Metastasis Of Gastrointestinal Stromal Tumor Research Articles

Combined model based on enhanced CT texture features in liver metastasis prediction of high-risk gastrointestinal stromal tumors.

To investigate the use of the combined model based on clinical and enhanced CT texture features for predicting the liver metastasis of high-risk gastrointestinal stromal tumors (GISTs). This retrospective study was conducted including 204 patients with pathologically confirmed high-risk GISTs from the Zhejiang Cancer Hospital from January 2015 to June 2021, and 76 cases of them were diagnosed with simultaneous liver metastasis. We randomly divided the cohort into a training cohort (n = 142) and a validation cohort (n = 62) with a ratio of 7:3. All volumes of interest (VOIs) of the high-risk GISTs were manually segmented on the portal venous phase CT images using the ITK-SNAP software. The least absolute shrinkage and selection operator (Lasso) algorithm was performed to determine the most valuable features from a total of 110 texture features extracted by the A-K software to reflect the texture information of the given VOIs. Texture-based predictive model was built from the selected texture features. Independent clinical risk factors were identified through univariate logistic analysis. Then, the texture-based model incorporated the clinical predictors to develop a combined model by multivariate logistic regression. Receiver operating characteristic curve, calibration curve, and decision curve analysis were utilized to analyze the discrimination capacity and clinical application value of the predictive models. The nine optimal texture features were remained after the reduction of dimension using Lasso method. Another four clinical parameters (BMI, location, gastrointestinal bleeding, and CA125 level) were included in the clinical-based predictive model. Finally, with the combination of remaining texture and clinical features, a multivariate logistic regression classifier was built to predict the liver metastasis potential of high-risk GISTs. The remarkable classification performance of the combined model for the prediction of liver metastasis in the subjects with high-risk GISTs was obtained with area under curve (AUC) = 0.919, sensitivity = 83.9%, specificity = 89.7%, and accuracy = 84.9% in our validation group. The texture-based radiomic signature derived from the portal venous phase CT images could predict liver metastasis of high-risk GISTs in a non-invasive way. Integrating additional clinical variables into the model further leads to an improvement of liver metastasis risk prediction.

Significance of circulating tumor cell monitoring in targeted therapy for gastrointestinal stromal tumors

Objective: To explore the significance of circulating tumor cell (CTC) monitoring in evaluating the efficacy of targeted therapy for gastrointestinal stromal tumor (GIST). Methods: A prospective cohort study was performed. The data of patients with locally advanced GIST or liver metastasis who were admitted to The Affiliated Hospital of Nantong University from August 2013 to December 2018 were collected. Inclusion criteria: (1) patients aged older than 18 years; (2) patients who were diagnosed with GIST based on pathology; (3) patients without surgery, whose preoperative imaging evaluation of GIST found the violations of the surrounding organs or partial transfer of an estimated difficulty to achieve R0 resection, or the maximum diameter of the tumor > 10 cm, or the liver metastasis, or the expectation of higher risk of surgical complications; (4) patients who were treated with the imatinib 400 mg/d for the first time; (5) Eastern Cooperative Oncology Group (ECOG) score of 0-2. Exclusion criteria: (1) genetic testing revealed a D842V mutation in exon 18 of the PDGFRA gene; (2) alanine aminotransferase and/or aspartate aminotransferase > 2.5 times the normal upper limit; (3) serum total bilirubin >1.5 times of normal upper limit; (4) neutrophil count < 1.5×10(9)/L, or platelet count < 75×10(9)/L, or hemoglobin < 60 g/L; (5) creatinine > normal upper limit; (6) patients had serious cardiovascular and cerebrovascular diseases within 12 months before enrollment; (7) female patients were pregnant or lactating; (8) patients suffered from other serious acute and chronic physical or mental problems, and were not suitable for participating in this study judged by researchers. The patients who could not tolerate treatment regimen, or developed serious adverse reactions and did not follow the medication scheme after enrollment were excluded. Before imatinib treatment and 1-month and 2-month after treatment, quantitative PCR was used to detect the DOG-1 expression of monocytes in peripheral blood, and the ratio of DOG-1/β-actin > 3×10(-5) was used as the CTC positive threshold of GIST. The positive rate of CTC, the efficacy of imatinib treatment (complete response, partial response, stable disease, progressive disease, and occurrence of adverse reactions), and the relationship between CTC positive rate and clinicopathological characteristics of patients were analyzed. Furthermore, the ratio of DOG-1 decrease/baseline DOG-1 after 1-month of treatment was used as an indicator to evaluate whether targeted therapy was effective. The receiver operating characteristic (ROC) curve was rendered, and the area under the curve (AUC) was calculated. Results: A total of 68 GIST patients were enrolled in this study, including 39 cases of locally advanced GIST and 29 cases with liver metastases, 32 males and 36 females with the mean age of (51.2±11.8) (range 31 to 74) years. After 2-month of imatinib treatment, 43 cases were evaluated as partial response, 11 cases as stable disease, and 14 cases as progressive disease, with an effective rate of 79.4% (54/68). During the treatment of imatinib, the incidence of grade 3 or higher adverse reactions was 22.1% (15/68), including 12 cases of grade 3 neutropenia and 3 of grade 4 drug eruption, which were all relieved after conservative treatment. The positive rates of CTC in 68 patients before treatment, 1-month and 2-month after treatment were 66.2% (45/68), 41.2% (28/68) and 23.5% (16/68), respectively. The positive rate of CTC was associated with tumor size, liver metastasis, mitotic count and risk level (all P<0.05). By analyzing the effective group and the ineffective group of targeted therapy, it was found that the positive rate of CTC in the effective group showed a decreasing trend, while the positive rate of CTC in the ineffective group showed an increasing trend. The AUC of predicting the efficacy of targeted therapy for GIST was 0.823 by detecting the change trend of CTC 1-month after treatment (P<0.001). When the DOG-1 content decreased by more than 57.5% 1-month after treatment, it can be used as an indicator to judge the effectiveness of the treatment, whose sensitivity was 72.2% and specificity was 100%. Conclusion: The detection of peripheral blood CTC can evaluate the efficacy of targeted therapy in GIST patients and can provide decision-making basis for further clinical treatment.

