Gastrointestinal Stromal Tumors Research Articles

A diagnostic challenge of KIT p.V559D and BRAF p.G469A mutations in a paragastric mass.

A patient with gastrointestinal stroma tumor (GIST) and KIT p.V559D and BRAF p.G469A alterations was referred to our institutional molecular tumor board (MTB) to discuss therapeutic implications. The patient had been diagnosed with B-cell chronic lymphocytic leukemia (CLL) years prior to the MTB presentation. GIST had been diagnosed 1 month earlier. After structured clinical annotation of the molecular alterations and interdisciplinary discussion, we considered BRAF/KIT co-mutation unlikely in a treatment-naïve GIST. Discordant variant allele frequencies furthermore suggested a second malignancy. NGS of a CLL sample revealed the identical class 2 BRAF alteration, thus supporting admixture of CLL cells in the paragastric mass, leading to the detection of 2 alterations. Following the MTB recommendation, the patient received imatinib and had a radiographic response. Structured annotation and interdisciplinary discussion in specialized tumor boards facilitate the clinical management of complex molecular findings. Coexisting malignancies and clonal hematopoiesis warrant consideration in case of complex and uncommon molecular findings.

Large-scale, prospective observational study of regorafenib in Japanese patients with advanced gastrointestinal stromal tumors in a real-world clinical setting.

Regorafenib improves overall survival (OS) of patients with advanced progressive gastrointestinal stromal tumors (GISTs) after standard chemotherapy in phase III trials in the 3rd-line setting. This large-scale, prospective observational study evaluated the safety and effectiveness of regorafenib in Japanese patients with GIST in a real-world clinical setting. Patients with GIST received oral regorafenib at a maximum daily dose of 160 mg for weeks 1-3 of each 4-week cycle (dose could be modified at investigator's discretion). The primary objective was to assess safety, particularly significant adverse drug reactions (ADRs), as well as the frequency of occurrence of ADRs, hand and foot syndrome (HFS), discontinuation of treatment due to disease progression and adverse events. A Cox proportional hazards model was used to evaluate associations between OS or time to treatment failure (TTF) and baseline characteristics or HFS. Between August 2013 and March 2021, 143 evaluable patients were enrolled. ADRs occurred in 90.2% of patients and led to treatment discontinuation in 28.3%. The most frequent ADRs were HFS, hypertension, and liver injury. The overall response rate was 11.3% and disease control rate 56.5% (RECIST) based on investigators' assessments. Median OS was 17.4 months (95% CI 14.24-23.68). Median TTF was 5.3 (95% CI 4.0-6.5) months. Improved OS and TTF responses occurred in patients with an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1. The outcomes in this real-world study were consistent with those seen in clinical trials. No new safety concerns were identified. https://clinicaltrials.gov, identifier NCT01933958.

A Rare Case Of Early Gastrointestinal Stromal Tumor In 34-Year-Old Woman: A Caution For Adnexal Tumor Mimicry

Introduction: Gastrointestinal Stromal Tumors (GISTs) are the leading type of mesenchymal tumor in the gastrointestinal (GI) tract, constituting 80% of these tumors and 0.1% to 3% of all gastrointestinal malignancies. They arise from spindle-shaped mesenchymal cells known as interstitial cells of Cajal. Its onset can be at any age, with the peak occurring in the sixth decade. Case Presentation: We report the case of a 34-year-old woman with a complaint about a lump in her lower abdomen that has been progressively enlarging over the past year without any significant symptoms following the lump. Findings in the ultrasound suggest an ovarian mass. Laparotomy was carried out, and while no ovarian mass was found, instead a mass was identified in the mesentery of the small bowel. As a result, a complete excision of the tumor was performed, with histopathologic and immunohistochemical results confirming a GIST diagnosis. Conclusion: Representing a tiny percentage of gastrointestinal tumors, GISTs are rare. GISTs may be asymptomatic or present without any typical symptoms. Sole reliance on clinical and radiological investigations can cause them to be easily overlooked. Awareness of GIST is critical and care must be taken in diagnosis since other tumor can mimic GISTs in endoscopic, imaging, and histological findings.

