Primary Gastrointestinal Stromal Tumors Research Articles

Analysis of potential Circular RNAs in regulating imatinib resistance of Gastrointestinal stromal tumor.

Recent studies have found that circular RNA is an abundant RNA species that belongs to part of the competing endogenous RNA network(ceRNA), which was proven to play an important role in the development, diagnosis and progress of diseases. However, the function of circRNAs in imatinib resistance in Gastrointestinal stromal tumor (GIST) are poorly understood so for. The present study aimed to screen and predict the potential circRNAs in imatinib resistance of GIST using microarray analysis. We determined the expression of circular RNAs in paired normal gastric tissues(N), primary GIST (gastrointestinal stromal tumor) tissues (YC) and imatinib mesylate secondary resistance GIST tissues(C) with microarray and predicted 8677 dysregulated circular RNAs. Compared with the YC group, we identified 15 circRNAs that were up-regulated and 8 circRNAs that were down-regulated in the C group. Gene ontology (GO)and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that these host linear transcripts that differentially express circular RNAs are involved in many key biological pathways, predicting the potential tumor-genesis and drug resistance mechanismrelated to HIF-1 pathway, later we draw the cirRNA-miRNA-mRNA network involved in the HIF-1 pathway and found several dysregulated circRNAs and the relationship between circRNA-miRNAs-mRNA, such as circRNA_06551, circRNA_14668, circRNA_04497, circRNA_08683, circRNA_09923(Green, down-regulation) and circRNA_23636, circRNA_15734(Red, up-regulation). Taken together, we identified a panel of dysregulated circRNAs that may be potential biomarkers even therapy relevant to the GIST, especially imatinib secondary resistance GIST.

Feasibility and efficacy of minimally invasive limited resection for primary duodenal gastrointestinal stromal tumors: a retrospective cohort study

BackgroundThe primary duodenal gastrointestinal stromal tumor (GIST) is a rare type of gastrointestinal tract tumor. Limited resection (LR) has been increasingly performed for duodenal GIST. However, only a few studies reported minimally invasive limited resection (MI-LR) for primary duodenal GIST.MethodsThe clinical data of 33 patients with primary duodenal GIST from December 2014 to February 2024 were retrospectively analyzed including 23 who received MI-LR and 10 who received laparoscopic or robotic pancreaticoduodenectomy (LPD/RPD).ResultsA total of 33 patients with primary duodenal GIST were enrolled and retrospectively reviewed. Patients received MI-LR exhibited less OT (280 vs. 388.5min, P=0.004), EBL (100 vs. 450ml, P<0.001), and lower morbidity of postoperative complications (52.2% vs. 100%, P=0.013) than LPD/RPD. Patients received LPD/RPD burdened more aggressive tumors with larger size (P=0.047), higher classification (P<0.001), and more mitotic count/50 HPF(P=0.005) compared with patients received MI-LR. The oncological outcomes were similar in MI-LR group and LPD/RPD group.All the patients underwent MI-LR with no conversion, including 12 cases of LLR and 11 cases of RLR. All of the clinicopathological data of the patients were similar in both groups. The median OT was 280(210-480) min and 257(180-450) min, and the median EBL was 100(20-1000) mL and 100(20-200) mL in the LLR and the RLR group separately. The postoperative complications mainly included DGE (LLR 4 cases, 33.4% and RLR 4 cases, 36.4%), intestinal fistula (LLR 2 cases, 16.7%, and RLR 0 case), gastrointestinal hemorrhage (LLR 0 case and RLR 1 case, 9.1%), and intra-abdominal infection (LLR 3 cases, 25.0% and RLR 1 case, 9.1%). The median postoperative length of hospitalization was 19.5(7-46) days in the LLR group and 19(9-38) days in the RLR group. No anastomotic stenosis, local recurrence or distant metastasis was observed during the follow-up period in the two groups.ConclusionsMinimally invasive limited resection is an optional treatment for primary duodenal GIST with satisfactory short-term and long-term oncological outcomes.

Identification and validation of protein biomarkers for predicting gastrointestinal stromal tumor recurrence

We conducted a proteomic analysis using mass spectrometry to identify and validate protein biomarkers for accurately predicting recurrence risk in gastrointestinal stromal tumors (GIST) patients, focusing on differentially expressed proteins in metastatic versus primary GIST tissues. We selected five biomarkers—GPX4, RBM4, TPM3, PFKFB2, and PGAM5—and validated their expressions in primary tumors of recurrent and non-recurrent GIST patients via immunohistochemistry. Our analysis of the association between these biomarkers with recurrence-free survival (RFS) and overall survival (OS), along with their interrelationships, revealed that immunohistochemistry confirmed significantly higher expressions of these biomarkers in primary GIST tissues of recurrent patients. Kaplan-Meier survival analysis showed that high expressions of GPX4, RBM4, TPM3, PFKFB2, and PGAM5 correlated with lower RFS, and GPX4 and RBM4 with lower OS. All biomarker pairs showed positive associations, with high expressions correlating with increased recurrence rates, and GPX4 and RBM4 with higher mortality rates. In conclusion, the biomarkers GPX4, RBM4, TPM3, PFKFB2, and PGAM5 are clinically relevant for predicting GIST recurrence, with their high expressions in primary tumors linked to poorer RFS and OS. They serve as potential prognostic indicators, enabling early treatment and improved outcomes. The observed interrelationships among these biomarkers further validate their accuracy in predicting GIST recurrence.