Humeral metastasis as the only recurrence of a 5-year resected gastrointestinal stromal tumor: a case report

IntroductionGastrointestinal stromal tumors represent the most frequently encountered primary mesenchymal tumors. Whereas the liver and the peritoneum are known to be the preferential metastasis sites, no therapeutic standard has yet been established for the management of bone metastases because of their very low incidence. We report a unique example of a single humerus metastasis of a jejunal gastrointestinal stromal tumor.Case presentationWe report the case of a 72-year-old European woman whose jejunal gastrointestinal stromal tumor was resected in 2013 and treated during the following 3 years with imatinib (400 mg daily). In 2018, she developed a single humeral bone lesion that was identified as a gastrointestinal stromal tumor metastasis. After 7 months of imatinib intake, reconstructive surgery was performed. Pathologists confirmed the satisfactory histological regression and assessed the complete tumor resection. The patient is still on imatinib maintenance therapy, with no recurrence reported so far. She fully recovered the upper limb function after following an appropriate rehabilitation program.DiscussionCurrent literature and published case reports indicate that bones are one of the rarest locations of gastrointestinal stromal tumor metastasis (about 1%), with occurrence mainly in the spine. Patients initially diagnosed with gastrointestinal stromal tumor of the small intestine and stomach are more likely to suffer from bone metastasis, compared with other gastrointestinal stromal tumor locations. The median overall survival rate is higher for patients with isolated bone metastasis compared with those having liver metastasis. Metastasis occurs on average 4 years after the primary, but it may take up to 20 years, emphasizing the need for long-term clinical and radiological monitoring. Although specific guidelines for such cases have not yet been established, we suggest that a multimodal concerted approach involving surgery or radiotherapy associated with tyrosine kinase inhibitor intake should be considered.ConclusionBones are one of the rarest locations of gastrointestinal stromal tumor metastasis. A multidisciplinary collaboration was set up to allow conservative surgery of our patient after several months of imatinib treatment. A year and a half later, the patient is still in complete remission. This specific case supports the concept of an intermediate stage between local and oligometastatic disease that should be managed with a curative aim, as much as possible.

GMP-compliant production of [68Ga]Ga-NeoB for positron emission tomography imaging of patients with gastrointestinal stromal tumor

Background[68Ga]Ga-NeoB is a novel DOTA-coupled Gastrin Releasing Peptide Receptor (GRPR) antagonist with high affinity for GRPR and good in vivo stability. This study aimed at (1) the translation of preclinical results to the clinics and establish the preparation of [68Ga]Ga-NeoB using a GMP conform kit approach and a licensed 68Ge/68Ga generator and (2) to explore the application of [68Ga]Ga-NeoB in patients with gastrointestinal stromal tumors (GIST) before and/or after interventional treatment (selective internal radiotherapy, irreversible electroporation, microwave ablation).ResultsValidation of the production and quality control of [68Ga]Ga-NeoB for patient use had to be performed before starting the GMP production. Six independent batches of [68Ga]Ga-NeoB were produced, all met the quality and sterility criteria and yielded 712 ± 73 MBq of the radiotracer in a radiochemical purity of > 95% and a molar activity of 14.2 ± 1.5 GBq/μmol within 20 min synthesis time and additional 20 min quality control. Three patients (2 females, 1 male, 51–77 yrs. of age) with progressive gastrointestinal stromal tumor metastases in the liver or peritoneum not responsive to standard tyrosine kinase inhibitor therapy underwent both [68Ga]Ga-NeoB scans prior and after interventional therapy. Radiosynthesis of 68Ga-NeoB was performed using a kit approach under GMP conditions. No specific patient preparation such as fasting or hydration was required for [68Ga]Ga-NeoB PET/CT imaging. Contrast-enhanced PET/CT studies were performed. A delayed, second abdominal image after the administration of the of [68Ga]Ga-NeoB was acquired at 120 min post injection.ConclusionsA fully GMP compliant kit preparation of [68Ga]Ga-NeoB enabling the routine production of the tracer under GMP conditions was established for clinical routine PET/CT imaging of patients with metastatic GIST and proved to adequately visualize tumor deposits in the abdomen expressing GRPR. Patients could benefit from additional information derived from [68Ga]Ga-NeoB diagnosis to assess the presence of GRPR in the tumor tissue and monitor antitumor treatment.

