Gastrointestinal Stromal Tumors Patients Research Articles

Immunohistochemical Expression of ROR2 in Gastrointestinal Stromal Tumor.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors affecting the digestive tract, comprising approximately 0.1-3% of all gastrointestinal cancers. ROR2, a member of the receptor tyrosine kinase orphan receptor subfamily, functions as a signaling receptor for Wnt ligands. This study aims to assess the prognostic significance of ROR2 expression in GIST. A total of 56 paraffin-embedded blocks of GIST cases originating from different parts of the gastrointestinal tract (GIT) were included in this study. Immunohistochemistry was performed to detect ROR2 expression. ROR2 expression was observed in 71.4% of GIST cases, and strong intensity of ROR2 staining was significantly associated with prolonged overall survival of GIST patients (p = 0.048). Furthermore, ROR2 positivity and the percentage of immunostaining showed an inverse correlation with tumor progression. GIST cases displaying ROR2 positivity exhibit a reduced likelihood of disease progression and demonstrate favorable prognostic characteristics.

Interpretable machine learning model based on CT semantic features and radiomics features to preoperatively predict Ki-67 expression in gastrointestinal stromal tumors

To develop and validate a machine learning (ML) model which combined computed tomography (CT) semantic and radiomics features to preoperatively predict Ki-67 expression in gastrointestinal stromal tumors (GISTs) patients. We retrospectively collected the clinical, imaging and pathological data of 149 GISTs patients. We randomly assigned the patients in a ratio of 7:3 to a training set (104 cases) and a validation (45 cases) set. We divided the patients into low and high Ki-67 expression group according to postoperative pathology. CT semantic features were analyzed from preoperative enhancement CT images and radiomics features were extracted from venous phase-enhanced images. We used intraclass correlation coefficient, maximal relevance and minimal redundancy and least absolute shrinkage and selection operator method to screen radiomics features and build radiomics label. 6 ML models were used for model construction. Receiver operating characteristic curves were used to evaluate the predictive efficiency of ML models. SHAP analysis was used to explain the contribution of different variables and their risk threshold. AUC of radscores in predicting Ki-67 expression of GIST patients were 0.749 and 0.729 in training and validation set. Among the 6 ML models, SVM exhibited best prediction accuracy. AUC of SVM model in predicting Ki-67 expression of GIST patients were 0.840, 0.767 and 0.832 in training, validation and test set. SHAP analysis showed that radscores and tumor diameter had highly positive contribution to the model. Therefore, the interpretable SVM model can predict Ki-67 expression of GISTs patients individually before surgery, which can provide reliable imaging biomarkers for clinical treatment decisions.

Analysis of the efficacy of adjusting the dose of imatinib with therapeutic drug monitoring in adjuvant treatment after complete resection of gastrointestinal stromal tumors

