Prediction of high Ki-67 proliferation index of gastrointestinal stromal tumors based on CT at non-contrast-enhanced and different contrast-enhanced phases.

OBJECTIVES: To evaluate and analyze radiomics models based on non-contrast-enhanced computed tomography (CT) and different phases of contrast-enhanced CT in predicting Ki-67 proliferation index (PI) among patients with pathologically confirmed gastrointestinal stromal tumors (GISTs). METHODS: A total of 383 patients with pathologically proven GIST were divided into a training set (n = 218, vendor 1) and 2 validation sets (n = 96, vendor 2; n = 69, vendors 3-5). Radiomics features extracted from the most recent non-contrast-enhanced and three contrast-enhanced CT scan prior to pathological examination. Random forest models were trained for each phase to predict tumors with high Ki-67 proliferation index (Ki-67>10%) and were evaluated using the area under the receiver operating characteristic curve (AUC) and other metrics on the validation sets. RESULTS: Out of 107 radiomics features extracted from each phase of CT images, four were selected for analysis. The model trained using the non-contrast-enhanced phase achieved an AUC of 0.792 in the training set and 0.822 and 0.711 in the two validation sets, similar to models trained on different contrast-enhanced phases (p > 0.05). Several relevant features, including NGTDM Busyness and tumor size, remained predictive in non-contrast-enhanced and different contrast-enhanced images. CONCLUSION: The results of this study indicate that a radiomics model based on non-contrast-enhanced CT matches that of models based on different phases of contrast-enhanced CT in predicting the Ki-67 PI of GIST. GIST may exhibit similar radiological patterns irrespective of the use of contrast agent, and such radiomics features may help quantify these patterns to predict Ki-67 PI of GISTs. CLINICAL RELEVANCE STATEMENT: GIST may exhibit similar radiomics patterns irrespective of contrast agent; thus, radiomics models based on non-contrast-enhanced CT could be an alternative for risk stratification in GIST patients with contraindication to contrast agent. KEY POINTS: • Performance of radiomics models in predicting Ki-67 proliferation based on different CT phases is evaluated. • Non-contrast-enhanced CT-based radiomics models performed similarly to contrast-enhanced CT in risk stratification in GIST patients. • NGTDM Busyness remains stable to contrast agents in GISTs in radiomics models.

Deep learning analysis for differential diagnosis and risk classification of gastrointestinal tumors.

OBJECTIVES: Recently, artificial intelligence (AI) has been applied to clinical diagnosis. Although AI has already been developed for gastrointestinal (GI) tract endoscopy, few studies have applied AI to endoscopic ultrasound (EUS) images. In this study, we used a computer-assisted diagnosis (CAD) system with deep learning analysis of EUS images (EUS-CAD) and assessed its ability to differentiate GI stromal tumors (GISTs) from other mesenchymal tumors and their risk classification performance. MATERIALS AND METHODS: A total of 101 pathologically confirmed cases of subepithelial lesions (SELs) arising from the muscularis propria layer, including 69 GISTs, 17 leiomyomas and 15 schwannomas, were examined. A total of 3283 EUS images were used for training and five-fold-cross-validation, and 827 images were independently tested for diagnosing GISTs. For the risk classification of 69 GISTs, including very-low-, low-, intermediate- and high-risk GISTs, 2,784 EUS images were used for training and three-fold-cross-validation. RESULTS: For the differential diagnostic performance of GIST among all SELs, the accuracy, sensitivity, specificity and area under the receiver operating characteristic (ROC) curve were 80.4%, 82.9%, 75.3% and 0.865, respectively, whereas those for intermediate- and high-risk GISTs were 71.8%, 70.2%, 72.0% and 0.771, respectively. CONCLUSIONS: The EUS-CAD system showed a good diagnostic yield in differentiating GISTs from other mesenchymal tumors and successfully demonstrated the GIST risk classification feasibility. This system can determine whether treatment is necessary based on EUS imaging alone without the need for additional invasive examinations.

The impact of contour maps on estimating the risk of gastrointestinal stromal tumor recurrence: indications for adjuvant therapy: an analysis of the Kinki GIST registry.