Cancer-associated fibroblast secretion of PDGFC promotes gastrointestinal stromal tumor growth and metastasis

Targeted therapies for gastrointestinal stromal tumor (GIST) are modestly effective, but GIST cannot be cured with single agent tyrosine kinase inhibitors. In this study, we sought to identify new therapeutic targets in GIST by investigating the tumor microenvironment. Here, we identified a paracrine signaling network by which cancer-associated fibroblasts (CAFs) drive GIST growth and metastasis. Specifically, CAFs isolated from human tumors were found to produce high levels of platelet-derived growth factor C (PDGFC), which activated PDGFC-PDGFRA signal transduction in GIST cells that regulated the expression of SLUG, an epithelial-mesenchymal transition (EMT) transcription factor and downstream target of PDGFRA signaling. Together, this paracrine induce signal transduction cascade promoted tumor growth and metastasis in vivo. Moreover, in metastatic GIST patients, SLUG expression positively correlated with tumor size and mitotic index. Given that CAF paracrine signaling modulated GIST biology, we directly targeted CAFs with a dual PI3K/mTOR inhibitor, which synergized with imatinib to increase tumor cell killing and in vivo disease response. Taken together, we identified a previously unappreciated cellular target for GIST therapy in order to improve disease control and cure rates.

TGF-\u03b21-mediated transition of resident fibroblasts to cancer-associated fibroblasts promotes cancer metastasis in gastrointestinal stromal tumor

Cancer-associated fibroblasts (CAFs) are the most abundant cells in the tumor microenvironment. Crosstalk between tumor cells and CAFs contributes to tumor survival in most epithelial cancers. Recently, utilizing gastrointestinal stromal tumor (GIST) as a model for sarcomas, we identified paracrine networks by which CAFs promote tumor progression and metastasis. However, the mechanisms by which CAFs arise in sarcomas remain unclear. Here, RNA sequencing analysis revealed that transforming growth factor-β1 (TGF-β1) is highly expressed in both tumor cells and CAFs. To determine the functional role of TGF-β1, we treated normal gastric fibroblasts (GFs) with recombinant TGF-β1, which caused the GFs to adopt a more stellate morphology, as well as increased the mRNA expression of CAF-mediated genes (CCL2, RAB3B, and TNC) and genes encoding fibroblast growth factors (FGFs). Moreover, while either GIST or CAF conditioned media enhanced the transition from GFs to CAFs, a TGF-β1-blocking antibody attenuated this effect. Transwell migration assays revealed that the TGF-β1-mediated transition from GFs to CAFs enhanced tumor cell migration. This migratory effect was abrogated by an anti-TGF-β1 antibody, suggesting that TGF-β1 secreted from GIST cells or CAFs is associated with GIST migration via GF-to-CAF transition. In addition, the murine spleen-to-liver metastasis model showed that GF pre-treated with TGF-β1 promoted GIST metastasis. Collectively, these findings reveal unappreciated crosstalk among tumor cells, CAFs, and normal resident fibroblasts in the stroma of sarcomas, which enhances a GF-to-CAF transition associated with tumor migration and metastasis.

Esophageal Gastrointestinal Stromal Tumor with Rare Intracranial Metastasis

Introduction. Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors and constitute the largest group of nonepithelial digestive neoplasms. However, they do not represent more than 1% of primary digestive tumors. They commonly metastasize to the liver and peritoneum, but brain metastases are extremely rare. Clinical Case. A 76-year-old woman with a diagnosis of esophageal GIST with liver and lung metastases for 13 years, medicated with imatinib, is presented. She was brought to the emergency department after falling and due to changes in behavior and vertigo with 24 hours of evolution. On physical examination, she presented changes in behavior, dysarthria, dysmetria on the right, gait imbalance, and no motor or sensory deficits. On brain computed tomography and posteriorly on magnetic resonance, 2 lesions were observed, left frontal and right cerebellar, compatible with metastatic lesions. After contribution of neurosurgery, histology was obtained that confirmed the lesions were GIST metastases. Imatinib was maintained, and whole brain radiotherapy was performed. After 6 months, she died. Discussion. The rarity of GIST brain metastases is noteworthy, and because of that, there is not enough experience to be certain of the best treatment. Our patient lived for 13 years with excellent disease control with imatinib, but the fact that it does not cross the blood-brain barrier makes it not useful in preventing or treating brain lesions. New tyrosine kinase inhibitors that may cross the blood-brain barrier could be the answer to these cases.

TUFM-knockdown inhibits the migration and proliferation of gastrointestinal stromal tumor cells.

