Gastrointestinal Stromal Tumors Research Articles

Treatment patterns in patients with advanced gastrointestinal stromal tumor in Japan: An administrative claims database study.

811 Background: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Tyrosine kinase inhibitors, including imatinib, sunitinib, and regorafenib, and the HSP90 inhibitor, pimitespib have been approved for advanced GIST in Japan, but few studies have examined the nationwide trend in treatment patterns. This study aimed to evaluate the real-world treatment patterns for advanced GIST in Japan. Methods: This retrospective cohort study used the Japanese hospital-based administrative claims database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan). Patients diagnosed with advanced GIST according to ICD-10 codes who received any approved standard drug in Japan, such as imatinib, sunitinib, regorafenib, or pimitespib (Approved in June 2022) between July 2013 and March 2023 were included. The primary endpoint was the proportion of patients with GIST who were treated with each approved standard drug. Secondary endpoints included treatment patterns, time to treatment failure (TTF), overall survival, adverse events, and the proportion of patients who underwent surgical intervention for GIST while taking standard drugs. Results: This study included 2702 patients with advanced GIST. The median age was 70.0 years, 17% of the patients were ≥80 years, and 59% were male. The most common primary tumor sites were the stomach (37%), small intestine (25%) and large intestine (12%). The proportions of patients with GIST treated with imatinib, sunitinib, regorafenib, and pimitespib were 94% (2536 patients), 26% (702 patients), 14% (376 patients) and 1% (37 patients), respectively. The most common first-line regimen was imatinib (2485/2702 patients; 92%), second-line regimen was sunitinib (560/672 patients; 83%), third-line regimen was regorafenib (200/317 patients; 63%), and fourth-line regimen was imatinib (55/119 patients; 46%). The median TTF was 30.4 months (95% CI 27.4–32.9) with imatinib, 6.4 months (95% CI 5.6–7.7) with sunitinib, 5.2 months (95% CI 4.4–6.2) with regorafenib and 2.5 months (95% CI 1.7–3.1) with pimitespib. The proportions of patients who underwent surgical intervention for GIST was 15% (403/2702 patients), and curative surgery was 10% (273/2702 patients). Conclusions: This is the first real-world study to provide insights into the patient characteristics and current treatment patterns for advanced GIST in Japan. The treatment patterns are consistent with the Japanese Clinical Practice Guidelines.

INSIGHT: A phase 3, randomized, open-label study of ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib with KIT exon 11 + 17/18 mutations.

TPS848 Background: Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal sarcoma, with approximately 80% of cases driven by KIT mutations. Most patients (pts) with advanced GIST experience disease progression following first-line treatment with imatinib due to KIT secondary resistance mutations occurring most commonly in the ATP-binding pocket (exons 13/14) and/or activation loop (exons 17/18). Sunitinib is approved as second-line therapy for advanced GIST. Ripretinib is a switch-control tyrosine kinase inhibitor approved for pts with GIST who received prior treatment with 3 or more kinase inhibitors, including imatinib. In the INTRIGUE phase 3 study (NCT03673501) in second-line therapy for advanced GIST, ripretinib was not superior to sunitinib in terms of progression-free survival (PFS); however, a more favorable safety profile was observed with ripretinib vs sunitinib (Bauer S et al. J Clin Oncol . 2022). Exploratory mutational analysis from INTRIGUE using baseline circulating tumor DNA (ctDNA) demonstrated that pts harboring primary KIT exon 11 mutations with secondary resistance mutations exclusively in KIT exons 17/18 derived PFS benefit with ripretinib vs sunitinib (median, 14.2 vs 1.5 months; HR, 0.22; 95% CI, 0.11 to 0.44; nominal P <0.0001; Heinrich MC et al. Nat Med . 2024). Here, we describe an ongoing phase 3 study for pts with advanced GIST previously treated with imatinib harboring KIT exon 11 + 17/18 mutations. Methods: INSIGHT (NCT05734105) is a phase 3, randomized, open-label study designed to evaluate the efficacy of ripretinib vs sunitinib in pts with advanced GIST previously treated with imatinib and who harbor KIT exon 11 + 17/18 mutations. Eligible pts must be ≥18 years old with histologically confirmed GIST and co-occurring KIT exon 11 + 17/18 mutations confirmed by ctDNA analysis. Pts must also have advanced disease with ≥1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1, radiologic progression on imatinib, and an Eastern Cooperative Oncology Group performance status ≤2. Key exclusion criteria include a KIT exon 9, 13, or 14 mutation confirmed via ctDNA analysis at screening and prior treatment with another line of therapy in addition to imatinib for advanced GIST. A total of 54 pts will be randomized (2:1) to receive ripretinib 150 mg once daily (QD; continuous) or sunitinib 50 mg QD (4 weeks on/2 weeks off) in 6-week cycles. The primary endpoint is PFS by independent radiologic review (IRR) per mRECIST v1.1; key secondary endpoints are objective response rate by IRR using mRECIST v1.1 and overall survival. Safety and patient-reported outcome measures will also be assessed. Pts randomized to the sunitinib arm may cross over to the ripretinib arm upon disease progression. This abstract was originally presented at ASCO 2023. Clinical trial information: NCT05734105 .