INTRODUCTION: Contour maps enable risk classification of GIST recurrence in individual patients within 10 postoperative years. Although contour maps have been referred to in Japanese guidelines, their usefulness and role in determining indications for adjuvant therapy is still unclear in Japanese patients. The aims of this study are to investigate the validity of contour maps in Japanese patients with GIST and explore the new strategy for adjuvant therapy. MATERIALS AND METHODS: A total of 1426 Japanese GIST patients who were registered to the registry by the Kinki GIST Study Group between 2003 and 2012 were analyzed. Patients who had R0 surgery without perioperative therapy were included in this study. The accuracy of contour maps was validated. RESULTS: Overall, 994 patients have concluded this study. Using contour maps, we validated the patients. The 5-year recurrence-free survival rates of patients within the GIST classification groups of 0-10%, 10-20%, 20-40%, 40-60%, 60-80%, 80-90%, and 90-100% were 98.1%, 96.6%, 92.3%, 48.0%, 37.3%, 41.0% and 42.4%, respectively. We confirmed that this classification by contour maps was well reflected recurrence prediction. Further, in the high-risk group stratified by the modified National Institutes of Health consensus criteria (m-NIHC), the 10-year RFS rate was remarkably changed at a cutoff of 40% (0-40% group vs. 40-100% group: 88.7% vs. 50.3%, p < 0.001). CONCLUSION: Contour maps are effective in predicting individual recurrence rates. And it may be useful for the decision of individual strategy for high-risk patients combined with m-NIHC.

Pimitespib for the treatment of advanced gastrointestinal stromal tumors and other tumors.

Pimitespib (TAS-116) is the first heat shock protein 90 (HSP90) inhibitor approved in Japan, and it is indicated for the treatment of gastrointestinal stromal tumors (GIST) that have progressed after treatment with imatinib, sunitinib and regorafenib. This review describes the preclinical and clinical research with pimitespib, including its mechanism of action, pharmacokinetics, clinical antitumour activity and safety. In a phase III study, pimitespib significantly prolonged progression-free survival compared with placebo (median 2.8 vs 1.4 months; hazard ratio 0.51; 95% CI 0.30-0.87; p = 0.006). Common treatment-related adverse events were diarrhoea, decreased appetite, increase in serum creatinine, malaise, nausea and eye disorders. The efficacy and safety of pimitespib are being investigated in other tumour types and in combination with other anticancer therapies.

What is this article about? This article provides information about pimitespib, a drug that recently became available in Japan for the treatment of advanced gastrointestinal stromal tumors, or 'GISTs'. GISTs are a type of cancer found in the gastrointestinal tract, and those that are considered 'advanced' have stopped responding to other treatments and have spread to other parts of the body. What have studies shown? Pimitespib works in a way unlike other drug treatments for cancer ­ it inhibits a protein called heat shock protein 90, and this stops cancer cells from developing and growing. Pimitespib is taken by mouth. Studies in Japanese patients with advanced GISTs showed an increase in the time taken for the cancer to progress further and in the length of time that patients survived among those treated with pimitespib, compared with patients who did not receive the drug. These studies also found that pimitespib was not associated with serious side effects, although diarrhoea occurred frequently. Eye disorders developed in some patients, but they could be managed by interrupting or stopping treatment with pimitespib. Pimitespib is also being studied for the treatment of other cancers, alone and in combination with other anticancer drugs. What conclusions can be made from these studies? There are very few treatments available for patients with advanced GISTs and, therefore, pimitespib is an important new option for such patients in Japan. If the results of ongoing studies are positive, pimitespib may become a treatment option for a wider range of cancer patients in the future.

Efficacy and Safety of Endoscopic Resection for Gastric Gastrointestinal Stromal Tumors Originating from the Muscularis Propria.

BACKGROUND: The role of endoscopic resection (ER) in gastric gastrointestinal stromal tumors (GISTs) has not been fully elucidated. AIMS: The purpose of this work was to evaluate the clinical effectiveness and safety of ER in patients with GISTs originating from the muscularis propria (MP). METHODS: A total of 233 consecutive patients with gastric GISTs originating from the MP layer, who underwent ER between February 2012 and May 2023, were included in this study. Clinical characteristics, tumor features, and outcomes were recorded and compared between patients who underwent en bloc resection and piecemeal resection. RESULTS: Among the 233 patients, the median size of GISTs was 12 mm (range 5-60 mm). Risk assessment categorized 190 patients as very low risk, 26 as low risk, 10 as moderate risk, and 7 as high risk. The procedures performed included endoscopic submucosal excavation (127 cases), endoscopic full-thickness resection (103 cases), and submucosal tunneling endoscopic resection (3 cases). The complete and R0 resection rate was 93.1%. Complications occurred in 4.7% of cases (perioperative perforations 1.7%, perioperative bleeding 1.3%, both 0.9%), resulting in conversion to surgery in 1.3% of cases. Risk factors associated with piecemeal resection were tumor size [odds ratio (OR) 0.402, 95% confidence interval (CI) 0.207-0.783; P = 0.007] and shape (OR 0.045, 95% CI 0.009-0.235; P < 0.001). CONCLUSIONS: ER is proven to be an effective and reasonably safe approach for gastric GISTs originating from the MP. Notably, larger tumor size and irregular shape are identified as risk factors for piecemeal resection during ER procedures.