Gastrointestinal stromal tumors (GISTs) are the most common pathologic type of mesenchymal tumor in the digestive tract. Patients with GIST face the risk of metastasis, postoperative recurrence and imatinib mesylate (IM) resistance. Mitochondrial Tu translation elongation factor (TUFM) is highly expressed in GISTs, and is associated with oncogenesis, progression and prognosis. There is evidence that TUFM is involved in tumor invasion and metastasis. However, the effect of TUFM on GIST-T1 cells and the IM-resistant GIST-IR cell line remains unclear. The present study aimed to evaluate the effects of TUFM on the proliferation, migration and apoptosis of GIST cells in vitro. TUFM short hairpin (sh)RNA expression plasmids were transfected into GIST-T1 and GIST-IR cells by electroporation. The expression levels of enhanced green fluorescent protein were observed by fluorescence microscopy to evaluate the electroporation efficiency. The expression levels of TUFM were detected by western blot analysis and reverse transcription-quantitative PCR. Cell proliferation was assessed by counting cells and using a Cell Counting Kit-8 assay. Cell migration was analyzed using wound healing and Transwell migration assays. Cell cycle distribution and late apoptosis were assessed by flow cytometry. TUFM shRNA expression plasmids were successfully transfected into the GIST cell line by electroporation. The transfection efficiency was >75%, and the TUFM gene silencing efficiency was 73.2±1.4%. TUFM-knockdown decreased the proliferation and migration capacity of GIST-T1 and GIST-IR cells. The proportion of cells in the pre-G1 stage was increased without change in the proportions of cells in the G1, S and G2/M stages after TUFM silencing in GIST-T1 and GIST-IR cells. TUFM may be related to GIST infiltration and metastatic recurrence, suggesting that TUFM may be an effective target for preventing the progression and metastasis of GISTs.

Differential diagnosis of liver metastases of gastrointestinal stromal tumors from colorectal cancer based on combined tumor biomarker with features of conventional ultrasound and contrast-enhanced ultrasound.

To explore the value of tumor marker CA125 and CEA linked with conventional ultrasound (US) and contrast-enhanced ultrasound (CEUS) features in differentiating gastrointestinal stromal tumors liver metastases (GISTLM) from colorectal cancer liver metastases (CRCLM). From December 2005 to February 2019, eighty patients with pathologically proven GISTLM together with 80 CRCLM patients were retrospectively evaluated with contrast-enhanced ultrasound (CEUS). Clinical characteristics such as CA125 and CEA were documented to compare the difference between GISTLM and CRCLM. Univariate analysis was performed to determine significant features in ultrasound and then these features were entered into multivariate logistic regression model to determine diagnostic criteria. By analyzing the tumor marker and imaging features, diagnostic performance was evaluated via receiver-operating characteristic (ROC) analysis. The sensitivity, specificity and accuracy were calculated for the diagnosis of GISTLM. Multiple logistic regression analysis showed that increased CA125 and normal CEA were the independent variables of GISTLM. On conventional US, the features of hypo- or mix-echogenicity and anechoic area were associated with GISTLM. On CEUS, capsule enhancement, starting time of washout > 40s and proportion of non-enhancement area > 20% were the features indicating GISTLM. All of the p values were < 0.05. When linking tumor marker with imaging features, the diagnostic sensitivity improved from 36.3-57.5% to 70.0%, and the area under the ROC (AUROC) curve improved from 0.681-0.750 to 0.838, with a specificity of 97.5%. Combining the imaging features of conventional US and CEUS with serum tumor markers provides a potentially effective diagnostic method in differentiation of GISTLM and CRCLM.

Zinc finger E-box-binding homeobox 1 (ZEB1): A novel predictor for the prognosis in gastrointestinal tumors.

e23515 Background: The gastrointestinal stromal tumors (GISTs) are the most common soft tissue sarcoma arising anywhere along gastrointestinal tract. The advanced and metastatic GISTs are the leading cause in GISTs inducing death. GISTs are the most commonly resulted from KIT or PDGFRA activation mutation. Currently adjuvant therapy with imatinib also targets the KIT and PDGFRA signals, which significantly increases the relapse-free survival and overall survival. However, KIT and PDGFRA mutation are not completely responsible for the progression of disease, especially metastasis of GISTs. So, there could be other molecular mechanism in GISTs progression. ZEB1 (zinc finger E-box-binding homeobox 1), as a member in zinc finger and homeodomain transcriptional factor family, plays a key role in metastasis of some epithelial carcinomas, such as colorectal cancer, breast cancer and NSCLC. We present that ZEB1, as a vital molecular in epithelial-mesenchymal transition, could be a promising marker in predicting the prognosis in GISTs. Methods: Immunohistochemistry staining for paraffin-embedding slices from 157 patients firstly diagnosed as GIST is applied for detecting the ZEB1 expression. Clinical, pathological, molecular and survival time were analyzed. All performances were approved by the Medical Ethics Committee in the First Affiliated Hospital of Chongqing Medical University. Results: In 157 patients, metastasis was found in 87 patients. In 87 patients with metastasis, high expression of ZEB1 almost exhibited (80 high/96 VS 7 non or low/96), while non or low expression was frequently detected in patients without metastasis (50 non or low/70 VS 20 high/70) (p &lt; 0.0001). There was no significant difference between high and non/low expression patients in gender (48% VS 46% for male rate; 52% VS 54% for female rate), age (53 vs 54 years for median age), primary location (esophagus 2% VS 1.8%; stomach 57% VS 52.6%; duodenum and small intestine 31% VS 31.6%; colorectum and anus 10% VS 14.0%), tumor size (0.5-24cm, median 9.7cm VS 1-25.5cm, median 10.1cm), mitotic index (55.0% VS 58.6% for &gt; 5/50HPF; 45.0% VS 41.4% for ≤5/50HPF), and risk stratification (low/intermediate risk 60.7% VS 63%; high risk 39.3% VS 37%). In addition, the 5-year OS rate was considerably lower in patients with ZEB1 high expression than those with ZEB1 none or low expression at baseline (37% vs 86%; p = 0.011). Conclusions: High expression of ZEB1 facilitates metastasis and indicates the poor prognosis in GISTs. ZEB1 could be a novel predictor for GIST’s prognosis.