Objective: To explore the efficacy of adjusting the dose of imatinib dose in the context of therapeutic drug monitoring (TDM) in patients with gastrointestinal stromal tumors (GISTs) who are receiving adjuvant therapy after complete resection of their tumors. Methods: This was a descriptive study. Inclusion criteria were (1) complete surgical resection with a pathological diagnosis of GIST, (2) postoperative adjuvant therapy with imatinib and dosage adjustment, (3) multiple TDM of imatinib, and (4) complete clinical, pathological, and follow-up data. The data of 70 patients with GISTs treated at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology between January 2015 and December 2023 were collected retrospectively. The study cohort comprised 15 (21.4%) men and 55 (78.6%) women of median age 60 years (range: 25-82). Of the eligible patients, 49 (70.0%) were at high-risk, 14 (20.0%) at intermediate-risk, six (8.6%) at low-risk, and one (1.4%) at very low risk. Patients were followed up by the gastrointestinal stromal tumor clinic every 2-3 months and their plasma concentrations of imatinib were checked. The dose was adjusted to 300 mg/d or 200 mg/d depending on whether they had had ≥ grade III adverse reactions, and whether the first plasma concentration of imatinib was ≥ 1,500 μg/L or between the expected range of 760 μg/L-1,100 μg/L. Studied indicators included adverse reactions, quality of life before and after dose adjustment, and overall survival and recurrence-free survival (RFS) after dose adjustment. Results: Before dose adjustment, all 70 patients received 400 mg of imatinib daily, with initial TDM values of 1,900 ± 568 μg/L, for a median duration of 8.3 months. After dose adjustment, 60 patients received 300 mg daily, with a TDM of 1,216 ± 350 μg/L, whereas 10 received 200 mg daily, with a TDM of 1,023 ± 269 μg/L. The median duration of treatment after dose adjustment was 23.4 months. Compared with those whose dosages were not adjusted, the incidence of bone marrow suppression was significantly lower (74.3% [52/70] vs. 51.4% [36/70], χ2=9.202, P=0.010); as were the incidences of edema (95.7% [67/70] vs. 50.0% [35/70], χ2=40.526, P<0.001); skin reactions (70.0% [49/70] vs. 32.9% [23/70), χ2=22.495, P<0.001); and gastrointestinal reactions (38.6% [27/70] vs. 10.0% [7/70], χ2=15.899, P<0.001) in those whose dosages were adjusted. The average total scores for physical health before and after dose adjustment were 76 ± 5 and 88 ± 4, respectively; whereas the mental health scores were 75 ± 6 and 89 ± 4, respectively. The median follow-up period was 36 months (range 6-126). During the first 3 years of follow-up, five high-risk patients with non-gastric GISTs developed recurrences. The 3-year overall survival rate was 100%, and the 3-year RFS rate was 92.8%, high-risk patients having a 3-year RFS rate of 89.8%. Conclusion: The adverse reactions and quality of life of GIST patients with severe adverse reactions to adjuvant imatinib therapy after complete resection can be mitigated by appropriately reducing the dosage of imatinib under the guidance of TDM.

Incidental Gastrointestinal Stromal Tumors in Thoracic and Bariatric Surgery

Background: Gastrointestinal stromal tumors (GISTs) are rare. This study aims to determine GIST rates in bariatric sleeve gastrectomy (SG) patients and esophageal cancer (EC) patients who receive esophagectomy. Methods: Retrospective review of an institution from 01/2022 to 03/2023 was performed. Incidental GIST rate was determined utilizing pathology reports. Results: One hundred thirteen patients were included (21% esophagectomy, 79% SG). Of EC patients, 21% had incidental GIST compared to 0 SG patients ( P &lt; .01). All GIST patients had a secondary malignancy and 50% had a tertiary malignancy. Conclusions: Esophagectomy patients with EC had a significantly higher rate of incidental GIST compared to bariatric SG patients and general population.

Impact of systemic steroids on the efficacy of first line imatinib treatment of patients with advanced gastrointestinal stromal tumors (GISTs).

Effective management of adverse events is required to maintain sufficient imatinib dosing when treating patients with gastrointestinal stromal tumors (GISTs). Skin rash is a common adverse event of imatinib, which can be effectively controlled by systemic steroid treatment without imatinib dose modification or interruption. However, the impact of the use of systemic steroids on the efficacy of imatinib treatment remains unclear. Between October 2014 and February 2022, 277 consecutive patients from a prospective registry of GIST patients were included as the study population. Patients who started systemic steroids due to grade ≥ 3 skin rash or grade 2 skin rash with grade 2 pruritis were classified as the steroid group, whereas patients who did not develop a skin rash or those who did not require steroids for a mild skin rash were classified as the control group. Efficacy outcomes were compared between the two groups. Among the 277 patients, 30 (10.8%) were treated with systemic steroids for skin rash. There was no significant difference in progression free survival (PFS) or overall survival (OS) between the steroid and control groups (3-year PFS, 67.7% vs. 65.1%, p = 0.53; 3-year OS, 91% vs. 89.9%, p = 0.67, respectively). The use of systemic steroids was not an independent factor associated with PFS (hazard ratio 0.73, 95% confidence interval 0.36-1.49, p = 0.39) and OS (hazard ratio 0.37, 95% confidence interval 0.12-1.18, p = 0.09). In the steroid group, patients who successfully maintained the imatinib dosage showed a trend toward more favorable survival outcomes than those who did not (3-year PFS, 73.3% vs. 44.4%, p = 0.34; 3-year OS, 95.8% vs. 75.0%, p = 0.15, respectively). The use of systemic steroids for the control of imatinib induced severe skin rash did not adversely affect the efficacy outcomes of imatinib in patients with advanced GIST.