A successful complete resection for multidrug-resistant giant gastrointestinal stromal tumor invading the transverse colon with multiple liver metastases in a young female: a case report

BackgroundGastrointestinal stromal tumors (GISTs) are rare in young people and are often detected after becoming symptomatic or at an advanced stage. Herein, we report a case of complete reduction surgery for a substantially large malignant gastric GIST with multiple liver metastases in a young woman who successfully resulted in R0 surgery.Case presentationAn 18-year-old woman presented to our hospital with anorexia and vomiting, and was diagnosed with a 17 cm gastric GIST with transverse colon invasion and multiple liver metastases. Due to being considered unresectable, tyrosine and multi-kinase inhibitor therapy were administered up to the fourth line yielding no response. After careful discussion at a multidisciplinary team conference, pancreatoduodenectomy or distal gastrectomy, transverse colectomy, and resection of the liver metastases were planned. Consequently, distal gastrectomy, transverse colectomy, resection of the liver metastases, and incidental peritoneal metastases were performed. Although the primary goal of the surgery was to reduce the volume of the tumor as much as possible, the results revealed that the complete removal of all detectable tumors was achieved. No recurrence was observed after surgery for 27 months with long-term adjuvant imatinib therapy.ConclusionsEven for highly advanced GISTs, aggressive surgery followed by adjuvant drug therapy may prolong survival in young patients.

Use of Endoscopic Ultrasound Elastography to Differentiate between Gastrointestinal Stromal Tumor and Leiomyoma Localized in the Upper Gastrointestinal Tract.

Gastrointestinal stromal tumors (GISTs) have malignant potential. Distinction of GISTs from leiomyoma is important to the decision of follow-up or treatment for upper gastrointestinal tract subepithelial lesions (SELs). There are few studies on the evaluation of gastrointestinal SELs with endoscopic ultrasound (EUS) elastography. To evaluate the efficiency of strain ratio (SR) measurement and Giovannini's classification (Gc) by EUS elastography in differentiating GISTs from leiomyomas. Twenty-three lesions with histopathological diagnoses of 13 GISTs and 10 leiomyomas were evaluated. The lesions' SR values were obtained from EUS reports retrospectively. Giovannini's classification was performed according to the elastography images recorded in the system. The effectiveness of SR and Gc in the distinction between GIST and leiomyomas was evaluated. Twelve of the GISTs and 3 of the leiomyomas were with scores 4 and 5 according to Gc (p = 0.006). Gastrointestinal stromal tumors had a higher SR than leiomyomas (p = 0.001). For the diagnosis of GISTs, sensitivity/specificity/diagnostic accuracy were 92.3%/80%/87% for SR alone, 92.3%/70%/82.6% for Gc alone, and 84.6%/80%/82.6% for the use of both SR and Gc. This is the first study in which semi-quantitative (SR) and qualitative (Gc) methods were evaluated together for the distinction of GISTs and leiomyomas. The sensitivity of SR alone for diagnosing GIST is higher than that of Gc alone or the combination of both methods. Although SR alone does not diagnose GIST, it can be used as an auxiliary method in biopsy and follow-up decisions. Erdem RE, Bektaş M, Ellik ZM, et al. Use of Endoscopic Ultrasound Elastography to Differentiate between Gastrointestinal Stromal Tumor and Leiomyoma Localized in the Upper Gastrointestinal Tract. Euroasian J Hepato-Gastroenterol 2024;14(1):20-23.

Novel method of phosphorous doped bismuth oxide with carbon aerogel for a selective voltammetry quantification of anti-cancer drug: Regorafenib

Regorafenib (REG) is an oral multikinase inhibitor derived from diphenylureas. This drug is prescribed to treat colorectal and gastrointestinal stromal tumors and hepatocellular carcinoma. Our present study demonstrates the non-enzymatic electrochemical determination of REG in human blood serum at low concentrations by applying phosphorous-doped bismuth oxide (P-BiO) and porous graphene oxide (PGO)/protonated graphitic carbon nitride (PGCN) combined Aerogel form a P-BiO/Aerogel nanohybrids fabricated glassy carbon electrode (GCE). The property of our proposed electrocatalyst was characterized using several spectroscopic techniques. Utilizing cyclic voltammetry and differential pulse voltammetry techniques the electrochemical performance of this designed sensor was analyzed. Our P-BiO/Aerogel/GCE sensor exhibited a lower detection limit (LOD) of 0.1 nM with a high sensitivity of 1.433 µA µM-1cm−2. As a part of the real-time functionality, our fabricated sensor quantified the trace levels of REG in the consumed patient’s blood serum samples at the recovery range of 99–103 %. Therefore, our P-BiO/Aerogel nanohybrid electrocatalyst is a promising electrocatalyst for the real-time monitoring of REG.