Surgical treatment in patients with advanced gastrointestinal stromal tumours (GISTs) in second-line and later stages: A single-centre cohort study.

818 Background: Gastrointestinal stromal tumour (GIST) after imatinib treatment failure usually progresses rapidly with limited overall survival. Previous studies have suggested that surgery is beneficial for advanced GISTs in disease control to imatinib, but the role of surgery in > = 2 line patients remains unclear. Methods: Imatinib-resistant patients with advanced GIST between May 2009 and Nov. 2023 were included. Surgical treatments included tumour reduction, radiofrequency ablation and TACE. The primary endpoint was overall survival (OS) and secondary endpoints were time to second-line treatment failure (TTF) and postoperative morbidity. To balance clinicopathological characteristics, 1:1 propensity score matching (PSM) was used. Results: A total of 242 patients with advanced GIST treated with 2nd-line or later drugs were included, including 125 in the surgical group and 117 in the non-surgical group. The median follow-up was 30.3 months. OS was significantly better in the surgical group than in the non-surgical group (pre-PSM: 51.7m vs 35.9m , p = 0.001; post-PSM: 50.8m vs 38.8m, p = 0.043). Univariate analysis showed that surgical treatment (HR 0.487, 95% CI 0.320-0.740, p = 0.001), age ≤60 years (HR 0.640, 95% CI 0.411-0.997, p = 0.049) and low tumour burden (HR 0.491, 95% CI 0.293-0.822, p = 0.007) were associated with prolonged OS. Multivariate analysis indicated that surgical treatment (HR 0.541, 95% CI 0.348-0.843, p = 0.007) and low tumour burden (HR 0.510, 95% CI 0.300-0.865, p = 0.012) were significantly associated with OS benefit. Patients (n = 84) who had surgical treatment during second-line treatment had longer TTF compared to patients (n = 158) who had TKI only (14.2m vs 8.1m , p = 0.003). There were 29 (14.8%) postoperative complications with Clavien-Dindo classification ≥3, including 5 deaths. Conclusions: Surgical treatment can provide a survival benefit for patients with second-line and later advanced GIST, but further studies are needed for a more detailed indication of the surgical population.

Clinical characteristics and esophageal motility in patients with gastric cardia submucosal tumors and associated changes after endoscopic resection.