Retrospective Analysis of Outcomes and Toxicity of Adjuvant Imatinib in Patients with Gastrointestinal Stromal Tumor in Clinical Oncology Department in Ain Shams University

Abstract Background Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal (GI) tract. Most of them (&amp;gt;75%) are driven by an oncogenic initiating event involving activating mutations of the genes encoding for tyrosine kinase, KIT or platelet derived growth factor receptor alpha (PDGFRA). Efficacy of the tyrosine kinase Inhibitor imatinib is now well established for localized and advanced disease. For localized GISTs, 3 years treatment is the recommended adjuvant therapy for high risk patients. This review aims to describe current knowledge on the issue of adjuvant therapy of primary GISTs in view of available results and to further refine the definition of the population of GIST patients at high risk of relapse including molecular criteria Aim of the Work The purpose of this study is to retrospectively analyze the outcomes and toxicity of adjuvant Imatinib in patients with gastrointestinal stromal tumor Patients and Methods This study is a retrospective study that included 40 patients attending the sarcoma clinic at the Clinical Oncology Department, Ain Shams University during the period from 1 January 2016 till 31 December 2022. Results A total of 40 patients were included. Of whom 47.5% of patients completed 3 year duration of treatment by Imatinib, whereas those who didn't complete their 3 years treatment were presented by 52.5%. Higher DFS was found in those who completed their treatment duration in comparison to the second group with median DFS 67.8 vs 47.9 months respectively P value &amp;lt;0.003 highly significant. Imatinib was generally tolerated and toxicity was reported only in 20% of the study population, and the commonly found side effect was skin rash, followed by hematological toxicities then GIT manifestations. 22.5% of patients developed recurrence of the disease and higher rate of recurrence was found among elderly&amp;gt;60 years, tumor size&amp;gt;10 cm, and higher Ki67. Conclusion treatment with adjuvant Imatinib appears to be associated with higher DFS and we'll tolerated side effects

Fourteen-year follow-up results of imatinib therapy in patients with unresectable and metastatic gastrointestinal stromal tumors.

Imatinib therapy is the gold standard for the treatment of unresectable and metastatic gastrointestinal stromal tumors (GISTs). However, few studies have reported the long-term outcomes of the treatment. Seventy patients who underwent imatinib therapy for unresectable and metastatic GISTs were enrolled between 2001 and 2009, and follow-up data were collected until October 2023. One hundred and sixty-eight months had passed since the final enrollment. The outcome measures were patient survival and the status of GIST and imatinib therapy. The cumulative incidence of disease progression (PD) and the chronological changes in PD hazard rate (HR) were also analyzed. The 5-, 10-, 15-, and 20-year overall survival rates were 64.3%, 30.0%, 16.8%, and 12.2%, respectively. Sixty of the 70 enrolled patients died before the data cutoff date: 47 (78.3%) patients died of GIST progression while the remaining 13 (21.7%) died of diseases other than GISTs. The cumulative incidence of PD logarithmically increased, and PD continued even after 10years of treatment. PD HR decreased over time to reach the lowest value at 9.6years after the initiation of treatment (HR 0.00027; 95% CI 0.00007-0.00174) and after that formed a small peak at 13years (HR 0.00144; 95% CI 0.00043-0.00436). Imatinib therapy showed high clinical efficacy in terms of long-term survival in GIST patients. However, patients undergoing imatinib therapy were at continuous risk of PD even after the 10-year treatment. Long-term treatment and follow-up beyond 10years are necessary for unresectable and metastatic GIST patients.