Long-term results of selective internal radioembolization (SIRT) to control progressive liver metastases of gastro-intestinal stromal tumors (GIST) beyond treatment with tyrosine kinase inhibitors (TKI).

11538 Background: Liver and peritoneum are the main area of metastatic spread in GIST. Liver resection does not play a role for hepatic metastases in comparison to f.e. colorectal cancer. If hepatic metastases are the only or major area of tumor progression and are resistant to available TKIs due to a missing mutation in KIT/PDGFRA/SDH ( ‘wildtype’) or after treatment with 1st/2nd/3rd/4th line therapy, interventional radioembolization with yttrium-90 (90Y) microspheres are promising treatment options, as radiation doses as high as 200Gy can be applied locally. We analyzed the long-term results of SIRT with respect to hepatic-progression-free survival (HEP-PFS) in a consecutive cohort of patients.. Methods: From 1/2008 to 1/2018, 25 pts (12f, 13m) with biopsy proven liver metastases of GIST which were the only (n = 13) or the dominant site of progression (n = 12) were treated by SIRT. Median age at GIST diagnosis had been 51.8 yrs and when receiving SIRT was 57.6yrs (range, 18–75yrs). The mutational status was ‘wildtype’ (n = 7, 2 NF-1), exon 11 (n = 7), exon 11+2nd mutation (n = 6), exon 9 (n = 3), exon 9+2ndmut (n = 1), and, exon 13 (n = 1). All patients except of two had prior TKI therapy: 1 line n = 3, 2 lines n = 11, 3-4 lines n = 9. Follow-up after SIRT was done via dynamic MRI and contrast-enhanced (CE)-CT, the median follow-up is 30.6 mos (range, 12-100mos) and all patients were followed until death. Results: The median hepatic-progression free survival (HEP-PFS) after SIRT was 17 months (range, 5-53+, 95%CI 11.8-22.1 mos). Of the patients with concomitant extrahepatic disease, the extraHEP-PFS was median 10 months. Twelve patients received next-line TKI therapy for progressive extrahepatic disease, whereas six patients required this for progressive liver metastases. When comparing the results according to the mutational status, patients with a ‘wildtype’ tumor showed a better median HEP-PFS of 19 mos (range, 12-53+, 95%CI 16.7-21.2 mos.) in comparison to KIT exon 9/11/13 mutated patients with only 14 months (range, 4-34 mos., 95%CI 6.5-21.4 mos), p &lt; 0.11 (Wilcoxon). Conclusions: 90Y radioembolization (SIRT) offers a safe and effective treatment for patients with liver metastases of GISTs being the dominant site of tumor progression and with no drug treatment options available. In patients known to have no mutation in KIT/PDGFRA (wt, also NF-1 associated) it looks whether the results might be even more promising and SIRT could be used in early treatment lines.

Computed tomography-based radiomics model for discriminating the risk stratification of gastrointestinal stromal tumors.

The pathological risk degree of gastrointestinal stromal tumors (GISTs) has become an issue of great concern. Computed tomography (CT) is beneficial for showing adjacent tissues in detail and determining metastasis or recurrence of GISTs, but its function is still limited. Radiomics has recently shown a great potential in aiding clinical decision-making. The purpose of our study is to develop and validate CT-based radiomics models for GIST risk stratification. Three hundred and sixty-six patients clinically suspected of primary GISTs from January 2013 to February 2018 were retrospectively enrolled, among which data from 140 patients were eventually analyzed after exclusion. Data from patient CT images were partitioned based on the National Institutes of Health Consensus Classification, including tumor segmentation, radiomics feature extraction and selection. A radiomics model was then proposed and validated. The radiomics signature demonstrated discriminative performance for advanced and nonadvanced GISTs with an area under the curve (AUC) of 0.935 [95% confidence interval (CI) 0.870-1.000] and an accuracy of 90.2% for validation cohort. The radiomics signature demonstrated favorable performance for the risk stratification of GISTs with an AUC of 0.809 (95% CI 0.777-0.841) and an accuracy of 67.5% for the validation cohort. Radiomics analysis could capture features of the four risk categories of GISTs. Meanwhile, this CT-based radiomics signature showed good diagnostic accuracy to distinguish between nonadvanced and advanced GISTs, as well as the four risk stratifications of GISTs. Our findings highlight the potential of a quantitative radiomics analysis as a complementary tool to achieve an accurate diagnosis for GISTs.