Is lymph node metastasis an event indicating an advanced gastrointestinal stromal tumor?

754 Background: The clinicopathological features and prognosis of gastrointestinal stromal tumors (GISTs) with lymph node metastasis remain controversial owing to their low incidence. A multicenter retrospective cohort study was conducted to compare the clinicopathological features and oncologic outcomes of GIST with and without lymph node metastases. Methods: The medical records of patients with GISTs in 16 large medical centers in China from January 2014 to December 2020 were reviewed. Patients were divided into three groups: no metastasis, lymph node metastasis without distant metastasis, and distant metastasis without lymph node metastasis. Propensity score matching (PSM) was performed to reduce confounding factors. Results: A total of 1109 cases of primary GIST were included in this study, comprising 607 males (54.7%) and 502 females (45.3%), with a mean age of 56.6±11.9 years. There were 1024 patients (92.3%) with no lymph node metastasis after surgery, and 85 patients (7.7%) had lymph node metastasis. Compared to that in GIST without lymph node metastasis, the proportion of non-gastric GIST was higher in GIST with lymph node metastasis (52.9% vs. 40.7%) with a larger tumor diameter (&gt;10 cm: 36.5% vs. 18.1%) and more patients with distant metastasis (11.8% vs. 3.5%). Tumor location not in the stomach, the largest tumor diameter, and distant metastasis were independent risk factors for GIST with lymph node metastasis (all P &lt; 0.05). After PSM, 96, 48, 24 patients comprised no metastasis, lymph node metastasis without distant metastasis, and distant metastasis without lymph node metastasis, respectively. The relapse-free survival (RFS) of the lymph node metastasis group was comparable to that of the distant metastasis group without lymph node metastasis ( P = 0.368) and significantly inferior to that of no metastases ( P = 0.042). Conclusions: The prognosis of patients with GIST with lymph node metastasis was comparable to that of patients with distant metastasis and significantly worse than that of patients without metastasis. Lymph node metastasis may be an advanced event in GIST.

Molecular and clinicopathological features of KIT/PDGFRA wild-type gastrointestinal stromal tumors.

Approximately 10% of gastrointestinal stromal tumors (GISTs) harbor reportedly no KIT and PDGFRA mutations (wild-type GISTs). The clinicopathological features and oncologic outcomes of wild-type GISTs based on molecular profiles are unknown. We recruited 35 wild-type GIST patients from the two registry studies of high-risk GISTs between 2012 and 2015 and primary GISTs between 2003 and 2014. Molecular profiling of wild-type GISTs was performed by targeted next-generation sequencing (NGS) using formalin-fixed paraffin-embedded tumor samples. Among 35 wild-type GISTs, targeted NGS analysis detected NF1, SDH, or BRAF mutation: 16 NF1-GISTs with various NF1 mutations, 12 SDH-GISTs (4 with SDHA mutations, 4 with SDHB mutations, and 4 with SDHB-negative staining), and 5 BRAF-GISTs with the V600E mutation. Two GISTs showed no mutations based on our targeted NGS analysis. Additional gene mutations were infrequent in primary wild-type GISTs and found in TP53, CREBBP, CDKN2A, and CHEK2. Most NF1-GISTs were located in the small intestine (N = 12; 75%) and showed spindle cell features (N = 15; 94%) and multiple tumors (N = 6, 38%) with modest proliferation activities. In contrast, SDH-GISTs were predominantly found in the stomach (N = 11; 92%), exhibiting epithelioid cell (N = 6; 50%) and multiple (N = 6, 50%) features. The overall survival of patients with SDH-GISTs appeared to be better than that of BRAF-GISTs (p = 0.0107) or NF1-GISTs (p = 0.0754), respectively. In conclusion, major molecular changes in wild-type GISTs include NF1, SDH, and BRAF. NF1-GISTs involved multifocal spindle cell tumors in the small intestine. SDH-GISTs occurred in young patients and were multifocal in the stomach and clinically indolent.

Gastrointestinal Stromal Tumor: A Clinicopathological Study and Management.

Background and aim Gastrointestinal stromal tumors (GISTs) account for a major portion of gastrointestinal mesenchymal tumors.The purpose of the current study is to examine the clinicopathological features, management, and therapeutic outcomes of primary GIST in a tertiary care hospital. Materials andmethods This is a prospective observational analysis. Seventeen patients with GIST have been detected and treated in the Department of Surgery of a tertiary care hospital with an attached medical institution over the last seven years. The clinical presentation, diagnosis method, tumor locations, histopathological results, surgical treatment, and postoperative results were analyzed. Results There were six females and 11 males with ages ranging between 35 to 72 years. All the patients had symptoms, with abdominal pain the most prevalent. The most frequent primary site for GIST was the stomach (60-70%), followed by the small intestine (25-30%), the rectum, the esophagus, and the colon(2%). Preoperative diagnosis was made through endoscopy and a contrast-enhanced CT scan. Ninety-two percent of the cases tested positive for CD117. Surgery has been conducted for all 17 patients, with the liver being the most common site of metastasis. Imatinib and sunitinib increased the survival as well as postoperative recurrence rate while decreasing metastasis. Conclusions The most general symptom of GIST wasabdominal pain. In most instances, it was treated with surgery as well as adjuvant imatinib and sunitinib, and had a favorable prognosis. With increasing size and mitotic activity, the five-year survival rate falls, and the prognosis worsens.