Advancing gastrointestinal stromal tumor management: The role of imagomics features in precision risk assessment.

Gastrointestinal stromal tumors (GISTs) vary widely in prognosis, and traditional pathological assessments often lack precision in risk stratification. Advanced imaging techniques, especially magnetic resonance imaging (MRI), offer potential improvements. This study investigates how MRI imagomics can enhance risk assessment and support personalized treatment for GIST patients. To assess the effectiveness of MRI imagomics in improving GIST risk stratification, addressing the limitations of traditional pathological assessments. Analyzed clinical and MRI data from 132 GIST patients, categorizing them by tumor specifics and dividing into risk groups. Employed dimension reduction for optimal imagomics feature selection from diffusion-weighted imaging (DWI), T1-weighted imaging (T1WI), and contrast enhanced T1WI with fat saturation (CE-T1WI) fat suppress (fs) sequences. Age, lesion diameter, and mitotic figures significantly correlated with GIST risk, with DWI sequence features like sphericity and regional entropy showing high predictive accuracy. The combined T1WI and CE-T1WI fs model had the best predictive efficacy. In the test group, the DWI sequence model demonstrated an area under the curve (AUC) value of 0.960 with a sensitivity of 80.0% and a specificity of 100.0%. On the other hand, the combined performance of the T1WI and CE-T1WI fs models in the test group was the most robust, exhibiting an AUC value of 0.834, a sensitivity of 70.4%, and a specificity of 85.2%. MRI imagomics, particularly DWI and combined T1WI/CE-T1WI fs models, significantly enhance GIST risk stratification, supporting precise preoperative patient assessment and personalized treatment plans. The clinical implications are profound, enabling more accurate surgical strategy formulation and optimized treatment selection, thereby improving patient outcomes. Future research should focus on multicenter studies to validate these findings, integrate advanced imaging technologies like PET/MRI, and incorporate genetic factors to achieve a more comprehensive risk assessment.

The Role of MSCT in Evaluating Tumor Size, Density, Immunohistochemical Classification, and Pathological Risk in GIST Patients

Objective: To investigate the role of multilayer spiral CT (MSCT) in evaluating patients with gastrointestinal stromal tumors (GIST), particularly its utility in determining tumor size, immunohistochemical classification, and pathological risk. Methods: A retrospective analysis was conducted on 22 GIST patients, confirmed by surgical pathology between January 2019 and December 2023. All patients underwent MSCT examination prior to surgery. Tumor size, density, and immunohistochemical classification from the MSCT results were compared with the postoperative pathological findings. Additionally, the ability of MSCT to predict GIST risk grade was evaluated in combination with immunohistochemical analysis results. Results: No significant differences were found between the preoperative MSCT findings and postoperative pathological results in terms of tumor size, density, or immunohistochemical classification in GIST patients. MSCT also enhanced the ability to predict GIST risk grades. Conclusion: MSCT demonstrates significant clinical value in the diagnosis and risk assessment of GIST, aiding in the prediction of the tumor’s biological behavior and patients’ treatment responses.

Immune priming and induction of tertiary lymphoid structures in a cord-blood humanized mouse model of gastrointestinal stromal tumor

ABSTRACT Gastrointestinal stromal tumors (GISTs) harbor diverse immune cell populations but so far immunotherapy in patients has been disappointing. Here, we established cord blood humanized mouse models of localized and disseminated GIST to explore the remodeling of the tumor environment for improved immunotherapy. Specifically, we assessed the ability of a cancer vascular targeting peptide (VTP) to bind to mouse and patient GIST angiogenic blood vessels and deliver the TNF superfamily member LIGHT (TNFS14) into tumors. LIGHT-VTP treatment of GIST in humanized mice improved vascular function and tumor oxygenation, which correlated with an overall increase in intratumoral human effector T cells. Concomitant with LIGHT-mediated vascular remodeling, we observed intratumoral high endothelial venules (HEVs) and tertiary lymphoid structures (TLS), which resemble spontaneous TLS found in GIST patients. Thus, by overcoming the limitations of immunodeficient xenograft models, we demonstrate the therapeutic feasibility of vascular targeting and immune priming in human GIST. Since TLS positively correlate with patient prognosis and improved response to immune checkpoint inhibition, vascular LIGHT targeting in GIST is a highly translatable approach to improve immunotherapeutic outcomes.