Bone Metastases of Gastrointestinal Stromal Tumor: A Review of Published Literature.

BackgroundWith the occurrence and improvement of immunohistochemistry and other pathological diagnostic techniques, gastrointestinal stromal tumor (GIST) has been gradually recognized. With the prolonged survival of patients with GISTs, reports about the bone metastasis of GIST increased. However, the knowledge of GISTs is rather limited due to its very low incidence.MethodsCochrane and Medline database (via PubMed) were searched in July 2019 with related keywords to acquire the literature related to the bone metastasis of GIST. Then, the literature was reviewed and references were also scanned to identify the possible related reports. Study data comprising age, sex, primary location, metastasis interval time, immunohistochemistry index, management and prognosis were recorded and analyzed.ResultsForty-five patients with bone metastases of GIST, with a mean age of 61.09 years, were included. The small intestine and stomach were the most common primary sites, followed by the rectum. Patients with small intestine primary sites had bone metastases that occurred earlier than the bone metastases stomach and rectum primary sites. The spine was the most common site of bony metastases. The mean survival time after GIST diagnosis was more than 64.02 months. Patients younger than 60 years old had a worse prognosis than those older than 60 years old. Furthermore, patients with spinal involvement had a worse prognosis than those without spinal involvement. Surgical interventions combined with targeted therapies guaranteed a better prognosis.ConclusionBone metastasis of GIST, which mainly occurs in the spine, is rather rare. Patients with GISTs of the small intestine and stomach suffered from bone metastasis more frequently and earlier than patients with GISTs in other primary sites. Age, sex, primary tumor location, treatment mode for the primary lesions and metastases, and spine involvement may be potential factors that affect the prognosis of GIST patients with bone metastases.

MiR-4510 acts as a tumor suppressor in gastrointestinal stromal tumor by targeting APOC2.

Dysregulation of microRNAs (miRNAs) expression has been demonstrated in gastrointestinal stromal tumor (GIST). In this study, we aimed to determine the differential miRNAs expression in GISTs and explore the functional mechanism of differential miRNAs in GIST cells. We measured differential miRNAs in six pairs of GIST tissues and matched adjacent tissues through a high-throughput sequencing, which was confirmed in 64 pairs of GIST tissues and adjacent tissues by real-time polymerase chain reaction. We found that miR-4510 expression was significantly downregulated in GIST tissues compared to matched control tissues. Luciferase reporter assay identified apolipoprotein C-II (APOC2) as a direct target of miR-4510. Overexpression of miR-4510 inhibited the mRNA and protein expression of APOC2. In addition, overexpression of miR-4510 suppressed GIST cell proliferation, migration, and invasion. Overexpression of miR-4510 also inhibited the phosphorylation of AKT and ERK1/2, reduced the expression of matrix metallopeptidase 2 (MMP2) and MMP9. APOC2 knockdown mimicked the effect of miR-4510 overexpression. Further investigation confirmed that APOC2 was notably upregulated in GIST tissues compared to adjacent control tissues. These results suggested that miR-4510 downregulation could promote GIST progression, including growth, invasion, and metastasis, through increasing APOC2 expression.

Thermal ablation versus hepatic resection for the treatment of liver metastases from gastrointestinal stromal tumors: a retrospective study

Objective The study aimed to compare effectiveness and safety of thermal ablation and hepatic resection in patients with liver metastases of gastrointestinal stromal tumors (GISTs). Method A total of 55 patients (27 in the ablation group and 28 in the surgery group) with liver metastases were included. Overall survival (OS) and progression-free survival (PFS) were assessed with Kaplan–Meier’s survival estimate curves. Univariate and multivariate regression analyses were carried out to identify potential prognostic factors. Results The median OS was 102.0 months in the ablation group and 117.0 months in the surgery group (p = .875). The 1-, 3- and 5-year OS rates were 100%, 88.9% and 74.1% in the ablation group and 92.8%, 82.1% and 78.6% in the surgery group, respectively. The 1-, 3- and 5-year PFS rates were 48.1%, 25.9% and 18.5% in the ablation group and 67.8%, 64.3% and 64.3% in the surgery group, respectively. Multivariate analysis showed that preoperative tyrosine kinase inhibitor (TKI) treatment (progressive disease, PD) (HR, 13.985; 95% CI, 1.791–109.187; p = .012) was the only significant independent prognostic factor for OS. Tumor number (HR, 1.318; 95% CI, 1.021–1.702; p = .034) was identified as an independent predictor for PFS in multivariate analysis. There were fewer postoperative complications (18.5% vs. 78.6%, p = .001) and shorter lengths of hospital stay (8.0 vs. 16.5 days, p = .001) in the ablation group. Conclusion Compared with resection, thermal ablation offered comparable OS for liver metastases of GISTs. Furthermore, thermal ablation had the advantages of fewer complications and shorter lengths of hospital stay.