Gastric gastrointestinal stromal tumors: therapeutic strategies and long-term prognosis

Objectives This study aimed to evaluate the clinical and prognostic characteristics of primary gastric gastrointestinal stromal tumors (GIST). Methods Patients who underwent resection for primary gastric GIST between January 2002 and December 2017 were included. Recurrence-free survival (RFS) was calculated by Kaplan–Meier analysis, and Cox proportional hazards model was used to identify independent prognostic factors. Results Altogether, 653 patients were enrolled. The median patient age was 59 years (range 15-86 years). Open, laparoscopic, and endoscopic resections were performed in 394 (60.3%), 105 (16.1%), and 154 (23.6%) patients, respectively. According to the modified NIH consensus classification, 132 (20.2%), 245 (37.5%), 166 (25.4%), and 88 (13.5%) patients were categorized into very low-, low-, intermediate-, and high-risk, respectively. A total of 136 (20.8%) patients received adjuvant imatinib treatment. The median follow-up time was 78 months (range 4–219 months), and the estimated 5-year RFS rate was 93.0%. In all patients, tumor size and rupture, mitotic counts, and adjuvant imatinib treatment were independent prognostic factors. The prognosis of gastric GIST treated with endoscopic resection was not significantly different from that of laparoscopic or open resection after adjusting for covariates using propensity score matching (log-rank p = .558). Adjuvant imatinib treatment (HR = 0.151, 95%CI 0.055–0.417, p < .001) was a favorable prognostic factor for high-risk patients, but was not associated with prognosis in intermediate-risk patients. Conclusion Patients with small gastric GISTs who successfully underwent endoscopic resection may have a favorable prognosis. Adjuvant imatinib treatment improve the prognosis of high-risk gastric GISTs, however, its use in intermediate-risk patients remains controversial.

The prognostic role of gastrointestinal bleeding in patients with a primary gastrointestinal stromal tumor: a long-term follow-up study.

Gastrointestinal (GI) bleeding is one of the common symptoms of GI stromal tumor (GIST). Although several studies have highlighted its prognostic role, conclusions have been inconsistent. This study aimed to investigate the prognosis of GIST patients with GI bleeding. Primary GIST patients who underwent complete resection and did not receive adjuvant imatinib therapy from January 2003 to December 2008 were reviewed. The Kaplan-Meier method was used to estimate recurrence-free survival (RFS), and multivariate analysis was performed using the Cox proportional hazard model. Propensity score matching (PSM) was conducted to reduce confounders. A systematic review of the published articles in the PubMed, Embase, Cochrane Collaboration, and Medline databases was also conducted, and the inclusion criteria were determined using PICOS (patients, intervention, comparison, outcomes, and study design) principles. In total, 84 patients presenting with GI bleeding and 90 patients without GI bleeding were enrolled in this study. The median time of follow-up was 140 months (range, 10-196 months), and 38 patients developed tumor recurrence/metastasis. For all patients, the multivariate analysis indicated that tumor location [hazard ratio (HR) =3.48, 95% confidence interval (CI): 1.78-6.82, P<0.001], tumor size (HR =1.91, 95% CI: 1.05-3.47, P=0.035), mitotic index (MI; HR =5.69, 95% CI: 2.77-11.67, P<0.001), and age (HR =2.68, 95% CI: 1.49-4.82, P=0.001) were the independent prognostic factors for poor RFS. However, GI bleeding was not associated with RFS (HR =1.21, 95% CI: 0.68-2.14, P=0.518). After PSM, 45 patients from each group were included, and it was found that GI bleeding was still not the independent prognostic factor (HR =1.23, 95% CI: 0.51-2.97, P=0.642). Moreover, the pooled results of our study and six previously reported studies showed that GI bleeding was not the independent prognostic factor (HR =1.45, 95% CI: 0.73-2.86, P=0.287). In this study, tumor location, tumor size, MI, and age were independent prognostic factors in primary GIST patients who underwent radical resection. However, GI bleeding was not associated with worse RFS.

Laparoscopic vs Open Treatment for Gastric and Non-Gastric Gastrointestinal Stromal Tumors: a Two-Center Experience.