Demographic Trends, Co-Alterations, and Imatinib Resistance across Genomic Variants in Gastrointestinal Stromal Tumors: An AACR Project GENIE Analysis

Introduction: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the gastrointestinal tract, the treatment of which represents a significant breakthrough in targeted cancer therapy. Given its overall rare nature, genomic differences and clinical implications between demographic groups have not been previously investigated. Methods: Anonymized demographic, clinical, and genomic data from 1,559 GIST patients in the American Association for Cancer Research Project GENIE database were analyzed using cBioPortal and custom Python scripts. Data on patient demographics, genomic alterations, and co-occurrence genetic alerations were collected and classified according to clinical implications using the OncoKB database. χ2 tests for differences in genomic alterations were used across various demographic factors and mutual exclusivity analysis was employed to identify co-mutation patterns. Results: Male patients demonstrated higher incidence of PDGFRA mutation (14.56% vs. 8.05%; p < 0.001), while female patients had higher likelihood of NF1 mutations (7.46% vs. 3.23%; p = 0.001). Asian patients had higher alteration rates at KIT (85.59%; p = 0.002). Co-occurrence analysis revealed KIT alterations frequently co-occurred with CDKN2A (q < 0.001), MTAP (q = 0.045), and PTEN (q = 0.056), while there was mutual exclusivity with PDGFRA (q < 0.001), NF1 (q < 0.001), and BRAF (q = 0.015). CDKN2A alterations co-occurred with MTAP (q < 0.001) and PIK3CA (q = 0.015), while being mutually exclusive with TP53 (q = 0.002) and NF1 (q = 0.007). Trends were similar among patients who had received no prior medical treatment. Imatinib-resistant mutations were more common among male patients (25.6% vs. 18.9%; p = 0.0056) and individuals under 55 (27.3% vs. 20.9%; p = 0.0228). Among patients with imatinib-resistant mutations, 77.78% had sunitinib resistance, while 70.25% maintained sensitivity to ripretinib. Conclusion: Sex and race/ethnic differences in genomic alterations, as well as co-mutations, were prevalent among patients with GIST. Variations in mutational profiles highlight the importance of distinct genetic drivers that may be targeted to treat different patient populations.

Gastrointestinal Stromal Tumors (GISTs) in Pediatric Patients: A Case Report and Literature Review.

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms that primarily affect adults, with pediatric cases constituting only 0.5-2.7% of the total. Pediatric GISTs present unique clinical, genetic, and pathological features that distinguish them from adult cases. This literature review aims to elucidate these differences, emphasizing diagnostic and therapeutic challenges. We discuss the resistance of pediatric GISTs to conventional chemotherapy and highlight the importance of surgical intervention, especially in emergency situations involving intra-abdominal bleeding. The review also explores the molecular characteristics of pediatric GISTs, including rare mutations such as quadruple-negative wild-type GIST with an FGF3 gene gain mutation. To illustrate these points, we conclude with a case from our clinic involving a 15-year-old female with multiple CD117-positive gastric GISTs and a quadruple-negative wild-type genetic profile who required urgent surgical intervention following a failed tumor embolization. This case underscores the critical need for early diagnosis and individualized therapeutic strategies combining oncologic and surgical care to improve outcomes in pediatric GIST patients.

Effect and safety of ripretinib in the treatment of advanced gastrointestinal stromal tumor: A systematic review and meta-analysis.

