagnose and treatment, we screened the lncRNAs in GC tissues from 5 patients. We found 6 lncRNAs had altered expression, and in the same time, the levels of their neighboring genes (located near 300 kb upstream or downstream of lncRNA locus) were significantly changed. After confirming the results of microarray by qRT-PCR in 82 GC patients, the biological function of LINC00628 was examined through cell proliferation and apoptosis, cell migration and invasion, colony formation assay and cell cycle detection. We confirmed that LINC00628 functions as a GC suppressor through suppressing proliferation, migration and colony formation of cancer cells. Furthermore, LINC00628 can also suppress the tumor size in mouse xenograft models. Although LINC00628 can modulate LRRN2 expression, the GC suppressor function of LINC00628 is not LRRN2 dependent. The result of mRNA microarray indicated that LINC00628 perform GC inhibitor function through long-range modulating cell cycle related genes. Importantly, we confirmed that LINC00628 mainly located in the nucleus and interacted with EZH2, and modulated genes expression by regulating H3K27me3 level. This research shed light on the role of dysregulated LINC00628 during GC process and may serve as a potential target for therapeutic intervention.

A rare gastric neuroendocrine carcinoma coexisting with Brunner's gland adenoma: A case report.

Gastric neuroendocrine carcinoma (G-NEC) is a rare neoplasm known for its aggressive behavior and poor prognosis. Brunner's gland adenoma (BGA) is a rare benign proliferative lesion that develops most commonly in the duodenum. To the best of our knowledge, no cases of G-NEC coexisting with BGA have previously been reported. The present study therefore reports the first case of G-NEC combined with BGA. A 67-year-old female presented with upper abdominal discomfort. No distant metastases were detected upon pre-operative abdominal computed tomography imaging. The patient underwent a radical distal gastrectomy, D2 lymphadenectomy and Billroth I gastroenterostomy. The resected masses were histologically confirmed to be G-NEC and BGA, respectively. The patient did not receive neoadjuvant or adjuvant chemotherapy or radiotherapy, and remains alive with no evidence of metastasis or recurrence at four years post-surgery.

Fibroblast growth factor receptor 4 protein expression and clinicopathological features in gastric cancer.

AIM: To investigate fibroblast growth factor receptor 4 (FGFR4) protein expression in Chinese patients with resectable gastric cancer (GC) and the association with clinicopathological characteristics and survival. METHODS: One hundred and seventy-five GC patients who underwent curative surgical procedures were enrolled in this study. The protein expression of FGFR4 in formalin-fixed, paraffin-embedded (FFPE) GC tissues was determined by immunohistochemical (IHC) analysis. Patient clinicopathological data and survival information were also collected and χ(2) statistical analysis was performed to analyze FGFR4 protein expression in the subgroups with differing clinicopathological characteristics including; gender, age, tumor location, differentiation, tumor-node-metastasis stage, macroscopic type, depth of invasion, lymph node metastases, distant metastasis, neural invasion and vascular invasion. Furthermore, some common molecular markers of GC in our cancer center, including p53, p27, topoisomerase IIα (Topo IIα) were also determined by IHC and their association with FGFR4 protein expression evaluated. The probability of survival for different subgroups with different clinicopathological characteristics was calculated using the Kaplan-Meier method and survival curves plotted using the log rank test. RESULTS: Seventy seven cases (44%) were found to have high expression of FGFR4 protein. Significantly different FGFR4 expression was observed between gastric cancers with differing expression of Topo IIα (log rank χ(2) = 9.4760, P = 0.0236). No significant differences were observed between subgroups defined by any of the other clinicopathological characteristics. The median survival time of the FGFR4 high expression (77 cases) and low expression groups (98 cases) was 27 mo and 39 mo, respectively. The five-year survival rates and median survival times of gastric cancers with high FGFR4 expression were worse than those with low expression (30.8% vs 39.2%, 27 mo vs 39 mo), respectively, however, no significant difference was observed in survival time (log rank χ(2) = 1.0477, P = 0.3060). Survival analysis revealed that high expression of FGFR4 was a predictor of poor outcome in GC patients if the tumor was small (less than or equal to 3 cm in size) (log rank χ(2) = 5.5033, P = 0.0190), well differentiated (log rank χ(2) = 7.9757, P = 0.0047), and of T1 or T2 stage invasion depth (log rank χ(2) = 4.8827, P = 0.0271). CONCLUSION: Our results suggest that high tumor expression of FGFR4 protein is not an independent risk factor for GC cancer initiation, but is a useful prognostic marker for GC patients when the tumor is relatively small, well differentiated, or in the early stages of invasion.