Endoscopic resection for the treatment of gastric gastrointestinal stromal tumors: a retrospective study from a large tertiary hospital in China.

BACKGROUND AND AIMS: With the continuous development of endoscopic technology, endoscopic resection (ER) has gradually become an optional method for the treatment of gastric gastrointestinal stromal tumors (GISTs). However, studies with a large sample or a long follow-up are lacking. Therefore, this research aims to evaluate the efficacy and safety of ER for gastric GISTs in the real-world setting with more than 300 enrolled patients and a follow-up period longer than 45 months. METHODS: From January 2013 to February 2023, 409 patients with a pathological diagnosis of GISTs after ER were retrospectively enrolled in this study. After excluding 86 patients with non-gastric GISTs, we assessed 323 patients with gastric GISTs. The main outcome measures were en bloc resection, complete resection, residual disease, recurrence, and complications. RESULTS: There were 194 (60.06%) females and 129 (39.94%) males, and the median age of the included patients was 58 years (51, 63). The median tumor size was 15.0 (10.0, 20.0) mm. According to the modified NIH criteria, 246 (75.85%) patients were classified as very low risk, 62 (19.20%) were classified as low risk, 12 (3.72%) were classified as moderate risk, and 3 (0.93%) were classified as high risk. A total of 287 (88.85%) patients achieved en bloc resection, and 287 (88.85%) also achieved complete resection. Only one patient showed residual and no recurrent lesions were noted during the follow-up. Regarding complications, three patients had complications, with a complication rate of 0.93%, and no severe complications requiring surgical intervention occurred. CONCLUSION: ER is an appropriate alternative method for the treatment of gastric GISTs, with an en bloc resection rate of 88.85% and a complication rate of 0.93%. No recurrence was noted during follow-up, even for GISTs with piecemeal resection.

Single-port intragastric wedge resection using the tunnel method: a novel surgical approach for treating endophytic gastric subepithelial tumors.

BACKGROUND: Intragastric wedge resection is an effective method for treating endophytic gastric subepithelial tumors (SETs). However, retracting the stomach wall to the umbilicus is difficult in certain patients. In response, we developed a novel surgical technique for single-port intragastric wedge resection, which we termed the "tunnel method." METHODS: A transumbilical incision is made, and a wound retractor is applied. After diagnostic laparoscopy, a gastrostomy is made on the greater curvature, lower body. Another small wound retractor is inserted into the gastrostomy, and extracted through the transumbilical incision, creating a tunnel from the gastrostomy site to the umbilicus. Articulating laparoscopic instruments are inserted via the tunnel, and intragastric wedge resection is performed. We collected and analyzed the clinicopathologic and operative data of patients who underwent intragastric wedge resection via the tunnel method. RESULTS: Twenty-seven patients who underwent single-port intragastric wedge resection via the tunnel method in a single tertiary referral hospital were included in this study. The mean age of the patients was 54.6 ± 11.4 years, body mass index was 26.5 ± 3.4 kg/m2. Twenty-four (88.9%) patients had tumors located in the upper third of the stomach. The average operative time was 65.0 ± 24.2 min. None of the patients experienced Clavien-Dindo grade IIIa or higher postoperative complications. The average postoperative hospital stay length was 2.5 ± 0.8 days. Thirteen gastrointestinal stromal tumors, nine leiomyomas, and one neuroendocrine carcinoma, schwannoma, lipoma, spindle cell proliferative lesion, and fibrotic lesion were pathologically diagnosed. The average tumor size was 2.6 ± 1.3 cm. All cases had negative resection margins. CONCLUSIONS: Single-port intragastric wedge resection by the tunnel method is a feasible and safe approach for treating endophytic gastric SETs.