Gastrointestinal stromal tumor with intracranial metastasis: case presentation and systematic review of literature

BackgroundIntracranial metastasis of Gastrointestinal Stromal Tumors (GISTs) is rare but presents unique treatment challenges. We present a case of intracranial metastasis of GIST with a systematic review of the literature. A literature search using key terms “‘gastrointestinal stromal tumor’ AND brain AND metastasis”” was conducted through May 2019 via Embase and Pubmed according to PRISMA guidelines. Only cases describing intradural metastases rather than calvarial or intraorbital metastases were included.Case presentationA 57-year-old woman with history of GIST metastatic to the liver presented with a six-week history of left facial weakness, left hearing loss, and left facial numbness, and a one-week history of headaches, gait disturbance, and dizziness. MRI revealed a contrast-enhancing dural-based left middle cranial fossa mass measuring 2.9 cm × 3.1 cm × 3.4 cm with extension into the internal auditory canal and cerebral edema. A left temporal craniotomy was performed to excise the lesion, and the patient was discharged to a rehabilitation facility at her preoperative baseline. Intraoperative pathology revealed a spindle cell neoplasm, postoperative MRI demonstrated gross total resection of the lesion, and microscopic analysis demonstrated sheets of spindled tumor cells with short ovoid, irregular, hyperchromatic nuclei and scattered large atypical nuclei without extensive necrosis. Immunohistochemical staining was positive for KIT proto-oncogene (CD117, c-KIT), and the patient was put on imatinib (400 mg/day).ConclusionsOf the 18 cases analyzed and our present case, metastasis typically involved the cerebrum with only one in infratentorial elements. The tumors in seven of the cases involved the dura, and one case metastasized to the pituitary. Eight patients died following treatment. Surgery remains the mainstay of intracranial metastatic GIST, however there are many reports of good responses to radiation or chemotherapy alone. More investigation is required to determine the best treatment course for these patients.

Identification of upstream miRNAs of SNAI2 and their influence on the metastasis of gastrointestinal stromal tumors

BackgroundSNAI2, a member of the snail zinc finger protein family, plays an important role in the metastasis of several types of carcinoma.ObjectiveThis study aims to investigate the upstream miRNAs of SNAI2 and their influence on the metastasis of gastrointestinal stromal tumors (GISTs).MethodsThe expression levels of SNAI2, CDH1, and CDH2 in GISTs were determined by immunohistochemistry, and the correlations with their clinicopathologic characteristics were analyzed. Subsequently, the miRNAs involved in regulating SNAI2 expression were predicted by bioinformatics technique, screened by miRNA microarray tests, and verified by real-time PCR, dual luciferase reporter assay, and invasion assay. The influence of SNAI2 and miRNAs on the invasive ability of the GIST cells and the related mechanism were detected.OutcomesSNAI2 expression significantly increased and CDH1 expression markedly decreased in the cases of GISTs with distant metastasis. Silencing of the SNAI2 gene impaired the invasiveness of GIST cells in vitro. MiR-200b-3p, miR-30c-1-3P, and miR-363-3P were verified as the upstream metastasis-associated miRNAs of SNAI2 in GISTs by miRNA microarray, real-time PCR, dual luciferase reporter assay, and invasion assay. They bound to the 3′-UTR of SNAI2, downregulated SNAI2 expression, and inhibited the invasiveness of GIST cells. SNAI2 targetedly bound to the promoter of the CDH1 gene, downregulated the expression of CDH1, and contributed to the metastasis of GISTs.ConclusionSNAI2 and CDH1 correlated with the metastasis of GISTs, and silencing of the SNAI2 gene impaired the invasiveness of GIST cells. MiR-200b-3p, miR-30c-1-3P, and miR-363-3P contribute to the metastasis of GISTs in vitro by mediating the SNAI2/CDH1 axis. SNAI2 may be a potential target for the treatment of GISTs in the future.

SURG-08. GASTROINTESTINAL STROMAL TUMOR WITH INTRACRANIAL METASTASIS: CASE REPORT AND SYSTEMATIC REVIEW OF LITERATURE

BACKGROUND: Intracranial metastasis of Gastrointestinal Stromal Tumors (GIST) is rare but presents unique treatment challenges. We present a case of intracranial metastasis of GIST with a systematic review of the literature regarding this rare clinical scenario. METHODS: A systematic review of the literature was performed to identify cases of intradural GIST metastases to the brain. Additionally, a patient case of GIST is discussed. RESULTS: Out of the 18 articles included for analysis in this review and our present case, fifteen of nineteen patients were male, and mean age was 58 years old (range 15–80 years, median 60 years). The primary site of the GIST along with site of intraperitoneal metastasis was variable. There was a large predilection for brain metastasis to the cerebrum with only one to infratentorial elements. The tumors in seven of the cases involved the dura, and there was one case with metastasis to the pituitary. Eight patients died following treatment of their intracranial disease. CONCLUSIONS: Surgery remains the mainstay of intracranial metastatic GIST, however there are many reports of good responses to radiation or chemotherapy alone. More investigation is required to determine the best course of treatment for patients with this unusual sequela of GIST.