HOTAIR Long Noncoding RNA Promotes Gastric Cancer Metastasis through Suppression of Poly r(C)-Binding Protein (PCBP) 1.

The objective of this study was to evaluate the role of HOTAIR long noncoding RNA in gastric cancer metastasis. We analyzed HOTAIR expression levels by real-time reverse transcription PCR and Northern blot analysis in 100 gastric tissues (50 gastric cancer tissues and 50 adjacent normal mucosa), and in four gastric cancer cell lines. Transient RNAi-mediated knockdown and pcDNA-mediated overexpression of HOTAIR were performed. Stable shRNA-mediated knockdown and lentiviral-mediated overexpression of HOTAIR were to study the role of HOTAIR on in vivo tumorigenicity and metastatic burden in the context of xenograft assays. Proteomic profiling was performed to decipher differential protein expression in cells with different HOTAIR expression levels. One of the differentially regulated proteins, Poly r(C)-binding protein (PCBP) 1, was subsequently validated and its function evaluated through xenograft assays. Expression of HOTAIR was significantly higher in cancerous tissues than in adjacent normal mucosa. HOTAIR expression levels dictated in vitro and in vivo tumorigenicity and metastatic potential in these cells. PCBP1 and HOTAIR have an inverse relationship, both at expression level and in function. A direct interaction between the two was confirmed through RNA immunoprecipitation coupled with quantitative real-time PCR. PCBP1 was confirmed to be an inhibitor of gastric cancer pathogenesis and as functionally opposite to HOTAIR long noncoding RNA. In conclusion, HOTAIR expression may serve as a potentially important disease biomarker for the identification of high-risk gastric cancer patients. Moreover, our findings provide mechanistic evidence for HOTAIR overexpression and PCBP1 downregulation and the ensuing malignant phenotype in both cultured and xenograft gastric cancer cells.

Gastrointestinal stromal tumor: 15-years' experience in a single center.

BACKGROUND: Gastrointestinal stromal tumor (GIST) is known for its wide variability in biological behaviors and it is difficult to predict its malignant potential. The aim of this study is to explore the characteristics and prognostic factors of GIST. METHODS: Clinical and pathological data of 497 GIST patients in our center between 1997 and 2012 were reviewed. RESULTS: Patients were categorized into very low-, low-, intermediate- and high-risk groups according to modified National Institutes of Health (NIH) consensus classification system. Among the 401 patients untreated with imatinib mesylate (IM), 5-year overall survival (OS) in very low-, low-, intermediate- and high-risk groups was 100%, 100%, 89.6% and 65.9%; and 5-year relapse-free survival (RFS) was 100%, 98.1%, 90.9% and 44.5%, respectively. Univariate analysis revealed that sex, tumor size, mitotic rate, risk grade, CD34 expression, and adjacent involvement were predictors of OS or RFS. COX hazard proportional model (Forward LR) showed that large tumor size, high mitotic rate, and high risk grade were independent risk factors to OS, whereas high mitotic rate, high risk grade and adjacent organ involvement were independent risk factors to RFS. The intermediate-high risk patients who received IM adjuvant therapy (n = 87) had better 5-year OS and RFS than those who did not (n = 188) (94.9% vs. 72.1; 82.3% vs. 56.3%, respectively). Similarly, advanced GIST patients underwent IM therapy (n = 45) had better 3-year OS and 1-year progression-free survival (PFS) than those who didn't (n = 42) (75.6% vs. 6.8%; 87.6% vs. 12.4%, respectively). CONCLUSIONS: Very low- and low-risk GISTs can be treated with surgery alone. Large tumor size, high mitotic rate, high risk grade, and adjacent organ involvement contribute to the poor outcome. IM therapy significantly improves the survival of intermediate-high risk or advanced GIST patients.

Two cases of neuroendocrine carcinoma of the gallbladder.