Comparative Analysis of Enbloc or Piecemeal Removal After Enbloc Resection of Gastrointestinal Stromal Tumors.

OBJECTIVE: To investigate the safety and prognosis of enbloc or piecemeal removal after enbloc resection of a gastric GIST by comparing the clinical data of endoscopic en block resection and piecemeal removal (EP) and en block resection and complete removal (EC) of gastric GISTs. METHODS: A total of 111 (43 endoscopic piecemeal, and 68 complete removal) patients with gastric GIST's ≥ 2 cm in diameter who underwent endoscopic therapy from January 2016 to June 2020 at the First Affiliated Hospital of Zhengzhou University were retrospectively analyzed. In all cases, it was ensured that the tumor was intact during the resection, however, it was divided into EP group and EC group based on whether the tumor was completely removed or was cut into pieces which were then removed. The patients' recurrence-free survival rate and recurrence-free survival (RFS) were recorded. RESULTS: There was no statistically significant difference in RFS rates between the two groups (P = 0.197). The EP group had relatively high patient age, tumor diameter, risk classification, and operation time. However, there was no statistically significant difference in the number of nuclear fission images, postoperative hospitalization time, postoperative fasting time, complication rate and complication grading between the two groups (P > 0.05). CONCLUSION: Endoscopic piecemeal removal after en block resection of gastric GIST is safe and effective and achieves similar clinical outcomes as complete removal after en block resection.

A systematic review and meta-analysis of neoadjuvant imatinib use in locally advanced and metastatic gastrointestinal stromal tumors.

BACKGROUND: Several doubts remain regarding the optimal use of neoadjuvant imatinib in gastrointestinal stromal tumors (GISTs), such as ideal treatment duration, patient selection, and long-term survival outcomes. This manuscript provides a comprehensive review on neoadjuvant imatinib treatment outcomes and facilitate evidence-based decision-making for the use of imatinib therapy in GISTs. METHODS: Four databases (PubMed, EMBASE, Scopus, and Cochrane Library) were searched from inception to September 9, 2023. Meta-analyses of proportions were performed for the outcomes of R0 resection, disease responses, and 1-year, 3-year, and 5-year overall survival (OS) as well as 1-year, 3-year, and 5-year disease free survival (DFS). Sensitivity analyses in the form of leave-one-out analyses, meta-regression, and subgroup analyses were performed for outcomes with substantial statistical heterogeneity. RESULTS: The search yielded 1254 articles, and 36 studies were included in our analysis. Meta-analysis of proportions revealed that 1-year, 3-year, and 5-year OS was 100%, 94%, and 88%, while 1-year, 3-year and 5-year DFS was 99%, 89%, and 79%, respectively. An R0 resection rate of 89% and a disease response rate of 67% was achieved after a mean duration of treatment of 8.41 ± 0.367 months. KIT exon 9 mutation was significantly associated with poorer 5-year DFS. CONCLUSION: This study quantified key outcomes for neoadjuvant imatinib in locally advanced and metastatic or recurrent GIST. Patients with gastric and rectal tumous stand to benefit from neoadjuvant imatinib with an optimal treatment duration of 8 months. Furthermore, the potential utility of mutational analysis in guiding treatment with neoadjuvant imatinib was demonstrated.

N6-methyladenosine-modified microRNA-675 advances the development of gastrointestinal stromal tumors via inhibiting myosin phosphatase targeting protein 1.

RNA N6-methyladenosine (m6A) modifications influence gastrointestinal stromal tumors (GISTs) development, but the detailed molecular mechanisms have not been fully studied. Here, microRNA-675 was found to be aberrantly elevated in cancerous tissues and cells of GISTs, compared to the corresponding normal counterparts, and GISTs patients with high-expressed microRNA-675 have worse outcomes. Additional experiments confirmed that silencing of microRNA-675 hindered cell division, mobility and tumorigenesis in vitro and in vivo, whereas triggered apoptotic cell death in GISTs cells. Furthermore, microRNA-675-ablation increased the expression levels of myosin phosphatase targeting protein 1 (MYPT1) to inactivate the tumor-initiating RhoA/NF2/YAP1 signal pathway, and downregulation of MYPT1 recovered the malignant phenotypes in microRNA-675-silenced GISTs cells. In addition, we evidenced that METTL3-mediated m6A modifications were essential for sustaining the stability of microRNA-675, and silencing of METTL3 restrained tumorigenesis of GISTs cells by regulating the microRNA-675/MYPT1 axis. To summarize, theMETTL3/m6A/microRNA-675/MYPT1 axis could be used as novel biomarkers for the diagnosis and treatment of GISTs.