We retrospectively reviewed the medical records of 109 patients who underwent curative laparoscopic or open resection for different types of gastrointestinal stromal tumors (GIST). Only primary GIST patients who did not receive preoperative chemotherapy or oral imatinib treatment were included in the analysis. We divided the patients into 2 groups according to the surgical approach:a laparoscopic group (LAP) and a laparotomic group (OPEN). Our aim was to confirm the feasibility and safety of laparoscopic surgery for GISTs that differed in size and location, and to assess its long-term oncologic outcome in terms of overall survival (OS) and disease-free survival (DFS). Furthermore, we performed a surgical short-term outcome analysis. The two groups did not differ with respect to age at operation, gender, BMI or comorbidities. Even the NIH and AFIP risk classifications were not significantly different between the two groups. Furthermore, in our analysis, there was no significant difference in mean tumor size or location between the two groups. Wedge resection was the most frequently performed procedure. The conversion rate was 7.8%. The operative time was 194.75 (60- 350) min for the open group and 181.70 (57-480) min for the laparoscopic group. Our data clearly indicated that the long-term oncologic outcome and DFS of laparoscopic resection were not inferior to those of traditional open operations and laparoscopic resection was still feasible in cases with large tumors: the median size of the tumor was 4.5 cm (3-25) and the tumor was larger than 4.5 cm in 47.7% of the cases in the LAP group. With regard to short-term outcomes, our study demonstrated that the LAP group had fewer complications, faster gastrointestinal recovery, reduced use of analgesic drugs and shorter postoperative hospital stay (each p<0.05). In conclusion, our experience confirms that GISTs are very uncommon cancers for which the prognosis is closely related to size, localization and class of risk. In light of our clinical data, laparoscopic resection for gastric and non-gastric GISTs is a safe, feasible and oncologically correct procedure. The most important advantage of this technique is that it ensures a better postoperative outcome compared with open surgery, without worsening the prognosis.

An interpretable AI model for recurrence prediction after surgery in gastrointestinal stromal tumour: an observational cohort study

There are several models that predict the risk of recurrence following resection of localised, primary gastrointestinal stromal tumour (GIST). However, assessment of calibration is not always feasible and when performed, calibration of current GIST models appears to be suboptimal. We aimed to develop a prognostic model to predict the recurrence of GIST after surgery with both good discrimination and calibration by uncovering and harnessing the non-linear relationships among variables that predict recurrence. In this observational cohort study, the data of 395 adult patients who underwent complete resection (R0 or R1) of a localised, primary GIST in the pre-imatinib era at Memorial Sloan Kettering Cancer Center (NY, USA) (recruited 1982-2001) and a European consortium (Spanish Group for Research in Sarcomas, 80 sites) (recruited 1987-2011) were used to train an interpretable Artificial Intelligence (AI)-based model called Optimal Classification Trees (OCT). The OCT predicted the probability of recurrence after surgery by capturing non-linear relationships among predictors of recurrence. The data of an additional 596 patients from another European consortium (Polish Clinical GIST Registry, 7 sites) (recruited 1981-2013) who were also treated in the pre-imatinib era were used to externally validate the OCT predictions with regard to discrimination (Harrell's C-index and Brier score) and calibration (calibration curve, Brier score, and Hosmer-Lemeshow test). The calibration of the Memorial Sloan Kettering (MSK) GIST nomogram was used as a comparative gold standard. We also evaluated the clinical utility of the OCT and the MSK nomogram by performing a Decision Curve Analysis (DCA). The internal cohort included 395 patients (median [IQR] age, 63 [54-71] years; 214 men [54.2%]) and the external cohort included 556 patients (median [IQR] age, 60 [52-68] years; 308 men [55.4%]). The Harrell's C-index of the OCT in the external validation cohort was greater than that of the MSK nomogram (0.805 (95% CI: 0.803-0.808) vs 0.788 (95% CI: 0.786-0.791), respectively). In the external validation cohort, the slope and intercept of the calibration curve of the main OCT were 1.041 and 0.038, respectively. In comparison, the slope and intercept of the calibration curve for the MSK nomogram was 0.681 and 0.032, respectively. The MSK nomogram overestimated the recurrence risk throughout the entire calibration curve. Of note, the Brier score was lower for the OCT compared to the MSK nomogram (0.147 vs 0.564, respectively), and the Hosmer-Lemeshow test was insignificant (P=0.087) for the OCT model but significant (P<0.001) for the MSK nomogram. Both results confirmed the superior discrimination and calibration of the OCT over the MSK nomogram. A decision curve analysis showed that the AI-based OCT model allowed for superior decision making compared to the MSK nomogram for both patients with 25-50% recurrence risk as well as those with >50% risk of recurrence. We present the first prognostic models of recurrence risk in GIST that demonstrate excellent discrimination, calibration, and clinical utility on external validation. Additional studies for further validation are warranted. With further validation, these tools could potentially improve patient counseling and selection for adjuvant therapy. The NCI SPORE in Soft Tissue Sarcoma and NCI Cancer Center Support Grants.

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.

Novel Genomic Risk Stratification Model for Primary Gastrointestinal Stromal Tumors (GIST) in the Adjuvant Therapy Era.