Imatinib (IMA) has received approval as the primary treatment for gastrointestinal stromal tumors (GIST). Nonetheless, approximately half of the patients with advanced GIST show disease advancement following IMA treatment. Presently, the efficacy of secondary and tertiary medications in addressing various GIST secondary mutations is somewhat restricted. Consequently, there is a significant medical demand for the creation of kinase inhibitors that extensively block secondary drug-resistant mutations in advanced GIST. Ripretinib (RPT) is a new, switch-control tyrosine kinase inhibitors that can suppress different mutations of KIT and PDGFRA via a dual mechanism of action. To investigate the literature on RPT to assess an effective, safe, and successful treatment strategy against advanced GIST. The present systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase, Cochrane, Web of Science and ClinicalTrials.gov databases were screened from January 1, 2003 to May 1, 2024. A total of 4 studies were included, with a total of 507 patients enrolled. The objective response rate (ORR) of the RPT-treated advanced GIST was 17% (95%CI: 0.11-0.27), while the disease control rate (DCR) was 66% (95%CI: 0.59-0.73). The overall occurrence of adverse events with varying degrees was 97% (95%CI: 0.93-1), whereas that of grade ≥ 3 adverse reactions was 42% (95%CI: 0.28-0.63). The sensitivity analysis revealed that omitting some studies did not yield statistically notable variances in the aggregate data regarding the ORR, DCR, and the occurrence of adverse events of grade 3 or higher. The publication bias was absent because no significant asymmetry was observed in Begg's funnel plot in all studies. RPT has favorable efficacy profiles in GIST patients, but the adverse reactions are obvious, and patient management needs to be strengthened to achieve better safety and tolerability.

Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors

BACKGROUND Gastrointestinal stromal tumors (GISTs) are typical gastrointestinal tract neoplasms. Imatinib is the first-line therapy for GIST patients. Drug resistance limits the long-term effectiveness of imatinib. The regulatory effect of insulin-like growth factor 2 (IGF2) has been confirmed in various cancers and is related to resistance to chemotherapy and a worse prognosis. AIM To further investigate the mechanism of IGF2 specific to GISTs. METHODS IGF2 was screened and analyzed using Gene Expression Omnibus (GEO: GSE225819) data. After IGF2 knockdown or overexpression by transfection, the phenotypes (proliferation, migration, invasion, apoptosis) of GIST cells were characterized by cell counting kit 8, Transwell, and flow cytometry assays. We used western blotting to evaluate pathway-associated and epithelial-mesenchymal transition (EMT)-associated proteins. We injected transfected cells into nude mice to establish a tumor xenograft model and observed the occurrence and metastasis of GIST. RESULTS Data from the GEO indicated that IGF2 expression is high in GISTs, associated with liver metastasis, and closely related to drug resistance. GIST cells with high expression of IGF2 had increased proliferation and migration, invasiveness and EMT. Knockdown of IGF2 significantly inhibited those activities. In addition, OE-IGF2 promoted GIST metastasis in vivo in nude mice. IGF2 activated IGF1R signaling in GIST cells, and IGF2/IGF1R-mediated glycolysis was required for GIST with liver metastasis. GIST cells with IGF2 knockdown were sensitive to imatinib treatment when IGF2 overexpression significantly raised imatinib resistance. Moreover, 2-deoxy-D-glucose (a glycolysis inhibitor) treatment reversed IGF2 overexpression-mediated imatinib resistance in GISTs. CONCLUSION IGF2 targeting of IGF1R signaling inhibited metastasis and decreased imatinib resistance by driving glycolysis in GISTs.

Intratumoral microbiome promotes liver metastasis and dampens adjuvant imatinib treatment in gastrointestinal stromal tumor

Understanding the determinants of long-term liver metastasis (LM) outcomes in gastrointestinal stromal tumor (GIST) patients is crucial. We established the feature selection model of intratumoral microbiome at the surgery, achieving robust predictive accuracies of 0.953 and 0.897 AUCs in discovery (n = 74) and validation (n = 34) cohorts, respectively. Notably, despite the significant reduction in LM occurrence with adjuvant imatinib (AI) treatment, intratumoral microbiome exerted independently stronger effects on post-operative LM. Employing both 16S and full-length rRNA sequencing, we pinpoint intracellular Shewanella algae as a foremost LM risk factor in both AI- and non-AI-treated patients. Experimental validation confirmed S. algae's intratumoral presence in GIST, along with migration/invasion-promoting effects on GIST cells. Furthermore, S. algae promoted LM and impeded AI treatment in metastatic mouse models. Our findings advocate for incorporating intratumoral microbiome evaluation at surgery, and propose S. algae as a therapeutic target for LM suppression in GIST.