Surgical management of gastrointestinal stromal tumors of gastric origin

Gastrointestinal Stromal Tumors (GISTs) account for 1 to 2% of gastrointestinal malignant tumors. They are characterized by overexpression of the tyrosine kinase (KIT). 60% of GISTs originate in the stomach. Managing them remains complex and varies depending on several factors such as location, size, molecular biology, type of clinical presentation, and the risks/benefits of surgical treatment. Surgery remains the only curative treatment, while tyrosine kinase inhibitors have demonstrated their efficacy as systemic treatment in the perioperative context. Risk stratification for recurrence guides the choice of adjuvant treatment, with a recommended duration of 3 years for high-risk patients.

Clinical features and prognosis of malignant small bowel tumors: Experience from a university hospital in Chile

BackgroundSmall bowel tumors (SBT) are infrequent and represent a small proportion of digestive neoplasms. There is scarce information about SBT in Latin America. AimTo describe the epidemiology, clinical characteristics, diagnostic methods, and survival of malignant SBTs. MethodsRetrospective observational study of adult patients with histopathological diagnosis of SBT between 2007 and 2021 in a university hospital in Chile. ResultsA total of 104 patients [51.9% men; mean age 57 years] with SBT. Histological type: neuroendocrine tumor (NET) (43.7%, n=38), gastrointestinal stromal tumors (GIST) (21.8%, n=19), lymphoma (17.2%, n=15) and adenocarcinoma (AC) (11.5%, n=10). GIST was more frequent in duodenum (50%; n=12) and NET in the ileum (65.8%; n=25). Metastasis was observed in 17 cases, most commonly from colon and melanoma. Nausea and vomiting were significantly more often observed in AC (p=0.035), as well as gastrointestinal bleeding in GIST (p=0.007). The most common diagnostic tools were CT and CT enteroclysis with an elevated diagnostic yield (86% and 94% respectively). The 5-year survival of GIST, NET, lymphoma and AC were 94.7% (95%CI: 68.1–99.2), 82.2% (95%CI: 57.6–93.3), 40.0% (95%CI: 16.5–82.8) and 25.9% (95%CI: 4.5–55.7%), respectively. NET (HR 6.1; 95%CI: 2.1–17.2) and GIST (HR 24.4; 95%CI: 3.0–19.8) were independently associated with higher survival compared to AC, adjusted for age and sex. ConclusionsMalignant SBT are rare conditions and NETs are the most common histological subtype. Clinical presentation at diagnosis, location or complications may suggest a more probable diagnosis. GIST and NET are associated with better survival compared to other malignant subtypes.

Survival of patients with ruptured gastrointestinal stromal tumour treated with adjuvant imatinib in a randomised trial

BackgroundPatients with ruptured gastrointestinal stromal tumour (GIST) have poor prognosis. Little information is available about how adjuvant imatinib influences survival.MethodsWe explored recurrence-free survival (RFS) and overall survival (OS) of patients with ruptured GIST who participated in a randomised trial (SSG XVIII/AIO), where 400 patients with high-risk GIST were allocated to adjuvant imatinib for either 1 year or 3 years after surgery. Of the 358 patients with confirmed localised GIST, 73 (20%) had rupture reported. The ruptures were classified retrospectively using the Oslo criteria.ResultsMost ruptures were major, four reported ruptures were reclassified unruptured. The 69 patients with rupture had inferior RFS and OS compared with 289 patients with unruptured GIST (10-year RFS 21% vs. 55%, OS 59% vs. 78%, respectively). Three-year adjuvant imatinib did not significantly improve RFS or OS of the patients with rupture compared with 1-year treatment, but in the largest mutational subset with KIT exon 11 deletion/indel mutation OS was higher in the 3-year group than in the 1-year group (10-year OS 94% vs. 54%).ConclusionsAbout one-fifth of ruptured GISTs treated with adjuvant imatinib did not recur during the first decade of follow-up. Relatively high OS rates were achieved despite rupture.Clinical Trial RegistrationNCT00116935.