Traditional risk stratification schemes in gastrointestinal stromal tumors (GIST) were defined in the pre-imatinib era and rely solely on clinicopathologic metrics. We hypothesize that genomic-based risk stratification is prognostically relevant in the current era of tyrosine kinase inhibitor (TKI) therapeutics. Comprehensive mutational and copy-number profiling using MSK-IMPACT was performed. We integrated clinicopathologic and genomic parameters and utilized an elastic-net penalized Cox proportional hazards machine learning model for outcome risk stratification. A 3-tier genomic risk stratification model for recurrence-free survival (RFS) in 152 primary localized gastric and 80 small bowel GISTs was proposed. Gastric GISTs were classified as high risk if chr1p deletion or SDHB loss was present, and intermediate risk if chr14q deletion was present or KIT exon 11 mutation was absent. Small bowel GISTs were classified as high risk if MAX/MGA/MYC, CDKN2A, or RB1 alterations were present, and intermediate risk if chr1p deletion or chr5q amplification was present. Compared with conventional risk stratification, genomic risk stratification both upgrades and downgrades, suggesting that conventional risk stratification may underestimate or overtreat some high-risk and low-risk patients, respectively. Longitudinal sequencing detected most KIT-independent genomic alterations at baseline. Subanalysis in 26 SDH-deficient GISTs revealed that presence of TP53 mutations or chr1q amplifications portends worse RFS and disease-free survival. We developed a novel, next-generation genomic risk stratification model for primary gastric and small bowel GISTs, complementing traditional clinicopathologic models. Future independent validation of our model in external cohorts is essential.

Immunotherapy of gastrointestinal stromal tumors: current view and future directions

Gastrointestinal stromal tumors (GIST) are most common mesenchymal tumors in gastrointestinal tract which originate from interstitial cells of Cajal and characterized by the mutations in the KIT or PDGFRA tyrosine kinase receptors. Thus, the common therapeutic approach for GIST therapy (including metastatic, recurrent and non-resectable forms) is based on inhibiton of activities of receptor tyrosine kinases indicated above by corresponding receptor tyrosine kinase inhibitors, including first-line therapeutic agent imatinib mesylate – Gleevec. Despite of high efficacy of IM-based therapy, most of GIST patients acquire resistance to this receptor tyrosine kinase inhibitor, which in turn requires second-, third- and fourth-line therapies. The review also describes the common molecular and genetic variants of GIST and the mechanisms of primary and secondary GIST resistance to the targeted-based therapies. In addition, the role of immune microenvironment in GIST and its relationship with tumor’s mutational burden are discussed in detail, thereby illustrating the immunotherapy as one of the attractive future directions for GIST therapy. Lastly, the manuscript provides the information about the ongoing clinical trials of GIST immunotherapy.

Percutaneous microcoil localization as an aid to ultrasound-guided hepatic gastrointestinal stromal tumor metastasis resection: A case report

Liver nodules that develop in children with cancer may represent primary malignancy, metastatic disease, or other conditions potentially requiring aggressive management. Laparoscopic methods have been utilized for nodule resection with perioperative ultrasonographic assistance. However, certain nodules in liver tissue can be difficult to identify on ultrasonography. Ultrasonography guided surgical resection after computer tomography (CT)-guided localization using microcoils is an innovative technique that has the potential to assist in the resection of small or deep liver nodules in children in these unique cases. A 15-year-old female presented with evidence of a hypermetabolic liver nodule on routine PET scan, 5 years following resection of a hepatic metastasis via right hepatic trisegmentectomy for primary gastrointestinal stromal tumor (GIST). Contrast-enhanced CT confirmed presence of a new suspicious liver nodule. Given the interval from initial treatment to the identification of this hepatic nodule, consent was received from patient and her family to surgically resect the nodule. However, pre-operatively the nodule could not be appreciated on ultrasonography. Interventional radiology was consulted for CT guided percutaneous microcoil localization of the hepatic nodule. CT-guided percutaneous microcoil localization with ultrasonographic guided liver resection allowed for complete resection of the liver nodule. We have successfully used an innovative technique of CT-guided microcoil placement to direct ultrasound-guided surgical resection of an otherwise ultrasound-occult liver nodule in the pediatric setting.

Utilization of Neoadjuvant Therapy in Gastrointestinal Stromal Tumors of the Stomach: Analysis of the 2006–2018 National Cancer Database

BackgroundNeoadjuvant tyrosine kinase inhibitor (TKI) therapy has reduced tumor burden and improved survival in both primary and recurrent gastrointestinal stromal tumors (GISTs). However, no clear guidelines exist on optimal patient selection for neoadjuvant therapy (NAT). Our aim was to analyze factors and outcomes associated with the therapeutic sequence of TKI therapy before and/or after surgery for gastric GISTs. MethodsWe performed a retrospective study of patients surgically treated for a gastric GIST utilizing the 2006–2018 National Cancer Database. We examined demographic, clinical, and pathological characteristics associated with NAT versus adjuvant therapy (AT) using logistic regression. ResultsOf the 3732 patients, 20.4% received NAT and 79.6% had AT. Among patients receiving therapy, NAT significantly increased over our study period (12% to 30.7%). A majority of the AT group received a partial gastrectomy (77.9%) compared with the NAT group who received more near-total/total gastrectomy or gastrectomy with en bloc resection (p < 0.001). In a multivariable model, patients were more likely to receive NAT when insured (private, aOR: 2.37, 95% CI: 1.31–4.29), treated at an academic/research program (aOR: 1.83, 95% CI: 1.49–2.56), had tumors located in the proximal stomach (aOR: 1.40, 95% CI: 1.06–1.86), tumor size > 10 cm (aOR: 1.88, 95% CI: 1.41–2.51), and received near-total/total gastrectomy (aOR: 1.81, 95% CI: 1.42–2.29). There were no differences in outcomes. ConclusionNAT for gastric GIST has increased in utilization. NAT was used in patients with larger tumors and who underwent more extensive resection. Despite these factors, outcomes were similar to patients receiving only AT. More studies are required to determine the therapeutic sequence for gastric GISTs.