Follow-up analysis and research of very low-risk and low-risk gastrointestinal stromal tumors after endoscopic resection

Currently, due to limited long-term evidence, there remains some controversy surrounding the recommended postoperative monitoring strategy for primary low-risk gastrointestinal stromal tumors (GISTs). This study recruited a total of 532 patients diagnosed with very low-risk and low-risk GISTs who underwent endoscopic resection from 2015 to 2021, including 460 very low-risk patients and 72 low-risk patients. Descriptive statistical analysis was used to evaluate the clinical and pathological characteristics of GIST patients, and Kaplan–Meier methods were employed for survival analysis. The results showed that the 5-year recurrence-free survival rates for very low-risk and low-risk patients were 98.5% and 95.9%, respectively. The 5-year disease-specific survival rates for both groups were 100%. Additionally, the 5-year overall survival rates were 99.7% for very low-risk patients and 100% for low-risk patients (P = 0.69). Therefore, it is suggested that routine follow-up monitoring, including endoscopic surveillance and imaging, may not be necessary for very low-risk and low-risk GISTs after endoscopic resection.

Iodothyronine Deiodinase 3 Gene Expression in Gastrointestinal Stromal Tumors: A Pilot Study to Contribute to Risk Assessment.

In the realm of gastrointestinal stromal tumors (GIST), understanding the molecular landscape and prognostic factors is crucial for effective management. The deiodinase 3 gene (DIO3), known for its role in thyroid hormone regulation and cell proliferation, has emerged as a potential player in GIST pathogenesis. Our study investigated DIO3 expression in GIST samples and its correlation with tumor characteristics, aiming to enhance prognostic stratification and personalized treatment strategies. Using a retrospective design, we analyzed data and formalin-fixed paraffin-embedded (FFPE) samples of patients diagnosed with GIST. The study cohort comprised 33 patients, predominantly female, with a median age of 66 years. The tumor characteristics were meticulously documented, including location, size, mitotic count, risk classification, and immunohistochemical markers. Gene expression analysis of DIO3 was conducted using FFPE samples, with a focus on relative quantification and association with immunohistochemical markers and prognostic risk. DIO3 overexpression was observed in 69.70% of tumors, while underexpression was noted in 30.30% of cases. Association analyses revealed intriguing insights. A notable association was identified between DIO3 expression and the frequency of DOG1, suggesting a potential interplay between these markers in GIST pathobiology. Furthermore, increased DIO3 expression was significantly higher in very low/low-risk prognostic patients, hinting at a possible link between DIO3 levels and tumor progression prognosis. The intricate interplay between DIO3 expression and GIST characteristics uncovered in this study underscores the potential of molecular markers in refining prognostic assessments and therapeutic strategies for GIST patients.

Different efficacy of tyrosine kinase inhibitors by KIT and PGFRA mutations identified in circulating tumor DNA for the treatment of refractory gastrointestinal stromal tumors

BackgroundWhile advanced gastrointestinal stromal tumors (GISTs) are primarily treated with tyrosine kinase inhibitors (TKIs), acquired resistance from specific mutations in KIT or PDGFRA frequently occurs. We aimed to assess the utility of circulating tumor DNA (ctDNA) as a modality of therapeutic decision-making in advanced GIST.MethodsWe conducted a pooled analysis of SCRUM-Japan studies for advanced GIST patients. We compared patient characteristics analyzed with tissue and blood samples, assessed gene alteration profiles, and evaluated prognostic implications from ctDNA status.ResultsIn 133 patients, tissue and blood samples were analyzed for 89 and 44 patients, respectively. ctDNA was detected in 72.7% of cases; no prior treatment or progressive disease was significantly associated with ctDNA-positivity. ctDNA-positive patients had significantly shorter progression-free survival compared with ctDNA-negative patients (hazard ratio = 3.92; P = 0.007). ctDNA genotyping revealed a complex landscape of gene alterations, characterized by multi-exonic mutations in KIT, compared with tissue-based analysis. Patients who received TKIs matched to the identified KIT mutation in ctDNA demonstrated significantly longer PFS than those with unmatched treatment (median, 8.23 vs. 2.43 months; P < 0.001).ConclusionsctDNA-based analysis facilitates assessment of disease status and genomic profiles, thus potentially assisting in identifying optimal therapeutic strategies for advanced GIST patients.

