CT features combined with RECIST 1.1 criteria improve progression assessments of sunitinib-treated gastrointestinal stromal tumors.

OBJECTIVES: To explore the auxiliary value of combining CT features with existing response evaluation criteria in the prediction of progressive disease (PD) in gastrointestinal stromal tumors (GIST) patients treated with sunitinib. MATERIAL AND METHODS: Eighty-one patients with GISTs who received sunitinib were included in this retrospective multicenter study and divided into training and external validation cohorts. Progression at six months was determined as a reference standard. The predictive performance of the RECIST 1.1 and Choi criteria was compared. CT features at baseline and the first follow-up were analyzed. Logistic regression analyses were used to determine the most significant predictors and develop modified criteria. RESULTS: A total of 216 lesions showed a good response and 107 showed a poor response in 81 patients. The RECIST 1.1 criteria performed better than the Choi criteria in predicting progression (AUC, 0.75 vs. 0.69, p = 0.04). The expanded/intensified high-enhancement area, blurred tumor-tissue interface, and progressive enlarged vessels feeding or draining the mass (EVFDM) differed significantly between lesions with good and poor responses in the training cohort (p = 0.001, 0.003, and 0.000, respectively). Multivariate analysis revealed that the expanded/intensified high-enhancement area (p = 0.001), progressive EVFDM (p = 0.000), and RECIST PD (p = 0.000) were independent predictive factors. Modified RECIST (mRECIST) criteria were developed and showed significantly higher AUCs in the training and external validation cohorts than the RECIST 1.1 criteria (training: 0.81 vs. 0.73, p = 0.002; validation: 0.82 vs. 0.77, p = 0.04). CONCLUSION: The mRECIST criteria, combining CT features with the RECIST 1.1 criteria, demonstrated superior performance in the prediction of early progression in GIST patients receiving sunitinib. CLINICAL RELEVANCE STATEMENT: The mRECIST criteria, which combine CT features with the RECIST 1.1 criteria, may facilitate the early detection of progressive disease in GIST patients treated with sunitinib, thereby potentially guiding the timely switch to late-line medications or combination with surgical excision. KEY POINTS: • The RECIST 1.1 criteria outperformed the Choi criteria in identifying progression of GISTs in patients treated with sunitinib. • GISTs displayed different morphologic features on CT depending on how they responded to sunitinib. • Combining CT morphologic features with the RECIST 1.1 criteria allowed for the prompt and accurate identification of progressing GIST lesions.

Characterization of a Human Gastrointestinal Stromal Tumor Cell Line Established by SV40LT-Mediated Immortalization.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the digestive tract and originate from the interstitial cells of Cajal (ICC), which is the pacemaker for peristaltic movement in the gastrointestinal tract. Existing GIST cell lines are widely used as cell models for in vitro experimental studies because the mutation sites are known. However, the immortalization methods of these cell lines are unknown, and no Chinese patient-derived GIST cell lines have been documented. Here, we transfected simian virus 40 large T antigen (SV40LT) into primary GIST cells to establish an immortalized human GIST cell line (ImGIST) for the first time. The ImGIST cells had neuronal cell-like irregular radioactive growth and retained the fusion growth characteristics of GIST cells. They stably expressed signature proteins, maintained the biological and genomic characteristics of normal primary GIST cells, and responded well to imatinib, suggesting that ImGIST could be a potential in vitro model for research in GIST to explore the molecular pathogenesis, drug resistance mechanisms, and the development of new adjuvant therapeutic options.

Retrospective study of the clinicopathological characteristics and prognostic factors of gastrointestinal stromal tumors in Chinese patients.