Racial differences in prognostic role of white blood cell ratios in gastrointestinal stromal tumors.

e23507 Background: Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors with an estimated 3,300 to 6,000 new cases per year in the United States. Per SEER database, significant racial disparity exists with an incidence rate twice as high for African Americans as compared to Whites. Currently, parameters used in stratification of disease risk can only be determined by postoperative histopathological evaluation. Cancer-related inflammation is linked to different stages of tumor development so markers found in peripheral blood have been studied as surrogates. We present a study comparing the predictive prognostic ability of preoperative serum inflammatory markers in primary untreated GIST and highlight the differences between Black and White patients. Methods: This is a retrospective analysis of 149 patients who underwent operative resection of primary untreated GIST. Preoperative blood samples were used for the analysis. Patients were excluded if they showed clinical signs of infection during time of pre-operative blood sampling or had non-GIST synchronous malignancy. Clinicopathological data was obtained from patient chart review and logistic regression models were used to evaluate data. There is ongoing next-generation sequencing data analysis. Results: 149 patients were included: 80 (53.7%) Black, 43 (28.9%) White, 26 (17.5%) were other. The mean values for neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio (MLR) were 3.62 (SD 3.07), 191.55 (SD 119.15), and 0.47 (SD 0.49) respectively. On univariate analysis NLR and PLR were significant prognostic indicators of high and intermediate risk GISTs per the National Institute of Health (NIH) categories [NLR p = 0.008, PLR p = 0.007]. Upon subgroup analysis, NLR and PLR showed the highest statistical significance for predictors of high and intermediate risk GISTs among the Black patient population [NLR odds ratio (OR) 2.685; 95% confidence interval (CI) 0.976-7.381; p = 0.05 and PLR OR 1.792; 95% CI 1.054-3.049; p = 0.031]. The same was not shown to be true for the White patient population. 11 out 149 patients progressed since diagnosis of which 8 were Black and 3 White. 7 were in the high risk category, 3 in low risk and 1 in intermediate risk with an overall mean NLR and PLR 5.25 and 244 respectively. The average time to progression was noted to 28 months. Conclusions: The NLR and PLR are easily obtainable and cost-effective indexes which have the prognostic ability to serve as surrogates for high and intermediate risk GISTs. They appear to be more predictive in the Black patient population than in White. Further study is warranted for incorporation into risk stratification systems.

Comprehensive genomic and transcriptomic profiling analysis of the recurrent gastrointestinal stromal tumor (GIST).

e23506 Background: The gastrointestinal stromal tumor (GIST) is a potentially malignant mesenchymal tumor (sarcoma), whose management has been transformed by approvals of TKIs. However, recurrence or metastasis is a formidable challenge in managing high-risk GIST. Comprehensive investigation of the transcriptome and genome in GIST is helpful to determine the therapy strategy for patients. This study aims to explore the molecular features of high-risk recurrence GIST. Methods: The tumor tissue samples of 42 patients with primary GIST were collected, in which all patients were divided into low-risk (n = 12), intermediate-risk (n = 11), and high-risk (n = 19) groups according to the NIH 2017th, in which 8 developed recurrence within three years and 11 without recurrence over three years in the high-risk group. Tumor-normal whole-exome and tumor mRNA sequencing was performed on baseline tissue DNA isolated from all patients. Results: Consistent with prior knowledge, KIT was the predominant mutation. The top mutated genes in GISTs were KIT (82%), PHLDA1 (39%), MUC6 (22%), ARID1B(20%), SURF2(20%), MGA(16%), MUC17(16%), MPRIP(16%) and PDGFRA(16%), which MUC6 was a significantly different mutation gene (DMG) associated with disease progression in terms of either high-risk(p = 0.04), recurrence(p = 0.02) or progression(p = 0.05). Interestingly, PDGFRA mutation co-occurs with CTNND2(p &lt; 0.01) and its correlated genes. Additionally, we further explored the somatic copy number variations (CNVs). amp_RAD51B(49%), amp_MLH3(41%), amp_CHEK2(37%), and amp_RB1(12%) seemed to be more frequent in the recurrence group, while these observations were not significant (p &gt; 0.05). Notably, del_NCOR1 or amp_NCOR1 was uniquely observed in the recurrence group. Compared with non-recurrence GIST, gene expression profiles revealed that mast cell activate (MCA)，M1-macrophages infiltration were higher in recurrence group, and mRNA was significantly upregulated in Systemic lupus erythematosus、Neutrophil extracellular trap formation、Viral carcinogenesis、Endocytosis. These pathways were indentified as being associated with recurrence and progression in other cancer studies. For example, the endocytosis pathway expression is positively associated with oncogenic pathway signaling in CRC, and neutrophil extracellular trap on cancer cells promotes liver metastasis in the tumor microenvironment. In the other, NCOR1 is a crucial regulator of T cell and B cell development. Conclusions: Here, we demonstrated the DNA/RNA profiles of GISTs. We observed higher CNVs in high-risk GIST. Especially, the high-risk recurred tumor presented different CNVs frequency and microenvironment. These results may contribute to understanding the mechanism of recurrence and improving recurrence detection.