This study aimed to investigate the clinical characteristics and esophageal motility of patients with gastric cardia submucosal tumors (SMTs) and the associated changes after endoscopic resection based on high-resolution impedance manometry (HRIM). From our electronic database, we identified patients who underwent pre-operative evaluation of gastric cardia SMTs between 2015 and 2023. All patients completed standardized symptom questionnaires and underwent endoscopic ultrasonography and HRIM. Endoscopic resection via submucosal dissection or submucosal tunnel endoscopic resection was performed, followed by esophagogastroduodenoscopy and HRIM three months later. Esophageal motility on HRIM was compared based on the updated Chicago Classification v4.0. Thirty patients (mean age, 47.4 ± 12.8years; male, 50%) were analyzed. Most patients were asymptomatic (43.3%), while others presented with epigastralgia, regurgitation, chest pain, or dysphagia. On endoscopic ultrasonography, the average tumor size was 16.7 ± 4.5mm (range, 10.0-30.0mm), and most tumors originated from the fourth layer (80%). On HRIM, eight patients (26.7%) had abnormal esophageal motility, including five with ineffective esophageal motility (IEM) and three with esophagogastric junction outflow obstruction. Complete resection was achieved in 25 of the 27 patients (92.6%) who underwent endoscopic treatment. Pathology revealed leiomyomas (96%) and gastrointestinal stromal tumors (4%). No significant differences in symptom profiles or HRIM parameters were observed after tumor resection. Three patients with pre-operative IEM exhibited normal motility at the follow-up HRIM. Up to 26.7% of patients with gastric cardia SMTs had abnormal esophageal motility on HRIM. Endoscopic resection of these SMTs was effective and safe and appeared to improve esophageal motility in patients with IEM.

18F-Fluorodeoxyglucose Uptake in PDGFRA-Mutant Gastrointestinal Stromal Tumors

The D842V platelet-derived growth factor receptor α (PDGFRA) mutation identifies a molecular subgroup of gastrointestinal stromal tumors (GISTs), primarily resistant to standard tyrosine kinase inhibitors and with an overall more indolent behavior. Although functional imaging with 18F-fluorodeoxyglucose-labeled positron emission tomography ([18F]FDG-PET) plays a proven role in GISTs, especially in early assessment of tumor response, less is known about [18F]FDG uptake according to the GIST molecular subtypes. To evaluate the degree of [18F]FDG uptake in PDGFRA-mutant GISTs and better define the role of functional imaging in this rare and peculiar subset of GISTs. This multi-institutional retrospective cohort study involving 7 GIST reference centers in Italy included patients with PDGFRA-mutant GIST who underwent [18F]FDG-PET from January 1, 2000, to December 31, 2023. Data on the maximum standardized uptake value (SUVmax) of primary tumor or metastatic disease were collected. PDGFRA-mutant GIST and [18F]FDG-PET. The primary outcome was the degree of [18F]FDG uptake of PDGFRA-mutant GISTs, with a focus on the D842V-mutant subgroup. Secondary objectives were to assess the association between the degree of [18F]FDG uptake and main clinicopathologic features. A total of 71 patients with PDGFRA-mutant GISTs were included in the analysis: 37 (52.1%) in the D842V subgroup (group A) and 34 (47.9%) in the non-D842V subgroup (group B). Additionally, 70 patients with KIT exon 11-mutant GIST served as a control group (group C). For all 141 participants, the median age at diagnosis was 59 (range, 26-89) years, and 81 patients (57.4%) were male. Overall, the median SUVmax was 4.4 (IQR, 0-10.1), while the median SUVmax for group A was 0 (IQR, 0-3.2); for group B, 3.6 (IQR, 0-5.1); and for group C, 10.1 (IQR, 5.1-13.9). The median SUVmax of PDGFRA-mutant GISTs was significantly lower than the median value of KIT exon 11-mutant GISTs (0 [IQR, 0-4.3] vs 10.1 [IQR, 5.1-14.0]; P < .001). Median [18F]FDG uptake was significantly lower in the D842V subgroup compared with the non-D842V subgroup (0 [IQR, 0-3.2] vs 3.6 [IQR, 0-5.1]; P = .02). Moreover, the triad of gastric primary tumor, tumor size greater than 10 cm, and SUVmax of 5.75 or less was associated with identification of PDGFRA-mutant GISTs. In this cohort study of patients with PDGFRA-mutant GISTs, the D842V-mutant GISTs were associated with an overall lower [18F]FDG uptake compared with other GIST subgroups. Therefore, the role of functional imaging with [18F]FDG-PET in this subset of GISTs may be limited and should be further explored for its potential prognostic and predictive value.