The purpose of this study was to investigate the clinicopathological characteristics and prognostic factors of patients with gastrointestinal stromal tumors (GISTs) in mainland China. We retrospectively analyzed the clinicopathological characteristics and survival data of 149 patients with GISTs admitted to Shengjing Hospital of China Medical University from July 2011 to October 2017. The following details were collected from all patients: sex, age, symptoms, preoperative examination, pathology, surgical procedures, and follow-up data. Recurrence-free survival (RFS) and overall survival (OS) were used to assess survival outcomes. The Kaplan-Meier method was performed to draw survival curves and calculate the survival rate. The log-rank test was performed for univariate analysis, and the significant factors were included in multivariate analysis using a Cox proportional hazards model to determine prognostic factors. The 5-year RFS rate was 78.5 % and 5-year OS rate was 83.2 %. The univariate analysis showed that the following prognostic factors could significantly predict 5-year RFS and OS: tumor size, initial status, modified NIH classification, mitotic index, CD117 expression, Ki67 index, and surgical procedure (P < 0.05). The multivariate analysis showed that mitotic index, CD117, and Ki67 index were independent prognostic factors associated with 5-year RFS and 5-year OS. This study provides a reference for the clinicopathological characteristics and prognostic factors of patients with GISTs in mainland China, and the results suggest that focusing on immunohistochemical markers in clinical practice may be more reliable for the prediction of clinical outcomes.

Advances in the research of the mechanism of secondary resistance to imatinib in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. At present, surgery is the first-line treatment for primary resectable GISTs; however, the recurrence rate is high. Imatinib mesylate (IM) is an effective first-line drug used for the treatment of unresectable or metastatic recurrent GISTs. More than 80% of patients with GISTs show significantly improved 5-year survival after treatment; however, approximately 50% of patients develop drug resistance after 2 years of IM treatment. Therefore, an in-depth research is urgently needed to reveal the mechanisms of secondary resistance to IM in patients with GISTs and to develop new therapeutic targets and regimens to improve their long-term prognoses. In this review, research on the mechanisms of secondary resistance to IM conducted in the last 5 years is discussed and summarized from the aspects of abnormal energy metabolism, gene mutations, non-coding RNA, and key proteins. Studies have shown that different drug-resistance mechanism networks are closely linked and interconnected. However, the influence of these drug-resistance mechanisms has not been compared. The combined inhibition of drug-resistance mechanisms with IM therapy and the combined inhibition of multiple drug-resistance mechanisms are expected to become new therapeutic options in the treatment of GISTs. In addition, implementing individualized therapies based on the identification of resistance mechanisms will provide new adjuvant treatment options for patients with IM-resistant GISTs, thereby delaying the progression of GISTs. Previous studies provide theoretical support for solving the problems of drug-resistance mechanisms. However, most studies on drug-resistance mechanisms are still in the research stage. Further clinical studies are needed to confirm the safety and efficacy of the inhibition of drug-resistance mechanisms as a potential therapeutic target.

Fourth-line rescue treatment ripretinib of advanced small intestine gastrointestinal stromal tumors who achieved partial response: a case report.

Background: With the advances in gastrointestinal stromal tumors (GISTs) research and the development of new immunotherapy drugs, the emergence of targeted drugs has greatly changed the diagnosis and treatment of GISTs and benefited more GIST patients. However, drug resistance has become increasingly challenging with the widespread application of targeted therapy in GIST patients. Based on the currently available evidence, the United States Food and Drug Administration (US FDA) has approved sunitinib as a second-line therapy and regorafenib as a third-line therapy, and research and development of more molecularly-targeted drugs are underway. Case Description: A middle-aged male patient was diagnosed with advanced small intestine GIST. Following the resection (R2) of tumors in the small intestine and pelvis, the patient received first-, second-, and third-line adjuvant therapies. However, follow-up examinations indicated progressive disease (PD). Ripretinib was then administered as the fourth-line therapy, and partial response (PR) was achieved 6 months later. To the best of our knowledge, this is a rare case in which the fourth-line adjuvant therapy for GIST achieved significant efficacy after unsuccessful systematic first-, second-, and third-line therapies. Conclusions: Imatinib, as the first-choice targeted therapy for advanced GISTs, has achieved notable clinical efficacy. After localized tumor progression on imatinib, second-line sunitinib may be applied. Third-line regorafenib therapy can be used in patients with GISTs who have failed both imatinib and sunitinib. In our current case, the patient experienced PD after regorafenib administration, and a satisfactory efficacy was obtained following the use of ripretinib. For patients with GISTs, after the failure of imatinib, sunitinib, and regorafenib, ripretinib may achieve a good therapeutic effect as a new targeted drug. Ripretinib is currently approved for use as a fourth-line or higher therapy in advanced GISTs, However, the ultimate place of ripretinib in metastatic or advanced GIST remains under investigation. This case achieved the therapeutic effect of PR through the treatment of repatinib, and there were no other obvious side effects except hair loss. Our findings may inform clinical decision-making regarding the treatment of GISTs. Keywords: Gastrointestinal stromal tumor (GIST); imatinib; ripretinib; case report.