Racial and ethnic disparities in presentation and outcomes of patients with gastrointestinal stromal tumors (GIST) in the era of targeted therapy.

e18573 Background: GIST is the most common malignant mesenchymal tumor of the gastrointestinal tract and is a compelling model for targeted therapies. Racial and ethnic minorities are underrepresented in clinical research, and information regarding disparities in GIST is limited. Our sarcoma center is located within a large and diverse population of Hispanic, LatinX, and African American/African Caribbean patients (pts). We aimed to identify racial and ethnic disparities among pts with GIST. Methods: We retrospectively reviewed all pts with primary or recurrent GIST between January 2003 and October 2022 in our institution. All data were retrieved from electronic medical records. SPSS Statistics was utilized, Fisher exact test and log-rank test were used for analysis. A two-sided p &lt; 0.05 was considered statistically significant. Results: A total of 1150 pts had a diagnosis of GIST during the study period. Information regarding race and ethnicity was available in 711 pts. There were 42.4% White Non-Hispanic/LatinX (WN), 33.2% Hispanic/LatinX (HL), and 24.4% Black Non-Hispanic/LatinX (BN). The stomach was the most common primary site in all three groups, especially in the BN population (80.9%) vs WN (53%) and HL (61.9%), followed by the small intestine (p &lt; 0.001). The WN pts more commonly presented with metastatic disease on diagnosis (16.2%) vs BN (12.7%) and HL (8.9) (p = 0.042) and had higher grade tumors (37.7%) vs BN (24.9%) and HL (23.7%) (p &lt; 0.001). Median disease-free survival (mDFS) after radical resection was significantly lower in BN population vs WN and HL (p = 0.014). Disease-specific survival (DSS) in BN was also significantly reduced compared to the other groups (p = 0.024). A total of 445 pts had some molecular testing done, and BN were significantly less tested (38.5%) (p &lt; 0.001). The most common primary driver mutation was KIT exon 11 throughout all groups, especially in the BN group corresponding to 80% of the cases tested (p = 0.008). The median overall survival (mOS) among pts with metastatic disease was 7.1 years (95% CI = 5.6-8.6). The HL population had a trend toward the longest mOS (8.8 years), followed by the WN (7.7 years), followed by the BN population (5.8 years) (p = 0.073). A total of 75 of these patients were tested for secondary mutations, with no statistical difference among the groups. Conclusions: We found in our study the WN population was significantly more likely to present with metastatic disease and higher-grade tumors than BN or HL pts. Nonetheless, the BN population were substantially less likely to undergo mutation testing and had a trend toward a worse mOS by more than 1 year. All pts had their care within the same healthcare system, implicating access to mutation testing and socioeconomic barriers playing a role in inferior outcomes. Further studies are needed to understand molecular differences and decrease the existing gap among these populations.

Differences in clinicopathological features, gene mutations, and prognosis between primary gastric and intestinal gastrointestinal stromal tumors in 1061 patients