Patient-derived xenograft models of gastrointestinal stromal tumors: a ready-to-use platform for translational research.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal malignancy of the gastrointestinal tract. Most GIST harbor mutations in oncogenes, such as KIT, and are treated with tyrosine kinase inhibitors (TKI), such as imatinib. Most tumors develop secondary mutations inducing drug resistance against the available TKI, which requires novel therapies. We established a GIST patient-derived xenograft (PDX) platform of GIST that can be used for preclinical drug testing. Tumor tissue from consenting GIST patients was transplanted subcutaneously to NMRI nu/nu mice. Once tumor growth was observed, the tumor was re-transplanted to a next generation of mice. Tumors were characterized histopathologically and molecularly at every re-transplantation and compared with the original patient tumor. We transplanted 112 tumor samples from 99 GIST patients, resulting in 12 established and well-characterized GIST models with different mutations and TKI sensitivity. Three models harbor secondary KIT mutations. One model is characterized by a primary, imatinib-resistant PDGFRA exon 18 p.D842V mutation. Our established platform of well-characterized GIST PDX models, covering the most relevant driver mutations, serves as an excellent tool for preclinical drug testing and tumor biology studies.

Diagnostic Value of Gastrin-Releasing Peptide Receptor-Targeted PET Imaging in Oncology: A Systematic Review.

Gastrin-releasing peptide receptor (GRPR), overexpressed in various cancers, is a promising target for positron emission tomography (PET). This systematic review investigated the diagnostic value of GRPR-targeted PET imaging in oncology. A systematic search was conducted on major medical databases until May 23, 2024. Keywords were modified to include clinical original studies on GRPR-targeted PET in cancer patients. Out of 1624 searched studies initially, 107 were eligible for the full-text review. Overall, data from 38 studies met inclusion criteria, investigating GRPR-targeting radiotracers in breast cancer, prostate cancer, gastrointestinal stromal tumours (GIST) and gliomas (including optic pathway glioma and glioblastoma multiforme). In breast cancer, GRPR-targeted PET effectively detected primary tumours and metastases, particularly in estrogen receptor (ER)-positive patients, and predicted treatment response. In prostate cancer, high sensitivity (up to 88%) and specificity (up to 90%) for detecting primary tumours were observed, providing added value when combined with magnetic resonance imaging (MRI). In biochemical recurrence, sites of prostate cancer were identified even at PSA levels below 0.5ng/dL. Compared with PSMA PET, GRPR-targeted PET showed comparable or superior detection rates. Considering GIST, GRPR-targeted PET imaging proved to be a valuable diagnostic tool, particularly when [18F] FDG PET results were inconclusive. Regarding gliomas, GRPR-targeted PET achieved a 100% detection rate (MRI reference), aiding localization, preoperative planning, and differentiation between recurrence and malignant transformation. GRPR-targeted PET shows promise in improving cancer diagnostics, particularly in ER-positive breast cancer, prostate cancer, and gliomas, and may enhance clinical decision-making.

Design, Synthesis, and SAR of Covalent KIT and PDGFRA Inhibitors─Exploring Their Potential in Targeting GIST.

Gastrointestinal stromal tumors (GIST), driven by KIT and PDGFRA mutations, are the most common mesenchymal tumors of the gastrointestinal tract. Although tyrosine kinase inhibitors (TKIs) have advanced treatment, resistance mutations and off-target toxicity limit their efficacy. This study develops covalent TKIs targeting drug-resistant GIST through structure-based design, synthesis, and biological evaluation. SAR studies provided key insights into mutant KIT and PDGFRA interactions, and the first crystal structure of PDGFRA bound to a covalent inhibitor is reported. These findings highlight the promise of covalent inhibitors for overcoming resistance and advancing safer, more effective therapies for advanced GIST.

Free-Hand Endoscopic Full-Thickness Resection for Duodenal Subepithelial Lesions.