Neuroendocrine carcinoma (NEC) of the gallbladder is a rare subtype of gallbladder tumor. Here, we report two cases of NEC in two patients initially suspected to have gallbladder carcinoma. No specific symptoms or abnormal blood test results were observed preoperatively. Abdominal computed tomography scans indicated intraluminal masses in the gallbladder and lymph node enlargement in the hepatic hilum. Radical cholecystectomy and regional lymphadenectomy were performed. The first patient also presented with liver invasion and therefore underwent resection of liver segment IV. A diagnosis of NEC was made upon postoperative pathological examination and immunohistochemical staining according to the WHO Classification of Tumors of the Digestive System (2010). One tumor was identified as poorly differentiated NEC and the other as poorly differentiated mixed adenoneuroendocrine carcinoma. Immunohistochemical staining data from both tumors showed positivity for chromogranin A and synaptophysin. The first patient received 4 cycles of chemotherapy consisting of cisplatin and etoposide. No metastases or recurrence were observed 12 mo following surgery. The second patient refused chemotherapy and presented with tumor recurrence 4 mo after surgery. In conclusion, NEC of the gallbladder is an aggressive tumor and the identification of a standardized optimal treatment still requires further research. Our experience together with published studies suggests that radical surgery and adjuvant chemotherapy may improve the prognosis.

Fibroblast growth factor receptor 4 Gly388Arg polymorphism in Chinese gastric cancer patients.

AIM: To investigate the contribution of the fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism as a genetic risk factor for gastric cancer (GC) and to investigate any associations between this polymorphism and clinicopathological parameters and survival. METHODS: Tumors and matched adjacent non-cancer tissues were collected from 304 GC patients, and 5 mL of venous blood was collected from 62 GC patients and 392 age- and sex-matched healthy controls without cancer history from the same ethnic population. DNA was extracted, and direct sequencing analyses were performed to genotype the FGFR4 Gly388Arg polymorphism in all the samples. Differences in the genotype frequencies of the FGFR4 Gly388Arg polymorphism between GC patients and healthy controls were estimated using the χ(2) test. Binary logistic regression was used for all analysis variables to estimate risk as the ORs with 95%CIs. The relationships between the FGFR4 genotype and clinicopathological parameters were tested with the χ(2) test. The Kaplan-Meier product-limit method, the log-rank test, and the Cox regression model were applied to evaluate the effect of the FGFR4 genotype on the overall survival of patients with GC. RESULTS: In the present GC cohort, 118 patients (38.8%) were homozygous for the Gly388 allele, 124 patients (40.8%) were heterozygous, and 62 patients (20.4%) were homozygous for the Arg388 allele. The frequencies of the Gly/Gly, Gly/Arg, and Arg/Arg genotypes in the healthy controls were 33.6%, 48.0%, and 18.4%, respectively. The distributions of genotypes (χ(2) = 3.589, P = 0.166) and alleles (χ(2) = 0.342, P = 0.559) of the FGFR4 Gly388Arg polymorphism were not different between the GC patients and the healthy controls. Although we observed no correlation between the FGFR4 Gly388Arg polymorphism and clinicopathological parameters or survival in the total cohort of GC patients, the presence of the Arg388 allele was associated with shorter survival time in patients with GC if the tumor was small (log rank χ(2) = 5.449, P = 0.020), well differentiated (log rank χ(2) = 12.798, P = 0.000), T1 or T2 stage (log rank χ(2) = 4.745, P = 0.029), without lymph node involvement (log rank χ(2) = 6.647, P= 0.010), and at an early clinical stage (log rank χ(2) = 4.615, P = 0.032). CONCLUSION: Our results suggest that the FGFR4 Gly388Arg polymorphism is not a risk factor for GC cancer initiation but that it is a useful prognostic marker for GC patients when the tumor is relatively small, well differentiated, or at an early clinical stage.

Correlation of human epidermal growth factor receptor 2 expression with clinicopathological characteristics and prognosis in gastric cancer.