Minimally invasive approach for retrorectal tumors above and below S3: a multicentric tertiary center retrospective study (MiaRT study)

BackgroundRetrorectal tumors are uncommon lesions developed in the retrorectal space. Data on their minimally invasive resection are scarce and the optimal surgical approach for tumors below S3 remains debated.MethodsWe performed a retrospective review of consecutive patients who underwent minimally invasive resection of retrorectal tumors between 2005 and 2022 at two tertiary university hospital centers, by comparing the results obtained for lesions located above or below S3.ResultsOf over 41 patients identified with retrorectal tumors, surgical approach was minimally invasive for 23 patients, with laparoscopy alone in 19, with transanal excision in 2, and with combined approach in 2. Retrorectal tumor was above S3 in 11 patients (> S3 group) and below S3 in 12 patients (< S3 group). Patient characteristics and median tumor size were not significantly different between the two groups (60 vs 67 mm; p = 0.975). Overall median operative time was 131.5 min and conversion rate was 13% without significant difference between the two groups (126 vs 197 min and 18% vs 8%, respectively; p > 0.05). Final pathology was tailgut cyst (48%), schwannoma (22%), neural origin tumor (17%), gastrointestinal stromal tumor (4%), and other (19%). The 90-day complication rates were 27% and 58% in the > S3 and < S3 groups, respectively, without severe morbidity or mortality. After a median follow-up of 3.3 years, no recurrence was observed in both groups. Three patients presented chronic pain, three anal dysfunction, and three urinary dysfunction. All were successfully managed without reintervention.ConclusionsMinimally invasive surgery for retrorectal tumors can be performed safely and effectively with low morbidity and no mortality. Laparoscopic and transanal techniques alone or in combination may be recommended as the treatment of choice of benign retrorectal tumors, even for lesions below S3, in centers experienced with minimally invasive surgery.

Incidental finding of an arteriovenous malformation originating from the diaphragm: Case report and literature review

Arteriovenous malformations (AVMs) are defined as aberrant linkages between arteries and veins in the absence of a capillary network. This case report will discuss the incidental finding of an AVM likely originating from the diaphragm. A 65-year-old female presents for an umbilical hernia repair. Her past medical history is significant for HTN, type 2 diabetes mellitus, gastroesophageal reflux disease, and class 1 obesity. She has a past surgical history of hysteroscopy in 2020 and laparoscopy in 1996. She has no history of tobacco use, alcohol use, or recreational drug use. She is allergic to contrast. A computed tomography (CT) scan was ordered and incidentally showed a soft tissue mass in the left upper quadrant adjacent to the stomach and diaphragm, possibly a gastrointestinal stromal tumor (GIST) or splenule, in addition to diastasis of the abdominal wall. Biopsies of the esophagus, stomach, and duodenum from the esophagogastroduodenoscopy (EGD) were all benign. A nuclear medicine scan of the liver and spleen found an estimated 2.3 cm soft tissue nodule located between the fundus of the stomach and the left hemidiaphragm that does not demonstrate sulfa colloid uptake and is therefore not consistent with a splenule. This is the only incidence cited of an AVM originating from the diaphragm. We suspect that the origin of this AVM is the inferior phrenic artery. The decision for management for this case was to get a CT scan of the abdomen and chest to trace the path of the AVM and manage with surveillance.

Cancer-associated mutations in protein kinase C theta are loss-of-function.

The Ca2+-independent, but diacylglycerol-regulated, novel protein kinase C (PKC) theta (θ) is highly expressed in hematopoietic cells where it participates in immune signaling and platelet function. Mounting evidence suggests that PKCθ may be involved in cancer, particularly blood cancers, breast cancer, and gastrointestinal stromal tumors, yet how to target this kinase (as an oncogene or as a tumor suppressor) has not been established. Here, we examine the effect of four cancer-associated mutations, R145H/C in the autoinhibitory pseudosubstrate, E161K in the regulatory C1A domain, and R635W in the regulatory C-terminal tail, on the cellular activity and stability of PKCθ. Live-cell imaging studies using the genetically-encoded fluorescence resonance energy transfer-based reporter for PKC activity, C kinase activity reporter 2 (CKAR2), revealed that the pseudosubstrate and C1A domain mutations impaired autoinhibition to increase basal signaling. This impaired autoinhibition resulted in decreased stability of the protein, consistent with the well-characterized behavior of Ca2+-regulated PKC isozymes wherein mutations that impair autoinhibition are paradoxically loss-of-function because the mutant protein is degraded. In marked contrast, the C-terminal tail mutation resulted in enhanced autoinhibition and enhanced stability. Thus, the examined mutations were loss-of-function by different mechanisms: mutations that impaired autoinhibition promoted the degradation of PKC, and those that enhanced autoinhibition stabilized an inactive PKC. Supporting a general loss-of-function of PKCθ in cancer, bioinformatics analysis revealed that protein levels of PKCθ are reduced in diverse cancers, including lung, renal, head and neck, and pancreatic. Our results reveal that PKCθ function is lost in cancer.