This work aims to evaluate the efficacy and safety of free-hand endoscopic full-thickness resection (EFTR) for duodenal subepithelial lesions (SELs). We performed a retrospective review of 105 patients with duodenal SELs who underwent free-hand EFTR. Free-hand EFTR means no other devices (over-the-scope clip or full-thickness resection device) are required. The preoperative baseline data, procedure-related characteristics, and postoperative outcomes were analyzed. The technical success rate was 99.0%, and the en bloc resection rate was 94.2%. A total of nine (8.7%) patients experienced major postoperative adverse events (AEs). The incidence of major AEs was significantly higher for lesions with a maximum diameter ≥ 2 cm (30.4%) than for lesions with a maximum diameter < 2 cm (2.6%) (p < 0.001). There were also significant differences in the incidence of major AEs for peri-ampullary lesions (37.5%), bulb lesions (4.8%), bulb-descending junction lesions (6.7%), and descending part lesions (12.5%) (p = 0.032). Multivariable regression analyses revealed that the maximum diameter ≥ 2 cm (OR = 18.108; 95% CI = 1.881-174.281; p = 0.012) and lesions located in peri-ampullary (OR = 18.950; 95% CI = 1.219-294.648; p = 0.036) were independent risk factors for major AEs. The mean duration of the follow-up period was 36.6 ± 21.3 months, and only one patient with gastrointestinal stromal tumors recurred. Free-hand EFTR is a safe and effective technique for nonampullary duodenal SELs with a maximum diameter of < 2 cm. Given the complexity of the duodenal anatomy, this procedure should be performed by experienced endoscopists.

Huaier inhibits the proliferation and migration of gastrointestinal stromal tumors by regulating the JAK2 / STAT3 signaling pathway.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the digestive tract, often accompanied by a high risk of recurrence and drug resistance. Huaier (Trametes robiniophila Murr), a traditional Chinese medicinal fungus, has demonstrated potent anticancer properties and is widely used as an adjuvant treatment for liver, breast, gastric, colon, and non-small cell lung cancers. However, its effects and molecular mechanisms in GIST remain unclear. This study aims to explore the inhibitory effects and underlying mechanisms of Huaier on GIST through network pharmacology and experimental validation. Initially, we utilized a publicly accessible database to identify the core targets and principal pathways associated with Huaier's therapeutic effects on gastrointestinal stromal tumors. To further evaluate its biological impact, cell viability, proliferation, migration, and invasion were assessed through CCK-8 and EdU assays, wound healing tests, and Transwell experiments. Apoptotic cell death was quantified using flow cytometry analysis. Additionally, the influence of Huaier extract on the expression levels of JAK2 and STAT3 proteins was examined via Western blotting. Finally, a subcutaneous xenograft mouse model was employed to investigate the anti-tumor efficacy of Huaier in vivo. In this study, GAPDH, TNF, STAT3, ESR1, EGFR, IL6, CCND1, PTGS2, BCL2L1, and MAPK3 were identified as shared molecular targets, with the JAK/STAT signaling pathway recognized as the pivotal regulatory mechanism. Experimental findings demonstrated that Huaier exerted inhibitory effects on the proliferation, migration, and invasion of GIST-T1 and GIST-882 cells, exhibiting both dose- and time-dependent responses. Furthermore, Huaier was found to promote apoptosis in these cells. Western blot analysis revealed that treatment with Huaier extract significantly decreased the phosphorylation levels of JAK2 and STAT3, thereby suppressing the activation of the JAK2 / STAT3 signaling cascade. In vivo experiments further substantiated these findings, showing that Huaier treatment markedly reduced tumor size and inhibited tumor progression. Our results suggest that Huaier may inhibit the growth of GIST cells by inhibiting the JAK2/STAT3 signaling pathway, reduce cell proliferation, induce apoptosis, reduce cell migration and invasion, and show anti-tumor effects in vivo and in vitro.

A green bioanalytical spectrofluorimetric approach for estimation of Avapritinib anti-tumor drug; application to quality control and clinical studies.