AIM: To investigate human epidermal growth factor receptor 2 (HER2) gene amplification and protein expression in Chinese patients with resectable gastric cancer and the association with clinicopathological characteristics and survival. METHODS: One hundred and ninety-seven gastric cancer patients who underwent curative surgery procedures were enrolled into this study. HER2 gene amplification and protein expression were examined using fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) analysis on formalin-fixed paraffin-embedded gastric cancer samples from all patients. For scoring, Hofmann's HER2 gastric cancer scoring system was adopted. All cases showing IHC3+ or FISH positivity were defined as HER2 positive. Patient clinicopathological data and survival information were collected. Finally, χ² statistical analysis was performed to analyze the HER2 positivity rate amongst the subgroups with different clinicopathological characteristics including; gender, age, tumor location, Lauren classification, differentiation, TNM staging, depth of invasion, lymph node metastases and distant metastasis. The probability of survival for different subgroups with different clinicopathological characteristics was calculated using the Kaplan-Meier method and survival curves plotted using log rank inspection. RESULTS: According to Hofmann's HER2 gastric cancer scoring criteria, 31 cases (15.74%) were identified as HER2 gene amplified and 19 cases (9.64%) were scored as strongly positive for HER2 membrane staining (3+), 25 cases (12.69%) were moderately positive (2+) and 153 cases (77.66%) were HER2 negative (0/1+). The concordance rate between IHC and FISH analyses was 88.83% (175/197). Thirty-six cases were defined as positive for HER2 gene amplification and/or protein expression, with 24 of these cases being eligible for Herceptin treatment according to United States recommendations, and 29 of these cases eligible according to EU recommendations. Highly consistent results were detected between IHC3+, IHC0/1 and FISH (73.68% and 95.42%), but low consistency was observed between IHC2+ and FISH (40.00%). The positivity rates in intestinal type and well-differentiated gastric cancer were higher than those in diffuse/mixed type and poorly-differentiated gastric cancer respectively (28.57% vs 13.43%, P = 0.0103; 37.25% vs 11.64%, P < 0.0001), but were not correlated with gender, age, tumor location or TNM stage, depth of invasion, lymph node metastases and distant metastasis. In poorly-differentiated gastric cancer patients, those without lymph node metastasis showed a higher HER2 positivity rate than those with lymph node metastasis (26.47% vs 7.14%, P = 0.0021). This association was not present in those patients with well-differentiated gastric cancer (28.57% vs 43.33%, P = 0.2832). Within our patient cohort, 26 cases were lost to follow-up. The median survival time for the remaining 171 patients was 18 mo. The median survival times of the HER2 positive and negative groups were 17 and 18.5 mo respectively. Overall survival was not significantly different between HER2-positive and negative groups (χ(2) = 0.9157, P = 0.3386), but in patients presenting well-differentiated tumors, the overall survival of the HER2-positive group was significantly worse than that of the HER2-negative group (P = 0.0123). In contrast, patients with poorly differentiated and diffuse/mixed subtype gastric cancers showed no significant differences in overall survival associated with HER2. Furthermore, the median survival time of the HER2 positive group did not show any statistically significant differences when compared to the subgroups of gender, age, tumor location, TNM classification, lymph node metastases and distant metastasis. CONCLUSION: Patients with intestinal type gastric cancer (GC), well-differentiated GC and poorly-differentiated GC without lymph node metastasis, may all represent suitable candidates for targeted therapy using Herceptin.

[Clinical analysis of laparoscopic and endoscopic cooperative surgery in the treatment of gastric gastrointestinal stromal tumor: report of 46 cases].

OBJECTIVE: To evaluate the feasibility and safety of laparoscopic and endoscopic cooperative surgery for treating gastric gastrointestinal stromal tumors(GIST). METHODS: Retrospective analysis was performed on the clinical data of 46 patients with gastric GIST undergoing laparoscopic and endoscopic cooperative surgery between June 2009 and June 2011 at the Renji Hospital of Shanghai Jiaotong University School of Medicine. RESULTS: There were 27 males and 19 females with the mean age of 58.5 years. Thirty-three patients received endoscopy-assisted wedge resection, and 13 cases received laparoscopy-assisted endoscopic resection. All the operations were successful. The mean operative time was (85.5±29.3) min, the mean blood loss was (31.4±12.2) ml, the mean post-operative gastrointestinal functional recovery time was (31.6±14.9) h, and the mean post-operative hospital stay was (5.1±2.9) d. No post-operative complication occurred. NIH risk assessment showed that 34 cases were very low risk and 12 low risk. No recurrence or metastasis was found during the follow-up ranging from 2 to 26 months(median, 12.6 months). CONCLUSION: Laparoscopic and endoscopic cooperative surgery for gastric GIST is both feasible and safe with minimal invasiveness, fast recovery and satisfactory short-term outcomes.