Addressing the Gap: Racial Disparities and Public Health Strategies in the Epidemiology of Gastrointestinal Stromal Tumors.

Background Gastrointestinal stromal tumors (GISTs) represent the most common mesenchymal neoplasms of the gastrointestinal tract, arising from the interstitial cells of Cajal. These tumors bridge the nervous system and muscular layers of the gastrointestinal tract, playing a crucial role in the digestive process. The incidence of GISTs demonstrates notable variations across different racial and ethnic groups, underscoring the need for in-depth analysis to understand the interplay of genetic, environmental, and socioeconomic factors behind these disparities. Linear regression analysis is a pivotal statistical tool in such epidemiological studies, offering insights into the temporal dynamics of disease incidence and the impact of public health interventions. Methodology This investigation employed a detailed dataset from 2009 to 2020, documenting GIST incidences across Asian, African American, Hispanic, and White populations. A meticulous preprocessing routine prepared the dataset for analysis, which involved data cleaning, normalization of racial terminologies, and aggregation by year and race. Linear regression models and Pearson correlation coefficients were applied to analyze trends and correlations in GIST incidences across the different racial groups, emphasizing an understanding of temporal patterns and racial disparities in disease incidence. Results The study analyzed GIST cases among four racial groups, revealing a male predominance (53.19%) and an even distribution of cases across racial categories: Whites (27.66%), Hispanics (25.53%), African Americans (24.47%), and Asians (22.34%). Hypertension was the most common comorbidity (32.98%), followed by heart failure (28.72%). The linear regression analysis for Asians showed a decreasing trend in GIST incidences with a slope of -0.576, an R-squared value of 0.717, and a non-significant p-value of 0.153. A significant increasing trend was observed for Whites, with a slope of 0.581, an R-squared value of 0.971, and a p-value of 0.002. African Americans exhibited a moderate positive slope of 0.277 with an R-squared value of 0.470 and a p-value of 0.201, indicating a non-significant increase. Hispanics showed negligible change over time with a slope of -0.095, an R-squared value of 0.009, and a p-value of 0.879, suggesting no significant trend. Conclusions This study examines GIST incidences across racial groups, revealing significant disparities. Whites show an increasing trend (p = 0.002), while Asians display a decreasing trend (p = 0.153), with stable rates in African Americans and Hispanics. Such disparities suggest a complex interplay of genetics, environment, and socioeconomic factors, highlighting the need for targeted research and interventions that address these differences and the systemic inequalities influencing GIST outcomes.

Survival trends of soft tissue sarcomas and gastrointestinal stromal tumors from 1995 to 2019: A SEER database analysis.

e23528 Background: In the last 25 years, new therapies have been developed for gastrointestinal stromal tumors (GISTs), while treatments for many soft tissue sarcomas (STSs) have remained relatively stagnant with 90% of phase I/II trials focusing on repurposing existing drugs. This study compares survival changes over time in patients with STSs and GISTs. Methods: Data from the Surveillance, Epidemiology, and End Results (SEER)-9 registry were analyzed for patients aged 20+ diagnosed with GISTs and STSs from 1995 to 2019. Patients were categorized into time periods: 1995-2004, 2005-2014, 2015-2019. The primary outcomes were the 5-year overall survival (OS) difference between GISTs and STSs and survival variations across the periods. Survival was calculated using the Kaplan–Meier method, and differences were assessed with log-rank tests. Results: 26,633 STS and 3,818 GIST patients were identified. The 5-year OS rate was 53.0% (95% CI: 52.4-53.7) for STSs and 68.7% (95% CI: 67.1-70.3) for GISTs (p &lt; 0.001), with a respective median OS of 72 (95% CI: 69-75) and 121 (95% CI: 113-128) months. For STS, the 5-year OS rate was 53.3% (95% CI: 52.3-54.4), 52.8% (95% CI: 51.9-53.8), and 54.2% (95% CI: 52.2-56.3) (p = 0.66) for groups 1995-2004, 2005-2014, and 2015-2019, respectively. For GIST, the 5-year OS rate was 60.7% (95% CI: 57.3-64.2), 70.6% (95% CI: 68.5-72.7), and 71.0% (64.5-78.3) (p &lt; 0.001). In the locoregional setting (L), the GIST median 5-year OS was 70.5% (95% CI: 66.9-74.3), 78.1% (95% CI: 75.9-80.3), and 79.0% (95% CI: 71.4-87.4) (p &lt; 0.001). In the metastatic setting (M) for GIST, the 5-year OS rate was 30.7% (95% CI: 24.8-37.9), 45.7% (95% CI: 41.1-50.7), and 46.3% (95% CI: 35.8-59.8) (p &lt; 0.001). However, no significant difference was seen for STSs in either setting (L1995-2004 61.6% 95% CI: 60.5–62.8, M1995-2004 11.2, 95% CI: 9.7–12.9, L2005-2014 61.5%, 95% CI: 60.5–62.5, M2005-2014 10.2, 95% CI: 8.9–11.7, L2015-2019 63.4%, 95% CI: 61.2–65.7, M2015-2019 12.1, 95% CI: 9.4–15.6, p(L) = 0.71 and p(M) = 0.74). Conclusions: While GIST survival rates significantly improved, those for other STSs remain unchanged, highlighting an urgent need for novel STS therapies. [Table: see text]