Gastrointestinal stromal tumors (GISTs) account for about 80% of the mesenchymal tumors of the GI tract. About 5000-6000 patients are diagnosed in the United States (US) alone, and up to 14.5 cases per million discovered in Europe annually. Avapritinib (AVP) is a potent selective targeted medication that has been recently approved, by the US Food and Drug Administration, in 2020 for treatment of GISTs. AVP is currently considered the first-line treatment for mutant GIST, which is resistant to other medications. This in turn stimulates the need for fast, green, and efficient methods for routine AVP estimation in quality control and clinical studies. The proposed approach designs a spectrofluorimetric tool to estimate AVP in different matrices, based on a nucleophilic substitution reaction. A highly fluorescent product was measured at 535 nm following excitation at 470 nm. The research procedure was bioanalytically validated within AVP range between 80 and 900 ng mL-1, where the limit of quantitation (LOQ) was 15.78 ng mL-1. The developed approach was successfully applied to investigate AVP in content uniformity testing of tablet dosage forms, and biological plasma in AVP pharmacokinetic study. The proposed approach could be recommended for AVP therapeutic drug monitoring.

Ligation-assisted endoscopic full-thickness resection combined with presuture for resection of a colonic gastrointestinal stromal tumor.

Ligation-assisted endoscopic full-thickness resection combined with presuture for resection of a colonic gastrointestinal stromal tumor.

Primary solitary fibrous tumor of the stomach: A case report and a review of literature.

Solitary fibrous tumors (SFTs) are spindle cell tumors that typically occur in the pleura and peritoneum, but very rarely in the stomach. To our best knowledge, there are only 10 cases reported in English literature. We reported a case of primary stomach SFT and summarized the characteristics of all previous cases, suggesting that pathologists and surgeons should include this disease in the differential diagnosis list of primary mesenchymal tumor of the stomach. The patient suffered from epigastric pain for 5 months. Gastroscopy revealed a submucosa mass along the greater curvature centered on the gastric body. A repeat gastroscopy after 6 months showed a slight increase in mass size. Endoscopic ultrasound showed the mass in the middle and lower portion of the stomach body, measuring 3.1cm in diameter, with a smooth surface. The patient was initially diagnosed with a gastrointestinal stromal tumor by gastroscopy. However, the pathologic morphology and immunohistochemical staining of resected specimens after surgery support a diagnosis of primary gastric SFT. The patient underwent a laparoscopic gastric mass resection. The patient returned to hospital after 3 months with no recurrence or postoperative complications. During the 18-month follow-up period, the patient did not experience any tumor recurrence or metastasis. This case teaches us that SFT should be included in the differential diagnoses of gastric primary spindle cell tumors, even though it is very rare in the stomach.

Traction-assisted endoscopic ultrasound-guided fine-needle biopsy using the clip-with-thread method for small gastric subepithelial lesions: Randomized controlled trial (with video).

Endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/B) is the gold standard for diagnosing gastric subepithelial lesions (SELs), but diagnosing lesions smaller than 20 mm remains challenging. We developed traction-assisted EUS-FNB (TA-EUS-FNB) using the clip-with-thread method to enhance diagnostic accuracy by stabilizing the lesion and providing counter-traction for easier needle access. This study evaluates the effectiveness of TA-EUS-FNB in diagnosing small gastric SELs. In this prospective, randomized, controlled cross-over trial (August 2019-November 2022), 30 patients with gastric SELs <20 mm were randomized to undergo TA-EUS-FNB or conventional EUS-FNB. Each patient underwent four punctures, two per method. The primary end-point was the adequate tissue sampling rate for both techniques. Secondary end-points included diagnostic yield and performance (sensitivity and specificity) in distinguishing gastrointestinal stromal tumors (GISTs) from non-GISTs. The mean tumor size was 15.0 mm, with diagnoses comprising GISTs (n = 15, 50%), leiomyomas (n = 8, 26.7%), schwannomas (n = 2, 6.7%), aberrant pancreas (n = 3, 10%), and inflammation (n = 2, 6.7%). TA-EUS-FNB demonstrated a significantly higher adequate-tissue sampling rate (90% vs. 66.7%, P = 0.035) anddiagnostic yield (86.7% vs. 63.3%, P = 0.037) than conventional EUS-FNB. Sensitivity (86.7%, 95% confidence interval [CI] 62.1-96.3% vs. 66.7%, 95% CI 41.7-84.8%; P = 0.20) and specificity (100%, 95% CI 79.6-100% vs. 100%, 95% CI 79.6-100%) were comparable between the methods. No adverse events were observed in the study. TA-EUS-FNB demonstrated superior tissue sampling rates and diagnostic yield for SELs <20 mm compared to conventional EUS-FNB, making it a viable option. Controlling lesion mobility is essential for successful EUS-FNB in small SELs.