Cytoreductive surgery for metastatic gastrointestinal stromal tumors followed by sunitinib compared to followed by imatinib-a multi-center cohort study.

BACKGROUND: The progression-free survival (PFS) is not optimal when imatinib was recommended for treatment of gastrointestinal stromal tumor (GIST) undergoing surgery after tumor local or multifocal progression. METHODS: We evaluate PFS of patients undergoing R0 resection or optimal cytoreductive surgery followed by sunitinib therapy compared with imatinib after tumor unifocal or multifocal progression. RESULTS: From January 2006 to June 2017, ninety-seven patients from thirteen medical centers were enrolled. Fifty-six patients continued imatinib therapy and 41 patients switched sunitinib treatment directly after R0 resection or optimal cytoreductive surgery. The PFS of sunitinib group was longer than that of imatinib group (30.0 months vs 12.0 months, p = 0.009). In subgroup analysis, the PFS of the sunitinib and imatinib groups were 25.5 months and 12.0 months in patients with tumor multifocal progression (p = 0.008), and 39.0 months and 13.0 months in patients with unifocal progression (p = 0.156), respectively. PFS of postoperative sunitinib group was also superior to the total PFS of postoperative imatinib group (PFS of postoperative imatinib plus PFS of subsequent sunitinib therapy (30.0 months vs 21.0 months, p = 0.012). The overall survival in the sunitinib and imatinib groups were 37.0 months and 33.0 months, respectively (p = 0.794). CONCLUSIONS: Surgery followed by sunitinib in GIST patients with unifocal or multifocal progression on imatinib may improve PFS, compared with surgery followed by imatinib.

KIT and platelet-derived growth factor receptor α wild-type gastrointestinal stromal tumor associated with neurofibromatosis type 1: Two case reports.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) associated with neurofibromatosis are uncommon compared to their gastrointestinal counterparts. Patients with neurofibromatosis type 1 (NF-1) have an increased risk of developing gastrointestinal tumors, including rare types such as GIST. CASE SUMMARY: A 60-year-old male Chinese patient was diagnosed with NF-1 10 years ago and presented with upper abdominal discomfort and black stools. Endoscopic ultrasonography and an enhanced abdominal computed tomography scan revealed a mass located 4 cm from the muscular layer of the descending duodenum. A 59-year-old Chinese woman who was diagnosed with NF-1 25 years ago presented with sudden unconsciousness and black stools. Multiple masses in the duodenum were noted by echogastroscopy and an enhanced abdominal computed tomography scan. Both patients presented with cutaneous neurofibromas. The histologic examination of tumors from both patients revealed spindle cells and low mitotic activity. Immunohistochemically, the tumor cells showed strong positivity for KIT (CD117), DOG-1, CD34, and Dehydrogenase Complex Subunit B, and negativity for SMA, desmin, S-100, and ß-catenin. None of the six tumors from two patients had KIT exon 9, 11, 13, or 17 or platelet-derived growth factor receptor α exon 12 or 18 mutation, which is a typical finding for sporadic GISTs. None of the six tumors from the two patients had a BRAFV600E mutation. The patients were alive and well during the follow-up period (range: 0.6-5 yr). CONCLUSION: There have been only a few previous reports of GISTs associated with NF-1. Although GISTs associated with NF-1 have morphologic and immunohistochemical similarities with GISTs, the pathogenesis, incidence, genetic background, and prognosis are not completely known. A medical history of NF-1 in a patient who has gastrointestinal bleeding or anemia and an intra-abdominal mass with nonspecific computed tomography features may help in diagnosing GIST by virtue of the well-known association of these two entities. Molecular genetic studies of cases indicated that GISTs in NF-1 patients have a different pathogenesis than sporadic GISTs.