Identifying intra-abdominal desmoid type fibromatosis mimicking recurrence/metastasis of GISTs using FAPI PET/CT.

e23516 Background: Intra-abdominal desmoid tumor (IADT) can mimic the recurrence/metastases of gastrointestinal stromal tumors (GISTs). However, it is difficult to radiologically differentiate IADT and recurrence/metastases of GISTs. This study aims to investigate the value of 18F fibroblast activation protein inhibitor ( [18F]FAPI-42) PET/CT in identifying intra-abdominal desmoid type fibromatosis mimicking recurrence/metastases of GISTs by comparing it to [18F]FDG PET/CT. Methods: This study retrospectively included a total of 24 patients (12 patients with IADT and 12 patients with recurrent/metastatic GISTs). The differences in [18F]FAPI-42 PET/CT parameters (SUVmax-FAPI and SUVTLR-FAPI ), [18F]FDG PET/CT parameters (SUVmax-FDG and SUVTLR-FDG), SUVfapi/SUVfdg ratio of IADT and GISTs were compared. The difference in PET/CT parameters (SUVmax, SUVTLR) of IADT between FDG PET/CT and FAPI PET/CT were compared. Immunohistochemical verification was performed on IADT lesions of all 12 patients and expression profiles of GEO datasets were analyzed to validate the FAP expression of IADT. Results: Both [18F]FAPI-42 PET/CT parameters, SUVmax-FAPI [8.8 (2.0, 16.0) vs 1.9 (1.0, 6.0), P&lt; 0.001]and SUVTLR-FAPI [7.3 (2.0, 15.8) vs 1.7 (0.5, 6.9), P&lt; 0.001], of IADT was significantly higher than that of GISTs, while there was no statistically significant difference in [18F]FDG PET/CT parameters, SUVmax-FDG and SUVTLR-FDG, between this two group. The ratio (SUVfapi/SUVfdg) of IADT was significantly higher than that of GISTs [3.3 (1.5, 8.0) vs 0.5 (0.1, 3.9), P= 0.001]. The SUVmax and SUVTLR of FAPI PET/CT of IADT were significantly higher than that of FDG PET/CT [8.8 (2.0, 16.0) vs 2.5 (1.1, 6.2), P&lt; 0.001; 7.3 (2.0, 15.8) vs 0.9 (0.4, 2.7), P&lt; 0.001; respectively]. FAP expression was found to be expressed in all the examined tissues and highly expressed in most of them. GEO database analysis shows that the FAP gene expression in DT is significantly higher than that in GISTs. Conclusions: FAPI PET/CT is a promising method in differentiating IADT from recurrence/metastases of GISTs compared with FDG PET/CT since FAP expression in DT is significantly higher than that in GISTs.

DCC-3116 in combination with ripretinib for patients with advanced gastrointestinal stromal tumor: A phase 1/2 study.

