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

Objectives: The modified National Institutes of Health (NIH) risk criteria for gastrointestinal stromal tumours (GISTs) have some limitations and need to be improved., Methods: Patients who underwent radical resection of primary GIST were retrospectively reviewed. Peripheral blood indices including the neutrophil-to-lymphocyte ratio (NLR) and prognostic nutritional index (PNI) were analysed. Recurrence-free survival (RFS) was calculated and compared. Multivariate analysis was conducted. Area under the receiver operating characteristic curve (ROC) was calculated., Results: A total of 492 patients were enrolled. Tumour size, mitotic index (MI), tumour location and PNI were independent prognostic factors. The modified NIH criteria could not distinguish among very low-, low- and intermediate-risk patients, and PNI was the only independent prognostic factors for them. The five-year RFS rate in the high risk (HR) group was significantly lower. A further modification to the NIH risk criteria was proposed (the 'NIH-PNI stratification'). Non-high risk (NHR) patients were divided into the NHR-PNI-H group (PNI > 48.05) and the NHR-PNI-L group (PNI ≤ 48.05), respectively. HR patients were divided according to tumour size and MI: the HR1, HR2 and HR3 groups. The five-year RFS rates of the NHR-PNI-H, NHR-PNI-L, HR1, HR2 and HR3 groups were 97.3%, 93.5%, 74.1%, 61.7% and 24.4%, respectively ( p  < .001). The area under the curve (AUC) for the NIH-PNI stratification, modified NIH criteria, NIH criteria (2002), AFIP criteria and nomogram were 0.857, 0.807, 0.817, 0.843 and 0.831, respectively., Conclusion: The proposed NIH-PNI stratification was able to distinguish among five groups in terms of risk of recurrence.

Most gastrointestinal stromal tumors (GIST) harbor mutated receptor tyrosine kinase (RTK) KIT/PDGFRA, which provides an attractive therapeutic target. However, a majority of GISTs ultimately develop resistance to KIT/PDGFRA inhibitor imatinib, multiple therapeutic targets will be identified as a reasonable strategy in imatinib-resistant GISTs. Biological mechanisms of non-RTK activated CDC42 associated kinase 1 (ACK1) are still unclear, which has been found to be activated in GISTs. In the current report, ACK1 overexpression is demonstrated in GIST cell lines and biopsies. RNA-seq analysis and immunoblotting show that ACK1 expression is dependent on imatinib treatment time in GIST-T1 cell line. The colocalization/complex of KIT and ACK1 in GIST cells are observed, and ACK1 activation is in a partially KIT and CDC42 dependent manner. Treatment with a specific ACK1 inhibitor AIM-100 or ACK1 siRNA, mildly suppresses cell viability, but markedly inhibits cell migration in imatinib sensitive and in imatinib resistant GIST cell lines, which is associated with inactivation of PI3K/AKT/mTOR and RAF/MAPK signaling pathways, and inhibition of epithelial-mesenchymal transition, evidencing upregulation of E-cadherin and downregulation of ZEB1, N-cadherin, vimentin, snail, and/or β-catenin after treatment with AIM-100 or ACK1/CDC42 shRNAs. Combination inhibition of ACK1 and KIT results in additive effects of anti-proliferation and pro-apoptosis as well as cell cycle arrest, and inhibition of invasiveness and migration in vitro and in vivo, compared to either intervention alone through dephosphorylation of KIT downstream intermediates (AKT, S6, and MAPK). Our data suggest that co-targeting of ACK1 and KIT might be a novel therapeutic strategy in imatinib-resistant GIST., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest associated with the contents of this article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The controlling nutritional status (CONUT) score is associated with the postoperative outcomes in various types of tumors, and its prognostic role in gastrointestinal stromal tumors (GISTs) needs to be clarified., Methods: Patients with completely resected primary GISTs in the absence of imatinib adjuvant therapy were included. Recurrence-free survival (RFS) was estimated with the Kaplan-Meier method and compared using log-rank test. Prognostic factors were compared using Cox proportional hazards model., Results: A total of 455 patients were included. The median follow-up time was 132.0 months (range: 7.0-253.0). Recurrence/metastasis developed in 92 (20.2%) patients. Patients were assigned to three groups: 219 (48.1%) were in normal nutrition group (CONUT = 0-1), 196 (43.1%) were in mild malnutrition group (CONUT = 2-4) and 40 (8.8%) were in moderate-severe malnutrition group (CONUT ≥ 5). Nongastric primary tumor site, large tumor size, high mitotic index, tumor rupture and high CONUT score were independent prognostic factors for shorter RFS using multivariate analysis (p < 0.05)., Conclusions: Elevated preoperative CONUT score was a predictor of recurrence for patients with resected GIST. The clinical application of the CONUT score is simple and feasible, and might contribute to the individualized treatment of GIST patients., (© 2022 Wiley Periodicals LLC.)

Aim: The majority of available data on the clinical efficacy of sunitinib in patients with imatinib-resistant or -intolerant gastrointestinal stromal tumours (GISTs) are from studies of western populations. We investigated the clinical outcomes of imatinib dose escalation versus sunitinib in first-line imatinib-failure Asian GIST patients to further guide clinical treatment., Methods: Patients received imatinib dose escalation and a shift to sunitinib (Group A) or a direct shift to sunitinib (Group B). The objective tumour response was assessed according to Choi's criteria. Progression-free survival (PFS) and overall survival (OS) were calculated. The relationship between genetic mutation and survival was analysed., Results: In total, 40 patients who fulfilled the inclusion criteria were recruited. The differences in survival between Group A and Group B were not significant for PFS (p = .776) or OS (p = .219). For patients with KIT exon 11 mutation, a trend towards a better PFS was found in Group B (p = .122), OS of Group B was better than Group A (p = .013). The median PFS and OS of sunitinib treatment were 8 and 24 months, respectively, and a clinical benefit was observed in 80%. Patients with KIT exon 11 mutations had better PFS compared to those with KIT exon 9 mutations or wild-type GISTs (p = .017, p = .040, respectively)., Conclusions: Both imatinib dose escalation and sunitinib were optional in Asian patients after failure of first-line imatinib, and patients with KIT exon 11 mutation benefited more from a direct shift to sunitinib.

Complete resection is the most effective therapy for gastrointestinal stromal tumors (GISTs). Complete resection of locally advanced primary GIST by less invasive procedure is usually difficult at initial diagnosis. Imatinib has been successful in treating locally advanced and metastatic GIST and this report shares the experiences in preoperative use of imatinib for patients with locally advanced primary GISTs. The procedure of treatment and completeness of resection were retrospectively accessed for locally advanced primary GIST. Disease-free survival (DFS) and overall survival (OS) after resection were analyzed. Thirteen patients were treated with imatinib preoperatively. All patients received surgical resection after a median imatinib treatment of 7 months when most tumors shrunk. All patients achieved R0 resection without tumor rupture. Two patients received an en-bloc multivisceral resection for the invasion of surrounding organs and 3 patients underwent Mile's operation for a low rectal tumor. Eleven patients were disease-free. Median DFS or OS had not been reached, while 1- and 3-year DFS were estimated to be 92.3 and 76.9 %, respectively. 1- and 3-year OS were both estimated to be 100 %. Preoperative use of imatinib is useful in locally advanced primary GIST by downsizing the tumor in most patients and facilitating complete resection through less invasive procedures without tumor rupture.