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

BACKGROUND: Small bowel tumors (SBT) are infrequent and represent a small proportion of digestive neoplasms. There is scarce information about SBT in Latin America. AIM: To describe the epidemiology, clinical characteristics, diagnostic methods, and survival of malignant SBTs. METHODS: Retrospective observational study of adult patients with histopathological diagnosis of SBT between 2007 and 2021 in a university hospital in Chile. RESULTS: A 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. CONCLUSIONS: Malignant 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.

Diagnosis, Treatment, and Prognosis of Patients with Primary Familial Gastrointestinal Stromal Tumor: A Case Report and Literature Review.

Gastrointestinal stromal tumors are the most common mesenchymal tumors of the digestive tract, most of which are sporadic, and familial GISTs with germline mutations are rarely seen. Here, we report a 26-year-old female with a germline p. W557R mutation in exon 11 of the KIT gene. The proband and her father and sister presented with multifocal GIST and pigmented nevi. All 3 patients underwent surgery and imatinib therapy. To date, only 49 kindreds with germline KIT mutations and 6 kindreds with germline PDGFRA mutations have been reported. Summarizing the reported kindreds, the majority of familial GISTs manifest as multiple primary GISTs complicated with special clinical manifestations, including cutaneous hyperpigmentation, dysphagia, mastocytosis, inflammatory fibrous polyps, and large hands. Familial GISTs are generally thought to exhibit TKI sensitivity similar to that of sporadic GISTs with the same mutation.

Efficacy and Safety of Avapritinib in Treating Unresectable or Metastatic Gastrointestinal Stromal Tumors: A Phase I/II, Open-Label, Multicenter Study.

BACKGROUND: Avapritinib is a type 1 kinase inhibitor designed to potently and selectively inhibit oncogenic KIT/PDGFRA mutants by targeting the kinase active conformation. This multicenter, single-arm, open-label, phase I/II bridging study of NAVIGATOR in Chinese patients evaluated the safety and the antineoplastic activity of avapritinib in Chinese patients with unresectable/metastatic gastrointestinal stromal tumors (GIST). METHODS: Phase I comprised dose escalation for safety and phase II dose determination. Phase II comprised dose expansion for safety/efficacy evaluations in patients with PDGFRA D842V mutations or patients having received at least 3 lines of therapy without PDGFRA D842V mutations. The primary endpoints were recommended phase II dose, safety, and Independent Radiology Review Committee (IRRC)-assessed objective response rate (ORR). RESULTS: No dose-limiting toxicities occurred (n = 10); the recommended phase II dose was avapritinib 300 mg once daily orally. Fifty-nine patients initially received avapritinib 300 mg. Common grade ≥3 treatment-related adverse events were anemia, decreased white blood cell count, increased blood bilirubin levels, and decreased neutrophil count. In patients with PDGFRA D842V mutations, IRRC- and investigator-assessed ORRs were 75% and 79%, respectively; clinical benefit rates were both 86%. Median duration of response/progression-free survival were not reached. IRCC- and investigator-assessed ORRs in patients in the fourth- or later-line setting were 22% and 35%, respectively. Median progression-free survivals were 5.6 months for both. Overall survival data were immature and not calculated. CONCLUSION: Avapritinib was generally well tolerated and showed marked anti-tumor activity in Chinese patients with GIST bearing PDGFRA D842V mutations and notable efficacy as fourth- or later-line monotherapy (ClinicalTrials.gov Identifier: NCT04254939).