Abstract 758: Long non-coding RNAH19 as a competing endogenous RNA of KIT in the progression of GIST

Abstract Background: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor with a wide range of biological behaviors, and activating mutations of KIT are particularly crucial to its development. Long non-coding RNAs (lncRNAs) have been identified as an oncogene in multiple cancer types, but data in GIST are missing. The aim of the study was to evaluate the contribution of lncRNA H19 to the malignant course of GISTs. Materials and Methods: RNA-seq analysis of lncRNA expression in five paired GIST and ANTs were analyzed to screen for differentially expressed lncRNAs. 274 human lncRNAs analyzed, exhibited significantly differential expressions with 186 genes being up-regulated and 88 genes being down-regulated compared to ANT (fold change&amp;gt;5, p&amp;lt;0.05). Unsupervised hierarchical clustering identified 48 lncRNAs and lncRNA H19 was the most overexpressed novel one. To assess the clinical importance of lncRNA H19 upregulation in GISTs, based on the expression levels 92 GIST patients were categorized into two groups: high (n=46) and low (n=46) lncRNA H19 expression. Results: After identifying lncRNA H19 as the most important one, validation in the expanded cohort confirmed the frequent upregulation of lncRNA H19 in GIST. Functional assays revealed that lncRNA H19 promotes GIST cell proliferation and metastasis. We could demonstrate that lncRNA H19 was predicted to sponge 19 miRNAs with six potential binding sites shared with KIT 3’-UTR using bio-informative database analysis. It was confirmed that lncRNA H19 was positively correlated with the expression of KIT, and the knockdown of lncRNA H19 led to the depression of KIT and its downstream pathway. Using luciferase reporter assays, lncRNA H19 was observed to sponge several miRNAs including miR-18a/b-5p, miR-19a/b-3p, miR-193a/b-3p, miR-216b-5p and mIR-3666. The combination of lncRNA H19 and KIT inhibition showed increased growth inhibition in GIST cell lines. Taken together, the data indicate that lncRNA H19 functions as a competing endogenous RNA (ceRNA) of KIT and promotes GIST progression. It could be shown that the expression levels of lncRNA H19 were significantly correlated with the progression markers of GIST, tumor size (P&amp;lt;0.001), mitosis count (P&amp;lt;0.001), and the modified NIH risk criteria (P&amp;lt;0.001) Conclusion: Our results indicate that lncRNA H19 can affect imatinib-induced apoptotic cell death and play a role in facilitating GIST progression by modulating the expression of KIT through the ceRNA network. High lncRNA H19 expression is associated with worse prognosis in patients with GIST and lncRNA H19 may serve as a new predictor of prognosis. Furthermore, targeting lncRNA H19/KIT ceRNA network appears to be a promising treatment for GIST. Citation Format: Peter Hohenberger, Lin Tu, Wenyi Zhao, Ming Wang Wang, Zizheng Zhang, Heike Allgayer, Hui Cao. Long non-coding RNAH19 as a competing endogenous RNA of KIT in the progression of GIST [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 758.

Parameter estimation and mathematical modeling for the quantitative description of therapy failure due to drug resistance in gastrointestinal stromal tumor metastasis to the liver.

In this work we develop a general mathematical model and devise a practical identifiability approach for gastrointestinal stromal tumor (GIST) metastasis to the liver, with the aim of quantitatively describing therapy failure due to drug resistance. To this end, we have modeled metastatic growth and therapy failure produced by resistance to two standard treatments based on tyrosine kinase inhibitors (Imatinib and Sunitinib) that have been observed clinically in patients with GIST metastasis to the liver. The parameter identification problem is difficult to solve, since there are no general results on this issue for models based on ordinary differential equations (ODE) like the ones studied here. We propose a general modeling framework based on ODE for GIST metastatic growth and therapy failure due to drug resistance and analyzed five different model variants, using medical image observations (CT scans) from patients that exhibit drug resistance. The associated parameter estimation problem was solved using the Nelder-Mead simplex algorithm, by adding a regularization term to the objective function to address model instability, and assessing the agreement of either an absolute or proportional error in the objective function. We compared the goodness of fit to data for the proposed model variants, as well as evaluated both error forms in order to improve parameter estimation results. From the model variants analyzed, we identified the one that provides the best fit to all the available patient data sets, as well as the best assumption in computing the objective function (absolute or proportional error). This is the first work that reports mathematical models capable of capturing and quantitatively describing therapy failure due to drug resistance based on clinical images in a patient-specific manner.