[Study of loss of heterozygosity at 9p21 and P16 expression in gastrointestinal stromal tumors].

OBJECTIVE: To evaluate the impact of loss of heterozygosity (LOH) at chromosome 9p21 and P16(INK4A)(CDKN2A) expression on the prognosis of gastrointestinal stromal tumor (GIST). METHODS: A total of 51 cases with GISTs were characterized by immunohistochemistry and evaluated for LOH at 9p21 by microsatellite analysis in 4 markers(D9S1751, D9S1846, D9S942 and D9S1748). Associations of LOH at 9p21 and P16(INK4A) expression encoded by CDKN2A with clinicopathological parameters and prognosis in GISTs were analyzed. RESULTS: The frequency of 9p21 LOH was 37.0% (10/27) at D9S1751, 37.5%(12/32) at D9S1846, 42.1%(16/38) at D9S942 and 24.2%(8/33) at D9S1748. The overall frequency of LOH at 9p21 was 63.3%(31/49). In 21 samples of 51 GISTs(41.2%), P16 expression was not detected. Loss of P16 expression was 60%(12/20) in high risk group and 23.5%(4/17) in very low and low risk groups(P<0.05). The 5-year overall survival rate of p16-negative patients was 70.8%, while in P16-positive patients it was 92.0%(P<0.05). CONCLUSIONS: LOH at 9p21 is a frequent event in GIST. Loss of CDKN2A gene at 9p21 may contribute to the progression and malignant transformation of GIST. P16 expression in GIST is associated with prognosis.

Loss of chromosome 9p21 and decreased p16 expression correlate with malignant gastrointestinal stromal tumor.

AIM: To investigate loss of heterozygosity (LOH) of chromosome 9p21 and the prognostic relevance of p16 expression in gastrointestinal stromal tumor (GIST). METHODS: Fifty-one GIST patients (30 men and 21 women; median age 59 years; range 29-80 years) treated surgically within a 10-year period were grouped by aggressive behavior risk (17 with very low and low, 14 intermediate, and 20 high risk). GISTs were characterized immunohistochemically and evaluated for LOH of 9p21 by microsatellite analysis at D9S1751, D9S1846, D9S942, and D9S1748. LOH of 9p21 and immunohistochemical expression of p16 protein encoded at 9p21 were correlated with clinicopathological parameters, and the prognostic significance of p16 alterations was evaluated. RESULTS: Thirty-one (63.3%) cases showed LOH with at least one microsatellite marker. LOH frequency was 37.0% at D9S1751, 37.5% at D9S1846, 42.1% at D9S942, and 24.2% at D9S1748. There was a higher LOH frequency of D9S942 in high-risk than in non-high-risk tumors (P < 0.05, χ(2) = 4.47). Gender, age, tumor size and site were not correlated with allelic loss. Ninety percent (18/20) of the GIST patients in the high risk group showed LOH with at least one of the 9p21 markers, while 57.1% (8/14) in the intermediate risk group and 33.3% (5/15) in the very low and low risk groups, respectively (P < 0.05, χ(2) = 12.16). Eight (28.5%) of 31 patients with LOH and 1 (5.6%) of 18 patients without LOH died of the disease during the follow-up period. Loss of p16 protein expression occurred in 41.2%, but in 60% of the high risk group and 23.5% of the very low and low risk groups (P < 0.05, χ(2) = 4.98). p16 loss was associated with poor prognosis (P < 0.05, χ(2) = 4.18): the 3- and 5-year overall survival rates were 84.8% and 70.8% for p16-negative and 100% and 92.0% for p16-positive patients, respectively. CONCLUSION: LOH at 9p21 appears to play an important role in GIST progression; decreased p16 expression in GIST is highly predictive of poor outcome.

Prognostic analysis of patients with gastrointestinal stromal tumors: a single unit experience with surgical treatment of primary disease.

