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.

Clinical analysis of laparoscopic and endoscopic cooperative surgery in the treatment of gastric gastrointestinal stromal tumor: report of 46 cases / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To evaluate the feasibility and safety of laparoscopic and endoscopic cooperative surgery for treating gastric gastrointestinal stromal tumors(GIST).</p><p><b>METHODS</b>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.</p><p><b>RESULTS</b>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).</p><p><b>CONCLUSION</b>Laparoscopic and endoscopic cooperative surgery for gastric GIST is both feasible and safe with minimal invasiveness, fast recovery and satisfactory short-term outcomes.</p>

Study of loss of heterozygosity at 9p21 and P16 expression in gastrointestinal stromal tumors / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>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).</p><p><b>METHODS</b>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.</p><p><b>RESULTS</b>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).</p><p><b>CONCLUSIONS</b>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.</p>

Prognostic analysis of patients with gastrointestinal stromal tumors: a single unit experience with surgical treatment of primary disease / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>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.</p><p><b>METHODS</b>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.</p><p><b>RESULTS</b>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.</p><p><b>CONCLUSIONS</b>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.</p>

Analysis of clinicopathology and prognosis in 181 patients with gastrointestinal stromal tumors / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate the therapeutic experience of gastrointestinal stromal tumors (GIST) and to analyze the pathological features and prognostic factors of GIST.</p><p><b>METHODS</b>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.</p><p><b>RESULTS</b>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.</p><p><b>CONCLUSIONS</b>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.</p>

Clinicopathological analysis of 34 cases of primary small intestine lymphoma / 上海第二医科大学学报

Objective To analyse the clinicopathological features of primary small intestine lymphoma(PSIL), and explore the relationship between clinical stage,histological findings,therapeutic modality and prognosis. Methods The clinical data of 34 cases of PSIL were collected,the pathohistological features and results of immunohistochemical examinations were obtained,and the follow-up findings were adopted for comprehensive analysis. Results Among these 34 cases of PSIL,abdominal pain or discomfort,gastrointestinal bleeding and abdominal mass were the predominant symptoms.PSIL mainly involved ileum,especially the bottom of ileum and ileocecal area.Among the 26 patients with follow-up for more than one year,the 1-year survival rate was significantly higher in patients without tumor perforation than those with tumor perforation(76.2% vs 20.0%)(P

Regulatory effects of tuberculin on growth and apoptosis of liver cancer and lung cancer cell lines / 上海第二医科大学学报

Objective To investigate the regulatory effects of tuberculin on growth and apoptosis of liver cancer and lung cancer cell lines. Methods HePG2(liver cancer) and A549(lung cancer) cell lines were treated with TB supernatant(TB-SN) with different concentrations. Cell viability was detected by using LIVE/DEAD Viability/Cytotoxicity cell kits including specific fluorescence primer,and cell apoptosis was detected by Vybrant apoptosis assay. Results After treatment with 5% TB-SN for 5 d,cell apoptosis was significantly increased in HePG2 and A549 cell lines.Cell growth of HePG2 and A549 cell lines was inhibited after treatment with TB-SN. Conclusion Tuberculin can induce cell apoptosis and inhibit cell growth of liver cancer and lung cancer cell lines.

Expression of thyroid transcription factor-1 in hepatocellular carcinoma / 上海第二医科大学学报

Objective To investigate the value of thyroid transcription factor-1(TTF-1) in the diagnosis and biological behavior assessment of hepatocellular carcinoma (HCC). Methods Thirty liver specimens obtained from benign lesions were analysed, among which 25 were hepatic cirrhosis and inflammatory diseases, and the other 5 were adenomas. And there were 176 specimens of liver tumors, among which 142 were HCC (well differentiated, n=12; moderately differentiated, n=57; poorly differentiated, n=73), 17 were intrahepatic cholangiocellular carcinoma (ICC) and the other 17 were liver metastatic carcinoma (MC). The expression of TTF-1 was examined immunohistochemically in the above tissues, and the difference in expression of TTF-1 among different tissues was examined by Fisher's exact test, Kruskal-Wallis test and Spearman rank correlation analysis. Results TTF-1 was significantly expressed in the cytoplasms of all the hepatocytes besides tumors and liver benign lesions. The expression rate of TTF-1 in HCC was 78.9% (112/142), however, TTF-1 was negatively expressed in ICC and MC(P

Clinicopathology of mixed epithelial and stromal tumor of kidney / 上海第二医科大学学报

Objective To investigate the pathological features and differential diagnosis of mixed epithelial and stromal tumor of the kidney(MESTK). Methods Three patients with MESTK were studied by light microscopy and immunohistochemistry,and related literatures were reviewed. Results In the three patients,two were females and one was male,with the mean age of 20 years old.Examined grossly,the tumors were well circumscribed and typically composed of multiple cysts and solid areas.Microscopically,the tumors were composed of epithelial and spindle cells,both of the which were well differentiated with no atypia and mitosis of the nuclei.The immunohistochemical staining showed positive for the cytokeratin in the epithelial cells,and Vimentin,SMA,actin,PgR or ER and WT-1 in the spindle cells.No tumor recurrence and metastasis was found in all the three patients by 25 to 29 months of follow up. ConclusionMESTK is an uncommon mixed renal neoplasm with a favorable prognosis.

Clinicopathological analysis of malignant triton tumor of the posterior mediastinum / 上海第二医科大学学报

Objective To investigate the pathologic appearances,immunohistochemical features,and genetic changes of malignant triton tumor(MTT). Methods One case of MTT was studied pathologically and immunohistochemically,and the related literatures were reviewed. Results A huge mass,demonstrated in the thorax by X ray and CT scan was seen in the posterior mediastinum in the surgery.Histologically,the tumor was composed of spindle cells with significant atypia.Some of the tumor cells had dense eosinophilic cytoplasm.Immunohistochemical staining revealed positive for myoglobin,desmin and S-100 in most of the tumor cells.The pathological diagnosis was MTT of the posterior mediastinum. Conclusion Cases of MTT in the mediastinum are very rare,with less specific clinical and imaging manifestations.The diagnosis is mainly made on the basis of pathological examination and immunohistochemical staining.