Mesenchymal stromal cells promote the drug resistance of gastrointestinal stromal tumors by activating the PI3K-AKT pathway via TGF-ß2.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the prevailing sarcomas of the gastrointestinal tract. Tyrosine kinase inhibitors (TKIs) therapy, exemplified by Imatinib mesylate (IM), constitutes the established adjuvant therapy for GISTs. Nevertheless, post-treatment resistance poses a challenge that all patients must confront. The presence of tumor heterogeneity and secondary mutation mechanisms fail to account for some instances of acquired drug resistance. Certain investigations suggest a strong association between tumor drug resistance and mesenchymal stromal cells (MSC) in the tumor microenvironment, but the underlying mechanism remains obscure. Scarce research has explored the connection between GIST drug resistance and the tumor microenvironment, as well as the corresponding mechanism. METHODS: Immunofluorescence and fluorescence-activated cell sorting (FACS) methodologies were employed to detect the presence of MSC in GIST samples. The investigation encompassed the examination of MSC migration towards tumor tissue and the impact of MSC on the survival of GIST cells under IM treatment. Through ELISA, western blotting, and flow cytometry analyses, it was confirmed that Transforming Growth Factor Beta 2 (TGF-ß2) triggers the activation of the PI3K-AKT pathway by MSC, thereby facilitating drug resistance in GIST. RESULTS: Our findings revealed a positive correlation between a high proportion of MSC and both GIST resistance and a poor prognosis. In vitro studies demonstrated the ability of MSC to migrate towards GIST. Additionally, MSC were observed to secrete TGF-ß2, consequently activating the PI3K-AKT pathway and augmenting GIST resistance. CONCLUSIONS: Our investigation has revealed that MSC within GISTs possess the capacity to augment drug resistance, thereby highlighting their novel mechanism and offering a promising target for intervention in GIST therapy.

Tumor-associated macrophages mediate gastrointestinal stromal tumor cell metastasis through CXCL2/CXCR2.

BACKGROUND: Tumor-associated macrophages (TAMs) are linked with the progression and poor prognosis of multifarious solid tumors, but the regulatory mechanisms involved in gastrointestinal stromal tumors (GIST) remain indistinct. This study intended to delve into the job of TAM-derived chemokines in promoting metastasis in GIST microenvironment. METHODS: Expression levels of M2-TAM markers and CXCL2 in primary and metastatic tissues of GIST were analyzed by bioinformatics methods, and we analyzed the correlation between CXCL2 and M2-TAM markers. Immunofluorescence was applied to assay CXCL2 and M2-TAM marker protein (CD68 and CD206) expression in tumor tissues. Serum CXCL2 concentration in metastatic and non-metastatic patients was assayed by ELISA. The differentiation of THP-1 cells was tested by flow cytometry. Cell function test was utilized to analyze the viability, invasion and migration of GIST cells. Western blot was used to examine the expression of epithelial-mesenchymal transition (EMT)-related proteins. The mouse liver metastasis model was established, and the effects of CXCL2 and EMT-related genes on metastasis were confirmed by hematoxylin-eosin staining and immunohistochemistry experiments. RESULTS: Bioinformatics analysis ascertained that M2-TAM marker proteins and chemokine CXCL2 were highly expressed in GIST metastatic tissues, and CXCL2 and TAM were co-located in tumor tissues. Results of in vitro cell function experiments displayed that CXCL2 secreted by M2-TAM promoted the invasion, migration and EMT of GIST tumor cells, and the anti-CXCL2 antibody could block the metastasis promoting effect of CXCL2. Additionally, the silencing of CXCR2 in GIST cells inhibited the metastasis promoting effect of CXCL2. Animal studies further confirmed that CXCL2 promoted liver metastasis of GIST in vivo. CONCLUSION: This study preliminarily revealed the mechanism of M2-TAM promoting tumor metastasis by secreting CXCL2 in GIST tumor microenvironment, and proffered theoretical reference for the development of immunotherapy strategies targeting M2-TAM.

Prediction of Ki-67 expression in gastrointestinal stromal tumors using radiomics of plain and multiphase contrast-enhanced CT.