Safety and efficacy of endoscopic resection for gastric gastrointestinal stromal tumors: a retrospective cohort study

Background The aim of this study was to verify the safety and efficacy of endoscopic resection (ER) for gastric gastrointestinal stromal tumors (GISTs). Methods Among a consecutive series of resections for gastric GISTs performed in a single center, the outcomes of patients who had ER were compared to standard surgical resection (SR). Results In the cohort, 329 consecutive primary localized gastric GISTs patients (n, ER/SR = 251/78) were enrolled. Patients receiving ER were revealed to have preferable post-treatment outcomes, prolonged overall survival (OS) and disease-free survival (DFS). Tumor diameter, the only independent risk factor for a complicated post-operative course, was utilized for propensity score matching (PSM). In the PSM cohort, patients receiving ER and SR with similar tumor size (4.0 [2.7–4.5] cm) shared similar aggressiveness in terms of stomach layers of tumor origination and invasion, and modified National Institutes of Health (mNIH) risk criteria. Shorter operative time, fewer economic costs, and shorter post-operative stay were still observed in the ER group (ER vs. SR: 80 [49–120] vs. 120 [98–160] minutes, p < 0.001; 44 [38–51] vs. 60 [49–84] thousand Renminbi [kRMB], p < 0.001; 7.0 [6.0–8.0] vs. 8.5 [6.0–12] days, p = 0.018, respectively). No significant difference in OS and DFS was demonstrated in the PSM cohort. Conclusions ER is safe and effective, thus a feasible treatment option for indicated gastric GISTs patients with the advantage of faster recovery and lower economic costs.

Rare subdural hematoma in a patient treated with avapritinib for gastrointestinal stromal tumor: A case report

Rare subdural hematoma in a patient treated with avapritinib for gastrointestinal stromal tumor: A case report

Liquid chromatography-tandem mass spectrometry for the quantification of ripretinib and its metabolites DP-5439 in human plasma.

Ripretinib, a broad-spectrum tyrosine kinase inhibitor, has been approved for the treatment of advanced gastrointestinal stromal tumors in adult patients. Clinical studies have shown that higher in vivo exposure of ripretinib correlates with improved efficacy, highlighting the potential clinical significance of therapeutic drug monitoring. In this study, a simple and stable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was attempted to be established and validated for pharmacokinetic studies of ripretinib and its metabolite DP-5439 and therapeutic drug monitoring in human plasma. Ripretinib and DP-5439 were separated by chromatography using a Thermofisher Hypersil GOLDTM C18 HPLC column. The mobile phase for gradient elution is composed of 0.1% formic acid in water and acetonitrile. Multiple reaction monitoring was implemented along with electrospray ionization positive mode for detection. The ion pairs of ripretinib, DP-5439 and internal standard D8-ripretinib were m/z 510.1→m/z 417, m/z 496.11→m/z 402.9 and m/z 518.15→m/z 420, respectively. Plasma samples from ripretinib-treated patients of our hospital were collected for pharmacokinetic analysis. Ripretinib and DP-5439 demonstrated a strong linear relationship over 10-5,000μg/L (R 2 > 0.99). Accuracy, precision, specificity, recoveries, matrix effect, stability, and dilution effect were all validated and found to meet the required criteria. Following validation, the method was utilized to determine plasma samples from patients treated with ripretinib. The median steady-state trough concentrations (Cmin, range) were 398.50 (66.98 ∼ 1,458.91) μg/L for ripretinib and 654.74 (30.71 ∼ 1,522.48) μg/L for DP-5439, with a total median concentration of 1,129.46 (140.95 ∼ 2,981.39) μg/L in patients receiving ripretinib at 150mg once daily. Meanwhile, using the established methods, the study conducted pharmacokinetics studies on four patients with ripretinib and DP-5439. This study developed and validated a robust LC-MS/MS method for determining ripretinib and its metabolite DP-5439 in human plasma. Furthermore, the practicality of this method in clinical sample analysis was demonstrated. This approach can serve as an effective tool for the pharmacokinetics analysis and therapeutic drug monitoring in patients treated with ripretinib.