Serum miR-518e-5p is a potential biomarker for secondary imatinib-resistant gastrointestinal stromal tumor.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the intestinal tract. Imatinib is used as first-line therapy for GIST patients; however, secondary imatinib resistance poses a significant clinical challenge. Here, we analyzed serum miRNA expression profiles to identify specific serum miRNAs that could be used as early diagnostic markers. Candidate miRNAs were validated using Taqman quantitative PCR with serum samples from secondary imatinibresistant GIST patients (n = 39), imatinib-sensitive GIST patients (n = 37), and healthy controls (n = 28). Serum miR- 518e-5p and miR-548e levels were higher in secondary imatinib-resistant GIST than imatinib-sensitive GIST patients or healthy controls (P less than 0.0001). However, ROC analysis indicated that only miR-518e-5p could distinguish imatinibresistant GIST. To discriminate imatinib-resistant from imatinib-sensitive GIST patients, the AUC for serum miR-518e-5p was 0.9938, with 99.8% sensitivity and 82.1% specificity. Serum miR-518e-5p could also discriminate imatinib-resistant GIST patients from healthy controls with 99.9% sensitivity and 97.4% specificity. These data indicate that serum miR-518e- 5p is a potentially promising non-invasive biomarker for early detection and diagnosis of secondary imatinib-resistant GIST.

Cathepsin F Knockdown Induces Proliferation and Inhibits Apoptosis in Gastric Cancer Cells.

Gastric cancer (GC) is one of the most common cancers in the world. The cathepsin F (CTSF) gene has recently been found to participate in the progression of several types of cancer. However, the clinical characteristics and function of CTSF in GC as well as its molecular mechanisms are not clear. Six GC cell lines and 44 paired adjacent noncancerous and GC tissue samples were used to assess CTSF expression by quantitative polymerase chain reaction (qPCR). We used lentivirus-mediated small hairpin RNA (Lenti-shRNA) against CTSF to knock down the expression of CTSF in GC cells. Western blot and qPCR were used to analyze the mRNA and related protein expression. The biological phenotypes of gastric cells were examined by cell proliferation and apoptosis assays. Microarray-based mRNA expression profile screening was also performed to evaluate the potential molecular pathways in which CTSF may be involved. The CTSF mRNA level was associated with tumor differentiation, depth of tumor invasion, and lymph node metastasis. Downregulation of CTSF expression efficiently inhibited apoptosis and promoted the proliferation of GC cells. Moreover, a total of 1,117 upregulated mRNAs and 1,143 downregulated mRNAs were identified as differentially expressed genes (DEGs). Further analysis identified the involvement of these mRNAs in cancer-related pathways and various other biological processes. Nine DEGs in cancer-related pathways and three downstream genes in the apoptosis pathway were validated by Western blot, which was mainly in agreement with the microarray data. To our knowledge, this is the first report investigating the effect of CTSF on the growth and apoptosis in GC cells and its clinical significance. The CTSF gene may function as a tumor suppressor in GC and may be a potential therapeutic target in the treatment of GC.

Comparison of Gene Expression Profile Between Tumor Tissue and Adjacent Non-tumor Tissue in Patients with Gastric Gastrointestinal Stromal Tumor (GIST).