OBJECTIVE: To study the value of radiomics models based on plain and multiphase contrast-enhanced CT to predict Ki-67 expression in gastrointestinal stromal tumors (GISTs). METHODS: A total of 215 patients with GISTs were retrospectively analyzed, including 150 patients in one hospital as the training set and 65 patients in another hospital as the external verification set. The tumor at the largest level of CT images was delineated as the region of interest (ROI). The maximum diameter of the ROI was defined as the tumor size. A total of 851 radiomics features were extracted from each ROI by 3D Slicer Radiomics. After dimensionality reduction, three machine learning classification algorithms including logistic regression (LR), random forest (RF), and support vector machine (SVM) were used for Ki-67 expression prediction. Using a multivariable logistic model, a nomogram was established to predict the expression of Ki-67 individually. RESULTS: Delong tests showed that the SVM models had the highest accuracy in the arterial phase (Z value 0.217-1.139) and venous phase (Z value 0.022-1.396). For the plain phase, LR and SVM models had the highest accuracy (Z value 0.874-1.824, 1.139-1.763). For the delayed phase, LR models had the highest accuracy (Z value 0.056-1.824). For the combined phase, RF models had the highest accuracy (Z value 0.232-1.978). There was no significant difference among the above models for KI-67 expression prediction (Z value 0.022-1.978). A nomogram was developed with a C-index of 0.913 (95% CI, 0.878 to 0.956). CONCLUSIONS: Radiomics of both plain and enhanced CT images could accurately predict the expression of Ki-67 in GIST. For patients who were not suitable to use contrast agents, plain scan could be used as an alternative. CLINICAL RELEVANCE STATEMENT: CT radiomics could accurately predict the expression of Ki-67 in GIST, which has a great clinical value in reflecting the proliferative activity of tumor cells and helping determine whether a patient is suitable for adjuvant therapy with imatinib. KEY POINTS: • Radiomics of both plain and enhanced CT images could accurately predict the expression of Ki-67 in GIST. • For patients who were not suitable to use contrast agents, plain scan could be used as an alternative. • A radiomics nomogram was developed to allow personalized preoperative evaluation with high accuracy.

CT features combined with RECIST 1.1 criteria improve progression assessments of sunitinib-treated gastrointestinal stromal tumors.

OBJECTIVES: To explore the auxiliary value of combining CT features with existing response evaluation criteria in the prediction of progressive disease (PD) in gastrointestinal stromal tumors (GIST) patients treated with sunitinib. MATERIAL AND METHODS: Eighty-one patients with GISTs who received sunitinib were included in this retrospective multicenter study and divided into training and external validation cohorts. Progression at six months was determined as a reference standard. The predictive performance of the RECIST 1.1 and Choi criteria was compared. CT features at baseline and the first follow-up were analyzed. Logistic regression analyses were used to determine the most significant predictors and develop modified criteria. RESULTS: A total of 216 lesions showed a good response and 107 showed a poor response in 81 patients. The RECIST 1.1 criteria performed better than the Choi criteria in predicting progression (AUC, 0.75 vs. 0.69, p = 0.04). The expanded/intensified high-enhancement area, blurred tumor-tissue interface, and progressive enlarged vessels feeding or draining the mass (EVFDM) differed significantly between lesions with good and poor responses in the training cohort (p = 0.001, 0.003, and 0.000, respectively). Multivariate analysis revealed that the expanded/intensified high-enhancement area (p = 0.001), progressive EVFDM (p = 0.000), and RECIST PD (p = 0.000) were independent predictive factors. Modified RECIST (mRECIST) criteria were developed and showed significantly higher AUCs in the training and external validation cohorts than the RECIST 1.1 criteria (training: 0.81 vs. 0.73, p = 0.002; validation: 0.82 vs. 0.77, p = 0.04). CONCLUSION: The mRECIST criteria, combining CT features with the RECIST 1.1 criteria, demonstrated superior performance in the prediction of early progression in GIST patients receiving sunitinib. CLINICAL RELEVANCE STATEMENT: The mRECIST criteria, which combine CT features with the RECIST 1.1 criteria, may facilitate the early detection of progressive disease in GIST patients treated with sunitinib, thereby potentially guiding the timely switch to late-line medications or combination with surgical excision. KEY POINTS: • The RECIST 1.1 criteria outperformed the Choi criteria in identifying progression of GISTs in patients treated with sunitinib. • GISTs displayed different morphologic features on CT depending on how they responded to sunitinib. • Combining CT morphologic features with the RECIST 1.1 criteria allowed for the prompt and accurate identification of progressing GIST lesions.

Risk stratification for 1- to 2-cm gastric gastrointestinal stromal tumors: visual assessment of CT and EUS high-risk features versus CT radiomics analysis.