Survival of advanced/recurrent gastrointestinal stromal tumors treated with tyrosine kinase inhibitors in Taiwan: a nationwide registry study

BackgroundMost gastrointestinal stromal tumors (GISTs) harbor c-KIT or PDGFRA mutations. Administration of tyrosine kinase inhibitors (TKIs) has significantly improved the survival of patients with GISTs. We aimed to evaluate the clinical outcome of advanced or recurrent GIST patients in Taiwan.MethodsPatients diagnosed between 2010 and 2020 were enrolled. The collected data included baseline characteristics, treatment pattern, treatment outcome, genetic aberrations and survival status. Progression-free survival (PFS) and overall survival (OS) were analyzed and plotted with the Kaplan–Meier method. Cox regression analysis was used to analyze the prognostic factors of survival.ResultsA total of 224 patients with advanced or recurrent GISTs treated with TKIs were enrolled. All patients received imatinib treatment. Ninety-three and 42 patients received sunitinib and regorafenib treatment, respectively. The 48-month PFS and OS rates for patients treated with imatinib were 50.5% and 79.5%, respectively. c-KIT exon 9 and PDGFRA mutations were prognostic factors for a poor PFS and PDGFRA mutation was a prognostic factor for a poor OS in patients treated with imatinib in multivariate Cox regression analysis. The median PFS of patients who received sunitinib treatment was 12.76 months (95% confidence interval (CI), 11.01–14.52). Patients with c-KIT exon 9 mutations had a longer PFS than those with other genetic aberrations. The median PFS of patients treated with regorafenib was 7.14 months (95% CI, 3.39–10.89).ConclusionsWe present real-world clinical outcomes for advanced GIST patients treated with TKIs and identify mutational status as an independent prognostic factor for patient survival.

Pilot Study by Liquid Biopsy in Gastrointestinal Stromal Tumors: Analysis of PDGFRA D842V Mutation and Hypermethylation of SEPT9 Presence by Digital Droplet PCR.

Tissue biopsy remains the standard for diagnosing gastrointestinal stromal tumors (GISTs), although liquid biopsy is emerging as a promising alternative in oncology. In this pilot study, we advocate for droplet digital PCR (ddPCR) to diagnose GIST in tissue samples and explore its potential for early diagnosis via liquid biopsy, focusing on the PDGFRA D842V mutation and SEPT9 hypermethylated gene. We utilized ddPCR to analyze the predominant PDGFRA mutation (D842V) in surgical tissue samples from 15 GIST patients, correlating with pathologists' diagnoses. We expanded our analysis to plasma samples to compare DNA alterations between tumor tissue and plasma, also investigating SEPT9 gene hypermethylation. We successfully detected the PDGFRA D842V mutation in GIST tissues by ddPCR. Despite various protocols to enhance mutation detection in early-stage disease, it remained challenging, likely due to the low concentration of DNA in plasma samples. Additionally, the results of Area Under the Curve (AUC) for the hypermethylated SEPT9 gene, analyzing concentration, ratio, and abundance were 0.74 (95% Confidence Interval (CI): 0.52 to 0.97), 0.77 (95% CI: 0.56 to 0.98), and 0.79 (95% CI: 0.59 to 0.99), respectively. As a rare disease, the early detection of GIST through such biomarkers is particularly crucial, offering significant potential to improve patient outcomes.