Objective: To analyze the clinicopathological features and gene mutations of primary gastrointestinal stromal tumors (GISTs) of the stomach and intestine and the prognosis of intermediate- and high-risk GISTs. Methods: This was a retrospective cohort study. Data of patients with GISTs admitted to Tianjin Medical University Cancer Institute and Hospital from January 2011 to December 2019 were collected retrospectively. Patients with primary gastric or intestinal disease who had undergone endoscopic or surgical resection of the primary lesion and were confirmed pathologically as GIST were included. Patients treated with targeted therapy preoperatively were excluded. The above criteria were met by 1061 patients with primary GISTs, 794 of whom had gastric GISTs and 267 intestinal GISTs. Genetic testing had been performed in 360 of these patients since implementation of Sanger sequencing in our hospital in October 2014. Gene mutations in KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 were detected by Sanger sequencing. The factors investigated in this study included: (1) clinicopathological data, such as sex, age, primary tumor location, maximum tumor diameter, histological type, mitotic index (/5 mm2), and risk classification; (2) gene mutation; (3) follow-up, survival, and postoperative treatment; and (4) prognostic factors of progression-free survival (PFS) and overall survival (OS) for intermediate- and high-risk GIST. Results: (1) Clinicopathological features: The median ages of patients with primary gastric and intestinal GIST were 61 (8-85) years and 60 (26-80) years, respectively; The median maximum tumor diameters were 4.0 (0.3-32.0) cm and 6.0 (0.3-35.0) cm, respectively; The median mitotic indexes were 3 (0-113)/5 mm² and 3 (0-50)/5 mm², respectively; The median Ki-67 proliferation indexes were 5% (1%-80%) and 5% (1%-50%), respectively. The rates of positivity for CD117, DOG-1, and CD34 were 99.7% (792/794), 99.9% (731/732), 95.6% (753/788), and 100.0% (267/267), 100.0% (238/238), 61.5% (163/265), respectively. There were higher proportions of male patients (χ²=6.390, P=0.011), tumors of maximum diameter > 5.0 cm (χ²=33.593, P<0.001), high-risk (χ²=94.957, P<0.001), and CD34-negativity (χ²=203.138, P<0.001) among patients with intestinal GISTs than among those with gastric GISTs. (2) Gene mutations: Gene mutations were investigated in 286/360 patients (79.4%) with primary gastric GISTs and 74/360 (20.6%) with primary intestinal GISTs. Among the 286 patients with gastric primary GISTs, 79.4% (227/286), 8.4% (24/286), and 12.2% (35/286), had KIT mutations, PDGFRA mutations, and wild-type, respectively. Among the 74 patients with primary intestinal GISTs, 85.1% (63/74) had KIT mutations and 14.9% (11/74) were wild-type. The PDGFRA mutation rate was lower in patients with intestinal GISTs than in those with gastric GISTs[ 0% vs. 8.4%(24/286), χ²=6.770, P=0.034], whereas KIT exon 9 mutations occurred more often in those with intestinal GISTs [22.2% (14/63) vs. 1.8% (4/227), P<0.001]. There were no significant differences between gastric and intestinal GISTs in the rates of KIT exon 11 mutation type and KIT exon 11 deletion mutation type (both P>0.05). (3) Follow-up, survival, and postoperative treatment: After excluding 228 patients with synchronous and metachronous other malignant tumors, the remaining 833 patients were followed up for 6-124 (median 53) months with a follow-up rate of 88.6% (738/833). None of the patients with very low or low-risk gastric (n=239) or intestinal GISTs (n=56) had received targeted therapy postoperatively. Among 179 patients with moderate-risk GISTs, postoperative targeted therapy had been administered to 88/155 with gastric and 11/24 with intestinal GISTs. Among 264 patients with high-risk GISTs, postoperative targeted therapy had been administered to 106/153 with gastric and 62/111 with intestinal GISTs. The 3-, 5-, and 10-year PFS of patients with gastric or intestinal GISTs were 96.5%, 93.8%, and 87.6% and 85.7%, 80.1% and 63.3%, respectively (P<0.001). The 3-, 5-, and 10-year OS were 99.2%, 98.8%, 97.5% and 94.8%, 92.1%, 85.0%, respectively (P<0.001). (4) Analysis of predictors of intermediate- and high-risk GISTs: The 5-year PFS of patients with gastric and intestinal GISTs were 89.5% and 73.2%, respectively (P<0.001); The 5-year OS were 97.9% and 89.3%, respectively (P<0.001). Multivariate analysis showed that high risk (HR=2.918, 95%CI: 1.076-7.911, P=0.035) and Ki-67 proliferation index > 5% (HR=2.778, 95%CI: 1.389-5.558, P=0.004) were independent risk factors for PFS in patients with intermediate- and high-risk GISTs (both P<0.05). Intestinal GISTs (HR=3.485, 95%CI: 1.407-8.634, P=0.007) and high risk (HR=3.753,95%CI:1.079-13.056, P=0.038) were independent risk factors for OS in patients with intermediate- and high-risk GISTs (both P<0.05). Postoperative targeted therapy was independent protective factor for PFS and OS (HR=0.103, 95%CI: 0.049-0.213, P<0.001; HR=0.210, 95%CI:0.078-0.564,P=0.002). Conclusions: Primary intestinal GIST behaves more aggressively than gastric GISTs and more frequently progress after surgery. Moreover, CD34 negativity and KIT exon 9 mutations occur more frequently in patients with intestinal GISTs than in those with gastric GISTs.

Long-term response to pimitespib in postoperative recurrent gastrointestinal stromal tumors with PDGFRA D842V mutation: a case report

BackgroundExon 18 D842V, which is a point mutation from aspartic acid to valine at codon 842, is the most frequent mutation in Platelet-Derived Growth Factor Receptor alpha (PDGFRA)-mutated gastrointestinal stromal tumor (GIST). In the Japanese GIST guidelines, no standard systematic therapy is available for this type of GIST, which is refractory after recurrence. Recently, pimitespib (PIMI), a novel heat shock protein 90 (HSP90) inhibitor, was approved for the treatment of advanced GIST in a phase III study. This report presents a case of a long-term response to PIMI in GIST with PDGFRA D842V mutation.Case presentationA 55-year-old woman was diagnosed with primary GIST of the stomach and underwent partial gastrectomy. Eight years after the operation, recurrent GISTs were identified as multiple recurrent peritoneal GISTs in the upper right abdomen and pelvic cavity. We administered tyrosine kinase inhibitors, but they achieved poor effects. After failure of the standard treatment, PIMI was administered and achieved a partial response in the patient. The highest reduction rate was 32.7%. After PIMI failed, we performed multiplex gene panel testing, which revealed the PDGFRA D842V mutation.ConclusionsWe report the first case of long-term response to PIMI in PDGFRA D842V mutant GIST. Pimitespib may be effective for treating GIST harboring this mutation by inhibiting HSP90.