Targeted Next-Generation Sequencing in Succinate Dehydrogenase-Deficient GI Stromal Tumor Identifies Actionable Alterations in the PI3K/mTOR Pathway.

Less than 5% of GI stromal tumors (GISTs) are driven by the loss of the succinate dehydrogenase (SDH) complex, resulting in a pervasive DNA hypermethylation pattern that leads to unique clinical features. Advanced SDH-deficient GISTs are usually treated with the same therapies targeting KIT and PDGFRA receptors as those used in metastatic GIST. However, these treatments display less activity in the absence of alternative therapeutic options. Therefore, it is critical to identify novel actionable alterations in SDH-deficient GIST. We performed a single-center, retrospective analysis of patients with SDH-deficient GIST together with next-generation sequencing (NGS) analysis from their respective tumor samples to identify mutations and copy number alterations and chromosomal alterations. NGS-tailored treatment was implemented whenever possible. Seventeen tumor samples from 14 patients with SDH-deficient GIST underwent NGS. Mutational load was low, although three patients (21%) displayed molecular events in relapse samples leading to PI3K/mTOR pathway hyperactivation. mTOR inhibition with everolimus obtained a sustained tumor response in a heavily pretreated patient. Other alterations, largely present in late-stage patients, uncovered genes involved in cell cycle regulation, telomere maintenance, and DNA damage repair. Chromosomal arm-level alterations differed from the canonical cytogenetic progression in KIT/PDGFRA-mutant GIST. This molecular landscape of SDH-deficient GIST uncovers novel molecular alterations, mostly in relapse and/or previously pretreated patients. The identification of genetic events leading to PI3K/mTOR dysregulation together with the remarkable activity of everolimus in one patient showcases the clinical relevance of this pathway, validates the utility of NGS in this population, and poses everolimus as a novel therapeutic alternative. Several other alterations were found at the genetic and genomic levels, underscoring novel biological processes likely involved during tumor evolution.

Identification and validation of serum MUC17 as a non-invasive early warning biomarker for screening of gastric intraepithelial neoplasia.

The early diagnosis and treatment of Gastric Intraepithelial Neoplasia (GIN) are pivotal for improving the survival rates of patients with gastric cancer (GC). Regrettably, reliable noninvasive biomarkers for GIN screening are currently lacking. mRNA data from the GEO database, pan-cancer data from the TCGA database, and a gene list of exocrine proteins were subjected to integrated analysis to identify a noninvasive biomarker for GIN. The scRNA-seq data analysis, IHC and Elisa were employed to validate the expression of the biomarker in the serum and tissues of clinical patients across different pathological stages. MUC17 has been identified as a non-invasive diagnostic marker for GIN. It is upregulated in GIN prior to the onset of gastric carcinogenesis and downregulated in other tumors, with high GC specificity. The area under the curve values of serum MUC17 for differentiating chronic gastritis (CG) from low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and early gastric cancer (EGC) were 0.8788, 0.8544, and 0.9513, respectively. Additionally, low plasma MUC17 levels were found to be significantly lower in gastric ulcer (GU), gastric neuroendocrine tumor (GNET), and gastrointestinal stromal tumor (GIST) compared to GIN. The AUC for differentiating between GIN and GU, GNET, or GIST was 0.7803, 0.9244 and 0.9796, respectively. These findings suggest that plasma MUC17 levels hold substantial promise as a screening biomarker for individuals with GIN and EGC, effectively identifying high-risk groups that necessitate further gastroscopy.

LINC00870 promotes imatinib resistance in gastrointestinal stromal tumor via inhibiting PIGR glycosylation modifications

LINC00870 promotes imatinib resistance in gastrointestinal stromal tumor via inhibiting PIGR glycosylation modifications