TPS11587 Background: Advanced cancers driven by mutations at or downstream of receptor tyrosine kinases (RTKs), including KIT- and PDGFRA-mutant gastrointestinal stromal tumor (GIST), activate autophagy as an escape mechanism in response to RTK pathway inhibitors. ULK1/2 kinases are key regulators that initiate autophagy in response to stress, such as KIT/PDGFRA inhibition in KIT- and PDGFRA-mutant GIST. Therefore, ULK1/2 inhibition represents a potential targeted approach to selectively inhibit autophagy and is an attractive strategy for combination with RTK pathway inhibitors, including ripretinib. Ripretinib is a switch-control KIT/PDGFRA tyrosine kinase inhibitor approved as a ≥fourth-line therapy for advanced GIST. In the INTRIGUE trial, ripretinib demonstrated comparable efficacy and more favorable safety compared with sunitinib in second-line advanced GIST. DCC-3116 is an investigational, selective, potent, switch-control kinase inhibitor of ULK1/2 in development for combination with targeted therapies that activate autophagy, such as ripretinib. In a GIST xenograft model, animals treated with ripretinib demonstrated stable tumor burden while treatment with ripretinib + DCC-3116 resulted in complete regressions. Here, we describe the design of a phase 1/2, multicenter, open-label study evaluating the safety, recommended phase 2 dose (RP2D), and preliminary efficacy of DCC-3116 in combination with ripretinib in advanced GIST (NCT05957367). Methods: This phase 1/2 study includes safety/dose-finding (part 1) and expansion (part 2). In part 1, patients (pts) ≥18 years must have pathologically confirmed GIST with a KIT or PDGFRA mutation and disease progression on or intolerance to ≥1 systemic regimen. Escalating doses of DCC-3116 will be assessed with ripretinib 150 mg once daily. Part 1 will use safety, pharmacokinetics, pharmacodynamics, preliminary efficacy, and a Bayesian optimal interval design to identify the RP2D for part 2 and the maximum tolerated dose. In part 2, second-line pts with confirmed GIST with a KIT exon 11 mutation and disease progression on or intolerance to first-line imatinib will be enrolled. Part 2 will use a two-stage design with non-binding futility and efficacy analyses after stage 1 to explore efficacy of the combination dose selected in part 1. Exclusion criteria for both parts include use of other anticancer treatments, such as ripretinib, and any investigational therapies within 14 days, use of moderate or strong inhibitors or inducers of cytochrome P450 3A4 or P-glycoprotein, symptomatic central nervous system metastases or leptomeningeal disease, and active infections. Primary objectives in part 1 are to identify adverse events and the RP2D. The primary objective of part 2 is to determine the objective response rate per modified Response Evaluation Criteria in Solid Tumors version 1.1. The study is currently enrolling. Clinical trial information: NCT05957367 .

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.

Localized GIST in Hispanic population in North and South America.

e23513 Background: Most studies of gastrointestinal stromal tumors (GIST) focus upon patients in a single country. However, differences in patient presentation, treatment, and outcomes may differ between nations. We sought to compare Hispanic patients with localized GIST treated in North and South America. Methods: We performed a retrospective analysis including all Hispanic GIST patients treated at 3 tertiary referral centers in the United States (US), Mexico (MX) and Argentina (AR), as well as those enrolled by 2 patient advocacy groups in US and MX from 2000-2022. Demographic, clinicopathologic and survival data were collected and compared using Pearson’s chi-square or one-way ANOVA test. Disease-specific survival (DSS) was calculated using the Kaplan-Meier method and compared using the log-rank test. Results: Overall, 1,504 Hispanic patients (54.5% female) were analyzed. Median age at diagnosis was significantly lower in US (48 y) than MX/AR (55/57 y, p = 0.001). Presentation stage varied by country. Localized presentation was more frequent in US/MX (77%/88%) than AR (60%, p = 0.001). In 1,208 patients (80.4%) with localized disease, 97.9% underwent surgical resection. Rates of adjuvant imatinib treatment varied from 82.4%/77.0% in US/MX to 35.6% in AR (p &lt; 0.001). Median duration of adjuvant therapy was longer in US (29 mos; range: 16-48) than MX (12 mos; range: 4-36, p &lt; 0.001). With a median follow up of 44 mos (range: 24-78) for patients presenting with localized GIST, the estimated median DSS was 136 mos (95% CI 104-167), being significantly longer in US (267 mos, 95% CI 95-439, p = 0.02). Conclusions: While most studies of disparities focus on differences between races/ethnicities in a single country, we found that disparities also exist within similar ethnic groups across nations. Underappreciated sociopolitical determinants of health likely lead to differences in presentation, management, and long-term outcomes of Hispanic GIST patients in the Americas. Prospective cooperative studies are needed to better define barriers to care in order to improve patient outcomes in Hispanic GIST patients. [Table: see text]

Advances in Drug Therapy for Gastrointestinal Stromal Tumour.