BACKGROUND: Gastrointestinal stromal tumor (GIST), the most common type of mesenchymal tumors of the gastrointestinal tract, is a recently recognized tumor. The biological behavior of GIST is highly variable. Surgical resection remains the major treatment for GIST. In this study we retrospectively analyzed our surgical experience with 181 GIST patients to determine the effects of the treatment and the pathological features and prognosis factors of these GIST patients. METHODS: The clinicopathological features and follow-up data of the 181 patients with GIST who had received surgical resection between January 1999 and December 2007 at Ren Ji Hospital were retrospectively reviewed. Immunohistochemical stains including CD117 (KIT), CD34, and other markers were used. Tumor size, mitotic index and other pathological parameters were recorded. According to the consensus of NIH risk-group stratification system based on maximum tumor size and mitotic index (per 50 high power field), tumors were classified into very-low-risk group (15 tumors, 8.3%), low-risk group (48, 26.5%), intermediate-risk group (52, 28.7%) and high-risk group (66, 36.5%). Prognostic factors were analyzed by Cox analysis including age, sex, tumor size, tumor site, mitotic index, NIH categories and surgical procedures. RESULTS: One hundred and seven (59.1%) of the 181 tumors were located in the stomach, 51 (28.2%) in the small intestine, 9 (5.0%) in the colon and rectum, and 14 (7.7%) in other sites including the omentum and mesentery. The median age of the patients was 58 (range, 24-84) years, and 102 patients (56.4%) were male. Tumor size ranged from 0.5 to 30 cm, while the mean size was 7.02 cm. Metastasis was found in 7 patients. One hundred and seventy-six (97.2%) of the 181 patients underwent radical resection, and among them 26 patients received extensive resection with the adjacent organ adherent to the tumors. The positive rate for the KIT protein (CD117) in immunostaining was 94.5% (171/181), while that for CD34 was 86.2% (156/181). The 1-, 3-, and 5-year survival rates of the 181 patients were estimated to be 95.2%, 87.9% and 78.5%, respectively. There was a significant difference in age, tumor size, tumor site, mitotic index, NIH categories, and presence or absence of multivisceral resection (P<0.05). But there was no significant difference in sex between the groups. Cox hazard proportional model revealed that advanced clinical stage and large tumor size contributed to worse prognosis. The patients who were treated with imatinib because of recurrence and metastasis or high recurrence risk showed stable disease. CONCLUSIONS: Surgical resection is the gold standard of treatment for primary GIST. NIH categorization is simple and effective to evaluate GIST behavior and prognosis. Targeted therapy such as imatinib, a KIT tyrosine kinase inhibitor, may play an important role in the treatment of GIST.

[Analysis of clinicopathology and prognosis in 181 patients with gastrointestinal stromal tumors].

OBJECTIVE: To investigate the therapeutic experience of gastrointestinal stromal tumors (GIST) and to analyze the pathological features and prognostic factors of GIST. METHODS: The clinicopathological and follow-up data of 181 patients with GIST admitted in Renji Hospital between January 1999 and December 2007 were analyzed retrospectively. All the cases were grouped according to Fletcher's risk scheme. Life table and COX regression model were used to evaluate the prognostic factors. RESULTS: Out of 181 tumors, 107(59.1%) were located in stomach, 51 (28.2%) in intestine and 23(12.7%) in colorectum or other sites. Distant metastases,including liver metastases were found in 7 patients intraoperatively. Tumor size ranged from 0.5 to 30 cm with the mean of 7.02 cm. The positive rate of CD117 was 94.5% (171/181) and that of CD34 was 86.2% (156/181). One hundred and seventy-six patients underwent complete resections, including multi-organ resections in 26 patients. The other patients underwent palliative operations. The 1-, 3- and 5-year overall survival rates of 181 patients were 95.2%, 87.9% and 78.5% respectively. Univariate analysis revealed age, tumor size, primary organ of tumor, mitotic count, Fletcher's classification and multi-organ resection were associated with survival rate. No significant difference of sex was existed among groups. COX hazard proportional model revealed that advanced stage and large tumor size indicated worse prognosis. Eight patients with high risk of recurrence and 3 patients with recurrence and metastasis were stable after receiving imatinib therapy. CONCLUSIONS: The diagnosis of GIST depends on endoscope and CT. Fletcher's classification is simple and effective to evaluate GIST behavior and prognosis. Surgical resection is still the main therapy for GIST and targeted therapy will play a more important role for prognosis in the future.