Gastrointestinal stromal tumors (GISTs) are defined as spindle cell and/or epithelioid tumors originated from interstitial Cajal cells or precursors in the digestive tract. This study was conducted to identify genes differing in expression between the gastric tumors and the adjacent non-cancerous mucosas in patients with primary gastric GIST. The gene expression profile was determined by using oligonucleotide-based DNA microarrays and further validated by quantitative real-time PCR. The Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis was performed to predict signaling pathways involved in gastric GIST. Our data showed that the expression levels of 957 genes (RAB39B, member RAS oncogene family; VCAN, versican; etc.) were higher and that of 526 genes (CXCL14, chemokine C-X-C motif ligand 14; MTUS1, microtubule-associated tumor suppressor 1; etc.) were lower in the gastric tumor tissues as compared with normal gastric tissues. Results from KEGG pathway analysis revealed that the differentially expressed genes were enriched into 16 signaling transduction pathways, including Hedeghog and Wnt signaling pathways. Our study may provide basis for identification of novel biomarkers associated with primary gastric GIST pathogenesis and for exploration of underlying mechanisms involved in this gastric sarcoma.

Identification of core miRNA based on small RNA-seq and RNA-seq for colorectal cancer by bioinformatics.

We aimed to identify the potential microRNA (miRNA) targets for colorectal cancer (CRC). Small RNA-seq and RNA-seq data of GSE46622 were downloaded from Gene Expression Omnibus (GEO) database, including samples of tumor tissue, metastasis tissue, and normal tissue from eight CRC patients. Data comparison of small RNA-seq and RNA-seq was performed through Bowtie and TopHat softwares, respectively. Then the expressed values of each sample were calculated by Cufflinks and Cuffdiff based on fragments per kilobase of exon per millionfragments mapped (FPKM) methods. The differentially expressed miRNAs and core miRNAs were identified by paired t-test. Besides, miRNA target genes were integrated through miRanda, MirTarget2, PicTar, PITI, TargetScan, and miRecords databases, followed by functional analysis of specific miRNA. The average comparison rate of sequence reads in miRNA, noncoding RNA, and other areas of the genome is 49.75, 2.90, and 47.35 %, respectively. A total of 49 miRNAs was differentially expressed. Compared with normal controls, 3 miRNAs were upregulated and 13 miRNAs were downregulated in tumor samples as well as 48 miRNAs were upregulated and 20 miRNAs were downregulated in the metastasis samples. Among them, 18 metastasis-specific expressed miRNAs, 2 tumor-specific expressed miRNAs, and 11 normal expressed miRNA were found. miRNA-1, miRNA-338-5p, miRNA-326, and miR-490-5p were selected as important miRNAs. Besides, miRNA-338-5p target gene RAB6B, FAP, and CTGF were identified as oncogenes. The miRNAs, such as miRNA-1, miRNA-338-5p, and miRNA-326 may be used as potential targets for CRC diagnosis and treatment.

Study of the expressions of p53 and bcl-2 genes, the telomerase activity and apoptosis in GIST patients.

AIM: To explore the relationship between clinicobiological behavior and the expression levels of telomerase activity, apoptosis, p53 gene and bcl-2 gene in gastrointestinal stromal tumors (GISTs). METHODS: The intensity of telomerase activity, apoptosis, p53 and bcl-2 expression in GISTs were detected by telomeric repeat amplification protocol, in situ end-labeling technique, and immunohistochemistry, respectively. RESULTS: The positive rates of telomerase activity of malignant GIST, potential malignant GIST and benign GIST were 85% (17/20), 22.8% (2/9) and 0 (0/9), respectively. The apoptosis indices of malignant GIST, potential malignant GIST, and benign GIST were 11.7 +/- 5.4, 30.2 +/- 5.6 and 45.2 +/- 7.2, respectively. The intensity of telomerase activity and apoptosis were related to the biological characteristics of GISTs (85% vs 22.8%, 0, 0; P < 0.01 or 11.7 +/- 5.4 vs 30.2 +/- 5.6, 45.2 +/- 7.2, 72.1 +/- 9.3; P < 0.05). The intensity of telomerase activity was negatively correlated with cellular apoptosis (22.9 +/- 8.4 vs 9.5 +/- 5.7, P < 0.01). The intensity of telomerase activity was positively correlated with p53, bcl-2 expression (40.0% vs 78.9%, 40.0% vs 84.2%; P < 0.05). CONCLUSION: The detection of telomerase activity, apoptosis and its control genes in GIST will be helpful for the discrimination of the malignant and benign GIST and evaluation of the prognosis.