Gastrointestinal stromal tumour (GIST) is a common gastrointestinal sarcoma located in the stromal cells of the digestive tract, and molecular studies have revealed the pathogenesis of mutations in KIT and PDGFRA genes. Since imatinib opened the era of targeted therapy for GIST, tyrosine kinase inhibitors (TKIs) that can treat GIST have been developed successively. However, the lack of new drugs with satisfactory therapeutic standards has made addressing resistance a significant challenge for TKIs in the face of the resistance to first-line and second-line drugs. Therefore, we need to find as many drugs and new treatments that block mutated genes as possible. We conducted a comprehensive collection of literature using databases, integrated and analysed the selected literature based on keywords and the comprehensive nature of the articles, and finally wrote articles based on the content of the studies. In this article, we first briefly explained the relationship between GIST and KIT/ PDGFRα and then introduced the related drug treatment. The research progress of TKIs was analyzed according to the resistance of the drugs. This article describes the research progress of some TKIs and briefly introduces the currently approved TKIs and some drugs under investigation that may have better therapeutic effects, hoping to provide clues to the research of new drugs.

Correlation between imatinib trough concentration and efficacy in patients with advanced GIST with different genotypes.

e23515 Background: Imatinib (IM) has significantly enhanced the prognosis of patients (pts) with advanced gastrointestinal stromal tumors (GISTs). The clinical outcomes may correlate with IM exposure. However, the efficacy threshold, particularly based on different primary KIT mutant, remains undefined. This study aimed to establish the efficacy threshold of IM plasma trough concentration (Cmin) at steady-state in Chinese pts with advanced GIST, additionally to define subgroup thresholds based on various primary KIT mutations. Methods: This was a single-center, prospective, observational cohort study. Pts with histologically confirmed recurrent/metastatic GIST who received regular IM treatment and had undergone at least two measurements of steady-state IM Cmin were enrolled from Jul 2017 to Jun 2022. Clinical outcomes including objective response rate (ORR), survival, and IM Cmin were assessed. Results: A total of 168 pts with a median age of 52y were enrolled. The primary lesion locations comprised stomach, small intestine, rectum and others. Metastatic lesions were found in the liver, peritoneum, both liver and peritoneum and others. Median sum of longest diameter of target lesions was 10.7cm. Of 168 pts, 117 (69.6%) harbored KIT 11, 27 (16.1%) harbored KIT 9, 5 (3.0%) harbored PDGFRA, and 9 (5.4%) were KIT/PDGFRA wild type. During IM response period, 104 pts combined with surgical treatment (surgery or interventional therapy). After a median follow-up duration was 50.6m (range, 16.3–189.8), 72 pts had disease progression and 20 died. Estimated median progression-free survival (mPFS) for all patients was 79.4m (95%CI 55.7–103.1). The median overall survival was not reached. A Cmin threshold of ≥738ng/ml defined by log-rank test was associated with longer PFS for the whole population (P = 0.002) irrespective of other clinical characteristics. Pts with an IM Cmin below 738ng/ml exhibited a shorter mPFS (25.3m, 95%CI 41.9–97.1) compared to those surpassing this threshold (96.7m, 95%CI 65.8–127.6). The ORR for the whole population was 73.0% (CR 2.2%, PR 70.8%), with no significant difference observed between pts with IM Cmin below and above 738ng/ml. For pts with KIT 11 and KIT 9 mutations, the efficacy thresholds for IM Cmin were ≥680ng/ml and ≥1877ng/ml, respectively. Multivariate Cox regression analysis revealed that IM Cmin ≥738ng/ml, primary gastric origin, liver-only metastasis, sum of target lesions diameter ≤5cm, KIT 11 mutation, and combined with surgical treatment were favorable prognostic factors. Conclusions: IM exposure significantly correlates with clinical benefits in advanced GISTs, with an IM Cmin above 738ng/ml associated with a longer PFS in Chinese population. Considering different primary KIT mutant, a threshold of 680 ng/ml could be considered for efficacy in KIT 11 mutations, while a higher Cmin of 1877 ng/ml was necessary for KIT 9 mutation.