OBJECTIVES: To investigate the ability of CT and endoscopic sonography (EUS) in predicting the malignant risk of 1-2-cm gastric gastrointestinal stromal tumors (gGISTs) and to clarify whether radiomics could be applied for risk stratification. METHODS: A total of 151 pathologically confirmed 1-2-cm gGISTs from seven institutions were identified by contrast-enhanced CT scans between January 2010 and March 2021. A detailed description of EUS morphological features was available for 73 gGISTs. The association between EUS or CT high-risk features and pathological malignant potential was evaluated. gGISTs were randomly divided into three groups to build the radiomics model, including 74 in the training cohort, 37 in validation cohort, and 40 in testing cohort. The ROIs covering the whole tumor volume were delineated on the CT images of the portal venous phase. The Pearson test and least absolute shrinkage and selection operator (LASSO) algorithm were used for feature selection, and the ROC curves were used to evaluate the model performance. RESULTS: The presence of EUS- and CT-based morphological high-risk features, including calcification, necrosis, intratumoral heterogeneity, irregular border, or surface ulceration, did not differ between very-low and intermediate risk 1-2-cm gGISTs (p > 0.05). The radiomics model consisting of five radiomics features showed favorable performance in discrimination of malignant 1-2-cm gGISTs, with the AUC of the training, validation, and testing cohort as 0.866, 0.812, and 0.766, respectively. CONCLUSIONS: Instead of CT- and EUS-based morphological high-risk features, the CT radiomics model could potentially be applied for preoperative risk stratification of 1-2-cm gGISTs. KEY POINTS: • The presence of EUS- and CT-based morphological high-risk factors, including calcification, necrosis, intratumoral heterogeneity, irregular border, or surface ulceration, did not correlate with the pathological malignant potential of 1-2-cm gGISTs. • The CT radiomics model could potentially be applied for preoperative risk stratification of 1-2-cm gGISTs.

Lymph node metastases in young patients with gastrointestinal stromal tumor: A nationwide analysis.

BACKGROUND: Children, adolescents, and young adults (CAYA) (age ≤39 years) with GIST have high rates of LNM, but their clinical relevance is undefined. This study analyzed the impact of LNM on overall survival (OS) for CAYA with GIST. METHODS: The National Cancer Database was queried for patients with resected GIST and pathologic nodal staging data from 2004-2019. Factors associated with LNM were identified. Survival was assessed stratified by presence of LNM. RESULTS: Of 4420 patients with GIST, 238 were CAYA (5.4%). When compared to older adults, CAYA more often had small intestine primaries (51.8% vs. 36.6%, p < 0.0001), T4 tumors (30.7% vs. 24.5%, p = 0.0275) and pN1 disease (11.3% vs. 4.7%, p < 0.0001). Within a multivariable Cox proportional hazards regression model adjusting for age, comorbid disease, mitotic rate, tumor size, and primary site, LNM were associated with increased hazard of death for older adults (hazard ratio [HR]: 1.83; confidence interval [CI]: 1.35-2.42; p < 0.0001), but not CAYA (HR: 3.38; CI: 0.50-14.08; p = 0.13). For CAYA, only high mitotic rate predicted mortality (HR: 4.68; CI: 1.41-18.37: p = 0.02). CONCLUSIONS: LNM are more commonly identified among CAYA with resected GIST who undergo lymph node evaluations, but do not appear to impact OS as observed in older adults. High mitotic rate remains a predictor of poor outcomes for CAYA with GIST.

Development and validation of an EUS-based nomogram for prediction of the malignant potential in gastrointestinal stromal tumors.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal (GI) tract that require different therapeutic interventions according to the malignancy. We aim to develop and validate a EUS (endoscopic ultrasonography)-based nomogram to predict malignant potential in patients with GIST. METHODS: 258 patients with pathological diagnosis of gastric GISTs were enrolled retrospectively in our hospital from June 2015 to October 2020. Patients were randomly divided into the development cohort (DC, n = 179) and the validation cohort (VC, n = 79). We established a nomogram using lasso regression based on DC data. The predictive effectiveness of the nomogram was evaluated by the area under the receiver operating characteristic curve (AUC). Through bootstrapping, a consistency index (C-index) and calibration chart are developed to evaluate the reliability and accuracy of the nomogram. RESULTS: A total of 192 patients with low-malignant potential (very low and low-risk) GISTs and 66 patients with high-malignant potential (intermediate and high-risk) GISTs were included in this study. The nomogram was constructed with the following 6 EUS indicators: ulceration, hemorrhage, tumor shape, irregular border, transverse diameter, and necrosis. Internal and external validation showed that the nomogram had a good ability to predict the malignant potential of GISTs (AUC = 0.881 and 0.908, respectively). The calibration curve shows that the nomogram has a good agreement between predicted and actual probabilities for differentiating GISTs malignancy (C-index = 0.868 and 0.907, respectively). CONCLUSIONS: This study developed and verified a EUS-based nomogram, which can effectively predict the malignant potential of patients with gastric GISTs.